Association between SARS-CoV-2 infection or vaccination and acquired hemophilia A: A case report and literature update

Acquired hemophilia A (AHA) is a rare, but often life-threatening, bleeding disorder due to the development of autoantibodies which neutralize the activity of coagulation factor VIII (FVIII) and/or accelerate its clearance []. The incidence of AHA has been estimated about 1.5 cases per million/year, showing an increase with age and being significantly more frequent in people over 65 years old, without gender difference [, , ]. It is likely, however, that the true incidence of AHA is underestimated, given the difficult in making the correct diagnosis, which is based on the laboratory demonstration of a prolonged activated partial thromboplastin time (aPTT), reduced plasma clotting FVIII levels and the detection of ant-FVIII autoantibodies []. Approximately half of the cases do not have any recognized cause associated with the development of anti-FVIII inhibitors and are, therefore, considered idiopathic AHA. According to the largest published series from studies or registries, the most common secondary forms are those associated with solid cancers and hematological malignancies, autoimmune diseases, particularly rheumatoid arthritis and systemic lupus erythematosus, pregnancy, infections, skin disorders and drugs, especially antibiotics and interferon []. Recently AHA has been diagnosed in patients with coronavirus 2-associated disease 2019 (COVID-19) or after anti-COVID-19 vaccination []. These findings are quite interesting although not surprising, considering the already known immune dysregulation following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection [] and the association between AHA and vaccinations, especially against influenza and tuberculosis [, ]. Possible pathophysiological mechanisms of vaccine-triggered autoimmunitiy lie in the activation of quiescent autoreactive T and B cells, as well as molecular mimicry. This latter pathomechanism could be also involved in AHA associated with SARS-CoV-2 infection []. In this paper, we describe a recent case regarding the association between vaccination against SARS-CoV-2 and AHA. We also revise the current literature about the link between SARS-CoV-2 infection or vaccination and AHA onset or relapse.

A 67-year-old man presented on May 18, 2021 at the emergency room of the Mantua city hospital with spontaneous cutaneous and muscle bleeding at the trunk and limbs. His hemorrhagic history was positive for two previous episodes of AHA (idiopathic in 2011 and associated with SARS-CoV-2 infection in 2020), in both cases successfully treated with steroids and cyclophosphamide. His medical history revealed a diagnosis of pulmonary sarcoidosis in 1996, of rheumatoid arthritis in 2020 (treated with steroids and methotrexate), of steroid diabetes (under insulin therapy) and a depressive state (under alprazolam therapy). Twenty-two days before the symptom onset, the patient had received the first dose of anti-COVID-19 mRNA vaccine (Spikevax, Moderna). Blood tests revealed mild normocytic anemia (hemoglobin 9.7 g/dL) with normal white cell and platelet count and a prolonged aPTT (ratio 1.86, normal range 0.82–1.18) with normal prothrombin time. A mixing study resulted in failure of aPTT correction, suggesting the presence of an inhibitor that was successively identified as directed against FVIII (FVIII activity <2.5 %, inhibitor titer 4 Bethesda units [BU]). The diagnosis of AHA was again made. Patient's bleeding was successfully treated with rFVIIa (90 μg/kg every 3 h until bleeding stopped). Inhibitor eradication was started with rituximab (four doses of 375 mg/m² administered intravenously one week apart; steroid use was contraindicated due to diabetes and depression). Before starting rituximab, the patient underwent a biopsy of a retroperitoneal mass detected during an abdominal ultrasound check. The diagnosis was of differentiated liposarcoma. Effective hemostasis during the invasive procedure was obtained using 6 doses of rFVIIa administered intravenously over 24 h at bolus injection intervals of 2 to 6 h using an automated bolus infusion pump (Perfusor Space, B. Braun, Milan, Italy). The response to rituximab was slow: the autoantibody started to decrease and FVIII to increase one week after the fourth dose of the monoclonal antibody (FVIII inhibitor: 2 BU; FVIII: 11.9 %) with progressive disappearance of hematoma. Complete remission (FVIII inhibitor: negative; FVIII: 74 %) was reached 5 weeks after the last rituximab dose. On 11 December 2021 the patient underwent surgical removal of the retroperitoneal mass, but unfortunately he died on December 31, 2021 secondary to post-operative complications (intestinal perforation and pancreatitis) while it was still in complete remission from AHA.

Although we cannot rule out an association between AHA onset and cancer diagnosis, the case reported here is exceptional because describes for the first time a possible double relapse of AHA following Coronavirus Disease 2019 (COVID-19) first (see case description in Table 1) and then after vaccination against SARS-CoV-2. A recent review on this topic by Jacobs and colleagues [] showed 58 cases of FVIII inhibitors associated with SARS-CoV-2 vaccination from the US Center for Disease Control and Prevention's Vaccine Adverse Evet Reporting System (CDC's VAERS) database, suggesting a rate of 1.2 cases per 10 million doses. Although this incidence appeared to be similar to that in the general population, this type of analysis suffers from some limitations that might affect accuracy of reporting (e.g., passive reporting, which may result in inaccurate risk estimates; absence of investigation for causality).

We performed a systematic review, analyzing the medical literature for published articles on the association between AHA and SARS-COV-2 infection or vaccination. A literature search of the MEDLINE (through PUBMED), EMBASE, SCOPUS, OVID, and Cochrane Library electronic databases was carried out from September 2020 to September 2022, using English language as a restriction. Only articles published following a peer reviewing process were included in the final analysis. The Medical Subject Heading (MeSH) and key words used were: (“COVID-19” OR “SARS-CoV-2” OR “coronavirus disease 2019”) AND (“vaccine” OR “vaccination”) AND (“acquired hemophilia” OR “factor VIII autoantibodies” OR “factor VIII inhibitors”). We also screened the reference lists of the most relevant review articles for additional studies not captured in our initial literature search. Our search identified 29 cases from 24 articles (see Table 1 for details). Of them, the majority (21/29, 72.4 %) regarded AHA associated with SARS-CoV-2 vaccine (in all cases mRNA vaccine), while the remaining (8/29, 27.6 %) occurred after SARS-CoV-2 infection. The median age at presentation was 73 years (range 39–95 years) with a male/female ratio of 2.5 (28 males and 11 females). The median days between SARS-COV-2 vaccination or infection and AHA onset were 14 days (range 4–90 days) and 7 days (range 1–120 days), respectively. In approximately half of the cases (10/21), AHA arose following the second dose of vaccine. In most cases (21/26, 80.8 %) FVIII autoantibody was at high titer (i.e., >5 Bethesda units), accounting for undetectable FVIII levels and a frequent severe clinical bleeding (mostly multiple-site hematomas) often requiring treatment with bypassing agents (21/27 cases, 77.8 %). Regarding inhibitor eradication, it was performed in 27/29 (93.1 %) cases and included steroids associated with immunosuppressive agents cyclophosphamide and/or rituximab. Complete remission (i.e., persistently normal FVIII levels [>70 %] with undetectable FVIII inhibitor) was reached in 17/28 (60.7 %) cases, with a mortality rate of 10.3 % (3/29), in line with data from international registries [].

In conclusion, the analysis of the literature data documented an increasing number over time of case reports of AHA associated with SARS-CoV-2 infection and, in particular, vaccination. Clinicians should be aware of this rare but potentially severe adverse event and hemostasis should be investigated, as previously reported, in all patients with COVID-19 and vaccinated individuals in the case of an otherwise unexplained onset of a hemorrhagic picture. Due to the particularly complex management, once diagnosed these AHA patients should be referred to specialized hemophilia centers.