Acquired hemophilia A (AHA) due to anti‐SARS‐CoV‐2 vaccination: A systematic review

Abstract Vaccination against SARS‐CoV2 has been the largest vaccination campaign over the past two decades. The aim of this study is to qualitatively assess the reported cases of acquired hemophilia A (AHA) that developed after COVID‐19 vaccination to further elaborate on incidence, presentation, treatment, and outcomes.We queried Medline (PubMed), Google Scholar, and Embase databases to find reported cases of AHA after COVID‐19 vaccines. We found 14 studies (19 cases) for this descriptive analysis. Most patients were elderly (mean age 73 years) and males (n = 12) with multiple comorbidities. All cases developed after mRNA vaccines ‐ BNT162b2 Pfizer‐BioNTech (n = 13) and mRNA‐1273 Moderna (n = 6). All except one patient were treated, with the most common therapy being a combination of steroids, immunosuppression, and rFVIII (n = 13). Two patients died due to acute respiratory distress, and gall bladder rupture with persistent bleeding, respectively. While evaluating a patient with bleeding diathesis after COVID‐19 vaccination, AHA should be kept in the differential diagnosis. Given the low incidence, we believe that the benefit of vaccination still outweighs the risk of disease acquisition.

F I G U R E 1 Preferred reporting items for systematic reviews and meta-analyses statement (PRISMA) flow chart for this study Paroxysmal nocturnal hemoglobinuria, vaccine-induced thrombotic thrombocytopenia (VITT), aplastic anemia etc. [5][6][7]. Hence, postmarketing surveillance to report rare vaccine-associated adverse events is very essential. The aim of this study is to qualitatively assess the reported cases of AHA that developed after COVID-19 vaccination to further elaborate on incidence, presentation, treatment, and outcomes For this systematic review, we did an electronic search in PubMed, Google Scholar, and Embase databases to find reported cases of AHA after COVID-19 vaccine using the keywords (either Mesh or Supplementary concept) -"COVID-19 vaccines" or "COVID-19 vaccine booster shot" or "2019-nCoV vaccine mRNA-1273" or "ChAdOx1 nCoV-19" or "BNT162 vaccine" OR "Ad26COVS1" and "Factor VIII deficiency, acquired" OR "hemophilia A, acquired" OR "hemophilia A" from inception till April, 2022. The study was performed following the preferred reporting items for systematic reviews and meta-analyses statement guidelines [ Figure 1] [8]. The title and abstracts were independently screened by two authors (FA, PM). After removing duplicated articles, data were extracted from the eligible studies b two independent authors (FA, PS). Any discrepancy was resolved with the consensus of authors. Additional articles were included by cross-referencing the reference list of the included articles. The inclusion criteria were as follows: (1) Case reports, case series, cohort studies, commentaries, abstracts to conference, or letter to editor. (2) Demographic data of individual patients were reported. (3) Laboratory data of individual patients were reported. Articles not reporting individual patient data and non-English publications were excluded from this review. In the end, 14 studies (19 cases) were included in this study. The methodological quality of the case reports and case series included in the study were assessed using the tool proposed by Murad et al. based on four domains-selection, ascertainment, causality, and reporting [9]. The mean assessment score was 4.9. The data collected from each manuscript are summarized in (Table 1). The variables collected include (1) author name and country of origin, (2)   Our review had similar demographics as found in the largest known AHA cohort called European Acquired Hemophilia registry where AHA was more commonly noted in older adults with median age 73.9 years with male predominance [25,26]. AHA has been associated with autoimmune and dermatological conditions like systemic lupus erythematosus, rheumatoid arthritis, epidermolysis bullosa, and pemphigus [27]. A total of 26% of had pre-existing diagnosis of immunological disorder-polymyalgia rheumatica, Sjogren syndrome, and Raynaud's phenomenon, but one patient developed concurrent bullous pemphigoid. The diagnosis of AHA can be challenging due to the rarity of this condition and complexity of laboratory workup. In all these studies, the authors reached a conclusion based on the temporal sequence of events and ruling out other causes of bleeding diathesis.
Hence, we propose this schematic representation to aid in diagnosis [ Figure 3].

F I G U R E 2
Representing possible pathophysiological cause of vaccine-induced acquired hemophilia A (AHA). Image created in biorender.com

F I G U R E 3 Representing the laboratory workup for diagnosis of vaccine-induced acquired hemophilia A (AHA). Image created in biorender.com
Unlike SARS-CoV2 adenoviral VITT for which mechanism has been well described, the pathophysiology behind mRNA-vaccineassociated AHA is not well understood. Two possible mechanisms, antigen mimicry and stimulation of dormant T or B cells, have been proposed [ Figure 2]. SARS-CoV2 spike protein has 37% similarity with A2 domain at 540-570 amino acid position of factor VIII using NCBI blast sequence alignment tool and one overlapping epitome (FVIII 543-554) at the same sequence using silico antigenic peptide prediction [28].
Therefore, molecular mimicry was proposed in the immunopathogenesis of AHA following vaccination due to induction of antispike IgG antibodies that might act as FVIII inhibitor. Hirsiger et al. attempted to study this concept in three patients with AHA and found weak FVIII cross-reactivity in antispike-IgG-enriched fraction [28]. Therefore, another hypothesis of activation of dormant T or B-cells was proposed. MHC class II-facilitated presentation of SARS-CoV2 spike peptides to pre-existing T cell clones specific to factor VIII can lead to their activation, resulting in production of autoantibodies. Polyclonal B cell can also be directly activated due to stimulation of broad Toll-like receptors, with production of factor VIII-specific antibodies of restricted isotypic heterogeneity. This is further supported by the fact that negative thymic selection of factor VIII-specific CD4 T cells is incomplete, with high numbers of naïve and memory T cells, which can expand in response to peculiar immunogenic trigger resulting in AHA [29].
Although another study done by Algiman et al. showed that anti-VIII IgG were present in healthy individuals without evidence of disease, these could merely represent natural IgG autoantibodies or antibodies against some epitopes with unknown allotypic polymorphism of factor VIII. In the setting of polyclonal activation, some AHA predisposed people can still expand these self-reactive clones or somatically mutated antigen driven B cell clones producing pathogenic IgG autoantibodies causing clinical disease [30]. In our study, bleeding occurred within 1-3 weeks of receiving vaccines, with bleeding being more severe in those who completed the two doses, which raises the suspicion of additive effect of antigen exposure leading to the outcome. Further understanding is required into the fact that no cases have been reported with adenoviral vaccination, whether that is a coincidence, or a reality is unknown.
There are two major goals of therapy: control of bleeding and neutralizing the inhibitor. For mild bleeding in nonsignificant organ or area, observation is preferred. For significant moderate to severe bleeding, either APCC or rFVIII is used. As per 2020 international AHA guidelines, early initiation of immunosuppressive therapy to eliminate the inhibitor has improved outcomes [31]. As per GTH study on AHA in 2010 (German Society of Thrombosis and Hemostasis research group), corticosteroids should be started for 3 weeks or till the achievement of partial remission. They define partial remission as factor VIII activity being >50% without needing any blood products and in the absence of any active bleeding. If partial remission cannot be achieved, initiation of cyclophosphamide around 4-6th week followed by rituximab from 7-10th week is recommended. However, the use of immunosuppressive therapy has to be done cautiously if World Health Organization performance status is poor on presentation as Acquired Hemophilia Working Group of the German, Austrian and Swiss Thrombosis and Hemostasis Society study has reported that the risk of immune system suppression-related mortality especially due to infection is higher than the risk of life-threatening bleeding due to AHA [32]. The use of immunosuppressants result in 60%-90% remission rates, but mortality rates can be as high as 28%-42% due to direct complications of bleeding or infection due to immunosuppressants [32]. In our review, two patients died due to gall bladder rupture and acute respiratory distress syndrome respectively. The other patients had favorable short term prognosis in terms of safe discharge from hospital and no bleeding-related life threatening complications. Most patients responded to the treatment, but long-term outcome for these patients is lacking and needs more studies in future to draw succinct conclusions.
Although there is a definite temporal association in the absence of any other inciting factors, causation cannot be proven. This was further corroborated by a study done by Cittone et al. who reported no statistically significant increase in AHA incidence in Switzerland during anti-SARS-CoV-2 vaccination campaign [11]. More evidence in the form of prospective studies is needed to prove the causation. The potential areas that need further exploration include whether these patients should receive the next dose of vaccine, and if yes, whether the same vaccine can be administered. It would be helpful if we will be able to identify and predict biomarkers as well. In the meantime, a shared decision making with the patients can be done. If a decision is taken to re-vaccinate with second dose or boosters, monitoring of the coagulation studies near the vaccination administration period should be undertaken and patients should be educated regarding the warning signs to present to the hospital in the event of occurence of any bleeding episodes. This study has several limitations including short time of disease emergence and postmarketing surveillance. There is always a concern of under-reporting, publication bias, and missing articles with any systematic review of case reports. We also have to acknowledge that some cases might have not been detected or might have self-resolved before a diagnosis could have been established.
In conclusion, the number of cases reported AHA since the beginning of COVID-19 vaccination is not significant enough to have definitive causal association between the two but allows us to direct more attention to epidemiological data on suspected vaccinerelated adverse events. Nonetheless, COVID-19 vaccination benefits far exceed the risk of potential immune-mediated hematological side effects as far as individual and public health is concerned, but AHA should always be kept in differential while evaluating a patient with bleeding diathesis post-COVID 19 vaccination.