key: cord-0747938-pxeec26e authors: Cattaneo, Marco title: Thrombosis with Thrombocytopenia Syndrome associated with viral vector COVID-19 vaccines date: 2021-05-25 journal: Eur J Intern Med DOI: 10.1016/j.ejim.2021.05.031 sha: ff78c96c7c7224bc428c3f6f1e8bb796324a948b doc_id: 747938 cord_uid: pxeec26e nan established; 2) the general reference to "vaccine" is not justified, as the syndrome has been observed only in association with 2 particular COVID-19 vaccines. The association of thrombosis and thrombocytopenia had been previously observed in patients with Heparin-Induced Thrombocytopenia (HIT), an immune prothrombotic disorder caused by antibodies directed against multimolecular complexes of polyanionic heparin and cationic platelet factor 4 (PF4), which activate platelets through their Fc receptor [3] . A combination of thrombocytopenia and thrombosis has also been observed in a similar syndrome affecting patients not treated with heparin, in which the PF4 binding function of heparin is taken over by other polyanions, such as condroitinsulfate, nucleic acids, polyphosphates or bacterial components: this HIT-like syndrome is termed autoimmune HIT [4] . Antibodies against polyanions/PF4 can be assessed by immunoassays, such as enzyme-linked immunosorbent assay (ELISA) and chemiluminescent immunoassay (CLIA). In case of positivity of these relatively unspecific screening tests, the diagnosis of classical HIT relies on confirmatory tests of activation of normal platelets by patients' sera, which, in the case of classical HIT activate platelets in presence of pharmacological concentrations of heparin (0.2 IU/mL), but not in the absence of heparin or in presence or very high heparin concentrations (100 IU/mL); in contrast, sera of autoimmune HIT may activate platelets also in the absence of heparin [4] . . The most common thrombotic event was CVST, the female sex was predominant, the vast majority of patients were young (<50 years), all displayed thrombocytopenia which was severe (<50x10 9 /L) in most cases and the death rate was 33%. Nine cases of arterial thrombosis and 6 cases of severe bleeding (5 intracranial) were also observed. Overall, only 11 cases of typical venous thromboembolism (deep vein thrombosis [DVT] and pulmonary embolism [PE]) were reported. Of these, 8 were PE with no detectable DVT, 1 was isolated DVT and only 2 were DVT + PE: the much lower frequency of DVT than PE, which is a complication of DVT, is rather surprising. Indeed, although PE may occur in the absence of detectable DVT, this happens in only about 20% of studied patients [9] . Similar findings were reported in patients with COVID-19, which led us to hypothesize that pulmonary occlusions that were interpreted as caused by PE in many COVID-19 patients were actually due to thrombi of the pulmonary vessels [10] . Our hypothesis was later confirmed by post-mortem studies. It is likely that also in TTS many cases of pulmonary vessels occlusions are caused by in situ thrombi rather than emboli from peripheral veins. Indeed, one TTS patient with pulmonary occlusion who died was found to have pulmonary thrombi at post-mortem analysis (Table 1) . Therefore, TTS is mostly characterized by venous thrombotic events at unusual sites, involving not only cerebral and splanchnic veins, but also pulmonary vessels. An important question that needs to be addressed is whether or not TTS is associated with Vaxzevria vaccination only or also with other COVD-19 vaccines. As of 12 April 2021 the following cases have been reported to VAERS (Vaccine Adverse Events Reporting System) in USA [11] : 6 cases of CVST and thrombocytopenia after 6,860,000 doses of the COVID-19 vaccine by Janssen/ Johnson&Johnson's (0.87 cases/1,000,000); zero cases after 97,900,000 doses of the COVID-19 vaccine by Pfizer-BionTech; 3 cases of CVST without thrombocytopenia, and therefore not to be considered cases of TTS, after 84,700,000 doses of the COVID-19 vaccine by Moderna [11] . More recently 6 additional patients with TTS (all with CVST, sometimes associated with thrombosis in other districts) that manifested 6-15 days after vaccination with the COVID-19 Janssen/Johnson&Johnson's vaccine in the USA have been reported together with the initial series of 6 patients [12] . All 12 patients had thrombocytopenia, high D-dimer and low fibrinogen plasma levels, positive ELISA tests anti-plolyanions/heparin and negative confirmatory functional tests for classical HIT [12] . Therefore, it appears that TTS is associated only with vaccination with viral vector vaccines (AstraZeneca and Janssen/Johnson&Johnson's) and not with mRNA vaccines Table 2 ). The mainstay of TTS treatment is the intravenous infusion of immunoglobulins (IVIg) at high doses (2 gr/Kg body weight over 2 to 5 days) ( Table 2) Oral AntiCoagulants (DOAC) that do not need heparin lead-in (apixaban and rivaroxaban) and fondaparinux. Other treatments may include corticosteroids and plasma exchange, which should be implemented for patients who proved unresponsive to IVIg. Platelet transfusions should be avoided ( Table 2) . There is limited data on the risk of TTS after the second dose of Vaxzevria to allow any firm conclusion on its implementation in the vaccination strategy. To the best of my knowledge, three cases of thrombosis+thrombocytopenia have been reported so far following the second dose, but these have not yet been validated. What is the risk-to-benefit balance of viral vector COVID-19 vaccines? Considering the extremely low number of TTS cases reported after the Janssen/Johnson&Johnson's vaccine, the question at this stage should actually be posed for vaccination with Vaxzevria only. EMA analyzed the risk/benefit balance, according to different age ranges of the population and three different scenarios of COVID-19 infection rates: high (886/100,000 population), medium (401/100,000) and low (55/100,000) [13] . The number of TTS cases for each age group was balanced against the number of COVID-19 deaths hypothetically saved by vaccination. A clear advantage of vaccination was evident for persons of >40 years of age in the high-risk and medium-risk scenarios, while the advantage in the low-risk scenario was manifest for persons of >60 years of age [13] . However, it is perhaps inappropriate and misleading to compare all cases TTS (which has a death rate of about 30%) with the number of COVID-19 deaths prevented. It is more appropriate to balance all cases of TTS with the number of prevented ICU admissions due to COVID-19: this type of analysis has been done by EMA and by the Winton Centre for Risk and Evidence Communication of the Cambridge University (UK) [14] . The analysis by EMA showed an advantage of vaccination for subjects >20 years of age in the high-risk scenario, >30 years in the medium-risk and >50 years in the low-risk scenarios. The analysis by the Cambridge University, which considered a slightly different prevalence of COVID-19 infection to define the 3 risk scenarios (high, 200/100,000; medium, 60/100,000; low, 20/100,000) showed an advantage of vaccination for subjects >20 years in high-risk scenario and >30 years in both the medium-and the low-risk scenarios. In conclusion, TTS is a very rare and severe syndrome, with a death rate of about 30%, that is COVID-19 Vaccine AstraZeneca: PRAC investigating cases of thromboembolic events -vaccine's benefits currently still outweigh risks -Update Why vaccine safety experts put the brakes on AstraZeneca's COVID-19 vaccine Pathogenesis of heparin-induced thrombocytopenia Autoimmune heparin-induced thrombocytopenia Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination Epub ahead of print Pathologic Antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19 Vaccination Prothrombotic immune thrombocytopenia after COVID-19 vaccine Platelet activation and its modulation in TTS Patients withisolated pulmonary embolism in comparison to those with deep venous thrombosis. Differences in characteristics and clinical evolution Pulmonary Embolism or Pulmonary Thrombosis in COVID-19? Is the Recommendation to Use High-Dose Heparin for Thromboprophylaxis Justified? Reports of cerebral venous sinus thrombosis with thrombocytopenia after Janssen COVID-19 vaccine US Case Reports of Cerebral Venous Sinus Thrombosis With Thrombocytopenia After Ad26.COV2.S Vaccination 3 -Visual risk contextualization News -Communicating the potential benefits and harms of the Astra-Zeneca COVID-19 vaccine The author has no conflicts of interest to declare Conflict of interest M.C. is member of the advisory boards of AstraZeneca, Eli-Lilly, Daiichy Sankyo and Novartis Farma.