Between December 2020 and March 2021, the European Medicines Agency (EMA) approved 4 vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on rigorous randomized, blinded, controlled trials, including the ChAdOx1 nCoV-19 vaccine (Aztra-Zeneca), a recombinant chimpanzee adenoviral vector encoding the spike protein of SARS-CoV-2 [1]; however, towards end of February 2021, a significant number of venous thromboses (VTE) in unusual sites (cerebral venous-sinus thrombosis [CVST], and splanchnic vein thrombosis [SVT]) in combination with thrombocytopenia were observed in individuals that received the Aztra Zeneca coronavirus disease 2019 (COVID-19) vaccine; which on March 15, 2021, prompted the temporary suspension of the administration of such vaccination by the EMA in several countries, including Austria, Germany, France, United Kingdom and Norway [2, 3]. After a careful safety assessment by the EMA pharmacovigilance assessment risk committee, evaluating benefits versus risks of the Aztra Zeneca COVID-19 vaccine, it was decided to resume vaccination campaigns by March 19, 2021 [3]. Notably, as of April 4th, 2021, a total of 169 cases of CVST and 53 cases of SVT were reported among 34 million people had been vaccinated in the European Union by that date [2]. Recently, Greinacher and colleagues described in detail the clinical and laboratory profiles of 11 patients from Germany and Austria in which thrombotic thrombocytopenia developed after the administration of the Aztra Zeneca ChAdOx1 nCoV-19 vaccine. Of the 11 patients, 9 were women, with a median age of 36 years (range of 22–49 years). Investigators also analyzed laboratory characteristics of 28 additional patients, in which there was a high clinical suspicion of ChAdOx1 nCoV-19 vaccine-induced thrombotic events. From all, nine out of 11 patients had CVST, three had SVT, and 4 had pulmonary embolism, some of these patients had thromboses in different vascular territories found at the same time (eg, CVST and SVT simultaneously); of these, 6 patients died [4]. All patients presented with concomitant thrombocytopenia (median nadir of platelet count of 20,000× mm3; range from 9000 to 107,000) and none of the patients had received any form of heparin before onset of symptoms. All the 28 additional patients included in the analysis tested positive for the platelet-factor 4 (PF-4)-heparin antibodies for both, ELISA, and the platelet-activation assays. Interestingly, the three patients who had SVT, also developed concomitantly CSVT, two cases were fatal, and one patient is recovering [4]. Symptom onset started approximately between 4–16 days post Aztra Zeneca COVID-19 vaccine administration. Investigators found that these thrombotic thrombocytopenic syndromes shared striking similarities with severe heparin-induced thrombocytopenia (HIT), a well-known hypercoagulable disorder caused by plateletactivating antibodies that recognize multimolecular complexes like those formed by PF-4 and anionic heparin, triggering prothrombotic events, with the exception that the above-described patients never were exposed to heparin, a variant known as autoimmune HIT [5, 6].

Greinacher and colleagues recommended a detailed diagnostic and therapeutic algorithm for these thrombotic thrombocytopenic syndromes, considering the administration of high doses of intravenous immunoglobulin (IVIG), with the aim of inhibiting platelet activation, increasing platelet count, and ameliorating hypercoagulability. It is also recommended to use non-heparin anticoagulants to treat HIT, like direct oral anticoagulants ([DOACs] eg …