Emicizumab Prophylaxis Research Articles

Management of surgery in persons with hemophilia A receiving emicizumab prophylaxis: data from a national hemophilia treatment center

BackgroundPersons with hemophilia A may require surgical procedures. Real-world data on invasive procedures in persons with hemophilia A receiving emicizumab prophylaxis are limited. ObjectivesTo evaluate the safety of invasive procedures in persons with hemophilia A receiving emicizumab prophylaxis and their outcomes in a longitudinally followed cohort. MethodsData from medical records of persons with hemophilia A with and without factor VIII (FVIII) inhibitors longitudinally followed at our tertiary center, who received emicizumab prophylaxis and underwent all types of invasive procedures, were retrieved. Outcomes of interest were bleeding and thrombotic complications. ResultsOverall, 35 patients underwent 56 invasive procedures, 18 (32.1%) were major. The median age was 36.3 years (IQR, 8.8-55.9 years); 12 patients (34.3%) were younger than 18 years at the time of procedure; 17 (48.6%) were patients with FVIII inhibitors. Among major procedures, orthopedic surgeries prevailed. All patients who underwent major procedures received factor replacement with either recombinant activated factor VII (patients with inhibitors) or FVIII (patients without inhibitors). Factor concentrates were administered prior to 32 (84.2%) of the minor procedures. Repeated doses were given according to international expert opinion recommendations and patients’ condition.There were 7 bleeding events in 6 patients, 5 were major bleeds, including 1 patient who underwent a minor procedure without factor replacement. None of the patients experienced a thrombotic complication. ConclusionInvasive procedures can be performed safely in patients receiving emicizumab prophylaxis with close surveillance after surgery. Factor concentrates may be advised in selected patients undergoing minor procedures.

HTRS2023.P2.18 Pediatric persons with hemophilia A on EHL-FVIII or emicizumab prophylaxis require iron therapy despite low annualized bleeding rate

HTRS2023.P2.18 Pediatric persons with hemophilia A on EHL-FVIII or emicizumab prophylaxis require iron therapy despite low annualized bleeding rate

Imlifidase, a new option to optimize the management of patients with hemophilia A on emicizumab

BackgroundEmicizumab is a bispecific, chimeric, humanized immunoglobulin G (IgG)4 that mimics the procoagulant activity of factor (F) VIII (FVIII). Its long half-life and subcutaneous route of administration have been life-changing in treating patients with hemophilia A (HA) with or without FVIII inhibitors. However, emicizumab only partially mimics FVIII activity; it prevents but does not treat acute bleeds. Emergency management is particularly complicated in patients with FVIII inhibitors receiving emicizumab prophylaxis in whom exogenous FVIII is inefficient. We have shown recently that Imlifidase (IdeS), a bacterial IgG-degrading enzyme, efficiently eliminates human anti-FVIII IgG in a mouse model of severe HA with inhibitors and opens a therapeutic window for the administration of exogenous FVIII. ObjectivesTo investigate the impact of IdeS treatment in inhibitor-positive HA mice injected with emicizumab. MethodsIdeS was injected to HA mice reconstituted with human neutralizing anti-FVIII IgG and treated with emicizumab. ResultsIdeS hydrolyzed emicizumab in vitro and in vivo, albeit, at slower rates than another recombinant human monoclonal IgG4. While F(ab’)2 fragments were rapidly cleared from the circulation, thus leading to a rapid loss of emicizumab procoagulant activity, low amounts of single-cleaved intermediate IgG persisted for several days. Moreover, the IdeS-mediated elimination of the neutralizing anti-FVIII IgG and restoration of the hemostatic efficacy of exogenous FVIII were not impaired by the presence of emicizumab and polyclonal human IgG in inhibitor-positive HA mice. ConclusionOur results suggest that IdeS could be administered to inhibitor-positive patients with HA receiving emicizumab prophylaxis to improve and ease the management of breakthrough bleeds or programmed major surgeries.

Physical Activity Limitations In Children With Severe Haemophilia A. Does Emicizumab Make A Difference?

To assess the effect of emicizumab on physical activity in children with severe haemophilia A. The prospective cohortstudy was conducted from October 2021 to April 2022 at the Paediatric Department of Kafrelsheikh University Hospital, Egypt, in collaboration with the Haematology out-patient clinic of the Paediatric Department, Zagazig University, Egypt, and the Paediatric Department of Cairo University Hospital, Egypt, and comprised children aged 4-18 years with severe haemophilia A who received emicizumab prophylaxis. Paediatric Haemophilia Activities List was used to assess physical activity at baseline and aftersix months of regular emicizumab prophylaxis. Data was analysed using SPSS 26. There were 29 children, all (100%) boys, with mean age 8.7±3.51 years(range 4-15 years. Of them, 17(58.62%) patients were negative for inhibitors. Median Paediatric Haemophilia Activities Listsum score was 59.54 (interquartile range: 50.15-62.05) at baseline which moved up to 84 (interquartile range: 79.05-86.35) post-intervention (p<0.001). Emicizumab prophylaxis improved the level of physical activity in children with severe haemophilia A.

Factor VIII inhibitors in hemophilia A treated with emicizumab: longitudinal follow-up of outcomes

BackgroundUsing emicizumab in lieu of immune tolerance induction (ITI) for patients with hemophilia A (HA) and factor (F)VIII inhibitors has been well described. However, decisions regarding ITI initiation, regimen, and preservation of tolerance remain to be elucidated. ObjectivesTo study the course of FVIII inhibitors in patients with HA and a history of FVIII inhibitors receiving emicizumab prophylaxis. MethodsPatients with HA, with and without FVIII inhibitors, initiating emicizumab prophylaxis were prospectively followed up in our center. All patients with current or previous inhibitors were included in this analysis. Plasma samples for FVIII inhibitor assays were obtained every 3 to 6 months or following FVIII exposure. Patients documented annual bleeding rate and any FVIII exposure days (EDs). ResultsOf 162 emicizumab-treated participants, 51 met the inclusion criteria. A decrease in annual bleeding rate was observed in all 51 participants followed up for a median of 3.3 years, with 31 breakthrough bleeding episodes reported in 22 of 51 participants. FVIII inhibitor level transiently increased following FVIII exposures in 5 of 15 failed ITI participants. Eight of 21 participants who did not undergo ITI were exposed to FVIII (1-2 EDs)), and 1 of these 8 participants demonstrated increased FVIII inhibitor levels after head trauma (following 1 ED). Among participants who underwent successful ITI, 8 of 15 patients were exposed to FVIII over a total of 13 EDs (1-2 ED(s) each) for traumatic breakthrough bleeds. In all these participants, inhibitor levels remained zero, indicating successful tolerance maintenance. ConclusionOur longitudinal follow-up of emicizumab-treated patients with HA and FVIII inhibitors shows that occasional exposure to FVIII may induce a transient anamnestic response. Nonetheless, no FVIII inhibitor recurrence was noted following FVIII exposures in patients who underwent successful ITI.

A real-world evidence analysis of the impact of switching from factor VIII to emicizumab prophylaxis in patients with hemophilia A without inhibitors

ABSTRACT Background This study retrospectively compared annualized billed bleed rates (ABRb) in people with hemophilia A (PwHA) without inhibitors who switched from factor VIII (FVIII) prophylaxis to emicizumab. Research design and methods A real-world comparison study was performed on the effect of switching from FVIII to emicizumab prophylaxis in male, non-inhibitor patients on ABRb using an all-payer claims database (APCD) dataset from 1 January 2014, to 31 March 2021. The identification period was from 1 November 2017, to 30 September 2020. Results One hundred and thirty-one patients were included with a total of 82 and 45 bleeds in the pre- and post-switch periods, respectively. The average follow-up period pre-switch was 978.37 days (SD 555.03), whereas the average follow-up period post-switch was 522.26 days (SD 191.36). No significant differences in mean ABRb were observed pre-/post-switch (0.25 and 0.20, respectively; P = 0.4456). Conclusions The results of this study demonstrate no significant reduction in ABRb, suggesting that switching from FVIII to emicizumab may not deliver incremental benefits to PwHA receiving prophylactic care.

Impact of switching prophylaxis treatment from factor VIII to emicizumab in hemophilia A patients without inhibitors

BackgroundFactor VIII (FVIII) replacement and emicizumab are effective at preventing bleeds in patients with hemophilia A (HA). Though benefits of emicizumab among inhibitor patients with HA (PwHA) are well established, more real-world evidence among non-inhibitor patients is needed.MethodsUsing a United States healthcare claims database, we compared billed annualized bleed rates (ABRb) and the total cost of care (TCC) before and after switching from FVIII prophylaxis to emicizumab among non-inhibitor male PwHA. Bayesian inferences were used to assess the difference in ABRb and TCC per patient per year (PPPY) pre- versus post-prophylaxis switch.ResultsWe included 101 non-inhibitor male PwHA aged between 3 and 63 years old who switched from FVIII prophylaxis to emicizumab prophylaxis in 2018 or 2019. The ABRb increased from 0.52 to 0.62 (p = 0.83) after switch. The posterior probability of the mean ABRb increasing after the switch was 75.54%. The TCC PPPY increased from $517,143 to $627,005 (p < 0.0001) after switch and the posterior probability of mean costs increasing after the switch was 99.80%.ConclusionsPersonalization of care through the identification of the most appropriate therapy for each patient can optimize clinical and economic outcomes. Future real-world evidence research could help establish the value of prophylactic options in targeted populations such as the non-inhibitor male PwHA.

Trends in prescribing practices for management of haemophilia: 1999–2021

People with haemophilia rely on specialists for their care, yet the specific dosing regimens of treatments prescribed by these specialists have not been widely studied. The objective of this study is to describe trends in clinician prescribing practices for the management of haemophilia in the United States (US). We administered surveys to members of the Hemostasis and Thrombosis Research Society via paper surveys at its in-person annual symposia in 1999 and 2015, and an online survey in 2021. The surveys collected information on haemophilia treatments including factor dosing, inhibitor therapy and gene therapy. Clinicians treating haemophilia for more than 50% of their practice time have increased from 37.5% of respondents in 1999 to 46.3% in 2021. Clinicians prescribing factor concentrates at >40 units/kg for routine bleeding events increased from 0% in 1999 to 29.3% in 2021 in haemophilia A (HA) and from 22.5% to 87.8% in haemophilia B (HB). In 2021, the clinicians reported prescribing emicizumab to treat HA patients (>89.5% paediatric, >85.7% adult) with or without inhibitors at least some of the time. Approximately 78.0% of respondents reported that they expected to recommend gene therapy at least some of time. These data indicate changing trends in prescribing practices among US haemophilia specialists during the past 22 years. Preference for high doses of factor (>40 units/kg) has increased during this period. Emicizumab prophylaxis has been prescribed for patients with and without HA inhibitors. Clinicians expect gene therapy to have value for some haemophilia patients.

Cerebellar hematoma in severe hemophilia with inhibitor on emicizumab prophylaxis: a case report

BackgroundEmicizumab is a novel prophylactic medication used to treat patients with hemophilia A. It is indicated to minimize the frequency of bleeding episodes and the severity of serious bleeding in patients with hemophilia A utilizing inhibitors. However, some cases of bleeding episodes have been reported, and more data are needed regarding their management and expected outcomes.Case presentationWe report a case of a 4-year-old Saudi Arabian boy with severe hemophilia A who presented with a post-traumatic cerebral hemorrhage. The patient, with high titer inhibitors, was on emicizumab prophylaxis therapy. On hospital admission, he received tranexamic acid (10 mg intravenously, every 6 hours), and recombinant activated factor VII 120 µg/kg every 2 hours for 2 days then every 4 hours for 4 days. On follow-up, the patient showed no signs of neurological deficit. There was no need for emergency neurosurgical intervention since the bleeding had been controlled throughout the first 2 days. There were no recorded thrombotic sequelae or neurological complications, with complete resolution within 10 days.ConclusionsThis case implies that low-dose recombinant activated factor VII might be used safely and effectively with patients with hemophilia A on emicizumab prophylaxis, to reduce the risk of cerebral hemorrhage or another episode of serious bleeding along with its long-term complications.

Emicizumab prophylaxis in haemophilia A with inhibitors: Three years follow-up from the UK Haemophilia Centre Doctors' Organisation (UKHCDO).

The UK National Haemophilia Database (NHD) collects data from all UK persons with haemophilia A with inhibitors (PwHA-I). It is well-placed to investigate patient selection, clinical outcomes, drug safety and other issues not addressed in clinical trials of emicizumab. To determine safety, bleeding outcomes and early effects on joint health of emicizumab prophylaxis in a large, unselected cohort using national registry and patient reported Haemtrack (HT) data between 01 January 2018 and 30 September 2021. Prospectively collected bleeding outcomes were analysed in people with ≥6 months emicizumab HT data and compared with previous treatment if available. Change in paired Haemophilia Joint Health Scores (HJHS) were analysed in a subgroup. Adverse events (AEs) reports were collected and adjudicated centrally. This analysis includes 117 PwHA-I. Mean annualised bleeding rate (ABR) was .32 (95% CI, .18; .39) over a median 42 months treatment with emicizumab. Within-person comparison (n = 74) demonstrated an 89% reduction in ABR after switching to emicizumab and an increase in zero treated bleed rate from 45 to 88% (p < .01). In a subgroup of 37 people, total HJHS improved in 36%, remained stable in 46% and deteriorated in 18%, with a median (IQR) within-person change of -2.0 (-9, 1.5) (p = .04). Three arterial thrombotic events were reported, two possibly drug related. Other AEs were generally non-severe and usually limited to early treatment, included cutaneous reactions (3.6%), headaches (1.4%), nausea (2.8%) and arthralgia (1.4%). Emicizumab prophylaxis is associated with sustained low bleeding rates and was generally well-tolerated in people with haemophilia A and inhibitors.

POSTER ABSTRACTS

POSTER ABSTRACTS

The dosing conundrum of emicizumab: To waste product or not?

The dosing conundrum of emicizumab: To waste product or not?

Emicizumab in people with moderate or mild haemophilia A (HAVEN 6): a multicentre, open-label, single-arm, phase 3 study

Clinical trial data are scarce for the use of prophylaxis in people with non-severe haemophilia A. The HAVEN 6 study aims to assess safety and efficacy of emicizumab prophylaxis in people with non-severe haemophilia A without factor VIII (FVIII) inhibitors. HAVEN 6 is a multicentre, open-label, single-arm, phase 3 study taking place in 22 specialty clinics and hospitals in Europe, North America, and South Africa. Eligible participants were people of all ages weighing at least 3 kg with a diagnosis of moderate (FVIII activity ≥1%-≤5%) or mild (FVIII >5%-<40%) haemophilia A without FVIII inhibitors requiring prophylaxis as assessed by the treating physician. Participants received subcutaneous emicizumab 3 mg/kg of bodyweight once weekly for 4 weeks, followed by the participant's choice of maintenance dose: 1·5 mg/kg once weekly, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks. Safety was the primary objective of the study. Safety endpoints included adverse events, serious adverse events, and adverse events of special interest including thromboembolic events and thrombotic microangiopathies. The primary efficacy endpoint was the annualised bleed rate for treated bleeds. Analyses were done for participants who received at least one dose of emicizumab. This study is registered with ClinicalTrials.gov, number NCT04158648, and is active but not recruiting. Between Feb 10, 2020, and Aug 31, 2021, we assigned 73 people to treatment. 72 participants received at least one dose of emicizumab (51 moderate [71%]; 21 mild [29%]; 69 male [96%]; three female [4%]; and 61 White [85%]). Median age was 23·5 years (IQR 12·0-36·0); median follow-up was 55·6 weeks (IQR 52·3-61·6) weeks. At baseline, 24 participants (33%) had target joints and 37 (51%) were receiving FVIII prophylaxis. 60 participants (83%) had at least one adverse event; the most common adverse events were headache (in 12 participants [17%]), injection-site reaction (12 [17%]), and arthralgia (11 [15%]). 15 (21%) had at least one emicizumab-related adverse event; no adverse events led to treatment withdrawal, modification, or interruption. Eight participants (11%) reported ten serious adverse events in total, none emicizumab-related. There were no deaths or thrombotic microangiopathies. One participant had grade 1 thrombosed haemorrhoids (classified as a thromboembolic event), unrelated to emicizumab. The annualised bleed rate was 0·9 (95% CI 0·55-1·52) for treated bleeds. 48 participants (67%) had no treated bleeds. All-bleed annualised bleed rates were 10·1 (95% CI 6·93-14·76) from 24 weeks pre-study and 2·3 (1·67-3·12) on-study after a median follow-up of 55·6 weeks. These data show efficacy and a favourable safety profile of emicizumab in people with non-severe haemophilia A without FVIII inhibitors who warrant prophylaxis, confirming emicizumab as a valuable treatment option in this population. F Hoffmann-La Roche.

Microsimulation to compare activity-related bleed risks between pharmacokinetic-guided rurioctocog alfa pegol prophylaxis and emicizumab

ABSTRACT Background Owing to a lack of clinical study data, computational modeling was used to estimate activity-related bleed risk during prophylaxis with either rurioctocog alfa pegol or emicizumab. Research design and methods A pharmacokinetic (PK)-based computational model was used to estimate factor VIII (FVIII) levels for individual patients in the PROPEL study who were treated with PK-guided rurioctocog alfa pegol prophylaxis targeting FVIII trough levels of 1–3% or 8–12%. Emicizumab was assumed to have 20% FVIII equivalency. Six hypothetical patient activity profiles were created using the National Hemophilia Foundation’s physical activity risk ratings scale. For each profile and treatment regimen combination, the total bleed risk over a 2-week period was estimated relative to a patient who was participating in a low-risk activity with 0% FVIII, and the overall relative bleed risks were compared. Results For all evaluated activity profiles, rurioctocog alfa pegol prophylaxis targeting either 1–3% or 8–12% FVIII trough levels was associated with a lower estimated bleed risk compared with emicizumab prophylaxis with assumed 20% FVIII equivalency (P < 0.001). Conclusion Although this model does not reflect actual patient outcomes, it suggests that PK-guided rurioctocog alfa pegol prophylaxis may reduce the bleed risk during physical activities.

A creative approach to managing a case of haemophilia A with inhibitors in a low-resource country: case report

Abstract The development of antibodies to therapeutic factor VIII, known as inhibitors, is a leading cause of morbidity and mortality in people with haemophilia. This is particularly challenging in areas where access to novel treatment options is limited. This case report presents a clinical scenario in South Western India involving a 16-year-old male with severe haemophilia A with high titre inhibitors, who sustained a tibia-fibula shaft fracture necessitating emergency surgical intervention. The successful management of this patient required a multidisciplinary approach, encompassing haemostasis optimisation, innovative factor replacement strategies to work around financial constraints, and a comprehensive rehabilitation plan. The patient’s history of multiple factor VIII concentrate transfusions contributed to inhibitor development. Limited funds for bypassing agents prompted the utilisation of fresh frozen plasma to achieve haemostasis before access to FEIBA and recombinant factor VII. Emicizumab, a subcutaneously administered bispecific antibody, was used to assist perioperative haemostasis. A comprehensive rehabilitation plan with regular physiotherapy was followed. Emicizumab prophylaxis was initiated and the patient now shows improvement. This case emphasises the importance of novel treatment options such as FEIBA and emicizumab in dealing with complications in haemophilia such as inhibitors. In resource-limited settings, there is still a need to improve the availability of these life-saving interventions to optimise surgical outcomes in such cases.

Evaluation of safety and efficacy of Emicizumab prophylaxis in Egyptian pediatric patients with Hemophilia A: Single center experience

Evaluation of safety and efficacy of Emicizumab prophylaxis in Egyptian pediatric patients with Hemophilia A: Single center experience

A prospective, multicenter, open-label phase III study of emicizumab prophylaxis in patients with acquired hemophilia A

BackgroundEmicizumab is a bispecific antibody that mimics the cofactor function of activated factor (F) VIII. It prevents bleeds in patients with congenital hemophilia A regardless of the inhibitor status; however, no prospective clinical studies have been conducted for emicizumab in patients with acquired hemophilia A (PwAHA). ObjectivesTo describe the primary analysis results from a prospective, multicenter, open-label phase III study evaluating the efficacy, safety, and pharmacokinetics of emicizumab in PwAHA (AGEHA; JapicCTI-205151). MethodsEmicizumab was administered subcutaneously at 6 mg/kg on day 1 and 3 mg/kg on day 2, followed by 1.5 mg/kg once weekly from day 8 onward. Predefined criteria for the completion of dosing included FVIII activity of >50 IU/dL. ResultsBy the cutoff date (April 23, 2021), 12 patients on immunosuppressive therapy were enrolled, and 11 of them (91.7%) completed emicizumab treatment. The mean trough plasma emicizumab concentration rapidly reached a steady state (1 week), achieving the efficacious level that was established in patients with congenital hemophilia A (>30 μg/mL). Before first emicizumab administration, 7 patients (58.3%) experienced 77 major bleeds. During emicizumab treatment, no major bleeds occurred in any patient. Neither death due to bleeding or infection nor any study treatment–related serious adverse event was reported. One asymptomatic, nonserious deep vein thrombosis was discovered with no laboratory findings indicating any trend toward hypercoagulation. ConclusionThese results suggest that emicizumab prophylaxis with the tested dosing regimen and completion criteria may have a favorable benefit-risk profile in PwAHA.

Efficacy and Safety of Emicizumab Prophylaxis in Patients with Acquired Hemophilia a Who Were Deemed Ineligible for Immunosuppressive Therapy: Additional Data from the Ageha Study

INTRODUCTION: Acquired hemophilia A (AHA) is a potentially fatal hemorrhagic disease caused by the appearance of autoantibodies against factor VIII (FVIII). Immunosuppressive therapy (IST) is started immediately after diagnosis to eradicate FVIII inhibitors. This leads to remission in most patients, but infections often occur as side effects, leading to death in many cases. Emicizumab is a bispecific antibody that mimics the cofactor function of activated FVIII and prevents bleeds in patients with congenital hemophilia A regardless of inhibitor status. Emicizumab prophylaxis is expected to reduce the risk of severe bleeds in patients with AHA (PwAHA), and also allow at-risk patients to consider reducing or postponing IST, which would minimize its side effects. To investigate the safety and efficacy of emicizumab in PwAHA, we are conducting an ongoing, prospective, multicenter, open-label, non-randomized, phase III study (AGEHA; JapicCTI-205151). Primary analysis results of AGEHA suggest that emicizumab prophylaxis with a new loading regimen and completion criteria has a favorable benefit-risk profile in PwAHA. However, all enrolled patients in that primary analysis (cutoff date: April 23, 2021) had received IST before starting emicizumab, and the influence of IST, especially on efficacy data, cannot be completely ruled out. Here, we present efficacy and safety data of emicizumab in PwAHA deemed ineligible for IST at enrollment, which were collected after cutoff date of the primary analysis. METHODS: AGEHA consisted of 2 cohorts: patients already undergoing or scheduled to immediately undergo IST at enrollment (Cohort 1), and patients deemed ineligible for IST at enrollment (Cohort 2). Emicizumab was administered subcutaneously at 6 mg/kg on Day 1 and 3 mg/kg on Day 2 followed by 1.5 mg/kg once weekly from Day 8. Predefined dosing completion criteria included FVIII activity >50 IU/dL. No restriction was set on IST use during the study. AGEHA was conducted in accordance with relevant ethical standards. Data from the 12 patients enrolled in Cohort 1 (Patients 1 to 12) is beyond the scope of this presentation. RESULTS: By the cutoff date for the presentation (September 10, 2021), 2 patients had been enrolled in Cohort 2, and 1 patient (Patient 13) had completed emicizumab treatment. Durations of emicizumab treatment were 7.1 weeks in Patient 13 and 16.3 weeks in Patient 14. Clinical courses of the 2 patients are shown in Figure 1. Patient 13 was an 82-year-old female who was diagnosed with AHA 6 days before enrollment. She was judged ineligible for IST because of her poor performance status and diabetes. After starting emicizumab, the bleeding symptoms immediately disappeared and her general condition dramatically improved. Following treatment with intensive insulin therapy for diabetes, the investigator judged that IST was applicable to her. IST with prednisolone and cyclophosphamide was started on Day 5 and Day 27, respectively, and then FVIII inhibitor titer decreased and FVIII activity gradually improved. Criteria for completion of emicizumab were met on Day 64. Patient 14 was a 59-year-old female with AHA of long disease duration (1009 days) who had been receiving a prophylactic regimen of activated prothrombin complex concentrate before enrollment. She was judged ineligible for IST because IST had not been effective for a long time in the past, and because IST was nearly contraindicated due to a complication of infections associated with osteonecrosis of the jaw. During the pre-treatment period, the 2 patients experienced a total of 3 treated bleeds, 1 of which was a treated major bleed in Patient 13. During the on-treatment period, no treated bleeds and no major bleeds occurred in either patient. The requirement for coagulation factor products or transfusions decreased between the pre- and on-treatment periods. Both patients experienced adverse events (AEs), all 9 of which were grade 1 or 2. One AE (rash) in Patient 13 was considered related to emicizumab, but no modification or discontinuation of emicizumab was required. No thrombotic events, serious AEs, AEs leading to study discontinuation, or anti-drug antibodies were reported. CONCLUSIONS: These results suggest that emicizumab prophylaxis with the new dosing regimen and completion criteria is safe and efficacious for PwAHA ineligible for IST. Further, efficacy under the non-influence of IST was also suggested. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Comparison of Activated Clotting Time to Hepcon Protamine Titration for Anticoagulation Management during Cardiopulmonary Bypass Surgery in a Patient with Severe Hemophilia a on Emicizumab Prophylaxis

Background: Emicizumab is a bispecific monoclonal antibody that bridges factor IXa and X, substituting the cofactor function of FVIII, but artificially shortens aPTT and interferes with aPTT-based assays. The activated whole blood clotting time (ACT) is the preferred point-of-care test to monitor anticoagulation with high-dose heparin in cardiopulmonary bypass (CPB). While theoretically ACT may be susceptible to the effects of emicizumab as the intrinsic pathway is involved, in vitro human clinical data suggest that emicizumab does not interfere with the ACT. There has been little experience managing patients with hemophilia A on emicizumab during CPB, and in most cases it is not feasible to delay surgery to await clearance of emicizumab due its long half-life. Heparin concentration by Hepcon protamine titration is an alternative monitoring method. Case: We describe the perioperative management of a patient with severe hemophilia A on maintenance emicizumab prophylaxis who underwent CPB with high-dose heparin monitored with both ACT and Hepcon. This 54-year-old male has a complex medical profile including Child Pugh B cirrhosis (baseline INR 1.5, platelets 100), Hepatitis C (treated), HIV on antiretroviral therapy (undetectable viral load), and remote portal vein thrombosis in the context of FEIBA and tranexamic acid use for a gastrointestinal bleed. He was diagnosed with Group B Streptococcus infective endocarditis. Despite optimal medical management, he developed aortic root abscess and aortic regurgitation necessitating operative intervention. A multidisciplinary team of hematology, cardiology, and cardiac surgery/anesthesia/intensive care deemed the risk of bleeding significant but not prohibitive and created a perioperative plan with liberal FVIII replacement followed by chromogenic FVIII levels postop (Table 1) to guide dosing. A bioprosthetic valve was chosen to reduce the need for postoperative anticoagulation. Emicizumab prophylaxis was continued. Intra-operative heparin titration was performed by the Hepcon point-of-care assay, but concurrent ACT measurements were taken to investigate the effect of emicizumab. INR, fibrinogen, hemoglobin, and platelet levels were measured as per surgical protocol. Preop FVIII replacement with moroctocog alfa (Xyntha®) (60 U/kg) was administered to target a ~120% FVIII level. Tranexamic acid was administered intraoperatively as per surgical protocol. He underwent a successful aortic valve replacement, bovine patch reconstruction and aortic root repair on CPB pump for a total of 175 minutes with no excessive intraoperative bleeding. Table 1 summarises the perioperative course, point-of-care testing results, hemostatic therapy, and FVIII levels. Following administration of protamine at the end of CPB (ACT 135s, Hepcon 0 U/mL) there was persistent oozing from the sternum which lessened with surgical packing and additional Xyntha®, but ultimately the chest was closed in favour of medical management. Two hours post-op there was ~1600mL of blood loss via chest tubes despite a FVIII level of 89%, platelets 147, and INR 1.7. Fibrinogen concentrate, fresh frozen plasma, and platelets were given prior to a repeat OR for exploration. Bleeding was confirmed from the sternal bone and muscle, and hemostasis was achieved with cautery and sutures. The remainder of the post-op course was uneventful with no further bleeding on emicizumab prophylaxis and FVIII replacement for 14 days. Discussion: The ACT and Hepcon results followed a similar trajectory over the operative course (Fig 1). Baseline and post-protamine ACT results were above normal reference range for non-anticoagulated patients (90-120s), and the intraoperative values were consistently above the target of 480s for CPB even when the Hepcon results fell below target (4.1 U/mL). The ACT results weren't artificially lowered with emicizumab, in fact elevated ACT values could have led to heparin underdosing risking circuit thrombosis. ACT is influenced by multiple variables including platelet count and function, antiphospholipids, factor deficiencies, temperature, and hemodilution. Therefore, the results may reflect derangements in one or more of these variables. We need further preclinical and clinical studies to better characterize the effect of emicizumab on ACT and identify the safest intraoperative monitoring strategy for patients on emicizumab requiring CPB surgery. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Nupower Study: Nuwiq for Perioperative Management of Patients with Haemophilia a on Emicizumab Regular Prophylaxis

Background: Surgery and other invasive procedures have the potential for excessive, uncontrolled bleeding in patients with hemophilia A. Simoctocog alfa (Nuwiq®) has been shown to be highly efficacious at controlling bleeding during and after surgery in hemophilia A patients. Sufficient factor VIII (FVIII) must be available for the surgery and to maintain postoperative coverage. Emicizumab is indicated for the prophylaxis of bleeding in patients with hemophilia A, but additional hemostatic cover may be required to manage bleeding during surgery, particularly major surgeries. To date, there are limited data available on the use of FVIII to provide additional hemostatic cover for surgery in patients on emicizumab. Aims: To evaluate the overall haemostatic efficacy of simoctocog alfa during major surgery in hemophilia A patients on regular emicizumab prophylaxis. Methods: NuPOWER is a prospective, open-label, single-arm, multicenter study to be conducted at approximately 15 study centers worldwide. Previously treated male patients ≥12 years of age with severe hemophilia A (FVIII:C <1%) and no current or past FVIII inhibitors, who have been on regular emicizumab prophylaxis for at least 3 months and scheduled for major elective surgery are eligible for the study. Simoctocog alfa will be administered once within 3 hours prior to surgery and repeated as necessary every 8-24 hours to achieve a FVIII plasma level of 80-100 IU/dL until adequate wound healing has been achieved. Simoctocog alfa dosing will continue for at least another 7 days to maintain a FVIII plasma level of 30-60 IU/dL (Figure 1). The primary endpoint is the overall perioperative hemostatic efficacy ("success" or "failure") of simoctocog alfa. Hemostatic efficacy will be assessed at the end of surgery and at the end of the postoperative period (i.e. up to 24 hours after the last injection of simoctocog alfa), both using an objective 4-point ordinal scale, and adjudicated by the Independent Data Monitoring Committee using a pre-defined algorithm. Secondary endpoints include thrombin generation potential, and incidence of adverse events including thrombotic events and inhibitor formation. Target enrollment is 23 patients to document 26 major surgeries. Each subject can have multiple independent surgeries that will be counted as separate procedures. Study start is planned for Q4, 2022. Conclusions: Results from the NuPOWER study will provide valuable data on the use of simoctocog alfa in patients on emicizumab prophylaxis who need to undergo major surgery. The data will help healthcare professionals to develop evidence-based guidelines for the management of bleeding in hemophilia A patients on emicizumab during surgery. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal