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Introduction and Aim: The British Columbia Adult Haemophilia Team recently adopted a patient-centred care approach. The team presented visual information on an individual's pharmacokinetic profile and bleed history and encouraged patients to participate in treatment decisions. This qualitative study explored how this approach changed patients' understanding of haemophilia and how it facilitated them to make treatment decisions., Methods: We interviewed 18 males with mild, moderate or severe haemophilia, using a convenience sample from the adult haemophilia clinic at St. Paul's hospital in Vancouver, Canada. Interviews were recorded and transcribed verbatim and analyzed using descriptive content analysis., Results: Most participants reported that reviewing visual information with the Clinic Team helped them in their communication with their care providers during their annual review clinic appointment. Despite this improved communication, for some the most important feature of their treatment was that they had switched from on-demand treatment to prophylactic treatment in recent years and were able to prevent bleeds. Almost half of the participants reported that the visual information presented increased their understanding of haemophilia and the pharmacokinetics of coagulation factor. Three patients improved their treatment adherence or had changed their prophylaxis schedules based on this. Most participants felt that they were involved in decision-making about their treatment schedule, which they appreciated. On the other hand, two participants thought the Clinic Team should make these decisions., Conclusion: Participants perceived the patient-centred prophylaxis approach helpful because it enhanced communication with the Clinic Team, increased their understanding of haemophilia and pharmacokinetics of coagulation factor and facilitated treatment decisions., (© 2019 John Wiley & Sons Ltd.)

Purpose: To understand the typical presentation, risk factors, location and size, treatment, neurological recovery and survival of spontaneous spinal epidural haematomas (SSEH) in children., Methods: A systematic review of the English literature from 1 January 1960 to 1 March 2018 was performed on children aged 18 years and younger. Individual patient data were extracted and collated. Outcome measures were mode of presentation, risk factors, initial neurological findings, initial presumed diagnosis, diagnostic investigations, site and size of the SSEH, treatment, neurological recovery and survival., Results: Thirty-one publications and 36 patients were reviewed. All age groups were affected. 83% of patients did not have a known risk factor. Back pain was reported in 61% and neurological dysfunction in 97% of patients, although not all articles defined these parameters. Initially 28% of patients were suspected of having an alternative diagnosis. All patients had an MRI and/or CT scan confirming the diagnosis. The cervical-thoracic region was most commonly affected, and the average haematoma size extended across 6.3 vertebral levels. Surgical decompression was performed in 72% of patients. Neurological function improved in 83% of patients. Two patients died as a consequence of their SSEH., Conclusions: SSEHs affect all paediatric age groups and typically present with neurological dysfunction and/or back pain. The initial diagnosis is incorrect in up to 28% of cases, but cross-sectional spinal imaging is diagnostic. Most SSEHs are located in the cervico-thoracic region and affect multiple spinal levels. The treatment depends on whether the patient has a bleeding disorder and their neurological status. These slides can be retrieved under Electronic Supplementary Material.

Introduction: Concern about weight gain among people has been high due to negative health consequences in addition to the increasing prevalence of the problem. Overweight and obesity also occur in patients with hemophilia. Analysis of literature shows that increased body weight might have a biomechanical effect on the spatial orientation of the pelvis and the lumbar spine. The aim of this study was to determine the correlation between body mass index (BMI) and the parameters characterizing the alignment of the sacrum (SS, sacral slope), the pelvis (PT, pelvic tilt; PI, pelvic incidence) and the angle value of lumbar lordosis (LL, lumbar lordosis) assessed in the sagittal plane among patients with hemophilia. Materials and methods: A total of 49 patients were subjected to the study, 23 of whom met the inclusion criteria. Body weight and height were measured. Measurement of the angle values of indicators characterizing the position of the lumbar-pelvic complex was established based on X-ray imaging analysis. Results: Analysis of the correlation between the BMI and sacral, pelvic, and lumbar indicators evaluated in the sagittal plane in the study group of patients with hemophilia showed a correlation between BMI and SS ( r = 0.48). SS values were significantly and positively related to PI ( r = 0.6; p = 0.002) and LL ( r = 0.46; p = 0.02). The results obtained indicate the BMI relationship with the setting of the sacrum in the sagittal plane (SS). After adjusting for the knee flexion contracture, the correlation on the border of significance ( b = 0.73, p = 0.07) between the body mass index and the spatial orientation of the pelvis and the spine was revealed. Conclusion: We hypothesize that increased body weight among people with hemophilia might have an effect on the positioning of the lumbosacral region. Therefore, it is believed that preventing obesity among people with hemophilia can contribute to a smaller number of intra-articular hemorrhages and better orthopedic condition of the limb joints, and thus could avoid changes in the lumbosacral region as well as their consequences.

Intracranial haemorrhage (ICH) is the most serious event in haemophiliacs, resulting in high rates of mortality and disability. Although the use of a prophylaxis regimen has improved outcomes, the mortality caused by ICH is still around 20%. ICH is more frequent at two different ages: in childhood (mostly in children aged ≤2 years) and in adulthood (with known risk factors such as hypertension and age ≥60 years). Our review shows how ICH remains one of the worst problems of patients with haemophilia. Greater attention to risk factors and early symptoms, together with an appropriate early prophylaxis, may reduce the risk of severe intracranial haemorrhagic events.

Introduction: Haematuria is a recognized complication of haemophilia A and B (HA, HB). Adult persons with haemophilia (PWH) have a higher prevalence of renal disease than the general population. There is limited literature investigating the prevalence of haematuria in paediatric PWH., Aim: Our paediatric haemophilia treatment centre (HTC) had previously used quality improvement methods to increase the frequency of screening urinalyses at annual comprehensive visits. We retrospectively reviewed the data collected to determine the prevalence of haematuria and explore for associations in those with haematuria., Methods: Retrospective chart review to identify the frequency of haematuria on screening urinalysis in all male PWH ≥2 years old. Haematuria was defined as ≥3 red blood cells (RBCs) per high power field. Univariate logistic regression was performed to evaluate for associations with haematuria., Results: A total of 93 patients met eligibility criteria. Sixty-seven with HA (11 mild, 17 moderate, 39 severe) and 26 with HB (three mild, 16 moderate, seven severe). Forty-two of ninety-three (45%) patients were identified as having haematuria (median RBCs 7, mean RBCs 332). Of those with haematuria, 76% were identified by screening UA, as opposed to clinical symptoms, and 52% had recurrent haematuria. Older age and HA were associated with an increased likelihood of haematuria., Conclusions: Our study demonstrated that the prevalence of haematuria was high in PWH treated at our paediatric HTC. Future investigation is needed to determine the population-wide prevalence of haematuria in paediatric PWH and its impact on renal function., (© 2019 John Wiley & Sons Ltd.)

: 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.

A 4-year-old boy with history of hemophilia B presented with increasingly enlarged scalp masses. Although they were initially thought as hematomas, unresponsiveness to the therapy lead to suspicion of malignancy, which prompted FDG PET/CT. The FDG PET/CT images demonstrated increased FDG uptake in the scalp masses and cervical lymph nodes. The pathology from the left scalp mass and the left cervical lymph nodes revealed precursor B-cell lymphoblastic lymphoma.

Bleeding into the joints represents the major morbidity of severe hemophilia and predisposes it to hemophilic arthropathy (HA). In a reproducible hemarthrosis mouse model, we found distinct changes in thrombin activity in joint tissue homogenate following exposure of the joint to blood in wide type (WT) and hemophilic B mice. Specifically, at early time points (4 h and 24 h) after hemarthrosis, thrombin activity in WT mice quickly peaked at 4 h, and returned to baseline after 1 week. In hemophilia B mice, there was no/minimal thrombin activity in joint tissues at 4 h and 24 h, whereas at 72 h and thereafter, thrombin activity kept rising, and persisted at a higher level. Nevertheless, prothrombin had not decreased in both WT and hemophilia. The pattern was also confirmed by Western blotting and immunostaining. To optimize the protection against development of HA, we tested different treatment regimens by administration of clotting factor IX into hemophilia B mouse after hemarthrosis induction, including a total of 600 IU/kg FIX within the first 24 h or the whole 2-week period. We concluded that timely (in the first 24 h) and sufficient hemostasis correction is critical for a better protection against the development of hemophilic arthropathy.

Introduction: In 2010, nonacog alfa became the first recombinant factor IX (rFIX) available in Japan for patients with haemophilia B., Aim: To determine real-world safety (adverse events, incidence of inhibitors) and effectiveness of nonacog alfa in Japan., Methods: This multicentre, prospective, observational, postmarketing surveillance study enrolled previously treated and untreated patients (PTPs and PUPs, respectively) who were observed for 1 and 2 years, respectively, after initiating nonacog alfa therapy. Safety and effectiveness were assessed for each treatment type. Annualized bleeding rate (ABR) and incremental recovery of rFIX were also evaluated., Results: Overall, 312 of 314 patients enrolled from 173 sites were eligible for the safety analysis set (PTPs, 281; PUPs, 28; other, 3). Mean age was 25.4 (PTPs) and 14.8 (PUPs) years. Haemophilic severity ranged from mild to severe, and 133 (42.6%) patients had haemophilic arthropathy. Of 285 patients (PTPs, 257; PUPs, 28) in the effectiveness set, 112 received on-demand treatment for 1161 bleeding episodes (effectiveness rate, 93.7%) and 185 received routine prophylaxis (effectiveness rate, 95.5%). No spontaneous bleeding was observed in 52.4% of patients during prophylactic treatment. Median ABR was lower during routine prophylaxis (2.0) vs the rest of the observation period (8.3). A weak negative correlation was found between body weight and the reciprocal of rFIX recovery. Eleven adverse drug reactions occurred in 7 PTPs (2.2% [7/312]); recurrence of inhibitor was observed in 1 patient, but no new inhibitor developed in PTPs or PUPs., Conclusion: Nonacog alfa therapy is safe and effective in the real-world scenario in Japan., (© 2019 The Authors. Haemophilia Published by John Wiley & Sons Ltd.)

The "Joint Outcomes Study" (JOS) demonstrated improved joint outcomes for patients receiving primary prophylaxis versus on-demand therapy. The impact of primary prophylaxis on inpatient health care utilization is not well-defined. To evaluate changes in hospitalization care of children with hemophilia before and after the 2007 JOS publication, this study utilized the Pediatric Health Information System (PHIS) to evaluate admissions for patients with hemophilia A or B (age, 2 to 7) admitted between January 2002 and 2006 (pre-JOS) and January 2010 and 2014 (post-JOS). Discharge diagnosis codes and clinical transaction classifications were used to differentiate bleeding episodes, infections, bypass agent use, length of stay, and intensive care unit (ICU) management. Overall, admissions for bleeding episodes did not change (26.5% of admissions pre-JOS vs. 23.6% post-JOS, P=0.10). However, admissions for suspected infections increased (3.0% of admissions pre-JOS vs. 7.2% post-JOS, P<0.01) while confirmed infections remained stable. Meanwhile, ICU utilization decreased (7.8% of admissions pre-JOS vs. 4.9% post-JOS, P<0.01). The necessity for ICU care in children with hemophilia has decreased since publication of the JOS. However, expanded adoption of primary prophylaxis is associated with more hospitalizations for suspected systemic infections, likely due to utilization of central venous catheters to deliver clotting factor concentrates.

Background Repeated haemarthroses affect approximately 90% of patients with severe haemophilia and lead to progressive arthropathy, which is the main cause of morbidity in these patients. Diagnostic imaging can detect even subclinical arthropathy changes and may impact prophylactic treatment. Magnetic resonance imagining (MRI) is generally the gold standard tool for precise evaluation of joints, but it is not easily feasible in regular follow-up of patients with haemophilia. The development of the standardized ultrasound (US) protocol for detection of early changes in haemophilic arthropathy (HEAD-US) opened new perspectives in the use of US in management of these patients. The HEAD-US protocol enables quick evaluation of the six mostly affected joints in a single study. The aim of this prospective study was to determine the diagnostic accuracy of the HEAD-US protocol for the detection and quantification of haemophilic arthropathy in comparison to the MRI. Patients and methods The study included 30 patients with severe haemophilia. We evaluated their elbows, ankles and knees (overall 168 joints) by US using the HEAD-US protocol and compared the results with the MRI using the International Prophylaxis Study Group (IPSG) MRI score. Results The results showed that the overall HEAD-US score correlated very highly with the overall IPSG MRI score (r = 0.92). Correlation was very high for the evaluation of the elbows and knees (r ≈ 0.95), and slightly lower for the ankles (r ≈ 0.85). Conclusions HEAD-US protocol proved to be a quick, reliable and accurate method for the detection and quantification of haemophilic arthropathy.

The life expectancy of patients with haemophilia has increased and therefore the interest in age-related comorbidities has grown. The aim of this study was to determine whether haemophilia patients have a different endothelial function compared with the general population. A total of 26 patients with severe or moderate haemophilia A or B, 14 controls and 36 patients with coronary artery disease (CAD) were included in this study. Five markers of endothelial dysfunction (MOEDs) were determined. Moreover, the endothelial function was examined using the Itamar Endo-PAT, and the reactive hyperemia index (RHI) was calculated from the results. The MOEDs soluble intercellular adhesion molecule-1 ( p  = 0.0095) and interleukin-6 ( p  = 0.010) were significantly higher for patients with haemophilia compared with the control group. The presence of increased adhesion molecule levels and low-grade inflammation is suggestive of a decreased endothelial function. RHI is impaired in CAD patients (1.862), whereas haemophilia patients have an RHI of 1.958 in comparison with 2.112 in controls ( p  = 0.127). Therefore, laboratory and functional measurements imply a possible higher risk for CAD in haemophilia patients., Competing Interests: This work was supported by a grant from Baxalta/Shire.W. M. has received grants and personal fees for lectures and consultancy from Bayer, Biogen Idec, Biotest, CSL Behring, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, Shire, Sobi and UniQure.S. A. has received grants and personal fees for lectures and consultancy from Bayer, Amgen, CSL Behring, LFB, Octapharma, Pfizer and Böhringer Ingelheim, Shire.S. B., R. S. and S. F. stated that they had no interests which might be perceived as posing a conflict or bias., (Georg Thieme Verlag KG Stuttgart · New York.)

Introduction: Brazil has the fourth largest world population of patients with haemophilia. However, mortality rates in this population are unknown., Aim: To analyse mortality and its causes in Brazilian patients with haemophilia from 2000 to 2014., Methods: The number of deceased patients with haemophilia and causes of death were obtained from the Brazilian National Mortality Information System (SIM), according to the 10th International Classification of Diseases (ICD-10). Standardized mortality ratios (SMR) were calculated to estimate the rate of overall death of patients with haemophilia relative to that of the Brazilian general male population., Results: A total of 784 deaths were identified in the period of 15 years. Mortality of patients with haemophilia was 13% higher when compared with the general male population (SMR 1.13, 95% CI: 1.01-1.16). Haemorrhage was the main cause of death (n = 254; 32.4%) of which 137 (54%) was intracranial haemorrhage. The total number of deaths due to HIV decreased over the years, and an increase in deaths due to cancer and cardiovascular disease was observed. A total of 129 deaths (16.5%) were related to hepatitis infection, of whom, 109 (86.5%) patients also presented with cirrhosis and hepatocellular carcinoma or other liver diseases., Conclusion: Mortality rate of Brazilian patients with haemophilia decreased over the evaluated period. Intracranial haemorrhage is still an important cause of death in these patients, which requires major effort for prevention. Death due to age-related cardiovascular disease and cancer has increased over the years, following the same tendency observed in developed countries., (© 2019 John Wiley & Sons Ltd.)

Radiosynovectomy (RS) is a simple, effective and safe procedure for the control of haemophilic synovitis that causes repetitive haemarthrosis. It must be done after confirming clinically (hard and painless mass on palpation) and by ultrasonography the existence of synovitis in a joint with recurrent haemarthrosis. RS should be the first invasive option (instead of arthroscopic synovectomy) for treatment of chronic synovitis. The technique is highly cost effective in comparison to arthroscopic synovectomy. The indication for RS is the presence of repeated haemarthroses associated with synovitis (confirmed clinically and by imaging techniques) that cannot be controlled by means of haematological treatment. No increase in the risk of cancer has been published and the dose of radiation utilized in RS is minimal. In haemophilic patients with recurrent haemarthrosis, RS should be performed under factor coverage as soon as possible, once the existence of synovitis has been confirmed by ultrasonography. RS should really be considered as a useful adjunctive procedure to the primary intervention, which is intensive replacement therapy., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: Lymphoma is the third most common cancer among children in the United States and Europe. Hemophilia is a congenital bleeding disorder characterized by deficiency of coagulation factor VIII or IX. Hemophilia B is a consequence of factor IX deficiency and has an incidence of 1 in 20,000 male births. A concurrence of these 2 uncommon diseases is rare except in patients infected with the human immunodeficiency virus (HIV). We report a case of a patient with both Burkitt lymphoma and hemophilia B; this is only such report in China since 1987., Patient Concerns: A 3-year-old boy was admitted to our hospital because of melena and jaundice for several days. His older brother had died due to hemophilia B and ventricular septal defect. The patient had not experienced any previous episodes of severe bleeding. Gradual abdominal distention was observed after admission; the patient's superficial lymph nodes were not enlarged. Results of blood routine and bone marrow examinations showed no abnormalities. He was diagnosed with sclerosing cholangitis, abdominal infection, and hepatitis. However, after treatment of reducing enzyme activity and eliminating jaundice, the patient's condition deteriorated. Hydrops abdominis was detected on abdominal ultrasonography. Tumor cells were found by pathological examination of peritoneal effusion. Both a c-myc gene translocation and a c-myc-IgH gene fusion were detected., Diagnosis: Burkitt lymphoma and hemophilia B., Interventions: The patient was transferred to the Pediatric Hematology Department of our hospital and treated with a modified B-NHL-BFM-95 protocol. During chemotherapy, platelet changes were monitored regularly and blood products were infused timely., Outcomes: The patient died of infection and bleeding after chemotherapy., Conclusion: Concurrent hemophilia and lymphoma are rare, especially in children. When encountering a patient with unexplained obstructive jaundice and massive ascites, the possibility of a tumor should be considered. Early diagnosis and adequate treatment of such tumor may improve prognosis.

Case: A 7-year-old boy presented with excruciating hip pain for 1 day, unable to bear weight. Magnetic resonance imaging (MRI) revealed small hip joint effusion and synovitis, which was treated by urgent operative aspiration to rule out infection. Subsequently, the postoperative site bled continuously, despite compression. The hip wound and blood cultures showed no growth. He was examined by a hematologist and had normal coagulopathy lab results. He was discharged and went home 4 days after aspiration and was scheduled for outpatient hematology work-up. He was readmitted 11 days after aspiration with continued pain and MRI was repeated, showing large hip hemarthrosis. Lab results at that time showed a prolonged partial thromboplastin time of 43.9 seconds. The patient was given fresh frozen plasma. The hip effusion was stable on ultrasound. He was found to have low factor IX <17% consistent with hemophilia B and was given recombinant factor IX (Benefix) of 2,000 units. The following day, his pain was markedly improved and he was discharged. At the 4-month follow-up, the patient was fully ambulatory., Conclusions: This is a case of unexpected bleeding after hip aspiration which led to the life-changing diagnosis of Hemophilia B in a pediatric patient. Orthopedists should be wary of bleeding dyscrasias and involve consultants as needed.

Background: Intracranial hemorrhage (ICH) is a life-threatening condition in children. Inherited bleeding disorders (IBD) have high risk of ICH., Aim: This single center study aims to identify the incidence, risk factors, and neurological outcome of ICH in children who suffer from IBD., Methods: From 2005 to 2017, 241 children with IBDs from Nanfang hospital, Department of Pediatrics, were evaluated. The ICH episodes were identified by medical history, general physical examination, detailed neurological examination, and computed tomographic or magnetic resonance imaging examination. The risk factors, location of ICH, management strategies, and outcome were noted., Results: ICH was confirmed in 54/241 (22.4%) children with IBD among them 52/54 (96.2%) (95% confidence interval [CI], 91.1%-99.9%) were hemophilia A and hemophilia B patients. The overall risk of ICH among children with IBD was 22.4% (95% CI, 17.2%-27.8%). The median age of ICH was 30 months (0 to 204) and 18/54 (33.3%) (95% CI, 20.3%-46.3%) children had an ICH in the first year of life. Twenty-eight of 52 (53.8%) hemophilic children with ICH were assessed for inhibitor of FVIII and FIX. Nine of 28 (32%) hemophilic children with inhibitor developed the ICH. Six of 52 (11.5%) (95% CI, 2.6%-20.5%) hemophilic children had multiple episodes of ICH in which 4 were inhibitor positive. Thirteen of 54 (24%) (95% CI, 12.3%-35.9%) had positive family history of IBD. Twenty-two (36%) (95% CI, 23.7%-48.5%) of 61 ICH episodes were caused by trauma and 39 (63.9%) (95% CI, 51.5%-76.3%) were nontrauma related. Subdural hematoma was most frequently observed. Mortality risk from ICH in children with IBD was 5/54 (9.2%) (95% CI, 1.3%-17.2%). Eleven (22.4%) (95% CI, 10.3%-34.6%) of 49 survivors had known neurological squeal, whereas 38 (77.5%) (95% CI, 65.4%-89.7%) had no documented evidence of neurological impairment., Conclusions: Hemophilia is the most common IBD and most frequently associated with ICH. Risk and consequences of ICH in IBD were high during the first year of life while in older children better outcome may be expected. The optimal management of ICH depends on immediate recognition and prompt replacement therapy.

Introduction: Numerous measuring instruments for the evaluation of hemophilic arthropathy have been developed. One of the most used systems is the Hemophilia Joint Health Score (HJHS) given its sensitivity to clinical changes appearing in the joints because of recurrent hemarthrosis., Objective: Assessing the interrater reliability, using the Spanish version of the HJHS (version 2.1) in children with hemophilia., Design: Reliability study to assess the interrater reliability of the Spanish version of HJHS., Methods: A sample of 36 children aged 7-13 years diagnosed with hemophilia A or B was used. Two physiotherapists performed physical assessments with the Spanish version of the HJHS. Descriptive statistics (range, mean, standard deviation) and the analysis of interrater reliability were calculated., Results: The interrater reliability was heterogeneous since the Kappa coefficient range (ĸ), although significant (p < 0.001), ranged 0.31-1.00 in the variables of HJHS (swelling, duration of swelling, muscle atrophy, crepitus on motion, flexion loss, extension loss, joint pain, strength, and global gait). In assessing the bias of observers with the Bland and Altman method, the observer 1 scored 0.41 (CI [-0.67, 1.49]) units above observer 2, and the difference between the two was significant (t(36) = 4.48), p < 0.001)., Conclusions: The interrater reliability of the Spanish population version of the HJHS is high. This scale should be used generically in evaluating musculoskeletal pediatric patients with hemophilia.

Haemorrhagic disorders combined with soft tissue inflammation and infection may lead to severe bleeding complications before, during or after dental treatment. In selected cases, a combined therapeutic approach involving clinical therapies and systemic and local medication could improve the treatment outcomes and the patient's quality of life. This clinical case report, presents for the first time a successful combined approach, completed in a 38-year-old male patient with severe type-B haemophilia in which an infected tooth was extracted, an immediate implant was inserted, bone grafting was performed and early implant loading was successfully applied. In addition to the clinical therapy, medication was provided orally, systemically and locally, thus preventing the haemorrhagic complications and improving the patient's quality of life., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

: Prophylaxis entails long-term continuous intravenous administration of concentrates of the deficient factor with a view to preventing spontaneous bleeds and the development of hemophilic arthropathy. Initiation of prophylaxis at an early age and continuous uninterrupted factor administration in patients with hemophilia have been hailed as essential by such organizations.The most widely used prophylaxis regimens include the Swedish (Malmö), the Dutch and the Canadian protocols. Different international groups have hailed prophylaxis as the most effective treatment in patients with hemophilia.Prophylaxis is effectiveness in preventing bleeding and arthropathy in children with (particularly early-onset) hemophilia. Although some retrospective trials confirm the benefits of prophylaxis, others point to a lack of conclusive data to support switching adult patients with established hemophilic arthropathy who always received on-demand treatment to prophylactic treatment.The potential effects of prophylaxis on the patients' sex lives, renal status, prostate involvement and cataract must be analyzed before indicating prophylactic treatment in elderly patients.The high efficacy of prophylactic treatment in patients with hemophilia and inhibitors has been widely reported in the literature.

Introduction: In sub-Saharan African countries, research on haemophilia is limited. Since 2015, a partnership has been established through the World Federation of Hemophilia (WFH)'s twinning programme between the haemophilia treatment centre (HTC) of the Centre Hospitalier universitaire of Yopougon in Abidjan, Côte d'Ivoire, and the Cliniques universitaires Saint-Luc of Brussels, Belgium., Aim: This study sought to collect accurate, and detailed demographic, clinical, and laboratory data on the whole identified Ivorian haemophilia population., Methods: A prospective study was conducted in 2017 in Yopougon's HTC. Participants were assessed through multidisciplinary workups including interviews, logbook review, pedigree establishment, clinical examination and laboratory testing., Results: Data on 81 patients with haemophilia (PWH) (78 severe and moderate) were collected. Postcircumcision bleeding was the most common diagnosis reason (32%). Mouth bleeds and skin wounds accounted for 55.2% of bleeds. Pedigrees revealed 63 deaths in affected relatives among 33 families. Most PWHs (76.5%) were treated on demand, and 21% had never been exposed to clotting factor. Non-substitutive therapies (tranexamic acid [43%], physiotherapy [11%] and DDAVP [0%]) were underused. Overweight was uncommon. Knees were the most clinically affected joints at the Hemophilia Joint Health Score. Inhibitors were present in 7.8% of previously treated PWHs., Conclusions: This study highlights the value of simple, feasible and inexpensive tools to collect data in the Ivorian haemophilia population and provides the basis for developing and implementing locally appropriate strategies to improve screening, diagnosis, preventive care, treatment and education. It demonstrated the WFH twinning programme benefits for haemophilia care in the developing world., (© 2019 John Wiley & Sons Ltd.)

Introduction: Health-related quality of life (HRQoL) studies are increasingly needed to prevent and improve the medical care of persons with haemophilia (PWH)., Aim: We assessed the impact of haemophilia on HRQoL and social status of adult Lebanese PWH compared to a reference population., Methods: In this case-control study, 60 severe and moderate PWH were compared to 112 healthy controls. Detailed socio-demographic data and disease characteristics were collected, and HRQoL was assessed using the SF-36 questionnaire., Results: Age, body mass index and the percentage of married people were similar in PWH and controls. A greater proportion of controls attained a higher educational level than cases (88.4% vs 59.3%, respectively, P < 0.001). PWH were more likely to have a job requiring physical activity than controls (55.9% vs 31.4%) and more likely to be unemployed (10.2% vs 1.0%), whereas more controls had higher socio-economic jobs (10.5% vs 1.7%). PWH had significantly (P < 0.001) worse scores in all SF-36 domains except for energy/fatigue. Affected targeted joints (2.7 ± 1.5) and monthly bleeding frequency (2.9 ± 2.4) were inversely correlated with almost all SF-36 domains. Only 26.7% of PWH walk normally, and walking abnormalities were inversely correlated with all SF-36 domains except role-emotional and emotional well-being., Conclusion: As compared with controls, the majority of Lebanese PWH has difficulties in social integration, has severe physical limitations and psychological impairments., (© 2019 John Wiley & Sons Ltd.)

Introduction: Effects of haemophilic arthropathy on neuromuscular control during gait are currently unknown., Aims: (a) To assess how haemophilic arthropathy affects the complexity of neuromuscular control during gait; (b) To investigate the relationship between complexity of neuromuscular control and joint impairment., Methods: Thirteen control subjects (CG) walked overground at their preferred and a slow velocity and thirteen people with haemophilic arthropathy (PWHA) walking at their preferred velocity. Surface electromyography (EMG) was collected from eleven leg muscles. Electromyography variance explained by muscle synergies (sets of co-activated muscles that can be recruited by a single signal) was calculated by the total variance accounted (tVAF). Three measures were used to evaluate complexity of neuromuscular control: (a) the number of synergies required for tVAF > 90%, (b) tVAF as a function of the number of muscle synergies, and (c) the dynamic motor control index (Walk-DMC). Impairment of ankle and knee joints was determined by the Haemophilia Joint Health Score (HJHS)., Results: The same number of the muscle synergies was found for each group (P > 0.05). For both walking velocities tested, tVAF1 was higher in PHWA (P < 0.05). The Walk-DMC of PWHA was lower than that of the CG for both walking velocities (P < 0.05). For PWHA, no significant correlation was found between HJHS (sum knee and ankle) and Walk-DMC index (r = -0.32, P = 0.28)., Conclusions: These results indicate differences between PWHA and CG in the neuromuscular control of gait. The Walk-DMC and tVAF1 may be useful measures to assess changes in neuromuscular control in response to treatment., (© 2019 John Wiley & Sons Ltd.)

Introduction: Patients with haemophilia (PWH) are experiencing a nearly normal life span with safe factor replacement therapy and effective antiviral treatments for co-infections. As a result, many ageing-related health issues are starting to emerge. One rarely discussed health issue is erectile dysfunction (ED). ED can affect overall well-being and predict future cardiac events, but is not well studied in PWH., Aim: This prospective study aims to examine the prevalence and risk factors for ED in PWH using the validated International Index of Erectile Function (IIEF) questionnaire., Methods: Patients with haemophilia A and B at all severities were invited to participate in IIEF questionnaire at the provincial Hemophilia Treatment Centre. Risk factors for ED including cardiovascular risk factors, prior surgeries, viral infections, medications and haemophilia-specific factors were obtained. Fasting laboratory tests including but not limited to renal function, haemoglobin, lipid profile, glucose and CRP were performed the same day. Blood pressure and anthropomorphic indices were measured. Endothelial function was assessed by brachial artery flow-mediated dilation (FMD and hyperaemic velocity time integral [VTI])., Results: Out of the 56 subjects approached, 44 completed the IIEF. Median age was 49 years. About 38.6% of the cohort reported ED symptoms. There was no significant difference in endothelial function measured by FMD and VTI between patient with ED and without. IIEF score correlated with age in multivariable analysis., Conclusion: Erectile dysfunction symptoms appear prevalent in PWH, particularly in the older group. This disorder along with the underlying causes needs to be explored further in future larger observational study., (© 2019 John Wiley & Sons Ltd.)

The standard therapy for patients with haemophilia is prophylactic treatment with replacement factor VIII (FVIII) or factor IX (FIX). Patients who develop inhibitors against FVIII/FIX face an increased risk of bleeding, and the likelihood of early development of progressive arthropathy, alongside higher treatment-related costs. Bypassing agents can be used to prevent and control bleeding, as well as the recently licensed prophylaxis, emicizumab, but their efficacy is less predictable than that of factor replacement therapy. Antibody eradication, by way of immune tolerance induction (ITI), is still the preferred management strategy for treating patients with inhibitors. This approach is successful in most patients, but some are difficult to tolerise and/or are unresponsive to ITI, and they represent the most complicated patients to treat. However, there are limited clinical data and guidelines available to help guide physicians in formulating the next treatment steps in these patients. This review summarises currently available treatment options for patients with inhibitors, focussing on ITI regimens and those ITI strategies that may be used in difficult-to-treat patients. Some alternative, non-ITI approaches for inhibitor management, are also proposed., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Increased number of patients with hemophilia have been identified to have osteoporosis at early ages. Low bone mineral density in the setting of hemophilia has been associated with decreased mobility, sedentary life style, on demand treatment or delayed prophylaxis, low body weight and viral infections. The aim of this study was to investigate the impact of hemophilia on bone health of adult patients living in a middle income country. A total of 61 adult patients with hemophilia who were followed at the Hematology Department of Cerrahpaşa Medical Faculty, Istanbul University-Cerrahpaşa were consecutively included in this study. Bone health of the patients was assessed using the bone mineral density (BMD) and vitamin D levels. Z and t scores are used for evaluation of BMD in patients with hemophilia aged < 50 and ≥ 50 years, respectively. Information on treatment and co-morbidities including viral diseases were obtained from the medical files of the recruited patients. Bone mineral density was found normal in 30, and low in 29 patients. Vitamin D levels were below 20 ng/ml in 46 patients. No significant relationship was found between the severity of hemophilia and bone density. Vitamin D levels were significantly lower in patients who had a history of joint intervention. Neither annual bleeding rate nor the treatment modality (on demand versus prophylaxis) were associated with the bone mineral density and vitamin D levels. Annual factor consumption was higher in patients whose bone mineral densities was low both in femoral and lumbar regions. The results of this study depicting the situation of adult hemophilia population from a middle income country show that bone mineral density and vitamin D levels were decreased in a considerable amount of patients at early ages.

There has been an ongoing debate as to whether hemophilia A (HA) is more severe than hemophilia B (HB), and there are studies supporting each side of the argument. The study aimed to investigate whether any differences in major bleeding events exist between patients with severe HA and HB. A nationwide, population-based retrospective cohort study using the National Health Insurance Research Database was conducted. We compared 658 patients with severe HA and 137 patients with severe HB without inhibitors from 1997 to 2013, during the period when adult patients older than 18 years old were treated with the on-demand therapy since birth. There was no significant difference between patients with severe HA and HB in the rate of major bleeding events, with an adjusted relative ratio of 0.79 (95% confidence interval [CI]: 0.36-1.71, P = .548). There was also no significant difference in the incidence rate of major bleeding events between adult patients with HA and HB with the on-demand therapy, and an adjusted hazard ratio (HR) of 0.82 (95% CI: 0.65-1.02). However, patients with HA had a lower incidence rate of intracranial hemorrhage, with an adjusted HR of 0.44 (95% CI: 0.25-0.79). In addition, no significant difference in the frequency of major bleeding events requiring hospitalization between patients with HA and HB was found, P > .05. In conclusion, the study demonstrated that patients with severe HB encountered a similar rate of major bleeding events to those with severe HA.

Hemophilic arthropathy from joint bleeding remains a complication with major morbidity in the increasingly aging patients with hemophilia. Prophylactic clotting factor infusions, based on pharmacokinetic dosing to reduce bleeding rates, are being explored more and more. However, there is little evidence on the benefits of pharmacokinetic dosing in direct association with bleeding events. Here, we prospectively followed a cohort of adult patients with hemophilia A and B (n = 26) and arthropathic joints on various clotting factor products over a period of 2 years with clinical and radiographic joint health assessments, frequent joint ultrasound, and pharmacokinetic studies. Joint bleeds and synovitis with synovial vascularity changes were objectively diagnosed by musculoskeletal ultrasound and power Doppler and analyzed in relation to pharmacokinetic, joint- and patient-specific parameters. Results revealed that, contrary to common beliefs, bleeding episodes were not readily explained by pharmacokinetic features, as they were not associated with more time spent below certain clotting factor thresholds. Joint bleeding was found to be associated with prominent vascularity changes, suggesting that vascular remodeling and leakiness may contribute to joint bleeding that cannot be prevented by clotting factor replacement alone.

Haemophilia is marked by joint bleeding (haemarthrosis) leading to cartilage damage (arthropathy). Lifelong prophylaxis-initiated after the first bleeding episode-leads to a dramatic decrease in arthropathy in haemophilia patients. However, adherence to continuous intravenous administrations of factor VIII (FVIII) or FIX products is challenging, and patients potentially suffer from breakthrough bleedings while on prophylaxis. Newer FVIII/FIX products with enhanced convenience attributes and/or easier infusion procedures are intended to improve adherence. However, pharmacokinetic data should be harmonised with information from individual attitudes and treatment needs, to tailor intravenous dosing and scheduling in patients who receive extended half-life products. Nor is there sound evidence as to how subcutaneous non-FVIII/FIX replacement approaches (concizumab; emicizumab; fitusiran) or single intravenous injections of adeno-associated viral vectors (when employing gene therapy) will revolutionize adherence in haemophilia. In rheumatoid arthritis, repeated ultrasound examination of a patient's major joints is a valuable tool to educate patients and parents to understand the disease and provide an objective framework for clinicians to acknowledge patient's adherence. Joint ultrasound examination in haemophilia significantly correlates with cartilage damage, effusion, and synovial hypertrophy evaluated by magnetic resonance imaging. Furthermore, in patients with haemophilia undergoing prophylaxis with an extended half-life product for a ≈ 2.8 year period, a significant continued improvement in joint health is detected at the physical examination. This provides the rationale for studies on repeated ultrasound examinations of joint status to attempt to remedy sub-optimal medication adherence and help identify which approach is most suited on which occasion and for which patient., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

In patients with hemophilia, osteoporosis is frequently observed for which the etiology remains unclear. The aim of this paper is to review the available experimental evidence indicating the presence of this disorder in patients with hemophilia, explore the potential mechanisms which may lead to reduced bone mineral density (BMD) and speculate on useful interventions to circumvent it. A narrative review of the English literature up to April 2018 was performed. The available evidence demonstrates an increased rate of bone resorption and an excess of osteoporosis among patients with hemophilia. FVIII and FIX may act through at least two pathways: promoting bone formation by a thrombin-mediated mitogenic effect on osteoblasts and by cytokine-mediated osteoclast activity. Another potential indirect mechanism mediated through the RANK-RANKL pathway has been suggested but remains controversial. The role of confounders such as lack of activity and immobility must be considered., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: To assess the reliability and validity of six patient-reported outcomes (PRO) instruments for evaluating health-related quality of life in adults with mild-severe hemophilia B and caregivers of children with hemophilia B, including affected women/girls., Methods: Adults with hemophilia B and caregivers completed separate online surveys containing several PRO instruments, which were administered to adult participants only (EQ-5D-5L, Brief Pain Inventory v2 Short Form, Hemophilia Activities List, and International Physical Activities Questionnaire), both adults and caregivers (Patient Health Questionnaire [PHQ-9]), or caregivers only (Generalized Anxiety Disorder 7-Item [GAD-7] scale). Construct validity and item-total correlation were assessed using Pearson product-moment correlation, internal consistency was assessed using Cronbach's alpha coefficient, and known-group validity was assessed by comparisons to self-reported characteristics based on the Kruskal-Wallis test., Results: Patient-reported outcomes instruments generally showed satisfactory reliability for adults (n = 299) and caregivers (n = 150). In adults, PRO instruments generally showed high construct validity. Most PRO instruments showed expected significant differences among known groups for adults and caregivers. PHQ-9 and GAD-7 did not show significant differences among caregiver age groups., Conclusions: Patient-reported outcomes instruments administered in B-HERO-S demonstrated reliability and validity in the broader population of adults with hemophilia B and caregivers when including all severities and genders., (© 2018 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd.)

Prophylaxis is currently considered the optimal care for severe haemophilia. For patients and their families one of the major difficulties with prophylaxis is the need for frequent venipunctures. The half-life of standard factor IX (FIX) concentrates is approximately 18 hours, which requires 2 or 3 intravenous infusions per week to achieve bleeding prevention in patients with severe haemophilia B. Prolonging the half-life of FIX can therefore reduce the frequency of infusions. Recently, extended half-life recombinant FIX (rFIX) concentrates have been developed. We designed a new rFIX molecule fused to coagulation FXIII-B sub-unit. This sub-unit is responsible for the long half-life of the FXIII molecule (10-12 days). The rFIX-LXa-FXIII B fusion protein contains a short linker sequence cleavable by activated FX (FXa), to separate rFIX from the carrier protein as soon as traces of FXa are generated, leaving rFIX free to perform its enzymatic role in the tenase complex. The rFIX-LXa-FXIII B fusion protein was expressed in human hepatic Huh-7 cells and Chinese hamster ovary cells, and both wild-type rFIX (rFIX-WT) and rFIX-LXa-FXIII B showed similar clotting activity and thrombin generation capacity in vivo after injection in haemophilia B mice compared with rFIX-WT. The half-life of the rFIX-LXa-FXIII B molecule in WT mice and rats was 3.9- and 2.2-fold longer, respectively, compared with rFIX-WT. A potential advantage of this new molecule is its capacity to bind to fibrinogen via FXIII-B, which might accelerate fibrin clot formation and thus improve haemostatic capacity of the molecule., Competing Interests: Sandra Le Quellec has received grants/research support from CSL Behring and honoraria from Shire, SOBI and LFB Biomedicaments. Nathalie Enjolras has received grants/research support from Pfizer. Eloïse Pérot and Jonathan Girard have no conflict of interest to declare. Claude Négrier has received grant/research support from Alnylam, Bayer, CSL Behring, Novo Nordisk, Pfizer, Octapharma and Shire; and honoraria from Bayer, CSL Behring, LFB, Novo Nordisk, Pfizer, Octapharma and Shire. Yesim Dargaud has received grants/research support from Bayer, Baxter, Novo Nordisk, CSL Behring, LFB, Pfizer, LeoPharma, Octaharma, Shire and DiagnosticaStago; and honoraria from Bayer, Baxter, Novo Nordisk, CSL Behring, Sobi and Octapharma., (Georg Thieme Verlag KG Stuttgart · New York.)

People with haemophilia (PWH) experience acute pain during joint bleeds and might develop chronic pain due to joint degeneration. However, there is a lack of standardized measures to comprehensively assess pain in PWH. This study aimed to develop a multidimensional questionnaire for haemophilia-related pain, the Multidimensional Haemophilia Pain Questionnaire (MHPQ), and to present initial validation data among adults.The questionnaire distinguishes between acute/chronic pain and queries about pain locations, duration, frequency, triggering factors, intensity, interference, strategies, specialists for pain management and satisfaction with treatment. An initial version was tested with 16 patients to ensure item comprehensibility and face validity. The final version was answered by 104 adults, with 82 (78.8%) reporting haemophilia-related pain in the previous year (mean age = 43.17; SD = 13.00). The non-response analysis revealed good item acceptability. Exploratory and confirmatory factor analysis (EFA/CFA), reliability (internal consistency, test-retest, inter-item and item-total correlations) and convergent validity were analysed for the intensity and interference dimensions of the questionnaire. A combined EFA with these two constructs supported a 2-factor structure distinguishing intensity (α = 0.88) from interference items (α = 0.91). CFA was tested for the interference dimension, demonstrating suitability for this sample. Item-total correlations were >0.30 on both dimensions and most inter-item correlations were <0.70. Test-retest reliability (n = 42) was good for intensity (r = 0.88) and interference (r = 0.73), and convergent validity was confirmed for most hypotheses (r>0.30).This questionnaire is a comprehensible tool, achieving a thorough assessment of relevant pain dimensions. The MHPQ can help guide treatment recommendations by highlighting relevant topics and contributing to more effective, integrated treatments., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Prophylaxis with replacement factor IX (FIX) reduces bleeding frequency and improves quality of life in haemophilia B patients. With prophylaxis, the likelihood of bleeding is lowered with increasing trough levels. New products with extended half-life (EHL) can maintain high factor activity levels over prolonged periods, compared with standard FIX products., Aim: To evaluate the safety, efficacy and pharmacokinetics of the new recombinant FIX EHL product, nonacog beta pegol (N9-GP), using pooled data, with a focus on-but not limited to-prophylaxis at 40 IU/kg., Methods: N9-GP has been investigated in males with congenital haemophilia B and FIX activity ≤2% in the paradigm™ clinical trial programme. This analysis includes pooled data from five completed paradigm™ trials conducted in previously treated adults, adolescents and children, focusing on results of prophylaxis with 40 IU/kg once-weekly intravenous dosing., Results: In total, 115 previously treated patients were exposed to N9-GP. Of 54 patients (47%) treated with N9-GP 40 IU/kg once-weekly prophylaxis, 72% experienced no spontaneous bleeds over 1 year. In all patients receiving 40 IU/kg once-weekly, median overall annualized bleeding rate (ABR) was 1.03 (interquartile range 0.00; 2.89); median spontaneous ABR was 0.00 (0.00; 0.80). No patients developed inhibitors. Estimated mean steady-state trough levels with N9-GP 40 IU/kg once-weekly were ≥15% overall; 27.3% in adolescents and adults., Conclusion: N9-GP 40 IU/kg once-weekly was well tolerated and effective in preventing bleeding, maintaining mean FIX activity levels ≥15% across all age groups. N9-GP may provide a new treatment option for preventing bleeding in haemophilia B patients., (© 2018 The Authors. Haemophilia Published by John Wiley & Sons Ltd.)

Chronic liver disease (CLD) is frequently seen in the hemophilia population. The ADVANCE Working Group conducted a cross-sectional study in which people with hemophilia (PWH) aged ≥40 years were included. This study aimed to assess the associations between CLD and its risk factors using data from the H3 study, and to suggest implications for optimal care.Data from 13 European countries were collected at a single time-point (2011-2013). Univariate and multivariate logistic regression (MLR) analyses were performed.A total of 532 PWH were included with either hemophilia A (n = 467) or hemophilia B (n = 65). A total of 127 (24%) were diagnosed with CLD. Hepatitis C virus (HCV), human immunodeficiency virus (HIV), total cholesterol, and severe hemophilia were significant risk factors in univariate logistic regressions. In MLR, HCV Ab+/PCR+ (OR = 17.6, P < .001), diabetes (OR = 3.0, P = .02), and HIV (OR = 1.9, P = .049) were positively associated with CLD. Total cholesterol (OR = 0.6, P = .002) was negatively associated with CLD. We found no evidence of interaction effects among the explanatory variables. No significant associations with age and type of or severity of hemophilia were observed in MLR.The main risk factors for CLD in this European cohort also apply to the general population, but the prevalence of HCV and HIV is considerably larger in this cohort. With new and improved treatment options, intensified eradication therapy for HCV seems justified to prevent CLD. Similarly, intensified monitoring and treatment of diabetes seem warranted.

Introduction: Clinical severity and impact of haemophilia on quality of life have been generally considered to be lower for haemophilia B (HB) compared with haemophilia A (HA) patients., Aims: To compare annual bleeding rate (ABR), target joint development and health-related quality of life (HRQoL) between adult (≥18 years) severe HA and HB patients using recent data from the Cost of Haemophilia in Europe: a Socioeconomic Survey (CHESS) study., Methods: Multivariate generalized linear models (GLM) were constructed to assess the relationship between haemophilia type, ABR, HRQoL (derived from EQ-5D index scores) and the presence of target joints while controlling for covariates., Results: Of the 1225 patients included, 77% (n = 949) had HA and 23% (n = 278) had HB. Of the 514 patients who completed the EQ-5D, 78% (n = 405) had HA, and 22% (n = 110) had HB. Unadjusted mean ABR was 3.79 in HA and 4.60 in HB. The presence of ≥1 target joint was reported in 59% and 54% of patients with HA and HB, respectively. Unadjusted mean EQ-5D index score was 0.78 in HA and 0.76 in HB. Haemophilia type was not a significant predictor of ABR, target joints or HRQoL when adjusted for confounding factors such as BMI, age and replacement therapy regimen., Conclusion: Data suggest comparable ABR, incidence of target joints and HRQoL between patients with HB and HA indicating comparable clinical severity and disease impact on patient quality of life., (© 2018 John Wiley & Sons Ltd.)

: Early joint damage in patients with haemarthrosis often escapes diagnosis because of insufficient investigation of biomechanical changes. Arthropathy in haemophilia requires complex assessment with several tools. Considering the increased emphasis on an integrated approach to musculoskeletal (MSK) outcomes, re-evaluation of MSK assessment to address individual patient needs is warranted. To advise on the optimal use of current assessment tools and strategies for tailored MSK evaluation in patients with haemophilia. A panel of experts in haemophilic arthropathy evaluated internationally recognized assessment tools through published literature and personal expertise. Each tool was considered, scored and ranked for their utility in the clinical assessment of MSK damage. Subsequently, a patient evaluation table detailing advice on type and frequency of assessments for different patient populations was constructed. To obtain a complete MSK assessment, multiple tools must be used to ensure each criterion is evaluated. For patients with haemophilia, clinical examination of the joint, disease-specific structure/function scores, and activity/participation scores including quality of life are important, and should be performed on a regular basis according to age and clinical condition. Joint imaging is recommended in the prevention, diagnosis and follow-up of haemophilic arthropathy and should be used in conjunction with joint structure and function scores. An integrated approach to MSK assessment using combinations of tools will allow earlier management of dysfunction and may improve long-term outcomes. This approach could be used in long-term follow-up of all patients independent of age and disease stage, especially in children to prevent arthropathy.

Objectives: We aimed to summarize the evidence for periprocedural and long-term strategies to both minimize the bleeding risk and ensure sufficient anticoagulation and antiaggregation in hemophilia patients undergoing coronary angiography with or without percutaneous coronary interventions (PCI)., Background: Hemophilia patients undergoing coronary angiography and PCI are at risk of bleeding due to deficiency of the essential clotting factors VIII or IX combined with the need of peri-interventional anticoagulation and antiaggregation and dual antiplatelet therapy (DAPT) after PCI., Methods: We report on a patient with moderate hemophilia B undergoing single-vessel PCI with administration of factor IX concentrate during the procedure and during the 1-month DAPT period. In addition, a systematic review of patients (n = 54, mean age 58 ± 10 years) with hemophilia A (n = 45, 83%) or B (n = 9, 17%) undergoing coronary angiography with or without PCI is presented., Results: Peri-interventional factor substitution was performed in the majority (42 of 54, 78%) but not all patients. In 38 of 54 (70%) patients undergoing coronary angiography, PCI with balloon dilation (n = 5), bare metal (n = 31), or drug-eluting stents (n = 2) was performed. For PCI unfractioned heparin (n = 24), low molecular weight heparin (n = 2), bivalirudin (n = 4), or no periprocedural anticoagulation at all (n = 8) were used. PCI was successful in all cases. After stenting, the majority (28 of 33; 85%) was treated with DAPT (median duration 1 month). Major periprocedural bleeding episodes occurred in 3 of 54 (6%) patients. Bleeding during follow-up occurred in 11 of 54 (20%) patients., Conclusions: Coronary angiography and PCI in patients with hemophilia are effective and safe when applying individualized measures to prevent bleeding., (© 2017 Wiley Periodicals, Inc.)

Introduction: Intracranial haemorrhage in children with inherited bleeding disorders is a potentially life-threatening complication and presents a significant therapeutic challenge., Aim: To define the characteristics, management and outcomes of intracranial haemorrhage presenting in UK children ≤16 years of age with inherited bleeding disorders from 2003 to 2015., Method: Retrospective analysis of children treated at UK haemophilia centres., Results: Of 66 children presenting with Intracranial haemorrhage (ICH), 82% had haemophilia A or B, 3% VWD and 15% a rare IBD. The IBD was a severe phenotype in 91%. The rates of ICH were 6.4 and 4.2 per 1000 patient years for haemophilia A and B, respectively. Median age at presentation was 4 months (33% neonates; 91% children <2 years of age). In neonates, delivery was spontaneous vaginal (SV) in 11, instrumental in 6, caesarean in 4 and unknown in 1. In children with haemophilia, the risk of ICH after instrumental delivery was 10.6 times greater than after SV delivery. Trauma was more common in children >2 years (67%) than in children 1 month to 2 years (18%; P = .027). Prior to ICH, only 4.5% of children were on prophylaxis. 6% of haemophiliacs had an inhibitor. The median duration of initial replacement therapy was 15 days. Mortality was 13.5%. Neurological sequelae occurred in 39% of survivors, being more common following intracerebral bleeding. In haemophilia survivors, 52% subsequently developed a FVIII inhibitor., Conclusion: Intracranial haemorrhage occurs most frequently in children with severe IBDs, during the first 2 years of life and in children not receiving prophylaxis. Intracranial haemorrhage often occurs without documented trauma., (© 2018 John Wiley & Sons Ltd.)

Introduction: Patients with haemophilia (PwH) suffer from haemophilic arthropathy which leads to an enhanced pain sensitivity. The aim of this study was to determine whether the individual pain condition in terms of pressure pain thresholds (PPT) at the knee joints is linked to changes of underlying anatomical structures in PwH., Material and Methods: Eleven landmarks at both knee joints of 36 PwH and 36 controls were examined in terms of PPT and ultrasound sonography (US). PPT were used to generate four groups: pain sensitive and insensitive knees of PwH and controls., Results: PPT of the knee joints were significantly decreased at all landmarks in PwH when compared to controls (P ≤ .004). US findings revealed that especially osteophytes are more pronounced in pain-sensitive knees of PwH in comparison with pain-insensitive knees of PwH or pain-(in)sensitive knees of controls. The synovia tissue was also thickened in PwH when PPT was altered. In contrast to findings in osteoarthritis-related pain, no differences between the groups were found regarding effusion, whether assessed, for example on the distal edge of m. vastus lateralis (P = .893) or on the lateral joint space (P = .417)., Conclusion: Particular degenerative changes in terms of osteophytes and thickness of synovial tissue are associated with an enhanced pain sensitivity in PwH. Altered PPT which were not associated with structural findings may be an indicator for a complex peripheral and/or central sensitization of the affected joints in PwH. The role of this mechanism should be clarified in further studies., (© 2018 John Wiley & Sons Ltd.)

Introduction: Patients with haemophilia may have lower levels of bone mineral density (BMD) compared with the general population. Moreover, haemophilic patients have increased risk factors for low bone mineral density (LBMD) such as arthropathy and resulting immobility, increasing their risk for osteoporosis and fractures., Aim: To assess the prevalence of LBMD and associated risk factors among a group of Colombian haemophilic patients., Methods: In this case-control study, 90 patients with haemophilia A and B, over the age of five, were recruited. Controls were healthy participants matched by age, gender, body mass index (BMI), socioeconomic status, and race. All participants underwent dual energy X-ray absorptiometry (DXA) and the Global Physical Activity Questionnaire. Blood tests were collected to evaluate LBMD determinants in cases., Results: BMD was lower in cases than in the control group. BMD of femoral necks was 0.907 g/cm 2 in cases vs. 1.020 g/cm 2 in controls (P = .019), and BMD of hips 0.930 g/cm 2 in cases vs. 1030 g/cm 2 in controls (P = .019). The greater the severity of haemophilia, the lower BMD in spine, femoral neck, and hips. Elevated C-protein levels were found in 44.1% of patients with LBMD and 14.8% with normal BMD (P = .003). The study found an adjusted prevalence ratio of 2.11, indicating that haemophilic patients are two times more likely to have LBMD (CI95% = 1.43-3.11 P < .001)., Conclusion: Results from the present study showed that haemophilia was associated with a higher frequency of LBMD. Severity of haemophilia, haemophilic arthropathy, and elevated C-reactive protein levels was directly associated with LBMD., (© 2018 John Wiley & Sons Ltd.)