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Introduction: Persons with haemophilia (PWH) born before the middle 1970s have spent a substantial part of their lives without the benefits of replacement therapy, that became available on a relative large scale only during the 1970s. As a consequence, this group of PWH, although still relatively young, suffers from musculoskeletal and functional problems that are typical of old people. Methods: We report herewith the short‐term results of a project based upon a multidisciplinary training programme led by a physiotherapist and an occupational therapist, that was implemented over a period of 12 months in 40 patients with severe or moderate hemophilia A or B born before the middle 1970s and regularly followed‐up at a comprehensive haemophilia treatment centre in Italy. The project was aimed to provide information and skills in order to empower the older PWH carrying physical handicaps and functional limitations that had resulted from the inadequate management in their early ages, and to enable them to cope more efficiently with their crippling disease and prevent further disabilities. Results and Conclusions: The comparison of the data obtained before and after the 12‐month programme found marginal improvements, but the purpose of this programme was indeed to offer a blueprint for the future. In this respect, the level of satisfaction for the programme was very high and we expect that it will be implemented long‐term by our older PWH. [ABSTRACT FROM AUTHOR]

Introduction Immune tolerance induction (ITI) is a standard intervention to eradicate inhibitors in haemophilic patients. However, information on the long-term condition of patients who eradicated the inhibitor totally or partially after ITI is scarce. Aim To perform a long-term follow-up to describe the status of patients reported as ITI success in the G-ITI study. Methods This was an international, multicentre, observational, retrospective study of the 57 haemophilic patients who were reported as ITI success in the G-ITI study. Demographics and post-ITI clinical data recorded until January 2015 were extracted from the medical records. A descriptive analysis was undertaken. Results Forty-four patients were evaluable. Post-ITI follow-up was 9.1 years in average. Thirty-seven target joints were affected in 21 patients; 38 patients presented bleeding with a mean of 1.0 ± 1.2 episodes year−1, most of them (271/330) treated with Fanhdi® (Grifols). Around half of the patients underwent at least one surgical procedure. Most venous access complications were of expected nature, requiring hospital stay in practically all cases. Fanhdi was used in 42 patients as the regular haemophilia treatment after ITI, mainly prophylactically. Three patients (6.8%) who were being treated with Fanhdi (prophylaxis), Kogenate (prophylaxis) and Emoclot (on demand), respectively, showed inhibitor relapse (at 29, 53 and 13 months after ITI, with 0.9, 3.65 and 12.5 BU respectively). All of them were successfully tolerized after rescue ITI. Conclusion After ITI success, all patients continued with regular successful FVIII treatment for haemophilia for more than 9 years. The few inhibitor relapses were successfully overcome after rescue ITI. [ABSTRACT FROM AUTHOR]

Aim This study explores the potential role of a novel interferon-containing regimen for treatment of patients with chronic hepatitis C ( CHC) and underlying haemophilia. Methods This trial ( NCT01741545) was an open-label, non-randomized phase 3 study, which included adult haemophiliacs with hepatitis C virus ( HCV). Patients with HCV genotypes ( GT)-2 or -3 were treated with Lambda- IFN/ribavirin ( RBV)/daclatasvir ( DCV) for 12 weeks (cohort A). Patients with HCV GT-1b or -4 were treated with Lambda- IFN/ RBV/ DCV for 12 weeks, followed by Lambda- IFN/ RBV for an additional 12 weeks (cohort B). The primary endpoint was the proportion of patients with a sustained virologic response at post-treatment follow-up week 12 ( SVR12). Clinical development of Lambda- IFN was discontinued during this trial leading to study termination before a 24-week post-treatment follow-up was obtained for all participants. Results Overall, 51 patients were treated (cohort A, n = 12; cohort B, n = 39). The proportion of patients achieving SVR12 was 92% in cohort A and 90% in cohort B. Therapy was generally well tolerated. The most common adverse events ( AEs) were related to elevations in serum transaminases and/or bilirubin. Five serious AEs, four discontinuations due to AEs, and no deaths were reported. The rate of grade 3-4 bilirubin elevations was 17-18% across cohorts. Conclusion Lambda- IFN/ RBV/ DCV treatment demonstrated a high SVR rate and was generally well tolerated with a safety profile consistent with expectations for this special patient population. This study supports use of DCV as part of a combination treatment regimen for haemophiliacs with CHC. [ABSTRACT FROM AUTHOR]

Introduction In the presence of high-titre inhibitors, haemostatic bypassing agents are used to control bleeding and perform surgery. In this setting, no specific laboratory test is yet available to guide drug choice, monitor treatment efficacy and predict the risk of bleeding. Aim The aims of this study, carried out in patients candidate to orthopaedic surgery, were to assess the dose-dependent increase in thrombin generation ( TG) after infusion of bypassing agents and to evaluate whether or not a correlation existed between the haemostatic efficacy of bypassing therapies and perioperative TG values. Methods and Results TG was measured in 16 inhibitor patients, 10 of whom underwent 11 major orthopaedic procedures. In the non-bleeding state, TG significantly improved 30 min after whichever dose ( P < 0.01), with no dose-response relationship when values obtained after different rFVIIa doses were compared. TG significantly improved 30 min after the preoperative bolus ( P < 0.05), while during the postoperative period TG values measured before and after dosing did not differ. Moreover, postoperative TG values were similar or even more impaired ( P ≤ 0.05) than those measured before preoperative dosing. No difference was found by comparing procedures with and without bleeding complications and yet no bleeding occurred in spite of persistently low TG values in one-third of procedures. Conclusion This study fails to support a definite role for the TG assay as a reliable laboratory tool to monitor the haemostatic efficacy of bypassing therapies and as a predictor of the risk of bleeding in inhibitor patients using these agents during orthopaedic surgery. [ABSTRACT FROM AUTHOR]

Haemophilia and its treatment interfere with patients' life, so health-related quality of life (HRQoL) should be assessed when evaluating treatments. This study investigated the HRQoL of patients with haemophilia A treated prophylactically with a new recombinant factor VIII. Two phase 3 trials investigated turoctocog alfa in patients with severe haemophilia A: one in children, one in adults and adolescents. HRQoL was a secondary endpoint assessed by the HAEMO-QOL age-specific, selfadministered questionnaires. Parent-completed versions were also included for parents of children and adolescents. All HAEMO-QOL questionnaires allow the calculation of domain-specific and total scores ranging from 0 to 100, lower scores indicating better HRQoL. Mean change in all scores was described for 25 children aged 4-7 years, 21 children aged 8-12 years, 18 adolescents aged 13-18 years and 129 adults, overall, and according to the treatment regimen received prior to the study (on-demand; prophylaxis; mixed). Mean changes in HAEMO-QOL total score were 1.4 for children aged 4-7 years, -2.6 for children aged 8-12 years, -5.8 for adolescents and -1.6 for adults. In parent-completed versions, mean changes in total score were -6.0 for children aged 4-7 years, -4.7 for children aged 8-12 years, and -10.0 for adolescents. Patients receiving ondemand treatment before the trial showed greater improvement in HRQoL scores than patients already on prophylaxis. HRQoL of patients remained fairly stable over the course of the trials. However, improvements were observed for adolescents. Switching to prophylaxis was identified as a potential driver of improvement of HRQoL in patients with haemophilia A. [ABSTRACT FROM AUTHOR]

The development of neutralizing antibodies to factor VIII ( FVIII) is the most serious complication of therapy for haemophilia A. There is now excellent documentation that a large number of both genetic and environmental factors contribute to the risk of FVIII inhibitor incidence. One of the environmental factors that has been proposed as an influence on this complication is the occurrence of FVIII product switching. There are only a small number of clinical studies that have addressed this question, and thus, the amount of objective information available to assess this association is limited. In this review, in addition to summarizing past evidence pertinent to this subject, we present the results of a complementary strategy, a Delphi analysis, to add to the considerations of product switching and FVIII immunogenicity. With the imminent arrival in the clinic of several new FVIII products, the haemophilia community must be prepared to collect prospectively controlled data to better address this important management issue. [ABSTRACT FROM AUTHOR]

The maintenance of a correct posture in haemophilic boys might contribute to prevent joint bleeds, chronic pain and dysfunction. This single-centre study was aimed at evaluating whether or not postural alterations are more common in haemophilic than in non-haemophilic boys and whether they are related to the orthopaedic status. Posture and balance were investigated in boys with severe/moderate haemophilia (cases) and in age-matched non-haemophilic peers (controls). Thirty-five cases (89% with haemophilia A: 74% with severe disease) were included in the study and compared with 57 controls. Posture was evaluated on digital pictures of anterior, lateral and posterior views of the habitual standing position. Balance was examined with a portable force platform with eyes open and closed. The trajectory of the total body centre of force (CoF) displacement over the platform was computed by multiple planes obtaining different measures: sway area, velocity, acceleration and body loads. The joint status of cases was assessed with the Haemophilia Joint Health Score. Cases were more disharmonic than controls (52% vs. 26% in controls; P = 0.04), swayed significantly less and more slowly than controls ( P < 0.05 for several parameters of CoF displacement) revealing stiffness of the musculoskeletal system. However, they were able to maintain their stance within a similar sway area. Haemophilic boys have more postural disharmonies than non-haemophilic peers, hence a global evaluation of the orthopaedic status should include also balance and posture examination to identify early dysfunction and establish a tailored physical or rehabilitation programme. [ABSTRACT FROM AUTHOR]

Most studies on immune tolerance induction ( ITI) therapy in haemophilia A patients are focused on primary ITI in children. Here we report on the ITI outcome in a large retrospective cohort, including adults and patients with rescue ITI, treated with a pd FVIII/ VWF concentrate. Retrospective data from haemophilic patients ( FVIII< 2%) with inhibitors from 22 centres in Spain, Italy and Germany, who underwent primary or rescue ITI with pd FVIII/ VWF concentrate, were collected. Complete success ( CS), partial success ( PS) and failure were defined based on the criteria of the consensus recommendations of the 2006 International ITI Workshop. A total of 41 cases of primary ITI (32 children and 9 adults) and 19 cases of rescue ITI (17 children and 2 adults) were evaluated. Success ( CS+ PS) rate of 87% was achieved in primary ITI and 74% in the higher risk profile of rescue ITI. Eight of nine (85%) patients with poorest prognosis (three or more of the known risk factors of poor response to ITI) achieved success ( CS+ PS). CS of 100% was observed in eight primary ITI patients with titre at start of ITI ≤2.5 BU and inhibitor peak ≤25 BU. The favourable response rates in primary and rescue ITI in children and in adult patients, even in the presence of poor prognostic factors, should be encouraged for broadening the indication of immune tolerance therapy in haemophilia A patients with inhibitors. [ABSTRACT FROM AUTHOR]

The ONE Registry ( OR) was an international prospective observational study of on-demand recombinant factor VIIa (rFVIIa) treatment for mild to moderate bleeds in haemophilia A/B patients with inhibitors. To describe real-world use of single and multi dose rFVIIa and to compare outcomes, including effectiveness, safety, quality of life and treatment satisfaction associated with treatment. Baseline data included demographics, treatment, medical and bleed history and patient/caregiver-reported outcomes regarding bleeds. rFVIIa was prescribed according to routine practice; regimens varied and initial dose was categorized as low ( LD, ≤120 μg kg−1), intermediate ( ID, >120 and <250 μg kg−1) or high ( HD, ≥250 μg kg−1). OR included 102 patients and 85 (83%) reported 494 bleeds overall. Mean age was 23 years ( SD 16.4), with 52% ≥18 years. Majority of bleeds ( n = 350, 71%) involved ≥1 joints; 46% involved a target joint. Median initial dose was 90 μg kg−1 in LD (range 87-120, n = 156), 174 μg kg−1 in ID, (range 121-249, n = 127) and 270 μg kg−1 in HD, (range 250-375, n = 211). For spontaneous bleeds, effective haemostasis rate at 9 h was 63% LD, 60% ID and 56% HD. Rates of combined partially effective/effective haemostasis was 85% LD, 96% ID and 86% HD. Median number of doses in HD was one (range 1-7), compared with two in LD (range 1-17) and ID (range 1-23). No thromboembolic events were reported in 1145 doses given. These observational data in real life are consistent with previous studies which have shown similar overall effectiveness of rFVIIa and similar effectiveness and safety across different patterns of standard initial dosing. [ABSTRACT FROM AUTHOR]

The Health Commission of the Conference between the Italian State and Regions recognized the need to establish an institutional accreditation model for Haemophilia Centres (HCs) to be implemented by 21 Regions in order to provide patients with haemophilia and allied inherited coagulations disorders with high and uniform standards of care. The Italian National Blood Centre, on behalf of the Commission, convened a panel of clinicians, patients, experts, representatives from Regions and Ministry of Health. The agreed methodology included: systematic literature review and best practice collection, analysis of provisions and regulations of currently avalable services, priority setting, definition of principles and criteria for the development of recommendations on the optimal requirements for HCs. The result was the formulation of two recommendations sets. Two sets of recommendations were produced. The first concerns regional policy planning, in which the following aspects of comprehensive haemophilia care should be considered for implementation: monitoring and auditing, multidisciplinary approach to clinical care, protocols for emergency management, home treatment and its monitoring, patient registries, drug availability and procurement, recruitment and training of health care professionals. The second set concerns the accreditation process and lists 23 organizational requirements for level 1 HCs and 4 additional requirements for level 2 HCs. These recommendations help to provide Italian Regional Health Authorities with an organizational framework for the provision of comprehensive care to patients with inherited coagulation disorders based on current scientific evidence. [ABSTRACT FROM AUTHOR]

Approximately 20-30% of patients with severe haemophilia A develop alloantibodies ('inhibitors') to infused FVIII rendering use of such replacement therapy ineffective. Once an inhibitor emerges, immune tolerance induction ( ITI) is the standard treatment. ITI involves giving regular doses of FVIII concentrate to eradicate the inhibitor and achieve immunogenic acceptance of administered FVIII. In the early 2000s, a retrospective analysis of inhibitor patients treated at a single centre in Germany indicated that success rates were higher when patients were treated with von Willebrand factor ( VWF)-containing plasma-derived FVIII (pd FVIII/ VWF) concentrate compared with recombinant or non- VWF-containing pd FVIII products. Importantly, pd FVIII/ VWF as rescue therapy was able to convert 8 of 10 patients who had failed primary ITI with recombinant or non- VWF-containing pd FVIII product. A subsequent study from Italy in patients with poor prognostic factors for ITI success also reported good success rates with pd FVIII/ VWF as rescue therapy (53% success; 41% partial success). The Grifols-Immune Tolerance Induction (G- ITI) Study represents the largest group of haemophilia A inhibitor patients treated with a single pd FVIII/ VWF concentrate (Alphanate®/Fanhdi®) to be reported to date. Data have been collected for 95 patients who underwent primary or rescue ITI at 46 centres in Europe and the US. Currently, published data are available for 33 patients in the US cohort (11 centres), and data from the European cohort are being analysed. Both groups contained patients with poor prognostic factors and most patients received a high-dose regimen (≥100 IU pd FVIII/ VWF kg−1 daily). As expected, the success rate was better for primary vs. rescue ITI and for patients with good vs. poor prognostic factors. However, more than half the patients in the US cohort receiving rescue ITI achieved success (33% complete success; 20% partial success). These results should encourage clinicians to consider the use of pd FVIII/ VWF concentrates for rescue ITI. Published outcomes data from the total global G- ITI cohort (95 patients) are awaited with anticipation. [ABSTRACT FROM AUTHOR]

. Thrombotic adverse events (AEs) after clotting factor concentrate administration are rare but the actual rate is unknown. A systematic review of prospective studies (1990-2011) reporting safety data of factor concentrates in patients with haemophilia A (HA), haemophilia B (HB) and von Willebrand disease (VWD) was conducted to identify the incidence and type of thrombotic AEs. In 71 studies (45 in HA, 15 HB, 11 VWD) enrolling 5528 patients treated with 27 different concentrates (20 plasma-derived, 7 recombinant), 20 thrombotic AEs (2 HA, 11 HB, 7 VWD) were reported, including two major venous thromboembolic episodes (both in VWD patients on prolonged replacement for surgery). The remaining thrombotic AEs were superficial thrombophlebitis, mostly occurring at infusion sites in surgical patients and/or during concentrate continuous infusion. The overall prevalence was 3.6 per 103 patients (3.6 per 104 for severe AEs) and 1.13 per 105 infusions, with higher figures in VWD than in haemophilia. Thrombotic AEs accounted for 1.9% of non-inhibitor-related AEs. Thrombosis-related complications occurred in 10.8% of patients with central venous access devices (CVADs) reported in six studies, the risk increasing with time of CVAD use. Data from prospective studies over the last 20 years suggest that the risk of thrombotic AEs from factor concentrate administration is small and mainly represented by superficial thrombophlebitis. These findings support the high degree of safety of products currently used for replacement treatment. [ABSTRACT FROM AUTHOR]

Rapid control of bleeding is the key to reducing bleeding complications and thereby preserving joint and musculoskeletal function in haemophilia patients with inhibitors. However, this requires early diagnosis following the onset of bleeding and strategies for rapid treatment in an outpatient setting. Overarching themes on the need for speed in managing bleeds in haemophilia patients were examined by a panel of clinicians experienced in managing inhibitor patients and joint disease during the Third Zürich Haemophilia Forum on 8 May 2009. This report summarizes the opinions of the panel on how to achieve rapid bleeding control in inhibitor patients and areas that were identified by the panel for future research or as needing new consensus guidelines. The consensus was that home treatment should be established for haemophilia patients with inhibitors, as it is associated with a faster time to treatment, as well as improvements in the quality of life of patients and their carers. In addition, as improved haemostatic control now allows inhibitor patients to participate in a wider range of physical activities, specific guidelines are required on which types of sport and work are appropriate. It was agreed that clear, systematic approaches are needed for early diagnosis of joint and muscle bleeds in inhibitor patients, which could facilitate rapid treatment. There may be opportunities for exploiting new diagnostic techniques from osteoarthritis to enable earlier diagnosis of haemophilic arthropathy. Overall, it was concluded that greater emphasis should be placed on education and patients' psychological needs, to enable inhibitor patients to cope up more effectively with their disease. [ABSTRACT FROM AUTHOR]

Current haemophilia treatment in children is based on regular intravenous infusions of concentrates for prolonged periods, according to prophylaxis regimens or immune tolerance induction treatment, in cases of inhibitor development. Therefore, a stable and uncomplicated venous access is required and as such peripheral veins represent the preferred option. However, frequent infusions in the home setting can be problematic in very young children and for this reason, central venous access devices (CVADs) have been widely used to improve treatment feasibility. Unfortunately CVADs’ use is associated with a high rate of complications, and infections and thrombotic occlusion can influence treatment outcome by causing unwanted treatment interruption. CVADs can be grouped into three main categories: external non-tunnelled, external tunnelled and fully implantable devices known as ports. The management of CVADs at home often represents a challenge because a strict adherence to sterile procedures is required. Indeed, the incidence of infections with ports is much lower than that reported for external devices; however, ports carry the inconvenience of needle sticks. More recently, arteriovenous fistula was shown to be a suitable alternative to CVADs because it is easy to use and is associated with a lower rate of complication. [ABSTRACT FROM AUTHOR]

The aim of this case–control study was to analyse the prevalence of gynaecological, obstetrical and other more general bleeding symptoms in 114 women affected by various inherited bleeding disorders, who were compared with 114 apparently healthy women. Retrospective information were collected by means of two specific questionnaires, one on gynaecological and obstetrical bleeding symptoms, with special focus on the presence of menorrhagia as defined by a pictorial blood loss assessment chart (PBAC); and the other on general bleeding symptoms, whose severity was graded by means of the bleeding score (BS). Compared to normal women, the whole group of women with inherited bleeding disorders had a higher prevalence of excessive bleeding at menarche (25% vs. 5%, P < 0.0001) and menorrhagia (59% vs. 46%, P = 0.06). Affected women also had a higher frequency than controls of general bleeding symptoms that scored as severe by a BS ≥ 12 (49% vs. 0%, P < 0.0001). In affected women, the BS increased according to the severity of the haemostasis defect. In conclusions, the BS and the PBAC are simple tools to evaluate the severity of general bleeding symptoms and menorrhagia in women with inherited bleeding disorders. These instruments may help to identify those women for whom a therapeutic intervention is warranted. [ABSTRACT FROM AUTHOR]

Development of inhibitors is a severe complication of haemophilia posing many management challenges. While a long-term goal in inhibitor patients is eradication of inhibitors through immune tolerance induction, bypassing agents such as recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrate (aPCC) are essential for control of bleeding episodes. Paediatric patients with haemophilia and inhibitors are at particular risk of recurrent haemarthroses, and management of these patients should seek to avoid joint damage and support the child’s full social and physical development. Current options for management of bleeding complications include on-demand treatment of acute bleeding episodes, secondary prophylaxis to avoid recurrent bleeds and surgery to treat affected joints. There is also a rationale for adopting prophylactic approaches to prevent bleeding in inhibitor patients, allowing this group similar opportunities for protection against arthropathy development as are given to non-inhibitor patients. This paper, based on a roundtable meeting of haematology experts at the first Zürich Haemophilia Forum in May 2008, reviews the current evidence supporting more intense and prophylactic approaches to manage bleeding risk in paediatric haemophilia patients with inhibitors, and highlights the need for investigations of primary prophylaxis in this vulnerable patient group, to support best long-term outcome. [ABSTRACT FROM AUTHOR]

At present, when resources allow, the main issue in preventing arthropathy in patients with haemophilia is determining the ‘optimal’ prophylaxis regimen rather than the choice between primary prophylaxis and on-demand treatment. Barriers to prophylaxis implementation are still relevant and include difficulties with venous access, adherence to treatment regimens and costs. Prospective studies with different prophylactic regimens and objective outcome measures are still needed to determine the best cost–benefit ratio. The results from large retrospective cohorts followed up for decades in several European countries have shown that regular prophylaxis started at an early age is able to reduce physical impairment from haemophilic arthropathy. The efficacy of primary prophylaxis was finally demonstrated also in the setting of a randomized clinical trial. [ABSTRACT FROM AUTHOR]

We recommend prophylaxis in haemophilic children with an inhibitor as a way of preventing the musculoskeletal impairment that is likely to affect them. This approach has been used for children without inhibitors with excellent results. If prophylaxis is not feasible, we suggest that intensive on-demand treatment should be given. Two agents, recombinant activated FVII (rFVIIa) and activated prothrombin complex concentrates (aPCC), are currently used to control haemostasis either for prophylaxis or intensive on-demand treatment. As it is recombinant, rFVIIa would seem more appropriate to be employed in children. aPCC could be used in adults, or in the event of an unsatisfactory response to rFVIIa. We recommend prophylaxis or, at least, intensive on-demand treatment in haemophilia children with inhibitors. Both rFVIIa and aPCC are being used for this purpose. It would seem that rFVIIa might be more appropriate for children as it is a recombinant product. Nevertheless, after skeletal maturity (in adults), both agents could be used indistinctively (taking into consideration that FEIBA is a plasma-derived product). We still need more well-designed comparative studies in order to be able to assert that our consensus-based conclusion is evidence based. In orthopaedic surgery, both aPCC and rFVIIa have been reported to be effective in controlling perioperative haemostasis, although in practice most centres have so far used rFVIIa for their orthopaedic procedures. We recommend rehabilitation programmes for all patients with inhibitors in order to mitigate the disabling and handicapping impact of their condition and thereby enable them to achieve social integration. Programmes for haemophilic children without inhibitors can be applied to children with inhibitors but should be individually tailored. [ABSTRACT FROM AUTHOR]

Today, total joint replacement is the treatment of choice for chronic haemophilic arthropathy of the knee and hip in developed and developing countries. After the last World Haemophilia Congress and Musculoskeletal Congress, we cannot say the same for haemophilic patients with inhibitors because elective surgery today is still limited to few centres and extremely few patients. This is because until the first half of the 1990s, performing surgery in haemophilic patients with inhibitors was associated with a high risk of bleeding. With the availability of activated recombinant factor VII, the first surgical procedures were performed, but they still remain limited because of the elevated costs of replacement therapy. Our goal for the future must be to ensure the same possibility of surgical intervention in haemophilic patients both with and without inhibitors. This will be possible, thanks to the experience of some centres with an increased number of patients, where today this kind of surgery is routinely performed. [ABSTRACT FROM AUTHOR]