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      Hypotheses behind the very rare cases of thrombosis with thrombocytopenia syndrome after SARS-CoV-2 vaccination


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          As of 4 April 2021, a total of 169 cases of cerebral venous sinus thrombosis (CVST) and 53 cases of splanchnic vein thrombosis were reported to EudraVigilance among around 34 million people vaccinated in the European Economic Area and United Kingdom with COVID-19 Vaccine AstraZeneca, a chimpanzee adenoviral vector (ChAdOx1) encoding the spike protein antigen of the SARS-CoV-2 virus. The first report of the European Medicines Agency gathering data on 20 million people vaccinated with Vaxzevria® in the UK and the EEA concluded that the number of post-vaccination cases with thromboembolic events as a whole reported to EudraVigilance in relation to the number of people vaccinated was lower than the estimated rate of such events in the general population. However, the EMA’s Pharmacovigilance Risk Assessment Committee concluded that unusual thromboses with low blood platelets should be listed as very rare side effects of Vaxzevria®, pointing to a possible link. The same issue was identified with the COVID-19 Vaccine Janssen (Ad26.COV2.S).

          Currently, there is still a sharp contrast between the clinical or experimental data reported in the literature on COVID-19 and the scarcity of data on the unusual thrombotic events observed after the vaccination with these vaccines. Different hypotheses might support these observations and should trigger further in vitro and ex vivo investigations. Specialized studies were needed to fully understand the potential relationship between vaccination and possible risk factors in order to implement risk minimization strategies.

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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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              Hypercoagulability of COVID‐19 patients in intensive care unit: A report of thromboelastography findings and other parameters of hemostasis

              Background The severe inflammatory state secondary to COVID‐19 leads to a severe derangement of hemostasis that has been recently described as a state of disseminated intravascular coagulation (DIC) and consumption coagulopathy, defined as decreased platelet count, increased fibrin(ogen) degradation products such as D‐dimer, as well as low fibrinogen. Aims Whole blood from 24 patients admitted at the intensive care unit because of COVID‐19 was collected and evaluated with thromboelastography by the TEG point‐of‐care device on a single occasion and six underwent repeated measurements on two consecutive days for a total of 30 observations. Plasma was evaluated for the other parameters of hemostasis. Results TEG parameters are consistent with a state of hypercoagulability as shown by decreased values, and increased values of K angle and MA. Platelet count was normal or increased, prothrombin time and activated partial thromboplastin time were near(normal). Fibrinogen was increased and D‐dimer was dramatically increased. C‐reactive protein was increased. Factor VIII and von Willebrand factor (n = 11) were increased. Antithrombin (n = 11) was marginally decreased and protein C (n = 11) was increased. Conclusion The results of this cohort of patients with COVID‐19 are not consistent with acute DIC, rather they support hypercoagulability together with a severe inflammatory state. These findings may explain the events of venous thromboembolism observed in some of these patients and support antithrombotic prophylaxis/treatment. Clinical trials are urgently needed to establish the type of drug, dosage, and optimal duration of prophylaxis.

                Author and article information

                Thromb Res
                Thromb Res
                Thrombosis Research
                Elsevier Ltd.
                15 May 2021
                15 May 2021
                [a ]University of Namur, Department of Pharmacy, Namur Research for Life Sciences, Namur, Thrombosis and Hemostasis Center, Namur, Belgium
                [b ]QUALIblood s.a., Namur, Belgium
                [c ]Clinique Saint-Luc Bouge, Department of Laboratory Medicine, Bouge, Belgium
                [d ]Départements de Médecine, Hôpitaux Universitaires de Genève, service d’angiologie et d’hémostase et Faculté de Médecine, Geneva, Platelet Group (GpG), Université de Genève, Geneva, Switzerland
                [e ]Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000, Lille, France
                [f ]Univ Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience & Cognition, F-59000, Lille. France
                [g ]Service d’hématologie biologique, CHU Clermont-Ferrand, Clermont-Ferrand, France
                [h ]University of California, Davis Health System, Thrombosis and Hemostasis Center, Sacramento, United States
                [i ]University Paul Sabatier, CHU of Toulouse, Laboratory of Hematology, F-31069 Toulouse
                [j ]CHU Grenoble Alpes, Department of Vascular Medicine, CNRS / TIMC-IMAG UMR 5525/Themas, Grenoble, France
                [k ]University of Tours, EA7501 GICC, CHRU de Tours, Department of Haemostasis, Tours, France
                [l ]Université de Reims, EA3801, CHU de Reims, France
                [m ]CHU UCL Namur, Université catholique de Louvain, Hematology Laboratory, Namur, Research for Life Sciences, Namur, Thrombosis and Hemostasis Center, Yvoir, Belgium
                Author notes
                [* ]Corresponding author at: University of Namur, Department of Pharmacy, Namur Thrombosis and Hemostasis Center, Namur Research for Life Sciences, QUALIblood s.a., Namur, Belgium.
                © 2021 Elsevier Ltd. All rights reserved.

                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.

                : 25 April 2021
                : 7 May 2021
                : 8 May 2021

                covid-19,vaccines,thrombosis,cerebral venous sinus thrombosis,azd1222,chadox1 ncov-19,covid-19 janssen vaccine,ad.26.cov2.s


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