Receiving Emicizumab Prophylaxis Research Articles

Factor X consumption attenuates the coagulation effect of emicizumab: a case of severe hemophilia A treated with emicizumab and factor VIII-bypassing agents.

In patients with hemophilia A with inhibitor (PwHA-I), emicizumab drastically reduces bleeding events. However, few studies have investigated the behavior and effects of factor X (FX) in patients who require intensive treatment with factor VIII-bypassing agents (BPA) and emicizumab. A 59-year-old man with HA-I receiving emicizumab prophylaxis was admitted to our hospital because of acute gangrenous cholecystitis. He received percutaneous transhepatic gallbladder drainage and laparoscopic cholecystectomy along with repeated administration of recombinant activated factor VII (rFVIIa). On day 10, a large hematoma developed around the residual gallbladder. Rotational thromboelastometry (ROTEM) suggested poor effect of rFVIIa and reduced activity of emicizumab. Considering that this could be due to consumption of FX, plasma-derived FVIIa/FX agent (pdFVIIa/X) was administered, and ROTEM parameters recovered considerably. The patient was discharged on day 19 uneventfully. Plasma assays revealed that FX antigen level (FX:Ag) was 107.5% at baseline but then decreased. Administration of pdFVIIa/FX restored FX:Ag (pre/post 47.2%/125.5%). ROTEM and thrombin generation assay with in vitro addition of anti-emicizumab antibody suggested that low FX:Ag was responsible for attenuating the effect of emicizumab, and pdFVIIa/FX administration restored coagulation potentials. In PwHA-I receiving intensive treatment with rFVIIa under emicizumab prophylaxis, FX consumption might attenuate the effect of emicizumab.

Reduced doses of emicizumab achieve good efficacy: Results from a national-wide multicentre real-world study in China.

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. This study aimed to investigate the efficacy and safety of emicizumab especially in those on reduced dose regimens in a real-world setting. 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. 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/4weeks, 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. 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.

Additional Factor X Enhances Emicizumab-Driven Coagulation Function in Patients with Hemophilia A and Hemophilia A Mice.

Bypassing agents are used for breakthrough bleedings in patients with hemophilia A with inhibitor (PwHAwI) receiving emicizumab prophylaxis. Previous study demonstrated a weak binding affinity between emicizumab and factor (F)X (K d; 1.85 μM), and that this value was much greater than the plasma FX concentration (∼130 nM). We speculated that increased FX levels could enhance coagulation potential in emicizumab-treated patients with hemophilia A (PwHA). To investigate the relationship between FX concentrations and emicizumab-driven coagulation. Plasma FX (up to 1,040 nM) and emicizumab (50 µg/mL) were added to FVIII-deficient plasmas, and plasma-derived FX (520 nM) or recombinant (r)FVIIa (2.2 µg/mL) was added to plasmas from three emicizumab-treated PwHAwI. The adjusted maximum coagulation velocity (Ad|min1|) by clot waveform analysis and peak thrombin (PeakTh) by thrombin generation assay in them were evaluated. Emicizumab (3.0 mg/kg), human (h)FIX (100 IU/kg), and various doses of hFX (100-500 IU/kg) were intravenously administered to HA mice. Clotting time/clot formation time (CT/CFT) were assessed using rotational thromboelastometry, and blood loss was estimated by a tail-clip assay. The addition of FX to FVIII-deficient plasma with emicizumab increased Ad|min1| and PeakTh. The coagulation parameters in emicizumab-treated PwHAwI spiked with additional FX remained within the normal range as well as the additional rFVIIa. In animal models, hFX injection shortened the CT and CT + CFT. The shorter CT and CT + CFT, and the lower blood loss were evident after 200 or 500 IU/kg hFX administration, and those indices were comparable to those in wild-type mice. Supplementation with FX may improve emicizumab-driven hemostasis in PwHA.

Bleeding control improves after switching to emicizumab: Real-world experience of 177 children in the PedNet registry.

Despite the rapid uptake of emicizumab in the paediatric haemophilia A (HA) population, real-world data on the safety and efficacy is limited. To report on bleeding and safety in paediatric patients receiving emicizumab prophylaxis. 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. 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. This study showed improved bleeding control compared to previous treatment and a favourable safety profile during emicizumab therapy in paediatric haemophilia A patients.

Health-related quality of life in children with severe hemophilia A on emicizumab prophylaxis

Background Emicizumab is a novel nonreplacement therapy for patients with hemophilia A. It is intended to reduce the frequency and severity of serious bleeding episodes in patients with hemophilia A. Aim To assess how emicizumab affected quality of life and physical activity in children with severe hemophilia A. Patients and methods Thirty-seven children with severe hemophilia A received emicizumab prophylaxis. We used EQ-5D-Y and pedHAL activity list questionnaires to assess quality of life and physical activity, respectively, at baseline (before receiving emicizumab prophylaxis) and after 1 year of regular emicizumab prophylaxis. Results The mean age of the children included in the study was 9.32 ± 3.75 years. Of them, 19 patients were with FVIII inhibitors (51.35%), and 18 patients were negative for FVIII inhibitors (48.65%). The median (interquartile range) PedHAL sum score was 57.6 (48.8–62) at baseline, then reached 76 (70–81.5) after a year of emicizumab prophylaxis; this change was found to be statistically significant (P&lt;0.001). Also, there was a significant increase in the proportion of patients with no problem in all EQ-5d-Y dimensions after a year of emicizumab prophylaxis (P&lt;0.05). The median (interquartile range) value of the visual analog scale score at baseline was 67 (54–75) and became 76 (70–81.5) after a year of receiving emicizumab prophylaxis. This improvement was statistically significant (P&lt;0.001). Conclusion Emicizumab prophylaxis improves quality of life and physical activity in children with severe hemophilia A.

Exploring the effects of Factor Xa inhibitors on thrombin generation in people with haemophilia

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.

Safety of recombinant activated factor VII for treatment of breakthrough bleeds in patients with congenital haemophilia A and inhibitors receiving emicizumab prophylaxis: Review of the real-world evidence.

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. 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. 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'. 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.

Pharmacokinetics and coagulation biomarkers in children and adults with hemophilia A receiving emicizumab prophylaxis every 1, 2, or 4 weeks

BackgroundEmicizumab is a bispecific antibody that bridges activated factor (F)IX and FX, mimicking the function of missing activated FVIII and thus improving hemostasis in people with hemophilia A. The efficacy and safety of emicizumab were demonstrated in 4 phase III clinical trials (HAVEN 1-4). ObjectivesHere, we describe pharmacokinetics (PKs), pharmacodynamics (PDs), and exploratory safety biomarkers in HAVEN 1 to 4. MethodsParticipants received emicizumab at a loading dose of 3 mg/kg weekly for 4 weeks, followed by maintenance doses of 1.5 mg/kg weekly, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks. PKs, PDs, and safety biomarkers were assessed in samples collected at regular intervals during the trials. ResultsEmicizumab plasma trough concentrations increased during the loading dose period, reaching a mean of 52.9 μg/mL (SD, 13.6 μg/mL) at week 5, and were sustained at 42.1 to 52.3 μg/mL thereafter with maintenance dosing. Activated partial thromboplastin time shortened following the first emicizumab dose. Mean FVIII-like activity and thrombin generation peak height increased to 25.2 IU/dL (SD, 6.9 IU/dL) and 115.2 nM (SD, 42.5 nM) at week 5, with levels sustained at 17 to 23 IU/dL and >116 nM thereafter, respectively. Emicizumab did not notably affect FIX or FX plasma antigen levels, prothrombin time, or concentrations of exploratory safety markers of coagulation activation (D-dimer, prothrombin fragment 1 + 2, and fibrinogen). ConclusionIn HAVEN 1 to 4, emicizumab demonstrated sustained PKs and PDs and improved coagulation parameters without affecting safety biomarkers.

Emicizumab Prophylaxis for the Treatment of Chinese Hemophilia A Patients in the Real World: A Multi-Center Retrospective Analysis

Background The real-world experiences of Hemophilia A (HA) patients receiving emicizumab prophylaxis in China are insufficient due to the high cost and later approval of emicizumab. In this study, we retrospectively analyzed Chinese HA patients with or without factor VIII (FVIII) inhibitors receiving emicizumab prophylaxis with the aim to investigate the efficacy and safety of emicizumab as well as the current status and effect of different doses of emicizumab in a real-world setting. Methods HA patients with or without FVIII inhibitors receiving emicizumab prophylaxis between June 2019 and June 2023 in China were included in the study. Data of HA patients including children and adults were retrospectively gathered from 27 hospitals all over the country. For each patient, the anonymized data were collected and telephone follow-ups were conducted to make sure the intact information collected as much as possible. Low dose and higher dose of emicizumab were defined as monthly dose &amp;lt;3 mg/kg and monthly dose ≥3 mg/kg, respectively. All analyses were performed using SPSS software version 25.0 (IBM Corporation, Armonk, New York, USA). Intraindividual comparisons were performed by nonparametric paired tests. Results A total of 127 male patients (10.2% [n=13] ≥18 years old; 89.8% [n=114] &amp;lt;18 years old) were enrolled in our study (severe: moderate = 103:24). Of these, 42 (33.1%) had FVIII inhibitors at initiating emicizumab. The median (interquartile range [IQR]) duration of emicizumab treatment was 16.0 (9.0-30.0) months. The median (IQR) annualized bleeding rate (ABR) and annualized joint bleeding rate (AJBR) after emicizumab were 0.5 (0-1.5) and 0 (0-0), respectively (calculated in patients treated with emicizumab &amp;gt;6 months). Among the 127 patients, 67 (52.8%) patients had no bleeds at all. No intracranial hemorrhage occurred after emicizumab. Adverse events were reported in 12 (9.4%) patients and 10 (83.3%) were injection-site reactions. There were no deaths, thromboembolic events, or thrombotic microangiopathies in our study. Two (8.0%) patients had treated epistaxis after emicizumab with low dose compared with 0 (0.0%) with higher dose ( P =0.037). Four (16.0%) patients had target joints after emicizumab with low dose compared with 1 (1.0%) with higher dose ( P =0.005) (Table 1). There were no significant differences between low dose and higher dose of emicizumab prophylaxis in ABR, AJBR, the proportion of zero bleeds, the proportion of adverse events, and so on. The median (IQR) ABR was 5.0 (2.0-14.0) with prior treatment compared with 0.5 (0-1.5) with emicizumab, an 90% reduction in ABR with P value &amp;lt;0.001 (Table 2).Also, the use of emicizumab was also associated with significant reduction in AJBR ( P &amp;lt;0.001), number of target joints ( P &amp;lt;0.001), number of intracerebral hemorrhages ( P &amp;lt;0.001), inhibitor titer ( P =0.016), and days away from school/work ( P &amp;lt;0.001). Conclusion In this multi-center study, we indicated the efficacy and safety of emicizumab and that low dose and higher dose of emicizumab had similar efficacy in Chinese HA patients without increasing adverse events.

An in Vitro Pilot Study of the Role of Factor IX As an Alternative to Bypassing Agents in the Treatment of Breakthrough Bleeds in Patients with Hemophilia a and Inhibitors Treated with Emicizumab

Introduction: Hemophilia A(HA) is an X linked disorder characterized by a deficiency in Factor VIII. 30% of patients with severe HA develop alloantibodies that inhibit the coagulant activity of FVIII. Emicizumab, a substitution therapy that bridges factor IX and X, is approved in patients with severe HA with and without inhibitors. Indeed, it is now the standard of care prophylactic therapy for patients with inhibitors. Breakthrough bleeds and perioperative management require the use of bypassing agents in addition to emicizumab, with recombinant VIIa deemed the safest of these options. Nevertheless there are still concerns about thrombotic risks and inability to monitor bypassing agents given to patients on emicizumab. Since the rate limiting step for FXa generation in the plasma of patients receiving emicizumab is the concentration of generated FIXa, we conducted an in vitro pilot study to evaluate the hemostatic effect of adding FIX to the plasma of patients on emicizumab prophylaxis. Methods: After informed consent was obtained, blood was collected in citrated tubes prefilled with 1.45mM of corn trypsin inhibitor(CTI) from 25 patients with HA receiving emicizumab prophylaxis. Aligning with previously published data, the added hemostatic effect of rFVIIa was studied in platelet rich plasma (PRP), while all other products were studied in platelet poor plasma (PPP). PRP was spiked with 0, 45, 90 and 270mg/kg of rFVIIa, and PPP was spiked with 0, 10, 20, 30 and 50 IU/kg of activated prothrombin complex concentrate (aPCC); 0, 25, 50 and 100 IU/kg of recombinant FIX(rFIX) and 0, 25, 50 and 100 IU/kg of plasma derived FIX(pdFIX). Thrombin generation was run on these spiked samples using the CAT method. Coagulation was triggered in PRP samples with tissue factor 1pM. PPP samples were activated using 1pM of TF and 1.5pM FIXa. Mean endogenous thrombin potential (ETP, area under the thrombin generation curve) values were compared between the different experiments and with samples obtained from controls. Baseline FIX concentrations were determined in these patients using bovine chromogenic assay. The mean plasma emicizumab concentration (+Standard Deviation) was 44.45 µg/mL (+15.83). Results: As shown in fig 1, ETP was significantly improved with increasing concentrations of aPCC, rFIX and pdFIX in PPP(p&amp;lt;0.005). Fig 2 shows that ETP normalized with the addition of rFVIIa 45mg/kg (p&amp;lt;0.0001) in most of the patients tested. Moreover, we did not see ETP above the upper limit of the normal range when FIX was added, while 50 IU/kg of aPCC and 270 mg/kg of rFVIIa clearly surpassed the upper limit of the normal range, suggesting a risk of hypercoagulability and thrombosis. FIX levels varied between 63.9% and 248.9% with a mean of 134.27%. ETP obtained after adding rFIX 100 IU/kg was significantly greater than that attained with pdFIX (p=0.027), that might be explained by the presence of the activated form of FIX in rFIX concentrates. No statistical significant difference between the doses of 50 IU/Kg of FIX and 100 IU/KG was observed (p&amp;gt;0.05), with a noted tendency to increased ETP with 100IU/KG dose. Conclusion: Our in vitro study demonstrates excess thrombin generation (and potential thrombosis risk) with higher concentrations of rFVIIa and aPCC that are used in the clinical care of patients. While addition of FIX at a range of doses appears to improve thrombin generation without exceeding the upper normal limits. These data suggest that FIX therapy may safely improve hemostasis in patients with HA and inhibitors receiving emicizumab prophylaxis. A clinical study looking at a starting dose of rFIX at 50 IU/KG for mild to moderate bleeds and 100 IU/Kg for more severe bleeds is warranted. In addition to the advantage of monitoring levels with FIX therapy, the longer half-life of FIX offers the potential advantage of controlling hemostasis with single dose administration. Future prospective clinical trials are needed to investigate the efficacy and safety of this therapy in this patient population.

Factor VIII Use in the Treatment of Breakthrough Bleeds in People with Moderate or Mild Hemophilia A without Factor VIII Inhibitors Receiving Emicizumab Prophylaxis: The Phase III HAVEN 6 Experience

Background: Emicizumab, a bispecific monoclonal antibody that bridges activated factor (F) IX and FX, substitutes for the function of deficient FVIII in people with hemophilia A (HA). Data from the Phase III HAVEN 6 trial (NCT04158648) show a favorable safety profile and efficacy of emicizumab in people with moderate or mild hemophilia A without FVIII inhibitors (Négrier et al. Lancet Haematol 2023). This analysis characterizes the dose and frequency of FVIII and tranexamic acid used for treatment of breakthrough bleeds in people with moderate or mild HA treated with emicizumab during HAVEN 6. Methods: HAVEN 6 is a multicenter, open-label, single-arm, Phase III study designed to assess safety and efficacy of emicizumab in people with moderate or mild HA. The full study design has been published (Négrier et al.). Eligible participants included people of all ages with moderate or mild HA without inhibitors, who warranted prophylaxis as assessed by the investigator. Participants received a standard loading dose of emicizumab 3 mg/kg once weekly for 4 weeks, then a maintenance dose of 1.5 mg/kg once weekly, 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks. The lowest FVIII dose required to achieve hemostasis was recommended for breakthrough bleeds. Self-reported bleeds were defined as per the International Society on Thrombosis and Haemostasis (Blanchette et al. J Thromb Haemost 2014); treated bleeds excluded surgical bleeds. Tranexamic acid use in the 24 hours before a surgical procedure was excluded from this analysis. Inferential statistical analyses were not conducted. Results: At the data cut-off (October 30, 2021), 72 participants were enrolled; 51 (70.8%) had moderate HA and 21 (29.2%) had mild HA. Median (range) follow-up was 55.6 (8.7, 89.9) weeks.At baseline, 18 (35.2%) participants with moderate HA and 6 (28.5%) with mild HA had ≥1 target joint ( Table 1). The mean (SD) number of bleeds in the 24 weeks prior to the study was 2.7 (3.1) for those with moderate HA and 9.3 (23.7) for those with mild HA. During the HAVEN 6 study, 48 (66.7%) participants did not experience a treated bleed. Sixteen (31.4%) of the 51 participants with moderate HA and 8 (38.1%) of the 21 participants with mild HA received on-demand FVIII to treat a breakthrough bleed. All participants who experienced a bleed remained on emicizumab, regardless of additional FVIII usage. Of the 71 treated bleeds, 57 (80.3%) were in those with moderate HA and 14 (19.7%) were in those with mild HA ( Table 2). A total of 56 (78.9%) of the 71 treated bleeds were traumatic and 15 (21.1%) were spontaneous. Four participants experienced ≥6 treated bleeds during the study; 28 (90.3%) of the 31 bleeds experienced by these participants were traumatic. Overall, the median (range) number of FVIII infusions per treated bleed was 2 (1, 47) for participants with moderate HA and 1 (1, 6) for those with mild HA. Of the 71 treated bleeds, 54 (76.1%) required 1-2 FVIII infusions. Two participants, both aged 13 years and with moderate HA, had &amp;gt;9 infusions for a bleed. One participant had 19 infusions for a traumatic joint bleed on the finger/thumb. The other participant experienced two traumatic bleeds in the thigh/knee, treated with a total of 47 infusions. The same participant experienced a spontaneous thoracic bleed treated with 19 infusions, a traumatic joint bleed on the left ankle treated with 18 infusions, and a traumatic joint bleed in the finger/thumb treated with 13 infusions. The median (range) cumulative FVIII dose per bleed was 67.1 (31.5, 170.0) IU/kg for those with moderate HA and 47.0 (40.1, 50.5) IU/kg for those with mild HA. The mean (SD) annualized number of infusions per participant was 4.1 (17.2) for those with moderate HA and 2.0 (4.7) for those with mild HA. Seven (13.7%) people with moderate HA and 1 (4.8%) person with mild HA received tranexamic acid, ranging in duration from 1 to 7 days. Tranexamic acid was given for indications including fall with soft tissue bleed, nose bleeds, prophylaxis for dental procedure, and other. No adverse events, including thrombotic events, occurred with concomitant use of emicizumab and tranexamic acid. No desmopressin usage was recorded. Conclusions: Reported bleeds were mainly traumatic and resolved after 1-2 doses of FVIII . No safety concerns were observed with concomitant use of emicizumab and FVIII and/or tranexamic acid. These data may inform breakthrough bleed treatment in people with moderate or mild HA receiving emicizumab.

Hemophilic Pseudotumor of Paranasal Sinuses in a Child with Severe Hemophilia a Receiving Emicizumab: A Case Report

Emicizumab, a bispecific humanized monoclonal antibody, bridges activated factor IX (FIX) and FX to restore the function of missing activated FVIII in individuals with hemophilia A (PwHA). Prophylaxis with subcutaneous emicizumab promotes adequate hemostasis in PwHA. Emicizumab prophylaxis in children with hemophilia A has been approved in the United States for use in PwHA ages newborn and older, with or without FVIII inhibitors. We report a 2-year-old boy with severe congenital hemophilia A who initially received prophylaxis with standard half-life factor VIII but later switched to subcutaneous emicizumab at 6 mg/kg every four weeks due to difficult IV access and parental preference. Shortly after starting emicizumab, the patient presented to the hospital with severe episodic epistaxis from the left nostril, requiring ICU admission and ENT consultation. Despite treatment, the condition did not improve, prompting the need for imaging studies. Subsequently, the patient developed ipsilateral eye proptosis and a mass protruding from the left nostril. CT and MRI imaging of the orbit revealed an expansible soft tissue mass measuring 2 x 2.5 x 4 cm occupying the right sphenoid sinus, extending to the nasal cavity. The mass had caused erosion of the clivus and the anterior cranial fossa floor, extending to the middle cranial fossa (Figures 1 &amp; 2). He underwent endoscopic nasal debulking of the left nostril mass, and the pathological examination revealed a cystic mass with a thick capsule and intra-cystic blood clots, consistent with the characteristics of a hemophilic pseudotumor (HP). The fibrous stroma contained hemosiderin-laden macrophages with no evidence of malignancy. Emicizumab was discontinued before the operation, and the patient received several doses of recombinant FVIII to maintain hemostasis. Despite the debulking procedure, the patient continued to experience episodic epistaxis and joint bleeding. An inhibitor assay was performed at that time and showed high levels, leading to a switch to on-demand FVIII treatment for hemophilia A with an inhibitor. Managing the bleeding episodes with bypassing agents proved challenging, and the family expressed dissatisfaction. A decision was made to resume emicizumab treatment, and the patient eventually stabilized, experiencing no bleeding for nearly six months. Additionally, he regularly follows up with ENT specialty, with no further intervention or progression of the tumor. Notably, he did not receive any bypassing agents concomitantly with emicizumab. HP is characterized by encapsulated blood clots accumulating in extravascular tissues, especially the musculoskeletal system, in patients with bleeding tendencies, particularly hemophiliacs. It is a benign, expansible, soft tissue-like mass that exerts pressure on surrounding structures, mimicking a locally invasive malignancy. HP is a hematoma that grows and causes bone erosion through repeated bleeding episodes. A literature review revealed that HP is a rare hemorrhagic complication that develops in 1-2% of patients with severe hemophilia (Magallón et al. Am J Hematol. 1994). Its occurrence in patients receiving emicizumab prophylaxis is extremely rare. The first reported case involved a Japanese child with hemophilia who presented with a pseudotumor occupying the left maxillary sinus after repeated episodes of epistaxis. The mass caused a downward deviation of the ipsilateral eye and bulged into the buccal cavity. The patient received monthly prophylaxis with emicizumab at 6 mg/kg (Kawahara et al. Int J Hematol. 2022), but unlike our patient, he received bypassing agents concomitantly. Our reported case is unique because HP developed independently of bypassing agent therapies, as the patient did not receive any bypassing agents before the tumor's development. The likely explanation is related to repeated bleeding insults to the same anatomical location, leading to the cumulative development of hematoma and HPs. Another possibility could be attributed to the known adverse thrombotic effects of emicizumab treatment. Physicians treating hemophilia should remain vigilant for abnormal clinical signs, such as new masses in patients receiving emicizumab, which could indicate HP.

Sequential Use of Monthly Low Dose Emicizumab and Factor VIII Concentrate Prophylaxis Among Patients with Hemophilia a: A Case Series Report

Introduction: The effectiveness of monthly low dose emicizumab of 1.0 to 2.0 mg/kg has been reported among patients with and without inhibitor. However, their trough level of emicizumab was rather low ranging from 5.9 to 11.9 mg/mL and breakthrough bleeding episodes often occurred at the 4 th week after administering emicizumab. Moreover, non-exposure to factor VIII is one concern among patients receiving emicizumab prophylaxis. Therefore, the study aimed to evaluate the effectiveness of sequential use of monthly low dose emicizumab and factor VIII concentrate prophylaxis among patients with hemophilia A. Methods: Patients with hemophilia A without inhibitor were recruited. Sequential use of monthly low dose emicizumab in the first week and factor VIII concentrate in the 4 th week was provided. Patients were closely monitored concerning the number and sites of bleeding episode, cause of bleeding from spontaneous or trauma-related conditions and the amount of additional factor VIII concentrate to treat breakthrough bleeding episodes. Also, the comparison of quality of life, hemophilia joint health score (HJHS), hemophilia early arthropathy detection by ultrasound (HEAD-US) and ultrasonography of bilateral elbows, knees and ankles before and after prophylaxis was conducted. Results: Five male patients (4 adults, 1 boy) with hemophilia A (severe 2, moderate 3) without inhibitor were enrolled in the study with the mean (SD) age of 26.8 (15.5) years. They encompassed low bleeding risk circumstances including avoidance of contact sports and high velocity activities. Four adults initially received episodic treatment and subsequent low dose prophylaxis at 15-20 units/kg twice weekly but breakthrough bleeding episodes frequently occurred. The only boy also received low dose prophylaxis at 14 units/kg once weekly at the age of 5.9 years and increased to twice weekly one month later due to frequent spontaneous bleeding at the right knee. However, the difficulty in venous access created constraint in achieving adequate prophylaxis. Therefore, all patients were switched to receive the whole vial of emicizumab at the monthly low dose ranging from 1.14 to 1.25 mg/kg without 4-loading doses for 2 years and sequential use of median (IQR) monthly low dose emicizumab of 1.50 (1.31, 1.65) mg/kg in the first week and factor VIII concentrate 15 units/kg twice weekly in the 4 th week in the third year. The duration of follow-up in the third year was 6 months. The results revealed the median (interquartile range, IQR) trough level of plasma emicizumab concentration at the 4 th weeks before factor VIII administration determined by a modified one stage factor VIII assay using emicizumab calibrator was maintained at 8.5 (6.2,10.8) µg/mL. The median (IQR) APTT of all patients at 6-month prophylaxis of 25.7 sec (25.3, 26.0) was shortened compared with a baseline of 66.9 sec (54.3, 105.1) demonstrating the presence of emicizumab and the likely absence of anti-emicizumab antibodies. Also, no inhibitor to factor VIII clotting activity was detected among all patients before and after prophylaxis. Their median (IQR) annual bleeding rate significantly decreased from baseline of 30.0 (13, 36.5) to 5.0 (3, 12.5) in the first year, 1.0 (0.5, 8.5) in the second year and 1 (0, 3) in the third year of prophylaxis with p-values of 0.043. Impressively, zero annual bleeding rate in the third year of the current study was found among 2 patients while 2 patients exhibited one episode of trauma-related bleeding at the ankle and one patient had frequent epistaxis from high PM 2.5 in his hometown. Ultimately, all patients achieved annual spontaneous joint bleeding rate ≤1 episode during a 6-month period of sequential use of emicizumab and factor concentrate prophylaxis. In addition, quality of life, HJHS, HEAD-US and ultrasonography study were improved in all studied patients. Factor VIII concentrate was helpful in preventing bleeding especially at the 4 th week after administering emicizumab and providing other biological activities beyond hemostasis related to bone remodeling, dysregulated macrophage polarization and inflammatory processes among studied patients. Conclusion: The sequential use of monthly low dose emicizumab and factor VIII concentrate prophylaxis showed effectiveness with annual spontaneous joint bleeding rate ≤1 episode among all studied patients. The musculoskeletal system and quality of life were also improved.

Longitudinal dynamic changes in factor VIII inhibitor titers in patients with hemophilia A and inhibitors receiving emicizumab prophylaxis.

Emicizumab prophylaxis dramatically reduces bleeding events in patients with hemophilia A (PwHA) with or without factor VIII (FVIII) inhibitors. However, long-term dynamic changes in FVIII inhibitor titers during emicizumab prophylaxis remain to be investigated. We conducted a retrospective follow-up study of FVIII inhibitor titers after initiation of emicizumab prophylaxis in 25 PwHA carrying current or historical FVIII inhibitors. Nineteen PwHA had FVIII inhibitors at initiation of emicizumab prophylaxis (age: median 22 [range 4-60] years and inhibitor titer: 30 [1.0-1450] BU/mL). In 17 of the 19 patients, the inhibitor titers markedly decreased to a median of 1.2 (< 0.6-58)BU/mL at a median follow-up of 71 (38-111) months. In two patients, titers were slightly elevated after initiation of emicizumab but decreased in the long term. The remaining six patients had negative inhibitor status (< 0.6BU/mL) when switched to emicizumab from FVIII prophylaxis. Five patients maintained negative titers. One patient had inhibitor recurrence, with a peak titer of 1.6BU/mL that decreased to 0.9BU/mL. In most cases, FVIII inhibitor titers can be expected to decrease spontaneously during emicizumab prophylaxis, but regular follow-up is necessary to manage breakthrough bleeds.

PB1286 Cardiac Surgery in a Patient with Severe Haemophilia A Receiving Emicizumab Prophylaxis - A Case Report

PB1286 Cardiac Surgery in a Patient with Severe Haemophilia A Receiving Emicizumab Prophylaxis - A Case Report

PB0641 Association between Physical Activity and Bleeding Events in People with Hemophilia A Receiving Emicizumab Prophylaxis: Interim Analysis of the TSUBASA Study

PB0641 Association between Physical Activity and Bleeding Events in People with Hemophilia A Receiving Emicizumab Prophylaxis: Interim Analysis of the TSUBASA Study

PB0627 Management of Invasive Procedures in Patients with Hemophilia A Receiving Emicizumab Prophylaxis: Real-World Data from a National Hemophilia Treatment Center

PB0627 Management of Invasive Procedures in Patients with Hemophilia A Receiving Emicizumab Prophylaxis: Real-World Data from a National Hemophilia Treatment Center

PB0658 Low-Dose Immune Tolerance Induction in Patients with Hemophilia A and Inhibitor Receiving Emicizumab Prophylaxis: Preliminary Results of the Brazilian Experience

PB0658 Low-Dose Immune Tolerance Induction in Patients with Hemophilia A and Inhibitor Receiving Emicizumab Prophylaxis: Preliminary Results of the Brazilian Experience

OC 43.3 Surgery in People with Hemophilia a Receiving Emicizumab Prophylaxis: Real-World Experience from a Single French Reference Center of Hemophilia

OC 43.3 Surgery in People with Hemophilia a Receiving Emicizumab Prophylaxis: Real-World Experience from a Single French Reference Center of Hemophilia

PO18 Successful Long-Term Tolerance in Patients with Hemophilia A and Inhibitors Receiving Emicizumab Prophylaxis: A Single Saudi Center Experience

PO18 Successful Long-Term Tolerance in Patients with Hemophilia A and Inhibitors Receiving Emicizumab Prophylaxis: A Single Saudi Center Experience