Outcomes of Emicizumab in Acquired Hemophilia Patients: A Systematic Review

Abstract

Background

Emicizumab, a bispecific factor VIII mimetic antibody, was approved in 2018 for bleeding prophylaxis in congenital hemophilia A with or without inhibitors. Since then, several case reports and case series have described the off-label use of emicizumab in acquired hemophilia A (AHA), and data from two clinical trials were recently published (AGEHA, GTH-AHA-EMI).

Objectives

To describe the reported data on the outcomes of emicizumab, highlighting its benefit/risk profile in treatment.

Methods

We conducted a literature search in PubMed, Scopus, Cochrane, and Google Scholar up to August 2024, including all scientific articles reporting clinical outcomes of emicizumab use in patients with AHA.

Results

Thirty-two studies were included in the final review, covering a total of 171 AHA patients. The majority started emicizumab for active bleeding management and prophylaxis with various regimens. Follow-up duration and remission criteria varied. Two clinical trials supported the use of emicizumab for bleeding prophylaxis with a new dosing regimen and completion criteria. Bleeding was well managed in all cases, with no major recurrent bleeds. Some adverse events were reported : 3 cases of deep venous thrombosis, 2 cases of stroke, and 2 cases of anti-emicizumab drug antibodies developing in patients with thromboembolic risk factors.

Conclusions

Based on published data, emicizumab appears to be effective in bleeding management and prophylaxis in AHA patients, with a favorable benefit/risk profile.

Introduction

Acquired hemophilia A (AHA) is a rare, life-threatening autoimmune bleeding disorder caused by the development of neutralizing autoantibodies against endogenous clotting factor VIII, ¹ with an overall incidence of 1.5 cases per million per year.^2,3 AHA primarily affects older individuals, often with cardiovascular and thromboembolism comorbidities, leading to a serious condition with a high mortality rate ranging from 8% to 48%.^3,4 Additionally, several risk factors including advanced age, malignancy, FVIII levels below 1%, severe bleeding, and higher corticosteroid doses, significantly increase the incidence of early death.^5,6 Younger women may also be affected during pregnancy or postpartum.^2,7 Many underlying etiologies have been reported, including autoimmune disorders, malignancies, infections, and drugs. However, AHA remains idiopathic in about half of the cases, with no identifiable causes or concomitant factors. ⁸

Management of AHA presents a challenge to achieve bleeding control and inhibitor eradication. Bypassing agents (BPAs) such as activated prothrombin complex concentrate (aPCC) and recombinant activated factor VIIa (rFVIIa) are the first-line conventional hemostatic treatments,^9–13 with a high efficacy rate of 93%. ⁹ Recombinant porcine factor VIII (rpFVIII) is used in for patients without cross-reactivity with an efficacity rate of 70%.^9,11–13 However, these therapies are limited by the need for intravenous infusions, the lengthy period of time required to achieve remission, the risk of thrombotic complications ranging from 0% to 4.8%,^2,10 and the potential development of anti-porcine antibodies when using rpFVIII. ¹⁰

According to AHA guidelines, inhibitor eradication is based on immunosuppressive therapy (IST), with corticosteroids as first-line treatment, either alone or in combination with cyclophosphamide. ¹³ However, achieving remission with IST takes longer and is associated with a high rate of severe side effects, particularly infections, which contribute to an overall mortality rate of up to 16%.^6,14 Given the complexity and challenges of managing AHA, many studies have described the efficacy of emicizumab as a novel hemostatic approach since 2018. Emicizumab is a bispecific humanized recombinant monoclonal antibody that mimics factor VIII (FVIII) cofactor function.^15–17 It binds activated factor IX (FIXa) and factor X (FX) to restore the tenase function mediated by activated FVIII (FVIIIa). ¹⁸ Emicizumab has been widely approved for bleeding prophylaxis in congenital hemophilia A (CHA) with or without inhibitors.^19–21

Due to its mechanism of action, emicizumab has been used off-label as a hemostatic agent in the management of AHA patients in many parts of the world, including Europe and the United States. It was recently approved for AHA in Japan. Several recent studies, mainly case reports and case series, have described the safety and efficacy of emicizumab in AHA patients, along with available results from a clinical trial in Japan (AGEHA) ²² and the final analysis of the German-Austrian GTH-AHA-EMI trial.^23,24 In this context, several considerations require special attention: indications, dosing regimens, follow-up periods, recognition of remission, interference with lab assays, concomitant use of other BPAs, thrombogenicity, adverse events, and particular situations such as surgery and childbirth. In this systematic review, we summarize the literature findings on the topic, focusing on the clinical presentations and outcomes of emicizumab, while highlighting its benefit/risk profile, limitations, and challenges in the management of AHA.

Materials and Methods

Guidelines

We conducted a systematic review on the efficacy of emicizumab as a hemostatic agent in the management of bleeding disorders related to AHA, focusing on clinical settings and outcomes based on all available evidence. The review was performed in accordance with the Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines. The PRISMA checklist is provided in Annex 1.

Search Strategy

The PubMed, Scopus, Cochrane, and Google Scholar databases were searched for publications, with English language as a restriction. The search was conducted using the keywords “acquired haemophilia” OR “acquired haemophilic” OR “acquired hemophilia” OR “acquired haemophiliacs” OR “acquired factor 8 deficiency” linked to “emicizumab” OR “hemlibra,” using Boolean operators AND. The search included studies published up until 12 August 2024.

Eligibility Criteria

Two authors (IG, HB) independently conducted the search and assessed the eligibility of each article. The eligibility criteria were based on the Population, Intervention, Comparator, Outcome, and Study design (PICOS) framework (Table 1).

Table 1.

Eligibility criteria.

		Inclusion criteria	Exclusion criteria
P	Participate	People with acquired hemophilia A	Healthy individuals, patients with other acquired or congenital bleeding diseases
I	Intervention	emicizumab	Physiopathology, immunology
C	Comparison	-	-
O	Outcome	efficacy of emicizumab	-
S	Study	Case report, case series, conference abstract, retrospective study containing patient population >1, clinical trials	Studies without a clinical outcome, review papers, editorials

Quality Assessment

The quality assessment of the studies was performed independently using the Joanna Briggs Institute (JBI) tool for assessing the methodological quality of case reports and case series, and the ROBINS-I tool for non-randomized studies (Annex 2)

Data Extraction

The following data were extracted from all included studies: publication information, patient age and sex, underlying disease, comorbidities, bleeding site, factor VIII levels and inhibitor titer, hemostatic and IST indication, emicizumab regimen (dose, frequency, duration), clinical response, FVIII levels upon emicizumab discontinuation, treatment downtime, time to remission, and adverse effects.

Statistical Analysis

Data are expressed as frequencies, medians, and ranges, as appropriate.

Results

A total of 508 records were identified. After removing duplicates and non-conforming papers, 32 studies including 25 full-text articles and 7 conference abstracts identified through reference checking were assessed for eligibility. The PRISMA flow chart is shown in Figure 1.

Figure 1.

Flow chart of study selection.

Study Characteristics

Given the rarity of the disease, most of the eligible studies were off-label studies conducted between 2019 and 2024 (Table 2). The use of emicizumab in AHA has been reported in 15 case reports, 7 case series from Vienna, 7 abstracts, and 2 clinical trials exploring bleed prevention in AHA. The Japanese AGEHA study combined emicizumab with IST in Cohort 1 (n = 11) and provided data on IST-ineligible patients in Cohort 2 (n = 2). The German-Austrian GTH-AHA-EMI study (N = 47) delayed IST during the initial 12-week efficacy period.

Table 2.

Review of Publications Evaluating the Emicizumab Outcomes in Acquired Hemophilia A with Patients Characteristics.

PublicationReferences type	Age/genderUnderlying disease	comorbidity	Bleeding site	FVIII levelInhibitor title (BU/ml)	Prior hemostatic agent/IST	Emicizumab indications	Dose/frequency	Efficacy	Emicizumab duration therapy	FVIII levels/inhibitor title on Emicizumab disruption	Complete remission/ periode time	Adverse effect
Dane 25 Case report	72/M AID	CAD	hematoma	Undetectable 409	aPCC; rp-FVIII/ Corticosteroids, rituximab, cyclosporine, cyclophos-phamide, azathioprine, bortezomib, mycophenolate, cladribine, tacrolimus	Prophylaxis to planned PCI Allow use of DAPT following DES placement for ACS	Standard Loading And maintenance doses	DAT tolorated without bleeding accident	>5months	NM	NM	None
Escobar 26 Case report	90/M/idiopathic	CAD, AF, AHT, CKD	NM	Undetectable 150.4	NM/ Rituximab, mycophenolate	Recurrent bleeding	Modified protocole : loading dose of 1.5 mg/kg/week for two doses, then maintenance dose of 1.5 mg/kg every 21 days, then increased to 1.5 mg/kg every 14 days	Breakthrough bleed resolved with increased dose to 1.5 mg/kg every 14 days	9 months	10%/NM	NM	NM
Escobar 27 Case report	57/F/idiopathic	NM	NM	NM 6.67	NM	Recurrent bleeding	Standard Loading and maintenance doses	immediate cessation of bleeding episodes	NM	NM	NM	NM
Publication References type	Age/gender Underlying disease	comorbidity	Bleeding site	FVIII level Inhibitor title (BU/ml)	Prior hemostatic agent/IST	Emicizumab indications	Dose/frequency	Efficacy	Emicizumab duration therapy	FVIII levels/inhibitor title on Emicizumab disruption	Complete remission/ periode time	Adverse effect
Knoebel 28 Case series (n = 12)	61/M, idiopathic	IS Infection CAD LD	haematoma, GI, post surgical site bleed	<1% 69	aPCC rFVIIIa rFVII/prednisone, rituximab	Active refractory bleeding	Standard loading and maintenance doses; median number of doses 5 (range, 3-9)	No recurrent bleeding 5 days after the first dose	Median 31 days [15–79]	FVIII:h > 30%/NM	FVIII:h > 50%/NM	Died 45 days after last dose of emicizumab from peritonitis
	51/M idiopathic	adiposity	Cutaneous bleed	<1% 79.4	None/prednisone, rituximab	Active bleeding		No recurrent bleeding	Median 31 days [15–79]	FVIII:h > 30%, NM	FVIII:h > 50%/104 days	None
	62/F, idiopathic	none	Cutaneous bleed, hematoma	3% 3.5	rFVIIa, rFVIII, rp-FVIII/ prednisone, rituximab	Active refractory bleeding		No further bleeding 3 days after first dose	Median 31 days [15–79]	FVIII:h > 30%, NM	(FVIII:b > 50%/403 days	None
	79/F, idiopathic	Infection Adiposity Peripheral arterial disease	Cutaneous bleed, haematoma, post-surgical site bleed	<1% 80.4	aPCC, rFVIIa /prednisone, rituximab	Active refractory bleeding		Bleeding controlled 15 days after first dose	Median 31 days [15–79]	FVIII:h > 30%, NM	(FVIII:b > 50%)/265 days	Minor stroke on day 16 after third dose of emicizumab, associted with rFVIIa used for surgery
	87/M, idiopathic	Diabetis Adiposity malignancy	Cutaneous bleed, haematoma	<1% 17.1	rFVIII, aPCC/rituximab	Prophylaxis NSTEMI on aPCC		bleeding controlled 4 days after first dose	Median 31 days [15–79]	FVIII:h > 30%, NM	(FVIII:b > 50%)/180 days	None
	82/F, idiopathic	Diabetes Adiposity malignancy	Cutaneous bleed, haematoma, post-surgical site bleed	<1% 14.5	rFVIIa/rituximab	Active refractory bleeding		Bleeding controlled 2 days after first dose	Median 31 days [15–79]	FVIII:h > 30%, NM	(FVIII:b > 50%)/120 days	none
	86/F, idiopathic	Arterial fibrillation	Cutaneous bleed, haematoma, post-surgical site bleed	<1% 228.5	rFVIIa/prednisone, rituximab	Active refractory bleeding		Bleeding controlled 4 days after first dose	Median 31 days [15–79]	FVIII:h > 30%, NM	(FVIII:b > 50%)/110 days	None
	79/M, idiopathic	Adiposity Atrial fibrillation Peripheral arterial disease CHD	Cutaneous bleed, haematoma, post-surgical site bleed	5% 3.6	rFVIIa, rFVIII/ Prednisone, rituximab	Active refractory bleeding		Bleeding controlled 3 days after first dose	Median 31 days [15–79]	FVIII:h > 30%, NM	(FVIII:b > 50%)/18 days	None
	67/F, idiopathic	depression	Cutaneous bleed, haematoma	<1% 27.6	rFVIIa/ Prednisone, rituximab	Active refractory bleeding		Bleeding controlled 3 days after first dose	Median 31 days [15–79]	FVIII:h > 30%, NM	(FVIII:b > 50%)/187 days	None
	65/M, idiopathic	DiabetesAdiposityLD	Cutaneous bleed, haematoma	11%8.9	rFVIII/rituximab	Active refractory bleeding		NM	Median 31 days [15–79]	FVIII:h > 30%, NM	(FVIII:b > 50%)/54 days	None
	69/M, idiopathic	AFLD	Mucocutaneous bleed, haematoma, haematuria, joint bleed, post-surgical site bleed	<1%2000	rFVIIa/ Prednisone, rituximab	Active refractory bleeding		Bleeding controlled 3 days after first dose	Median 31 days [15–79]	FVIII:h > 30%, NM	(FVIII:b > 50%)/>175 days	None
	79/F, idiopathic	Malignancy depression	Cutaneous bleed, haematoma	1%8.8	rFVIIa/ Prednisone, rituximab	Active refractory bleeding		Bleeding controlled 3 days after first dose	Median 31 days [15–79]	FVIII:h > 30, NM	(FVIII:b > 50%)/27 days	None
Jena 29 Case report	78/M/cancer	AHT	Cutaneous bleed, GI bleed	2.5%34	rFVIII, aPCC/ Steroids, cyclophosphamide	Active refractory bleeding	NM	No further bleeding	NM	NM	NM	NM
Chen 30 Case series (n = 8)	85/F, idiopathic	NM	Cutaneous bleed, haematoma	3%40	rFVIIa/ rituximab	Active refractory bleeding	standard loading and maintenance dose of 3 mg/kg /2 weeks	No further bleeding	3 months	NM	NM	None
	78/MAID	NM	Cutaneous bleed, haematoma	<1%33	None/rituximab, prednisone	Active refractory bleeding	standard loading dose	No further bleeding	4 weeks	29%/NM (71 days after starting emicizumab)	NM	None
	85/F, idiopathic	NM	Cutaneous bleed, haematoma	2%9.5	rFVIIa/ rituximab, prednisone	Active refractory bleeding	standard loading dose	No further bleeding	4 weeks	86%/NM (91 days after starting emicizumab)	NM	None
	69/F, idiopathic	NM	Post-surgical site bleed	<1%107.5	None/ rituximab	Active refractory bleeding	standard loading dose	No further bleeding	4 weeks	NM	NM	None
	87/M, idiopathic	NM	hematuria	1%9.5	rFVIIa/ rituximab	Active refractory bleeding	standard loading dose	recurrent haematuria required embolisation	4 weeks	NM	NM	None
Publication References type	Age/gender Underlying disease	comorbidity	Bleeding site	FVIII level Inhibitor title (BU/ml)	Prior hemostatic agent/IST	Emicizumab indications	Dose/frequency	Efficacy	Emicizumab duration therapy	FVIII levels/inhibitor title on Emicizumab disruption	Complete remission/ periode time	Adverse effect
	93/F, idiopathic	NM	Cutaneous bleed	1%9.2	none/ rituximab, prednisone	Active refractory bleeding	standard loading dose	No further bleeding	4 weeks	NM	NM	None
	54/M, malignancy	NM	Haematoma, bronchial artery bleed	2%10	rFVIIa/ rituximab	Active refractory bleeding	standard loading dose	No further bleeding	4 weeks	NM	NM	None
	47/F, malignancy	NM	Cutaneous bleed, epistaxis	9%26	none/ rituximab, prednisone	Active refractory bleeding	standard loading dose	No further bleeding	4 weeks	NM	NM	None
El banna 31 Case report	87/F/idiopathic	AF	GI bleed, chest and pelvic hematomas	<1%>100	aPCC 50 units/kg every 12 h for 2 weeks./ none	Bleeding prophylaxis	Standard loading and maintenance dose	No further bleeding	>2 months	NM	NM	None
Ganslmeier 32 Case report	59/M/idiopathic	COPD, T2DM, obesity, AHT	retroperitoneal haemorrhage	Undetectable136	rFVIIa, ac tranexamique/prednisone, cyclophosphamide	Recurrent bleeding	Loading dose unspecifiedMaintenance dose 2.7 mg/kg /4weeks	No further bleeding/7 days	>10 months	NM	NM	Eczema in the neck with the second injection
Hess 33 Case report	91/M/idiopathic	AHT, benign prostatic hyperplasia, AF, mitral valve replacement	Hematuria, psoas hematomas	<1%44	rFVII 90 μg/kg/prednisone, cyclophosphamide	Recurrent bleeding	Standard loading then maintenance dose of 1.5 mg/kg every 2 weeks.	No further bleeding	6 months	86/1.9	NM	none
Publication References type	Age/gender Underlying disease	comorbidity	Bleeding site	FVIII level Inhibitor title (BU/ml)	Prior hemostatic agent/IST	Emicizumab indications	Dose/frequency	Efficacy	Emicizumab duration therapy	FVIII levels/inhibitor title on Emicizumab disruption	Complete remission/ periode time	Adverse effect
Mohnel 34 Case report	83/M/idiopathic	congestive heart failure, AF, CKD, DVT, PE	GI bleed, haematoma, mucocutaneous bleed	<1%97	rFVIII, aPCC, FXIII, and fibrinogen/ prednisolone ; rituximab ; IVIG	Recurrent bleeding	modified dose at 3 mg/kg for first dose, 1.5 mg/kg for second dose 1 week later and 1.5 mg/kg for third dose at 20 days post-first dose	No further bleeding	20 days	10%/ 2 (35 days after last dose)	NM	Died 36 days after last dose of emicizumab due to an arrhythmic event
Flommersfeld 35 Case report	21/FAID	NM	post chirurgical bleed, hematoma	<0.25%40	rFVII/ Dexamethasone ; cyclophosphamide, ofatumumab, bortezomib and daratumumab ; ITT with IVIG and high-dose FVIII substitution	Recurrent bleeding	Standard loading and maintenace doses	led after tooth extraction requiring rFVIIa for 7 days	<3months	NM	NM	NM
Chen 36 Case series (n = 4)	57/F, idiopathic	T2DMHyperlipidaemia, obsesity, hypothyroidism	hematoma	<1%10	rpFVIII ; rFVIIa/ Rituximab ; cyclophosphamide	Recurrent bleed	Standard loading and maintenance doses	Traumatic elbow bleed resolved with hemostatic concentrate factor	61 days	normolized FVIII and eradication of inhibitor	CR/NM	none
	67/M, idiopathic	T2DM, CAD, AHT, gout, MGUS, dementia	Haematoma, GI bleed, epistaxis	<1%162	rpFVIII/ rituximab	Recurrent bleed	Standard loading and maintenance doses	No reccurent bleed	216 days	normolized FVIII and eradication of inhibitor	CR /NM	none
	74/M, idiopathic	T2DM, COPD, diverticulitis	Haemarthrosis, haematoma	1%85	rpFVIII/ rituximab	Recurrent bleed	Standard loading and maintenance doses	No reccurent bleed	102 days	normolized FVIII and eradication of inhibitor	CR/NM	none
	68/M, idiopathi	CAS, AHT	Hematoma	<1%9	rpFVIII/prednisone Rituximab ; cyclophosphamide	Recurrent bleed	Standard loading and maintenance doses	No reccurent bleed	>211days	Still on emicizumab	Still on emicizumab	none
Chen 37 Case series (n = 11)	84/Fidiopathic	NM	Ecchymosis, hematoma	3%40	None/rituximab	Active refractory bleeding	3 mg/kg weekly for 4 weeks then3 mg/kg every 2 weeks to complete 3 months	No reccurent bleed	4 month	FVIII activity to > 50% with a negative inhibitor	CR/NM	none
	77/Midiopathic	Rheumatoid arthritis, AF	Traumatic hematoma hematuria	<1%33	rFVIIa/rituximab, prednisone	Active refractory bleeding	Standard loading dose	No reccurent bleed	1 month	FVIII activity to > 50% with a negative inhibitor	CR/NM	none
	84/Fidiopathic	Factor V Leiden	ecchymoses, abdominal hematomarequiring artery embolization	2%9.5	rFVIIa/rituximab, prednisone,	Active refractory bleeding	Standard loading dose	No reccurent bleed	1 month	FVIII activity to > 50% with a negative inhibitor test	CR/NM	none
	68/Fmalignancy	Recurrent liposarcoma	post-procedual bleeding	<1%107.5	rFVIIa/rituximab	Active refractory bleeding	Standard loading dose	No reccurent bleed	1 month	FVIII activity to > 50% with a negative inhibitor	CR/NM	none
	87/Midiopathic	Benign prostatic hyperplasia	spontaneous hematuria requiring prostate artery embolization.	1%9.5	rFVIIa/rituximab	Active refractory bleeding	Standard loading dose	No reccurent bleed	1 month	FVIII activity > 50% but with detectable inhibitor	PR /NM	none
	93/Fidiopathic	AF	traumatic ecchymoses	<1%9.2	None/rituximab	Active refractory bleeding	Standard loading dose	No reccurent bleed	1 month	FVIII activity to > 50% with a negative inhibitor	CR/NM	none
	54/Mmalignancy	Tonsillar squamous cell carcinoma	hematoma hemoptysis.	2%10	rFVIIa/ritixumab,	Active refractory bleeding	Standard loading dose	No reccurent bleed	1 month	FVIII activity > 50% but with detectable inhibitor	PR/NM	none
	47/Fmalignancy	acute myeloid leukemia	hematoma ecchymoses requiring vascular embolization	9%26	None/rituximab, prednisone	Active refractory bleeding	Standard loading dose	No reccurent bleed	2 weeks (insurrance approval)	FVIII activity to > 50% with a negative inhibitor	CR/NM	none
	70/Fidiopathic	venous thromboembolism (FVL+)	Post-surgery hematoma requiring artery embolization	6%47	Acide tranexamique /rituximab	Active refractory bleeding	Standard loading dose	No reccurent bleed	1 month	FVIII activity to > 50% with a negative inhibitor	CR/NM	none
	72/Midiopathic	NM	hematuria hemarthrosis	<1%103	rFVIIa/rituximab	Active refractory bleeding	Standard loading dose	Rebleeding occurred on day 24 after initiating emicizumab	1 month	NM	Refractory disease	none
	81/MCovid-19	COVID-19 vaccination	Traumatic ecchymoses	<1%84	None/rituximab	Active refractory bleeding	Standard loading dose	No reccurent bleed	1 month	FVIII activity to > 50% with a negative inhibitor test in the absence of haemostatic and IST	CR/NM	none
Publication References type	Age/gender Underlying disease	comorbidity	Bleeding site	FVIII level Inhibitor title (BU/ml)	Prior hemostatic agent/IST	Emicizumab indications	Dose/frequency	Efficacy	Emicizumab duration therapy	FVIII levels/inhibitor title on Emicizumab disruption	Complete remission/ periode time	Adverse effect
Poston 38 Case series (n = 24)	Median 73[34–87]M > FAIDCancerPeripartum	Metabolic syndromeVascular diseasePrior venous thrombosis	HematuriaHemarthrosisRetroperitonealGI	<1% (1%-28%)54 (0.8–749)	rFVII, FEIBA, recombinant porcine/glycocorticoids (86%), cyclophosphamide (17%), mycophenolate mofetil (13%), daratumumab (4%).	Bleeding prophylaxis	Standard loading and maintenance doses	Bleeding resolvedRecurrent bleeding (hematuria, GI)	13 days (1–217)	NM	NM	DVT (1 case) 2 Death not attribuated to emicizumab
Happaerts 39 Case report	75/MMAI, Covid-19 vaccine (astrazeneca)	CKD, AHT, hypertension, complicated IDDM	multiple hematomas, hemorrhagic bullous pemphigoid, and GI ulcer	Undetectable 135	rFVIIa/ rituximab, methylprednisolone	Active bleeding, started concurrent with rFVII	3 mg/kg, 2gifts	No further bleeding events	15 days	13%/75	NM	death unrelated to emicizumab
Karthick 40 Case report	84/MCovid	AHT	Extensive ecchymotic patches	<1%1.8	FFP, rFVIIa, FEIBA/Azathioprine, Rituximab	Active refractory bleeding	One dose (210 mg)	No further bleeding	1 day	NM	NM	Death related to cardiac arrest after covid treatement
Publication References type	Age/gender Underlying disease	comorbidity	Bleeding site	FVIII level Inhibitor title (BU/ml)	Prior hemostatic agent/IST	Emicizumab indications	Dose/frequency	Efficacy	Emicizumab duration therapy	FVIII levels/inhibitor title on Emicizumab disruption	Complete remission/ periode time	Adverse effect
Nishiki 41 2 cases report	82/F/NM59/F/NM	DiabetesNM	NMNM	<1%58<1%33	rFVIIaaPCC	Patient ineligible for ISTPatient ineligible for IST	6 mg/kg on Day 1 and 3 mg/kg on Day 2 followed by 1.5 mg/kg weekly from Day 86 mg/kg on Day 1 and 3 mg/kg on Day 2 followed by 1.5 mg/kg weekly from Day 8	No further bleedingNo further bleeding	7.1 weeks16.3 weeks	NMNM	FVIII > 50% on day 64FVIII > 50% on day 116	RashRash
Hansenne 42 2 cases report	73/MIdiopathic93/MCancer	gout, AHT, chronic alcohol consumptionprostatic adenocarcinoma, AHT	Hematomashematomas	<1%15.21%11	rFVIIa / methylprednisolone, rituximab, cyclosporinenone/methylprednisolone, rituximab	ProphylaxisActive bleeding	Standard loading dose then 6 mg/kg onceStandard loading and maintenance doses	No recurrent bleedingNo recurrent bleeding	NMNM	NM63%	NMNM	Nonenone
Hayden 43 Case report	90/Midiopathic	NM	hematoma	<1%3315	rFVIIa/prednisone, ritixumab	Active refractory bleeding	Standard loading dose then at 1.5 mg/kg every 3 weeks	No recurrent bleeding	NM	29%	NM	none
Gelbenegger 44 Case report	75/MCovid-19	myocardial infarction with coronary stenting, AHT, hyperlipidaemia, infrarenal aortic aneurysm	hematoma	<1%41.8	rFVII/prednisone	Bleeding prophylaxis	3 mg/kg weekly for the first 3 weeks, thereafter with 1.5 mg/kg every 2–4 weeks	No further bleeding 4 days after the first injection	105 days	FVIII : h : 10–30%	CR : FVIII : b > 50% negative inhibitor, no active bleeding after stopping any haemostatic drug for >24 h	none
Kaunchale 45 Case report	60/M/NM	T2DM, asthma,	Extensive bruising	1.3%8	FEIBA/steroid	Bleeding prophylaxis	1.5 mg/Kg (one dose)	No further bleeding	1 day	NM	NM	none
Yates 46 Case report	83/M/NM	AF, DITInfection AHT, LGLPD	Spontaneous ecchmosis,Abdominal hematoma	<1%197	rFVIIa, tranexamic acid, aPCC, /prednisone, cyclophosphamide, rituximab	Bleeding prophylaxis	Loading dose 1.5 mg/kg	Recurrent bleeding 5 days after emicizumab initiation needed rFVIIa	224 days	34%0.6	NM	none
Shima et al 23 Clinical Trial (n = 11)	6 M/6F/median age 76 (50–92)	AID malignancies.	NM	1 (<0.8–36.6) 40.5 (1–149)	none/ Prednisolone in all with cyclophosphamidein 3and cyclosporine in one	Bleeding prophylaxis	6 mg/kg (day 1), 3 mg/kg (day 2) + 1.5 mg/kg/weak (from day 8)	No further bleeding within 1 week after the first loading dose 5 minor bleeds in 2 patients	44.5 (8–208)	FVIII >50% and no bleeds within 72 h		Asymptomatic DVT related to emicizumabADA
Knoebl et al 47 Case serie (n = 20)	11 M/9F79[ 51–87]	NM	NM	<1%69 (3–2300)	rFVIIa/corticosteroids, rituximab	Active refractory bleeding	Standard loading dose then 1.5 mg/kg/2–4 wks	No further bleeding	115 days	FVIII > 50%	FVIII > 50%	none
Publication References type	Age/gender Underlying disease	comorbidity	Bleeding site	FVIII level Inhibitor title (BU/ml)	Prior hemostatic agent/IST	Emicizumab indications	Dose/frequency	Efficacy	Emicizumab duration therapy	FVIII levels/inhibitor title on Emicizumab disruption	Complete remission/ periode time	Adverse effect
Latef et al 48 Case report	Middle age/F/infection	HIV	NM	NM	BPA /Corticosteroids, cyclophosphamide	Recurrent bleeding	Standard loading and maintenance doses	No further bleeding	NM	NM	NM	none
Crossette et al 49 Case report	F/post-partum	SARS-Covid/vaccination	NM	NM	rpFVIII, BPA/Corticosteroids, azathioprine	Recurrent bleeding	Standard loading and maintenance doses	No further bleeding	NM	NM	NM	none
Al banaaet al 50 Case report	M/79/idiopathic	AF, T2DMRA	Musculoskeletal bleeds, ecchymoses, hematoma	<1%627	FVIIa, rpFVIII/prednisone	Recurrent bleeding	Standard loading and maintenance doses then 1.5 mg/kg/2wk (reduced after DVT and restrat apixaban)	No further bleeding	9 months	NM	NM	DVT
Tiede et al 24 Clinical Trial (n = 47)	23F/24M76 years [66–80]Autoimmune diseases malignancies postpartum	D2TCardiac disordersRenal disordres	NM	1.4 [0.3–5.6] 12.2 [4.1–47.2]	NM/None for the first 11 weeks then 29 received IST	Bleeding prophylaxis	6 and 3 mg/kg on day 1 and 2, 1.5 mg/kg weekly until week 12	No further bleeding in 33 patients7 patients had one bleed, 6 had 2 bleeds and 1 had 3 bleeds	12 weeks and Follow up until 24 weeks	NM	NM	One Stoke4 death not related to emiciczumab
Engelen et al 51 Case serie (n = 7)	NM	NM	hematoma intramuscular bleeding haematuria gastro-intestinal bleeding	0%[0–1]182 BU/mL[ 104–228]	Three patients received activated FVIIa/IS	Bleeding prophylaxis	3 mg/kg for 4 weeks then every 2 weeks until inhibitor regression	No further bleeding	NM	NM	NM	none
Ahmed et al 52 2 cases reports	M/66/idiopathic	Gout, hypertension	Extensive ecchymosis hematoma	<1%430 BU/mL	Factor VIIa, pFVIII/prednisone,retixumab,cyclophosphamide	Bleeding prophylaxis	loading dose 3 mg/kg/2–3weeklymaintenance doses 1.5 mg/kg/3weeks	No further bleeding	3 months	FVIII = 35%Inhibiteur = 0	1 year	none
	M/64/idiopathic	T2DM/ CKD/ gout	Ecchymosisretroperitonealhematoma	<1%353BU/ml	Factor VIIa/ prednisone,retixumab,cyclophosphamide	Bleeding prophylaxis	loading dose 3 mg/kg/2–3weeklymaintenance1.5 mg/kg/3weeks	No further bleeding	3 months	FVIII > 50%Inhibiteur = 0	1 year	none
Shima et al 22 Clinical trials (2 cohorts) Cohort 1 23 (n = 11) IST ligible patients Cohort2 (n = 2) IST-ineligible patients	Cohort 2F/82	T2D	Major bleeds	<1%33	None/none	Delayed IST	6 mg/kg on Day 1, 3 mg/kg on Day 2, and 1.5 mg/kg once weekly from Day 8	2 major bleeds stopped within the following day 3	64 days	M	NM
	F/59	Hashimoto's disease multiple myeloma	Major bleeds	<1%58	aPCC/none	IST not tolorated	6 mg/kg on Day 1, 3 mg/kg on Day 2, and 1.5 mg/kg once weekly from Day 8	Bleeding stopped on day 15	450 days	NM	NM	ADA
	Cohort 1F/88	NM	Major bleeds	NM	rFVIIa/low dose of IST	Reduced IST dose to avaoid side effect	6 mg/kg on Day 1, 3 mg/kg on Day 2, and 1.5 mg/kg once weekly from Day 8	Bleeds decreased in the latter half of emicizumab periode of treatment	639 days	NM	NM	ADA

AID: auto-immune disease; ACS: acute coronary syndrom;ADA: ant-emicizumab drug antibodies, aPCC: activated prothrombin complex concentrate; AHT: arterial hypertension; AF: arterial fibrillation; BPA: bypassing agents, CAS: carotid artery stenosis; CAD: coronary artery disease ; CKD : chronic kidney disease; COPD: chronic obstructive pulmonary disease ; CHD : chronic heart disease ; CR : complete remission ; DES : drug eluting stent ; DAPT : dual antiplatelet therapy ; DIT : drug induced thrombocytopenia ; DVT :deep vein thrombosis ; F : female ; FVIII:h : factor VIII level using human reagent ; FFP :fresh frozen plasma ; FVL: V leiden factor ; GI = gastrointestinal ; IDDM : insulin-dependent diabetes mellitus ; IST : immunosupression therapy ; IS : immunosupression ; IBD : inflammatory bowl disease ; ITT : induce tolerated therapy ; IVIG :intravenous immunoglobulin ; LGLPD : low grade lymphoproliferative disorder ; LD : lung disease ;M = male ; MGUS : monoclonal gammapathy of underterminated significance ; NSTEMI : non-ST elevation myocardial infarction ; NM : not mentionned ; PCI : percutaneous coronary intervention ; PE : pulmonary embolism ; PR : partial remission ; rpFVIII :recombinant porcine FVIII ; rFVIIa : recombinant activated factor FVII ; T2DM :type 2 diabetes mellitus ; Standard loading dose : 3 mg/kg subcutaneous weekly for 4 doses ; Maintenance dose : 1.5 mg/kg weekly;PR : FVIII > 50% with no active bleeds, CR : PR with inhibitor eradication.

Population Characteristics

One hundred seventy-one AHA patients were treated with emicizumab. The median age was 68 years (range: 21-93), with 55.8% being male. AHA was considered secondary to malignancy, autoimmune disease, COVID-19, and HIV infection in 13.4%, 7.7%, 7.6%, and 2% of patients, respectively.^{23–25,29,30,35,37–40,42,44,48,49,52} It was idiopathic in 69.8% of patients.^{25–28,30–34,36,37,42,43,50,52} Every patient had at least one comorbidity with a higher frequency of metabolic syndrome conditions and commonly arterial fibrillation and coronary artery disease.

Clinical Bleeding Symptoms

AHA patients presented with a range of clinical signs of hemorrhagic diathesis. The most common symptoms were mucocutaneous bleeds (74.1%), hematomas (72.2%), post-surgical bleeds (18.5%), and less frequently hemarthrosis (5.5%).^{23,25,28–31,34–38,42–44,46,50–52} The symptoms were spontaneous and occurred at multiple sites. Additionally, most of the patients met the criteria for severe bleeding, and four patients required an embolization procedure. ³⁷

Laboratory Methods

In 68.5% of patients, FVIII levels were undetectable or lower than 1% at the onset of AHA diagnosis or emicizumab initiation.^{7,22,23,25,26,28,30–34,36–40,42–44,46,50–52} FVIII levels were measured using a chromogenic assay with either bovine coagulation factors^{23,32–37,39,42–44,47,50,52} or human reagents^{28,42,44,47,51} Shima et al described a new laboratory tool based on a one-stage clotting assay with emicizumab in plasma samples neutralized by adding two anti-emicizumab idiotype monoclonal antibodies ex vivo (OSAwEN).^22,23 Inhibitor levels ranged between 1 and 2300 Bethesda units per milliliter (BU/ml) (Table 2). Plasma emicizumab concentration was assessed in three studies.^23,26,35

Hemostatic Treatement and Antibody Eradication

Of 171 patients, 65.5% received initial hemostatic treatement prior to emicizumab initiation.^{22,25,28–52} Hemostatic agents were not required in 19.4% patients.^{22,23,26–28,30,37,41,42}

The most commonly used hemostatic agent were rFVIIa (56.6%), human or porcine FVIII (23.8%) and aPCC (15.9%).^{24,25,28–36,38–47,49–52}

Immunosuppressive therapy was used in 109 patients.^{23,25,28–30,32–34,36–40,42–50} Prednisolone (75%) and rituximab (75%) were the main agents used for antibody eradication followed by cyclophosphamide (14%). The combination of rituxumab and prednisolone was observed in 27.5% of the cases.

Emicizumab Indications

Emicizumab was used as a second-line therapy for active bleeding refractory to BPA (52/171, 30.4%) and for recurrent bleeding (13/171, 7.6%).^{26–30,32–37,40,43,47–50} Bleeding prophylaxis was the primary indication of emicizumab (n = 101/171, 59%).^{22–25,28,31,38,42,44–46,51,52} Some manuscripts reported the use of emicizumab in active bleeds as a firstline treatment, either alone (4.6%)^28,30,37 or in combination with rFVIIa (1.7%). ³⁹ Additionally, emicizumab was initiated in cases of IST failure or ineligibility (6%),^22,23,41 to minimize immunosupression and BPA adverse effects^22,24,28,38 and in case of anti-platelet therapy initiation. ²⁵

Emicizumab Regimen (Dose, Frequency, Plasma Concentration, Duration Therapy)

The standard emicizumab loading dose conventionally used in congenital hemophilia A (3 mg/kg/week for 4 weeks) was initiated in 99 out of 171 patients^{25,27,28,30,31,33,35–38,42–44,47–51} while 69 patients received a modified loading dose regimen.^{23,24,26,34,39–41,45,46,52}

Two recent clinical trials employed a new regimen based on a higher loading dose distributed over 2 days (6 mg/kg on day 1 and 3 mg/kg on day 2, followed by 1.5 mg/kg from day 2 to day 7), then weekly maintenance doses from day 8.^22,24 This accelerated regimen was indicated for bleeding prophylaxis in patients with or without IST. The maintenance dose was continued in 149 patients, including 130 on the standard maintenance dose (1.5 mg/kg weekly)^{22–25,27,28,30,31,35–38,42,44,47–52} and 8 on a modified regimen^{26,32–34,41–43} The maintenance doses of 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks, derived from licensed regimens for CHA, were applied in 11 patients. Twenty-two patients did not receive any maintenance dose.^{30,37,39,40,42,45,46} The duration of emicizumab therapy varied widely, ranging from 1 day to over 224 days.

Different emicizumab plasma concentrations, ranging from 9 to 51 µg/ml, were reported to be effective in stopping bleeding.^23,26,35 This variation depends on the dosing regimen and the timing of concentration measurement.

Follow up Duration of Emicizumab Therapy

Follow-up period was reported in 9 studies^{23,24,26,28,30,31,33,42,50} ranging from 14 days to over 10 months.

Emicizumab Efficacy

All cases reported the effectiveness of emicizumab in resolving active or recurrent bleeding, with a median time of 5 days (range: 0–15).^23,32,37 Bleeding was controlled after the first emicizumab loading dose in 62.8% of patients, with a median time of 4.5 days (range: 1–15). However, rebleeding occurred in 40 cases, of which 7 required additional hemostatic agents.^{23,24,35–38,46}

Remission Criteria

Eight studies reported data on remission time.^{22,24,28,36,37,41,44} Remission criteria were heterogeneous, based on FVIII levels using different reagents, inhibitor levels, and clinical bleeding signs. Partial remission was defined as FVIII levels >50% with no active bleeding. ³⁷ Complete remission (CR) was defined by the following criteria: (1) no bleeding without hemostatic treatment for at least 24 h; (2) FVIII levels >50%; and (3) a negative inhibitor test.^37,44 CR was achieved in a median of 96.5 days (range: 9–270).

Emicizumab Adverse Events

Adverse events were proclaimed in 10 cases : 3 cases of deep vein thrombosis (DVT),^23,38,50 2 cases of stroke,^24,28 one case of atopic eczema, ³² 2 cases of rash ⁴¹ and 2 cases of developed anti-emicizumab drug antibodies (ADAs) without a clear pharmacokinetics impact.^22,23 Thrombotic events were observed due to the concomitant use of bypassing agents, including one case of stroke and two cases of deep vein thrombosis (DVT). No case of death was related to emicizumab.

Emicizumab Disruption Time

Emicizumab disruption time varied from 1 to 99 days with a median of 58 days. FVIII levels after discontinuation of the first dose of emicizumab ranged from 10% to 123%.

Discussion

The introduction of emicizumab has significantly transformed the treatment approach for CHA in very young, untreated patients with severe diseases, as demonstrated by the recent HAVEN 7 clinical trial. ⁵³ This advancement hints at a similar transformative potential for managing AHA. This systematic review has consistently highlighted the efficacy of “off-label” emicizumab use in AHA patients, with partial support from two clinical trials.^23,24 “Although the included studies were assumed to be of rigorous methodological quality, this assessment is limited by the fact that 7 of 32 papers were only available as abstracts. This lack of full data hinders a thorough evaluation of their methodological rigor and may influence the interpretation of the results.” The effectiveness of emicizumab still has to be considered with caution given the small sample size and the absence of randomized clinical trials. However, the strict inclusion/exclusion criteria and the validated tools used to mesaure the outcomes ensure high reliability and reproductibility of data supporting the validity and the strength of the findings. In future search, it would be useful to replicate clinical trials with a large sample and with randomized series.

Emicizumab Indications

Emicizumab has shown promise as a second-line therapy for active or recurrent bleeding refractory to conventional hemostatic agents. Interestingly, bleeding was controlled from the first emicizumab loading dose in 62.8% of patients,^{23,28,31,32,34,37,42} with a median time of 4.5 days. Few cases reported the use of emicizumab as a first-line therapy alongside IST.^28,30,37,42 Moreover, thrombin generation studies have shown that emicizumab mimics FVIII activity levels of 10 to 15 IU/dL, improving the bleeding phenotype from severe to mild.^20,54 Despite this, additional therapy with BPA is still needed for breakthrough bleeding or invasive procedures. ⁵⁵ Due to its pharmacokinetic and pharmacodynamic properties, emicizumab is not intended for treating acute bleeds and BPA remain preferred for their short-life time and easier monitoring ¹³

Emicizumab, approved for bleeding prophylaxis in CHA with and without inhibitors,^19,56 may also be highly beneficial for AHA patients who have a greater risk of bleeding. AGEHA trial have shown that emicizumab improves hemostasis and significantly reduces bleeding rates with an accerelated loading dose, ²³ even in patients without concomitant IST. ²² More recently, the GTH-AHA trial showed a significant reduction in bleeding rate (0.04) in patients without concomitant IST compared to the historical rate of (0.15) documented in patients with IST.^24,57 These data suggest that emicizumab alone can effectively prevent most bleeding in patients resistant to or slowly responding to IST.

During the COVID-19 pandemic, when the impact of IST can be critical, emicizumab was considered the only option for bleeding prophylaxis when inhibitor eradication was not achievable.^{37,39,40,44,49}

Emicizumab Regimen

The dosing regimen for emicizumab varied significantly due to differences in bleeding risk and patient phenotypes. The GTH-AHA working group recommends tailoring emicizumab loading regimens to specific patient need. ⁵⁸ The accelerated dosing regimen used in the AGEHA and GTH-AHA-EMI trials—starting with 6 mg/kg on day 1 and 3 mg/kg on day 2—achieves steady-state levels within one week, with a trough concentration of 30 μg/mL.^23,24 These studies reported promising results, including low bleeding (0%-4%) and thrombotic event rates (2%-4%) over a 12-week period.^23,24 This regimen should be considered for rapid prophylaxis from the time of diagnosis. ⁵⁸

Thus, higher loading doses with a reduced duration could enhance the efficacy of emicizumab, leading to an earlier clinical response due to its long half-life (approximately 30 days), even if endogenous FVIII levels remain low and inhibitor eradication is not achieved.

The saturation regimen of 3 mg/kg once a week for 4 weeks, as used in the HAVEN study for CHA patients, achieves steady-state levels of emicizumab within 4 weeks, with a trough concentration of 20 μg/ml.^28,59 This lower dosing could be a viable alternative for managing AHA patients with a low bleeding tendency,^52,58 even in the presence of high inhibitor levels. Observations from CHA studies suggest that even lower emicizumab plasma concentrations can be effective for bleeding prophylaxis.^60,61

The recommended maintenance dose of emicizumab was 1.5 mg/kg once per week. ⁵⁸ Longer dosing intervals (3 mg/kg/2weeks or 6 mg/kg/ 4weeks) may be applied for resistant or ineligible IST patients needed a long remission time. ⁵⁸ Emicizumab should be discontinued once remission is ashieved. ⁵⁸ Earlier discontinuation can be considered in stable patients achieving FVIII > 30%. ⁵⁸ The optimal timing for discontinuation of emicizumab needs further investigation.

Emicizumab Versus IST

The risk of potentially fatal bleeding complications justifies the early initiation of IST to promptly eradicate autoantibodies. ¹³ Immunosupression should be administered based on the patient's physical status. ⁵⁸ For ineligible patients, emicizumab may be used to delay IST initiation to avoid infection while being protected against recurrent bleeding risks.^24,41,62 Hart et al compared the outcomes of GTH-AH 01/2010 ⁶ (IST without hemostatic prophylaxis) and GTH-AHA-EMI ²⁴ studies (hemostatic prophylaxis with emicizumab without IST) and concluded that using emicizumab instead of IST during the early phase of AHA diagnosis (within 12 weeks) reduced bleeding and fatal infections and improved overall survival. ⁵⁷

Patients treated with IST experienced a higher bleeding rate compared to those treated with emicizumab during the first 5 weeks. The mean bleeding rate decreased from 0.128 to 0.042 with emicizumab, showing a significant rate ratio of 0.325 (95% CI, 0.182–0.581; P < .001). ⁵⁷ Despite this, bleeding can still occur, and IST may be needed to further reduce bleeding risk by achieving partial remission (PR). Most patients received IST after week 12 without any infections by week 24. ⁵⁷ This fact was supported in AGEHA results suggesting that delaying IST may reduce risks.^22,57

An ongoing trial in the United States (AHA-EMI, NCT05345197) aims to evaluate the risk/benefit ratio of early IST within the first 12 weeks alongside an accelerated or modified emicizumab dosing regimen.

Survival rates at 24 weeks were significantly higher with emicizumab (90%) compared to IST (76%). ⁵⁷ Emicizumab prophylaxis offers greater flexibility in timing IST, potentially improving the risk/benefit ratio of less intensive treatments.

Emicizumab and Antithrombotic Therapy

Recent data indicate that antithrombotic therapy can be safely used in AHA patients on emicizumab, as it reduces bleeding risks.^24,25,46 EHA-ISTH-EAHAD-ASO guidelines allow for oral anticoagulants or antiplatelet drugs in CHA patients with clotting factor levels above 20 IU/dL, though careful monitoring is required. ⁶³ These recommendations could be adapted for AHA patients, taking into account their higher thrombotic risk compared to CHA patients.

Emicizumab Laboratory Monitoring

The use of emicizumab requires specialized laboratory expertise due to its interference with standard clotting assays. Emicizumab bridges FIXa and FX, restoring intrinsic tenase function usually mediated by FVIIIa, which is deficient in hemophilia patients. However, this mechanism can artificially shorten the aPTT-based FVIII activity test, leading to falsely normal results at low emicizumab concentrations due to an overestimation of FVIII levels. ⁶⁴

Chromogenic assays using bovine-derived reagents, are unaffected by emicizumab and are recommended for FVIII activity and inhibitor titers monitoring to achieve remission.^18,58,65

Chromogenic FVIII testing with human-derived factors effectively reflects emicizumab's hemostatic activity and had a good correlation with emicizumab plasma level.^18,64

FVIII inhibitors are accurately detected with modified Bethesda assays or ELISA tests, both unaffected by emicizumab. ⁶⁵

The OSAwEN method provides a viable alternative for monitoring emicizumab in vivo. Shima et al found a correlation between OSAwEN method and chromogenic bovine assay which could serve as complementary tool to detect low inhibitor titers. ²³ However, it's crucial to recognize that the diagnostics for AHA and the monitoring of emicizumab therapy are not routinely accessible in many healthcare institutions.

Remission Criteria

Recent clinical trials, including AGEHA and GTH-AHA-EMI, have established remission criteria and follow-up protocols for emicizumab in AHA.^22,24 Remission is typically defined by the normalization of FVIII activity levels and the eradication of FVIII inhibitors. The AGEHA trial suggests that patients can be considered for remission once FVIII levels consistently exceed 30% and bleeding episodes are controlled without additional hemostatic agents. The GTH-AHA-EMI trial further emphasizes the importance of sustained FVIII activity and the absence of bleeding events as key remission indicators. Follow-up duration in these trials generally extends for 12 to 24 weeks, during which patients are closely monitored for both bleeding events and potential thrombotic complications. This period is crucial to ensure that remission is stable and to assess whether emicizumab can be safely discontinued or if further treatment adjustments are necessary.

Emicizumab Safety

This systematic review indicates that emicizumab can be safely used in AHA patients, including those with cardiovascular risk factors. While thrombosis related to BPAs was notably highlighted in the EACH2 study, ⁷ the thrombotic risk associated with emicizumab appears to be low, though not fully defined. The GTH-AHA-EMI study reported fewer thromboembolic events compared to the GTH-AH01/2010 study, likely due to a decreased reliance on BPAs. ⁵⁷ In fact, the combination of emicizumab with rFVIIa or rpFVIII^39,45 has been reported efficious and safe from cumulative risk of thromboembolic complications while aPCC increased thrombotic microangiopathy. ⁶⁶ However, an analysis of adverse events from the EudraVigilance pharmacovigilance database revealed 24 thromboembolic events in patients treated with emicizumab, with 25% occurring in combination with rFVIIa. ⁶⁷ Some of these patients had AHA, and most complications were linked to multiple thromboembolism risk factors. Although the low rate of thromboembolism observed in the GTH-AHA-EMI study is promising, further investigation into this risk is needed.

In the absence of safety data, combining emicizumab with BPAs should be avoided in elderly patients with high cardiovascular risk. In cases where IST is effective, the combined effect of restored endogenous FVIII activity and ongoing emicizumab treatment may increase the risk of hypercoagulation. This transitional period requires careful monitoring and regular screening for signs of hypercoagulation.

Although the development of alloantibodies against emicizumab has been observed in individuals with CHA, it may also potentially occur in those with AHA. Two cases of anti-drug antibodies (ADAs) were detected only during the safety follow-up period after emicizumab administration. ²² Future monitoring is essential, as autoimmune conditions might increase the risk of developing ADAs. Further research is needed to explore any potential temporal link between the discontinuation of emicizumab treatment due to AHA remission and the emergence of ADAs.

Emicizumab Efficacy

While emicizumab reduces the frequency of bleeding in AHA patients, it does not entirely prevent breakthrough bleeding or even life-threatening hemorrhages. A few cases of rebleeding have been reported in patients taking emicizumab. This bleeding was mostly trigged by surgery,^30,35,37,38 trauma injury^23,26,36,38 or insufficient dose.^26,46 For major surgeries under emicizumab, concurrent BPA with factor replacement is recommended. ⁶⁸ rFVIIa and rpFVIII are preferred over aPCC for treating breakthrough bleeding due to concerns about thrombotic microangiopathy.Human FVIII concentrates may be used if the preferred agents are unavailable especially for patients with low-titer inhibitors. ⁵⁸ Rehabilitation and minor surgeries can be safely performed under emicizumab prophylaxis. ²² Additionally, long-term emicizumab prophylaxis, lasting up to 1.75 years, has demonstrated sustained bleed prevention. ²²

Further research is needed to address remaining questions about emicizumab, including its thrombotic risks when used with BPA and its safety during pregnancy, breastfeeding, and in pediatric populations. While emicizumab has been effective in pregnant women with congenital hemophilia, ⁵⁶ its use in similar scenarios for AHA patients requires clinical trials to address these uncertainties.

Study Limitations

This systematic review has several limitations. First, the quality of evidence is limited, as most studies were case series, case reports, or conference abstracts with small sample sizes. Even the prospective AGEHA and GTH-AHA studies are constrained by limited sample sizes and the absence of a placebo control group, which may affect the analysis of results. Additionally, some published papers have limited data on patient follow-up.

Conclusion

The early use of emicizumab provides a novel approach to managing AHA, offering rapid and effective hemostatic control with significantly lower bleeding rates, thromboembolic events, and fatal infections, along with promising survival outcomes.Emicizumab is primarily intended for long-term prevention rather than acute bleeding episodes. It should be considered for AHA patients at diagnosis, with patient consent, though it is not yet licensed specifically for AHA. The adjusted dosing regimen over 2 days aims to quickly achieve hemostatic effectiveness and allows for deferral of IST for up to 12 weeks in ineligible patients. Despite minor risks of adverse events, emicizumab should be used with caution, especially in patients with high cardiovascular risk. Biological monitoring should be conducted regularly using chromogenic assays with bovine reagents until complete response and for several months thereafter. Due to the limited quality of current studies, further research is needed to assess the long-term safety of emicizumab, and establish a regular monitoring schedule to meet treatment completion criteria.