key: cord-1017270-dsnljo53 authors: Moulis, Guillaume; Crickx, Etienne; Thomas, Laure; Massy, Nathalie; Mahévas, Matthieu; Valnet-Rabier, Marie-Blanche; Atzenhoffer, Marina; Michel, Marc; Godeau, Bertrand; Bagheri, Haleh; Salvo, Francesco title: De novo and relapsed immune thrombocytopenia after COVID-19 vaccines: results of French safety monitoring date: 2022-03-17 journal: Blood DOI: 10.1182/blood.2022015470 sha: 7d9233eaaeb54ce60af3e0d41403f3a99f381c01 doc_id: 1017270 cord_uid: dsnljo53 nan The development of new vaccines against SARS-CoV-2, along with the observation of immune thrombocytopenia (ITP) following COVID-19, 1 raised the concern about ITP triggered by COVID-19 vaccines. A soon as January 2021, a fatal case of ITP after BNT162b2 (Pfizer-BioNTech) vaccine was reported in the United States of America. 2 Recently, a study conducted in the vaccine Adverse Events reporting System (VAERS) on March 19, 2021 described 77 de novo ITP: 40 with BNT162b2 and 37 with mRNA-1273 (Moderna). 3 However, data about ITP after adenovirus vaccines (ChadOx1-S -AstraZenecaand Ad26COV2 -Janssen) are scarcer. [4] [5] [6] In France, the four above mentioned vaccines have been marketed for adults. We here describe the cases of de novo ITP and ITP relapses reported to the national French COVID-19 vaccine safety program up to August 15, 2021. The French National Agency for the Safety of Medicine and Health Products (ANSM) set up an active monitoring for COVID-19 vaccine adverse drug reactions (ADRs), relying on the French Pharmacovigilance network. 7 All ADRs are reported by health practitioners or patients on a secure platform, and then analyzed by pharmacologists. They assess drug causality and record ADRs into a national database, encoded using the Medical Dictionary for Regulatory Activities (MedDRA) classification. 7, 8 All cases reported up to August 15, 2021 with the terms "thrombocytopenia", "immune thrombocytopenia", "purpura", "thrombocytopenic purpura", "thrombotic thrombocytopenia" (to detect ITP cases miscoded as vaccine-induced immune thrombotic thrombocytopenia -VITT) were first reviewed by senior pharmacologists in the regional pharmacovigilance centers in charge of COVID-19 vaccine safety monitoring to detect potential cases of ITP. Medical charts were reviewed to provide more information about diagnosis and evolution if needed. Each de-identified selected case (n=201) has been subsequently analyzed by two experts of ITP (G.M. and E.C./M.Ma.). Eventually, 123 cases that occurred within the six weeks after vaccination were included (Supplementary Material, Figure S1 ). De novo ITP were subsequently classified by certain ITP when all other causes of thrombocytopenia were excluded, and probable ITP when the presentation and evolution were highly evocative of ITP but with missing data to formerly exclude other diagnoses. Descriptive analyses were conducted overall and by vaccines, and, as sensitivity analysis, by certain vs. probable de novo ITP. We also calculated the frequency of de novo or relapsed ITP reports by number of vaccine doses dispensed up to July 31, 2021 in France. The two-week period between dispensing data and the assessment of ADRs in the database was driven from the median time of vaccine-induced ITP. De novo ITP (n=106) are described in Table 1 . They were mostly reported with BNT162b2 (Table 1) . Two intracranial hemorrhages were described (Supplementary Material, Table S1 ). Seven patients were exposed to another dose of vaccine: 3 relapsed ITP (with BNT162b2) while 4 did not (1 with BNT162b2 and 3 with ChadOx1-S). The characteristics of de novo ITP cases were similar between BNT162b2 and ChadOx1-S vaccines, except with BNT162b2 a higher proportion of cases after the second dose (40.3% vs. 11.4%, respectively), a slightly shorter median time to onset (9 vs. 12 days) and a higher proportion of spontaneous recovery (17.6% vs. 12.9%) or after corticosteroids  IVIg (70.6% vs. 45.2%). In sensitivity analysis, the characteristics of certain versus probable de novo ITP cases were similar, except a higher median platelet count (15 vs. 4 x 10 9 /L), a lower frequency of bleeding (65.2% vs. 94.6) and a higher frequency of spontaneous recovery (30.3% vs. 1.9%) in the group of probable ITPs (Supplementary Material, Table S2 ). Relapses of known ITP (n=17) were also mostly described with BNT162b2 (n=12; Table 2 ). The median time from vaccination (first dose: 70.6%) was 5 days. The median lowest platelet count was 6 x 10 9 /L (min-max: 0-61 x 10 9 /L), 88.3% of patients had bleeding and all recovered with (72.7%) or without (27.3%) treatment. Three patients were exposed to another dose of vaccine: 1 relapsed (mRNA-1273 vaccine) and 2 did not (BNT162b2). The rate of de novo or relapsed ITP reports by million of vaccine doses administered was 1.69 (95% CI: 1.42-2.01). It was the highest with ChadOx1-S, particularly after Dose 1 (Supplementary Material, Table S3 ). Overall, the characteristics of the 106 de novo ITP following COVID-19 vaccine in this series are in line with the 77 reported cases in VAERS, 3 except a slightly longer median time after vaccine in our study (11 vs. 8 days) . Of note, all reported cases in VAERS were associated with mRNA vaccines, whereas 42.5% of our cases were due to ChadOx1-S, with a slightly longer median time between vaccination and ITP, as previously reported in Australian series of 12 and 17 cases. 4, 5 Reported relapses of known ITP were rare. Previous series demonstrated that if a mild decrease of platelet count has been observed in up to 50% of patients, severe relapses needing rescue treatment were rare, accounting from <10% of patients from referral centers (i.e. possibly a subpopulation of severe, refractory ITP). 3, [9] [10] [11] Noteworthy, relapses of ITP could occur after Dose 1 or Dose 2. The rate of reported ITPs by number of dispensed doses of vaccines was the highest with ChadOx1-S. We cannot exclude a reporting bias favoring cases of thrombocytopenia after the media coverage of VITT. An Australian study observed a rate of 8.0 per 1,000, 000 doses (95%CI: 5.4-12.7). 5 Population-based studies identified an increased risk of hospital contact for thrombocytopenia within the 28 days after ChadOx1-S vaccination (albeit lower than after a positive SARS-CoV-2 test), 12, 13 but not within the 42 days after BNT162b2. 14 This study has other limitations. We identified very few cases reported after mRNA-1273 and Ad26COV2. Consequently, our results regarding these vaccines should be interpreted with caution. We described spontaneous reports and cannot ensure the full collection of cases; reporting bias may have also favored more severe cases. The six-week risk period between vaccination and ITP occurrence for case selection is often used for such studies but remains arbitrary. Lastly, the causal mechanism is not ascertained and it is possible that some cases occurred during he risk period by chance. However, this series provides important clinical insights for knowledge and management of this very rare event, with a slightly longer time from vaccine to ITP onset with ChadOx1-S vaccine, a good response to usual management of ITP including in rare severe cases, and an unpredictable effect of rechallenge. There may be a pharmacovigilance signal for a higher frequency of ITP with ChadOx1-S in comparison with BNT162b2. The authors have no conflict of interest relevant to this article to disclose. Data may be obtained from a third party and are not publicly available. The data of the SNDS are anonymous. They can be accessed by submitting a request to the Health-Data-Hub at https://www.health-data-hub.fr/depot. The data management and statistical analysis code is available on reasonable request from the corresponding author. Tables Table 1 . Characteristics of cases of de novo immune thrombocytopenia following COVID-19 vaccination. All cases (n=106) BNT162b2 (Pfizer-BioNTech, n=58) ChadOx1-S (AstraZenaca, n=45) mRNA-1273 (Moderna, n=2) Ad26COV2 (Janssen, n=1) Clinical characteristics, management and outcome of COVID-19-associated immune thrombocytopenia: a French multicentre series Thrombocytopenia following Pfizer and Moderna SARS-CoV-2 vaccination SARS-CoV-2 Vaccination and Immune Thrombocytopenia in de novo and pre-existing ITP patients Immune thrombocytopenia following vaccination during the COVID-19 pandemic Immune thrombocytopenia following immunisation with Vaxzevria ChadOx1-S (AstraZeneca) vaccine COVID-19 vaccination associated severe immune thrombocytopenia French organization for the pharmacovigilance of COVID-19 vaccines: A major challenge Pharmacovigilance and drug-induced rare diseases: Strengths of the French Network of Regional Pharmacovigilance Centres Safety of anti-SARS-CoV-2 vaccination for patients with immune thrombocytopenia Platelet trends after Covid-19 vaccination in patients with chronic or persistent immune thrombocytopenia SARS-CoV-2 vaccination in patients with autoimmune cytopenias: The experience of a reference center Risk of thrombocytopenia and thromboembolism after covid-19 vaccination and SARS-CoV-2 positive testing: selfcontrolled case series study Arterial events, venous thromboembolism, thrombocytopenia, and bleeding after vaccination with Oxford-AstraZeneca ChAdOx1-S in Denmark and Norway: population based cohort study Safety of the BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting The authors deeply thank the French Pharmacovigilance network.