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L'hémophilie acquise A est une maladie auto-immune rare secondaire au développement d'anticorps (inhibiteur) dirigés contre le FVIII, avec un pronostic vital encore engagé. Le diagnostic est en règle évoqué devant des ecchymoses sous-cutanées plus ou moins diffuses associées à un allongement du TCA. Le plus souvent idiopathique, elle peut être associée à une maladie auto-immune, un cancer, la grossesse ou le post-partum ou à la prise de médicaments. La prise en charge thérapeutique passe par la correction éventuelle du syndrome hémorragique par des agents hémostatiques (facteur VII recombinant activé, concentré de complexe prothrombique ou facteur VIII humain porcin recombinant). L'éradication de l'inhibiteur fait appel à un traitement immunosuppresseur par corticoïdes seuls souvent associés à un agent cytotoxique ou du rituximab, dont l'indication doit tenir compte du taux de FVIII résiduel et du titre d'inhibiteur. Le but de cette revue est de faire le point sur les données épidémiologiques, cliniques, physiopathologiques, diagnostiques et de discuter les recommandations thérapeutiques actuelles. Acquired hemophilia A (AHA) is a rare autoimmune disorder due to autoantibodies against factor VIII, with a high mortality risk. It should be suspected in subjects with abnormal bleedings, especially subcutaneous bleed associated with prolonged activated partial thromboplastin time (aPTT). AHA is often idiopathic but is associated with autoimmune diseases, malignancies, pregnancy and postpartum period or drugs. Treatment is based on haemostatic agents as by-passants agents such as factor VIIa and activated prothrombine concentrate complex or recombinant porcine factor VIII for severe bleeding. Eradication of inhibitor should be established as soon as the diagnosis is confirmed with steroid alone often associated with cytotoxic agents or rituximab, depending on FVIII activity and inhibitor titer. The purpose of this review is to summarize the epidemiology, etiopathogenesis, diagnosis, treatment of AHA and discuss current recommendations. [ABSTRACT FROM AUTHOR]

For several decades, therapeutic options for inherited deficiencies of factor VIII or IX (hemophilia A or B, respectively) have largely been the replacement of the missing clotting factor with plasma-derived or recombinant products. Hemostasis laboratories use standard activated partial thromboplastin time (aPTT)-based clotting or chromogenic assays to monitor plasma factor levels to guide therapy. The emergence in the past 10 years of extended half-life replacement products and other novel therapies for hemophilia has led to a reappraisal of assay suitability, with studies of product measurement showing some existing assay types or reagents to be unsuitable for some products. The hemostasis laboratory must adapt to the changing landscape by adding new assays or modifying existing assays to ensure accurate results for product measurement. These strategies include switching from a chromogenic assay to a clotting assay, or vice versa, changing an aPTT reagent brand, or introducing product specific calibrators. This article evaluates the effects of some of the newer treatment options on the laboratory testing of factor levels and related assays. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to characterise baseline disease and treatment burden in a large population with haemophilia A/B, both with (HAwI/HBwI) and without (HA/HB) inhibitors. Methods: The prospective, non‐interventional explorer6 study included patients ≥12 years old with severe HA, severe/moderate HB or HAwI/HBwI of any severity, treated according to local standard of care (excluding previous/current exposure to concizumab or emicizumab). Baseline characteristics and historical clinical data were collected and patient‐reported outcomes, including treatment burden, were assessed. Results: The explorer6 study enrolled 231 patients with haemophilia (84 HAwI/HBwI) from 33 countries. At baseline, patients with HA/HB treated with prophylaxis had the lowest median annualised bleeding rates (ABRs; 2.0), irrespective of haemophilia type; of these patients, 27.5% (HA) and 31.4% (HB) had target joints. Patients with HAwI/HBwI treated episodically reported the highest treatment burden. Of these patients, 28.5% (HAwI) and 25.1% (HBwI) performed sports activities in the month before screening. Conclusion: Despite receiving routine clinical care, historical and baseline information from patients enrolled in explorer6 showed that patients with HA/HB treated episodically and patients with HAwI/HBwI had higher ABRs, higher treatment burden and participated in sports less than those with HA/HB treated with prophylaxis. Emerging treatments could be beneficial in addressing these unmet medical needs. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Highlights In Thailand, an upper‐middle‐income country, managing haemophilia A (HA) with inhibitors poses significant challenges, often necessitating bypassing agents (BPAs) for bleeding control. This study evaluates the cost‐effectiveness and budget impact of emicizumab, a novel prophylactic agent, as an alternative to both episodic and prophylactic BPA treatments from a societal perspective.A Markov model was employed to estimate the lifetime societal costs and outcomes of emicizumab prophylaxis for HA patients with inhibitors. Treatment efficacy, cost, and epidemiological data were obtained through a comprehensive literature review and incorporated into the model. A 5‐year budget impact analysis complemented the cost‐utility analysis, with a 3% annual discount rate applied to future costs and outcomes.In the base‐case scenario, emicizumab prophylaxis in HA patients aged 2 years and above demonstrated superior cost‐effectiveness, yielding 18.1 quality‐adjusted life years (QALYs) per patient over a lifetime and resulting in cost savings of 138 million Thai Baht (THB) compared to BPA prophylaxis. Compared to episodic BPA treatment, emicizumab yielded 30.5 QALYs and saved 25 million THB per patient. The 5‐year budget impact was projected at 1775 million THB.Emicizumab offers a cost‐saving approach for HA treatment with inhibitors in Thailand, promising significant health benefits and budgetary savings. This supports its potential inclusion in Thailand's National List of Essential Medicines to enhance haemophilia care access. Managing haemophilia A (HA) with inhibitors in Thailand, an upper‐middle‐income country, faces challenges due to limited access to effective treatments or newer drugs for bleeding management. Emicizumab prophylaxis found to as a cost‐effective and viable alternative to traditional treatments, effectively preventing bleeding in Thai HA patients over 2 years old with inhibitors. Demonstrating improved clinical outcomes and reduced costs, emicizumab prophylaxis outperforms episodic BPA treatments, positioning it as a superior treatment option for HA patients with inhibitors in Thailand. [ABSTRACT FROM AUTHOR]

Since June 2021 in France, patients with haemophilia A with anti-factor VIII inhibitors and patients with severe haemophilia A without anti-factor VIII inhibitors have the choice between the community and the hospital pharmacy for dispensing emicizumab (Hemlibra®). This study aims to investigate patient-centred access to treatment by evaluating and comparing the dimensions of the Penchansky and Thomas model, between community and hospital pharmacies. The evaluation of access to treatment was based on the dimensions of the Penchansky and Thomas model: accessibility, availability, acceptability, accommodation and affordability. These were assessed using appropriate and specific indicators in the study context and calculated for patients choosing community pharmacy or hospital pharmacy for emicizumab dispensing. Geographical data collected as part of the national 'PASO DOBLE DEMI' study were used for this analysis. The findings reveal that dispensing emicizumab in community pharmacies improves accessibility by significantly reducing travel time. The availability of healthcare services is also improved due to the territorial coverage of community pharmacies. The extended opening hours and low waiting time also contribute to better access to emicizumab in community pharmacies. The dimension of acceptability must be improved, and further investigations are needed to address the affordability dimension. Several months after emicizumab became available in French community pharmacies, access to treatment has significantly improved, reducing the burden of this rare chronic disease for patients and their careers. These results suggest that this innovative model could be extended to other medicines and even other therapeutic areas. [ABSTRACT FROM AUTHOR]

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Introduction Aim Methods Results Conclusions The management of bleeding events (BEs) in haemophilia A (HA) and B (HB) patients with inhibitors necessitates the use of bypassing agents. The recombinant factor VIIa bypassing agent eptacog beta has demonstrated efficacy at treating BEs and managing perioperative bleeding in adults in phase three clinical studies.To provide real‐world descriptions of eptacog beta use for BE treatment in patients on emicizumab or eptacog beta prophylaxis.This is a retrospective case series of 14 patients who received eptacog beta at seven haemophilia treatment centres, with HA (n = 11) or HB (n = 3) and inhibitors or anaphylaxis to factor replacement.Twenty‐four spontaneous and traumatic BEs are described (muscle hematomas, joint hemarthroses, port site, and epistaxis) involving 11 subjects. Eptacog beta was effective for acute bleed treatment as both first‐line therapy and for treatment of BEs refractory to eptacog alfa in 23/24 events. When eptacog beta was used for prophylaxis, 2/3 patients reported a decreased frequency of breakthrough BEs compared with prophylactic eptacog alfa and one patient experienced a similar frequency of breakthrough BEs compared with prophylactic activated prothrombin complex concentrate. Eptacog beta provided effective bleed control for three subjects who underwent minor surgical procedures. Treatment with eptacog beta was estimated to be 46%–72% more cost‐effective than eptacog alfa. No safety concerns or adverse events were reported.In this case series, eptacog beta was safe, effective, and economical as first‐line therapy, treatment of refractory BEs, management of perioperative bleeding, or prophylaxis in haemophilia patients with inhibitors. [ABSTRACT FROM AUTHOR]

Background: Treatment for haemophilia A has expanded from plasma-derived factor VIII (pdFVIII) and standard half-life (SHL) recombinant FVIII (rFVIII) to extended half-life (EHL) rFVIII and non-factor products that mimic FVIII activity. Objective: To determine amounts of clotting factor concentrates (CFCs) and emicizumab dispensed and associated healthcare expenditures in Japanese patients with haemophilia A. Methods: This retrospective, non-interventional, observational study analysed data from 2016 to 2020 from a large-scale, hospital-based administrative database. Patients had haemophilia A without inhibitors and ≥ 2 prescriptions of the same CFC or emicizumab. Results: In total, 974 patients with haemophilia A (median age, 30.0 years; median follow-up, 3.7 years) were included. Outpatient use of EHL rFVIII and emicizumab increased, although pdFVIII/SHL rFVIII were still used over the study. Median annual total healthcare expenditures/patient increased from ¥9,200,230 in 2016 to ¥19,748,221 in 2020. Overall, the median annual drug expenditure/patient increased from ¥8,723,120 in 2016 to ¥18,051,689 in 2020. Drug expenditure was highest with emicizumab, with an increase in median annual expenditure/patient from 2018 (n = 4, ¥26,030,206) to 2020 (n = 107, ¥45,430,408). Overall, 233 patients (23.9%) switched from an SHL to an EHL product. Although amounts of FVIII prescribed increased in the 3 months after switching, overall, there was no noticeable difference before and after switching. Median total healthcare and FVIII product expenditures increased following switching. Conclusions: Prescribing of EHL products increased over the study and healthcare expenditures increased for patients who switched from SHL to EHL rFVIII products. [ABSTRACT FROM AUTHOR]

Abstract Treatment of type 3 von Willebrand disease by infusion of von Willebrand factor (VWF) and factor VIII (FVIII) concentrates may lead to the development of anti‐VWF antibodies, challenging haemostasis management. The systematic review of the literature presented here retrieved 15 such cases (surgery n = 11, bleeding n = 4). The heterogeneous patient management mostly involved continuous infusion of FVIII, or recombinant FVIIa together with various other strategies. Off‐label infusion of the bispecific monoclonal antibody emicizumab was prescribed in three cases and in a complex local case, ultimately well‐controlled with emicizumab. This illustrates the fact that emicizumab appears as a therapeutic option in this context of allo‐immunisation.

Patients with acquired haemophilia A (PwAHA) can present with severe bleeding and may require lengthy treatment with bypassing agents and immunosuppression. We present two cases of the implementation of emicizumab in PwAHA. The first patient, an 82-year-old man with rheumatoid arthritis (RA), presented with acquired haemophilia A (AHA) and spontaneous left tibia hematoma complicated by a persistent wound and infections. After a month of intermittent bleeding at the site and immunosuppression, the inhibitor level remained elevated and he was placed on emicizumab. While on therapy, debridement of the wound required activated factor VII therapy, which was complicated by a venous thromboembolism (VTE). He was successfully managed with anticoagulation while on emicizumab until his inhibitor level was undetectable. The second patient is a 62-year-old woman, also with RA and with a persistently positive dilute Russell viper venom time who presented with intracerebral haemorrhage (ICH) and was found to have AHA. After a period of time on bypassing agents, emicizumab was started due to a persistent inhibitor level and the ICH remained stable. She only required two doses initially, however, had a relapse with recurrent factor VIII inhibitor and received three additional doses without any complications. These cases highlight that emicizumab is a viable option in the care of PwAHA in challenging scenarios such as in the context of VTE and ICH.

rFVIIa, a human recombinant activated coagulation factor VII, has been used worldwide for more than two decades for the treatment of bleeding episodes and prevention of bleeding in patients undergoing surgery/invasive procedures with congenital haemophilia A or B with inhibitors (CHwI A or B), acquired haemophilia (AH), congenital factor VII deficiency and Glanzmann thrombasthenia (GT), refractory to platelet transfusion. The approved dosage, administration and indication of rFVIIa in the US, Europe and Japan differ, depending on the needs of the patient population and regulatory practices. This review presents an overview of the current status and future prospects, including that from a Japanese perspective, of using rFVIIa in the treatment of approved indications. The efficacy and safety of rFVIIa in the approved indications has been demonstrated in several randomised and observational studies and data from registries. The overall incidence of thrombosis across all approved indications in a retrospective safety assessment of clinical trials and registries, prelicensure studies and postmarketing surveillance studies of rFVIIa use was 0.17%. Specifically, the risk of thrombotic events was 0.11% for CHwI, 1.77% for AH, 0.82% for congenital factor VII deficiency and 0.19% for GT. Emerging non-factor therapies such as emicizumab have changed the treatment landscape of haemophilia A, including preventing bleeding in patients with CHwI. However, rFVIIa will continue to play a significant role in the treatment of such patients, particularly during breakthrough bleeding or surgical procedures. [ABSTRACT FROM AUTHOR]

The management of hemophilia A has undergone a remarkable revolution, in line with technological advancement. In the recent past, the primary concern associated with Factor VIII (FVIII) concentrates was the risk of infections, which is now almost resolved by advanced blood screening and viral inactivation methods. Improving patients' compliance with prophylaxis has become a key focus, as it can lead to improved health outcomes and reduced health care costs in the long term. Recent bioengineering research is directed toward prolonging the recombinant FVIII (rFVIII) coagulant activity and synthesising higher FVIII yields. As an outcome, B-domain deleted, polyethylene glycolated, single-chain, Fc-fused rFVIII, and rFVIIIFc-von Willebrand Factor-XTEN are available for patients. Moreover, emicizumab, a bispecific antibody, is commercially available, whereas fitusiran and tissue factor pathway inhibitor are in clinical trial stages as alternative strategies for patients with inhibitors. With these advancements, noninfectious complications, such as inhibitor development, allergic reactions, and thrombosis, are emerging concerns requiring careful management. In addition, the recent approval of gene therapy is a major milestone toward a permanent cure for hemophilia A. The vast array of treatment options at our disposal today empowers patients and providers alike, to tailor therapeutic regimens to the unique needs of each individual. Despite significant progress in modern treatment options, these highly effective therapies are markedly more expensive than conventional replacement therapy, limiting their access for patients in developing countries. [ABSTRACT FROM AUTHOR]

von Willebrand disease (VWD) is a very heterogenous disease, resulting in different phenotypes and different degrees of bleeding severity. Established therapies (i.e., desmopressin, antifibrinolytic agents, hormone therapy for heavy menstrual bleeding, and von Willebrand factor [VWF] concentrates) may work in some subtypes, but not in all patients. In recent years, progress has been made in improving the diagnosis of VWD subtypes, allowing for more specific therapy. The impact of VWD on women's daily lives has also come to the fore in recent years, with hormone therapy, tranexamic acid, or recombinant VWF as treatment options. New treatment approaches, including the replacement of lacking factor VIII (FVIII) function, may work in those subgroups affected by severe FVIII deficiency. Reducing the clearance of VWF is an alternative treatment pathway; for example, rondaptivon pegol is a VWFA1 domain-binding aptamer which not only improves plasma VWF/FVIII levels, but also corrects platelet counts in thrombocytopenic type 2B VWD patients. These approaches are currently in clinical development, which will be the focus of this review. In addition, half-life extension methods are also important for the improvement of patients' quality of life. Targeting specific mutations may further lead to personalized treatments in the future. Finally, a few randomized controlled trials, although relatively small, have been published in recent years, aiming to achieve a higher level of evidence in future guidelines. [ABSTRACT FROM AUTHOR]

Introduction: Reduced doses of emicizumab improve the affordability among patients in developing countries. However, the relationship between variant dose selection and efficacy in the real world of China is still unclear. Aim: This study aimed to investigate the efficacy and safety of emicizumab especially in those on reduced dose regimens in a real‐world setting. Methods: We carried out a multicentre study from 28 hospitals between June 2019 and June 2023 in China and retrospectively analysed the characteristics including demographics, diagnosis, treatment, bleeding episodes, and surgical procedures. Results: In total, 127 patients with haemophilia A, including 42 with inhibitors, were followed for a median duration of 16.0 (IQR: 9.0–30.0) months. Median age at emicizumab initiation was 2.0 (IQR: 1.0–4.0) years. Median (IQR) consumption for loading and maintenance was 12.0 (8.0–12.0) and 4.2 (3.0–6.0) mg/kg/4 weeks, respectively. While on emicizumab, 67 (52.8%) patients had no bleeds, whereas 60 (47.2%) patients had any bleeds, including 26 with treated bleeds. Compared to previous treatments, patients on emicizumab had significantly decreased annualized bleeding rate, annualized joint bleeding rate, target joints and intracerebral haemorrhage. Different dosages had similar efficacy except the proportion of patients with treated spontaneous bleeds and target joints. Adverse events were reported in 12 (9.4%) patients. Postoperative excessive bleeding occurred following two of nine procedures. Conclusion: This is the largest study describing patients with HA receiving emicizumab prophylaxis on variant dose regimens in China. We confirmed that nonstandard dose is efficacious and can be considered where full‐dose emicizumab is ill affordable. [ABSTRACT FROM AUTHOR]

Introduction: Valoctocogene roxaparvovec, a gene therapy evaluated in the phase 3 GENEr8‐1 trial, supports endogenous factor VIII (FVIII) production to prevent bleeding in people with severe haemophilia A. Individuals receiving emicizumab, an antibody mimicking the function of activated FVIII, were excluded from GENEr8‐1 enrolment since emicizumab was an investigational therapy at the time of trial initiation. Aim: Utilize pharmacokinetic simulations to provide guidance on best practices for maintaining haemostatic control while transitioning from emicizumab prophylaxis to valoctocogene roxaparvovec. Methods: To estimate bleeding risk at weekly intervals following valoctocogene roxaparvovec infusion, a published emicizumab pharmacokinetic model was used to simulate emicizumab concentrations and merged with FVIII activity time‐course data for participants in GENEr8‐1. The analysis investigated three approved emicizumab dosing regimens for two transition scenarios that varied whether the last dose of emicizumab was administered on the same day or 4 weeks after valoctocogene roxaparvovec infusion. Results: Simulations demonstrated administering the last emicizumab dose the day of valoctocogene roxaparvovec infusion and 4 weeks after offered similar levels of haemostatic control, and bleeding risk was similar for all emicizumab dosing regimens. An algorithm was developed to provide guidance for discontinuation of emicizumab. Theoretical cases based on GENEr8‐1 participants are presented to illustrate how decisions may vary among individuals. Conclusion: Pharmacokinetic simulations demonstrated no clinically meaningful difference in bleeding risk caused by decaying emicizumab levels and rising gene therapy‐derived endogenous FVIII for all examined emicizumab doses and dosing regimens. Therefore, multiple approaches can safely transition individuals from emicizumab prophylaxis to valoctocogene roxaparvovec. [ABSTRACT FROM AUTHOR]

Background: The incidence of cardiovascular diseases is increasing in persons with hemophilia A (HA). Therefore, anticoagulant therapy based on direct oral anticoagulants (DOACs) may be needed, despite the bleeding risk. In case of surgery or bleeding, such patients may be concomitantly treated with emicizumab (routine prophylaxis), factor (F)VIII products, and DOAC. Their concomitant presence constitutes a hemostatic challenge. Recent international guidelines stated that data are scarce on the hemostatic balance of plasma samples from patients with HA receiving emicizumab and DOAC. Objectives: The aim of this observational study was to assess the coagulation of FVIII-deficient plasma spiked with DOAC and emicizumab and to evaluate the effects of FVIII addition. Methods: Prothrombin time, activated partial thromboplastin time, and thrombin generation (TG) using the calibrated automated thrombogram method were evaluated in aliquots of a commercial severe HA plasma supplemented with emicizumab (0, 12.5, 25, 50, and 100 ng/mL), DOAC (0, 50, 100, 200, and 400 ng/mL of apixaban, rivaroxaban, edoxaban, or dabigatran) and FVIII (0%, 5%, 15%, 50%, and 100%). Results: DOAC rapidly induced a TG decrease. Emicizumab could counter this effect only for the lowest DOAC dose. FVIII addition to the FVIII-deficient plasma containing a DOAC and emicizumab improved TG and countered the anticoagulant effect of DOAC at ≤100 ng/mL. Conclusion: Our findings indicate that FVIII can be safely used with emicizumab to counter the anticoagulant effect of DOAC at ≤100 ng/mL. The TG assay is an efficient tool to monitor plasma containing anti-FXa DOAC, but not dabigatran (anti-FIIa).

Objective: The treatment of Hemophilia A and B has significantly evolved. Study design: we conducted a retrospective, observational study among patients with HA and HB managed in a Pediatric Hematology and Oncology Unit for almost 22 years for a total of 34 patients. Results: Until 2009, more than 80 % of patients were treated only on demand, while in 2022,100 % of patients with moderate and severe disease were receiving continuous prophylaxis. The median age at the start of prophylaxis passed from 10,9 to 1,65 years. In 2022, only one patient was on Standard-half-life-rFVIII, 7 patients were on Extended Half-Life (EHL)-rFVIII/rFIX and 7 patients were on Emicizumab; 1 patient was on Concizumab. The mean ABR passed from 5,7 in the period 2001–2009 to 0,8 in the period 2019–2022. We performed 106 ultrasonographic exams in 19 patients to evaluate the HEAD-US score: a percentage of 45,3 % of these exams revealed a score of 0 and the HEAD-US score resulted inferior in patients who started prophylaxis at an age below the median age at the initiation of prophylaxis. The score showed a tendency to correlate with the number of previous hemarthrosis. In our cohort, the overall prevalence of inhibitors is 0,09 among all patients, and 0,14 in severe HA/HB. 4 patients needed a Central Venous Line (CVL), and 3 patients developed at least one severe complication. Before 2017, we observed 4 cases of life-threatening bleeding in children less than 2 years old not on prophylaxis. Results: our real-life experience reflects the changes in hemophilia management in the last two decades. In the future, other drugs are expected.

Despite major advances in prophylaxis, no repeated dosing regimen with currently employed extended-half-life or non-factor products replaces the advantages of a long-term cure in persons with severe congenital hemophilia A and B (HA, HB). They indeed live with the risk of breakthrough bleedings, and treatment is still invasive, both physically and psychologically. Early studies showed that adeno-associated virus-based in vivo gene therapy (AAV-based in vivo GT), could convert hemophilia persons from a severe to mild a phenotype for years. However, the proportion of the hemophilia population likely to benefit from this transformative strategy was uncertain. Current evidence is expanding the eligibility criteria, and helps to predict risks, complications and unexpected side effects of this advanced treatment. Thus, among future options, AAV-based in vivo GT is likely to become the treatment of choice in HA and HB, if real-life data confirm its negligible short-term adverse events. However, while the global use of AAV-based in vivo GT is endorsed as a key objective of future studies in hemophilia, the liberating capability of a potentially one-off treatment on individuals with chronic diseases for whom lifelong cure has been inaccessible so far remains to be thoroughly recognized by government bodies. This is critical for reimbursement agencies to absorb the cost of the cure and calls for a partnership between health care systems and the pharmaceutical industry. However, bridging the gap between the costs of the advanced treatments approved for commercialization and their readiness to persons with HA and HB is still a challenging task.

This article discusses the transition of patients with severe hemophilia A from emicizumab prophylaxis to valoctocogene roxaparvovec gene therapy. Emicizumab is a routine prophylaxis for patients with severe hemophilia A, while valoctocogene roxaparvovec is a gene therapy that delivers a functional copy of the factor VIII-encoding gene to prevent bleeding. The article presents a real-world clinical experience of transitioning a patient from emicizumab to gene therapy without a washout period. The patient experienced no notable adverse events and continues to do well after the transition. The article provides additional confidence for clinicians considering transitioning their patients from emicizumab to valoctocogene roxaparvovec gene therapy. [Extracted from the article]

This article discusses the use of emicizumab, a bispecific antibody, in the treatment of acquired hemophilia A (AHA), a severe bleeding disorder. Traditionally, AHA has been treated with bypassing agents and immunosuppressive therapy. However, emicizumab has shown promise in preventing bleeding in AHA patients. The article presents data from three patients who received emicizumab and achieved measurable plasma levels within 48 hours. The authors conclude that emicizumab can effectively control bleeding in AHA patients, but individual responses may vary and clinical monitoring is necessary. [Extracted from the article]

Abstract Acquired hemophilia A (AHA) is a rare autoimmune bleeding disorder caused by autoantibodies against FVIII. Severe AHA is life‐threatening. Currently, licensed hemostatic agents for the treatment of severe AHA have short half‐lives and require intravenous administration, leading to a need for hospitalization, higher costs, and negative effects on quality of life. We present two cases of severe AHA with high inhibitor titers where emicizumab was safely and effectively used with intensive immunosuppression. These reports suggest in vivo efficacy even in high inhibitor environments. The optimal dosing regimen (accelerated vs. standard loading, maintenance frequency) is unknown and we discuss the current approaches.

• Activated factor VIII (FVIIIa) functions as a cofactor for FIXa in the tenase complex. • Emicizumab is a humanized bispecific monoclonal antibody acts as a FVIIIa-mimetic. • We examined the binding affinity among emicizumab, FIXa and FX by FRET. • Emicizumab orientates FIXa and FX in close proximity on phospholipid membranes. [ABSTRACT FROM AUTHOR]

Optimal management of cardiovascular disease (CVD) in people with haemophilia (PWH) is a growing issue, given the continuing improvement in life expectancy among PWH. The evolving treatment paradigms targeting higher trough levels and the advent of non-factor replacement therapies (NFRT) means much of the 'protection' PWH were thought to have against CVD may be lost. There is a paucity of evidence regarding the safety of using anticoagulants in PWH. We designed a study assessing the thrombin generation (TG) of PWH of different severities and treatments, compared to non-haemophilia patients receiving a Factor Xa (FXa) inhibitor (apixaban or rivaroxaban), healthy controls, and assessing TG parameters of adding FXa inhibitor to the plasma of PWH receiving emicizumab prophylaxis. In total, 40 patients were included. TG was initiated with 5pM tissue factor (TF) using the calibrated automated thrombinoscope. Compared to those with mild haemophilia, patients receiving a FXa inhibitor had higher endogenous thrombin potential (ETP) (1278.42 vs 1831.36) and velocity index (40.71 vs 112.56), but both had a similar peak height (154.0 vs 262.63) and time to peak (both 5.83). People with severe haemophilia receiving emicizumab had significantly improved TG parameters compared to those not receiving emicizumab – ETP 1678.11 vs 809.96 and peak height 233.8 vs 92.05; however, when FXa inhibitor was added their TG parameters deteriorated to the severe haemophilia range (ETP 1179.60 and peak height 103.05). TG may provide additional useful information regarding the use of anticoagulants in PWH. • People with haemophilia now have a life expectancy approaching the general population and may develop cardiovascular disease • Little is known about the use and safety of anticoagulants in people with haemophilia • Thrombin generation (TG) assays may be able to provide additional information regarding the use of anticoagulants in this setting. • People with mild haemophilia (factor level 5-20%) have similar tTG profiles to non-haemophilia patients receiving FXa inhibitors • People with severe haemophilia receiving emicizumab have TG parameters closer to normal, but when FXa inhibitor is added in vitro, these parameters return to the severe haemophilia range [ABSTRACT FROM AUTHOR]

The hemostatic effect of recombinant (r) factor (F)VIIa after repetitive intermittent administration may be attenuated in patients with hemophilia A (PwHA) with inhibitors (PwHAwI) creating a clinically unresponsive status, although mechanism(s) remain to be clarified. In patients receiving prophylaxis treatment with emicizumab, concomitant rFVIIa is sometimes utilized in multiple doses for surgical procedures or breakthrough bleeding. We identified 'unresponsiveness' to rFVIIa, based on global coagulation function monitored using rotational thromboelastometry (ROTEM) in 11 PwHAwI and 5 patients with acquired HA, and investigated possible mechanisms focusing on the association between plasma FX levels and rFVIIa-mediated interactions. Our data demonstrated that FX antigen levels were lower in the rFVIIa-unresponsive group than in the rFVIIa-responsive group (0.46 ± 0.14 IU/mL vs. 0.87 ± 0.15 IU/mL, p < 0.01). This relationship was further examined by thrombin generation assays using a FX-deficient PwHAwI plasma model. The addition of FX with rFVIIa was associated with increased peak thrombin (PeakTh) generation. At low levels of FX (<0.5 IU/mL), rFVIIa failed to increase PeakTh to the normal range, consistent with clinical rFVIIa-unresponsiveness. In the presence of emicizumab (50 μg/mL), PeakTh was increased maximally to 80 % of normal, even at low levels of FX (0.28 IU/mL). Unresponsiveness to rFVIIa was associated with reduced levels of FX in PwHAwI. Emicizumab exhibited in vitro coagulation potential in the presence of FX at concentrations that appeared to limit the clinical response to rFVIIa therapy. • Effect of rFVIIa is often attenuated after repeated use in hemophilia(H)A patients. • The response to rFVIIa was examined by ROTEM in 16 HA patients with inhibitor. • A lack of response was associated with a decrease in circulating FX to ∼0.5 IU/mL. • Emicizumab supported coagulation reactions in vitro at a low FX level (0.28 IU/mL). [ABSTRACT FROM AUTHOR]

• NXT007 is a bispecific IgG engineered from emicizumab to potentiate the activity. • The natural anticoagulant function of AT is unaffected by the presence of emicizumab. • NXT007 was here found not to affect the AT-function despite its enhanced FX-binding. • The results suggest that NXT007 would not increase the AT-related thrombotic risk. [ABSTRACT FROM AUTHOR]

Introduction: Patients with Haemophilia (PWH) need orthopaedic treatments and often they undergo surgery. Classically, PWH with inhibitors have to face such procedures earlier than other patients. Major orthopaedic surgery is not easy and complications are frequent. Emicizumab is the first monoclonal antibody introduced for haematological prophylaxis for PWH with inhibitors, achieving an efficacious haemostasis also in patients with severe haemophilia A with inhibitors, later demonstrated for PWH without inhibitors. A few years ago, emicizumab was also proposed for PWH undergoing surgery, as it supports excellent bleeding control. The literature on orthopaedic surgery using an emicizumab protocol is scarce: only isolated case reports with short-term follow-ups are available. Aim: The purpose of this study is the assessment of the mid-term outcomes of major orthopaedic surgery performed in a population of patients with and without inhibitors and an emicizumab regimen. Methods: We reviewed the records of 13 PWH (eight with high-titre inhibitors, five without) with a mean age of 54.6 years, undergoing 15 orthopaedic surgical procedures between 2017 and 2022: primary knee and hip arthroplasty, revision, pseudotumor excision, or amputation. Their prophylaxis consisted of the combination of emicizumab and boluses of rFVIIa (PWH with inhibitors) or rFVIII (PWH without inhibitors). The clinical parameters of evaluation were: VAS, Haemophilic Joint Health Score (HJHS), and standard radiologic studies. Follow-up was conducted at 1, 3, 6 months, and then yearly. The survival rate of all implants was also assessed. Results: The mean follow-up was 38.8 months (range: 12–65). All patients were successfully treated without complications during surgery. During the postoperative period, a patient affected by a septic complication two months after his pseudotumor excision underwent an above-the-knee amputation. All patients were regularly discharged to the rehabilitative ward, reporting satisfaction for pain reduction and improved joint and global function at the VAS and HJHS scores. No revisions or implant failures were recorded. Conclusions: A prophylaxis regimen with emicizumab and factor replacement in PWH with or without inhibitors undergoing major orthopaedic surgery ensures effective bleeding control and good postoperative clinical outcomes at mid-term follow-up, and may be routinely adopted in dedicated high-volume hospitals. This series is the most consistent to date reported at a single Haemophilia centre. [ABSTRACT FROM AUTHOR]

This article discusses a rare case of a pregnant woman with severe hemophilia A and an inhibitor who was treated with emicizumab during pregnancy and postpartum. The article provides details about the patient's medical history, clinical course during pregnancy, and the effect of emicizumab on the newborn. It also discusses the transplacental transfer of emicizumab and its presence in breast milk. The article concludes that while this case provides valuable insights, further research is needed to determine the safety and transmissibility of emicizumab during pregnancy and breastfeeding. [Extracted from the article]

Introduction: Despite the rapid uptake of emicizumab in the paediatric haemophilia A (HA) population, real‐world data on the safety and efficacy is limited. Aim: To report on bleeding and safety in paediatric patients receiving emicizumab prophylaxis. Methods: Data were extracted from the multicentre prospective observational PedNet Registry (NCT02979119). Children with haemophilia A, and ≥50 FVIII exposures or inhibitors present receiving emicizumab maintenance therapy were analysed. Data were summarized as medians with interquartile range (IQR, P25–P75). Mean (95% confidence interval (CI)), annualized (joint) bleeding rate (A(J)BR) during emicizumab and ≤2 years before emicizumab prophylaxis were modelled and compared using negative binomial regression. Results: Total of 177 patients started emicizumab at median 8.6 years (IQR 4.8–13.1), most had no FVIII inhibitors (64%). Follow up before emicizumab was median: 1.68 years (IQR: 1.24–1.90) and during emicizumab: 1.32 years (IQR:.94–2.11). In patients without inhibitors, mean ABR reduced after starting emicizumab from 2.41 (CI 1.98–2.95) to 1.11 (CI.90–1.36, p <.001), while AJBR reduced from.74 (CI.56–.98) to.31 (CI.21–.46, p <.001). Concordantly, in patients with inhibitors, mean ABR reduced from 5.08 (CI 4.08–6.38) to.75 (CI.56–1.01, p <.001), while AJBR reduced from 1.90 (CI 1.42–2.58) to.34 (CI.21–.56, p <.001). Five emicizumab‐related adverse events were reported (3% of the cohort), including one patient with antidrug antibodies. Conclusion: This study showed improved bleeding control compared to previous treatment and a favourable safety profile during emicizumab therapy in paediatric haemophilia A patients. [ABSTRACT FROM AUTHOR]

Background: Emicizumab (Emi) is used as haemostatic prophylaxis for patients with haemophilia A (PwHA). Disseminated intravascular coagulation (DIC) is a condition characterized by persistent systemic activation of coagulation, but there is yet no information on coagulation and fibrinolysis potentials in Emi‐treated PwHA with DIC. Aim: To examine the effect of Emi on coagulation and fibrinolysis potentials in HA‐model DIC plasmas. Methods: Plasma from a patient with sepsis‐DIC (seven patients) was treated with anti‐factor (F)VIII monoclonal antibody (HA‐model DIC plasma) and incubated with Emi (50 µg/mL). The plasma was then assessed using clot‐fibrinolysis waveform analysis (CFWA). Coagulation and fibrinolysis parameters were expressed as ratios relative to normal plasma (|min1|‐ratio and |FL‐min1|‐ratio, respectively). Patients and results: In case 1, coagulant potential was slightly high and fibrinolytic potential was extremely low, presenting a coagulant‐dominant state (|min1|‐ratio/|FL‐min1|‐ratio: 1.1/.38). In cases 2–5, fibrinolytic potential was not suppressed, but there were marked hypercoagulant potentials, indicating relative coagulant‐dominant states. In case 6, coagulant and fibrinolytic potentials were increased but well balanced (|min1|‐ratio/|FL‐min1|‐ratio: 1.38/1.28). In case 7, both potentials were severely deteriorated in not only CFWA but also the thrombin/plasmin generation assay. The addition of Emi into the HA‐model DIC plasmas increased |min1|‐ratio values in all cases, but the coagulant potentials did not exceed the initial ones (DIC plasma before treatment with anti‐FVIII antibody). Conclusions: The presence of Emi in the HA‐model DIC plasma improved coagulation potentials, but did not increase coagulation potentials beyond those of DIC plasma in non‐HA states. [ABSTRACT FROM AUTHOR]

A survey of pediatric Hemophilia Treatment Center (HTC) Medical Directors in the U.S. found that the majority would consider using emicizumab as a prophylactic treatment for infants under 12 months of age, even in those who have not been previously treated or minimally treated. The main reason for this decision is to prevent intracranial hemorrhage, which is a high risk for children with hemophilia. While there is a lack of data and experience in this age group, real-world data and the HAVEN 7 study support the safety and efficacy of emicizumab in infants. It is important for providers and families to engage in shared decision-making when considering this treatment option. However, the survey has limitations, such as a small sample size and potential variation in practices among different hematologists, and further studies are needed to explore the rationale for delaying emicizumab initiation. [Extracted from the article]

Introduction/Aim. Hemophilia A is an antihemophilic factor deficiency which requires life-long treatment. The aim of this analysis was to present the effects of prophylactic non-factor replacement therapy in ten patients with hemophilia A. Patients and This retrospective analysis was conducted on ten male patients (4 children, 1 adolescent, and 5 adults) with severe hemophilia A and a history of antihemophilic factor replacement prophylaxis, prior to the initiation of emicizumab prophylaxis. A single adult patient developed inhibitors during the course of factor replacement prophylaxis. Four adult patients had already developed hemophilic arthropathy before the initiation of non-factor replacement prophylaxis. Two adult patients received emicizumab prophylaxis every four weeks, while others received emicizumab every two weeks. After a 14-month period (average) of non-factor replacement prophylaxis, we analyzed the number of breakthrough bleeding episodes, annualized bleeding rate, involvement of target joints, adverse drug reactions, and interviewed the patients regarding their satisfaction with the non-factor replacement treatment. Results. None of the patients on emicizumab prophylaxis experienced breakthrough bleeding or clinical worsening of the affected target joints during the period of emicizumab prophylaxis. Annualized bleeding rate was zero in all patients on emicizumab prophylaxis. No adverse drug reactions occurred in our patients during emicizumab prophylaxis. All patients reported greater treatment satisfaction compared to the replacement prophylaxis. Conclusion. By providing safety from bleeding events and potentially the stability of the affected joints, emicizumab prophylaxis enables greater activity and increases the quality of life of treated patients. [ABSTRACT FROM AUTHOR]

Despite major advances in prophylaxis, no repeated dosing regimen with currently employed extended-half-life or non-factor products replaces the advantages of a long-term cure in persons with severe congenital hemophilia A and B (HA, HB). They indeed live with the risk of breakthrough bleedings, and treatment is still invasive, both physically and psychologically. Early studies showed that adeno-associated virus-based in vivo gene therapy (AAV-based in vivo GT), could convert haemophilia persons from a severe to mild a phenotype for years. However, the proportion of the hemophilia population likely to benefit from this transformative strategy was uncertain. Current evidence is expanding the eligibility criteria, and helps to predict risks, complications and unexpected side effects of this advanced treatment. Thus, among future options, AAV-based in vivo GT is likely to become the treatment of choice in HA and HB, if real-life data confirm its negligible short-term adverse events. However, while the global use of AAV-based in vivo GT is endorsed as a key objective of future studies in hemophilia, the liberating capability of a potentially one-off treatment on individuals with chronic diseases for whom lifelong cure has been inaccessible so far remains to be thoroughly recognized by government bodies. This is critical for reimbursement agencies to absorb the cost of the cure and calls for a partnership between health care systems and the pharmaceutical industry. However, bridging the gap between the costs of the advanced treatments approved for commercialization and their readiness to persons with HA and HB is still a challenging task. [ABSTRACT FROM AUTHOR]

Summary: The hallmark of haemophilia A (HA) therapy is prophylaxis, aimed at spontaneous bleeding prevention. Emicizumab provides a viable alternative to intravenous factor replacement therapy. However, data on its use in infants are limited. This single‐centre open arm prospective study reports on emicizumab prophylaxis in infants. We included severe HA patients under 1 year who started emicizumab prophylaxis since 2018, with longitudinal follow‐up. The study collected data on demographics, clinical and laboratory variables, the occurrence of bleeding events, surgeries and treatment outcomes. Of the 27 enrolled infants, whose median age at prophylaxis initiation was 7 months, 24 primarily choose to start emicizumab therapy (3/27 switched from FVIII prophylaxis due to development of FVIII inhibitors). The median age for prophylaxis initiation decreased to 3 months in 2023. Following emicizumab initiation, the median calculated ABR decreased, and no intracranial haemorrhages were observed. Thrombin generation showed a significant improvement in peak height and endogenous thrombin potential at steady state after a loading period. Our study highlights a shift towards early prophylaxis in the era of non‐replacement therapies. It underscores the need for continuous evaluation and refinement of treatment approaches, emphasizing personalized care and diligent monitoring in the evolving field of paediatric haemophilia care. [ABSTRACT FROM AUTHOR]

Introduction: Haemophilia nursing practice has experienced a shift in the past decade, as the historic chief focus on factor infusions shifted to extended half‐life products, bispecific antibody therapies and other non‐replacement therapies. This evolution has driven a need for changes in nursing practice in many haemophilia treatment centres. Aim: This article intends to provide insights to the haemophilia nurse to champion practice changes at their haemophilia treatment centres. Methods: Two popular change theories, Lewin's three‐step change model and Kotter's eight‐step change model are discussed as a framework for haemophilia nurses to think, structure and be leaders in change. Conclusion: Examples of these models in practice could give guidance and examples to reflect on for haemophilia nurses needing to make changes in their practice settings. These models of change, alongside existing haemophilia nurse competencies and tools such as the shared decision‐making tool from the World Federation of Hemophilia, can assist the nurse to be a capable change agent to usher in these new innovations. [ABSTRACT FROM AUTHOR]

Registries are excellent sources of data to address questions that are typically not evaluated in randomized clinical trials, including natural history, disease prevalence, treatment approaches and adverse events, and models of care. Global and regional registries can provide data to identify differences in outcomes and in haemophilia care between countries, economic settings, and regions, while facilitating research and data sharing. In this manuscript, we highlight five bleeding disorder registries: Country registries from Australia and China, Paediatric Network on Haemophilia Management (PedNet) data on children who have received emicizumab, data from the European Haemophilia Safety Surveillance (EUHASS) system, and data on women and girls with haemophilia from the World Federation of Haemophilia (WFH) registries. Data from these and other bleeding disorder registries have been and will continue to be used to advance patient care, understand treatment patterns and adverse reactions, and identify areas of increased need and focus. [ABSTRACT FROM AUTHOR]

Introduction: Over the last decades progress in haemophilia treatment has been remarkable and prophylaxis with clotting factor concentrates in haemophilia A and B has been established as the standard of care in individuals with haemophilia and a severe bleeding phenotype. Besides clotting factor products with prolonged half‐life non‐factor therapies were developed which enable prophylaxis via subcutaneous administration. Factor VIIIa mimetics like emicizumab facilitate the coagulation pathway and are used in routine clinical practice for indivdiduals with haemophilia A. Rebalancing therapeutic agents like fitusiran, concizumab, marstacimab and serpin PC block the anticoagulant pathway and clinical trials using these products in individuals with haemophilia A and B are ongoing. Aim and Methods: A narrative review to asess the benefits and risks of non‐factor therapies taking in to account re‐defined haemophilia treatment goals. Results: Prophylaxis for prevention of bleeds using non‐factor products by subcutaneous administration is effective and results in reductions of bleeding episodes in individuals with haemophilia A or B with and without inhibitors. The treatment with emicizumab showed tolerable safety both in clinical trials and long‐term real‐world observations with few thrombotic events. In some clinical trials with rebalancing therapies (fitusiran and concizumab) thrombotic events occurred. Monitoring of the haemostatic function of novel therapies especially with concomitant haemostatic treatment is not yet established. Conclusion: With the advent of novel therapeutic agents including factor concentrates with ultra‐long half‐life and improved FVIIIa mimetics aimed at raising the bar of protection into the non‐hemophilic range redefinition of haemophilia treatment goals is eagerly needed. [ABSTRACT FROM AUTHOR]

Introduction: Prophylaxis has become standard of care for all persons with haemophilia (PWH) with a severe phenotype. However, 'standard prophylaxis' with either factor or non‐factor therapies (currently only emicizumab available) is prohibitively expensive for much of the world. We sought to address the question of 'How much prophylaxis is enough?' and 'Can it be individualized?' and specifically 'Can emicizumab be individualized?'. Methods: We reviewed the literature on prophylaxis in haemophilia since its inception in the 1950s to the present, the development of more and less intense factor prophylaxis regimens and their outcomes and additionally the published outcomes of prophylaxis with low dose emicizumab. Results: What these experiences collectively show is that low dose emicizumab does result in significant benefits to patients whilst being much less expensive than a "one size fits all" emicizumab prophylaxis approach. We also took note that some non‐factor therapies still in development are individualized given that high doses of these can potentially put patients at risk. Conclusions: Prophylaxis is now clearly accepted as standard of care for PWH with a severe phenotype but now in a very short time a large assortment of different treatment options for prophylaxis have become/are becoming available and the haemophilia community will need to determine how to best use these recognizing that no 'one treatment fits all'. [ABSTRACT FROM AUTHOR]

Introduction. The case is presented of a 10-year-old boy with severe Haemophilia A, in whom standard therapy led to the development of an inhibitor to factor VIII. Immunological tolerance induction (ITI) did not yield the expected result, and inhibitor titers were not reduced. Due to numerous recurrent bleeds, prophylaxis with activated prothrombin complex concentrate (aPCC) was initiated, with recombinant factor VIIa administered in the case of bleeding episodes. Despite second and third-line ITI treatments, desired outcomes were not achieved, leading to therapy discontinuation and initiation of emicizumab treatment. The new therapy significantly reduced bleeding occurrences. Results. This case clearly illustrates the greater efficacy of emicizumab compared to other drugs, confirming its application in patients with developed factor VIII inhibitors where ITI therapy was ineffective. Prophylaxis with this antibody significantly reduces bleeding frequency and improves the patient's quality of life. [ABSTRACT FROM AUTHOR]

Les anticorps thérapeutiques font désormais partie intégrante de l'arsenal médical dans le traitement de nombreuses affections, y compris en hémostase. Ce sont tous des anticorps monoclonaux humanisés – au suffixe "zumab" – permettant de restaurer partiellement l'hémostase (emicizumab, concizumab), ou ayant une action d'antidote (idarucizumab) pour antagoniser l'effet de certains anticoagulants (dabigatran) ou des antiagrégants plaquettaires (bentracimab encore à l'étude) ; d'autres ont été ou pourront être utilisés pour leur propre pouvoir antiagrégant (abciximab arrêté en septembre 2019 ou le futur antiagrégant antiGPVI, glencozimab). Le caplacizumab est quant à lui un nanobody indiqué dans la phase aiguë du purpura thrombotique thrombocytopénique acquis. Therapeutic antibodies are now an integral part of the therapeutic arsenal in the treatment of many conditions, including haemostasis. They are all humanized monoclonal antibodies (suffix : zumab) that can partially restore hemostasis (emicizumab, concizumab), or used as an antidote (idarucizumab) to antagonize the effect of certain anticoagulant (dabigatran) or platelet antiagregants (bentra-cimab, still under study). Others therapeutic antibodies have been or may be used for their own antiagregant properties (abciximab, discontinued in September 2019, or the future anti-GPVI antiagregant glencozimab, still under study). As for caplacizumab, it is a nanobody indicated in the acute phase of acquired throm-botic thrombocytopenic purpura. [ABSTRACT FROM AUTHOR]

Introduction: Recombinant porcine factor VIII (rpFVIII) is a treatment option for break‐through bleeds in patients with congenital haemophilia A with inhibitors (CHAwI) on emicizumab. However, there are limited data about the measurement of rpFVIII in the presence of emicizumab. Aim: To analyse whether rpFVIII can be measured with a chromogenic assay with bovine component (bCSA) in plasma from CHAwI on emicizumab treatment. Methods: In the first part of the study, FVIII deficient plasma was spiked with rpFVIII, in the second part, commercial plasma from CHAwI was spiked with emicizumab and rpFVIII, and in the third part, plasma from CHAwI on emicizumab treatment was spiked with rpFVIII. FVIII was then measured with bCSA and a chromogenic assay with human component (hCSA). Thrombin generation (TG) and clot‐waveform analysis (CWA) were also carried out. Results: The recovery of rpFVIII measured with bCSA is approximately 80% and is further influenced by the presence of an anti‐porcine inhibitor. rpFVIII assessed with hCSA was influenced by emicizumab. CWA and TG showed a weak correlation with baseline emicizumab concentration, but peak thrombin and CWA correlated well with increasing emicizumab concentrations and rpFVIII activities. Conclusion: This study indicates that rpFVIII can be measured in the presence of emicizumab with a bCSA. A calibration curve for the measurement of rpFVIII with bCSA should be established. [ABSTRACT FROM AUTHOR]

Background: Emicizumab is used as a subcutaneous prophylaxis for prevention of bleeding episodes in patients with haemophilia A (HA) with and without inhibitors. While low bleeding rates were observed in clinical trials, patients still experience breakthrough bleeds (BTBs) with emicizumab in the real‐world. Current guidelines recommend use of recombinant activated factor VII (rFVIIa) for treatment of BTBs in patients with inhibitors. Due to thrombotic events observed in the HAVEN 1 study, activated prothrombin complex concentrate (aPCC) should be used with caution. Objectives: The objective of this review is to identify and discuss real‐world data on the frequency of BTBs and the safety of concomitant rFVIIa use in patients with inhibitors on emicizumab prophylaxis. Methods: A search of the following databases was conducted on 15 July 2022: BIOSIS Previews®, Current Contents Search®, Embase®, MEDLINE®. Search terms included 'real world', 'haemophilia A', and 'emicizumab'. Results and conclusions: Eleven relevant publications were identified (seven original research articles and four congress abstracts). The frequency of BTBs specifically for HA patients with inhibitors was described in three publications with 5%–56% patients on emicizumab reporting ≥1 bleeding episode. Treatment of these BTBs appeared to be managed according to relevant guidelines. Importantly, no thrombotic complications occurred during concomitant rFVIIa use. Due to the nature of real‐world studies, direct comparison of the results between studies is limited. However, real‐world data show that BTBs in inhibitor patients during emicizumab prophylaxis can be safely treated with rFVIIa. [ABSTRACT FROM AUTHOR]

This article discusses the stability of emicizumab, a medication used to treat patients with hemophilia A, in blood samples under various conditions. The study found that emicizumab remains stable for at least 5 days in whole blood and at least 24 hours in plasma. Additionally, short-term and long-term storage at -80°C and one or two freeze-thaw cycles did not affect the concentration of emicizumab. However, the article also highlights that heat treatment at 56°C or 58°C, commonly used to inactivate factor VIII, resulted in a decrease in the apparent concentration of emicizumab. These findings have implications for laboratory practices and the detection of neutralizing antibodies in patients receiving emicizumab treatment. [Extracted from the article]

Introduction: Emicizumab is the initial subcutaneously administered bispecific antibody approved as a prophylactic treatment for patients with haemophilia A (PwHA). Aim: This study assessed the economic evaluation of emicizumab treatment for non‐inhibitor severe haemophilia A (HA) patients in India. Methods: A Markov model evaluated the cost‐effectiveness of emicizumab prophylaxis compared to on‐demand therapy (ODT), low‐dose prophylaxis (LDP; 1565 IU/kg/year), intermediate‐dose prophylaxis (IDP; 3915 IU/kg/year) and high‐dose prophylaxis (HDP; 7125 IU/kg/year) for HA patients without factor VIII inhibitors. Inputs from HAVEN‐1 and HAVEN‐3 trials included transition probabilities of different bleeding types. Costs and benefits were discounted at a 3.5% annual rate. Results: In the base‐case analysis, emicizumab was cost‐effective compared to HDP, with an incremental cost‐effectiveness ratio (ICER) per quality‐adjusted life‐years (QALY) of Indian rupees (INR) 27,869. Compared to IDP, ODT and LDP, emicizumab prophylaxis could be considered a cost‐effective option if the paying threshold is >1 per capita gross domestic product (GDP) with ICER/QALY values of INR 264,592, INR 255,876 and INR 305,398, respectively. One‐way sensitivity analysis (OWSA) highlighted emicizumab cost as the parameter with the greatest impact on ICERs. Probabilistic sensitivity analysis (PSA) indicated that emicizumab had a 94.7% and 49.4% probability of being cost‐effective at willingness‐to‐pay (WTP) thresholds of three and two‐times per capita GDP. Conclusion: Emicizumab prophylaxis is cost‐effective compared to HDP and provides value for money compared to ODT, IDP, and LDP for severe non‐inhibitor PwHA in India. Its long‐term humanistic, clinical and economic benefits outweigh alternative options, making it a valuable choice in resource‐constrained settings. [ABSTRACT FROM AUTHOR]

Abstract Emicizumab is a monoclonal antibody that bridges activated factor IX (FIX) and factor X (FX) to replace the function of missing activated factor VIII (FVIII) in hemophilia A patients irrespective of FVIII inhibitor status. This study assessed the effectiveness of emicizumab in preventing bleeding episodes in patients with hemophilia A. This observational study included patients with moderate to severe hemophilia A who were undergoing episodic FVIII replacement therapy. The primary endpoint was the difference in annualized bleeding rates (ABR) and the secondary endpoint was the difference in Hemophilia Joint Health Score (HJHS) before and after emicizumab prophylaxis. A total of 30 male hemophilia patients were included, the mean age was 16.7 (SD: ±8.1) years, and most of them had moderate hemophilia A [63.3%]. Before prophylaxis, the median ABR was 48 (interquartile range [IQR]: 35–60), and 93.3% of patients had ABR greater than eight, whereas after prophylaxis the median ABR decreased significantly (median [IQR]: 0 [0.0–0.4], p

This study presents a transversal investigation that we performed at Fundeni hospital (Bucharest, Romania) into the therapeutic benefits and efficacy of Emicizumab, a non-factor therapy, in the context of hemophilia A. Ten patients diagnosed with hemophilia A were closely monitored using clinical and laboratory resources during Emicizumab treatment, with an average of 12.8 months. Among these patients, six exhibited anti-factor VIII inhibitors, changing the medical strategy and adding complexity to their clinical profiles. A comprehensive approach was adopted to assess the coagulation status of patients under Emicizumab therapy. The study employed several key coagulation monitoring tools, including thrombin generation time (TGT) and thrombelastography (TEG). These methodologies generated valuable results in evaluating the patients’ coagulation profiles during the treatment regimen. Additionally, traditional coagulation assays were utilized to gain a profound understanding of the overall coagulation dynamics and to evaluate the therapeutic response. During prophylaxis with Emicizumab all patients experienced a reduced number of bleeding events. Moreover, a subset of these patients underwent major surgical procedures (orthopedic joint replacements, cholecystectomy) with successful outcomes. These findings underscore the potential of Emicizumab therapy as an effective option for hemophilia A patients, including those with inhibitors. Our research provides physicians several insights, offering a potential avenue for improved patients’ care and treatment strategies that translate in enhanced quality of life for hemophilia A patients undergoing Emicizumab therapy.

This article discusses the use of emicizumab, a medication used to treat haemophilia A (HA), in children under 12 years old in Uruguay. HA is a genetic disorder characterized by a deficiency of coagulation factor VIII. The standard treatment for severe HA involves regular prophylaxis with factor VIII concentrates, but this can still leave patients at risk of bleeding. Emicizumab is a monoclonal antibody that mimics the function of factor VIII and has shown efficacy in preventing bleeding in adult and teenage patients. This study aimed to assess the efficacy and safety of emicizumab in a pediatric population in Uruguay. The results showed that emicizumab was effective in reducing bleeding episodes, with a low rate of adverse events. This study provides valuable insights into the treatment of HA in Uruguay and contributes to the broader understanding of managing this condition. [Extracted from the article]