Emicizumab in Acquired Hemophilia A: A Real-World Case Series with Patient-Level Outcome Analysis

Abstract

Acquired Hemophilia A (AHA) is a rare bleeding disorder caused by factor VIII inhibitors. Standard therapies are limited by thrombotic risk and prolonged hospitalization. Emicizumab, approved for congenital Hemophilia A, has emerged as a potential alternative in AHA based on case reports and early clinical trial data. To evaluate the efficacy and safety of Emicizumab in AHA through a retrospective real-world case series and a systematic literature review with patient-level data analysis. We retrospectively analyzed five AHA cases treated with Emicizumab at two Italian centers and performed a PRISMA-compliant systematic review of published reports, extracting and analyzing patient-level data using Joanna Briggs Institute tools. In the real-world cohort, early Emicizumab use in five patients with high-titer inhibitors and severe bleeding led to rapid hemorrhagic control, early withdrawal of bypassing agents, and no thrombotic or adverse events. All five patients received immunosuppression, and inhibitor eradication was achieved in 60% of patients, but for 40% follow up is still ongoing. The literature review identified 24 patients from 18 publications. Early Emicizumab administration (at admission) was associated with reduced bleeding recurrence (0% vs. 56.3%), shorter in-hospital stay (median 23.5 days vs. 39 days), and lower bleeding-related mortality (0% vs. 12.5%) compared with delayed administration. Early Emicizumab initiation appears to be a safe and effective strategy for AHA management, particularly in fragile or high-risk populations. Its subcutaneous route, favorable safety profile, and ability to reduce hospitalization support its integration into first-line therapeutic algorithms. Further prospective studies are warranted to define.

Keywords

acquired hemophilia A - Emicizumab - bleeding control - hospitalization - comorbidities - patient-level data

Acquired Hemophilia A (AHA) is a rare autoimmune disease marked by the development of inhibitors against endogenous FVIII, leading to an acquired coagulopathy.[1] The estimated incidence in Europe is approximately 1.5 cases per million of population.[2] Peaks in incidence occur during pregnancy and in individuals older than 60 years.[3] [4] Diagnosis is typically suspected when isolated prolongation of activated partial thromboplastin time (aPTT) is observed, accompanied by bleeding episodes due to reduced FVIII activity, without family or personal history of Hemophilia.[5] In patients with AHA, the bleeding phenotype is severe. Most individuals present with spontaneous bleeding, commonly involving cutaneous, intramuscular, or retroperitoneal sites. However, bleeding may also be precipitated by trauma or invasive procedures.[6] Bleeding events are frequently severe at presentation, often associated with a significant drop in hemoglobin levels necessitating red blood cell (RBC) transfusions, and may rapidly progress to life-threatening complications.[7] Current clinical management relies on international expert consensus recommendations originally issued in 2009[8] and 2010[9] and subsequently updated in 2020, incorporating evidence from EACH2 and other European and U.S. registries[10]; additional guidance has also been produced by national expert groups, including those from the United Kingdom and Italy.[11] [12] However, these approaches often require intensive inpatient care and are associated with substantial thrombotic risk, particularly in elderly or comorbid patients, underscoring the need for more effective and accessible therapeutic strategies.[9]

Therapeutic options for AHA are limited and include bypassing agents such as recombinant activated factor VII (rFVIIa), activated prothrombin complex concentrates (aPCC), and Porcine FVIII (prFVIII) concentrates.[13] The use of rFVIIa and aPCC is limited by their short half-lives and the need for intravenous administration, necessitating hospital-based care. These agents are not approved for routine prophylactic use beyond the perioperative period, and their hemostatic effects cannot be reliably assessed through standard laboratory monitoring. Furthermore, as both contain activated factors, their use carries an inherent risk of thrombotic complications.[14]

Emicizumab, a bispecific monoclonal antibody that mimics the function of activated FVIII, has been investigated as a therapeutic option for patients with AHA. The efficacy and safety of Emicizumab to prevent bleeding in AHA were explored by recent clinical trials.[15] [16] Across studies, Emicizumab has exhibited a favorable safety profile in patients with AHA. The most common adverse events reported were mild injection site reactions. Notably, no thrombotic microangiopathies or thromboembolic events were associated with Emicizumab monotherapy. However, caution is advised when combining Emicizumab with aPCCs, as thrombotic events have been reported in such scenarios in congenital Hemophilia A.[17] [18] [19] [20] [21] Notably, the GTH-AHA-EMI trial,[15] an open-label, single-arm, multicenter phase 2 study, evaluated the efficacy and safety of Emicizumab prophylaxis in 47 adult patients with newly diagnosed AHA who had not received prior immunosuppressive therapy. The study reported consistently low rates of clinically relevant new bleeding during the 12-week treatment period, with no significant variations across age, sex, baseline FVIII activity, or inhibitor titer. Emicizumab was well-tolerated, and no thrombotic events were observed.[22] These findings suggest that Emicizumab is an effective and safe option for bleeding prophylaxis in patients with AHA, offering advantages such as subcutaneous administration and reduced use of bypassing agents.

We evaluate the efficacy and safety of Emicizumab in AHA through a retrospective real-world case series and a systematic literature review with patient-level data analysis.

Materials and Methods

Study Cohort

This is a retrospective review of a series of patients with AHA admitted to Federico II University Hospital, Naples, and to Salerno University Hospital, Italy. We retrospectively reviewed medical records for the period between June 2024 and June 2025. Only patients who received Emicizumab treatment were included in the present study. For all patients gender, age at diagnosis of AHA, underlying clinical conditions and comorbidities, site and severity of bleeding episodes, baseline FVIII activity levels and inhibitor titers, haemostatic therapy and immunosuppressive treatment, Emicizumab treatment regimen (initial dose, maintenance dose, frequency, and duration), clinical response to therapy, FVIII activity levels upon Emicizumab discontinuation, duration of treatment; time to clinical remission, adverse events associated with Emicizumab administration were recorded.

FVIII was assessed before starting the Emicizumab treatment with the one-stage FVIII clotting assay. Chromogenic substrate assays using bovine reagents were used to assess FVIII levels during the Emicizumab treatment.[23] Inhibitors were detected by the Nijmegen–Bethesda inhibitor assay. Written informed consent was obtained from the patients included in the present study. All identifying information was removed for this report. The study was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.

Systematic Review of Literature Data

We developed a protocol for this systematic review of literature data, defining the search strategy, the outcomes, the inclusion and exclusion criteria, and the statistical methods.

A systematic review was conducted in accordance with PRISMA guidelines.[24] A comprehensive literature search was performed across the PubMed, Scopus, Cochrane Library, and Google Scholar databases. The search strategy employed the keywords: “acquired Hemophilia” and “Emicizumab” and (“case” or “case report” or “case series” or “trial” or “adverse effect”), utilizing Boolean operators to optimize sensitivity and specificity. The search encompassed all studies published up to April 2025, without language restrictions. Following removal of duplicates, titles and abstracts were independently screened by two reviewers (CDL and IC) to identify potentially eligible studies. Full-text articles were retrieved and assessed for inclusion based on predefined criteria: (1) patients diagnosed with AHA, (2) management involving Emicizumab, and (3) availability of individual patient data or aggregated clinical outcomes. Randomized and nonrandomized clinical trials were excluded, as our aim was to capture the granularity of real-world experiences and individual patient-level outcomes not typically available in such studies.

The methodological quality of the selected studies was evaluated independently by two reviewers using the Joanna Briggs Institute critical appraisal tools, specifically designed for the assessment of case reports and case series. Any discrepancies in quality assessment were resolved through discussion or consultation with a third reviewer (GDE). Data extraction was performed independently and included the following variables: patient demographics (age, sex); underlying clinical conditions and comorbidities, site and severity of bleeding episodes; baseline FVIII activity levels and inhibitor titers; indications for haemostatic therapy and immunosuppressive treatment; Emicizumab treatment regimen (initial dose, maintenance dose, frequency, and duration); clinical response to therapy; FVIII activity levels upon Emicizumab discontinuation; duration of treatment; time to clinical remission; adverse events associated with Emicizumab administration. Extracted data were tabulated and analyzed descriptively. For patient-level outcome analysis, continuous variables were reported as medians and ranges, while categorical variables were expressed as frequencies and percentages.

Results

Real-World Case Series

Eight consecutive patients were retrospectively identified to be included in the present study. We included five patients diagnosed with AHA, managed with a treatment strategy combining immunosuppressive therapy and Emicizumab, as suggested by Italian Drug Agency (AIFA) criteria: AHA confirmed diagnosis with at least two bleeds in the previous 2 months and inefficacy of steroid and immunosuppressant therapy after 2 weeks of treatment, until the FVIII reaches 20%.[25] [Table 1] summarizes patients' demographics and clinical data. The series includes three AHA in elderly and one AHA in an adult patient, and one postpartum AHA (C1). The other three cases were excluded from the analysis because they did not receive Emicizumab and were treated only with bypassing agents. No patient was treated with cyclophosphamide (CCX).

Table 1 Clinical and demographic characteristics of clinical cases

Variable	C1	C2	C3	C4	C5
Age (y)	40	80	80	45	76
Sex	Female	Male	Female	Female	Male
Underlying conditions	Puerperium	Idiopathic	Breast cancer (in remission)	Pemphigus vuglaris	Idiopathic
Comorbidities	Undifferentiated connective disease	Polyvascular atherosclerosis, arterial hypertension, paroxysmal atrial fibrillation, chronic obstructive pulmonary disease	Polyvascular atherosclerosis, arterial hypertension, and severe osteoporosis	Arterial hypertension	Previous stroke, type 2 diabetes mellitus, frontal meningioma surgically removed
Type of Bleed	Hematuria, hematomas	Ileopsoas + cutaneous	Hematomas, epistaxis	Ileopsoas + cutaneous	Gluteal hematoma
Body surface hematoma (>50%)	Yes	Yes	No	Yes	Yes
Number of blood transfusions	4	12	2	5	2
Number of bleeds preemicizumab	2	2	2	3	1
Number of bleeds during Emicizumab	0	0	0	0	0
aPTT ratio	2.68	2.3	2.7	2.4	3.08
FVIII (%)	0.4	0	3	0	0
Inhibitor titer (BU/mL)	16	286	8.7	9.21	128
Hb levels at admission (g/dL)	11.5	10.2	12.3	9.7	5.9
Hb levels at discharge (g/dL)	13.4	11.6	14.2	11.8	11.6
Days at discontinuation of bypassing agents	0	0	0	0	2
Hospitalization duration (d)	38	32	36	38	36

All patients developed severe spontaneous bleeding manifestations, including diffuse subcutaneous hematomas involving > 50% of body surface, iliopsoas hemorrhage (C2; C3), hematuria (C1), and epistaxis (C3), all requiring multiple RBC transfusions with a median transfused RBC units of four (IQR: 4–5). Particularly, patient C2 was admitted to the emergency room for severe anemia due to bilateral iliopsoas muscle and massive cutaneous hematoma with life-threatening bleeding severity, requiring more than five RBC transfusions, triggering cardiac supraventricular arrhythmia. Median hemoglobin at admission was 10.2 g/dL (IQR: 5.9–12.3 g/dL). All patients included reported significant comorbidities ([Table 1]). Patient C1 tested positive for anti-nuclear antibodies suggestive of a potential diagnosis of undifferentiated connective tissue disease. Patient C2 reported arterial hypertension, supraventricular extrasystole with paroxysmal atrial fibrillation, polyvascular atherosclerotic disease, chronic obstructive pulmonary disease, and hypercholesterolemia. Patient C3 reported breast cancer in relapse-free follow-up, polyvascular atherosclerotic disease, arterial hypertension, and severe osteoporosis. Patient C4 reported a diagnosis of pemphigus vulgaris and hypertension. Patient C5's past medical history included type 2 diabetes mellitus, previous cerebrovascular accident (stroke), and prior surgical removal of a frontal meningioma. Patients C2, C3, and C5 were in treatment with low-dose aspirin as a secondary prevention strategy. As laboratory findings: all patients exhibited recent onset of markedly prolonged aPTT, absent correction on mixing studies, negative lupus anticoagulant, low factor VIII activity (median: 0; IQR: 0–3%), and the presence of high-titer FVIII inhibitors (median: 16; IQR: 8.7–286 BU/mL), confirming the diagnosis of AHA and excluding diagnosis of congenital HA. For all the included patients, standard first-line immunosuppression with corticosteroids (CCS; prednisone 1 mg/kg/day) was initiated when the diagnosis of AHA was confirmed. However, due to suboptimal clinical or laboratory response, the anti-CD20 monoclonal antibody, Rituximab, was introduced in weekly doses (375 mg/m² for 4 weeks) in all five patients.

To improve hemorrhagic control and reduce bleeding recurrence and reliance on bypassing agents, due to the cardiovascular comorbidities and concomitant thrombotic risk, Emicizumab was initiated as early as possible in the clinical course in all five patients. Dosing schedules included loading and maintenance regimens according to the following therapeutic scheme for patient C1: 3 mg/kg weekly for 4 weeks (induction), followed by maintenance dosing of 1.5 mg/kg every week. For patients C2 to C5, the following therapeutic scheme was adopted: 6 mg/kg on the first day, 3 mg/kg on the second day (induction); 1.5 mg/kg after another 7 days and every 7 days (maintenance). Emicizumab treatment was continued thereafter until FVIII reached 20%, according to AIFA recommendations.[25] In all cases, Emicizumab effectively prevented bleeding recurrence ([Fig. 1]), facilitated clinical stabilization, and allowed for the safe tapering or cessation of bypassing agents. The use of Emicizumab was associated with no adverse or thrombotic events. Median hospitalization duration was 36 (IQR: 33–40) days. Early Emicizumab administration leads to rapid and sustained hematologic stabilization with a median hemoglobin at discharge of 13.4 g/dL (IQR: 11.6–14.2 g/dL). In all five patients, hemoglobin levels increased consistently from admission to discharge, with improvements ranging from +1.4 to +5.7 g/dL, despite baseline heterogeneity and comorbidities ([Supplemental Fig. S1], available in the online version only). Inhibitor eradication was ultimately achieved in three patients, with complete FVIII recovery documented within approximately 4 weeks after the last rituximab dose. No thrombotic events occurred. For two patients, the follow-up is still ongoing ([Table 1]; [Fig. 2]).

Fig. 1 Comparison between bleeding events before Emicizumab and during Emicizumab treatment.

Fig. 2 Cases clinical FVIII and Inhibitor titer over time.

Systematic Review and Patient-Level Analysis

Study Selection

The study selection process followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.[24] A total of 84 records were identified through database searching (PubMed, Scopus, Cochrane Library, and Google Scholar) using the predefined search strategy. After removal of duplicates (42 records), 42 unique records remained. These were screened based on titles and abstracts, resulting in the exclusion of 10 articles that did not meet inclusion criteria (e.g., unrelated topics, animal studies, review articles without individual patient data). Full-text versions of 32 articles were retrieved and assessed for eligibility, and 11 articles were excluded for the following reasons: lack of detailed Emicizumab treatment information, incomplete clinical data, and irrelevant patient populations (e.g., congenital Hemophilia A). Finally, 18 articles[24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] including 24 individual cases, were included in the final qualitative and quantitative data analysis ([Table 2]). A flow diagram summarizing the identification, screening, eligibility, and inclusion stages was constructed according to PRISMA 2020 standards ([Supplemental Fig. S2], available in the online version only).

Table 2 Summary of included studies in the systematic review of literature

Author	Year	n	Age/sex	Hospitalization period (d)	Emicizumab (dose/timing)
Patrick[32]	2019	1	83 M	39	3 mg/kg weekly × 3 then 1.5 mg/kg every 2–4 wk
Yates[27]	2022	1	83 M	71	3 mg/kg then 1.5 mg/kg
Hansenne[26]	2021	2	93 M	8	3 mg/kg weekly × 4 6 mg/kg once or 3 mg/kg wk
			73 M	12
Happaerts[43]	2022	1	75 M	15	NR
Gelbenegger[40]	2023	1	75 M	21	3 mg/kg weekly × 3 then 1.5 mg/kg every 2–4 wk
Al-Banaa[28]	2019	1	87 F	30	3 mg/kg weekly × 4 then 1.5 mg/kg weekly
Ahmed[29]	2024	2	66 M	29	3 mg/kg weekly × 2–3 wk then 1.5 mg/kg weekly × 3
			64 M	NR
Jena[30]	2021	1	78 M	11	NR
Chung[35]	2021	1	65 M	37	NR
Gomez[29]	2023	1	66 M	27	3 mg/kg single dose then 3 mg/kg at relapse for 4 wk
Tiede[36]	2021	4	83 F	42	3 mg/kg weekly × 4 then 1.5 mg/kg weekly
			60 F	NR
			29 F	NR
			72 M	NR
Hess[42]	2020	1	91 M	71	3 mg/kg weekly × 4 then 1.5 mg/kg weekly
Dane[39]	2019	1	72 M	NR	3 mg/kg weekly × 4 then 1.5 mg/kg weekly
Nowak[50]	2022	1	68 F	145	3 mg/kg weekly × 4 wk then 1.5 mg/kg × 2 wk
Hayden[37]	2022	2	70 F	21	3 mg/kg weekly × 4 wk then 1.5 mg/kg weekly
			90 M	37
Ragavan[32]	2024	1	15 M	20	3 mg/kg weekly × 4 wk
Ganslmeier[33]	2021	1	59 M	252	3 mg/kg weekly × 2 wk then every 4 wk
Al-Banaa[38]	2021	1	79 M	NR	3 mg/kg weekly × 4 or 3 mg/kg weekly × 2 then 1.5 mg/kg weekly × 2

Abbreviation: NR, not reported.

Study Characteristics

Principal characteristics of subjects enrolled in the included studies are shown in [Table 3]. The mean age was 72.5 years (min: 15; max: 93), and 75% were male. Common comorbidities included hypertension (37.5%), atrial fibrillation (25%), and chronic renal failure (12.5%). Twelve patients had muscle-cutaneous bleeding (50%), with reduced FVIII activity, prolongation of the aPTT, and reduced hemoglobin levels at hospital admission. Patients were divided into two groups: E0, who did not receive Emicizumab administration at admission, and E1, who were treated with Emicizumab since their first bleeding episode.

Table 3 Literature cases characteristics at ED admission

Patients' characteristics at ED admission
Number of cases		24
Age (y)		72.5 [15–93]
Male (%)		18 (75.0%)
Hemoglobin (g/dL)		6.8 [2.6–8.7]
Inhibitor titer (UB/mL)		136 [4–627]
Bleeds	Ecchymosis	2
	Muscular	12
	Articular	0
	Gastrointestinal	4
	Gynecological	1
	Hematuria	1
	Chronic	2
Days at discontinuation of bypassing agents		Not evaluable for lack of data

Patient-Level Outcomes Analysis

Among the 24 patients evaluated in the included studies, 8 patients (33.3%) received Emicizumab at admission to the Emergency Department (E1 group),[26] [27] [28] [29] [30] [31] [32] [33] and 16 patients (66.7%) received Emicizumab in the second phase of the ward admission as a rescue treatment (E0 group). The most common Emicizumab schedule was 3 mg/kg weekly administration for 4 weeks, followed by 1.5 mg/kg weekly for 2 to 4 weeks ([Table 2]). During hospitalization, the E0 group (16 patients) received immunosuppressive therapy: 11 patients (68.75%) were treated with CCS, 2 (12.5%) with CCX, and 3 (18.75%) received Rituximab. For seven patients[27] [33] [34] [35] [36] [37] [38] inhibitor titer was evaluated after the immunosuppressive drugs, with a mean reduction of −147.7 ± 214.7 BU/mL (Δ = − 79.7%). Among these patients, one was discharged[39] (6.25%), while nine experienced bleeding recurrence (56.3%), six of them muscular bleedings (37.5%),[27] [34] [37] [38] [40] [42] and required further administration of prFVIII and rFVIIa. Two patients (12.5%)[36] [37] died during hospitalization. The remaining 13 patients (81.3%) were admitted again to wards and received Emicizumab. The overall duration of management of these patients was 39 (IQR: 12–252) days. In the E1 group, six patients (75%) received CCS, four (50%) Rituximab, and two (25%) CCX with inhibitor titer reduction of −78.5 ± 18.5 BU/mL (Δ = − 31.7%), and no new bleeding episodes were reported since Emicizumab was initiated. One of these patients (12.5%) experienced atrial fibrillation and acute renal failure complicated by sepsis[43] and died 15 days after admission. The overall duration of management of these patients was 23.5 (IQR: 8–22) days on the ward. The new onset bleeding rate in the E1 group was significantly lower (0%) compared to the E0 group (56.3%). Hospitalization duration was shorter in E1 patients, 23.5 (IQR: 8–22), versus E0 patients, 39 (IQR: 12–252). Bleeding-related mortality was 0% in the E1 group versus 12.5% (two patients) in the E0 group. No thrombotic events were reported in the two groups.

Discussion

This study presents both a systematic review of the literature and a real-world case series evaluating the use of Emicizumab in the bleeding prevention of patients with AHA. Given the rarity of AHA and the limited number of randomized trials currently available, our focus was restricted to real-world data from case reports and case series, which provide granular insights into patients' management and outcomes not always captured in larger studies.

To our knowledge, recent systematic reviews conducted by Pasca et al and Ikbel et al were carried out without a patient-level outcome analysis,[44] [45], which we report in our study for the 24 cases described. Our findings confirm that early administration of Emicizumab significantly reduces bleeding rates, consistent with the published evidence. By promptly restoring hemostatic balance, Emicizumab minimized the need for repeated bypassing agent administration and enabled earlier hospital discharge. These outcomes are particularly relevant in elderly patients, where comorbidities and frailty increase the risk of complications.[46] In this population, prolonged hospitalization is independently associated with a higher incidence of nosocomial infections, thromboembolic events, and mortality.[47] Although the sample size is limited and precludes definitive conclusions, no thrombotic microangiopathy or thromboembolic events have been reported with Emicizumab monotherapy in AHA patients across our cohort and the available patient-level literature, including elderly and highly comorbid patients. Moreover, the pharmacovigilance signal observed in congenital Hemophilia A cannot be directly extrapolated to AHA, a biologically and clinically distinct setting, so the thrombotic risk should be regarded as a potential concern requiring vigilance, particularly if Emicizumab is combined with aPCC.[48] Therefore, the observed reduction of hospitalization duration with Emicizumab not only improves clinical outcomes but also contributes to lower healthcare resource utilization and treatment costs.[2] [9] In our cohort of five patients, we estimated an average saving of 22 mg of rFVIIa per patient, suggesting that early adjustment of dosing intervals after achieving bleeding control can significantly reduce overall drug consumption without compromising clinical efficacy. In this context, thromboembolic risk should be interpreted within a multifactorial framework. While bypassing agents such as rFVIIa and aPCC have been linked to thrombotic events, especially in elderly and multimorbid patients, and according to Emicizumab-pharmacovigilance registries data,[41] [49] the overall incidence reported in the literature appears low and derives largely from heterogeneous real-world series.[2] [9] Emicizumab may mitigate the thrombotic risk indirectly, reducing the intensity and duration of exposure to bypassing agents, considering that thromboembolic risk should be systematically assessed and monitored throughout treatment, with caution when combining Emicizumab with high-dose/continuous aPCC.

In our systematic review analysis, a single mortality event was recorded in the Emicizumab-treated cohort.[27] However, the cause of death was not attributed to hemorrhagic complications but rather to the development of acute kidney injury and sepsis.[50] Notably, the patient had significant baseline comorbidities, including diabetes mellitus, pulmonary arterial hypertension, and chronic kidney disease. This case underscores the critical influence of underlying comorbidities on prognosis in AHA, even when effective bleeding control is achieved. These findings highlight the need for multidisciplinary care and close monitoring in complex patients.[51] The timing of Emicizumab initiation emerged as a key determinant of clinical outcome. Patients treated during the acute phase, prior to the establishment of immune tolerance, showed rapid bleeding control and no recurrence during hospitalization. Notably, despite the off-label context, which in routine practice might delay access, Emicizumab was initiated at diagnosis or shortly after admission from the emergency department in all our patients. This underscores both the feasibility and the potential clinical benefit of an upfront hemostatic strategy in AHA. Our clinical data mirrored this trend, with early Emicizumab therapy resulting in adequate hemostatic control, effective prevention of bleeding episodes, withdrawal of bypassing agents, without thrombotic or adverse events throughout follow-up. The lack of FVIII normalization is related to the ongoing follow-up.

In our postpartum case (C1), bleeding control was a primary goal for multiple reasons: to allow early discharge, prevent infectious complications, and facilitate maternal-infant bonding, including timely initiation of breastfeeding.[52] [53] [54] [55] The latter may contribute to enhanced oxytocin secretion and improved maternal haemostasis.[55] Although the patient was unable to breastfeed initially due to hemorrhagic symptoms, Emicizumab allowed for a stable recovery and discharge to home care.

In elderly patients with multiple comorbidities (cases C2, C3, and C5), early Emicizumab use provided two major benefits: rapid control of bleeding, thereby limiting exposure to bypassing agents with prothrombotic potential, and a substantial reduction in hospitalization duration. Maintenance of stable hemoglobin levels was also clinically relevant; one patient experienced a supraventricular arrhythmic event secondary to acute anemia. Such complications reinforce the notion that effective bleeding control directly impacts cardiac and systemic stability in fragile patients. Mortality in AHA among elderly individuals has been reported to exceed 20 to 30%, largely due to bleeding complications and treatment-related adverse effects.[2] [9]

These findings support a shift from the traditional sequential model prioritizing immunosuppressive therapy before initiating hemostatic treatment toward an integrated approach in which bleeding control is addressed immediately using Emicizumab, particularly in patients at high risk of morbidity.[19]

Pezeshkpoor et al suggest that immunogenicity to Emicizumab should be explicitly acknowledged in AHA, even if anti-drug antibodies (ADA) are rare; when detected, they are most often nonneutralizing and not associated with clinically meaningful complications, documented in one AHA patient[56] with no neutralizing activity. Careful clinical and laboratory surveillance is warranted: monitoring for unexpected bleeding, recurrence of aPTT prolongation, or attenuated pharmacodynamic response may help promptly identify the exceptional patient in whom ADAs have functional relevance.

This study has several limitations. First, the small sample size reflects both the rarity of AHA and the recent off-label adoption of Emicizumab in this clinical context. Although our findings are consistent with those reported in the literature, the generalizability of the results should be interpreted with caution due to substantial heterogeneity in patient characteristics, treatment regimens, and follow-up durations. However, unlike previous reports, our report includes a patient-level outcome analysis, allowing for a more detailed evaluation of efficacy and safety across individual cases and enhancing the clinical relevance of our observations. Second, follow-up duration varied among patients and may not fully capture late-emerging adverse events, including delayed thrombotic complications or inhibitor recurrence. To our knowledge, there are no studies that assess the noninferiority of Emicizumab compared to rFVIIa agents, but future studies could investigate this aspect. Finally, although our systematic review provides supportive evidence, the heterogeneity in study designs, patient characteristics, and Emicizumab dosing regimens among published reports limits the ability to draw definitive conclusions.

Despite these limitations, our findings have important clinical implications. The early use of Emicizumab in AHA appears to offer a safe and effective therapeutic option for controlling bleeding, even in the presence of active high-titer inhibitors. This approach could be particularly beneficial in high-risk populations such as postpartum women or elderly patients with multiple comorbidities, where traditional treatment strategies are often associated with increased side effects.

Conclusion

The inclusion of Emicizumab into clinical algorithms may help reduce transfusion requirements, exposure to bypassing agents, and duration of hospitalization, while potentially lowering the risk of infection and cardiac complications. Clinicians should consider early Emicizumab prophylaxis not merely as a rescue therapy, but as a proactive component of a comprehensive, patient-centered strategy for the management of AHA. Future studies should aim to define optimal dosing strategies, long-term safety, and the role of Emicizumab in standardized treatment algorithms for AHA. Until then, real-world data continue to build up a strong rationale for early Emicizumab incorporation as a cornerstone in the management of AHA.

Conflict of Interest

None declared.

Authors' Contributions

I.C., C.D.L., A.T., and M.D.M.: conception and design of the study. A.G., C.C., E.C., G.D.E., P.C., and R.R.: acquisition of data. I.C. and C.D.L. analysis and interpretation of data. I.C., C.D.L., and C.M.: drafting the article. A.T. and M.D.M.: revising it critically for important intellectual content. All authors approved the final version to be submitted.

Declaration of GenAI Use

During the preparation of this article, the authors used ChatGPT (OpenAI, GPT-4o, July 2025) to assist in improving the language, structure, and clarity of the text. The AI was used exclusively for language polishing and editorial refinement. No content was generated without human supervision. All outputs were carefully reviewed, edited, and validated by the authors, who take full responsibility for the integrity and accuracy of the final article.

^* These authors contributed equally to this article.

• References

• 1 Mingot-Castellano ME, Rodríguez-Martorell FJ, Nuñez-Vázquez RJ, Marco P. Acquired haemophilia A: a review of what we know. J Blood Med 2022; 13: 691-710
• 2 Knoebl P, Marco P, Baudo F. et al; EACH2 Registry Contributors. Demographic and clinical data in acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2). J Thromb Haemost 2012; 10 (04) 622-631
• 3 Lehoczki A, Fekete M, Mikala G, Bodó I. Acquired hemophilia A as a disease of the elderly: a comprehensive review of epidemiology, pathogenesis, and novel therapy. Geroscience 2025; 47 (01) 503-514
• 4 Dewarrat N, Gavillet M, Angelillo-Scherrer A. et al. Acquired haemophilia A in the postpartum and risk of relapse in subsequent pregnancies: a systematic literature review. Haemophilia 2021; 27 (02) 199-210
• 5 Mameli A, Marongiu F, Fenu L. et al. Role of the hemostasis and thrombosis unit in the management of patients with acquired hemophilia A. Turk J Haematol 2024; 41 (04) 264-270
• 6 Marino R. Acquired hemophilia A: bleeding pattern and hemostatic therapeutic strategies. Medicina (Kaunas) 2023; 59 (10) 1739
• 7 Poston J, Kruse-Jarres R. The role of emicizumab in acquired hemophilia A. Hematology (Am Soc Hematol Educ Program) 2023; 2023 (01) 24-30
• 8 Huth-Kühne A, Baudo F, Collins P. et al. International recommendations on the diagnosis and treatment of patients with acquired hemophilia A. Haematologica 2009; 94 (04) 566-575
• 9 Collins P, Baudo F, Huth-Kühne A. et al. Consensus recommendations for the diagnosis and treatment of acquired hemophilia A. BMC Res Notes 2010; 3: 161
• 10 Tiede A, Collins P, Knoebl P. et al. International recommendations on the diagnosis and treatment of acquired hemophilia A. Haematologica 2020; 105 (07) 1791-1801
• 11 WCollins P, Chalmers E, Hart D. et al; United Kingdom Haemophilia Centre Doctors' Organization. Diagnosis and management of acquired coagulation inhibitors: a guideline from UKHCDO. Br J Haematol 2013; 162 (06) 758-773
• 12 Coppola A, Franchini M, Tripodi A. et al; ad hoc Working Group (Appendix 1). Acquired haemophilia A: Italian Consensus Recommendations on diagnosis, general management and treatment of bleeding. Blood Transfus 2022; 20 (03) 245-262
• 13 Zanon E. Acquired hemophilia A: an update on the etiopathogenesis, diagnosis, and treatment. Diagnostics (Basel) 2023; 13 (03) 420
• 14 Erdoes G, Goobie SM, Haas T, Koster A, Levy JH, Steiner ME. Perioperative considerations in the paediatric patient with congenital and acquired coagulopathy. BJA Open 2024; 12: 100310
• 15 Tiede A, Klamroth R, Scharf RE. et al. Prognostic factors for remission of and survival in acquired hemophilia A (AHA): results from the GTH-AH 01/2010 study. Blood 2015; 125 (07) 1091-1097
• 16 Shima M, Suzuki N, Nishikii H. et al. Final analysis results from the AGEHA study: emicizumab prophylaxis for acquired hemophilia A with or without immunosuppressive therapy. Thromb Haemost 2025; 125 (05) 449-459
• 17 Iarossi M, Hermans C. Emicizumab as first-line therapy in acquired hemophilia A. Res Pract Thromb Haemost 2024; 8 (04) 102438
• 18 Kizilocak H, Marquez-Casas E, Malvar J, Young G. Safety of FEIBA and emicizumab (SAFE): Dose escalation study evaluating the safety of in vivo administration of activated prothrombin complex concentrate in haemophilia A patients on emicizumab. Haemophilia 2023; 29 (01) 100-105
• 19 Shima M, Amano K, Ogawa Y. et al. A prospective, multicenter, open-label phase III study of emicizumab prophylaxis in patients with acquired hemophilia A. J Thromb Haemost 2023; 21 (03) 534-545
• 20 Tiede A, Hart C, Knöbl P. et al. Emicizumab prophylaxis in patients with acquired haemophilia A (GTH-AHA-EMI): an open-label, single-arm, multicentre, phase 2 study. Lancet Haematol 2023; 10 (11) e913-e921
• 21 Hart C, Klamroth R, Sachs UJ. et al. Emicizumab versus immunosuppressive therapy for the management of acquired hemophilia A. J Thromb Haemost 2024; 22 (10) 2692-2701
• 22 Shima M, Hanabusa H, Taki M. et al. Long-term safety and efficacy of emicizumab in a phase 1/2 study in patients with hemophilia A with or without inhibitors. Blood Adv 2017; 1 (22) 1891-1899
• 23 Bowyer A, Kitchen S, Maclean R. Effects of emicizumab on APTT, one-stage and chromogenic assays of factor VIII in artificially spiked plasma and in samples from haemophilia A patients with inhibitors. Haemophilia 2020; 26 (03) 536-542
• 24 Page MJ, McKenzie JE, Bossuyt PM. et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021; 372 (71) n71
• 25 (AIFA). AIdF. Allegato 1: Scheda tecnica e condizioni di impiego ai sensi della L. 648/96. Accessed on March 11, 2024, at: https://www.aifa.gov.it/documents/20142/1873590/allegato-1_emicizumab.pdf2023
• 26 Hansenne A, Hermans C. Emicizumab in acquired haemophilia A: about two clinical cases and literature review. Ther Adv Hematol 2021; 12: 20 406207211038193
• 27 Yates SG, Webb CB, Sarode R, Ibrahim IF, Shen YP. Utilization of emicizumab in acquired hemophilia A: a case report. Transfus Apher Sci 2022; 61 (06) 103457
• 28 Al-Banaa K, Alhillan A, Hawa F. et al. Emicizumab use in treatment of acquired hemophilia A: a case report. Am J Case Rep 2019; 20: 1046-1048
• 29 Ahmed F, Kasianchyk M, Moreno A, Chang S, Maharaj S. Emicizumab for acquired hemophilia A: report of two cases and dosing strategies. eJHaem 2024; 5 (02) 387-391
• 30 Jena SS, Meher D, Dhankar N. Unforeseen encounter of acquired hemophilia A in a preoperative case of periampullary carcinoma: a case report. Int J Surg Case Rep 2021; 79: 146-149
• 31 Ocaña Gómez MA, Esquivel Negrín J, Ríos De Paz M, De Dios García MD. [Translated article] Utilization of emicizumab in the treatment of a case of acquired haemophilia A. Farm Hosp 2024; 48 (01) T45-T47
• 32 Ragavan N, Jayaraman D, Suman FR, Pandian N, Scott JX. Successful management of an adolescent male with acquired hemophilia-A with intracranial bleeding using emicizumab. Pediatr Blood Cancer 2024; 71 (08) e31083
• 33 Ganslmeier M, Pekrul I, Heinrich DA, Angstwurm M, Spannagl M, Möhnle P. Persistent inhibitor in acquired haemophilia A: a case for emicizumab?. Haemophilia 2021; 27 (04) e502-e505
• 34 Möhnle P, Pekrul I, Spannagl M, Sturm A, Singh D, Dechant C. Emicizumab in the treatment of acquired haemophilia: a case report. Transfus Med Hemother 2019; 46 (02) 121-123
• 35 Chung SY, Shen JG, Sticco KL. Acquired haemophilia A: successful treatment of a patient using upfront immunosuppressive therapy and haemostatic agents. BMJ Case Rep 2021; 14 (06) e242876
• 36 Tiede A, Kemkes-Matthes B, Knöbl P. Should emicizumab be used in patients with acquired hemophilia A?. J Thromb Haemost 2021; 19 (03) 637-644
• 37 Hayden A, Candelario N, Moyer G. Recombinant porcine factor VIII in acquired hemophilia A: experience from two patients and literature review. Res Pract Thromb Haemost 2022; 6 (02) e12688
• 38 Al-Banaa K, Gallastegui-Crestani N, von Drygalski A. Anticoagulation for stroke prevention after restoration of haemostasis with emicizumab in acquired haemophilia A. Eur J Case Rep Intern Med 2021; 8 (11) 002984
• 39 Dane KE, Lindsley JP, Streiff MB, Moliterno AR, Khalid MK, Shanbhag S. Successful use of emicizumab in a patient with refractory acquired hemophilia A and acute coronary syndrome requiring percutaneous coronary intervention. Res Pract Thromb Haemost 2019; 3 (03) 420-423
• 40 Gelbenegger G, Traby L, Rahimi N, Knöbl P. Management of acquired haemophilia A in severe COVID-19: haemostatic bridging with emicizumab to keep the balance between bleeding and thrombosis. Br J Clin Pharmacol 2023; 89 (02) 908-913
• 41 Abbattista M, Ciavarella A, Noone D, Peyvandi F. Hemorrhagic and thrombotic adverse events associated with emicizumab and extended half-life factor VIII replacement drugs: EudraVigilance data of 2021. J Thromb Haemost 2023; 21 (03) 546-552
• 42 Hess KJ, Patel P, Joshi AM, Kotkiewicz A. Utilization of emicizumab in acquired factor VIII deficiency. Am J Case Rep 2020; 21: e922326
• 43 Happaerts M, Vanassche T. Acquired hemophilia following COVID-19 vaccination: case report and review of literature. Res Pract Thromb Haemost 2022; 6 (06) e12785
• 44 Pasca S, Zanon E, Mannucci PM, Peyvandi F. Emicizumab in acquired hemophilia A: pros and cons of a new approach to the prevention and treatment of bleeding. Blood Transfus 2023; 21 (06) 549-556
• 45 Ikbel G, Hela B, Yassine KM, Hamida K, Kamel BS. Outcomes of emicizumab in acquired hemophilia patients: a systematic review. Clin Appl Thromb Hemost 2024; 30: 10 760296241298661
• 46 Matsuo A, Takamori A, Kawaura F. et al. Risk for prolonged hospitalization and mortality in aged community acquired pneumonia patients: a retrospective study in Japan. J Clin Biochem Nutr 2020; 67 (03) 302-306
• 47 Di Minno MN, Di Minno G, Di Capua M, Cerbone AM, Coppola A. Cost of care of haemophilia with inhibitors. Haemophilia 2010; 16 (01) e190-e201
• 48 Sidonio Jr RF, Young G, Escuriola Ettingshausen C. et al. Activated prothrombin complex concentrate in patients receiving emicizumab prophylaxis: from evidence to clinical practice. Res Pract Thromb Haemost 2025; 9 (04) 102926
• 49 Li T, Huang D, Jiang Y. A real-world pharmacovigilance analysis of the FDA adverse event reporting system database for emicizumab. Thromb Res 2025; 254: 109422
• 50 Qian J, Kuang L, Chen F, Liu X, Che L. Prognosis and management of new-onset atrial fibrillation in critically ill patients. BMC Cardiovasc Disord 2021; 21 (01) 231
• 51 Singh M, Stewart R, White H. Importance of frailty in patients with cardiovascular disease. Eur Heart J 2014; 35 (26) 1726-1731
• 52 Brites-Lagos C, Maranhão C, Szumilewicz A, Santos-Rocha R. Development and validation of the physical exercise program “active mums” for postpartum recovery: application of the CReDECI-2 guidelines. BMC Pregnancy Childbirth 2024; 24 (01) 378
• 53 Parriott AM, Arah OA. Patient volumes and pre- and postdischarge postpartum infection: a retrospective cohort study. Am J Infect Control 2016; 44 (01) 30-35
• 54 Smith ER, Locks LM, Manji KP. et al. Delayed breastfeeding initiation is associated with infant morbidity. J Pediatr 2017; 191: 57-62.e2
• 55 Xia M, Luo J, Wang J, Liang Y. Association between breastfeeding and postpartum depression: a meta-analysis. J Affect Disord 2022; 308: 512-519
• 56 Pezeshkpoor B, Sereda N, Becker-Gotot J. et al. Comprehensive evaluation of anti-emicizumab antibodies in acquired hemophilia A: a detailed case study and methodological evaluation. J Thromb Haemost 2025; 23 (01) 85-96

Publication History

Received: 28 August 2025

Accepted: 13 January 2026

Accepted Manuscript online:
14 January 2026

Article published online:
28 January 2026