Cases of acquired hemophilia A following COVID‐19 vaccines: Cogent safety signal or possible reporting/detection bias? Preliminary evidence from Tuscany, Italy

Abstract

Purpose Several case reports of acquired hemophilia A (AHA) following COVID‐19 vaccines were recently published. A possible increased incidence of AHA during the COVID‐19 vaccination campaign was also suggested. We aimed at generating evidence for the preliminary assessment of the association between AHA and COVID‐19 vaccination through an ecological study in one Italian region, Tuscany. Methods An ecological study was performed using the population‐based administrative data source of Tuscany. Per each year between 2017 and 2021, we included patients aged 5+ and active into the database as of January 1. Temporal patterns of annual incidence of possible AHA cases and AHA‐tested patients were respectively observed. The rates of possible AHA cases per AHA‐tested patients were calculated in 2021 and 2017–2019, respectively (calendar year 2020 was excluded because non‐representative of the pre‐pandemic era). Age–sex standardization was applied. Poisson's 95% confidence intervals (95% CI) were estimated. Statically significant differences were defined as absence of 95% CI overlap. Results In 2021, standardized incidence of both possible AHA cases (5.6/million subjects/year; 95% CI = 3.4–8.7) and AHA‐tested patients (60.7/1000 subjects/year; 95% CI = 60.4–60.9) showed the lowest point estimates, though only the latter was statistically different compared to previous calendar years. The standardized rate of possible AHA cases per AHA‐tested patients was 9.2/100000 (95% CI = 5.6–14.3) in 2021 and 12.5/100000 (95% CI = 8.2–18.1) during 2017–2019. Conclusions These preliminary findings do not support the hypothesis of an increased incidence of AHA cases during the COVID‐19 vaccination campaign. However, in 2021, the still ongoing healthcare access restrictions might have contributed to the low incidence of AHA and laboratory tests observed. Therefore, large‐scale multi‐database studies are warranted.

Conducting and interpreting disproportionality analyses derived from spontaneous reporting systems

“…An emerging use of DA is represented by the combination with other source of data, including in vitro/ex vivo assays to corroborate the biological plausibility (Salem et al, 2019), or electronic healthcare records (EHRs) to substantiate (or refuse) the research hypothesis or, under certain circumstances, to enhance signal detection for events with high background incidence (Pacurariu et al, 2015;Roberto et al, 2023;Wang et al, 2023). The correlation between disproportionality measures and pharmacokinetic/ pharmacodynamic features (e.g., lipophilicity, receptor affinity/ occupancy) may be used to explore the underlying pharmacological basis.…”

Innovative Therapies for Acquired Hemophilia A

“…5 AHA cases secondary to infections and vaccinations, including SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection and vaccination, have also been reported. [5][6][7][8][9] The mainstay of the management of AHA encompasses the treatment of bleeding (when present), eradication of the inhibitor, and the identification and treatment (when possible) of the underlying disorder associated with AHA onset. 5 First-line eradication therapy for AHA includes steroids alone or in association with cyclophosphamide (the latter being indicated particularly in poor-prognosis patients, i.e.…”