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.

A new era for hemophilia B treatment.

In this issue of Blood, Santagostino et al, in their phase 3 study, demonstrate efficacy and safety of recombinant fusion protein linking coagulation factor IX (FIX) with albumin (rIX-FP) which, along with the other 2 extended half-life FIX products, heralds a new era for the treatment of hemophilia B.

Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial.

A global phase 3 study evaluated the pharmacokinetics, efficacy, and safety of recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in 63 previously treated male patients (12-61 years) with severe hemophilia B (factor IX [FIX] activity ≤2%). The study included 2 groups: group 1 patients received routine prophylaxis once every 7 days for 26 weeks, followed by either 7-, 10-, or 14-day prophylaxis regimen for a mean of 50, 38, or 51 weeks, respectively; group 2 patients received on-demand treatment of bleeding episodes for 26 weeks and then switched to a 7-day prophylaxis regimen for a mean of 45 weeks. The mean terminal half-life of rIX-FP was 102 hours, 4.3-fold longer than previous FIX treatment. Patients maintained a mean trough of 20 and 12 IU/dL FIX activity on prophylaxis with rIX-FP 40 IU/kg weekly and 75 IU/kg every 2 weeks, respectively. There was 100% reduction in median annualized spontaneous bleeding rate (AsBR) and 100% resolution of target joints when subjects switched from on-demand to prophylaxis treatment with rIX-FP (P< .0001). The median AsBR was 0.00 for all prophylaxis regimens. Overall, 98.6% of bleeding episodes were treated successfully, including 93.6% that were treated with a single injection. No patient developed an inhibitor, and no safety concerns were identified. These results indicate rIX-FP is safe and effective for preventing and treating bleeding episodes in patients with hemophilia B at dosing regimens of 40 IU/kg weekly and 75 IU/kg every 2 weeks. This trial was registered at www.clinicaltrials.gov as #NCT0101496274.

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.

Is Continuous Low-Dose Prophylaxis Superior to On-Demand Treatment for Patients with Hemophilia?

Long-term (or continuous) prophylaxis is generally accepted as the best form of treatment for patients with severe hemophilia A and B. Results of recent prospective, randomized clinical trials, as well as observational studies performed in the last decades, have provided strong and convincing evidence that continuous prophylaxis leads to reduction in the number of bleeding episodes, better joint status and improved health-related quality of life as compared with on-demand (or episodic) treatment. Nevertheless, many questions regarding long-term prophylaxis still remain open, for instance: when should prophylaxis be started (before or after the first joint bleeding), what is the optimal dosage to replace the missing factor, when should discontinuation of long-term prophylaxis be considered, what is the best way to measure the outcome of prophylaxis, etc. Moreover, there are numerous obstacles to widespread use of prophylactic therapy. The most challenging seem to be adequate venous access (particularly in younger patients) and patients' adherence. The crucial barrier to long-term prophylaxis is, however, the remarkably high cost of clotting factor concentrates. For most countries high-dose or intermediate-dose prophylaxis regimens are not affordable due to lack of economic resources. So, is continuous prophylaxis reserved exclusively for wealthy societies? Fortunately, there is an increasing body of evidence to suggest that low-dose prophylaxis offers significant benefits over on-demand treatment with comparable amounts of factor concentrate (and much lower amounts if compared with intermediate or high-dose prophylaxis regimens). The aim of this article is to discuss the clinical and economical aspects of continuous prophylaxis in hemophilia with emphasis on the low-dose regimens.

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.

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.

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.

Inhibitor-Immunology-Study. Different HLA-types seem to be involved in the inhibitor development in haemophilia A.

UNLABELLED: The development of inhibitors is one of the most important complications of replacement therapy in haemophilia, affecting mortality and morbidity. Inhibitor development is based on complex immunological factors. Cytokines and their receptors, T-cell receptors, and the Major Histocompatibility Complex may play important roles in the development of inhibitors. Earlier studies showed non significant associations between HLA class and inhibitor development. Later studies found an increased risk of inhibitor development if there was a combination between certain factor VIII mutations and HLA antigens. We performed HLA typing in 50 patients with haemophilia A in an effort to find associations with inhibitor development. RESULTS: 25 patients had developed an inhibitor (11 low titre, 14 high titre), and 25 never had. In logistic regression analysis, HLA-A 34, DRB1 0405, DRB1 1301 seemed to be involved in inhibitor development and HLA-A 30, B 13, B15, B 57, Cw 12, DQB1 0303, DPB1 0201 protection against inhibitor development. In our patients, the HLA-associations with inhibitor development were different from those in previous publications.

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.

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.

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.