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Leonard A Valentino,1,2 Judith R Baker,3 Regina Butler,4 Miguel Escobar,5 Neil Frick,1 Susan Karp,6 Kollet Koulianos,1 Susan Lattimore,7 Diane Nugent,3 Joseph N Pugliese,8 Michael Recht,7,9 Mark T Reding,10 Michelle Rice,1 Constance B Thibodeaux,11 Mark Skinner12,13 1National Hemophilia Foundation, New York, NY, USA; 2Departments of Internal Medicine and Pediatrics, Rush University, Chicago, IL, USA; 3Center for Inherited Blood Disorders, Orange, CA, USA; 4Children’s Hospital of Philadelphia, Philadelphia, PA, USA; 5Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA; 6University of California, San Francisco, San Francisco, CA, USA; 7Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA; 8Hemophilia Alliance, Lansdale, PA, USA; 9American Thrombosis and Hemostasis Network, Rochester, NY, USA; 10Department of Internal Medicine, University of Minnesota Medical Center, Minneapolis, MN, USA; 11Departments of Internal Medicine and Pediatrics, Hemophilia Center, Tulane University School of Medicine, New Orleans, LA, USA; 12Institute for Policy Advancement Ltd, Washington, DC, USA; 13Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, CanadaCorrespondence: Leonard A ValentinoNational Hemophilia Foundation, 7 Penn Plaza Suite 1204, New York, NY, 10001, USATel +1 212 328 3700Fax +1 212 328 3777Email lvalentino@hemophilia.orgAbstract: Rare, chronic diseases such as hemophilia and other congenital coagulation disorders require coordinated delivery of services for optimal outcomes. Hemophilia Treatment Centers (HTCs) are specialized, multidisciplinary health-care centers providing team-based care to meet the physical, psychosocial, and emotional needs of people with hemophilia (PWH) and may serve as a model for other rare coagulation disorders. Health-care purchasers, as well as the general medical community, may not appreciate the breadth and quality of services provided by HTCs. They exemplify the acculturalization and actualization of integrated care by providing comprehensive diagnostic and treatment services that reduce morbidity, mortality, avoidable emergency room visits, hospitalizations, and overall costs, while promoting a longer lifespan and improved patient functioning and outcomes. This is accomplished by a team-based approach relying upon a shared decision-making model to effectively prevent complications and manage symptoms in PWH, who are dependent on high-cost treatments. This article provides a concise yet comprehensive description of the core components of an HTC and the regional and national networks in the United States, which together achieve their incomparable value for all stakeholders.Keywords: hemophilia, coagulation disorders, integrated care, patient-centered care, health-care delivery network, multidisciplinary

Christine L Kempton,1 Michael Wang,2 Michael Recht,3 Anne Neff,4 Amy D Shapiro,5 Amit Soni,6 Roshni Kulkarni,7 Tyler W Buckner,2 Katharine Batt,8 Neeraj N Iyer,9 David L Cooper9 1Departments of Pediatrics and Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA; 2Hemophilia and Thrombosis Center, University of Colorado School of Medicine, Aurora, CO, USA; 3The Hemophilia Center, Oregon Health & Science University, Portland, OR, USA; 4Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH, USA; 5Indiana Hemophilia & Thrombosis Center, Indianapolis, IN, USA; 6Center for Inherited Blood Disorders and CHOC Children’s Hospital/UC Irvine, Orange, CA, USA; 7MSU Center for Bleeding and Clotting Disorders, Michigan State University, East Lansing, MI, USA; 8Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC, USA; 9Clinical, Medical and Regulatory Affairs, Novo Nordisk Inc., Plainsboro, NJ, USA Background: Hemophilia is marked by frequent joint bleeding, resulting in pain and functional impairment.Objective: This study aimed to assess the reliability of five patient-reported outcome (PRO) instruments in people with hemophilia (PWH) in a non-bleeding state.Methods: Adult male PWH of any severity and inhibitor status, with a history of joint pain or bleeding, completed a pain history and five PRO instruments (EQ-5D-5L, Brief Pain Inventory v2 [BPI], International Physical Activity Questionnaire [IPAQ], Short Form 36 Health Survey v2 [SF-36v2], and Hemophilia Activities List [HAL]) during their routine comprehensive care visit. Patients were approached to complete the PRO instruments again at the end of their visit while in a similar non-bleeding state. Concordance of individual questionnaire items and correlation between domain scores were assessed using intra-class correlation coefficient (ICC).Results: Participants completing the retest (n=164) had a median age of 33.9 years. Median time for completion of the initial survey with PRO instruments was 36.0 minutes and for the five PRO instruments, median retest time was 21.0 minutes. The majority of participants had hemophilia A (74.4%), were white and non-Hispanic (72.6%), and self-reported arthritis/bone/joint problems (61%). Median/mean test-retest concordance was EQ-5D-5L 80.0%/79.1%, BPI 54.5%/58.9%, IPAQ 100%/100%, SF-36v2 77.8%/76.4%, and HAL 77.4%/75.9%. ICCs for test-retest reliability were EQ-5D-5L index 0.890; BPI – severity 0.950; BPI – interference 0.920; IPAQ total activity 0.940; SF-36v2 overall health 0.910; HAL total score 0.970.Conclusion: All five PRO scales showed acceptable test-retest reliability in adult PWH. Therefore, the choice of instrument to be used for research or clinical care should be driven by instrument characteristics other than reliability. Keywords: hemophilia, pain, patient-reported outcome, reliability

Katharine Batt,1 Michael Recht,2 David L Cooper,3 Neeraj N Iyer,3 Christine L Kempton4 1Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC, 2The Hemophilia Center, Oregon Health & Science University, Portland, OR, 3Novo Nordisk Inc., Plainsboro, NJ, 4Departments of Pediatrics and Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA Background: People with hemophilia (PWH) experience frequent joint bleeding, resulting in pain and functional impairment. Generic and disease-specific patient-reported outcome (PRO) instruments have been used in clinical studies, but rarely in the comprehensive hemophilia care setting. Objective: The objective of this study was to assess construct validity of PRO instruments measuring pain, functional impairment, and health-related quality of life in US PWH with a history of joint pain/bleeding. Methods: Adult male PWH completed 4 PRO instruments (EQ-5D-5L with visual analog scale, Brief Pain Inventory v2 Short Form [BPI], SF-36v2, Hemophilia Activities List [HAL]) and underwent a musculoskeletal examination (Hemophilia Joint Health Score v2.1 [HJHS]). Construct validity between index and domain scores was evaluated by Pearson product-moment correlation coefficient. Results: A total of 381 PWH were enrolled. EQ-5D-5L Mobility correlated with BPI, SF-36v2, and HAL domains related to pain, physical function, and activity of the lower extremities. EQ-5D-5L Self-Care correlated only with HAL Self-Care. EQ-5D-5L Usual Activities correlated with BPI Pain Interference and domains within SF-36v2 and HAL related to pain and physical function/activities (particularly those involving the lower extremities). EQ-5D-5L Pain/Discomfort correlated with Bodily Pain and Physical Summary on SF-36v2, HAL Overall Activity, and all BPI pain domains. EQ-5D-5L Anxiety/Depression correlated with social/emotional/mental aspects of SF-36v2. On BPI, most pain domains correlated with Bodily Pain and Physical Health Summary on SF-36v2 and Overall Activity on HAL. On SF-36v2, Physical Functioning, Role Physical, Bodily Pain, and Physical Health summary scores correlated with all the domains of HAL except Self-Care. For HJHS, Ankle and Total scores correlated with SF-36v2 Physical Functioning and HAL Lying/Sitting, Leg Function, Complex Lower Extremity Activity, and Overall Activity. Conclusion: All PRO instruments have high construct validity but provide different levels of detail in describing effects of hemophilia. Instrument choice may depend on individuals’ symptoms, treatment planning goals, or outcome tracking research objectives, with consideration for administrative burden. Keywords: hemophilia, patient-reported outcomes, construct validity, pain, functional impairment, quality of life

Introduction: To address the need for a patient‐reported outcome that can measure clinically and personally meaningful change in people with haemophilia (PwH) on prophylaxis, an approach based on Goal Attainment Scaling (GAS) was developed: the GAS‐Hēm. Aim: To establish real‐world feasibility of GAS‐Hēm in PwH. Methods: Patients aged 5‐65 years were enroled from four North American centres for a 12‐week study. The primary outcome was the proportion of participants who completed GAS‐Hēm interviews at baseline, 6 and 12 weeks. GAS‐Hēm scores were obtained by subject‐ and clinician‐rated goal attainment at Weeks 6 and 12, and compared with quality of life (QoL) measures and annualized bleed rate (ABR) for construct validity. Goals were evaluated qualitatively for content validity. Responsiveness was calculated using standardized response means (SRM). Results: Forty‐two participants set 63 goals. Participants preferred to define (37/63) their own goals or further individualize (23/63) from the GAS‐Hēm menu. Thirty of the 37 self‐defined goals were matched to goals on the GAS‐Hēm menu. The most common goal areas were: weight, exercise and nutrition (n = 17); leisure activities (n = 8); and joint problems (n = 7). Both participant‐ and clinician‐rated GAS‐Hēm scores at 6 weeks (n = 40) and 12 weeks (n = 41) demonstrated satisfactory goal attainment (SRM [subject‐rated] at 12 weeks for adult and paediatric groups was 1.25 and 1.16, respectively). Correlations of GAS‐Hēm scores with QoL measures and ABR were uniformly small. Conclusion: GAS‐Hēm was feasible and tapped constructs not captured by ABR or QoL measures. [ABSTRACT FROM AUTHOR]

Introduction: Standardized and disease‐specific patient‐reported outcome (PRO) instruments assessing pain, functional impairment and health‐related quality of life (HRQoL) in people with haemophilia (PWH) have been used in studies, but infrequently in comprehensive care settings for individual assessment or treatment planning. Aim: To assess the impact of pain and functional impairment on HRQoL in PWH. Methods: P‐FiQ enrolled 381 adult PWH with a history of joint pain/bleeding and included 5 PROs and a clinical joint evaluation (Hemophilia Joint Health Score v2.1 [HJHS]). Results: Median age was 34 years; 49.9% reported a history of joint procedure or surgery. On EQ‐5D‐5L, most reported problems with mobility (61.4%), usual activities (53.2%) and pain/discomfort (76.1%). On Brief Pain Inventory v2 Short Form, median worst pain (range 0‐10) was 6, least pain 1, average pain 3 and current pain 2. Ankles were most frequently reported as the most painful joints (37.4%), followed by knees (23.7%) and elbows (18.9%). On International Physical Activity Questionnaire, 51% reported no activity in the prior week. On SF‐36v2 health survey, median subscores were worse for 4 physical health domains vs 4 mental health domains. Among Hemophilia Activities List domains (range 0 [worst]‐100 [best]), functions of the legs (median, 66.7) and lying/sitting/kneeling/standing (median, 67.5) were most impacted and self‐care least impacted (median, 100.0). On HJHS, ankle scores (median, 6.0; range, 0‐40) were worse than elbow/knee scores (median, 4.0/4.0). Results were consistent across PROs/HJHS. Conclusion: Data demonstrate challenges of predominantly ankle/knee pain and lower extremity functional impairment in US adult PWH, affecting HRQoL across PROs/HJHS. [ABSTRACT FROM AUTHOR]

Introduction Haemophilia is characterized by frequent haemarthrosis, leading to acute/chronic joint pain. Aim To assess self-reported prevalence, description and management of pain in adult males with mild-to-severe haemophilia and history of joint pain/bleeding. Methods Participants completed a pain survey and five patient-reported outcome instruments assessing pain, functional impairment and health-related quality of life (HRQoL). Results Of 381 participants enrolled, median age was 34 years; 77% had haemophilia A, 71% had severe disease and 65% were overweight/obese. Many (56%) were not receiving routine infusions; 30% never received routine infusions. During the prior 6 months, 20% experienced acute pain, 34% chronic pain and 32% both acute/chronic pain. Subjects with both acute/chronic pain (vs. none, acute or chronic) were more likely to be depressed (30% vs. 0-15%), obese (35% vs. 20-29%) and have lower HRQoL (mean EQ-5D visual analog scale, 69 vs. 83-86) and function (median overall Hemophilia Activities List, 60 vs. 88-99). Most common analgesics used for acute/chronic pain during the prior 6 months were acetaminophen (62%/55%) and non-steroidal anti-inflammatory drugs (34%/49%); most common non-pharmacologic strategies were ice (65%/33%) and rest (51%/33%). Hydrocodone-acetaminophen was the most common opioid for both acute/chronic pain (30%); other long-acting opioids were infrequently used specifically for chronic but not acute pain (morphine, 7%; methadone, 6%; fentanyl patch, 2%). Conclusion Patients with chronic pain, particularly those with both acute/chronic pain, frequently experience psychological issues, functional disability and reduced HRQoL. Treatment strategies for acute pain (e.g. routine infusions to prevent bleeding) and for chronic pain (e.g. long-acting opioids) may be underused. [ABSTRACT FROM AUTHOR]

The article presents interim results from a large multinational extension trial (guardianTM2) using turoctocog alfa for prophylaxis and treatment of bleeding in patients with severe haemophilia A. Topics include the study stated to have enrolled previously treated male patients with severe haemophilia A, and the haemostatic effect of turoctocog alfa was assessed by the patients based on a predefined four-point scale.

Osteopenia and osteoporosis have increasingly become a recognized morbidity of factor VIII (FVIII) deficiency. Recently, we demonstrated that FVIII knockout ( KO) mice had significantly decreased bone mass and bone strength despite the fact that they did not have haemarthroses. The aim of this study was to explore the mechanism of bone disease associated with FVIII deficiency. We compared biochemical markers of bone formation and osteoclastogenesis, inflammatory cytokines, as well as static and dynamic histomorphometry of genetically engineered FVIII KO male mice to those of wild-type ( WT) controls. At 20 weeks of age, FVIII KO mice, as well as WT controls, were sacrificed. Serum and bones were obtained at the time of sacrifice to study biochemical markers of bone formation (osteocalcin) and osteoclastogenesis (receptor activator of nuclear factor kappa-β and osteoprotegerin), levels of inflammatory cytokines (interleukin-1α and interferon-β) and to perform static and dynamic histomorphometry of tibia cancellous bone. There was no difference in the biochemical markers of bone formation or osteoclastogenesis. However, there were differences in the two bone-associated cytokines studied. In addition, histomorphometric examination revealed cancellous osteopenia in FVIII KO mice as evidenced by decreased bone area and trabecular number and increased trabecular separation. Bone formation parameters were normal in FVIII KO mice. In contrast, osteoclast-lined bone perimeter was increased. These data demonstrate that bone disease in FVIII KO mice is due to an increased rate of bone resorption. [ABSTRACT FROM AUTHOR]

The development of an inhibitor represents one of the most challenging complications in patients with haemophilia A. Optimal management is immune tolerance induction (ITI), typically through the administration of high doses of factor VIII (FVIII) concentrate. Among 12 patients who underwent ITI using Advate, a third-generation recombinant FVIII product that is free of animal and human protein additives, tolerance was achieved in nine (75%), including seven of 10 patients (70%) with high-titre inhibitors. ITI is ongoing in two patients and not yet successful; immune tolerance failed in the third patient. The median time to success was 4.0 months for group as a whole and for patients with high-titre inhibitors. Treatment was well tolerated, and no adverse events were observed. Advate was found to be equivalent to other FVIII products with regard to both ITI success rates and the incidence of adverse effects when used in these immune tolerance regimens. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine if symptoms of inattention (IN) and hyperactivity-impulsivity (HI) differ for boys with and without haemophilia and to determine if IN and HI are the essential behavioural dimensions on which the two groups differ. Using a quasi-experimental design, parents’ and teachers’ ratings of IN and HI for boys with and without haemophilia (ages 6–14 years) were compared. IN and HI were also assessed with a psychometric task, as were reading and math, psychopathology, and educational status via various techniques. Boys with haemophilia ( n = 19) were rated higher on dimensions of HI and IN by teachers ( P = 0.01, P = 0.02, respectively) but only on HI by parents ( P = 0.01). In addition, the haemophilia group committed more impulsivity errors on a psychometric task ( P = 0.01). Trends, but not statistically significant differences, were found on reading and math scores, and the haemophilia group had more special education participation. Compared to national norms, borderline range scores on the attention-deficit/hyperactivity disorder (ADHD)-related dimensions of HI and psychometrically measured impulsivity characterized the boys with haemophilia. Although not addressing formal diagnoses, this study found that boys with haemophilia risk ADHD-spectrum problems, especially HI, and special education participation, but not frank academic deficits. [ABSTRACT FROM AUTHOR]

Osteoporosis in adult males is an under-recognized problem. Patients with haemophilia have several predisposing factors for developing decreased bone mineral density (BMD) including prolonged periods of immobility, reduced weight bearing and co-morbidities associated with bone loss. To establish prevalence and risk factors associated with decreased BMD in patients with haemophilia. Adults with moderate or severe haemophilia A or B underwent dual-energy X-ray absorptiometry (DXA). BMD was correlated to laboratory values, joint mobility measurements and physical activity questionnaires. Thirty patients completed evaluations. The median age was 41.5 years (range 18–61). Median lowest T-score by DXA was −1.7 (range: −5.8 to +0.6), with the femoral neck being the site of the lowest T-scores. Based on World Health Organization criteria, 70% of patients had decreased BMD. Twenty-seven per cent of the participants ( n = 8) had osteoporosis and 43% ( n = 13) had osteopenia. Variables associated with increased bone loss included lower serum 25-hydroxyvitamin D levels ( P = 0.03), lower body mass index ( P = 0.047), lower activity scores ( P = 0.02), decreased joint range of motion ( P = 0.046), HIV ( P = 0.03), HCV ( P = 0.02), history of inhibitor ( P = 0.01) and age ( P = 0.03). Adults with haemophilia are at increased risk for developing osteoporosis. A history of HCV and HIV infections, decreased joint range-of-motion, decreased activity levels, history of an inhibitor and low body weight predict bone loss and suggest a population to target for screening. A high prevalence of vitamin D insufficiency was observed. Future studies should investigate interventions, including vitamin D supplementation, to prevent bone loss and fractures for this at-risk population. [ABSTRACT FROM AUTHOR]

BeneFix®, the only recombinant factor IX (FIX), has been reformulated. The reformulation involves a change in diluent and allows for more concentrated infusions of recombinant FIX. A double-blind, randomized, pharmacokinetic (PK) crossover study demonstrated that reformulated BeneFix was bioequivalent to original BeneFix and follow-up PK evaluation after 6 months of treatment demonstrated the PK stability of reformulated BeneFix after multiple exposures. Favourable efficacy and safety profiles, consistent with those already well-established for original BeneFix, were observed: 81.1% of haemorrhages resolved with only a single infusion; 85.3% of initial treatment response ratings were Excellent or Good; more than half of the subjects using reformulated BeneFix for routine prophylaxis (11 of 17, 64.7%) had no spontaneous haemorrhages during their 6–12 month course of prophylactic treatment, with an overall spontaneous bleeding rate of 0.72 year−1; and for the single surgical procedure (knee washing), treatment was rated Useful. In addition, there was no FIX inhibitor development, allergic-type manifestations, or thrombogenic complications with more than 1100 infusions (nearly 5.2 million IUs) administered in this trial. All efficacy and safety outcomes from this study were achieved with more concentrated recombinant protein infusions than that possible with original BeneFix, and utilization of the 2000 IU per vial dosage strength, newly introduced with the reformulated product, was high (>62%). The reformulation of BeneFix allows smaller delivery volumes and an increased choice of dosage strengths without altering the PK properties (including incremental recovery and half-life) or the established efficacy and safety profile of recombinant FIX. [ABSTRACT FROM AUTHOR]

The article discusses a study on the stability of transgene expression and long-term safety of factor IX gene therapy in patients with severe hemophilia B in 2014. Based on results, a dose-dependent increase in circulating factor IX to a 1-6% level of normal value over a 3.2-year median occurred, after an intravenous infusion of AAV8 vector in all patients. The article states that the infusion resulted in a long-term therapeutic factor IX expression linked to clinical improvement.