Breakthrough Bleeding Episodes Research Articles

Evaluation of Safety and Efficacy of Emicizumab Prophylaxis in Egyptian Pediatric Patients with Hemophilia A: Single Center Cross Sectional Study.

Hemophilia A (HA) is an X-linked hereditary bleeding disorder caused by deficiency of coagulation factor VIII activity. Emicizumab is a bispecific monoclonal antibody that replaces the function of activated FVIII and prevents bleeds in patients with hemophilia A. Emicizumab is expected to reduce the risk of severe bleeds in those patients with their subsequent complications. However, data about its safety and efficacy in patients with hemophilia A is limited. We aimed to evaluate safety and efficacy of Emicizumab prophylaxis in Egyptian pediatric patients with HA. A prospective cohort study was conducted on 88 HA patient who received prophylaxis with Emicizumab. Breakthrough bleeding episodes as well as annualized bleeding rate(ABR) were reported for all patients before and after Emicizumab prophylaxis. All adverse events during prophylaxis were reported to evaluate the safety of Emicizumab. Joint bleeds were present in 94 % of the patients. 58% of them had one target joint, 36.4% had more than one target joint while 5.6% had no target joints. 17% of patients were positive for FVIII inhibitors. The median annualized joint bleeding rate (AJBR) was reduced remarkably after Emicizumab prophylaxis (36 before versus zero after Emicizumab. Also, the median ABR was 48 before Emicizumab versus zero after Emicizumab. Eight patients developed mild breakthrough bleeding episodes. The most common adverse events were local reaction at the injection sites, headache, arthralgia, fever and diarrhea. Emicizumab prophylaxis was associated with significantly lower rate of bleeding events in patients with HA with and without inhibitors. The majority of patients had zero bleeds with Emicizumab prophylaxis.

Patient Perspective on Disease Burden and Gene Therapy for Hemophilia A and B: The "Haemvolution for Patients" Italian Survey.

Hemophilia is a rare X-linked congenital bleeding disorder due to a deficiency of factor VIII (hemophilia A [HA]) or factor IX (hemophilia B [HB]). Replacement and nonreplacement treatments are available but have limitations. Gene therapy (GT) provides an effective, long-term, single-dose treatment option, now approaching clinical practice. This study aimed to understand patient perspectives on GT for HA and HB in Italy using a qualitative questionnaire distributed through Italian patient associations, addressing patient views on daily life, treatments, unmet needs, quality of life (QoL), and GT for hemophilia. In total, 141 participants had HA, and 14 had HB (severe 78.6%). Daily life was most affected by pain and/or joint function limitations (57.5% of participants), high infusion frequency (42.5%), management of breakthrough bleeding episodes (40.3%), and anxiety/fear of severe or sudden bleeding (38.8%). Despite current treatments, about half of the participants experienced three or more annual bleeding episodes. Most participants knew of GT (87.2%) and expected improvements in QoL (60.5%), reduced frequency of current treatments (53.5%), and a permanent cure (49.1%); 46.4% were unaware of its once-off dosage and 46.4% were not concerned about the costs they anticipated to be associated with GT. Although several fears were reported, 25.0% of participants were willing to undergo GT with the support of a multidisciplinary team. This survey provided valuable insight into patient perspectives on hemophilia and GT in Italy. Overall, relevant proportions of patients still experience limitations affecting their daily life. Most were positive about GT and anticipated improvements in their clinical outcomes and QoL.

Mimetik antihemofiličnog faktora - novo poglavlje u profilaktičkom lečenju hemofilije A

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 methods. 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.

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.

Laboratory and Bleeding Frequency Changes in Pediatric Patients after Transitioning from Factor VIII to Emicizumab Prophylaxis -Real World Evidence in Patients with Severe Hemophilia a

Background: Emicizumab, a monoclonal antibody which functions as a bypassing agent by bridging activated factor IX and factor X in the absence of normal factor VIII levels, has recently been approved for routine prophylaxis against bleeding episodes in both adults and pediatric patients with hemophilia A. While complete blood counts are typically normal in patients living with hemophilia, it is generally accepted that some patients with unusually heavy bleeding or persistently long bleeds can have low hemoglobin. This anemia may be more common as a previous study revealed that patients with hemophilia had lower that average values for hemoglobin cross all ages and degrees of severity as evidenced by 31% of patients with values less than the third percentile, 46% less that then tenth percentile, and 83% less than the mean value. Real world impact on hemogram in pediatric patients who have been switched to Emicizumab has not been reported in the past after the medication was approved by FDA for hemophilia management. Methods: We performed a retrospective chart review of a cohort of 12 male pediatric patients with hemophilia A who were transitioned from factor VIII to emicizumab prophylaxis between May 2019 and May 2022 to determine changes in laboratory values and bleeding frequencies. Results: Hematologic metricies in severe hemophilia patients pre and post emicizumab switch :Complete blood counts before emicizumab transition revealed a mean hemoglobin 12.8 g/dL (range 10.4-15.7 g/dL), MCV 80.8 fL (range 67.2-99.1 fL), RDW 13.8% (range 11.8-16.6%), and platelets 297 bil/L (range 166-490 bil/L). Following emicizumab initiation, follow up blood counts demonstrated mean hemoglobin 14.8 g/dL (range 12.0-17.1 g/dL), MCV 83.3 fL (range 77.2-95.4 fL), RDW 12.9% (range 12.0-13.9%), and platelets 303 bil/L (range 199-514 bil/L). Mean hemoglobin was noted to have a significant increase after emicizumab was started (P<0.001). Both minor and breakthrough bleeding frequencies were noted to decrease in all patients. Bleeding Frequency and Overall Satisfaction : The patient /caregiver input to assess changes in bleeding frequency was obtained, after stable treatment with emicizumab was tolerated for at least 6 months. The bleeding frequencies of our cohort of patients on FVIII prophylaxis had a wide range with minor bleed frequencies (defined as any joint, soft tissue or other hemorrhage not requiring additional FVIII administration) occurring as often as daily to once yearly. Breakthrough bleeds that required additional episodic FVIII administration occurred 2-3x/monthly to once yearly. Following transition to emicizumab, patients had a reported an overall decrease in bleeding frequencies with minor bleeds averaging from 2x/month previously to never. 3 of these patients had breakthrough bleeding episodes requiring FVIII with 2 episodes attributed to trauma. Overall, patients' parents were asked to give a subjective verbal rating from 1 to 10 of their experience with emicizumab with 1 being worst and 10 being best. The mean verbal rating of our cohort of patients was 9.3. 11 of 12 patients remain of emicizumab prophylaxis as of May 2023 with one patient returning to FVIII prophylaxis due to pain at injection site. Conclusion: An increase in mean hemoglobin concentration in conjunction with reported decreased bleeding frequencies may suggest emicizumab facilitates an overall reduction in prolonged bleeding episodes. At our center, hemophilia A patients transitioned from factor VIII to emicizumab prophylaxis demonstrated a statistically significant increase in hemoglobin concentrations. This data combined with a notable reported decrease in minor and breakthrough bleeding frequencies in all patients suggests an overall reduction in prolonged bleeding episodes. Patients and their families appear to be very satisfied with emicizumab prophylaxis which may promote changes in the standard of care for hemophilia A patients.

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.

Eptacog Beta (rFVIIa) Has a Low Incidence of Spontaneous Rebleeding through 24 and 48 Hours in Adult and Adolescent Patients with Hemophilia A or B with Inhibitors

Introduction Bypassing agents (BPAs [ie, recombinant FVIIa (rFVIIa) or activated prothrombin complex concentrate]) are the primary treatment option to control breakthrough bleeding episodes (BEs) in persons with hemophilia A or B with inhibitors (PwHABI). BPAs can have variable efficacy that may lead to rebleeding following initial successful hemostasis; this can result in additional product usage for rebleed treatment or prevention, delayed recovery, and possible re-hospitalization or prolonged hospitalization. Eptacog beta (SEVENFACT®; HEMA Biologics and LFB) is a human rFVIIa that is approved for use in the US for the treatment and control of BEs in PwHABI (aged ≥12 years). In the PERSEPT 1 trial (PwHABI aged ≥12 years), 2 dosing regimens were investigated for the treatment of mild/moderate BEs: the 225µg/kg initial dose regimen (IDR) and the 75µg/kg IDR (Fig 1). Efficacy at 12h was 91% (225µg/kg IDR) and 82% (75µg/kg IDR); efficacy at 24h was 99.5% (225µg/kg IDR) and 96.7% (75µg/kg IDR). The median number of doses to treat a mild/moderate BE were 1 (225µg/kg IDR) and 2 (75µg/kg IDR). No thrombotic events were observed. Aims The aim of this analysis is to examine the incidence of rebleeding in PwHABI ≥12 years when using eptacog beta to treat mild/moderate BEs. Methods PERSEPT 1 (NCT02020369) was a prospective, randomized, crossover trial that investigated eptacog beta (225µg/kg and 75µg/kg IDRs). Informed consent/assent was obtained. Subjects with hemophilia A or B with inhibitors (who were not using prophylaxis) received an initial dose of eptacog beta (225µg/kg or 75µg/kg) for BE treatment followed by 75µg/kg doses at predefined intervals determined by clinical response (Fig. 1). Treatment success for mild/moderate BEs was defined as a patient-reported hemostasis evaluation of excellent or good (using a predefined 4-point scale) with no use of additional eptacog beta, alternative hemostatic agents or blood products, and no increase in pain following the first excellent or good assessment. Rebleeding through the first 24h was reported by the subject and defined as a BE in the same anatomical location after an initial excellent/good assessment. Rebleeding through 48h was an exploratory analysis of all BE data on a subject-by-subject basis: if subsequent bleeds occurred in the same anatomical location, and the initial doses of eptacog beta for each BE were administered within 48h of each other, then the latter BE was considered a rebleed. Results Twenty-seven subjects (aged 12-54) enrolled in PERSEPT 1; 465 mild/moderate bleeds were reported. Subjects used the same IDR to treat both the initial BE and the rebleed. All rebleeds were reported as mild/moderate. During the first 24h of BE treatment a single rebleed was reported (1/465; 0.2% incidence; Table 1). During the first 48h following initial treatment of a BE, this intention-to-treat analysis identified 19 rebleeds at the same anatomical location (incidence of 4.1%) in 11 subjects; the incidence by IDR is shown in Table 1. The majority (91%) of rebleeds through 48h treated with the 225µg/kg IDR were controlled with a single 225µg/kg dose (1 rebleed required an additional 75 µg/kg dose); 50% (4/8) of those treated with the 75µg/kg IDR required a single 75µg/kg dose to achieve bleed control (the remainder required 2 or 3 75µg/kg doses). All rebleeds achieved hemostasis by 12h and none required a hospital/HTC visit. A second analysis that excluded 2 rebleeds in 1 subject who was removed from the trial due to lack of treatment adherence and 1 rebleed in a 2nd subject that was a result of traumatic reinjury, resulted in a 3.4% incidence of rebleeding during the first 48h (Table 1). Conclusion Eptacog beta has a low incidence of rebleeding through 24h (0.2%) and 48h (4.1%) as observed in PERSEPT 1; in the few cases where rebleeding did occur, the majority of rebleeds required a single dose of only eptacog beta to achieve hemostasis and none required a hospital/HTC visit. In hemophilia without inhibitors, it is typical to be able to administer a minimal number of FVIII/FIX doses to control a BE and have a low risk of rebleeding; the data reported in PERSEPT 1 suggest a similar outcome for the control of mild/moderate BEs in inhibitor patients with eptacog beta. These new data may permit providers to make informed treatment decisions for inhibitor patients to reduce or avoid the possibility of rebleeding without the need for additional doses and their associated cost. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Dilemma of the Perpetual Previously Untreated Patient with Hemophilia a

BACKGROUND: Inhibitor development is the most dreaded complication of contemporary hemophilia therapy affecting 30 to 40% of previously untreated patients with hemophilia A and typically occurring within 20 to 50 exposure days. The advent of emicizumab has broadened the therapeutic panorama for hemophilia A, especially for persons with inhibitors. However, could the exclusive use of emicizumab in previously untreated patients delay inhibitor development until the second decade of life because of infrequent exposures to rFVIII? Moreover, administration of high-dose, high-intensity rFVIII for breakthrough bleeding events, trauma, or during surgery may accentuate inhibitor development risk (Sharathkumar et al. JTH, 2003). METHOD: The literature was perused for articles addressing exclusive emicizumab use in previously untreated patients. Additionally, we sought out the advice of physicians on the relevance of exogenous FVIII in persons with hemophilia A and the clinical/psychosocial impact of delayed inhibitor development in previously untreated patients treated exclusively with emicizumab. With this information we propose a therapeutic algorithm for previously untreated patients (Figure 1). RESULTS: Previously untreated patients treated exclusively with emicizumab may generate enough thrombin to recapitulate a mild hemophilia A phenotype. Real-world data on bleeding patterns showed that 51% (36/70) and 61% (43/70) of prospectively followed patients treated with emicizumab experienced at least one episode of spontaneous or traumatic bleeding event, respectively (Levy-Mendelovich et al. J Clin Med 2021). Patel et al. (J Med Econ, 2019) estimate that inhibitor development may be delayed for approximately 14 years after emicizumab exposure. Mason and Young (Haemophilia 2021) describe 4 infant cases highlighting the treatment challenges confronting families and physicians- 3 chose emicizumab prophylaxis cognizant of the prolonged inhibitor risk and 1 chose rFVIII prophylaxis followed by emicizumab to reduce anxiety regarding inhibitor development. An advisory board comprising physician thought leaders in hemophilia was convened to address the relevance of rFVIII as the foundation of hemophilia A therapy. Figure 1 depicts an algorithm to illustrate 2 therapeutic pathways- 1 using a human cell line-derived FVIII product and the other using emicizumab- and the potential patient-related complications with each therapy. Physician feedback suggests that following the rFVIII pathway the time to inhibitor development is finite and afterward breakthrough bleeding episodes become the major therapeutic concern. Following the emicizumab pathway the time to inhibitor development and high-risk treatment periods (breakthrough bleeding episodes, trauma and surgery) with rFVIII will persist until adolescence. Families and physicians will need to constantly think about inhibitor development and plan for this complication. CONCLUSION: Our hypothesis that previously untreated patients exposed exclusively to emicizumab (or other non-factor therapies) may experience a protracted timeline to reach 50 exposure days, which may result in a "perpetual" previously untreated patient status. High-risk treatment periods will be inevitable. Factor and non-factor treatment strategies are available each with its respective set of trade-offs, and families and healthcare providers must consider downstream consequences when selecting one strategy over another. Long-term clinical scrutiny and further research are required to resolve issues arising from this new therapeutic paradigm. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Hemophilia: The Past, the Present, and the Future.

Hemophilia: The Past, the Present, and the Future.

Breakthrough bleeding episodes in pediatric severe hemophilia a patients with and without inhibitors receiving emicizumab prophylaxis: a single-center retrospective review

Emicizumab has been widely used for prophylaxis in patients with hemophilia A (HA) of all ages, with or without factor VIII inhibitors. Data on emicizumab efficacy are certainly significant; however, protection against bleeding is not absolute, and the breakthrough bleeding risk can be approximately equivalent to that of patients with mild HA. This single-center retrospective review aimed to present the rate and management of breakthrough bleeding events in pediatric HA patients with and without inhibitors who are on emicizumab prophylaxis. Fifty-one pediatric patients on emicizumab prophylaxis that were followed up at Birmingham Children’s Hospital between March 1, 2018, and May 15, 2021, were included in the current study. Our results showed that 56.8% (29/51) experienced no bleeding events, and 80.3% (41/51) had no major treated bleeds during the follow-up period. A total of 29.4% (15/51) had minor bleeds that resolved spontaneously or with antifibrinolytics. Overall, 19.6% (10/51) of the patients received additional FVIII to prevent or treat breakthrough bleeding. One patient had a major bleeding event in the form of hematuria. However, it resolved without treatment. Both major and minor bleeding episodes occurred in 7.8% (4/51) of patients. None of the patients with inhibitors (5/51) developed breakthrough bleeding. Only a few, mostly minor, breakthrough bleeding episodes were reported in our cohort. The balance between bleeding control and the risk of inhibitor development after episodic factor administration should be considered. Therefore, careful decisions should be made in managing bleeding events. Supplemental data for this article is available online at

Effectiveness of Monthly Low-Dose Emicizumab Prophylaxis without 4-Week Loading Doses Among Patients with Hemophilia a with and without Inhibitor: A Case Series Report

Introduction: Emicizumab is a humanized, bispecific, monoclonal antibody proven as an effective prophylaxis for patients with hemophilia A with and without inhibitor. After the weekly loading of 3 mg/kg for 4 doses followed by maintenance dose of 1.5 to 6 mg/kg at 1 to 4-week intervals, the equivalent factor VIII was maintained at approximately 15% and showed an effective prophylaxis in reducing annual bleeding rate. Due to the health care resource constraint, the dose of emicizumab was reduced to maintain the prophylaxis factor VIII at 1-3%.Methods: The effectiveness of monthly low dose emicizumab prophylaxis without 4 loading doses was evaluated among patients with hemophilia A with and without inhibitor for at least 6 months. The bone mineral density (BMD), ultrasonography of bilateral ankle, elbow and knee as well as Hemophilia Joint Health Score (HJHS) were initially evaluated and planned to be repeated after one year treatment. The vitamin D level was determined initially, and vitamin D supplement was prescribed for 3 patients with low vitamin D levels at 13.3, 23.2 and 24.6 ng/mL. Moreover, the quality of life assessment using Hemo-QoL and CHO-KLAT was performed in 3-month intervals.Results: Five patients without inhibitor (3 severe, 2 moderate) and 1 patient with severe hemophilia A with inhibitor enrolled in the study. They all behaved in low bleeding risk circumstances such as avoidance of contact sport. Their ages ranged from 4 to 40 years of age. The youngest boy had difficulty at peripheral venous access for regular prophylaxis while the remaining 4 patients without inhibitor experienced frequent breakthrough bleeding episodes while receiving a low dose prophylaxis at 500 to 1,000 units of factor VIII concentrate twice weekly. All refused to receive more frequent prophylaxis. For patient with inhibitor, the high inhibitor titer of 65 Bethesda units (BU) declined during the 2 years of immune tolerance induction (ITI) at the intermediate dose of 100 units/kg of extended half-life factor VIII concentrate 3 times weekly. His lowest inhibitor was at 10 BU and was documented as failed ITI. He experienced frequent bleeding at the muscles and joints for which bypassing agents could not be adequately provided.For the baseline study, 2 patients had low BMD Z score ≤-2.0 while the remaining 4 patients had normalized BMD Z score >-2.0. The ultrasonography of bilateral ankle, elbow and knee at anterior, medial, lateral and posterior/inferior spaces revealed joint distension reflecting varying-degree synovial hypertrophy and/or bleeding component of 0-14.0, 0-9.8, 0-9.4, 0-12.8; 0-14.4, 0-17.8, 0-10.7, 0-18.6 and 0-23.8, 0-15.3, 0-17.1, 0-12.9 millimeter, respectively. Varying-degree hyperemia from the ultrasonography reflecting active inflammation of synovium was found in 4 ankles, 6 elbows and 4 knees of the total 36 joints in 4 of 6 patients. The HJHS scores ranged from 6 in the youngest patient to 56 in the patient with inhibitor. All patients except the 4-year-old boy had 1 to 3 target joints.All the studied patients received 1 each of the whole vial of emicizumab at 30, 75, 105 mg monthly except 3 patients receiving 60 mg monthly which was equal to 1.1 to 1.6 mg/kg of emicizumab. The monthly trough levels of emicizumab determined by a modified one stage factor VIII assay using emicizumab calibrator were maintained at 3.8 to 9.8 µg/ml which were equivalent to the levels of FVIII at 1 to 3% (0.3% FVIII per µg/ml of emicizumab). The bleeding rate was markedly decreased from 4-8 episodes monthly to 0-1 episode monthly. The monthly zero bleeding rate was found among 4 patients. Moreover, the swollen target joint gradually dissolved. Their quality of life markedly improved evaluated by the Hemo-QoL and CHO-KLAT. They could attend regular school and work happily. The HJHS and ultrasonography have not been repeated yet.Conclusion: The monthly low dose emicizumab prophylaxis of the whole vial at 1.1 to 1.6 mg/kg without loading dose could achieve emicizumab trough levels at 3.8 to 9.8 µg/ml which were equivalent to the levels of FVIII at 1 to 3%. It showed effective prophylaxis among patients with hemophilia with and without inhibitor who performed low bleeding risk activity. The 3 aspects of body functions and structures, activities and participation were gradually improved. DisclosuresNo relevant conflicts of interest to declare.

Real-World Data on the Effectiveness and Safety of wilate for the Treatment of von Willebrand Disease.

Background The efficacy and safety of wilate (human von Willebrand factor/coagulation factor VIII) in patients with von Willebrand disease (VWD) has been demonstrated in clinical trials. Here, we present real-world data on the use of wilate for the routine care of patients with VWD. Objectives The objectives of this observational, prospective, phase 4 study were to evaluate the safety, tolerability, and effectiveness of wilate in on-demand treatment of bleeding episodes (BEs), long-term prophylaxis, and surgical prophylaxis among patients with any type of VWD. Methods Patients were enrolled at 31 study centers in 11 countries and followed for up to 2 years. Safety endpoints included adverse drug reactions (ADRs) and drug tolerability. Effectiveness was assessed using annualized bleeding rates (ABRs) during prophylaxis and predefined criteria for the treatment of BEs and surgical prophylaxis. Results A total of 111 patients (76 [68%] female) including 41 (37%) children were treated with wilate. Twenty-five patients received prophylaxis, 29 on-demand treatment, and 62 surgical prophylaxis. Tolerability was rated by patients as “excellent” for 96.2% of 6,497 infusions. No unexpected ADRs or thrombotic events were reported. Median ABR during prophylaxis was 1.9. Effectiveness was assessed as “excellent” or “good” by patients and investigators for 100% of BEs treated on-demand, 98% (patient rating) and 99% (investigator rating) of breakthrough BEs, and 99% of surgical procedures (investigator rating). Conclusion wilate was safe, well tolerated, and effective for the prevention and treatment of bleeding in pediatric and adult VWD patients in a real-world setting.

Individualized Prophylaxis with BAY 81-8973: Clinical Experience in an Italian Patient with Severe Hemophilia A

Introduction: Prophylaxis with a factor VIII (FVIII) product is the standard of care for patients with severe hemophilia A to prevent bleeding episodes and development of target joints and hemophilic arthropathy. In patients with established joint disease, prophylaxis can slow progression of joint damage, which can improve health-related quality of life. Adherence to prophylaxis is critical to its success. Missing or skipping a prophylaxis infusion can cause FVIII levels to fall below the desired target level, which can increase the risk of breakthrough bleeding episodes. To promote adherence to prophylaxis, healthcare providers and patients must work together to ensure that the prophylaxis regimen is manageable for each patient. In this case report, we describe the strategy we used to improve adherence, including changes to the prophylaxis dosing regimen, in a patient with severe hemophilia A.Demographics and medical history: A 54-year-old patient was diagnosed with severe hemophilia A in early childhood and treated on demand with a plasma-derived FVIII product, despite meeting criteria for use of prophylaxis. In 2000, he began tertiary prophylaxis with a standard-acting recombinant FVIII (rFVIII) product given twice weekly. At that time, he had target joints in both knees and both elbows and a Hemophilia Joint Health Score (HJHS) of 16. In 2007, he underwent surgical replacement of the left knee. In 2010, prophylaxis with a rFVIII was started at 3000 IU (32 IU/kg) 3 times per week. The patient's job as a vendor in outdoor markets affected his ability to adhere to this prophylaxis regimen. To facilitate adherence, prophylaxis dosing was decreased to twice weekly. The patient's comorbidities included obesity and hepatitis C infection, which did not respond to combined treatment with interferon and ribavirin.Current prophylaxis treatment: In 2015, because of weight gain (to 110 kg), joint bleeding episodes (2-3 per year), repeated occurrence of left ankle pain, and further joint deterioration (HJHS score, 25), prophylaxis dosing was increased to 4000 IU (40 IU/kg) 3 times per week. Adherence to this regimen was again difficult for the patient. In March 2017, based on pharmacokinetic results obtained in this patient with BAY 81-8973 (Kovaltry®, Bayer, Berkeley, CA; Table 1), he was transitioned to BAY 81-8973 5000 IU (45 IU/kg) twice weekly (every 84 hours, on Monday morning and Wednesday evening). This prophylaxis regimen accommodated his work schedule, and no bleeding episodes occurred after the patient started BAY 81-8973 prophylaxis.Conclusion: This case illustrates that the prophylaxis dose and dosing interval can be individually tailored, keeping in mind the clinical goal of treatment and the patient's bleeding phenotype and daily activities. In this patient, tailored prophylaxis dosing with BAY 81-8973 was key to improved adherence, outcomes, and health-related quality of life. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Use of plasma‐derived factor X concentrate in neonates and infants with congenital factor X deficiency

BackgroundCongenital factor X deficiency (FXD) is a rare bleeding disorder that often presents with severe bleeding in the neonatal period. Long‐term prophylaxis with infusions of FX‐containing products is recommended in patients with FXD and a personal or family history of severe bleeding. A plasma‐derived FX concentrate (pdFX) is approved for on‐demand and prophylactic therapy in adults and children with FXD. The safety and efficacy of pdFX has been demonstrated in patients <12 years of age, yet limited data exist regarding its use in infants. Patients/MethodsThis retrospective case series details clinical experience using pdFX in four neonates with moderate and severe FXD across four institutions. Results and ConclusionsAll four patients presented in the first week of life with severe bleeding. Following treatment of the acute bleed, prophylactic pdFX was initiated at an average of 29 days of life and a dose of 69 IU/kg every 48 hours. Incremental recovery (IR) in three infants averaged 1.42 IU/dL per IU/kg (min‐max: 1.06‐1.67 IU/dL per IU/kg). One patient experienced thrombotic complications in the setting of sepsis. After a median follow‐up of 26.5 months, no patient has experienced breakthrough bleeding episodes. Our study supports the use of pdFX in neonates and infants and suggests that higher pdFX dosing of 70 to 80 IU/kg every 48 hours based on the smallest available vial size is feasible. Because of variability in IR, close monitoring of FX activity should be used to guide dosing in this age group.

Inhibitor Development with Simoctocog Alfa in Previously Untreated Patients with Severe Haemophilia a: Final Results of the Nuprotect Study

Introduction FVIII inhibitor development is the greatest challenge when treating previously untreated patients (PUPs) with hemophilia A (HA). The SIPPET study reported a cumulative inhibitor incidence of 44.5% (28.4% high-titre) in PUPs treated with recombinant FVIII (rFVIII) products produced in hamster cell lines and 26.8% (18.6% high-titre) with plasma-derived FVIII products containing von Willebrand factor (pdFVIII/VWF). Simoctocog alfa (Nuwiq®) is a 4th generation rFVIII produced in a human cell line without chemical modification or protein fusion. The NuProtect study assessed the immunogenicity, efficacy and safety of simoctocog alfa in PUPs with severe HA. A prespecified interim analysis was published with data up to 20 and 50 EDs (Haemophilia 2018; 24:211) and here we report the final results. Methods NuProtect was a prospective, multinational, open-label, non-controlled, phase III study. True PUPs (no prior FVIII treatment) with severe HA of any age and ethnicity were to be enrolled and treated for 100 exposure days (EDs) or a maximum of 5 years with simoctocog alfa for prophylaxis, on-demand treatment, treatment of breakthrough bleeding episodes (BEs) and surgical prophylaxis. Type of treatment and dose were determined by the investigator. Inhibitor screening (modified Bethesda assay) was performed at screening, every 3-4 EDs until ED20, then every 10-12 EDs or at least every 3 months, at completion, and if inhibitor development was suspected. Inhibitor levels of ≥0.6 to &amp;lt;5 Bethesda units [BU]/mL were defined as low-titer and ≥5 BU/mL as high-titer. Cumulative inhibitor incidence (primary endpoint) and 95% confidence intervals (CIs) were calculated (Kaplan-Meier). Efficacy endpoints (inhibitor-free periods) included the annualized bleeding rate (ABR) during prophylaxis and efficacy in treating BEs/surgical prophylaxis (4-point objective scales: excellent, good [successful]; moderate or none). Adverse events (AEs) were monitored throughout the study. Results Of 108 subjects consented, 105 PUPs, median age of 12 months (range 0-146) at ED1 were evaluable for inhibitor development. They were treated for a median of 101 EDs (range 1-1164), with 96 patients treated for ≥100 EDs (or until inhibitor development, including 5 patients with 97-99 EDs). The majority of patients with available genetic data had null F8 gene mutations (90/102 [88.2%]) and 13 (12.0%) had a family history of inhibitors. Cumulative inhibitor incidence was 17.6% (95% CI: 10.0%, 25.3%) for high-titre inhibitors and 27.9% (95% CI: 19.1%, 36.7%) for all inhibitors (Figure 1). No PUPs with non-null F8 mutations developed inhibitors. In 50 PUPs on continuous prophylaxis for ≥6 months, the mean (SD) ABR was 0.54 (1.07) [median 0] for spontaneous BEs and 3.61 (3.82) [median 2.53] for all BEs. The treatment of BEs was successful in 92.9% (747/804) of rated BEs in 85 patients with treated BEs and 91.9% of BEs were controlled with 1 or 2 infusions. Surgical prophylaxis was successful for 94.7% (18/19) of rated procedures and moderate for 5.3% (1/19). Excluding inhibitors, only one (0.9%) patient had an AE classified as serious by the investigator (hospitalization due to a mild rash that resolved with anti-histamine treatment). Conclusions Simoctocog alfa had a similar inhibitor incidence in PUPs with severe HA as pdFVIII/VWF products in SIPPET. No inhibitors occurred in PUPs with non-null F8 mutations. Simoctocog alfa had a median spontaneous ABR of 0 during prophylaxis and was successful in the treatment of 92.9% of BEs and in 94.7% of surgical procedures. These results complement results in previously treated patients (PTPs) and support the use of simoctocog alfa in the prevention and treatment of BEs in PUPs and PTPs. References Liesner R, et al. Haemophilia 2018; 24: 211-20. Disclosures Liesner: Octapharma, Bayer, Takeda, Novo Nordisk, CSL Behring, Roche: Research Funding; Octapharma, SOBI, Novo Nordisk: Speakers Bureau; Octapharma, Bayer, Takeda: Consultancy. Neufeld:Octapharma, Shire Pharmaceuticals (Baxalta), Novo Nordisk, Celgene, NHLBI/NIH: Research Funding; Octapharma, Agios, Acceleron, Grifols, Pfizer, CSL Behring, Shire Pharmaceuticals (Baxalta), Novo Nordisk, ApoPharma, Genentech, Novartis, Bayer Healthcare: Consultancy; Octapharma: Other: study investigator, NuProtect study (Octapharma-sponsored).

Clinical Study to Investigate the Efficacy and Safety of Wilate during Prophylaxis in Previously Treated Patients with Von Willebrand Disease (VWD)

Background: Inherited von Willebrand disease (VWD) is the most common inherited hemorrhagic disorder, with an estimated prevalence of 1 in every 100 individuals. Type 1 and type 3 (the most severe form) are characterized by a quantitative deficiency of von Willebrand factor (VWF) and type 2 arises from a qualitative deficiency of VWF. Treatment of VWD depends on the type and severity of the disease. Severe bleeding is reported in patients with all subtypes, leading to progressive joint disease as well as diminished quality of life (QoL). VWF/factor VIII (FVIII) concentrates have become the mainstay of VWD treatment for these patients with severe disease or for those patients in whom other treatments (e.g., desmopressin) are ineffective or contraindicated but this is broadly applicable only for on demand treatment. Aims: The primary objective of this study is to determine the efficacy of VWF/FVIIII concentrate in the prophylactic treatment of previously treated patients with type 3, type 2 (except 2N), or severe type 1 VWD. Secondary objectives of this study will be to collect data to 1) Assess the VWF:Ac and VWF:Ag incremental IVR of VWF/FVIIII concentrate over time and, 2) Assess the safety and tolerability of VWF/FVIIII concentrate in this indication. The study will also examine, the efficacy of VWF/FVIIII concentratein the treatment of breakthrough bleeding episodes (BEs), and in surgical prophylaxis, as well as the QoL during prophylaxis with VWF/FVIIII concentrate. Methods: The study is planned to enroll 28 patients aged ≥6 years and with VWD type 1, 2A, 2B, 2M, or 3. Eligible patients must be receiving on-demand treatment with a VWF-containing product, with at least 1, and an average of ≥2, documented spontaneous BEs per month in the preceding 6 months requiring treatment with a VWF-containing product. This will be assessed as part of a run-in observational study to collect the bleeding profile prior to the start of prophylaxis. From the beginning of the study, patients will receive prophylactic treatment with VWF/FVIIII concentrate for 12 months and record all BEs in a patient diary. Based on these data, the frequency of BEs and the annualized bleeding rate (ABR) under prophylactic treatment will be calculated. Treatment efficacy of BEs will be assessed by the patient (together with the investigator in case of on-site treatment) using a 4-point scale (excellent, good, moderate, none) In patients that undergo surgeries, efficacy of VWF/FVIIII concentratewill be assessed at the end of surgery by the surgeon and at the end of the postoperative period by the haematologist. In both cases, predefined assessment criteria will be used. In addition, an overall assessment of efficacy will be made at the end of the postoperative period by the investigator. Results: Data will be monitored on an ongoing basis and the study is expected to end Q2 2021. Conclusions: Prophylactic treatment in other congenital bleeding disorders is widely accepted as the standard of care to prevent bleeding and preserve QoL in patients but to date, this form of treatment in VWD is not well characterized. This study will provide data on the efficacy of prophylactic treatment in reducing the rate of bleeding and on the impact of prophylaxis on the QoL in VWD patients. Disclosures Sidonio: Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Research Funding; Uniqure: Membership on an entity's Board of Directors or advisory committees. Schwartz:Octapharma: Employment.

Thrombin Generation Assay in Plasma from Hemophilia a Patients with or without Inhibitors on Concizumab Prophylaxis: Spiking with rFVIIa or aPCC

Introduction: Concizumab is a humanized monoclonal antibody that inhibits tissue factor pathway inhibitor (TFPI). Concizumab is currently in clinical development as a subcutaneous prophylactic therapy for hemophilia A and B patients with and without inhibitors. Breakthrough bleeding episodes experienced by inhibitor patients while on concizumab prophylaxis may be treated with the bypassing agents recombinant activated factor VII (rFVIIa; NovoSeven®) or activated prothrombin complex concentrate (aPCC; FEIBA®). Aim: To investigate the in vitro effect of rFVIIa and aPCC on hemophilia A plasma containing concizumab using a thrombin generation assay and pooled plasma spiked with concizumab or samples from patients treated prophylactically with concizumab. Methods: Pooled hemophilia A plasma was spiked with concizumab at 1, 3 and 10 nM and patient plasma samples from explorer4 (n=16; hemophilia with inhibitors; NCT03196284) and explorer5 (n=30; hemophilia A; NCT03196297) before and during concizumab prophylaxis at steady state exposure levels were assessed. Samples were spiked with rFVIIa (25 or 75 nM) or aPCC (0.25, 0.5 or 1 U/mL), and analyzed using a thrombin generation assay initiated with tissue factor (PPP-Low, Thrombinoscope). The effects of rFVIIa or aPCC in the absence or presence of concizumab were compared using ANOVA methodology. Results: Addition of rFVIIa or aPCC to hemophilia A plasma with or without inhibitors increased peak thrombin generation both in the absence and presence of concizumab. A significant additional effect of rFVIIa and aPCC was observed for all concizumab concentrations spiked to the plasma pool. Overall, the effects of the combination of concizumab and rFVIIa or aPCC were mainly additive; however, a small but statistically significant drug-drug interaction was observed for rFVIIa (25 nM or 75 nM) and aPCC (0.5 U/ml or 1 U/mL) in the presence of 10 nM concizumab. At this concizumab concentration, the additive effect of aPCC corresponded to 68% of the total observed effect and the additive effect of rFVIIa to 85% of the total observed effect. At lower concizumab concentrations (1 and 3 nM), statistically significant drug-drug effects were only observed in combination with aPCC. No excessive thrombin generation above the level obtained with 1 IU/mL recombinant factor VIII (rFVIII) was observed at 1 nM concizumab combined with either rFVIIa (25 and 75 nM) or aPCC 0.5 U/mL. However, addition of 1 U/mL aPCC to 1 nM concizumab resulted in a thrombin peak modestly above the upper 95% confidence interval of the rFVIII range. In the experiments using plasma from patients treated with concizumab, the increase in thrombin peak upon addition of rFVIIa was within or below the range observed by spiking with 1 IU/mL rFVIII. The increase in thrombin peak upon addition of aPCC was within or above the rFVIII range. The effects of concizumab and rFVIIa or aPCC were mainly additive; however, a small, statistically significant contribution caused by drug-drug interaction was observed for concizumab and rFVIIa (75 nM) in both plasma from patients with and without inhibitors, and for 1 U/mL aPCC in plasma from patients with inhibitors. The additive effects of concizumab and rFVIIa corresponded to between 60% (25 nM rFVIIa, plasma without inhibitors) and 75% (75 nM rFVIIa, inhibitor plasma), and the additive effects of concizumab and 1 U/mL aPCC corresponded to 77% of the total observed effects. Conclusions: Addition of rFVIIa or aPCC to hemophilia A plasma with or without inhibitors increased peak thrombin generation as expected both in the absence and presence of concizumab. Thus, the bypassing agents function as expected in plasma containing concizumab. The effects of concizumab and rFVIIa or aPCC were mainly additive. A small but statistically significant contribution was synergistic in accordance with the concizumab mechanism of action (Hilden I et al, Blood, 2012). These in vitro results support the concomitant use of bypassing agents to treat breakthrough bleeding episodes in hemophilia with inhibitor patients on concizumab prophylactic treatment. Disclosures Kjalke: Novo Nordisk A/S: Employment, Honoraria. Kjelgaard-Hansen:Novo Nordisk A/S: Employment, Equity Ownership. Andersen:Novo Nordisk A/S: Employment, Equity Ownership, Honoraria. Hilden:Novo Nordisk A/S: Employment, Equity Ownership, Patents &amp; Royalties.

Assessment of an Electronic Intervention in Young Women with Heavy Menstrual Bleeding

Study Objective, Design, Setting, Participants, Interventions, and Main Outcome MeasuresBleeding disorders (BD) occur in up to 50% of adolescents with heavy menstrual bleeding (HMB). This presents unique challenges to health care providers because of the complexity of treating the condition and such complexity can result in difficulty with patients understanding basic information about their condition, limit communication with medical providers, and patient compliance. The aim of the study was to use an electronic approach to enhance patient compliance with medications used to treat their HMB, and to provide educational access to adolescents with BD. This was a prospective cohort study involving patients in a Young Women's Bleeding Disorder Clinic at a single children's hospital. Subjects were given an iPod Touch (Apple Inc, Cupertino, CA) device (ITD), preloaded with the iPeriod (Winkpass Creations) application. Participants recorded information about their BD that they learned about on BD Web sites, and menses, and medications. Electronic and charted data were collected to monitor compliance with prescribed treatment regimens. All ITD allowed Wi-Fi access to allow teens to explore BD Web sites and knowledge was assessed. ResultsTwenty-three of 45 subjects completed the study. The mean age was 14.1 ± 1.9 years. Subjects who were compliant with the ITD (group 1), charted on baseline symptoms, menstrual flow (83.3%), cramps (100%, 23/23), breakthrough bleeding (95.6%, 22/23), mood (95.6%, 22/23), and medication use (91.7%) for a mean of 9.3 ± 3.1 months. Subjects who were nonusers (group 2) did not report on symptoms, their condition, or medication use in the device (n = 22). More than 75% (17/23) of subjects in group 1 used hormones alone or hormones with antifibrinolytic agents to control HMB. No subjects stopped or missed medications who were in group 1 intentionally, and also there were 9 enrollees within this same group who missed a medication related to awaiting the prescription to be filled from pharmacy. In group 2, 17 enrollees missed medications, resulting in 19% (4/22) of these enrollees being admitted to hospital for 1-2 days. In addition, enrollees in group 2 missed more medications on average compared with group 1. No subjects in group 1 required admission for HMB treatment failure during the study period, compared with those in group 2 (P = .006). All subjects in group 1 reported accessing Web sites using their ITD to learn about their BD. Groups 1 and 2 did not differ in the number of medications that were prescribed during the time frame (P = .77) or the number of follow-up clinic visits (P = .49). Furthermore, those in group 1 reported fewer breakthrough bleeding episodes than those in group 2 according to clinic notes (P = .03). Users of the ITD were given a set of knowledge questions. Group 2 subjects were not consistent users of the ITD use and did not complete the knowledge questions. Group 1 and 2 could not be compared with regard to knowledge as a result. ConclusionITD is an excellent tool for adolescents with HMB and BD to allow self-monitoring, provider monitoring, and improve educational access through engaging technology; compliance with device use was associated with several parameters suggestive of improved clinical outcomes.

Investigator-Prescribed Prophylaxis of rFIX (BeneFIX®) in Children

Prophylaxis is increasingly prescribed in treatment of hemophilia. The therapeutic benefit is believed to be most significant for the youngest patients since hemophilic arthropathy may be prevented if prophylaxis is initiated prior to recurrent hemarthroses. While clinical prophylaxis data is readily available for hemophilia A, analogous data for hemophilia B is limited. A prospective clinical study of recombinant human FIX (rFIX; BeneFIX®) was recently completed in which the efficacy and safety of rFIX were evaluated in children <6 years of age with severe hemophilia B (FIX activity £1%). In this study, subjects received rFIX according to investigator-prescribed modality (on-demand or prophylaxis) and regimen (dose and infusion schedule). Nearly all children who participated in the study were prescribed prophylaxis (22/25; 88%) at a schedule of 1 or 2 infusions per week over a mean of 6.6 months (range, 1.9–11.4 months). The median prophylactic dose per infusion was 57.6 IU/kg. Spontaneous bleeding was rare (rate, 0.05 per month) with 77% (17/22) of subjects experiencing no spontaneous breakthrough bleeding episodes. Most bleeding episodes, when they did occur, were due to injury (84%; 37/44), involved soft tissue/muscle sites (68%; 30/44), and started more than 48 hours after an rFIX infusion (61%; 27/44). Nearly all hemorrhages were resolved with 1 or 2 infusions of rFIX (39/44; 89%). The observed data predict <1 spontaneous bleed per year for either prophylaxis infusion schedule (0.84 and 0.34 per year, for 1 and 2 infusion per week schedules, respectively). Although not a randomized study designed for a direct comparison, patients prescribed on-demand therapy had a higher annualized spontaneous bleeding rate of 3.9 per year. Prophylaxis infusion schedules were well tolerated by these young children, including the youngest subjects (6 subjects were <2 years of age). During the course of their treatments, there was no thrombosis and only 2 of 22 (9%) children prescribed prophylaxis had adverse events related to rFIX. For 1 subject, who was a previously untreated patient (treatment naïve) at study entry, the events, which occurred on the 13th rFIX exposure day, constituted allergic reaction (concurrent rash and urticaria), and were later confirmed to be associated with FIX inhibitor development. The low-titer inhibitor (peak titer, 2.4 Bethesda units) developed in the context of on-demand treatment and then resolved in the setting of prophylaxis; the subject received 19 subsequent infusions following premedication (antihistamine and corticosteroid), with no allergic manifestations or anamnestic inhibitor response. The other subject had mild rash. Nine (9; 41%) children practicing prophylaxis were known to have an implanted venous access device for administrations, and there was 1 report of a catheter infection. Four (4) subjects who were initially prescribed on-demand regimens were later switched to prophylaxis during the study. Prescribed prophylaxis infusion schedules were not changed during the course of treatment for any subjects, consistent with patient/caregiver and study investigator satisfaction with the therapeutic response and tolerability provided by 1 or 2 infusions of rFIX per week. The choice of prophylaxis for nearly all subjects reflects the increasing use of this treatment modality for children with severe hemophilia B. The data from this investigation support both the safety and efficacy of rFIX in children <6 years old with severe hemophilia B, with routine regimented administration of rFIX preventing spontaneous bleeding in the majority of children.Table 1. Bleeding Rate During Prophylaxis by Infusion ScheduleBleeding Rate (per 30 Days)Infusion ScheduleNo. PatientsPatient Age (years) (median, range)Duration of Prophylaxis (mean ± SD months)SpontaneousInjury RelatedTotal1 per week92.5 (0.6-4.3)8.0 ± 2.70.070.180.251−2 per week11.0 (NA)2.5 ± (NA)00.400.402 per week123.6 (1.2-4.8)5.9 ± 1.10.030.330.35All Schedules222.9 (0.6-4.8)6.6 ± 2.30.050.260.30NA = not applicable; No. = number.

Acquired Factor XI Deficiency Associated with Chronic Hepatitis C in Patients with Inherited Bleeding Disorders.

In the past many patients with inherited bleeding disorders contracted hepatitis C infection from the use of untreated plasma products leading to chronic liver disease. FVII, because of its short half-life has traditionally been used as a sensitive marker for subtle liver damage. In this study we measured Factors II, V, VII, X and XI in a cohort of 25 haemophilia patients who had longstanding hepatitis C infection in order to assess the effects of liver damage on these coagulation factors. The table below shows the number of patients with deficiencies of the measured factors together with the median levels in deficient patients. Also shown are the medians levels in cirrhotic and non cirrhotic patients.Frequencies of acquired factor deficiencies and median valuesFactor (Ref Range)FII (78–117)iu/dlFV (66–114)u/dlFVII (82–179)iu/dlFX (87–145)iu/dlFXI (76–136)u/dlNumber of patients with deficiency5/253/258/259/2516/25Median value in deficient patients(range)52.6iu/dl (25.3–86.6))50.2u/dl (39.9–51.7)60.6iu/dl (18.1–65.5)73.5iu/dl (33.2–82)52.2u/dl (20.5–68.9)Median value for cirrhotics(range)52.6iu/dl (25.3–86.6)51.7u/dl (39.9–76.3)60iu/dl (18.1–65.5)61.7iu/dl (33.2–73.5)36.1u/dl (20.5–63.3)Median value for non cirrhotics(range)89.6iu/dl (74.6–118.27)118.2u/dl (84.9–174.3)100.4iu/dl (49.5–150.3)99.1iu/dl (78–146.8)66.7u/dl (30.8–127)Total patients = 25This data demonstrates that an acquired deficiency of FXI is much more common and severe than the other coagulation factors. 16 patients had low FXI levels compared to only 8 patients with low FVII. 5/25 patients had evidence of cirrhosis (median FVII-60iu/dl; median FXI-36.1u/dl). In the non-cirrhotic group, only 3 patients had low FVII compared to 11 patients with low FXI. 15/25 patients were non-cirrhotic with persistent hepatitis C viraemia (median FVII-100.4iu/dl; median FXI-66.7u/dl). 5/25 had cleared the hepatitis C virus after treatment with combination therapy with interferon and ribavarin with only one patient with persistently low FXI level (median FVII-112.9iu/dl; median XI-88.2u/dl). Our data suggests that low FXI levels have a greater discriminatory value for liver damage and possibly for liver regeneration after successful treatment for hepatitis C. This deficiency is a quantitative defect as the functional levels of FXI correlated with FXI antigen levels. Factor XI deficiency causes variable bleeding symptoms which are not predictable by the degree of deficiency. In contrast, deficiencies of Factors II, V, VII, X need to be severely reduced before bleeding symptoms are experienced. In the context of patients with inherited bleeding disorders the presence of an additional, acquired factor XI deficiency may have an impact on the severity of bleeding symptoms and patient management. This may be evidenced by breakthrough bleeding episodes on adequate prophylaxis or protracted resolution of a bleeding episode despite appropriate treatment with Factor VIII or IX concentrates. Increasing the dose of Factor VIII or IX concentrates may only partially resolve the bleeding episode but has significant impact on the cost of care for these patients. It is therefore crucial to be aware of the need to measure and monitor FXI levels in patients with haemophilia and hepatitis C. In these circumstances replacement of factor XI may need to be considered.