Factor Replacement Therapy Research Articles

Inherited bleeding disorders in oral procedures. Assessment of prophylactic and therapeutic protocols: a scoping review.

This scoping review aimed to map available evidence regarding minor/major oral procedures in patients with inherited bleeding disorders (IBDs). Studies in medicine or dentistry that reported minor and major oral procedures in individuals presenting IBDs (e.g. haemophilia A or B, von Willebrand disease) were selected. Search and screening were performed in PubMed/Medline, Scopus, Web of Science and Cochrane Library by two independent researchers. Initial search yielded 4152 citations, of which 257 were included in the final analysis. Most of the evidence for prophylaxis use was derived from observational studies and the most-commonly reported prophylactic protocols were fresh frozen plasma and factor VIII concentrate. A considerable number of studies reported postoperative complications and hospitalizations. The present study identified that (1) there is room for new studies to assess the use of antifibrinolytic agents with no factor replacement; (2) to date, the use of factor replacement therapy is the most indicated approach when treating patients with IBDs with adjunct systemic or local antifibrinolytic agents to reduce post-operative complications; and (3) there is a critical need for high-quality evidence studies since much of the conclusions of the included studies are not supported by statistical analysis.

Cost of hemophilia A in Turkey: an economic disease burden analysis

Objective Hemophilia A is the second most common bleeding disorder causing patients to have lifelong follow-up and treatment. Despite being a rare disease, hemophilia A has a high economic burden on individuals and the public. The purpose of this study was to estimate the total disease cost of hemophilia A in Turkey. Materials and Methods Data used in this analysis were collected through literature review, including studies conducted in Turkey in December 2018. A disease burden analysis was performed by modeling hemophilia A-related costs among patients, their relatives, and the social security system. Two expert panels were held to evaluate real-world data sources and to provide further information. All direct medical and non-medical costs were calculated annually from the Social Security Institution of the Republic of Turkey perspective, while indirect costs were estimated from the patient and community perspective. Results For the calendar year of 2018, the number of hemophilia A patients in Turkey were estimated to be 5,055, with an average weight of 64.7 kg. The average annual direct medical, direct non-medical, and indirect costs of hemophilia A were calculated as €93,268 ($109,286; ₺502,717), €2,533 ($2,968; ₺13,655), and €7,957 ($9,323; ₺42,888) per patient, respectively, with a total annual cost of €103,759 ($121,578; ₺559,259). For the management of patients with inhibitors (4.9%), the average annual total cost was calculated to be €325,439 ($381,330; ₺1,754,117) per patient. The total annual disease burden of hemophilia A in 2018 was estimated to be about €524 million ($614 million; ₺2.82 billion), which corresponded to 1.6% of the total health expenditure in Turkey. Conclusion The most important reason hemophilia A has a significant economic burden in Turkey is that replacement therapy is expensive. The major cost contributor was identified as factor replacement therapy. With inhibitor development, the average annual cost increased more than 3-fold.

Management of bleeding events and invasive procedures in patients with haemophilia A without inhibitors treated with emicizumab.

Emicizumab (Hemlibra®, Hoffmann-La Roche, Switzerland) is now available for haemophilia A patients with or without factor VIII inhibitors. Management of bleeding events and replacement therapy for invasive procedures have to be adapted. To provide a practical guidance for the management of breakthrough bleeding events and elective or urgent surgery in adult and paediatric patients with haemophilia A without inhibitors treated with emicizumab. Based on the available literature and the experiences collected from adult and paediatric patients treated in Switzerland, the Working Party on Haemostasis of the Swiss Society of Haematology and the Swiss Haemophilia Network worked together to reach a consensus on the management of bleeding events and invasive procedures. Minor bleeding events and invasive procedures associated with low bleeding risk can be treated without factor replacement therapy in most cases, whereas major bleeding events and high-risk surgery require additional factor VIII replacement at usual doses, at least for the first days. Emicizumab treatment should be continued throughout the procedure and during the postoperative period. Elective major surgery should be planned according to emicizumab dosing for patients with a once-a-month posology. Of note, so far only few data are available on the management of major bleeds and surgery in patients with haemophilia A treated with emicizumab and this practical guidance will have to be regularly updated with growing experience. &nbsp.

Pathological mechanism of joint destruction in haemophilic arthropathy.

Haemophilic arthropathy (HA), caused by intra-articular haemorrhage, is one of the most common complications in patients with haemophilia. Factor replacement therapy provides missing coagulation factors to prevent children with haemophilia from joint bleeding and decreases their risk for HA. However, haemophilia patients in developing countries are still suffering from HA due to insufficient replacement therapy. Symptoms such as pain and activity limitations caused by HA seriously affect the functional abilities and quality of life of patients with HA, causing a high disability rate in the haemophilia cohort. The pathological mechanism of HA is complicated because the whole pathological mainly involves hypertrophic synovitis, osteopenia, cartilage and bone destruction, and these pathological changes occur in parallel and interact with each other. Inflammation plays an important role in the whole complex pathological process, and iron, cytokines, growth factors and other factors are involved. This review summarizes the pathological mechanism of HA to provide background for clinical and basic research.

Potential role of NGF, BDNF, and their receptors in oligodendrocytes differentiation from neural stem cell: An in vitro study

Neural stem cells (NSCs) or neuronal progenitor cells are cells capable of differentiating into oligodendrocytes, myelin-forming cells that have the potential of remyelination. Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are two neurotrophic factors that have been studied to stimulate NSC differentiation thus playing a role in multiple sclerosis pathogenesis and several other demyelinating disorders. While several studies have demonstrated the proliferative and protective capabilities of these neurotrophic factors, their cellular and molecular functions are still not well understood. Thus, in the present study, we focus on understanding the role of these neurotrophins (BDNF and NGF) in oligodendrogenesis from NSCs. Both neurotrophic factors have been shown to promote NSC proliferation and NSC differentiation particularly into oligodendroglial lineage in a dose-dependent fashion. Further, to establish the role of these neurotrophins in NSC differentiation, we have employed pharmacological inhibitors for TrkA and TrkB receptors in NSCs. The use of these inhibitors suppressed NSC differentiation into oligodendrocytes along with the downregulation of phosphorylated ERK suggesting active involvement of ERK in the functioning of these neurotrophins. The morphometric analysis also revealed the important role of both neurotrophins in oligodendrocytes development. These findings highlight the importance of neurotrophic factors in stimulating NSC differentiation and may pave a role for future studies to develop neurotrophic factor replacement therapies to achieve remyelination.

Homoeopathic Management of a Case of Severe Haemophilia Type A with Inhibitor Positive: Case Report

AbstractHaemophilia is an X-linked inherited immunogenetic bleeding disorder resulting from deficiency of clotting Factor VIII (haemophilia A) or Factor IX (haemophilia B). Haemophilia patients suffer from complication of developing autoantibodies/inhibitor against clotting factors used for the treatment; most commonly patients are treated with Factor VIII replacement therapy. In modern medicine, haemophiliacs with inhibitor positive status are treated with bypassing agents such as Factor VIII inhibitor bypassing agent and immune tolerance induction therapy (ITI) because such patients do not respond to traditional factor replacement therapy during an event of active bleeding. Treatment with ITI is very expensive and it requires medical expertise. Moreover, high cost of such treatment is one part of the problem, while its availability is another problem especially in developing countries. The inhibitor status among haemophilia patients is identified by conducting a blood test which measures the Bethesda units (BU) levels in the blood. In this case report, the homoeopathic management of a patient with haemophilia A severe type (Factor VIII <1%), inhibitor positive (4 BU/mL), is presented. The patient underwent treatment for a span of 4 years. After closely assessing the patient's condition and applying the principles of homeopathy medicine selection, his frequent bleeding episodes were treated with homoeopathic medicines such as Hamamelis Virginica Q, Phosphorus, Arnica montana, Rhus toxicodendron, Calendula officinalis, and Pulsatilla nigricans. Intercurrent medicine—Tuberculinum bovinum—was given when the most indicated medicine failed to relieve the symptoms of the case and was given during non-bleeding phase. The medicines not only helped in reducing haemophilia-related bleeding episodes but also improved complaints of pain, relieved skin complaints, and showed improvement in overall psychological status of patient. It can be concluded that homeopathy medicines were able to successfully reduce the frequency of bleeding and intensity of pain in this patient. Owing to reduced bleeding, he required relatively a smaller number of factor replacement treatment compared with earlier when he was not taking homeopathy. Homoeopathy proved to be effective in managing severe haemophilia patient as a supportive therapy and was able to contribute toward reduced inhibitor levels in severe haemophilia patient.

PBI55 Patient Preferences for GENE Therapy in Hemophilia: Results from the Paving Threshold Technique Survey

The aim of the Patient preferences to Assess Value IN Gene therapies (PAVING) study was to investigate trade-offs that adult Belgian hemophilia A and B patients are willing to make when choosing between prophylactic factor replacement therapy (PFRT) and gene therapy. The threshold technique was used to quantify the minimum acceptable benefit (MAB) of a switch from PFRT to gene therapy for ‘Annual bleeding rate’ (ABR), ‘Chance to stop prophylaxis’ (STOP), and ‘Quality of life’ (QOL). ‘Time that side effects have been studied’ was also included as an attribute. An educational tool provided patients with information on gene therapy. The design was supported by stakeholder (including HTA, payers and patients) involvement. Threshold intervals were analyzed using interval regression models in Stata 16. A total of 117 patients completed the survey. Mean thresholds were identified for all benefits (ABR, STOP and QOL), but substantial preference heterogeneity was observed. Heterogeneity in STOP thresholds was found to be most extreme and the majority of patients could be classified in two opposite groups. Time spent on the educational tool and residence were found to impact MAB thresholds. Most patients (88%) would accept gene therapy if it would result in 0 bleeds per year (vs. 6 for PFRT), 90% chance to stop prophylaxis, had no impact on QOL, and if there was 10 years of follow-up on side effects (vs. 30 for PFRT). Results from this study confirmed the value of educating patients on novel treatments (e.g. through educational tools) prior to measuring their preferences. Moreover, preference heterogeneity for novel treatments can be expected and was confirmed in this study. In making decisions on gene therapy, regulators, HTA and payers should consider preference heterogeneity and the impact of patient education on acceptance.

Characterisation of healthcare utilisation and cost of haemophilia care in real-life: A 4-year follow-up study in Finland.

Characterisation of outcomes and costs of haemophilia care in common practice settings is essential for evaluation of new treatment options and for developing clinical practices. In Finland, haemophilia care is mostly centralised to University Hospitals, but treatment practices and costs in adult patients have not been systematically evaluated. This study was designed to characterise healthcare resource utilisation and treatment costs of adult inhibitor-negative haemophilia patients managed in Finnish University Hospitals. The study was based on a nationwide cohort, which consists of all adult haemophilia A (HA; n=120) and B (HB; n=35) patients treated in University Hospitals from 2012 to 2016. Patient characteristics and data on healthcare utilisation and factor replacement use were collected from medical records. Direct costs of care were evaluated based on wholesale drug prices and healthcare service utilisation with standard unit costs. Most of HA (79%, n=96) and HB (84%, n=31) patients received factor replacement therapy. The median annual bleeding rate (ABR) was low, at 0.8 for HA and 0.5 for HB, also among the patients with on-demand therapy. Over 94% (n=149) of the patients had outpatient visits during the follow-up period. The mean total annual costs of treatment ranged from €2520 to €176,330. The highest individual cost was factor replacement therapy. The outcomes of centralising the management of care to University Hospital Treatment Centres show low ABR and lower treatment costs compared with earlier reports from other high-income European populations. Management strategies, including choosing the right therapy between prophylaxis and on-demand, has been successful in Finland.

Retrospective Chart Review of Gastrointestinal Bleeding in Patients with Von Willebrand Disease

Background: Recurrent overt or occult gastrointestinal (GI) bleeding is a serious complication of von Willebrand Disease (VWD) and is the most common cause of hospitalization for patients with VWD. Data from the VWD Prophylaxis Network (VPN) emphasized the importance of prophylaxis in minimizing bleeding episodes in VWD; however, the management of GI bleeding in these patients remains challenging. Despite the availability of von Willebrand factor (VWF) replacement therapy, GI bleeding may be refractory and require the use of multiple treatment approaches. Currently, there are limited published data and no consensus regarding the most effective treatment for GI bleeding in patients with VWD. Aims: To describe the natural history of treatment and management of GI bleeds in patients with VWD, stratified by those patients who have a history of GI bleeding that precedes this chart review versus patients who experienced their first GI bleed within the 5 years of this chart review. Outcomes following the use of VWF replacement products and adjuvant therapy, including recombinant VWF were collected. Methods: This ongoing retrospective, multicenter, observational chart review (abstraction initiated 2019) will include up to 20 patients from 6 US centers with confirmed congenital VWD with ≥1 GI bleed within the last 5 years. Demographics and clinical information, including potential etiology, treatment regimens, will be gathered from patient records on all recorded GI bleeds within the last 5 years. Clinical effectiveness will be defined by treatment response, change in duration of treatment, or time to bleed resolution across treatment cohorts (e.g., prophylaxis vs on-demand; recombinant VWF [rVWF] vs plasma-derived VWF [pdVWF]), at the time of a GI bleed and for any subsequent period of prophylactic treatment to prevent GI bleed recurrence. Data will be analyzed descriptively. Results: To date, data on 37 bleeds in 13 patients with Type 1 (23%), Type 2 (46%) or Type 3 (31%) VWD have been abstracted; 54% were female, mean (±SD) age was 53.9 (22.0) years, 85% had ≥1 recorded GI-specific morbidity, 6 patients (46%) had no history of prior GI bleeding. Three patients (23%) were on regular prophylaxis using pdVWF-factor VIII (FVIII) concentrates at initial GI bleed presentation. All were receiving Humate-P; dose was not recorded for 2 patients and 1 patient received 50 IU/kg. Out of 37 bleeding episodes, 9 (24%) occurred in patients during VWF prophylaxis, of which 7 occurred in 1 patient. Among the 7 patients with a previous history of GI bleeding, 1 was on a prophylactic regimen prior to the initial GI bleeding episode. None of the patients without a history of GI bleeding were on a prophylactic regimen at the initiation of the chart review; 1 patient was receiving prophylaxis at the time the fourth bleed was documented. On-demand treatment for GI bleeding included aminocaproic acid, tranexamic acid, pdVWF-FVIII concentrates, rFVIII, rVWF, corticosteroids, polypectomy, and thalidomide. After resolution of the GI bleeding episode, in 17/37 bleeding events, prophylactic treatment continued (either as part of the final treatment regimen to resolve the bleed and sustained prophylaxis, or after the final treatment regimen purely as prophylaxis). At the conclusion of data collection for the current patients, 4 out of 6 without a GI bleeding history, and 1 out of 7 with a GI bleeding history, were receiving prophylaxis. Conclusions: Data from this retrospective chart review are the first to describe prophylactic regimens prior to and after GI bleeding, in VWD patients with and without a GI bleeding history. More patients with congenital VWD and a history of GI bleeding were treated with prophylaxis following GI bleeds, compared to patients without a history of GI bleeds. These data describe the role of prophylaxis in management of GI bleeding and add to existing data from the VPN describing a modest reduction of GI bleeding in some patients on prophylaxis. These data underscore the continuing unmet need of the successful management of GI bleeding in VWD. Further data will be collected, and additional analyses performed to determine if this trend persists in a larger sample of patients with VWD. Disclosures Roberts: uniQure:Consultancy;Takeda:Consultancy, Research Funding, Speakers Bureau;Pfizer:Consultancy;Novo Nordisk:Consultancy, Speakers Bureau;Sanofi:Consultancy, Speakers Bureau;Octapharma:Consultancy, Speakers Bureau.Escobar:National Hemophilia Foundation:Consultancy, Membership on an entity's Board of Directors or advisory committees;Takeda:Consultancy, Membership on an entity's Board of Directors or advisory committees;Sanofi:Consultancy, Membership on an entity's Board of Directors or advisory committees;Pfizer:Consultancy, Membership on an entity's Board of Directors or advisory committees;Genentech, Inc.:Consultancy, Membership on an entity's Board of Directors or advisory committees;Novo Nordisk:Consultancy, Membership on an entity's Board of Directors or advisory committees.Acharya:Novonordisk, BPL:Membership on an entity's Board of Directors or advisory committees.Hwang:Takeda:Honoraria;Shire:Honoraria.Wang:Bioverativ Inc:Honoraria;CSL Behring:Honoraria;Biomarin:Honoraria;Genentech:Honoraria;Takeda:Honoraria;Bayer:Honoraria.Hale:Takeda Pharmaceutical Company Limited:Current Employment.Oladapo:Takeda:Current Employment, Current equity holder in publicly-traded company.Asghar:HCD Economics:Current Employment.

Hematology Utilization Group Studies Part VII (HUGS VII): Costs and Impact of Disease in Older Persons with Hemophilia

BACKGROUD Improved care and prophylactic factor replacement therapy have lengthened life expectancy for persons with hemophilia (PWH). These advancements have created a new hemophilia cohort of senior persons not seen since the previous human immunodeficiency viruses (HIV) years, and little is known about their age-related health outcomes. OBJECTIVES We describe the impact of hemophilia on comorbidities, joint problems, healthcare utilization and health related quality of life (HRQoL) from the HUGS VII baseline data. METHODS HUGS VII prospectively examines the cost and burden of hemophilia, including HRQoL, arthropathy, and economic impact in persons with hemophilia A or B age ≥ 40 years who obtained care from three US Hemophilia Treatment Centers. Participants completed a standardized interview to collect clinical and sociodemographic characteristics, hemophilia treatment regimen, pain, joint problems, comorbidities, and HRQoL using EQ-5D-3L. Clinical chart reviews documented hemophilic severity and treatment. Participants' characteristics were compared between two age groups: 40-49 years and ≥ 50 years using Chi-square tests for categorical variables and T-tests for continuous variables. RESULTS This analysis includes a total of 70 male with hemophilia, 64.3% aged ≥50 years, 75.7% with hemophilia A. Individuals ≥ 50 years had higher rates of being married or with a partner (71.11% vs. 56.0%, P=0.20), retired/not employed (66.7% vs. 28.0%, P=0.002), and having mild or moderate hemophilia (68.9% vs. 40.0%, P=0.02) than those 40-49 years old. Use of prophylaxis was similar among age groups in severe hemophilia but lower for older mild/moderate PWH. Among persons with mild/moderate hemophilia, those ≥ 50 years old reported a higher rate of joint pain (83.8% vs 70.0%, P=0.37) or range of motion limitation (73.3% vs, 60.0%, p=0.45) than the younger group, although the differences were not statistically significant. Compared to those 40-49 years old, individuals ≥ 50 years old reported fewer emergency room visits (4.6% vs. 20.8%, P=0.03), and physical therapy visits (16.0% vs. 41.7%, P=0.06). The older age group had significantly higher rates of self-reported myocardial infarction (11.6% vs. 0%, P=0.08) and diabetes (24.4% vs. 4.0%, P=0.03) than those 40-49 years. Self-reported comorbidities were measured by asking "Has a doctor ever told you that you have certain conditions?" The most frequently reported comorbidities were hepatitis C infection (75.7%, 79.3% of persons with infected hepatitis C had been treated and, 82.7% cleared the hepatitis C virus), hypertension (47.1%), depression (23.2%) and anxiety (21.7%). Mean covariates adjusted EQ-5D index score was lower in older persons (0.79 vs. 0.87, P=0.09). CONCLUSIONS Older PWH are over-represented by individuals with mild/moderate disease, potentially due to premature death among those with severe disease. Although this group included a larger proportion of mild disease than younger PWH, it presented prevalent comorbidities both of aging and of hemophilic arthropathy, despite lower rates of healthcare utilization and use of preventive therapies. Disclosures Curtis: USC Hemophilia Utilization Group Study (HUGS): Consultancy; Patient Reported Outcomes, Burdens and Experiences: Consultancy; Bayer: Consultancy; Novo Nordisk: Consultancy. Konkle:Pfizer: Consultancy, Research Funding; Roche: Consultancy; BioMarin: Consultancy; Sigilon: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Takeda: Research Funding; Uniquire: Research Funding; CSL Behring: Consultancy; Baxalta: Research Funding; Spark: Consultancy, Research Funding. Kulkarni:Sanofi/ Bioverativ, Bayer, Biomarin, Shire/Takeda, Novo Nordisk, Freeline: Other: clinical trial research grants ; Bioverativ/Sanofi, BPL, Genentech, Kedrion, Novo Nordisk, Octapharma, Pfizer, Takeda, Catalyst Bioscience Bayer: Membership on an entity's Board of Directors or advisory committees. Wu:Baxalta US Inc., Bannockburn, IL (a Takeda Company), CSL Behring L.L.C., and Octapharma USA, Inc.: Research Funding. Tran:Takeda: Consultancy; Novo Nordisk: Consultancy; Bayer: Consultancy; Bioverativ: Consultancy. Nichol:Global Blood Therapeutics: Research Funding; CSL Behring: Research Funding; Octapharma: Research Funding; Genentech Inc.: Research Funding; Baxalta US Inc., Bannockburn, IL (a Takeda Company): Research Funding; Pfizer: Research Funding.

Bleeding in Patients with Clinically Severe Von Willebrand Disease: Preliminary Results of Athn 9, a Natural History Study of the Safety, Effectiveness, and Practice of Treatment for People with Severe Von Willebrand Disease (VWD)

Bleeding in Patients with Clinically Severe Von Willebrand Disease: Preliminary Results of Athn 9, a Natural History Study of the Safety, Effectiveness, and Practice of Treatment for People with Severe Von Willebrand Disease (VWD)

Real-World Clinical Management of Patients with Congenital Hemophilia and Inhibitors: Interim Analysis of the FEIBA Global Outcome Study (FEIBA GO)

Introduction and Objective: Development of inhibitory antibodies is a major complication of factor replacement therapy in patients with congenital hemophilia A or B. The FEIBA Global Outcome study (FEIBA GO) assessed the long-term safety and real-world effectiveness of activated prothrombin complex concentrate (aPCC; Baxalta US Inc, a Takeda company, Lexington, MA, USA) as prophylaxis or on-demand treatment in patients with congenital hemophilia A or B with inhibitors (PwHI) across different clinical settings. Methods: FEIBA GO (EUPAS6691) is a post-authorization, prospective, observational, multicenter cohort study. Male PwHI diagnosed before study entry and prescribed treatment with aPCC as part of routine clinical practice were followed over 4 years; treatment regimens were prescribed at the physician's discretion. Ethics approval and patient consent were obtained. These data report on an interim analysis (data cutoff, May 16, 2019) on the annualized bleeding rate (ABR) calculated per patient-year of follow-up and aPCC consumption in patients receiving aPCC prophylaxis. Results: Enrollment was started on September 3, 2014 and completed on December 31, 2017. Fifty-one enrolled PwHI have received aPCC prophylaxis (n=37) or on-demand (n=14) treatment from 26 sites in 11 countries (hemophilia A: n=50, hemophilia B: n=1; median [range] age at baseline: 17 [2-71] years). As of May 2019, mean±SD (median, range) ABR was 7.2±8.2 (5.7, 0-30) per patient-year for the 14 patients with ≥2 to <4 years' study follow-up (mean±SD: 3.0±0.6 years). In the 3 patients with ≥4 years of study follow-up (mean±SD: 4.0±0.03 years), mean±SD (median, range) ABR was 14.7±25.3 (0.2, 0-44) per patient-year. Patients received a variety of prophylaxis regimens; data on dosages per infusion and number of weekly infusions administered are provided in the Table. Conclusions: This interim analysis describes the real-world use and effectiveness of aPCC prophylaxis and supports previous data on the prevention of bleeding events in PwHI. The data also highlight the variety of dosing regimens reflecting the real-world use of aPCC prophylaxis in clinical practice. Although patient numbers were small, these data suggest that increased weekly doses are used in patients with more severe bleeding phenotypes. Figure 1 Disclosures Hermans: Kedrion:Speakers Bureau;Octapharma:Consultancy, Speakers Bureau;Roche:Consultancy, Speakers Bureau;Pfizer:Consultancy, Research Funding, Speakers Bureau;Novo Nordisk:Consultancy, Speakers Bureau;LFB:Consultancy, Speakers Bureau;Shire, a Takeda company:Consultancy, Research Funding, Speakers Bureau;Sobi:Consultancy, Research Funding, Speakers Bureau;Bayer:Consultancy, Research Funding, Speakers Bureau;EAHAD:Other;WFH:Other;CSL Behring:Consultancy, Speakers Bureau;CAF-DCF:Consultancy, Speakers Bureau;Biogen:Consultancy, Speakers Bureau.Négrier:CSL Behring, Octapharma, Shire/Takeda, Sobi:Research Funding;CSL, F. Hoffmann-La Roche Ltd, Sobi:Other: Travel support;Bayer, Biomarin, CSL Behring, Freeline, LFB, Novo Nordisk, Octapharma, Pfizer, F. Hoffmann-La Roche Ltd, Sanofi, Shire/Takeda, Sobi, Spark:Consultancy.Holme:Sobi:Honoraria, Research Funding;Bayer:Honoraria, Research Funding;CSL Behring:Honoraria;Novo Nordisk:Honoraria;Octapharma:Research Funding;Pfizer:Honoraria, Research Funding;Shire, a Takeda company:Honoraria, Research Funding.Escuriola:Grifols:Honoraria;CSL Behring:Consultancy, Honoraria, Research Funding;Biotest:Honoraria, Research Funding;Biomarin:Honoraria;Bayer:Honoraria;Kedrion:Honoraria;Shire, a Takeda company:Honoraria;Octapharma:Consultancy, Honoraria, Research Funding;Novo Nordisk:Consultancy, Honoraria;Roche:Honoraria;Sobi:Honoraria, Research Funding.Cid:Roche:Consultancy, Honoraria;Sobi:Consultancy, Honoraria;Novo Nordisk:Honoraria;Shire, a Takeda company:Honoraria.Kemenyash:Takeda Pharmaceutical International AG:Current Employment, Current equity holder in publicly-traded company.Botha:Takeda Pharmaceutical International AG:Current Employment, Current equity holder in publicly-traded company.Cano-Garcia:Sanofi Genzyme:Current Employment, Current equity holder in publicly-traded company;Shire, a Takeda company:Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months.Windyga:Sanofi:Honoraria, Research Funding;Alexion:Honoraria, Research Funding;Alnylam:Honoraria, Research Funding;Baxalta/Shire, a Takeda company:Honoraria, Research Funding;Bayer:Honoraria, Research Funding;Siemens:Honoraria, Research Funding;Sobi:Honoraria, Research Funding;Werfen:Honoraria, Research Funding;CSL Behring:Honoraria, Research Funding;Ferring Pharmaceuticals:Honoraria, Research Funding;Novo Nordisk:Honoraria, Research Funding;Octapharma:Honoraria, Research Funding;Rigel Pharmaceuticals:Honoraria, Research Funding;Roche:Honoraria, Research Funding.

First-in-Human Phase 1/2 Clinical Trial of SIG-001, an Innovative Shielded Cell Therapy Platform, for Hemophilia Α

First-in-Human Phase 1/2 Clinical Trial of SIG-001, an Innovative Shielded Cell Therapy Platform, for Hemophilia Α

The Influence of Personalized 2-Year Physiotherapy on Musculoskeletal Health and Quality of Life in Severe Hemophilia Patients with Inhibitor - Interim Analysis after 1 Year of the Program

Development of factor VIII (FVIII) inhibitor is a serious complication of factor replacement therapy observed in about 15-30% of severe hemophilia A (HA) patients. Inhibitors interfere with the treatment by neutralizing intravenously injected FVIII. Although bleeding rate is not increased in severe HA patients who developed the inhibitor, the inhibitors reduce the efficacy of factor replacement therapy during bleeding episodes and in consequence accelerate the progression of hemophilic arthropathy. In Poland, prophylaxis in hemophilia with inhibitors has been introduced in 2016, and therefore many HA patients with inhibitor still suffer from particularly severe arthropathy, and have a reduced quality of life. The aim of the study was to evaluate the musculoskeletal health and quality of life in patients with severe hemophilia A with inhibitor before initiation of personalized physiotherapy and after 2 years of the personalized physiotherapeutic program. The study was performed in 24 persons with severe HA with inhibitor (mean age 42.1 years, median age 42 years) receiving prophylaxis regimen with aPCC 85 ± 15 IU/kg 3 times a week. At the beginning of the project, the patients were examined by hematologist and physiotherapist. Joint condition was evaluated using the Hemophilia Joint Health Score (HJHS) and magnetic resonance imaging of the most affected joint. Quality of life was evaluated using EQ-5D scale (EuroQoL). aPCC dosing schedule in context of rehabilitation program was adjusted by the hematologist. Each patient was enrolled to a personalized exercise program developed based on age, general condition, stage of arthropathy, date of the last bleeding episode, and a history of physiotherapy. The program consisted of weekly 60 to 90 minutes rehabilitation sessions at home, and participated in four 5-day rehabilitation camps with 5 hours of rehabilitation sessions a day organized in Poznan after 6, 12, 18 and 24 months of the program. All patients were examined by hematologist, and the rehabilitation was provided only to the patients on regular prophylaxis with aPCC provided that a dose of aPCC was always administered 1 hour before the initiation of rehabilitation session. HJHS varied among the participants, with mean value at baseline 34.2 (median 36.5). Baseline mean EQ-5D score was 54.2 (median 60). Evaluation at month 12 was performed in 18 participants (2 patients withdrawn from the program, and 4 patients could not participate in the evaluation due to COVID-19 pandemics). The results obtained at month 12 show a significant improving the quality of life and musculoskeletal health of patients with HA after combined prophylaxis and personalized rehabilitation. Mean HJHS decreased from 34.2 to 30.4 points (median from 36.5 to 31 points). An average 3.8 point decrease confirms positive effects of long-term aPCC prophylaxis with personalized, regular rehabilitation. Increase in mean EQ-5D score from 54.2 to 70.1 (median from 60 to 72) show enhancing patients' mood resulted from the improved health status and regained capability to conduct more normal lifestyle. After the first year of the project we can conclude that regular prophylaxis with aPCC and personalized, once-a-week rehabilitation program positively influence joint status and quality of life of adult HA patients with inhibitor complicated with significant arthropathy. Regular rehabilitation may slow down the progression of arthropathy due to the choice of the exercise program appropriate for each patient. These positive effects justify the continuation of the project in patients with hemophilia A with inhibitor. Figure Disclosures No relevant conflicts of interest to declare.

Examination and Validation of a Patient-Centric Joint Metric: “Problem Joint”; Empirical Evidence from the CHESS US Dataset

Examination and Validation of a Patient-Centric Joint Metric: “Problem Joint”; Empirical Evidence from the CHESS US Dataset

MG1113, a specific anti–tissue factor pathway inhibitor antibody, rebalances the coagulation system and promotes hemostasis in hemophilia

BackgroundReplacement therapy is the most common treatment for reduction of bleeding and control of episodic bleeding in individuals with hemophilia. Despite the proven effectiveness of factor replacement therapy, repeated intravenous administration is a heavy burden to individuals with hemophilia. ObjectivesTo reduce the burden, therapeutic agents that can be subcutaneously administered need to be developed, and an anti–tissue factor pathway inhibitor (TFPI) antibody may be a suitable candidate for this purpose. MethodsMG1113 is an IgG4 monoclonal antibody that binds to Kunitz‐2 domain (KD2) of TFPI. To confirm the coagulation potential of MG1113, several tests were conducted using factor VIII (FVIII)‐ or IX (FIX)‐deficient plasma. For the ex vivo spiking test, platelet‐poor plasma samples from 14 individuals with hemophilia were spiked with MG1113. The in vivo efficacy was determined using blood loss tests, modified prothrombin time (mPT), and free TFPI quantification after intravenous or subcutaneous administration of MG1113 into hemophilia A (HA)‐induced rabbits. ResultsRadiographic crystallography demonstrated the specific binding site between MG1113 and KD2. In FVIII‐deficient plasma and the plasma of individuals with hemophilia, peak thrombin and endogenous thrombin levels were increased by MG1113 in a concentration‐dependent manner. Rotational thromboelastometry assay revealed that clotting time, clot formation time, and maximum clot firmness were normalized in MG1113‐treated blood of patients. Intravenous or subcutaneous injection of MG1113 into HA‐induced rabbits resulted in rebalancing of blood loss, mPT, and free TFPI levels. ConclusionsThese results indicate that subcutaneous administration of MG1113 neutralizes the function of TFPI and regulates bleeding in individuals with hemophilia.

Orthopedic treatment of musculoskeletal disorders in hemophilic patients

目的探讨血友病性骨骼肌肉病变的外科手术治疗方法及围手术期凝血因子消耗情况。方法回顾性分析1996年1月至2019年12月在中国医学科学院北京协和医院骨科因骨骼肌肉病变接受手术治疗的261例血友病患者。根据手术创伤大小选择凝血因子替代治疗方案。记录病变的临床表现、手术种类、围手术期凝血因子消耗、输血率及再手术情况，对比单次麻醉下单部位手术与多部位手术的凝血因子消耗及费用。结果261例患者均为男性，平均年龄为30.6（6~65）岁。血友病A 235例，血友病B 26例；重型（因子活性<1%）141例，中间型（因子活性1%~5%）91例，轻型（因子活性>5%）29例。共施行手术338例次（关节内出血及关节炎226例次、血友病并发肌腱肌膜出血挛缩61例次、血友病假瘤45例次、其他6例次）。338例手术中，大型手术270例（79.9%），关节置换203例（60.1%）。因手术部位病变复发再手术14例，再致残率为4.2%。共55例（21.1%）患者在围手术期接受红细胞输注。血友病A患者术前FⅧ的平均用量为（44.4±8.1）IU/kg，术后2周内FⅧ总用量平均为（647±177）IU/kg（40 962 IU）。术后3个月康复期内，6例（2.3%）患者发生手术部位再出血。7例患者术后检出FⅧ抑制物，平均抑制物水平为（13.7±11.2）BU/ml。单次麻醉下多关节手术组（68例）与单关节手术组凝血因子消耗量及费用差异无统计学意义。结论针对血友病性骨骼肌肉病变，在合理补充凝血因子条件下，根据病变的具体情况选择合适的手术治疗方案是有效的缓解症状的方法。单次麻醉及凝血因子替代治疗下进行多关节手术不增加凝血因子消耗，具有更佳的成本效益。

Risk factors for post-extraction bleeding in patients with haemophilia: a retrospective cohort study

Many guidelines and studies describe haemostatic management protocols for patients with haemophilia, but few have evaluated the risk factors for post-extraction bleeding. This retrospective cohort study was performed to investigate these risks among this group of patients. We used medical records to identify patients with haemophilia who underwent tooth extraction(s) between April 2006 and April 2019 in the Department of Oral and Maxillofacial Surgery at Nara Medical University Hospital, Nara, Japan, and conducted logistic regression analyses to identify risk or protective factors for post-extraction bleeding in procedures involving factor replacement therapy. Post-extraction bleeding was defined as bleeding that could not be stopped by biting down on gauze, and that required medical treatment between 30min and 14 days after the extraction. A total of 151 extractions (84 interventions) in 55 patients fulfilled the inclusion criteria (130 extractions (72 interventions) in 48 patients with haemophilia A, and 21 extractions (12 interventions) in seven patients with haemophilia B). Post-extraction bleeding was observed in nine patients (16.3%), 10 interventions (11.9%), and 12 extractions (7.9%). On average, it occurred six days after the intervention, and on the fifth postoperative day after extractions. Use of mouth splints significantly reduced the risk (odds ratio: 0.13; p=0.01) in patients on factor replacement therapy. We will conduct a prospective study to investigate the optimal type of splint and optimal splint-wearing period.

Haemostatic efficacy of single-dose factor administration in neonates with severe haemophilia undergoing circumcision.

Perioperative management of children with haemophilia undergoing surgery is a complex and understudied topic. Circumcision is the most common procedure performed in the neonatal period, and guidelines to prevent bleeding complications from circumcision are lacking. Treatment protocols vary widely, and many centres treat patients with factor products for up to two weeks after circumcision. There is an unmet need for studies evaluating optimal factor replacement therapy around the time of circumcision in neonates with severe haemophilia. To determine the efficacy of a single dose of factor replacement before circumcision to prevent bleeding complications in neonates with severe haemophilia. We conducted a retrospective chart review of male infants born between January 2000 and June 2019. Male neonates with severe haemophilia diagnosed at the Iowa Hemophilia and Thrombosis Center (n=22) and healthy newborn controls who underwent circumcision at the University of Iowa Hospitals were included. Data were collected from the electronic medical record. Neonates with severe haemophilia were separated into two groups-those pretreated with one dose of factor replacement before circumcision and those without pretreatment. We observed that neonates with severe haemophilia pretreated with a single dose of factor VIII or factor IX replacement had significantly reduced bleeding complications, shorter hospital stay and required less therapeutic intervention compared with untreated patients. Importantly, pretreated patients had outcomes similar to healthy controls. Our results demonstrate that a single dose of factor replacement before circumcision is effective to prevent bleeding in neonates with severe haemophilia.

Risk of deep venous thrombosis after total knee arthroplasty in patients with haemophilia A

Venous thromboprophylaxis remains controversial in patients with haemophilia undergoing major orthopaedic surgery, due to clotting factor replacement therapy to correct the patient's inherent haemostatic defect during procedure, at least in theory. We have previously reported that deep venous thrombosis (DVT) was not detected on ultrasonography (US) after total knee arthroplasty (TKA) in 36 Japanese patients with haemophilia. To evaluate the prevalence of DVT after TKA among haemophilic A patients using not only US, but also contrast-enhanced CT prospectively. This study enrolled 11 TKAs in 11 Japanese patients with haemophilia A not having any history of inhibitor. A pneumatic compression device was used from the beginning of the operation until the patient could perform standing exercises (day 2). US of the lower extremities was performed before and after surgery (day 2) to detect DVT. Contrast-enhanced CT was performed after surgery (day 7) to detect VTE. D-dimer was measured at pre- and postoperative time. Mean (±standard deviation) age at the time of operation was 50.5±12.3years. DVT was not found on either pre- or postoperative examinations by US, but contrast-enhanced CT was detected DVT in two cases. No patients showed clinical signs for VTE during hospitalization, and no additional treatment for VTE. No episodes of unexpected bleeding were encountered. Contrast-enhanced CT detected DVT in 18% of haemophilia A patients who underwent TKA despite no detection of DVT on US. We must consider how to prevent and treat VTE in patients with haemophilia scheduled to undergo orthopaedic surgery.