Investigating a Signal of Acquired Hemophilia Associated with COVID-19 Vaccination: A Systematic Case Review

Abstract

Acquired hemophilia A (AHA), a rare but life-threatening disorder, most commonly occurs in older people and during pregnancy. During the coronavirus disease 2019 (COVID-19) vaccination campaign, an unexpected number of newly diagnosed AHA patients have been identified in clinical practice that were temporally related to COVID-19 vaccination. We present the result of a signal detection analysis aimed at exploring a possible association between COVID-19 immunization and occurrence of AHA. A disproportionality analysis on the World Health Organization (WHO) database was performed to investigate the presence of a signal of risk for AHA associated with COVID-19 vaccines. Reports of AHA associated with any COVID-19 vaccine included in the WHO database were then integrated with those available on the Food and Drug Administration Vaccine Adverse Events Reporting System and those published in the medical literature. The WHO database included 146 reports of AHA. The information component (IC) was significant for the association of AHA with all COVID-19 vaccines (IC025: 1.1) and with the vaccine product BNT162b2 (IC025: 1.6). After duplicate exclusion, 96 unique cases of AHA following COVID-19 vaccines have been reviewed. Median time to diagnosis was 18 days and 40% of cases documented the occurrence after the second dose. Overall, in 57% of the investigated cases, a preexisting condition predisposing to AHA was excluded. About 22% of cases occurred in subjects with age ≤65 years and there was no case associated with pregnancy. Mortality was 11%. Although we cannot exclude that the unexpected frequency of AHA diagnosis can be explained by a detection bias, the signal for COVID-19 vaccine-related AHA is robust and deserves further investigations.

Hematological Questions in Personalized Management of COVID-19 Vaccination

“…Massimo Franchini et al conducted a disproportionality analysis and systematic case review using the data from VigiBase, VAERS, and a literature search. The result showed that the information component (IC) was significant for the association of AHA with all SARS-CoV-2 vaccines and BNT162b2 with an IC025 at 1.1 and 1.6, respectively, suggesting that the signal of AHA associated with COVID-19 vaccination is robust [ 46 ]. Approximately 22% of cases occurred in individuals younger than 65 years, with a mortality of 11%.…”

Autoimmune Diseases Affecting Hemostasis: A Narrative Review

“…A specific mention deserves attention, being recently identified acquired hemophilia A following coronavirus disease 2019 (COVID-19) vaccination. Although a causality link between vaccine and acquired hemophilia A has not been definitely ascertained, several of such cases have already been reported [ 29 , 30 , 31 , 32 , 33 ]. A possible explanation is that vaccines may foster or boost immune reactions, followed by insurgence of new autoimmune events or exacerbation of pre-existing but latent immune dysregulations, which can ultimately drive the clonal selection of B cells producing specific autoantibodies, including those against FVIII.…”

“…Happaerts et al described a case of acquired hemophilia A post vaccination, and reviewed 17 other cases reported in the literature [ 31 ]. Of interest, unlike VITT, which is associated with the use of adenovirus vaccines, most cases of acquired hemophilia A have been associated with mRNA-based vaccines (Pfizer [BNT162b2/Comirnaty] and Moderna [mRNA-1273/Spikevax]) [ 29 ]. Like COVID-19 above, vaccination against COVID-19 has also reportedly associated with ITP [ 108 , 109 ] and TTP [ 110 ].…”

Maintaining Hemostasis and Preventing Thrombosis in Coronavirus Disease 2019 (COVID-19)—Part IV

“…We continue discussion of possible vaccine-related adverse events in the next contribution Franchini and colleagues, 13 who evaluate the possibility of a signal for acquired hemophilia A (AHA) as associated with COVID-19 vaccination. AHA is a rare but life-threatening disorder, and most commonly occurs in older people or during pregnancy.…”