Current perspectives on novel therapies in acquired hemophilia A—a clinical practice review

Introduction

Acquired hemophilia A (AHA) is a rare bleeding disorder that is caused by an inhibitory autoantibody (inhibitor) inactivating the coagulation factor (F) VIII (1-4). It is characterized by more involvement in older patients, no known genetic inheritance, extensive hematomas, and bruising, rare hemarthroses. Life-threatening bleeding may occur (2). The estimated incidence from numerous studies was 1.3 to 1.5 cases of AHA per million people per year (1,5,6). The median age of diagnosis from the European Acquired Hemophilia Registry between 2003 and 2008 was 73.9 years old, and males were slightly more affected than females (1). It is worth noting that the age distribution is biphasic, with a small peak occurring between 20 and 30 years, primarily females being affected due to pregnancy-associated AHA, and a major peak in elderly patients aged 68–90 years and those with other comorbidities and malignancies (2,7-12). However, AHA is underdiagnosed due to its rarity and difficulty in diagnosing (3,13-15). The mortality rate of AHA ranges from 7% to 38%. Of those who died with the diagnosis of AHA, the most common cause of death was sepsis/infection, followed by comorbid malignancy, cardiac/myocardial infarction, and fatal bleeding (5,16,17). In patients treated with first-line immunosuppressive therapy, a complete remission (CR) rate was achieved in 46% of patients, of whom 25% had relapsed (16). The median survival between patients treated with steroids alone and those treated with steroids and cytotoxics was not significantly different (2.1 vs. 2.7 years, P=0.33) (6).

We conducted a literature search, including clinical studies, case reports, and systemic reviews on PubMed and Web of Science up to February 2025, by using the key terms “acquired hemophilia A”, “inhibitor”, and “novel therapies”. This review will cover the diagnosis process, conventional treatment, and new remedies for AHA.

Etiopathogenesis in AHA

FVIII (anti-hemophilic factor) is synthesized in the liver hepatocytes and, when secreted into the bloodstream, circulates in plasma as a noncovalent complex and binds to its chaperone von Willebrand Factor (VWF). The structure of FVIII comprises A1, A2, A3, C1, and C2 domains, where A1-A2-B domains form the heavy chain, and A3-C1-C2 form the light chain (12,18). The physiological role of FVIII is to participate in the clotting cascade by accelerating the cleavage of FX by activated FIX. Thus, the intrinsic tenase complex can be formed, and the common pathway can be initiated (19). Reduced levels of FVIII may result from a defective FVIII-coding gene (F8), called congenital hemophilia A (HA) (20), or from a neutralizing autoantibody against FVIII. The latter is named AHA (3,4). Interestingly, the FVIII inhibitors demonstrate different kinetic profiles, in which the alloantibodies against the FVIII in congenital HA exhibit type I (first order) kinetics. In contrast, autoantibodies in AHA usually show type II (second order) kinetics (2,3,10).

The antibodies causing AHA are of immunoglobulin (Ig)G class, typically polyclonal and mainly in the IgG4 and IgG1 subclasses. They usually target the C2 domain and the A2 or A3 domain (2). The precise mechanism of how the body develops the FVIII neutralizing autoantibody remains unknown. A small portion of the healthy population was found to have low-level non-neutralizing FVIII antibodies; however, it is still unclear whether these antibodies will further develop to become neutralizing autoantibodies in AHA (12,21). Studies also found that CD4⁺ T-cell activation significantly inhibits the FVIII function by targeting the C2 and A3 domains (12).

Although AHA is unlike HA, a congenital, inherited disorder, certain genetic factors can cause the development of AHA. CTLA-4 gene is a member of the immunoglobulin superfamily, and its downstream product can inhibit T cell activation. CTLA-4 is involved in autoimmune modulation (60G/A and -318C/T polymorphism) and is considered a risk factor for developing inhibitors in congenital HA. However, the CTLA-4 49G allele was found to be associated with AHA, particularly in females and patients with underlying autoimmune diseases (22). Besides the CTLA-4 gene, the F8 variants and HLA polymorphism are also associated with developing AHA (23,24). Another genetic factor that may potentially contribute to the pathogenesis of AHA is epigenetic modification. In a small study of 10 patients, Tigu et al. found significant alterations in the transcriptomes of ncRNA (non-coding RNA) in the peripheral blood of AHA patients compared to severe congenital HA and healthy controls (25).

Approximately 50% of AHA is idiopathic, meaning the underlying causes of formation of anti-FVIII autoantibody are not found. Of the rest, identifiable causes include autoimmune diseases, malignancies, dermatologic disorders, infectious diseases, pregnancy, and medications (3,10,13). Of note, although rare, AHA was reported in association with anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination (26), in patients who received surgery (27), in IgG4-related disease (28), and in patients treated with immune checkpoint inhibitors (29).

Clinical manifestation and diagnostic approach to AHA

Patients with AHA are presented with sudden onset of severe bleeding and ecchymoses, spontaneously or post-procedure, and have no personal or familial history of bleeding disorders. Unlike congenital HA, joint bleeding is uncommon. Approximately 30% of AHA cases do not have bleeding at diagnosis. The other 70% of cases have significant bleeding. Bleeding in AHA cases is mostly subcutaneous (80%), followed by muscle hematoma (45%), gastrointestinal bleeding (21%), genitourinary bleeding (9%), and retroperitoneal bleeding (9%) (10,21).

Figure 1 depicts the coagulation cascade, including the extrinsic, intrinsic, and common pathways, the involving factors, and the acting sites of the drugs that will be mentioned in this article. Laboratory investigations of patients with AHA usually show increased activated partial thromboplastin time (aPTT) with normal thrombin time (TT), prothrombin time (PT), and platelet count. If no anticoagulants are involved, a mixing study with a 1:1 mix (patient’s plasma and normal plasma) with incubation of 2 hours at 37 ℃ is done to determine if there is a factor deficiency or factor inhibitor. If the aPTT is corrected after the mixing study, there is a factor deficiency on the intrinsic pathway or von Willebrand disease (VWD). Otherwise, no correction of mixing study suggests there is either a factor inhibitor or lupus anticoagulant. Antibodies in patients with AHA exhibit time and temperature dependency, which means they may correct immediately after mixing but show no correction after the incubation. Conversely, lupus anticoagulants are time and temperature independent and show no correction immediately or after incubation. A Bethesda assay, Nijmegen modified Bethesda assay, or an enzyme-linked immunosorbent assay with an anti-FVIII antibody can confirm a FVIII inhibitor level. The quantitation of inhibitors is described by Bethesda unit (BU), defined as the amount of inhibitors that can neutralize 50% of 1 unit of FVIII:C activity in normal plasma after 2-hour incubation at 37 ℃ (30). An algorithm for diagnosing AHA is illustrated in Figure 2. Criteria for AHA diagnosis require FVIII:C <30 IU/dL and FVIII inhibitor titer ≥1 BU/mL. Patients with FVIII inhibitors ≤5 BU/mL can be treated with FVIII replacement therapy, whereas those with FVIII inhibitors >5 BU/mL may require FVIII bypassing agents (BPAs) and immunosuppressive therapy (31). CR means the inhibitor titer is <0.6 BU/mL, FVIII:C >50 IU/dL, and without bleeding symptoms (16).

Figure 1 Coagulation cascade and the action sites of rFVIIa, aPCC, rpFVIII and emicizumab. aPTT, activated partial thromboplastin time; aPCC, activated prothrombin complex concentrate; HMWK, high molecular weight kallikrein; PL, phospholipid; PT, prothrombin time; TF, tissue factor; rF, recombinant activated factor; rpF, recombinant porcine factor.

Figure 2 Approach to diagnose AHA. AHA, acquired hemophilia A; aPTT, activated partial thromboplastin time; F, factor; LA, lupus anticoagulant; TT, thrombin time; VWD, von Willebrand disease; VWF, von Willebrand Factor.

As previously pointed out, the AHA inhibitors follow the second-order kinetics, meaning the residual FVIII activity will reach equilibrium quickly. However, the levels of residual FVIII do not correlate with the bleeding phenotype and severity (3).

Hemostatic therapies

AHA is an extremely rare disease and potentially fatal condition. The diagnosis remains challenging for clinicians, and consultation with experts in hemophilia/bleeding disorders is strongly advised. The treatment for AHA requires multiple efforts, including hemostasis management, eradication of inhibitors, and treating the identifiable underlying etiologies. Three agents were approved for hemostatic therapy in AHA patients: BPAs [recombinant activated FVII (rFVIIa) and activated prothrombin complex concentrate (aPCC)] and recombinant porcine factor VIII (rpFVIII). Recently, emicizumab was also approved for treating AHA.

BPAs

BPAs bypass the need for FVIII in the coagulation cascade to produce thrombin, overcoming the interference of anti-FVIII inhibitors. Two agents fall into this category: recombinant activated FVII (rFVIIa) and aPCC. Recombinant activated FVII, licensed under the name of NovoSeven^® (Novo Nordisk) or NiaStase RT^® in Canada, was first used by Macik et al. in 1989 for a patient with chronic hemophilia with inhibitor (CHwI) who cannot achieve hemostasis with FVIII, immunoadsorption techniques or plasmapheresis (32). The mechanism of action of rFVIIa was thought to be a tissue factor-related “site of injury” where a complex of tissue factor and/or phospholipids with FVIIa activate FX into FXa, thus bypassing the need for FVIII or FIX (32,33). Therefore, these agents are so-called BPAs. However, the precise mechanism of rFVIIa is complex, and whether rFVIIa’s action is tissue factor-dependent or independent remains debatable.

Nevertheless, rFVIIa is the most used agent in treating AHA with efficacy ranging from 80–92% (15,16,34,35), and was granted FDA approval for treating hemophilia A or B with inhibitors for bleeding episodes in 1999. FEIBA^® (Baxalta Innovations, Vienna, Austria; now Takeda) is a plasma-derived aPCC that contains FII, FIX, and FX in non-activated form and FVII in activated form (36). It was first used in 1977 to treat a patient with CHwI successfully (37). The FDA approved FEIBA^® for prophylactic hemophilia A or B with inhibitor treatment in 2013. Like rFVIIa, aPCC was AHA’s second most used BPA and showed similar efficacy in the EACH2 study (34). The FEIBA^® Acquired Hemophilia A Italian Registry (FAIR) study, conducted by Zanon et al., reported the effects of FEIBA^® on 56 patients at 12 Italian hemophilia centers (38). FEIBA^® was used as a first-line treatment in 82.2% of bleeding cases with a mean dose of 72.6±26.6 units per kg and was deemed effective in 96.4% of bleeds. No thromboembolic events occurred. After the first bleeding episode, 26.8% of the patients received FEIBA^® for prophylaxis, and bleeding relapses were significantly lower in patients who received prophylactic treatment with FEIBA^®. Preference for the BPA used in AHA cases may differ based on the clinician; however, numerous studies show that both BPAs are highly effective at managing bleeding events in patients with AHA, and both are well-tolerated (5,21,39,40).

rpFVIII (Obizur^®)

rpFVIII also known as susoctocog-alfa and sold under the brand Obizur^®, is a 1448 amino acid heterodimer capable of treating bleeding events caused by AHA, and it is produced in baby hamster kidney cells. It has domains with the sequence A1-A2-B-A3-C1-C2; the B domain is partially deleted (41). rpFVIII is a second-line treatment used when managing hemorrhages in AHA cases. In a phase II study reported by Mahlangu et al. (42) in 2017, 9 subjects between the ages of 14 and 34 received rpFVIII at up to 8 treatment doses of 50–150 U/kg. Twenty-five bleeding episodes were treated by 40 OBI-1 (Obizur/BAX801; Baxalta Inc., Deerfield, IL, USA) injections. Out of the 25 bleeding episodes, 20 (80%) were controlled with one treatment dose of OBI-1. All 25 bleeding episodes were controlled with rpFVIII. There were 28 participants in the study, and all 28 responded positively to the treatment within 24 hours after the first dose. None of the 28 participants developed any thrombotic events or severe adverse effects. rpFVIII is a highly effective and safe treatment for bleeding events caused by AHA.

Emicizumab (Hemlibra^®)

Emicizumab is the first non-clotting factor medicine to prevent hemorrhages in patients with HA and AHA, with or without factor VIII inhibitors. Emicizumab is sold under Hemlibra^®, a bispecific agent used as a FVIII mimetic (43). Shima et al. reported the results of Japan’s first multicenter, prospective, open-label phase III clinical trial (AGEHA) (44). Twelve patients were enrolled. Eleven of 12 patients (91.7%) completed the emicizumab treatment. Prior to administrating emicizumab, 11 patients (91.7%) experienced 110 bleeds, with 30 of them classified as treated bleeds (a bleed following treatment with coagulation factor products), and 7 patients (58.3%) experienced 77 major bleeds. During emicizumab treatment, no patients underwent any major bleeds, and 5 patients (41.7%) experienced all 27 bleeds, with 5 of them classified as treated bleeds. During the follow-up period, no major bleeds and treated bleeds were reported. All 12 patients experienced a total of 78 adverse events, with the majority being unrelated to emicizumab. The reported emicizumab-related adverse events were thrombocytopenia (1 patient), prothrombin fragment 1+2 increased (1 patient), and deep vein thrombosis (DVT) (1 patient), of which only DVT had interrupted emicizumab doses. Emicizumab is an effective treatment to prevent bleeding caused by HA and AHA, both with and without inhibitors. However, AHA is a rare disease, so the dosing schemes and treatment duration for emicizumab in AHA cases have not been standardized.

Immunosuppression and inhibitor eradication therapies

Inhibitor eradication with immunosuppressive treatment (IST) is equally important to hemostatic therapy and should be implemented as soon as AHA is diagnosed. The first line of treatment is corticosteroids with or without cyclophosphamide, while rituximab is the second line for inhibitor eradication. In the EACH2 registry, 294 of 331 (89%) patients received IST, of which steroids alone were given to 142 (43%) patients, steroids with cyclophosphamide were given to 83 (25%) patients, and rituximab was used in 51 (15%) patients. The CR rate was highest in steroids with the cyclophosphamide group (80%), with a lower relapse rate and more stable CR compared to steroids alone (58%) or steroids with rituximab (64%). However, the adverse effects were also higher in steroids with cyclophosphamide (41% compared to 25% in steroids alone and 37% in rituximab-based therapy), with infection being the most common side effect followed by neutropenia, diabetes, and psychiatric disorders (45). Borg et al. reported in the SACHA registry that the majority (94%) of patients received IST, with an excellent CR rate (98% in 1 year). No significant difference between steroids versus steroids with cyclophosphamide was observed. Five patients received rituximab; two were in CR at 3 and 12 months (17). Similarly, the GTH-AH 01/2010 study showed that prednisolone was the most used IST (99%), followed by prednisolone plus cyclophosphamide (34%) and prednisolone plus rituximab (11%). Partial remission (PR) was used as the primary endpoint in this study, and the overall PR was 83% (54% in prednisolone alone, 60% in prednisolone plus cyclophosphamide, and 66% in prednisolone plus rituximab). The overall CR was 61%, but no subgroup information was available (46). In the CARE registry of AHA in China, of 187 patients enrolled, steroids plus cyclophosphamide were used in 41%, and 87.5% went into CR, whereas 25% of patients received steroids alone with 62.2% CR rate and 34% received rituximab-based treatment with CR rate of 90.9%. They also showed that steroids plus cyclophosphamide had a shorter time from initiation of IST to PR and CR (47).

Although IST is a very effective treatment for AHA, several drawbacks are worth considering. Firstly, the majority of AHA patients are old and are thus prone to the adverse effects associated with IST. As reported, death from infection related to IST is the most common cause of mortality, equal to fatal bleeding (EACH2 registry; 16% of deaths due to IST complications versus 17% of deaths due to fatal bleeding) (1) or surpass (SACHA registry; 37% due to sepsis versus 11% due to bleeding) (16). Personalized precision medicine based on FVIII levels and FVIII inhibitor titer to titrate the IST would be the key to avoiding such adverse effects. Secondly, looking for an alternative, safer IST will be of importance. Rituximab, anti-CD20 monoclonal antibody, is in favor and could be considered a first-line IST agent. It should be used as an initial treatment if other IST is contraindicated (8,48). Cautions should be taken when giving rituximab as immunosuppression with increased risk of viral infections and hepatitis B reactivation are the primary concerns (21). Besides rituximab, an anti-CD38 monoclonal antibody is currently under investigation (Clinicaltrials.gov ID: NCT05849740).

Current clinical trials under investigation

Table 1 summarizes 3 clinical trials that are actively recruiting patients with acquired hemophilia for investigation, one of which is a pathophysiological study of the lymphocyte population and myeloid-derived suppressor cells in acquired hemophilia and its autoimmunity (ClinicalTrials.gov ID: NCT04805021). One study is a phase II multicenter study to investigate the efficacy of emicizumab in the prevention of bleeding in patients with AHA (ClinicalTrials.gov ID: NCT05345197), and another is to study the side effects related to Obizur^® intravenous injection and the efficacy of Obizur^® in improving the bleeding symptoms of AHA (ClinicalTrials.gov ID: NCT06461533). The last study is interesting; the researchers in China seek to investigate whether an anti-CD38 agent (daratumumab) can treat AHA. CD38 is a transmembrane glycoprotein with enzymatic activity and is expressed in various cell surfaces, but mainly on the hematopoietic cells, especially the plasma cells. Daratumumab is a monoclonal antibody engineered to target CD38 and approved for treating multiple myeloma (49,50). There were case reports that daratumumab was used to immunosuppress patients with AHA who were resistant or refractory to initial treatments. Liu et al. reported the successful treatment of 4 patients with AHA with daratumumab (dose range from 4 milligrams per kg per week to 8 milligrams per kg per week) combined with corticosteroids (methylprednisolone or dexamethasone). All four patients achieved and remained in CR (51). Further studies are required to explore the mechanism of action of daratumumab and investigate its efficacy and safety in treating AHA.

Conclusions

AHA is a rare bleeding disorder that requires clinicians to be familiar with its clinical features and diagnostic and therapeutic approaches. Novel agents like rpFVIII and emicizumab are widely used and may become the first-line treatment. The anti-CD38 monoclonal antibody showed favorable outcomes, but more clinical trials are needed to evaluate its efficacy and effectiveness in treating relapse/refractory AHA.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-25-11/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-25-11/coif). The authors have no conflicts of interest to declare.

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