Prophylaxis in hemophilia

Hemophilia is an inherited X-linked coagulopathy defined by a deficiency or abnormality in the clotting function of factor VIII (Hemophilia A) or factor IX (Hemophilia B). Prophylaxis ­ the regular administration of therapeutic products to maintain hemostasis and prevent bleeding ­ is the mainstream of treatment. Addressing the development and scientific evidence for administrating prophylaxis is the goal of this review. Prophylaxis is the therapeutic modality of choice for people with severe hemophilia, being considered, in principle, a lifelong treatment. It should have an early onset, ideally as a primary, or at least secondary. Even lifelong tertiary prophylaxis seems to offer benefit, although further studies are still lacking. Individualized strategies should lead to an optimization of the dilemma between better joint outcomes versus involved costs.

Avaliação do perfil clínico-terapêutico e da resposta à profilaxia dos portadores de hemofilia A e B em um centro de referência no Ceará / Evaluation of the clinical-therapeutic profile and the response to prophylaxis of patients with hemophilia A and B in a reference center in Ceará

Objetivo: Avaliar o perfil clínico-terapêutico e a resposta à profilaxia em pacientes hemofílicos A e B em um centro de referência no Ceará. Métodos: Estudo de coorte retrospectivo, com dados de 133 hemofílicos A e B, em profilaxia entre 2016 e 2021, por meio de prontuários médicos e sistema Web Coagulopatias. Resultados: Os pacientes todos do sexo masculino em sua maioria foram hemofílicos A (93,2%), na forma grave, residentes em Fortaleza, com maior prevalência do município de Guaiúba. A maioria fazia uso de Fator VIII recombinante e em profilaxia secundária, em relação ao comprometimento articular a maioria não apresentou relato de hemartroses (66,9%), articulação-alvo (87,9%) ou artropatia (54,9%), porém os hemofílicos em profilaxia terciária apresentaram um maior comprometimento articular em relação a profilaxia primária e secundária. Verificou-se uma correlação negativa entre o tempo de profilaxia e a dose de fator utilizada, demonstrando que quanto maior o tempo de profilaxia menor a dose do fator utilizada. Um total de 13 hemofílicos A grave desenvolveram inibidor de fator VIII realizando imunotolerância (ITI) com sucesso total em 84,6%. Por meio da curva ROC, foi verificado uma associação entre a necessidade de ITI e a dose de fator de coagulação, com acurácia de 67,7% de que o uso de doses maiores de fator predispõe ao desenvolvimento de inibidores. Conclusão: Os dados do estudo permitem inferir que quanto mais precoce o tratamento de profilaxia menor é comprometimento articular, dose do fator utilizada e menor predisposição de desenvolver inibidores dos fatores da coagulação.

Objective: to evaluate the clinical-therapeutic profile and response to prophylaxis in hemophiliac A and B patients at a referral center in Ceará. Methods: Retrospective cohort study, with data from 133 hemophiliacs A and B, undergoing prophylaxis between 2016 and 2021, using medical records and the Web Coagulopathies system. Results: Most of the patients were male patients with severe hemophilia A (93.2%), residing in Fortaleza, with a higher prevalence in the city of Guaiúba. Most made use of recombinant Factor VIII and in secondary prophylaxis, in relation to joint involvement, the majority did not report hemarthroses (66.9%), target joint (87.9%) or arthropathy (54.9%). however, hemophiliacs on tertiary prophylaxis showed greater joint impairment in relation to primary and secondary prophylaxis. There was a negative correlation between the prophylaxis time and the factor dose used, demonstrating that the longer the prophylaxis time, the lower the factor dose used. A total of 13 severe A hemophiliacs developed factor VIII inhibitor performing immunotolerance (ITI) with total success in 84.6%. Using the ROC curve, an association was verified between the need for ITI and the dose of coagulation factor, with an accuracy of 67.7% that the use of higher doses of factor predisposes to the development of inhibitors. Conclusion: The study data allow us to infer that the earlier the prophylaxis treatment, the less joint impairment, the dose of the factor used and the less predisposition to develop coagulation factor inhibitors.

Clinical, humanistic, and economic burden of severe haemophilia B in adults receiving factor IX prophylaxis: findings from the CHESS II real-world burden of illness study in Europe.

BACKGROUND: Real-world studies of the burden of severe haemophilia B in the context of recent therapeutic advances such as extended half-life (EHL) factor IX (FIX) products are limited. We analysed data from the recent CHESS II study to better understand the clinical, humanistic, and economic burden of severe haemophilia B in Europe. Data from male adults with severe haemophilia B receiving prophylaxis were analysed from the retrospective cross-sectional CHESS II study conducted in Germany, France, Italy, Spain and the United Kingdom. Inhibitors were exclusionary. Patients and physicians completed questionnaires on bleeding, joint status, quality of life, and haemophilia-related direct and indirect costs (2019-2020). All outcomes were summarised using descriptive statistics. RESULTS: A total of 75 CHESS II patients were eligible and included; 40 patients (53%) provided self-reported outcomes. Mean age was 36.2 years. Approximately half the patients were receiving EHL versus standard half-life (SHL) prophylaxis (44% vs 56%). Most patients reported mild or moderate chronic pain (76%) and had ≥ 2 bleeding events per year (70%), with a mean annualised bleed rate of 2.4. Mean annual total haemophilia-related direct medical cost per patient was €235,723, driven by FIX costs (€232,328 overall, n = 40; €186,528 for SHL, €290,620 for EHL). Mean annual indirect costs (€8,973) were driven by early retirement or work stoppage due to haemophilia. Mean quality of life (EQ-5D) score was 0.67. CONCLUSIONS: These data document a substantial, persistent real-world burden of severe haemophilia B in Europe. Unmet needs persist for these patients, their caregivers, and society.

Réévaluation de RebinynMC (nonacog bêta pégol): hémophilie de type B / RebinynTM (nonacog beta pegol): type B Hemophilia (re-evaluation)

MANDAT: À la demande du fabricant Novo Nordisk Canada Inc., l'Institut national d'excellence en santé et en services sociaux (INESSS) a procédé à la réévaluation du produit du système du sang RebinynMC (nonacog bêta pégol), un facteur IX (FIX) de coagulation humain recombinant à demi-vie prolongée qui s'administre par voie intraveineuse. Au Canada, le nonacog bêta pégol est indiqué pour la maîtrise et la prévention des épisodes hémorragiques ainsi que pour la maîtrise et la prévention des saignements dans un contexte périopératoire chez les adultes et les enfants atteints d'hémophilie B (déficit congénital en facteur IX ou maladie de Christmas). Il est aussi indiqué pour la prophylaxie de routine afin de prévenir les épisodes hémorragiques ou d'en réduire la fréquence chez les patients de 18 ans et plus atteints d'hémophilie B. Les indications visées pour cette réévaluation sont identiques à celles reconnues par Santé Canada. Le nonacog bêta pégol a déjà été évalué par l'INESSS (avis de juin 2020). Lors de son évaluation précédente, l'INESSS a formulé une recommandation défavorable à son ajout sur la Liste des produits du système du sang du Québec, car la valeur thérapeutique n'avait pas été reconnue par le Comité scientifique permanent de l'évaluation des médicaments aux fins d'inscription (CSEMI). Il s'agit de la deuxième évaluation de ce produit. Les cinq FIX suivants sont présentement inscrits sur la Liste des produits du système du sang du Québec et ont servi de comparateurs : BeneFIXMC (nonacog alfa; FIX recombinant à action standard), RixubisMC (nonacog gamma; FIX recombinant à action standard), AlprolixMC (eftrénonacog alfa; FIX recombinant à demi-vie prolongée), IdelvionMC (albutrepenonacog alfa; FIX recombinant à demi-vie prolongée), ImmunineMC (FIX d'origine plasmatique). DÉMARCHE D'ÉVALUATION: Une revue des données issues de la littérature et de celles fournies par le fabricant a été réalisée afin de documenter l'efficacité, l'innocuité et l'efficience du nonacog bêta pégol. Des données contextuelles et expérientielles issues de la consultation d'experts sont également présentées. DÉMARCHE D'ÉVALUATION: Une revue des données issues de la littérature et de celles fournies par le fabricant a été réalisée afin de documenter l'efficacité, l'innocuité et l'efficience du nonacog bêta pégol. Des données contextuelles et expérientielles issues de la consultation d'experts sont également présentées. BESOIN DE SANTÉ: L'hémophilie B, causée par une défaillance du FIX, se manifeste par des temps de coagulation plus longs que la normale. Dans les cas sévères, le déficit en FIX mène à des épisodes de saignement fréquents aux articulations, appelés hémarthroses, et aux tissus mous même sans traumatisme. La prophylaxie à l'aide de FIX plasmatique ou recombinant constitue le traitement privilégié. Celle-ci consiste en plusieurs injections intraveineuses hebdomadaires pour remplacer le FIX manquant. Malgré une bonne prise en charge de l'hémophilie B au Québec, certaines lacunes liées aux traitements actuels demeurent. Outre le souhait d'un traitement curatif permanent, les besoins suivants ont été reconnus par les experts rencontrés : une meilleure prévention contre le développement d'inhibiteurs (anticorps neutralisants contre le FIX), la prévention d'arthropathies hémophiliques et des douleurs chroniques, des traitements offrant une protection hémostatique supérieure qui perdure plus longtemps et l'atténuation des contraintes liées aux injections intraveineuses répétées. RÉSULTATS: La combinaison des données d'une étude canadienne en contexte réel de soins, des données du rapport de surveillance postcommercialisation du nonacog bêta pégol et des données des études cliniques évaluées aux fins de l'avis précédent a été considérées. PERSPECTIVE DES EXPERTS: À la lumière des données présentées dans le cadre de cette réévaluation, les experts consultés sont d'avis que l'efficacité de la prophylaxie avec le nonacog bêta pégol est comparable à celle des comparateurs, soit tous les FIX inscrits à la Liste. Selon les experts, le profil de l'innocuité du nonacog bêta pégol est comparable à celui des autres options disponibles pour la population ciblée. De plus, les préoccupations relatives à l'accumulation potentielle de PEG dans le plexus choroïde demeurent théoriques chez l'humain et ne les empêcheraient pas d'utiliser le produit chez la population québécoise indiquée. RECOMMANDATIONS DE L'INESSS SUR LE NONACOG BÊTA PÉGOL: À la lumière des informations disponibles, l'INESSS recommande d'ajouter RebinynMC (nonacog bêta pégol) à la Liste des produits du système du sang du Québec pour la maîtrise et la prévention des épisodes hémorragiques et la maîtrise et la prévention des saignements dans un contexte périopératoire chez les adultes et les enfants atteints d'hémophilie B (déficit congénital en facteur IX ou maladie de Christmas) ainsi que pour la prophylaxie de routine afin de prévenir les épisodes hémorragiques ou d'en réduire la fréquence chez les patients de 18 ans ou plus atteints d'hémophilie B. Précision sur la recommandation: Dans une perspective de justice distributive, le remboursement du nonacog bêta pégol pour l'indication demandée constituerait une décision responsable, juste et équitable si le coût d'utilisation du nonacog bêta pégol ne surpasse pas celui des FIX à demi-vie prolongée lors du prochain appel d'offres.

MANDATE: At the request of the manufacturer Novo Nordisk Canada Inc., the Institut national d'excellence en santé et en services sociaux (INESSS) re-evaluated the blood system product RebinynTM (nonacog beta pegol), an intravenously injected recombinant factor IX (FIX) indicated in adults and children with hemophilia B (congenital factor IX deficiency or Christmas disease) for the control and prevention of bleeding episodes and in the perioperative setting as well as in patients 18 years and above with hemophilia B for routine prophylaxis to prevent or reduce the frequency of bleeding episodes. The indications assessed for this re-evaluation are identical to those accorded by Health Canada. INESSS previously evaluated nonacog beta pegol (evaluation of June 2020). During the first evaluation, INESSS issued an unfavourable recommendation for the addition of the product to the Liste des produits du système du sang du Québec because the therapeutic value had not been recognized by the Comité scientifique permanent de l'évaluation des médicaments aux fins d'inscriptions (CSEMI). This is the second evaluation of this product. The following five FIX currently listed on the Liste des produits du système du sang du Québec were used as the comparators of nonacog beta pegol: BeneFIXTM (nonacog alfa; standard half-life recombinant FIX), RixubisTM (nonacog gamma; standard half-life recombinant FIX), AlprolixTM (eftrénonacog alfa; extended half-life recombinant FIX), IdelvionTM (albutrepenonacog alfa; extended half-life recombinant FIX), ImmunineTM (plasma-derived FIX). EVALUATION PROCESS: Published trials and manufacturer data were reviewed to document the efficacy, safety and efficiency of nonacog beta pegol. Experiential and contextual data from expert consultations and patients are presented as well. HEALTH NEED: Type B hemophilia is caused by a deficiency in FIX and is characterized by longer clotting times. In severe cases, FIX deficiency leads to frequent bleeding episodes in joints (hemarthrosis) and soft tissue in the absence of trauma. Prophylaxis with plasma or recombinant FIX is the preferred treatment. This consists of several weekly intravenous injections to replace the missing FIX. Despite a good management of Quebecers living with type B hemophilia, the need for new treatment remains. In addition to permanent curative treatment, the following needs were identified by the experts consulted: better prevention of inhibitor development (neutralizing antibodies against FIX), prevention of hemophilic arthropathies and chronic pain, treatments that provide superior hemostatic protection that lasts longer and alleviates the stresses associated with repeated intravenous injections. RESULTS: Combined data from a real-world Canadian study, a post-market surveillance report on nonacog beta pegol, as well as previously evaluated clinical studies were considered for this evaluation. RECOMMANDATIONS DE L'INESSS SUR LE NONACOG BÊTA PÉGOL: In light of the available data, INESSS recommends that RebinynTM (nonacog beta pegol) be added to the Liste des produits du système du sang du Québec for the treatment of hemophilia B (congenital factor IX deficiency or Christmas disease) in adults and children for the control and prevention of bleeding episodes and in the perioperative setting as well as in patients 18 years and above with hemophilia B for routine prophylaxis to prevent or reduce the frequency of bleeding episodes. Precision regarding the recommendation: From a distributive justice perspective, the reimbursement of nonacog beta pegol for the requested indication would constitute a responsible, fair and equitable decision if the cost of using nonacog beta pegol does not exceed that of extended half-life FIX during the next call for tenders.

RebinynMC, Facteur IX de coagulation (recombinant): nonacog bêta pégol / RebinynTM (nonacog beta pegol): coagulation factor IX (recombinant)

MANDAT: L'Institut national d'excellence en santé et en services sociaux (INESSS) a procédé à l'évaluation du produit du système du sang RebinynMC (nonacog bêta pégol, N9-GP), un facteur IX recombinant (FIXr) administré par injection intraveineuse. Le nonacog bêta pégol est indiqué chez les adultes et les enfants atteints d'hémophilie B (déficit congénital en facteur IX ou maladie de Christmas) pour la maîtrise et la prévention des épisodes hémorragiques et la maîtrise et la prévention des saignements dans un contexte périopératoire ainsi que chez les patients de 18 ans ou plus atteints d'hémophilie B pour la prophylaxie de routine, afin de prévenir les épisodes hémorragiques ou d'en réduire la fréquence. Quatre FIX recombinants sont présentement inscrits à la Liste des produits du système du sang du Québec et ont été utilisés comme comparateurs : BeneFIXMC (nonacog alfa), RixubisMC (nonacog gamma), AlprolixMC (eftrénonacog alfa) et IdelvionMC (albutrepenonacog alfa). DÉMARCHE D'ÉVALUATION: Une revue des données issues de la littérature et de celles fournies par le fabricant a été réalisée afin de documenter l'efficacité, l'innocuité et l'efficience du nonacog bêta pégol. Des données expérientielles et contextuelles issues de la consultation d'experts et de patients sont également présentées. BESOIN DE SANTÉ: L'hémophilie B est une pathologie génétique récessive liée au chromosome X et caractérisée par un déficit congénital en facteur IX (FIX). Ce déficit se traduit par un temps de coagulation prolongé menant à des épisodes de saignements fréquents aux articulations (hémarthroses), aux muscles, ainsi qu'aux muqueuses. Certains épisodes de saignements peuvent mettre en danger la vie de l'individu ou mener à des handicaps moteurs importants. Les traitements de remplacement par FIX actuels permettent aux hémophiles de type B du Québec de prévenir et de traiter leurs épisodes de saignements. Parmi les besoins recensés auprès des experts et patients consultés, on retrouve une meilleure prévention contre le développement d'inhibiteurs, la prévention d'arthropathies hémophiliques et des douleurs chroniques, des traitements offrant une protection hémostatique supérieure qui perdure plus longtemps et l'atténuation des contraintes liées aux injections intraveineuses répétées. RÉSULTATS: Les résultats d'efficacité du nonacog bêta pégol sont basés sur quatre études de phase III ouvertes et non contrôlées. En raison de la restriction de l'indication du nonacog bêta pégol, les résultats de l'efficacité de la prophylaxie à long terme pour les moins de 18 ans n'ont pas été considérés. La force de la preuve de l'efficacité du nonacog bêta pégol a été jugée très faible. DÉLIBÉRATION SUR LE NONACOG BÊTA PÉGOL: Délibération RebinynMC: Les membres du Comité scientifique permanent de l'évaluation des médicaments aux fins d'inscription sont unanimement d'avis que la valeur thérapeutique de RebinynMC n'est pas démontrée pour les adultes et les enfants atteints d'hémophilie B (déficit congénital en facteur IX ou maladie de Christmas) pour la maîtrise et la prévention des épisodes hémorragiques et la maîtrise et la prévention des saignements dans un contexte périopératoire ainsi que chez les patients de 18 ans ou plus atteints d'hémophilie B pour la prophylaxie de routine, afin de prévenir les épisodes hémorragiques ou d'en réduire la fréquence. MOTIFS DE LA POSITION UNANIME: Les membres du Comité ont reconnu l'importance du fardeau associé à la prise en charge de la maladie. Ils ont également reconnu que la fréquence réduite des injections représente un avantage pour les patients. Néanmoins, après un examen minutieux de l'ensemble de la preuve, les constats suivants ont été établis: En raison de la faiblesse de la preuve, les études disponibles ne permettent pas de reconnaitre une valeur thérapeutique non inférieure à RebinynMC par rapport aux autres produits actuellement disponibles; Des préoccupations ont été soulevées par les membres en lien avec l'accumulation de PEG dans le cerveau des animaux observée lors d'études précliniques ainsi qu'aux risques potentiels à long terme leur étant associés; Considérant la disponibilité d'autres options de traitement bien établies, les membres préconisent la prudence. CONSIDÉRANT LA DISPONIBILITÉ D'AUTRES OPTIONS DE TRAITEMENT BIEN ÉTABLIES, LES MEMBRES PRÉCONISENT LA PRUDENCE: À la lumière des informations disponibles, l'INESSS ne recommande pas l'ajout de RebinynMC (nonacog bêta pégol) à la Liste des produits du système du sang du Québec puisque la valeur thérapeutique du produit n'a pas été démontrée. Davantage de données d'efficacité et d'innocuité provenant d'études avec un meilleur niveau de preuve sont requises pour soutenir une reconnaissance de la valeur thérapeutique.

MANDATE: The Institut national d'excellence en santé et en services sociaux (INESSS) evaluated the blood system product RebinynTM (nonacog beta pegol), an intravenously injected recombinant factor IX (FIX) indicated in adults and children with hemophilia B (congenital factor IX deficiency or Christmas disease) for the control and prevention of bleeding episodes and in the perioperative setting as well as in patients 18 years and above with hemophilia B for routine prophylaxis to prevent or reduce the frequency of bleeding episodes. The following four recombinant FIX, currently indicated for the treatment of hemophilia B and listed in the Liste des produits du système du sang du Québec, served as comparators: BeneFIXTM (nonacog alfa), RixubisTM (nonacog gamma), AlprolixTM (eftrenonacog alfa) et IdelvionTM (albutrepenonacog alfa). EVALUATION PROCESS Published trials and manufacturer data were reviewed to document the efficacy, safety and efficiency of nonacog beta pegol. Experiential and contextual data from expert consultations and patients are presented as well. HEALTH NEED: Hemophilia B is an X chromosome-linked recessive genetic disease characterized by coagulation factor IX (FIX) deficiency. This deficiency prolongs coagulation times, which can lead to frequent bleeding episodes in the joints (hemarthrosis), muscles and mucus membranes. Some bleeding events can also lead to severe motor handicaps or even be life-threatening. The current FIX replacement therapies enable Quebecers who are type B hemophiliacs to prevent or stop their bleeding episodes. Experts and patients were queried about health needs in the hemophilia B community. Treatments that better prevent the development of inhibitors, hemophiliac arthropathies and chronic pain, and therapies that provide superior, longer-lasting hemostatic protection with fewer intravenous injections were among the needs mentioned most frequently. RESULTS: Efficacy: The efficacy evaluation for nonacog beta pegol was based on four phase III, open-label and non-controlled trials. As a result of the restriction of the indication, efficacy results for the prophylactic use of nonacog beta pegol in children and adolescents under 18 years f age were not considered. The overall efficacy evidence was considered very low. DELIBERATION ON NONACOG BETA PEGOL: Deliberation on RebinynTM: Members of the Comité scientifique permanent de l'évaluation des médicaments aux fins d'inscription (CSEMI) unanimously share the opinion that the therapeutic value of RebinynTM (nonacog beta pegol) has not been demonstrated for the treatment of hemophilia B (congenital factor IX deficiency or Christmas disease) in adults and children for the control and prevention of bleeding episodes and in the perioperative setting as well as in patients 18 years and above with hemophilia B for routine prophylaxis to prevent or reduce the frequency of bleeding episodes. Reasons for the unanimous position: Members of the Committee recognized the considerable burden associated with the disease. They also recognized that the reduced injection frequency is considered an advantage for patients. Nevertheless, after careful examination of all the evidence, the following observations were made: Given the weakness of the evidence, the available studies do not permit us to conclude that the therapeutic value of nonacog beta pegol is noninferior to that of the other recombinant FIXs currently available; Concerns were raised by the members of the CSEMI regarding the accumulation of PEG in the brain of animals during preclinical studies as well as the potential risks associated with long term deposits of PEG; Considering the availability of safer therapeutic options, the members advise caution. INESSS' recommendation regarding RebinynTM: In light of the available data, INESSS recommends that RebinynTM (nonacog beta pegol) not be added to the Liste des produits du système du sang du Québec since the product's therapeutic value has not demonstrated. Additional efficacy and safety data with a higher level of evidence are required to support the therapeutic value for the proposed indications.

Adherence to prophylactic treatment.

: Prophylaxis has helped improve patients' perception of their quality of life, enabling them to lead a more normal life. For these reasons prophylactic treatment is nowadays considered a gold standard in the treatment of severe hemophilia A or B. Despite its benefits in terms of preventing bleeding and preserving patients' health, this intensive treatment is not always adhered to by patients with hemophilia - promotion of adherence should involve a multidisciplinary team which addresses not only the clinical aspects of a condition but also the different psychosocial aspects affecting patients and their (social, family and healthcare) environment.

Consensus statements on vaccination in patients with haemophilia-Results from the Italian haemophilia and vaccinations (HEVA) project.

Vaccination against communicable diseases is crucial for disease prevention, but this practice poses challenges to healthcare professionals in patients with haemophilia. Poor knowledge of the vaccination requirements for these patients and safety concerns often result in vaccination delay or avoidance. In order to address this issue, a panel of 11 Italian haemophilia and immunization experts conducted a Delphi consensus process to identify the main concerns regarding the safe use of vaccines in patients with haemophilia. The consensus was based on a literature search of the available evidence, which was used by the experts to design 27 consensus statements. A group of clinicians then rated these statements using the 5-point Likert-type scale (1 = strongly disagree; 5 = strongly agree). The main issues identified by the expert panel included vaccination schedule for haemophilic patients; protocol and optimal route of vaccine administration; vaccination of haemophilic patients with antibodies inhibiting coagulation factor VIII (inhibitors); and vaccination and risk of inhibitor development. This manuscript discusses these controversial areas in detail supported by the available literature evidence and provides evidence- and consensus-based recommendations. Overall, participants agreed on most statements, except those addressing the potential role of vaccination in inhibitor formation. Participants agreed that patients with haemophilia should receive vaccinations according to the institutional schedule for individuals without bleeding disorders; however, vaccination of patients with haemophilia requires comprehensive planning, taking into account disease severity, type and route of vaccination, and bleeding risk. Data also suggest vaccination timing does not need to take into consideration when the patient received factor VIII replacement.

Impact of Exercise/Sport on Well-being in Congenital Bleeding Disorders.

Physical activity provides many benefits in patients with congenital bleeding disorders. Patients with hemophilia are encouraged to participate in exercise and sports, especially those patients receiving prophylaxis. Several publications and guidelines have explored this issue in hemophilia patients, evaluating in particular the impact of physical activity on patients' well-being and quality of life. The other rare congenital bleeding disorders are less studied; they are heterogeneous in terms of clinical bleeding phenotype, incidence of hemarthrosis, and arthropathy. Furthermore, prophylaxis in these patients is less common than in hemophilia patients, which must be considered when choosing the type of physical and sporting activity. In this review, the authors have analyzed the literature focusing their attention on those rare coagulation disorders that may be complicated by arthropathy and the role of exercise and sports in this context.

Prevention and Management of Bleeding Episodes in Children with Hemophilia.

Regular prophylactic treatment with factor VIII (FVIII) and factor IX (FIX) concentrates in hemophilia A and B, respectively, is introduced in early infancy and has resulted in dramatic improvement of the conditions. Recombinant FVIII and FIX concentrates have been available for > 25 years and have been modified and refined through the years; however, unfortunately frequent intravenous administrations are still necessary. The half-lives of these products have now been extended (EHL) by fusion with albumin, the Fc-portion of IgG, or by being PEGylated. This has been very successful for EHL-FIX, with 3-5 times longer half-life, and to a lesser degree for EHL-FVIII with a half-life extension of only 1.5 times the conventional products. New treatment principles using FVIII mimetics or monoclonal antibodies that rebalance the pro- and anti-coagulation system by interfering with production of anti-thrombin or tissue factor pathway inhibitor have the benefits of long-lasting activity, subcutaneous administration, and being useful in patients both with and without neutralizing antibodies. As the ultimate treatment, recent progress has also been made with gene therapy of both hemophilia A and B.

The benefits of prophylaxis in patients with hemophilia B.

INTRODUCTION: The health benefits of prophylactic dosing regimens for clotting factor therapy in patients with hemophilia include reduced joint damage and improved quality of life; as such, prophylaxis is recommended in treatment guidelines. However, many patients with hemophilia B are treated on demand, and prophylaxis has been utilized less frequently than in hemophilia A. Areas covered: This review discusses the opportunities and evidence for prophylaxis in hemophilia B, in the context of treatment guidelines and with regard to factor IX (FIX) replacement therapies, including long-acting recombinant FIX (rFIX). Expert commentary: Long-acting rFIX concentrates may increase uptake of and adherence to prophylaxis regimens through attainment of higher trough levels with longer dosing intervals. In this new era of hemophilia B treatment, physicians may be able to achieve better clinical outcomes for their patients and reconsider treatment goals. Maintaining higher FIX trough levels will undoubtedly have long-term benefits for patients, such as preserving joint function. The long-acting rFIX concentrates support robust prophylaxis regimens and offer physician's flexibility in treating patients to best suit their needs, whether to enable an active lifestyle, to achieve higher trough levels for better bleed protection, or simply to decrease the burden of treatment by reducing injection frequency.

Iranian Low-dose Escalating Prophylaxis Regimen in Children with Severe Hemophilia A and B.

Establishing an appropriate prophylaxis regimen for children with hemophilia is a critical challenge in developing countries. Barriers including availability and affordability, catheter-related complications, and inhibitor development risks have led to the introduction of new tailored prophylaxis regimens in different countries. This study emphasizes on the benefits of the Iranian low-dose escalating prophylaxis regimen in a Hemophilia Comprehensive Care Center in Iran. Referred patients with hemophilia less than 15 years of age, who were subject to prophylaxis regimen, are studied retrospectively. A once-weekly prophylaxis regimen of 25 IU/kg was started for the patients primarily. Their prophylaxis regimen was changed to 25 IU/kg twice a week and then 3 times a week when they experienced 3 joint bleedings, 4 soft tissue bleedings, or a 1 life-threatening bleed without a specific trauma history. Overall, 25 patients with severe hemophilia and at least 6-month history of on-demand (OD) treatment were studied. A mean of 1754 IU/kg/yr of coagulation factors, used for OD and prophylaxis purposes, was sufficient to decrease the mean annual bleeding rate (ABR) to 1.86 after prophylaxis. It also reduced the mean hospitalization days and the mean number of target joints to 0.24 and 0.16, respectively. Overall, 19 (76%) patients were continuing their once-weekly regimen at the end of the follow-up. None of the patients needed 3-times-a-week regimen or central venous catheterization and none developed inhibitors in the follow-up. Benefits of the Iranian low-dose escalating prophylaxis regimen prove equal to some of the previous 3-times-a-week prophylaxis regimens in reducing the ABR and hospitalizations.

Primary prophylaxis in haemophilia care: Guideline update 2016.

This paper reviews the current status on recommendations or guidelines for primary prophylaxis based on recent published papers from organizations or group of experts as well as some original key papers. A rather uniform view exists that prophylaxis should be initiated at an early age before or after no more than a single joint bleed and, if possible, preferably be continued for life. The dose and dose frequency of prophylaxis is dependent on the goal of treatment, bleeding phenotype, compliance, venous access and economic resources in the health care system and should be tailored individually based on clinical outcome and pharmacokinetics. For children, the effectiveness of prophylaxis is more dependent on maintaining minimum trough levels than in adults. Novel extended half-life products are being introduced, which should not affect the decision on when to start prophylaxis nor the initial dose, but which may be helpful for patients with difficult venous access and which may enable higher trough levels of factor VIII.

Recent advances in hemophilia B therapy.

Hemophilia B is a hereditary bleeding disorder caused by the deficiency in coagulation factor IX. Understanding coagulation and the role of factor IX as well as patient population and diagnosis are all critical factors in developing treatment strategies and regimens for hemophilia B patients. Current treatment options rely on protein replacement therapy by intravenous injection, which have markedly improved patient lifespan and quality of life. However, issues with current options include lack of patient compliance due to needle-based administration, high expenses, and potential other complications (e.g., surgical procedures, inhibitor formation). As a result, these treatment options are also limited to developed countries. Recent advantages in hemophilia B treatment have focused on addressing these pain points. Emerging commercial products based on modified factor IX aim to reduce injection frequency. Exploratory research efforts have focused on novel drug delivery systems for orally administered treatment and gene therapy as a potential cure. Such alternative treatment methods are promising options for hemophilia B patients worldwide.

Partnering to change the world for people with haemophilia: 6(th) Haemophilia Global Summit, Prague, Czech Republic, 24-26(th) September 2015.

The 6(th) Haemophilia Global Summit was held in Prague, Czech Republic, in September 2015. The programme was designed by an independent Scientific Steering Committee of haemophilia experts and aimed to share optimal management strategies for haemophilia at all life stages, explore recent potential advances in the management of haemophilia A and B and discuss challenges in haemophilia care. In this supplement from the meeting, Dan Hart reviews the lessons that can be learnt from cost-constrained environments with regard to improving care for people with haemophilia globally. Sébastien Lobet discusses the importance of physical activity for optimising care and Roseline d'Oiron and Jan Blatný consider the role of real-world data in understanding the effect of treatment in a clinical setting over the long term and the true impact of treatment on the day-to-day life of the patient. Gili Kenet addresses the current challenges relating to the optimal management of prophylaxis, and Gerry Dolan and Cedric Hermans discuss the value of pharmacokinetic (PK) parameters in informing treatment decisions. Cedric Hermans and Valérie Libotte explore the importance of considering social and occupational development factors as an integral part of haemophilia care, and Jan Astermark reviews key strategies to predict and prevent inhibitor development.

The first Team Haemophilia Education meeting, 2015, Amsterdam, The Netherlands.

Haemophilia remains a complex disorder to diagnose and manage, requiring close cooperation between multidisciplinary healthcare professionals. There are still many unmet challenges in haemophilia care. The first Team Haemophilia Education (THE) meeting, held on 7-8 May 2015 in Amsterdam, The Netherlands, aimed to promote the optimal care of haemophilia patients through education of the multidisciplinary treatment team. This was achieved by reviewing the latest developments in haemophilia management, considering how these can be implemented in the clinic to improve patient care and providing a platform for networking and debate for all haemophilia treatment team members. Haemophilia treatment centres from several countries were asked to complete a premeeting online questionnaire to establish the biggest challenges that they face when managing patients. The concerns expressed were used to develop the agenda, which comprised a combination of formal presentations, case studies and informal workshops covering such topics as pharmacokinetics, laboratory assays and tailoring of treatment to individual patients. This report is a summary of the key developments in haemophilia care presented by various investigators and healthcare professionals at THE meeting 2015.

Advances in hemophilia and the role of current and emerging prophylaxis.

The primary goal of hemophilia treatment and management is the prevention of painful, disabling, and costly joint arthropathy that results from its characteristic bleeding into joints and muscles. Prophylactic treatment with clotting-factor concentrates has been shown to prevent hemophilic arthropathy and is, therefore, the standard of care for hemophilia A and B. Data has demonstrated the clinical efficacy and overall benefits of prophylaxis in young children, adolescents, and adults. Early initiation with prima-ry prophylaxis is ideal, but secondary prophylaxis in adolescents and adults has also demonstrated significant success. Because the standard of care includes prophylaxis with factor-concentrate replacement in order to prevent joint damage in patients with hemophilia, prophylaxis is now more common and needs to be addressed in all clinical settings, including managed care. However, further research is needed to help clinicians develop individualized factor-replacement protocols and under-stand the impact of long-term use into adulthood. World Federation of Hemophilia guidelines do not have definitive recommendations on continuation of prophylaxis into adulthood. The optimal regimen for initiating prophylaxis, duration of treatment, and dosing regimens continue to be studied.

Objective quantification of adherence to prophylaxis in haemophilia patients aged 12 to 25years and its potential association with bleeding episodes.

BACKGROUND: The treatment of choice for patients with severe haemophilia is prophylaxis with clotting factor. Effective prophylaxis requires optimal adherence. Most published studies are based on surveys and interviews with patients or their parents. However, studies based on objective measurements of adherence are few and inconclusive. OBJECTIVE: The main purpose of this study was to assess adherence to prophylaxis using an objective method in patients with haemophilia aged 12 to 25years as well as to assess its potential association with bleeding episodes. Secondary objectives included comparing objective and subjective adherence (questionnaire) and identifying factors potentially associated with treatment adherence. METHODS: A retrospective observational study was designed to collect data on treatment adherence and clinical course of patients in 2013. The study included haemophilia patients on prophylaxis with clotting factor concentrate; the age range was 12 to 25years. Objective adherence to treatment was measured through pharmacy dispensing records. Dispensing dates within 2013 were used for calculation. Adherence (%) was calculated by dividing the total number of International Units (IU) of factor dispensed by the total estimated number of IU and multiplying by 100. Subjective adherence was measured using an ad hoc questionnaire which was completed by the patient. The number of bleeding episodes (joint, muscle and others) was obtained from interviews with the patient at the consultation with the pharmacist and was subsequently confirmed with the patient's clinical history. Other parameters were also evaluated. RESULTS: We included 52 patients in the study. Average adherence of patients resulting from the analysing of dispensing records was 85.72 (SD=23.76%). The global average of bleeding episodes was 2.2 (SD=2.69). 32.6% (seventeen) patients presented with at least one joint bleeding episode versus 67.3% (thirty five) who showed no joint bleeding episodes. Likewise, only 10% (five) patients presented with one muscle bleeding episode. Even though a significant association between the rate of objective adherence and the number of bleeding episodes was not observed, a higher number of hemarthrosis was observed in less-adherent patients. Subjective adherence perceived by patients as reported by the questionnaire showed that 36 (83.7%) of the 43 patients who completed the questionnaire considered their adherence as good, whereas 7 (16.3%) of the 43 patients considered it as fair. A statistically significant relationship was found between objective adherence expressed as a percentage using dispensing records, and subjective adherence perceived by the patient (p=0.004). The other parameters evaluated were not associated with adherence to prophylaxis. CONCLUSIONS: Measuring objective adherence using pharmacy dispensing records is a simple and useful tool. No significant correlation was found between the rate of objective adherence observed and the number of bleeding episodes; however, a higher number of hemarthrosis was observed in less-adherent patients.