key: cord-0914485-zcj24byp authors: Maayan, Hannah; Kirgner, Ilya; Gutwein, Odit; Herzog‐Tzarfati, Katrin; Rahimi‐Levene, Naomi; Koren‐Michowitz, Maya; Blickstein, Dorit title: Acquired Thrombotic Thrombocytopenic Purpura: a rare disease associated Acquired with BNT162b2 vaccine date: 2021-06-08 journal: J Thromb Haemost DOI: 10.1111/jth.15420 sha: 60dfc59e3553dabc72ad5cc69645c4f6ed58b79d doc_id: 914485 cord_uid: zcj24byp In December 2020 the Israeli Health Ministry began a mass vaccination campaign with the BNT162b2 vaccine. This was an important step in overcoming the severe acute respiratory syndrome corona virus 2 (SARS‐CoV‐2) pandemic. Autoimmune phenomenon have been described after receiving vaccinations. Here we describe a case series of patients who developed acquired Thrombotic Thrombocytopenic Purpura, a rare autoimmune disease, within several days of receiving the BNT162b2 vaccine. A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13(ADAMTS13) activity should be evaluated in patients with history of aTTP before and after any vaccination, especially the SARS‐CoV‐2 vaccination, and immunosuppression treatment should be considered before vaccination in cases of low ADAMTS13 activity. Patients should be closely monitored after the vaccine for clinical situation and laboratory data. Post vaccination thrombocytopenia assessment should include immune thrombocytopenic purpura, vaccine‐induced immune thrombotic thrombocytopenia and acquired thrombotic thrombocytopenic purpura. In December 2020 the Israeli Health Ministry began a mass vaccination campaign with the BNT162b2 vaccine. This was an important step in overcoming the severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) pandemic. Autoimmune phenomenon have been described after receiving vaccinations. Here we describe a case series of patients who developed acquired Thrombotic Thrombocytopenic Purpura, a rare autoimmune disease, A disintegrin and metalloproteinase within several days of receiving the BNT162b2 vaccine. in activity should be evaluated ) ADAMTS13 if, member 13( with a thrombospondin type 1 mot patients with history of aTTP before and after any vaccination, especially the SARS-CoV-2 vaccination, and immunosuppression treatment should be considered before vaccination in cases of low ADAMTS13 activity. Patients should be closely monitored after the vaccine for clinical situation and laboratory data. Post vaccination thrombocytopenia assessment should include immune thrombocytopenic purpura, vaccine-induced immune thrombotic thrombocytopenia and acquired thrombotic thrombocytopenic purpura. • Acute/relapsed aTTP may be associated with BNT162b2 vaccine. • Patients with aTTP should be evaluated for ADAMTS13 activity before and after vaccination. • Immunosuppression should be considered before vaccination in cases of low ADAMTS13 activity. • One should consider the possibility of aTTP when evaluating post vaccination thrombocytopenia. Coronavirus disease 2019 (Covid-19), caused by the severe acute respiratory syndrome corona virus 2 (SARS-CoV-2), a highly contagious illness which can cause severe morbidity and mortality especially in older adults and with co-existing medical conditions (1) . It was declared a global pandemic in March 2020, and resulted in devastating medical, economic and social consequences (1) . This challenge posed the need for a safe and effective vaccine against SARS-CoV-2. In December 2020, results of the phase 2/3 part of the global trial evaluating the safety, immunogenicity, and efficacy of the BNT162b2 vaccine in adults 16 years and older, were published (1). BNT162b2 was shown to be 95% effective in preventing Covid-19 compared to placebo, with low incidence of serious adverse events (1). These data resulted in emergency approval of the BNT162b2 vaccine in several western countries. Israel initiated a mass vaccination campaign in December 2020 and nearly five million people received the BNT162b2 vaccine (2) . Here we present a case series of aTTP developing up to 28 days following the BNT162b2 vaccination. The study was approved by the local IRB committees. Four patients from two academic medical centers were identified from mid-February to mid-March 2021. Presumed diagnosis of aTTP was made using the PLASMIC score (5) and prompt treatment was initiated. Diagnosis was confirmed in all cases showing low ADAMTS13 activity and high antibody levels. This article is protected by copyright. All rights reserved. (121 U/ml). Ten weeks after treatment ADAMTS13 activity is 0%, ADAMTS13 antibodies are low, and the patient continues caplacizumab. Serology for S and N antigens was done using the LIAISON® SARS-CoV-2 S1/S2 IgG (DiaSorin, Italy) and Elecsys Anti -Sars-cOv-2(Cobas, Roche Germany), respectively. Patients demographic and laboratory data are summarized in Table 1 . Mean age at presentation was 33 years, with first aTTP episode in two and relapse following long periods of remission in two cases. Patients presented at a mean of 14 days following BNT162b2 vaccination. All were negative for COVID19 infection by PCR analysis, while serology was positive for the S antigen and negative for the N antigen in the two patients tested (one and two). All patients received PEX, corticosteroids and caplacizumab, whereas rituximab was given to three. Patients rapidly responded to treatment (defined as platelets>150 k/µl and LDH<1.5xULN) with mean 4 days following presentation. At the time of this report, all patients are in clinical and laboratory response. Normalization of ADAMTS13 activity was confirmed in three cases. This article is protected by copyright. All rights reserved. The prevalence of aTTP in western countries is estimated as 2-6 cases per 10 6 per year (7). This is roughly two-three cases per year in any Israeli hospital. We report on four cases of aTTP presenting within four weeks after BNT162b2 vaccination. This raised the suspicion of a shared precipitating event, and a presumptive association with the BNT162b2 vaccine. aTTP is more prevalent in women (8) with risk factors including pregnancy (9) and hormonebased treatments. Here, 50% of our small cohort were female and none of them were pregnant or on hormonal therapy. The addition of caplacizumab to PEX and steroids resulted in rapid response (6) similar to that reported in the HERCULES study (10) . This article is protected by copyright. All rights reserved. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting British Committee for Standards in Haematology. Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies Autoimmune thrombotic thrombocytopenic purpura (TTP) associated with COVID-19 External validation of the PLASMIC score: a clinical prediction tool for thrombotic thrombocytopenic purpura diagnosis and treatment Redefining outcomes in immune TTP: an international working group consensus report Thrombotic thrombocytopenic purpura: diagnostic criteria, clinical features, and long-term outcomes from 1995 through 2015 Thrombotic thrombocytopenic purpura This article is protected by copyright. All rights reserved. subsequent pregnancy outcomes Efficacy and safety of open-label caplacizumab in patients with exacerbations of acquired thrombotic thrombocytopenic purpura in the HERCULES study Do COVID-19 RNA-based vaccines put at risk of immune-mediated diseases? In reply to "potential antigenic cross-reactivity between SARS-CoV-2 and human tissue with a possible link to an increase in autoimmune diseases Vaccine-induced autoimmunity: the role of molecular mimicry and immune cross reaction Refractory thrombotic thrombocytopenic purpura following influenza vaccination Acute thrombotic thrombocytopenic purpura after pneumococcal vaccination Rabies vaccine-associated thrombotic thrombocytopenic purpura Thrombocytopenia following Pfizer and Moderna SARS-CoV-2 vaccination Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination Tel Aviv Sourasky and Shamir Medical Center The authors thank their colleagues at the Medical Center for collaboration on the care of the patients.