World Federation Of Hemophilia Research Articles

Guidelines for the management of haemophilia in Egypt

Abstract These guidelines have been developed by an expert panel of haemophilia treaters to support the appropriate management of people with haemophilia in Egypt. Although the guidelines are based primarily on the World Federation of Hemophilia (WFH) Guidelines for the Management of Hemophilia, they aim to address unmet needs and local requirements in the Egyptian setting.

Gene Therapy in Hemophilia: An Assessment of Hematologists' Knowledge Gaps and Attitudes

BACKGROUND: Currently available treatments for hemophilia A and B require frequent intravenous infusions. Gene therapy, by contrast, offers the hope of a functional cure through endogenous expression of the factor VIII or factor IX genes. To identify and address practice gaps among healthcare providers who manage patients with hemophilia, a collaboration between the National Hemophilia Foundation (NHF), European Haemophilia Consortium (EHC), World Federation of Hemophilia (WFH), and Medscape Education was established. The objective of the current study is to assess clinicians' needs with regard to understanding the science and mechanism for gene therapy, the different technologies being proposed, identifying candidates for gene therapy, disease areas for which gene therapy is being explored, and the latest data on the potential role of gene therapy in hemophilia A and B.METHODS: A continuing medical education (CME)-certified clinical practice assessment comprising 25 multiple choice questions that measured knowledge, attitudes, and perspectives about gene therapy was developed. The survey instrument was made available online to physicians without monetary compensation or charge. Respondent confidentiality was maintained and responses were de-identified and aggregated prior to analyses. The activity launched on March 03, 2018; data through July 27, 2018 are presented, but data collection is ongoing.RESULTS: At the time of this analysis, 194 physician participants indicated that they actively manage patients with hemophilia. Demographics are presented in Table 1; confidence and attitudes about gene therapy in Table 2. Among hematologists/oncologists (n=54; hem/onc), identified knowledge gaps include, •46% could not identify the liver as the tissue/cell type that is the primary target for gene therapy in hemophilia•46% thought that current approaches to gene therapy in hemophilia involved some form of host gene editing•39% did not realize that gene therapy strategies only affect somatic cells and not the germline•22% thought current gene therapy strategies would prevent or reduce the severity of hemophilia in subsequent generations of patients•33% were unable to correctly identify adeno-associated virus (AAV) as the viral vector that is the current basis for the majority of gene therapy trials in hemophilia•81% had misconceptions regarding the key characteristics of the AAV vector•56% did not recognize that the AAV vector does not routinely integrate into the host genome•19% were unfamiliar with the maximum gene cassette capacity of AAV•57% were unfamiliar with the results from the pivotal University College London (UCL)/St Jude trial of scAAV2/8-LP1-hFIXcovector in patients with hemophilia B•63% were unfamiliar with the clinical trial data for SPK-8011 in hemophilia A•67% were unfamiliar with the results at the 12 month time-point for valoctocogene roxaparvovec in hemophilia A trials•57% had misconceptions with regard to the causes for and treatment of ALT elevations seen in hemophilia AAV gene therapy trialsCONCLUSIONS: Gene therapy has the potential to fundamentally alter the management of hemophilia. This educational activity identified clear deficits about - and attitudes toward - gene therapy among healthcare providers who currently care for patients with hemophilia. Furthermore, the great majority of healthcare providers lacked confidence in their understanding of gene therapy for hemophilia A. These findings will be used to inform the development of educational programs and to prepare providers for anticipated changes to the hemophilia treatment landscape. [Display omitted] DisclosuresPasi:Catalyst Bio: Honoraria; Octapharma: Honoraria; NovoNordisk: Speakers Bureau; Bioverativ: Honoraria, Research Funding; Apcintex: Honoraria; Shire: Speakers Bureau; Bayer: Speakers Bureau; Pfizer: Speakers Bureau; Sobi: Honoraria; Biomarin: Honoraria, Research Funding; Alnylam: Honoraria, Research Funding.

The unusual pattern of hereditary bleeding disorders in the province of Newfoundland and Labrador—Canada’s most Eastern Province

Newfoundland and Labrador (NL), the most eastern province of Canada, is characterized by a unique topography and pattern of settlement. The current population is descended from a small founding population of indigenous Innu, Inuit and Mi’kmaq and an estimated 28,000 settlers. These settlers originated from Southwest England and Southeast Ireland and came to invest and work in one of the world’s richest fisheries. They settled in bays, coves and islands off the coast, in small settlements called out-ports. These isolated communities developed unusual patterns of genetic disease including an unusual prevalence of some extremely rare Hereditary Bleeding Disorders (HBD). This study was designed to document the prevalence of these rare disorders, at a snapshot in time, using our provincial HBD registry. These diagnoses were verified by reviewing the original initial diagnostic coagulation results to confirm or refute each diagnosis. When available, we also recorded the underlying mutation. Population based prevalence rates were then compared with data published from the World Federation of Hemophilia (WFH) Global Registry. The results are striking. Using the WFH data the per capita prevalence in NL of Hemophilia A, Factors V, XI, and XIII Deficiency are higher than that of mainland Canada minus Labrador by a factor of 2.89, 4.54, 5.44 and 9.22, respectively. The increased prevalence of mild Hemophilia A is explained by a founder effect of the Val 2016 Ala mutation. All the severe FXIII deficient patients are homozygotes for c.691-1 G > A mutation. These results show that NL’s unique geography and population distribution led to a genetic drift that increased the prevalence of some rare factor deficiencies. This comparatively high prevalence provides a potential pool of patients for genotype/phenotype research.

Clinical and Radiological Evaluation After Chemical Synovectomy With Rifampicin in Hemophilic Arthropathy: Korean Experience With a 2-Week Interval Protocol.

ObjectiveTo assess the clinical outcome of chemical synovectomy with rifampicin in hemophilic arthropathy by using the World Federation of Hemophilia (WFH) scoring system and plain radiograph.MethodsWe performed rifampicin synovectomy (RS) on 30 joints of 28 hemophilic patients diagnosed as hemophilic arthropathy stage I–III (based on Fernandez-Palazzi clinical classification). Clinical status (bleeding frequency, pain, joint physical status) and radiological staging were evaluated as parts of the WFH scoring system before and 1 year after RS. The patients were divided into two groups by the Arnold-Hilgartner scale of the initial X-ray as stage 3 or less for the low-stage group (n=17) and over 3 for the high-stage group (n=13).ResultsTotal WFH joint physical scores were reduced after injection, and the number of bleeding episodes and pain showed especially significant improvement. For other subscores of the WFH joint physical score, only swelling, range of motion, and crepitus showed statistically significant improvement. According to the severity of the radiologic finding, the WFH joint physical score of both the low-stage and high-stage groups showed significant improvement. In the radiological aspect, the low-stage group, without joint space narrowing at the initial plain radiograph, showed no further aggravation after injection. However, in the high-stage group, radiology found aggravation regardless of the procedure.ConclusionIt is suggested that chemical synovectomy with rifampicin may prevent hemarthrosis and improve clinical symptoms. Especially in the early stage of arthropathy without joint-space narrowing, it seems to have an additional benefit that delays radiological aggravation and preserves joint status.

First‐year results of an expanded humanitarian aid programme for haemophilia in resource‐constrained countries

The gaps in haemophilia treatment around the world are enormous; approximately 60% of an estimated 475000 individuals are not identified. Of the 187000 diagnosed, 30% (57000) access clotting factor replacement therapy. Since 1996, humanitarian aid distributed by the World Federation of Hemophilia (WFH) has played a minor, yet vital role providing life-saving clotting factor to countries in emergency situations. Donated amounts have been small and sporadic, often salvaging short-dated products, providing little opportunity to leverage donations with governments. In 2015, a prospective donation programme of 100 million I.U. per year of extended half-life factor VIII and IX over 10years was established, necessitating the development of new logistics and training programmes by WFH. To measure the impact of a greatly expanded haemophilia humanitarian aid program. In 2016, the first full year of the expanded programme, WFH, distributed products to 58 countries with factor VIII usage <1I.U. per capita, a level incompatible with long-term survival and far below the 4I.U. FVIII per capita minimum established in Europe. The scope of the programme and utilization data for 2016 indicate primarily use for acute bleeding, orthopaedic and emergency surgeries. Compared to 2014, 2016 data showed substantial increases in patients served (5.9-fold, from 2119 to 14579), surgeries performed (37-fold) and bleeds treated (6.9-fold). Patients on prophylaxis rose from 0 to 852, including 458 children under 10years old. The expanded humanitarian aid programme impacts an estimated 10% of individuals with haemophilia previously unable to access treatment. This programme represents an unprecedented public-private partnership to deliver medicines to individuals with no access. Further, the programme offers the prospective opportunity to engage governments to take more responsiblity for increasing training, medical management, and product supply in 58 resource constrained countries.

Principles of haemophilia care: The Asia‐Pacific perspective

Optimal haemophilia care is best established and implemented through a well-coordinated plan guided by clearly defined principles and priorities. A document which enunciates those details is therefore important. A successful example of this approach is the definition of principles of haemophilia care (PHC) outlined by the European Association for Haemophilia and Associated Disorders (EAHAD) and also the World Federation of Hemophilia. A similar document applicable to the Asia-Pacific region must take into account not only the highly varied healthcare systems but also the tremendous socio-economic and cultural diversities which impact provision of such care. The Asia-Pacific Haemophilia Working Group (APHWG), representing the countries in this region, has prepared this perspective of the PHC. While endorsing the overall framework outlined by EAHAD, this APHWG document emphasizes regional priorities on education and training of healthcare personnel in the diagnosis and management of hereditary bleeding disorders. Central coordinating agencies with wide stakeholder input, networks of haemophilia treatment centres and national registries as well as robust processes for procurement and distribution of safe and effective clotting factor concentrates (CFCs), implementation of prophylaxis programmes and management of patients with inhibitors should also be developed. The implementation of these strategies should lead to establishment of good comprehensive care programmes. This document should also be an advocacy tool to lobby for improved care for people with haemophilia (PWH) in the region. We urge national healthcare policy makers to consider these principles and initiate strong and decisive action to reach these goals.

PP93 HTA Role In CoreHEM, A Multi-Stakeholder Core Outcome Set Project

Introduction:Hemophilia gene therapy trials demonstrate a “cure” could be achievable, thereby changing disease management. CoreHEM aims to develop multi-stakeholder consensus around a clearly defined, core outcome set (COS) - a minimum set of outcomes that should be measured and reported in all clinical trials of a specific condition - that will demonstrate and allow differentiation of the effectiveness and value of gene therapy relative to the current standard of care. Health technology assessment (HTA) frequently suffers from a lack of relevant, consistently reported outcomes. When uniformly implemented, COS increase the predictability and consistency of appraisals, coverage, and reimbursement decisions by payers and HTA agencies.Methods:A COS was developed using a modified Delphi process, including online surveys and an in-person consensus meeting. A literature review and key informant interviews were used to create an initial list of outcomes for voting. Participants (patients, including representatives from the National Hemophilia Foundation and the World Federation of Hemophilia, healthcare providers, payers, HTA agencies, regulators and industry representatives) condensed and prioritized the list by rating each outcome on a scale of 1 (not important to include) to 9 (essential). Participants could also suggest outcomes for voting. Outcomes were eliminated from consideration if &lt;70 percent rated the outcome from 7–9, unless the patient stakeholder group average score was ≥7.Results:After two Delphi rounds, there was consensus on three outcomes: frequency of bleeds, factor activity level, and duration of expression. Additional outcomes included after an in-person consensus meeting were chronic pain, mental health status, and utilization of the healthcare system (direct costs). Adverse events of interest were evaluated and separately reported.Conclusions:Including the coreHEM COS in clinical development programs will ensure that relevant, consistent outcomes are available for decisions by HTA agencies, clinicians, and patients. This should result in faster access to novel, high-value therapies for appropriate patients.

Adolescent feedback on the Haemophilia Transition Programme between Our Lady’s Children’s Hospital and St. James’s Hospital Dublin Ireland

Introduction: Haemophilia is an X-linked congenital bleeding disorder caused by the absence or low level of particular proteins called clotting factors, specifically factor VIII or factor IX in the blood (1). The complexity of the condition be can be particularly challenging during adolesence, as the young adult assumes responsibility for managing their condition. In order to improve and standardise the transition pathway for young adults with haemophilia in Ireland, a Transition Programme was established in 2012 between the National Paediatric Coagulation Centre , Our Lady’s Children’s Hospital (OLCHC) and the National Coagulation Centre (NCC), St. James’s Hospital, Ireland. Targeted population: To determine if the Transition Programme was addressing the needs and preferences of this patient group, a satisfaction survey was distributed to 83 patients in July 2016. The questionnaire comprised of 50 qualitative and quantitative questions and incorporated categories relating to the paediatric and adult service, knowledge of condition, self- management and general health. The questionnaire was approved by the NCC Patient Partnership Panel. The response rate was 23% (N=19) Highlights: 90% respondents reported that they felt prepared for their move from paediatric to adult services. Respondents expressed satisfaction with staff interactions, describing staff as helpful and pleasant.53% were not confident that they knew how to access the adult service after 5pm and 33% reported that they required additional information about the adult service. 26% of adolescents reported that they were not confident that they could recognise a bleeding episode. 21% of the adolescents surveyed were unsure about appropriate oral care. Five patients (26%) highlighted the need for access to personalised information about managing their condition and relevant services in the adult treatment centre. A shared action plan was developed as follows: Develop a Transition information leaflet. Develop a “Transition Pack” ” containing information leaflets about the adult services, condition specific information and transition information. Facilitate group meetings for parents and adolescents. Distribute a parental satisfaction survey. Develop a shared electronic nursing care plan. Develop a patient portal where adolescents can access information about their treatment centre, condition, self-management and relevant education. This will also include an online transition education programme. Comments on Transferability: The questionnaire utilised can be adapted for evaluating other chronic disease transition programmes and the improvement initiatives could be adopted to develop transition programmes in haemophilia services internationally. Conclusions: Feedback on the Transition Programme between OLCHC and NCC revealed that the majority of young adults surveyed felt adequately prepared to transfer to the adult service. However; significant knowledge gaps about their condition and a lack of awareness regarding services available were also discovered. The multidisciplinary team in OLCHC and NCC have identified a number of initiatives that will improve adolescent satisfaction and develop the adolescent’s condition knowledge and self-management skills.

ТЕСТ ВОССТАНОВЛЕНИЯ И ЕГО ЗНАЧЕНИЕ ДЛЯ ОЦЕНКИ ЭФФЕКТИВНОСТИ ДЛИТЕЛЬНОЙ ПРОФИЛАКТИЧЕСКОЙ ТЕРАПИИ ПАЦИЕНТОВ С ГЕМОФИЛИЕЙ А

Введение. Гемофилия А (ГФА) — сцепленное с Х-хромосомой рецессивное врожденное заболевание, обусловленное недостаточностью VIII фактора свертывания крови (FVIII). Главным признаком заболевания является склонность к кровотечениям. Клинические проявления ГФА, как правило, коррелируют с уровнем активности FVIII. Единственным эффективным лечением гемофилии в настоящее время является заместительная терапия препаратами дефицитного фактора. Материалы и методы. Проведен ретроспективный анализ результатов обследования 28 пациентов (14 детей в возрасте от 3 до 17 лет и 14 взрослых в возрасте от 21 до 57 лет) с тяжелой формой ГФА. Все пациенты находились на длительной профилактической терапии препаратами FVIII — как рекомбинантными, так и плазматическими. Для подбора оптимального режима профилактики пациенту с ГФА проводили тест восстановления (in vivo recovery) — определение активности FVIII в двух пробах крови; определяли также прирост показателя восстановления (incremental recovery), активированное частичное тромбопластиновое время и каолиновое время. Результаты. Проведена оценка теста восстановления фактора свертывания VIII при применении плазматических и рекомбинантного препаратов фактора VIII у пациентов с тяжелой гемофилией А; изучена корреляция теста восстановления с фармакодинамическими показателями, характеризующими состояние коагуляции. Заключение. Ввиду наличия внутрииндивидуальных и межиндивидуальных колебаний фармакокинетических показателей препаратов фактора свертывания VIII у пациентов с ГФА рекомендуется проведение теста восстановления как при назначении препарата фактора свертывания VIII, так и в процессе длительной профилактики с целью контроля за терапией и ее оптимизации в случае необходимости. Introduction. Hemophilia A (HРA) is a recessive X-linked congenital disease caused by the defi ciency of VIII coagulation factor (FVIII). Hemorrhagic tendency is the main sign of the disease. As a rule, clinical manifestations of HPA correlate with level of FVIII activity. At present time substitution therapy with medication of defi cit factor is the only eff ective treatment for hemophilia. Materials and methods. We performed a retrospective study analysis of 28 patients (14 children aged from 3 to 17 years and 14 adults aged from 21 to 57 years) examination with severe HРA. All patients received prolonged preventive therapy with recombinant factor VIII products. To select the optimal prophylaxis mode for patients with HPA we performed a recovery test (in vivo recovery), determination of FVIII activity in two blood samples, determined index of incremental recovery, activated partial thromboplastin time and kaolin time. Results. We assessed recovery test for coagulation factor VIII using plasma and recombinant factor VIII products in patients with severe haemophilia A and studied correlation of recovery test with pharmacodynamic parameters that characterized coagulation state. Conclusion. Due to intra-individual and inter-individual fl uctuations in pharmacokinetic parameters of recombinant factor VIII products in patients with HPA we recommend to perform a recovery test both at appointment of coagulation factor VIII product and also during of long-term prophylaxis for monitoring and optimization of therapy.

Efficacy of a modified coagulation factor substitution for total hip arthroplasty in patients with end-stage haemophilic arthropathy.

Total hip arthroplasty (THA) is an effective treatment for end-stage haemophilic arthropathy, and substitution therapy plays a key role in the success of THA. The aim of this study was to evaluate the efficacy of a modified coagulation factor substitution regime in THA. Nineteen haemophiliac patients (20 hips) who received primary cementless THA were enrolled. Based on World Federation of Haemophilia (WFH) guideline, a modified coagulation factor substitution regime was adopted. Blood loss, implant survival rates and complications were reviewed, retrospectively. The mean age at surgery was 29.7 years (15-49 years) and the mean follow-up period was 91 months (43-151 months). Mean total blood loss, external blood loss and hidden blood loss were 3543 (1494-7576), 1435 (600-3440), and 2110 ml (534-4402), respectively. Mean intraoperative blood loss and postoperative drainage were 715 (300-2000) and 713 ml (200-2950), respectively. Mean red blood cell transfusion used was 5 U (0-14). All prostheses were found to have bony ingrowth. One patient had hematoma formation in the thigh and one with a lower limb deep vein thrombosis, postoperatively. Other complications included one skin ulcer, one femur splitting fracture, and one transient neuropraxia. Intraoperative blood loss and wound drainage, in our study, were similar to that in haemophiliac patients and nonhaemophilic patients in literature. This supports the efficacy of the modified coagulation factor substitution strategy in our study.

Measuring the quality of haemophilia care across different settings: a set of performance indicators derived from demographics data.

Haemophilia is a rare disease for which quality of care varies around the world. We propose data-driven indicators as surrogate measures for the provision of haemophilia care across countries and over time. The guiding criteria for selection of possible indicators were ease of calculation and direct applicability to a wide range of countries with basic data collection capacities. General population epidemiological data and haemophilia A population data from the World Federation of Hemophilia (WFH) Annual Global Survey (AGS) for the years 2013 and 2010 in a sample of 10 countries were used for this pilot exercise. Three indicators were identified: (i) the percentage difference between the observed and the expected haemophilia A incidence, which would be close to null when all of the people with haemophilia A (PWHA) theoretically expected in a country would be known and reported to the AGS; (ii) the percentage of the total number of PWHA with severe disease; and (iii) the ratio of adults to children among PWHA standardized to the ratio of adults to children for males in the general population, which would be close to one if the survival of PWHA is equal to that of the general population. Country-specific values have been calculated for the 10 countries. We have identified and evaluated three promising indicators of quality of care in haemophilia. Further evaluation on a wider set of data from the AGS will be needed to confirm their value and further explore their measurement properties.

Let's Talk Period: Preliminary Results of an Online Bleeding Awareness Knowledge Translation Project and Bleeding Assessment Tool Promoted on Social Media

Background: Undiagnosed bleeding disorders can pose significant health risks, especially for women. As many as 1 in 1000 individuals have a bleeding disorder, many of whom are undiagnosed. Lack of understanding about the difference between normal and abnormal bleeding, particularly menstrual bleeding, is a barrier to diagnosis. Recently, a self-administered bleeding assessment tool (Self-BAT) was validated as a screening tool for von Willebrand disease (VWD).Objective: Our objective was to increase awareness of undiagnosed bleeding disorders through the use of an informational website (http://letstalkperiod.ca) targeted at women in their reproductive years. Here we report the results from the first 10 weeks of this knowledge translation project.Methods:The Let’s Talk Period website was built in consultation with a medical communications company, with the aim of clearly presenting key messages around menstrual bleeding. Focus groups with young women were held to determine optimal communication strategies and an iterative process of expert review was undertaken prior to launch. Upon completion of the integrated Self-BAT application, the result of whether the bleeding score is normal or abnormal is displayed to the user, along with a recommendation to seek medical attention if the score is positive/abnormal (≥6 for adult females,≥4 for adult males, ≥3 for individuals < 18 years). Queen’s University Legal Department provided advice regarding website disclaimers. Research Ethics Board approval was sought but deemed unnecessary, given that no identifiable information is collected. Website users must electronically indicate that they have read and understood a disclaimer about the use of the Self-BAT application before being granted access, and must enter their age and gender.The website was promoted through an interview with the senior author that aired on Canadian national television in the context of a segment on VWD. Additional promotion occurred using social media such as Facebook and Twitter, as well as during local interviews at Queen's University and Kingston General Hospital. The social media networks of the Canadian Hemophilia Society, the World Federation of Hemophilia, the Foundation for Women and Girls with Blood Disorders were also engaged to promote the website.Results: For the 10-week period beginning May 14, 2016 there were 4,907 page views and 3,001 sessions initiated by 2,597 individual users from 62 countries. The average session length was 1 minute and 12 seconds; 15 were longer than 30 minutes. The majority of sessions (60%) were initiated in Canada. Table 1 outlines the countries with the highest volume of website visits.A total of 460 individuals, 438 (95%) of whom were female, completed the online Self-BAT. Individuals ranged in age from 12 to 71 years (mean 36 years). Individuals aged 35 to 44 years represented the largest proportion of users who completed the Self-BAT (31%), followed by those aged 25 to 34 years (28%). The mean Self-BAT score was 6 and scores ranged from 0 to 44. Abnormal age and gender specific Self-BAT scores were reported in 45% of the respondents (n=209), of which 98% were female. Of the individuals with abnormal Self-BAT scores the most commonly reported symptoms (Table 2) were menorrhagia (99%), post-partum hemorrhage (84%), bleeding from the oral cavity (78%), cutaneous bleeding (74%) and epistaxis (56%). Frequency of specific symptoms of menorrhagia are outlined in Table 3. The most common symptom of post-partum hemorrhage reported was bleeding longer than 6 weeks after delivery (16%). Surgery or ICU admission post-partum was required in 3 women.Conclusion: Initial results from the first 10 weeks of an informational website demonstrated that this platform is capable of reaching users from around the world. We have demonstrated that an online screening tool will be used by individuals concerned about abnormal bleeding. In women, the predominant symptoms of abnormal bleeding reported were menorrhagia and post-partum hemorrhage. In future, we plan to expand the educational content of the Let's Talk Period website, including information directed at medical professionals and a regular blog directed at the public. Additionally, we plan to seek research ethics approval for knowledge translation research tracking the outcomes of abnormal bleeding scores in local website users. [Display omitted] [Display omitted] [Display omitted] DisclosuresJames:Bayer: Research Funding; CSL Behring: Research Funding; Octapharma: Research Funding; Biogen: Consultancy; Basalt: Consultancy.

Safety and Efficacy of Recombinant Factor XIII (FXIII) in Patients with Congenital FXIII A-Subunit Deficiency, Results from the Mentor™2 Trial

Safety and Efficacy of Recombinant Factor XIII (FXIII) in Patients with Congenital FXIII A-Subunit Deficiency, Results from the Mentor™2 Trial

Prophylaxis in Patients with Hemophilia a and Its Impact on Quality of Life Using the Specific Index Haem-a-Qol at a Hospital in Paraguay

Prophylactic replacement therapy with FVIII is considered the standard of care for patients with hemophilia although a protocol for administering the prophylaxis has yet to be defined by the World Federation of Hemophilia. Gaona in 2012 demonstrated a significant reduction in the number of hospitalizations due to bleeding episodes in patients with Hemophilia A treated with secondary prophylaxis at the Hematology Service of the Hospital Central del Instituto de Prevision Social (HCIPS) with a regimen of 25 IU/Kg per week in two infusions by reporting results from such regimen that had started at the HCIPS in 2010. This is a lower dose to those most frequently used in high resource countries like the Malmo or Utrecht protocols.The goal of this study was to assess the impact of our lower dose prophylaxis regimen on bleeding events, hospitalizations and quality of life as an alternative for low resource countries that cannot afford to provide their patients with higher dose treatments.The Dutch group Haemo-QoL designed the specific questionnaire for adult patients with hemophilia, the Haem-A-QoL with a Spanish version available for patients aged 17 and up.Results: The HCIPS currently has 36 patients receiving prophylactic treatment with FVIII. From these 18 patients consented to filling out the questionnaire. The mean age of the patients was 28. 3 of the patients were married, 2 were in a stable relationship and 13 were single. 62% of patients lived within 20 km of the Hospital and 38% lived further away going up to 200 km. 17 of the 18 patients had the highest level of education possible for their age. Only one patient, the oldest one, had stopped his education at primary school. All of them had severe disease with one or more affected joints.The average FVIII use per year was 68,000 IU ranging from 8,000 IU to 96,000 IU or 917 IU/kg/year. The strongest determinant for receiving less FVIII was missing appointments. Distance to the Hospital was not of significance. Bleeding episodes prior to prophylactic treatment was 2-3 minor traumatic bleeding episodes per week (after brushing their teeth, easy bruising from minor trauma), 2-3 joint bleeds per month at which point they would seek medical assistance and 1-2 major bleeding episodes per year requiring hospitalization. In the last year 5 patients were hospitalized once. One for pneumonia, one for phlebitis, one for dengue fever and two for hemathrosis. They reported a decrease in bleeding episodes at home from 2-3 joint bleeds per month to 1 every other month. Patients reported after traumatic events their bleeding was "normal" (i.e. when brushing their teeth if they started bleeding they would continue bleeding for days at a time whereas when in prophylaxis they would bleed right after the brushing and then it stopped which they took to be normal).Converting the results from the Haem-A-QoL questionnaire to a scoring system of 1-100 being 1 the best QoL and 100 the worst, the average QoL was 52. With scores of 60 for physical health, 50 for feelings, 52 for view of themselves, 48 for work/school, 53 for treatment, 56 for future, 47 for family planning and 45 for dating. Scores for sports and leisure though only amounting to 64, 33% of patients said that category did not apply to them since they did not practice any sports and the dealing category with a score of 37 was the lowest of all. When compared to results published by a Blood Center in Brazil with an on demand regimen patients with severe hemophilia in that study showed a physical health score of 55, 40 for feelings, 35 for self-perception, 60 for sports and leisure, 35 for work and school, 20 for coping, 45 for treatment, 45 for future and 25 for dating with an average overall score of 40. With an annual average usage of 63,683 IU on the severely affected patients.In summary, the proposed dosing of 25IU/kgs/week seems at first glance to reduce bleeding episodes among patients with severe hemophilia as well as hospitalizations. In general patients treated at the HCIPS have a regular to poor quality of life as measured by the Haem-A-QoL questionnaire which contrasts with results from the Brazilian study on quality of life from patients with on demand treatment and roughly same FVIII usage per year showing their patients with severe hemophilia had an overall quality of life from regular to good. Perhaps the psychological factor comes in to play? A follow up study after patients receive proper psychological evaluations may help clarify results. DisclosuresNo relevant conflicts of interest to declare.

Strategies to encourage physical activity in patients with hemophilia to improve quality of life.

Hemophilia is a bleeding disorder caused by a congenital abnormality of blood coagulation. Until the mid-1970s, patients with hemophilia (PWH) were advised to refrain from physical activity (PA) because of a perceived increased risk of bleeding. Since then, PA, which is recognized as being essential for health maintenance, is now recommended by the World Federation of Hemophilia. Moreover, a number of studies reported that PA can improve treatment efficacy and prevent bleeding in PWH. Physical assessment and intervention in PA are currently used in clinical practice. However, the necessity of PA is not emphasized, and many PWH generally have low- to- no PA. Therefore, a behavior change approach to encourage patient motivation is becoming ever more important. In this article, we review articles addressing PA in PWH and discuss strategies to encourage PA through a behavior change approach by focusing on factors relevant to hemophilia, such as benefits and bleeding risk of PA, risk management of bleeding, PA characteristics, and difficulty with exercise adherence. The trust relationship between clinicians and patients, a transtheoretical model of behavior change, and motivation theory as approaches to promote PA are introduced. Finally, we review a case report of the clinical success of a behavior change approach to promote PA. Many PWH find it difficult to continue PA because of aging, fear of bleeding, insufficient recognition of PA benefits, and psychological problems. Therefore, it is essential and important to perform prophylaxis with PWH and to heighten their understanding of the benefits and risks of PA, before initiating the exercise regimen. For those patients who find it difficult to participate in PA, it is necessary to plan individual-based behavior change approach and encourage self-efficacy.

Prophylaxis in congenital coagulation disorders: past, present and future.

Prophylaxis in congenital coagulation disorders: past, present and future.

National and international registries of rare bleeding disorders.

Rare bleeding disorders (RBDs) are autosomal recessive disorders, representing 3-5% of all the inherited deficiencies of coagulation factors. Their frequency in the general population ranges from 1:500,000 to 1:2 millions. In countries with a high rate of consanguineous marriages RBDs occur more frequently, representing a significant clinical and social problem. Patients affected by RBDs have a wide spectrum of clinical symptoms that vary from a mild or moderate bleeding tendency to potentially serious or life-threatening haemorrhages. Current treatment is based on both replacement therapy and non-transfusional treatment. However, despite the existence of several concentrates, there is no Factor V concentrate available for the treatment of Factor V deficiency, yet. In 2004, to improve the understanding of RBDs prevalence, diagnosis and treatments, the Rare Bleeding Disorders database (RBDD, www.rbdd.org) was developed. The RBDD project allowed the collection of epidemiological information on 3,230 patients from 66 Centres scattered all over the world. Epidemiological data can also be derived from the annual survey of the World Federation of Hemophilia (www.wfh.org) and from other existing national registries. However, these data are not homogenous and global surveys provide a non-real picture of the distribution of RBDs, as about 50% of data refers to European patients. Hence, we focused on Europe and, thanks to a European project (EN-RBD), we set up a network of 10 Treatment Centres to develop a homogeneous communication tool for inserting, managing and viewing information on RBD patients (www.rbdd.eu). This on-line database resulted to be a powerful tool to improve the quality of data collection. Preliminary results showed that a homogeneous and harmonized data collection using a unique model will help to have more accurate data for statistical analysis.

Principles of treatment and update of recommendations for the management of haemophilia and congenital bleeding disorders in Italy.

Patients with congenital bleeding disorders (CBD) in Italy are regularly followed by 52 Haemophilia Treatment Centres (HTCs) distributed throughout the country1. The expertise gained from these HTCs is coordinated within the framework of the Italian Association of Haemophilia Centres (AICE, Associazione Italiana Centri Emofilia). This medical organisation promotes an uniform approach to the treatment of haemophilic syndromes, developing shared therapeutic strategies, conducting collaborative clinical research activities and handling the organisational aspects of the facilities providing care of CBD patients in Italy. AICE collaborates with the National Institute of Health (Istituto Superiore di Sanita, ISS) in the management and updating of the National Registry of Congenital Coagulopathies1. It also holds a database for the census and monitoring of patients with CBD, registries collecting data on specific aspects of treatment (e.g., AICE Registry of Immune Tolerance Induction [ITI] in severe haemophilia A patients with inhibitors; RENAWI, National Registry of von Willebrand disease) and databases of gene mutations in haemophilia A and B patients. Some HTCs members of AICE participate in the European Haemophilia Safety Surveillance (EUHASS). The management of patients with CBD is essentially based on home treatment2 which allows replacement therapy to be carried out as soon as possible and is associated with a higher therapeutic efficacy and a better quality of life3. Self-treatment at home does, however, imply that the patient (and/or his caregiver) is specifically trained to take decisions on the proper timing of administration of replacement therapy, to adhere strictly to the prescribed dosage, to recognise any side effects, and to keep accurate records of each infusion made. To this purpose, the HTCs periodically organise courses and training educational activities to grant qualification for home treatment to the patients or their family members. The HTCs are also responsible for a periodic review and assessment of skills for self-management of home treatment for each individual patient. All these procedures are governed by specific regional regulations4. In the last decade there have been significant advances in the therapy of haemophilia and related inherited bleeding disorders. The technological evolution of the processes of purification and viral inactivation has allowed the marketing of new plasma-derived concentrates5, while progress with the production of factor VIII (FVIII) and factor IX (FIX) in animal cells by recombinant DNA technology has enabled the progressive elimination of human and animal proteins from various stages of the manufacturing process. Some recombinant products have, therefore, been replaced by newer generation products and other innovative molecules are currently in an advanced experimental or registration stage6. Considering these important developments, the AICE working group has updated the Italian treatment guidelines7, taking into account the recommendations by the World Federation of Haemophilia (WFH)8, by the European Association of Haemophilia and Allied Disorders (EAHAD)9, and the recent approval of an agreement of the national State-Regions Conference, which defined care pathways to meet the specific needs of CBD patients and to ensure uniform levels of care throughout the country4. The AICE working group also carried out systematic reviews of the literature aimed to assess the quality of the available evidence on issues still controversial, in particular the risk of development of inhibitor in previously untreated patients (PUPs) with severe haemophilia A10. In addition, a survey among Directors of HTCs that are members of AICE, which was attended by 77% (40/52) of them, was carried out11. An ad hoc questionnaire (19 questions), was specifically designed to determine the opinion of clinicians about the most important aspects of the treatment of haemophilia, including the choice of products for replacement therapy in patients with different clinical characteristics, indications for prophylaxis and ITI treatments and the modality of implementation of these regimens. The reviews of the literature and the results of the survey were used to define cornerstone “principles” for the management and treatment of patients with CBD, which have been shared with the Italian Federation of Haemophilia Associations (FedEmo, Federazione delle Associazioni Emofilici) and were approved by AICE members on October 8, 2013.

Rare coagulation disorders: an emerging issue.

Rare coagulation disorders: an emerging issue.

First Report on the Safety and Efficacy of a Long-Acting Recombinant FVIII (turoctocog alfa pegol, N8-GP) during Major Surgery in Patients with Severe Hemophilia a

IntroductionN8-GP (turoctocog alfa pegol) is an extended half-life, recombinant factor VIII (FVIII) that has a site-specific glycoPEGylation in the truncated B-domain. Upon activation, the glycopegylated domain is cleaved from N8-GP yielding FVIIIa, which is identical to endogenous FVIIIa. PathfinderTM 2 and pathfinder™3 (www.ClinicalTrials.gov identifiers: NCT01480180 and NCT01489111, respectively) are ongoing international, open-label, non-randomized, phase 3 clinical trials of N8-GP in patients aged ≥12 years with severe hemophilia A and with a documented history of at least 150 exposure days to other FVIII products, in line with regulatory guidelines. All patients in the pivotal pathfinderTM 2 trial are offered entry into pathfinderTM 3 if major surgery is required, thus enabling patients to undergo surgery without having to switch to another FVIII product. After completion of pathfinderTM 3, patients returned to the prophylactic or on-demand treatment arm in pathfinderTM 2 as per their prior participation in the trial. We report a planned main phase interim analysis of the single-arm pathfinderTM 3 trial evaluating the efficacy and safety of N8-GP during surgical procedures in patients with severe hemophilia A.MethodsPatients recruited into the pathfinderTM 3 trial were males aged ≥12 years (aged ≥18 years in France and the Netherlands) with severe hemophilia A (FVIII activity level <1 IU/dl). Eligible patients undergoing major surgery received N8-GP before, during, and after surgery. At screening (0-3 weeks prior to surgery), all eligible patients received a single dose of N8-GP 50 U/kg at the clinic to evaluate FVIII activity recovery and required dose level for surgery. On the day of surgery, all patients received a fixed pre-operative loading dose of N8-GP (50 U/kg), up to 2 hours prior to the start of surgery. During and after surgery, N8-GP dosing was at the investigators' discretion. The dose level of N8-GP during this trial was chosen so that FVIII activity levels recommended by World Federation of Hemophilia (WFH) guidelines were targeted; higher levels could be necessary depending on type of surgery and standard practice at the site. Postoperative assessments, including monitoring for FVIII activity, were conducted daily for Days 1-6, and once between Days 7-14. Efficacy of N8-GP during surgical procedures was assessed using a 4-point scale of "excellent, good, moderate, or poor". In addition, transfusion requirements, consumption and estimated blood loss were recorded as part of the efficacy assessment. Blood sampling for FVIII activity and laboratory safety parameters was done at all trial visits.ResultsThe main phase interim analysis includes results from 16 patients (median age of 36.5 years; range: 15−66 years) who underwent 18 major surgical procedures (including synovectomy, joint replacement, ankle arthrodesis, and psoas pseudo tumor excision). All surgeries were effectively performed with N8-GP. Hemostasis was successful (i.e., rated as 'excellent' or 'good') on completion of surgery in 17 (94.4%) procedures, and no change of treatment regimen was needed in any patient. For one procedure (complicated total hip replacement) the hemostatic response was rated 'moderate' (5.6%) in a patient with multiple comorbidities and low platelet count at day of surgery. The postsurgical hemostatic effect success rate with N8-GP was 100%. N8-GP was well tolerated and no safety issues were identified during this trial; no FVIII inhibitors were detected, and no thromboembolic events occurred.ConclusionsAs the first report for a longer-acting glycoPEGylated FVIII product, the results from pathfinder™ 3 indicate that N8-GP is effective and well tolerated with a favorable safety profile for perioperative management of major surgical procedures in patients with severe hemophilia A. DisclosuresHampton:Novo Nordisk: Honoraria. Chowdary:CSL Behring: Consultancy, Research Funding; Bayer: Consultancy; SOBI: Consultancy; Biogen Idec: Consultancy; Baxter: Consultancy; Novo Nordisk: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Dunkley:Baxter: Consultancy; Novo Nordisk: Honoraria; Bayer: Honoraria; Pfizer: Honoraria. Ehrenforth:Novo Nordisk: Employment. Jacobsen:Novo Nordisk: Employment. Neff:Alexion: Speakers Bureau; Baxter: Speakers Bureau; Novo Nordisk: Research Funding, Speakers Bureau. Santagostino:Bayer: Speakers Bureau; Octapharma: Speakers Bureau; Roche: Speakers Bureau; Biogen/Sobi: Speakers Bureau; Baxter/Baxalta: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Biotest: Speakers Bureau; Novo Nordisk: Speakers Bureau; CSL Behring: Speakers Bureau; Kedrion: Speakers Bureau. Takedani:Novo Nordisk: Speakers Bureau; Baxter: Speakers Bureau; Bayer: Speakers Bureau; Kaketsuken: Speakers Bureau; Pfizer: Speakers Bureau. Takemoto:Novo Nordisk: Research Funding; Mast Therapeutics: Speakers Bureau. Négrier:Biogen/Sobi: Consultancy; Novo Nordisk: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; LFB: Consultancy; Bayer: Consultancy, Research Funding; Baxter: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding.