Introduction A comprehensive treatment for patients with haemophilia (PwH) should focus on how the disease interferes with their mental, emotional and social environment to analyse if all the therapeutic efforts invested in their physical status have positive impact on a life worth living. Aim To analyse the correlation between the physical status of a cohort of adults with haemophilia and their mental, emotional and social states regarding their treatment modality; Also, to investigate which variables are most related to quality of life (QoL), joint health and emotional, mental and social states. Methods In this cross-sectional, 102 adults with haemophilia divided into a prophylactic group (G1, n = 77) and on-demand group (G2, n = 25) were included. Demographic and clinical characteristics, health joint (HJHS), presence of synovitis with ultrasound, self-perceived functionality (HAL) and QoL (A36-HaemoQoL), were analysed. Results In G1 all the variables that defined the physical status correlated (rho: 0.33 to 0.72) to the mental and social spheres. The emotional state correlated with the self-perceived ones. In G2 physical status did not correlate with the three states. According to the regression models, HAL was the variable that most influenced the QoL (together with the bleedings in the last year, R2 = 0.61), emotional (R2 = 0.16), mental (together with HJHS, R2 = 0.41) and social states (R2 = 0.39). In addition, the HJHS was influenced by synovitis, HAL, mental health, age and the bleeding history (R2 = 0.83). Conclusion Emotional, mental and social states of PwH in prophylaxis are correlated to their physical status, being the self-perceived functionality the variable that most influenced in their QoL.

Strength exercise training is advised for people with hemophilia (PWH); however, few studies have been published and have methodological limitations. The purpose of this study was to evaluate the effectiveness of progressive elastic resistance training on quality of life and perceived functional abilities in PWH.

Objective: Tendinopathy is a prevalent condition in young athletes and in older nonathletic people. Recent tendinopathy research has shown a growing interest in the role played by genetic factors, basically genes involved in collagen synthesis and regulation, in view of collagen disorganization typically present in tendon pathologies. Design: A case–control, genotype–phenotype association study. Setting: La Ribera Hospital, Valencia, Spain. Participants: A group of 137 young athletes (49 with rotator cuff tendon pathology and 88 healthy counterparts) who played upper-limb–loading sports were clinically and ultrasound (US) assessed for rotator cuff tendinopathy were included. Intervention: Genetic analysis was performed to determine whether there was a relationship between rotator cuff pathology and the genotype. Main Outcome Measures: We hypothesized that the following single nucleotide polymorphisms: COL5a1 rs12722, COL11a1 rs3753841, COL11a1 rs1676486, and COL11a2 rs1799907 would be associated with rotator cuff tendinopathy. Results: A direct relationship between CC genotype and bilateral US pathological images was statistically significant (χ2 = 0.0051) and confirmed by the Fisher test, with a correlation coefficient of 0.345 and a Cramer's v of 0.26. Conclusion: A significant association was found between COL5a1 rs12722 genotype and rotator cuff pathology, with the CC genotype conferring increased risk of tendon abnormalities and being associated with rotator cuff pathology.

BACKGROUND:Haemophilic arthropathy is one of the main causes of morbidity in people with haemophilia (PWH), inducing pain and reduced functionality. Therefore, PWH are complex patients and must be approached from a multidisciplinary perspective. OBJECTIVES:To evaluate the effectiveness of a therapeutic exercise and cognitive-behavioural therapy (CBT) combined protocol on functionality, pain, and joint health of PWH, arthropathy and chronic pain. Treatment satisfaction was also evaluated. METHODS:A single-blinded clinical trial with 21 PWH in prophylactic regimen was carried out. Participants were divided into an experimental group (EG, n = 11) and a control group (CG, n = 10). The EG underwent a 4-month programme of home-based therapeutic exercise plus CBT, whilst CG performed their daily activities. Patients were evaluated at baseline, post-intervention and after 12 additional weeks. Measures of functionality (Haemophilia Activities List, Timed Up and Go Test, 2-Minutes-Walking-Test and Sit-to-Stand Test), pain (PainDETECT and Visual Analogue Scale) and joint health (Haemophilia Joint Health Score) were taken. Related dimensions of the A36 Haemophilia Quality of Life Questionnaire were calculated. Effects were calculated using a two-factor ANOVA. RESULTS:The EG showed significant improvements in function (p < .001), pain (p < .001), joint damage (p = .006), and satisfaction with the treatment (p = .006) dimensions of the A36 Haemophilia Quality of Life Questionnaire, as well as in pain measured with the Visual Analogue Scale (p = .008) and PainDETECT (p = .035). CONCLUSIONS:The combined physiotherapy and CBT protocol showed a partial improvement in functionality, pain and joint health of PWH, arthropathy and chronic pain. In addition, participants were satisfied with the treatment.

ABSTRACTIntroductionMore than half of adult patients with severe haemophilia (PWH) suffer pain daily, with chronic pain (CP) in more than 15% of cases, thereby reducing their quality of life (QoL). However, there are no evidence‐based therapeutic guidelines for pain management.AimTo evaluate the effectiveness of a combined protocol based on psychology and physiotherapy in the improvement of CP self‐efficacy in PWH with CP. Secondary outcomes are changes in QoL, emotional status, pain and kinesiophobia.MethodsIn this prospective controlled trial study, recruited patients were allocated either to an experimental group (EG, n = 10) or to a control group (CG, n = 9). EG received interventions over four months: one cognitive‐behavioural therapy (CBT) session per month and three home exercise sessions per week.Self‐efficacy (Chronic Pain Self‐Efficacy Scale), QoL (A36 Hemophilia‐QoL), emotional status (Hospital Anxiety and Depression Scale and Rosenberg's Self‐esteem Scale), pain (Visual Analogue Scale) and kinesiophobia (Tampa Scale for Kinesiophobia) were assessed at three time points (Week 0, Month 4 and Month 7). The intervention effects were determined with mixed 2‐factor ANOVAs.ResultsThe EG showed a significant improvement (p < .05) in the control of symptoms and pain management scores on the Self‐Efficacy Scale, QoL, self‐esteem emotional status, pain and kinesiophobia. The intervention effects remained significant (p < .05) over time for pain management, QoL, pain and kinesiophobia.ConclusionThe non‐pharmacological treatment applied based on CBT and physiotherapy showed to be effective in improving CP self‐efficacy, QoL and emotional status, while reducing pain and kinesiophobia in PWH with CP.

INTRODUCTION:The Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) system and scoring scale has proven to be an accurate and time-efficient imaging method for identifying joint damage in patients with haemophilia. AIM:Observational, multicentre, cross-sectional study conducted in 8 centres in Spain that assessed the joint status of adult patients with severe haemophilia A (SHA) using HEAD-US. METHODS:Joint status of the elbow, knee and ankle was evaluated in adults with SHA receiving on-demand (OD) treatment, or primary (PP), secondary (SP), tertiary (TP) or intermittent (IP) prophylaxis. RESULTS:Of the 95 patients enrolled, 87 received prophylaxis (6.3% PP, 38.9% SP, 43.2% TP and 3.2% IP). Mean age was 35.2 years, and 59% of patients had not undergone image testing in the last year. The HEAD-US score was 0 in all joints in 6.3% of patients. The ankle was the most affected joint, regardless of treatment regimen. Patients receiving OD treatment, TP or IP had the overall worst scores, mainly in the ankles and elbows; a similar but milder profile was observed in patients on SP; and patients on PP had the best score in all joints. CONCLUSION:Joint function may be effectively preserved in patients with SHA on PP, but OD treatment or later initiation of prophylaxis does not seem to prevent progression of arthropathy. Disease worsening was observed in patients OD, TP or IP, most often affecting ankles and elbows. Closer ultrasound imaging monitoring may improve management of these patients.

Eccentric training has been associated with several specific physiological adaptations. The flywheel machine is one of the easiest ways of performing eccentric overload training. However, no studies evaluated its feasibility, safety and muscle activity in patients with haemophilia (PWH).

Introduction People with haemophilic arthropathy (PWHA) have impairments in postural control. However, little is known about the effects of demanding conditions, including the unipedal stance and dual tasks, on postural control in PWHA. Aim Determine the effects of performing dual tasks while in the one-leg stance on postural sway and postural control complexity in PWHA vs. healthy active (HAG) and non-active (HNAG) groups of individuals. Methods Fifteen PWHA and 34 healthy subjects (18 active and 16 non-active) were recruited. Vertical (V), mediolateral (ML) and anteroposterior (AP) centre of mass signals were acquired using a 3-axis accelerometer placed at the L3/L4 vertebrae of subjects as they performed the one-leg stance under single and dual-task conditions. Sway balance and the complexity of postural control were studied via root mean square (RMS) acceleration and sample entropy, respectively. Increased complexity of postural sway was attributed to increased automatism of postural control. Results RMS values for PWHA were higher than HAG under both conditions for the V and ML axes, and higher than HNAG under the dual-task condition for the ML axis. Sample entropy was lower in PWHA than healthy individuals under the dual-task condition for V and ML axes, and the single-task condition for the ML axis (P < .05). Conclusion PWHA had poorer postural sway and decreased postural control complexity when performing a one-leg stance than healthy people, especially when the dual-task condition was applied. These results may help to design new approaches to assess and improve postural control in PWHA.

Hemophilic arthropathy is the result of repetitive intra-articular bleeding and synovial inflammation. In people with hemophilic arthropathy (PWHA), very little is known about the neural control of individual muscles during movement. The aim of the present study was to assess if the neural control of individual muscles and coordination between antagonistic muscle pairs and joint kinematics during gait are affected in PWHA. Thirteen control subjects (CG) walked overground at their preferred and slow velocity (1 m/s), and 14 PWHA walked overground at the preferred velocity (1 m/s). Joint kinematics and temporal gait parameters were assessed using four inertial sensors. Surface electromyography (EMG) was collected from gluteus maximus (GMAX), gluteus medius (GMED), vastus medialis (VM), vastus lateralis (VL), rectus femoris (RF), medial gastrocnemius (MG), lateral gastrocnemius (LG), soleus (SOL), tibialis anterior (TA), semitendinosus (ST), and biceps femoris (BF). Waveforms were compared using the time-series analysis through statistical parametric mapping. In PWHA compared to CG, EMG amplitude during the stance phase was higher for LG (for both velocities of the CG), BF (slow velocity only), and ST (preferred velocity only) (p < 0.05). Co-contraction during the stance phase was higher for MG-TA, LG-TA, VL-BF, VM-ST, LG-VL, and MG-VM (both velocities) (p < 0.05). MG and LG were excited earlier (preferred velocity only) (p < 0.05). A later offset during the stance phase was found for VL, BF, and ST (both velocities), and BF and GMAX (preferred velocity only) (p < 0.05). In addition, the range of motion in knee and ankle joints was lower in PWHA (both velocities) and hip joint (preferred velocity only) (p < 0.05). In conclusion, the neural control of individual muscles and coordination between antagonistic muscles during gait in PWHA differs substantially from control subjects.

BACKGROUND Ankles and knees are commonly affected in people with hemophilia and thus are targets for prevention or rehabilitation. However, to our knowledge, no studies have evaluated muscle activity and safety during exercises targeting the lower limbs in people with hemophilia; this lack of information hinders clinical decision-making. OBJECTIVE The aim of this study was to compare the tolerability of, safety of, and muscle activity levels obtained with external resistance (elastic or machine)-based and non-external resistance-based lower limb exercises in people with hemophilia. DESIGN This was a cross-sectional study. METHODS Eleven people who had severe hemophilia and were undergoing prophylactic treatment participated. In a single experimental session, participants performed knee extension and ankle plantar flexion during 3 exercise conditions in random order: elastic band-based resistance (elastic resistance), machine-based resistance (machine resistance), and no external resistance. Exercise intensities for the 2 external resistance-based conditions were matched for perceived exertion. Muscle activity was determined using surface electromyography (EMG) for the rectus femoris, biceps femoris, gastrocnemius lateralis, and tibialis anterior muscles. Participants were asked to rate exercise tolerability according to a scale ranging from "very well tolerated" to "not tolerated" and to report possible adverse effects 24 and 48 hours after the session. RESULTS No adverse effects were reported, and exercise tolerability was generally high. In the knee extension exercise, the rectus femoris normalized EMG values during the elastic resistance and machine resistance conditions were similar; 29% to 30% higher activity was obtained during these conditions than during the non-external resistance condition. In the ankle plantar flexion exercise, the gastrocnemius lateralis normalized EMG value was 34% higher during the machine resistance condition than without external resistance, and the normalized EMG values during the elastic resistance and other conditions were similar. LIMITATIONS The small sample size and single training session were the primary limitations of this study. CONCLUSIONS Exercises performed both with elastic bands and with machines at moderate intensity are safe, feasible, and efficient in people with severe hemophilia, providing comparable activity levels in the agonist muscles.

Objective Strength training is recommended for people with hemophilia; however, published data are anecdotal and have methodological limitations. The purpose of this study was to evaluate the safety and effectiveness of progressive moderate-to-vigorous intensity elastic resistance training on physical function and pain in this patient population. Methods A randomized controlled trial was conducted in a university laboratory setting where 20 patients (17 with severe, 1 with moderate, and 2 with mild hemophilia) aged 21 to 53 years received evaluations at baseline and 8-week follow-up. Participants were allocated to intervention (progressive strength training) or control (usual daily activities) groups. The intervention group trained 2 days per week during 8 weeks with elastic resistance. Intensity during the first 2 weeks was a 20-repetition maximum and increased progressively toward 15, 12, and finally 10 repetition maximum. The primary outcome was muscle strength. Secondary outcomes were the Timed “Up and Go” Test score, sit-to-stand, range of motion, Haemophilia Joint Health Score, kinesiophobia score, global impression of pain change, general self-rated health status, and desire to exercise. Results The intervention group showed greater strength improvements than the control group in almost all of the joints, with moderate to high effect sizes. The intervention group also showed better Timed “Up and Go” and sit-to-stand scores than the control group (moderate effect size), greater range of motion at the knee flexion with the right leg (trivial effect size), and better Haemophilia Joint Health Score at the left knee (small effect size). The intervention group showed greater overall pain reduction, self-rated overall status, and desire to exercise than the control group. Conclusions Progressive strength training with elastic resistance performed twice a week during 8 weeks is safe and effective in people with hemophilia to improve muscle strength and functional capacity, reduce general pain, and improve self-rated health status and desire to exercise. Impact This study provides evidence for the use of a specific strength training regimen for people with hemophilia. Lay Summary People with hemophilia of differing levels of severity, with adequate coverage with clotting factor, can safely engage in progressive strength training and can improve their functioning.

AIM:The objective of this survey was to understand the global trends of imaging assessments in persons with haemophilia, focusing on point-of-care ultrasound (POCUS). Insights into the barriers impeding its widespread proliferation as a frontline imaging modality were obtained.METHODS:The survey opened in September of 2017 and closed in May of 2018. Haemophilia Treatment Centres (HTCs) treating both paediatric/adult patients were the population of interest. A REDCap survey of 25 questions was disseminated to 232 clinical staff in 26 countries.RESULTS:The majority of respondents (88.3%, 91/103) reported that POCUS is most useful to confirm or rule out a presumed acute joint bleed. European HTCs reported the highest routine use of POCUS at 59.5% (22/37) followed by HTCs in the "Other" countries of the world at 46.7% (7/15) and North American HTCs at 43.9% (25/57). At the time of the survey, physiotherapists were identified as the clinical staff who perform POCUS 52.8% (28/53) of the time, in contrast with nurses/nurse practitioners who represent only 5.7% (3/53) of users. The greatest perceived barriers to the implementation of POCUS are the lack of trained healthcare professionals who can perform POCUS at 69.2% (74/107) and the overall time commitment required at 68.2% (73/107).CONCLUSION:Despite POCUS being used in 49.5% (54/109) of sampled HTCs, it is still utilized almost 30% less globally than full diagnostic ultrasound. A list of barriers has been identified to inform HTCs which challenges they will likely need to overcome should they choose to incorporate this imaging modality into their practice.

The purpose of this study was to develop a tool able to distinguish between subjects who have haemophilic arthropathy in lower limbs and those who do not by analyzing the centre of pressure displacement. The second objective was to assess the possible different responses of haemophiliacs and healthy subjects by creating a classifier that could distinguish between both groups. Fifty-four haemophilic patients (28 with and 26 without arthropathy) and 23 healthy subjects took part voluntarily in the study. A force plate was used to measure postural stability. A total of 276 centre of pressure displacement parameters were calculated under different conditions: unipedal/bipedal balance with eyes open/closed. These parameters were used to design a Quadratic Discriminant Analysis classifier. The arthropathy versus non-arthropathy classifier had an overall accuracy of 97.5% when only 10 features were used in its design. Similarly, the haemophiliac versus non-haemophiliac classifier had an overall accuracy of 97.2% when only 7 features were used. In conclusion, an objective haemophilic arthropathy in lower limbs evaluation system was developed by analyzing centre of pressure displacement signals. The haemophiliac vs. non-haemophiliac classifier designed was also able to corroborate the existing differences in postural control between haemophilic patients (with and without arthropathy) and healthy subjects.

Dear Editor, The appropriate management of patients with inhibitors represents the main challenge for physicians who specialize in haemophilia. Immune tolerance induction (ITI) is the primary therapeutic strategy for achieving inhibitor eradication.1 ITI represents an intensive and continuous exposure to FVIII until a patient gains complete or partial tolerance against the factor. To contribute to the data from an experienced centre in managing haemophilic patients, the present mixed retrospective and prospective study was aimed to analyse the association between the ITI success rate with a series of clinical variables. The medical records of severe haemophilia A patients from a Congenital Coagulopathies Unit, who started an ITI regimen between March 1980 and July 2015, were reviewed. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. Eligible subjects included both children and adults diagnosed with severe haemophilia A (FVIII:C <1%) and treated for primary or rescue ITI with plasma-derived FVIII concentrates (pdFVIII), either purified FVIII or von Willebrand factor (VWF)-containing (pdFVIII/VWF), or with recombinant (rFVIII) concentrates. Rescue ITI was defined as the ITI treatments undergone after failure of the primary ITI course. The definitions of ITI success and failure were generally consistent with those currently in use.1 The time to outcome was measured from initiation of ITI until achievement of success (complete or partial), failure or rescue ITI. The decision of whether ITI was a failure, or to continue ITI treatment longer, was made according to the physician's discretion. For pharmacokinetic measurements, after 3 days of infused FVIII washing, FVIII:C levels were determined (“pre”). Then, 50 IU/kg FVIII was administered and FVIII:C was determined again after 15 minutes (“post”), 1, 2, 6, 24 and 48 hours (although last 7 years, measurements were taken at three time points: pre, post and 48 hours). For association analyses, a L1-penalized logistic regression model, LASSO (Least Absolute Shrinkage and Selection Operator), was used. Those variables not penalized to zero were considered as being associated with ITI success. Peak titre was log-transformed before the analyses because of its high right skewness. The use of penalized models is required in cases such as in this study, in which the number of variables was high in relation to the number of assessments. Kaplan-Meier survival analysis was constructed for the time elapsed in the percentage of patients: (a) reaching inhibitor elimination; (b) reaching a normal FVIII recovery and (c) reaching a normal half-life of infused FVIII. Discrimination by infused FVIII dose (<100 IU/kg/d; ≥100 IU/kg/d) was also made. The generalized Wilcoxon test was used for comparison. Software R (The R Foundation, Vienna, Austria) version 3.2.1 was used for calculations and analysis. Results showed that 26 patients started an ITI course during the study period. Of these, three patients are still under treatment while 23 ended primary ITI and were therefore evaluated. Data collected were retrospective in patients who started ITI up to year 2000 (n = 11) and prospective after that year (n = 12 patients). Details of patient characteristics and ITI data are shown in Table 1. Just over half of the patients (n = 13; 57%) started ITI within 1 year after inhibitor diagnostic (47% of complete success [CS]), while in nine patients (39%) the lapse took between 1 and 5 years, and one patient showed an extreme value of 11 years. Eighteen patients (78%) were <5 years old at the time of ITI initiation (50% of CS). The majority of the patients (n = 18; 78%) showed an inhibitor titre <10 BU/mL at start of ITI (55% of CS) but five of them had titre ≥10 BU/mL (60% of CS). Overall, primary ITI success was 57% (13/23 patients), which was lower than that shown in previous studies ranging 63%-100%.2-7 A possible reason may be the inclusion of all screened patients in the study, thus mimicking a group with intention of treatment, which has shown a lower success rate. Similarly, premature changes of product type or dose regimen in some patients as well as the high historical inhibitor peak titre in our population could have a role in reducing the chances of success. Nevertheless, less strict criteria than ours for reporting an outcome of successful ITI have been described in other studies6, 8 and in a registry.9 The median time of ITI treatment was 11.4 months (Q1, Q3: 9, 24). Fourteen patients (61%) received pdFVIII (13 pdFVIII/VWF and 1 purified FVIII) for ITI. There was a higher rate of CS in patients treated with pdFVIII (10/14; 71%) rather than those treated with rFVIII (3/9; 33%). Interestingly, the percentage of patients with at least one risk factor for poor response to ITI10 was higher in those pdFVIII-treated than in rFVIII-treated (64%, 9/14 vs 33%, 3/9, respectively), as seen in Table 1. FVIII dosage was <100 IU/kg/d in 17 patients, 10 of them treated with pdFVIII (71%) and seven treated with rFVIII (78%). CS was reached in 8/17 (47%) patients treated with a dose <100 IU/kg/d, and in 5/6 (83%) patients treated with a dose ≥100 IU/kg/d. The FVIII infusion with a central venous catheter (CVC) was performed in 30% (n = 7) of the patients and almost all of them (6/7; 86%) suffered infection episodes. Haemorrhagic episodes during ITI were common (n = 20; 80%) and recurrent (median: 3; Q1, Q3: 1.5, 13) among all patients. Of those, 26% (n = 6) used a bypassing agent as prophylaxis. Those patients with a FVIII daily dose ≥100 IU/kg showed the lowest number of haemorrhagic episodes (median: 1.5; Q1, Q3: 1, 3). Eight patients (35%) received concomitant medication, and all of them achieved CS. Immunomodulatory agents were the most frequently prescribed (Table 1). Rescue ITI was performed with pdFVIII/VWF in almost all failure patients (8/10) after an initial failure, although data from one patient were not available for analysis due to withdrawal after ITI initiation (Table 1). All rescue patients were children (<9 years old) who required between two and five rescue ITI courses to achieve CS (3/7; 43%) or partial success (PS) (2/7; 29%). Results of the two remaining patients were not considered in the success calculation, as their treatment was unfinished by the end of the study. Remarkably, the overall success rate, after primary or rescue ITI, was 86% (n = 18/21) despite several subjects had factors for poor response to ITI as reported in registries.5, 9 Statistical analysis by LASSO regression reported three variables to be associated with the probability of ITI success. Two variables showed a negative association: infusion of rFVIII (odds ratio [OR] = 0.51) and inhibitor peak titre during ITI (OR = 0.88; Figure 1). The third variable associated with outcome was pdFVIII/VWF infusion although the effect was clinically negligible (7 × 10−14). However, the estimation for this variable was affected by the fact that only one patient out of the 14 patients receiving pdFVIII concentrate did not receive pdFVIII/VWF. The inverse relation of ITI success rate and the inhibitor peak titre during ITI is supported by the results of other reports.2, 9, 11 However, our study did not find a relationship between ITI success and the historical peak titre, nor the titre at ITI start, as previously reported.3, 6, 9, 12 The effect of the type of concentrate infused was also highlighted by LASSO. A better outcome resulted in patients treated with pdFVIII rather than rFVIII, consistent with previous publications.13, 14 However, there is some controversy because the use of rFVIII with a good success rate has also been described.8, 15 Nevertheless, in all cases, comparisons should be made with caution due to the differences in methodologies, protocols and outcome criteria. The use of pdFVIII/VWF has been reported to improve ITI success.7, 11 Although in our study the LASSO analysis yielded an extremely small effect associated with pdFVIII/VWF, such statistical effect could not be quantified with accuracy because only one patient out of 14 was not infused with pdFVIII/VWF. The FVIII dosages given in this study did not influence the ITI outcome. Personalized doses were used, depending on the peak titre of each patient, similar to the procedures applied by other groups.12 The Kaplan-Meier analysis showed no statistically significant differences in time to success when comparing the two dose groups established (<100 IU/kg/d; ≥100 IU/kg/d). Other parameters described to may influence ITI outcome but not found in our patient series were as follows: type of mutation, age at ITI start, delay from inhibitor detection of ITI start and infection of the CVC.5, 9 Although the cohort of patients recruited was relatively small and almost half of the patient data were retrospective, which could be considered a study limitation, it is a real-world study; the fact that patients were unselected and all data came from a single centre with consistent routine procedures for more than 20 years confers robustness and homogeneity to the data. In conclusion, in this study, a high ITI success rate of 86% was found in severe haemophilia A patients from a single centre who were screened over a 25-year period. Moreover, low inhibitor titre peak during ITI and the infusion of pdFVIII were found to be predictors of a higher ITI success rate. Jordi Bozzo PhD, CMPP (Grifols) is acknowledged for medical writing and editorial support in the preparation of the manuscript, under the direction of the authors. Grifols is a manufacturer of plasmatic FVIII/VWF concentrate. SH has given lectures at educational symposiums organized by Novo Nordisk, Pfizer, Grifols and Baxter; Advisory boards from Shire. CS has given lectures at educational symposiums organized by Pfizer, Roche, Merck and Astellas. ARC has given lectures at educational symposiums organized by Novo Nordisk, Pfizer, Grifols and Baxter. FQ has received grants from Baxter, Bayer, Pfizer and Novonordis; has given lectures at educational symposiums organized by Novo Nordisk, Pfizer, Baxter and Shire. SB has given lectures at educational symposiums organized by Novo Nordisk, Pfizer, Grifols, Bayer, Roche, LFB, Octapharma, Shire, SOBI and CSL Behring; Advisory boards from Pfizer, Bayer, Roche, Shire, LFB, SOBI and CSL Behring. BA, DH, and PC declare no conflict of interests. SH designed the research study, performed the research, recruited the patients and wrote the paper; CS and PC designed the research study and supervised the study; ARC, BA, FQ and SB recruited the patients; and DH analysed the data. All authors read and approved the final manuscript.

HaemophiliaVolume 25, Issue 3 p. e215-e218 LETTER TO THE EDITOR Cross-sectional comparative study of pharmacokinetics and efficacy between sucrose-formulated recombinant factor VIII (Kogenate®) and BAY 81-8973 (Kovaltry®) in patients with severe or moderate haemophilia A in prophylaxis Juan Eduardo Megías-Vericat, Corresponding Author Juan Eduardo Megías-Vericat megias_jua@gva.es orcid.org/0000-0002-0369-5341 Pharmacy Department, Drug Clinical Area, Hospital Universitari i Politècnic La Fe, Valencia, Spain Haemostasis and Thrombosis Unit, Hospital Universitari i Politècnic La Fe, Valencia, Spain Correspondence Juan Eduardo Megías-Vericat, Pharmacy Department, Drug Clinical Area, Hospital Universitari i Politècnic La Fe, Valencia, Spain. Email: megias_jua@gva.esSearch for more papers by this authorSantiago Bonanad, Santiago Bonanad Haemostasis and Thrombosis Unit, Hospital Universitari i Politècnic La Fe, Valencia, SpainSearch for more papers by this authorSaturnino Haya, Saturnino Haya Haemostasis and Thrombosis Unit, Hospital Universitari i Politècnic La Fe, Valencia, SpainSearch for more papers by this authorAna Rosa Cid, Ana Rosa Cid Haemostasis and Thrombosis Unit, Hospital Universitari i Politècnic La Fe, Valencia, SpainSearch for more papers by this authorMaría Remedios Marqués, María Remedios Marqués Pharmacy Department, Drug Clinical Area, Hospital Universitari i Politècnic La Fe, Valencia, SpainSearch for more papers by this authorEmilio Monte-Boquet, Emilio Monte-Boquet Pharmacy Department, Drug Clinical Area, Hospital Universitari i Politècnic La Fe, Valencia, SpainSearch for more papers by this authorSofía Pérez-Alenda, Sofía Pérez-Alenda orcid.org/0000-0002-0841-5767 Haemostasis and Thrombosis Unit, Hospital Universitari i Politècnic La Fe, Valencia, Spain Department of Physiotherapy, University of Valencia, Valencia, SpainSearch for more papers by this authorPau Bosch, Pau Bosch Haemostasis and Thrombosis Unit, Hospital Universitari i Politècnic La Fe, Valencia, SpainSearch for more papers by this authorFelipe Querol, Felipe Querol Haemostasis and Thrombosis Unit, Hospital Universitari i Politècnic La Fe, Valencia, Spain Department of Physiotherapy, University of Valencia, Valencia, SpainSearch for more papers by this authorJosé Luis Poveda, José Luis Poveda Pharmacy Department, Drug Clinical Area, Hospital Universitari i Politècnic La Fe, Valencia, SpainSearch for more papers by this author Juan Eduardo Megías-Vericat, Corresponding Author Juan Eduardo Megías-Vericat megias_jua@gva.es orcid.org/0000-0002-0369-5341 Pharmacy Department, Drug Clinical Area, Hospital Universitari i Politècnic La Fe, Valencia, Spain Haemostasis and Thrombosis Unit, Hospital Universitari i Politècnic La Fe, Valencia, Spain Correspondence Juan Eduardo Megías-Vericat, Pharmacy Department, Drug Clinical Area, Hospital Universitari i Politècnic La Fe, Valencia, Spain. Email: megias_jua@gva.esSearch for more papers by this authorSantiago Bonanad, Santiago Bonanad Haemostasis and Thrombosis Unit, Hospital Universitari i Politècnic La Fe, Valencia, SpainSearch for more papers by this authorSaturnino Haya, Saturnino Haya Haemostasis and Thrombosis Unit, Hospital Universitari i Politècnic La Fe, Valencia, SpainSearch for more papers by this authorAna Rosa Cid, Ana Rosa Cid Haemostasis and Thrombosis Unit, Hospital Universitari i Politècnic La Fe, Valencia, SpainSearch for more papers by this authorMaría Remedios Marqués, María Remedios Marqués Pharmacy Department, Drug Clinical Area, Hospital Universitari i Politècnic La Fe, Valencia, SpainSearch for more papers by this authorEmilio Monte-Boquet, Emilio Monte-Boquet Pharmacy Department, Drug Clinical Area, Hospital Universitari i Politècnic La Fe, Valencia, SpainSearch for more papers by this authorSofía Pérez-Alenda, Sofía Pérez-Alenda orcid.org/0000-0002-0841-5767 Haemostasis and Thrombosis Unit, Hospital Universitari i Politècnic La Fe, Valencia, Spain Department of Physiotherapy, University of Valencia, Valencia, SpainSearch for more papers by this authorPau Bosch, Pau Bosch Haemostasis and Thrombosis Unit, Hospital Universitari i Politècnic La Fe, Valencia, SpainSearch for more papers by this authorFelipe Querol, Felipe Querol Haemostasis and Thrombosis Unit, Hospital Universitari i Politècnic La Fe, Valencia, Spain Department of Physiotherapy, University of Valencia, Valencia, SpainSearch for more papers by this authorJosé Luis Poveda, José Luis Poveda Pharmacy Department, Drug Clinical Area, Hospital Universitari i Politècnic La Fe, Valencia, SpainSearch for more papers by this author First published: 13 March 2019 https://doi.org/10.1111/hae.13733Citations: 6Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume25, Issue3May 2019Pages e215-e218 RelatedInformation

Introduction The joint range of motion (ROM) is an important clinical parameter used to assess the loss of functionality resulting from joint bleedings in people with haemophilia. These episodes require a close follow-up and, to decrease patients' hospital dependence, telemedicine tools are needed. Therefore, this study is aimed to analyse the validity of the Microsoft Kinect V2 sensor with corrected angle measurement to be used in the monitoring of elbow ROM in people with haemophilia. Methods A convenience sample of 10 healthy controls (CG) and 10 patients with haemophilia with elbow arthropathy (HG) participated in this study. Full ROM of elbow joints was measured in the frontal view with a 10-degree sweep using: (a) a clinical goniometer; (b) the Kinect V2; (c) the Kinect V2 with angle correction; and (d) using a photograph. Bland-Altman graphs (mean and 95% Limits of Agreement [LOA]) and Wilcoxon test were used to determine differences between measurements and groups. Results The angle-corrected Kinect V2 measurement removed the skew in the original data, reducing the average errors from 7.9 degrees (LoA = -10.3 degrees; 26.0 degrees; CG) and 9.5 degrees (LoA = -7.9 degrees; 26.9 degrees; HG) to -0.1 degrees (LoA = -8.1 degrees; 7.9 degrees; CG) and -0.7 degrees (LoA = -10.7 degrees; 9.3 degrees; HG). Conclusions These error levels allow the use of Kinect V2 in the clinical practice. Kinect V2 with angle correction can complement the classical goniometry allowing an efficient and touchless measurement of ROM.

HaemophiliaVolume 25, Issue 1 p. e27-e29 LETTER TO THE EDITOR Assessment of tensile mechanical properties of the Achilles tendon in adult patients with haemophilic arthropathy. Reproducibility study Carlos Cruz-Montecinos, Corresponding Author Carlos Cruz-Montecinos carloscruz@uchile.cl orcid.org/0000-0002-3835-3368 Department of Physical Therapy, Laboratory of Clinical Biomechanics, Faculty of Medicine, University of Chile, Santiago, Chile Laboratory of Biomechanics, Hospital San José, Santiago, Chile Department of Physiotherapy, University of Valencia, Valencia, Spain Correspondence Carlos Cruz-Montecinos, Department of Physical Therapy, Laboratory of Clinical Biomechanics, Faculty of Medicine, University of Chile, Santiago, Chile. Email: carloscruz@uchile.clSearch for more papers by this authorSofía Pérez-Alenda, Sofía Pérez-Alenda orcid.org/0000-0002-0841-5767 Department of Physiotherapy, University of Valencia, Valencia, SpainSearch for more papers by this authorFelipe Contreras-Sepúlveda, Felipe Contreras-Sepúlveda Chilean Society of Hemophilia, Santiago, ChileSearch for more papers by this authorFelipe Querol, Felipe Querol Department of Physiotherapy, University of Valencia, Valencia, SpainSearch for more papers by this authorMauricio Cerda, Mauricio Cerda orcid.org/0000-0003-3447-1815 Anatomy and Developmental Biology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, ChileSearch for more papers by this authorHuub Maas, Huub Maas orcid.org/0000-0002-2304-2735 Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam, The NetherlandsSearch for more papers by this author Carlos Cruz-Montecinos, Corresponding Author Carlos Cruz-Montecinos carloscruz@uchile.cl orcid.org/0000-0002-3835-3368 Department of Physical Therapy, Laboratory of Clinical Biomechanics, Faculty of Medicine, University of Chile, Santiago, Chile Laboratory of Biomechanics, Hospital San José, Santiago, Chile Department of Physiotherapy, University of Valencia, Valencia, Spain Correspondence Carlos Cruz-Montecinos, Department of Physical Therapy, Laboratory of Clinical Biomechanics, Faculty of Medicine, University of Chile, Santiago, Chile. Email: carloscruz@uchile.clSearch for more papers by this authorSofía Pérez-Alenda, Sofía Pérez-Alenda orcid.org/0000-0002-0841-5767 Department of Physiotherapy, University of Valencia, Valencia, SpainSearch for more papers by this authorFelipe Contreras-Sepúlveda, Felipe Contreras-Sepúlveda Chilean Society of Hemophilia, Santiago, ChileSearch for more papers by this authorFelipe Querol, Felipe Querol Department of Physiotherapy, University of Valencia, Valencia, SpainSearch for more papers by this authorMauricio Cerda, Mauricio Cerda orcid.org/0000-0003-3447-1815 Anatomy and Developmental Biology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, ChileSearch for more papers by this authorHuub Maas, Huub Maas orcid.org/0000-0002-2304-2735 Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam, The NetherlandsSearch for more papers by this author First published: 30 October 2018 https://doi.org/10.1111/hae.13622Citations: 2Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume25, Issue1January 2019Pages e27-e29 RelatedInformation

Hemophilia is currently a relatively well known disorder to the general population and, naturally, to healthcare providers. Although the condition is still a rare, difficult-to-treat-and-diagnose disorder, there is enough readily available information for healthcare providers to be able to act in a judicious manner [1]. The World Federation of Hemophilia, as well as different patient federations and associations from all over the world, publish guidelines as well as general and more specific treatment recommendations. For the purposes of this article, it is important to focus on the recommendations addressed to patients and their family members, as the prevention of the sequelae of hemophilia, that is the repeated lesions experienced by the patients, requires active patient collaboration and an awareness of the available prophylaxis treatments and of the basic care programs for acute lesions [1]. A sequela is defined as a disorder that persists following recovery from a disease or an injury, in our case of a hemorrhagic nature. Sequelae may result in more or less severe symptoms, among them pain, sensory alterations, limited mobility, loss of strength and, naturally, disability, which is the most common complication. Starting with the basics, hemophilia is defined as a congenital x chromosome-linked hemorrhagic disorder, that is it is transmitted by women and it is suffered by men. The most frequent bleeds, which are responsible for the functional sequelae of the disease, tend to occur within the musculoskeletal system [2]. The first clinical manifestations of the disease are superficial hematomas, which usually appear during early childhood. But it is at the beginning of the crawling and toddling stages that patients with severe hemophilia start experiencing muscular and intra-articular bleeds, even if they have participated in coagulation factor replacement programs. It is these bleeding events that cause dysfunction and damage key structures (Fig. 1), and which may progressively result in arthropathy, the main disabling and gradually incapacitating sequela of hemophilia.Fig. 1: Hematoma in a patient with hemophilia.A description of the main lesions and a summary of their distinguishing features are included in the sections below. A characterization of their functional sequelae and of the way to diagnose them is also presented. Hematomas A hematoma is defined as a localized collection of blood in the body's tissues. Hematomas are classified into superficial and deep (muscle hematomas) [3,4]. Muscle hematomas are apt to cause problems that may eventually bring about sequelae, depending on their severity, size, location and depth, proximity to the bone (Fig. 2).Fig. 2: Muscular hematoma near the bone (open arrows).Bleeding into a muscle usually leads to a deterioration of the muscle's structure and may give rise to fibrotic scar formation, which weakens the muscle, alters joint motion and is a likely source of pain. In the acute phase, hematomas may cause paralysis of the involved segment. Lastly, proximity of the hematoma to the bone cortex poses a risk of skeletal involvement and of a hemophilic pseudotumor, which could have disastrous consequences and more often than not result in severe sequelae such as limb amputation. Particularly severe hematomas include those affecting the psoas, gastrocnemius and forearm muscles (Volkmann's contracture) [1]. Hemarthrosis Hemarthrosis is defined as the presence of intra-articular bleeding resulting from some kind of trauma [5]. The bleeding could even go unnoticed by the patient. Although diagnosis is fundamentally symptomatic, ultrasound can at present provide objective confirmation (Fig. 3).Fig. 3: Knee hemarthrosis (left image) and ultrasound (right image) showing an effusion (black anechoic space) and synovial alteration (structure inside the effusion).Acutely hemarthrosis causes inflammation, pain, antalgic gait, impaired range of motion and loss of strength. Treatment, which must be provided as soon as possible, consists in factor replacement therapy, immobilization and cold application [2]. Even one single hemarthrosis may cause synovitis and cartilage damage and result in severe hemophilic arthropathy, which can completely destroy the joint, severely restrict its function and have a disabling effect on the patient. Synovitis An intra-articular bleeding episode invariably results in an acute synovial alteration. In response to the presence of blood, vascularization of the subsynovial plexus is increased to facilitate absorption of the effusion, which leads to an initially temporary hypertrophy that could result in hyperplasia with multiplication of the synovial villi (Fig. 4). This, in turn, could modify cartilage nutrition and trigger the well known hemorrhage-synovitis-mechanical dysfunction-hemorrhage vicious circle [6].Fig. 4: Clinical and ultrasound image of a vascularized synovitis responsible for the increased risk of bleeding.Chronic synovitis is a sequela that could increase the patient's bleeding rate in spite of prophylactic factor replacement therapy. It also causes pain (at certain positions of the joint), which limits range of motion, causes swelling, reduces muscle strength, disrupts propioception and impairs function (gait, running, jumping etc.). Hemophilic arthropathy Hemophilic arthropathy is defined as the progressive destruction of a joint resulting from repetitive bleeding. At first, hemarthrosis causes distension of the capsule, synovial inflammation and altered chondrocyte differentiation, which is the first structural sequela of a bleeding event. Subsequently, alterations may appear in the bony epiphyses as a result of soft tissue hyperemia, disuse osteoporosis and cartilage degeneration. Progressive alterations of the subchondral bone, such as the development of erosions and cysts, are also observed. The final stage comprises the destruction of the joint with a loss of bone alignment [7]. All of these signs can be evaluated using the Pettersson score [8] (Table 1).Table 1: Radiologic evaluation of joints: recommended by Advisory Committee of World Federation of HemophiliaThe sequelae that characterize each stage of the disease elicit clinical manifestations of increasing severity, all of them associated with pain, restricted mobility, loss of strength and, in short, a dysfunction that hinders performance of the activities of daily living and decreases quality of life. Functional alterations and sequelae in the most frequently involved joints in patients with hemophilia. Assessment of bodily damage: upper limbs (elbow) and lower limbs (knee and ankle). There is no universally agreed elbow score to assess elbow joint injuries and their sequelae. All we have is a series of different elbow scores typically used to evaluate the sequelae arising from car accidents. However, all such scores focus on function and consider four items: pain (mild, moderate, severe), range of motion (active range ≥100°, active range 50–<100°, active range <20°); stability (stable, moderate instability, frank instability); activities of daily living (combing oneself, eating, personal hygiene, getting dressed, putting on one's shoes). At the same time, an analysis of the function of the upper limbs also looks at whether the lesion affects the dominant side or not (right/left). Dexterity in the performance of any activity will depend on the side affected by the lesion. For example, for right-handed persons, limited range of motion of the right elbow may hinder personal hygiene and driving a left-hand drive car. The American Medical Association has published guidelines to assess permanent disabilities. In Spain, IMSERSO (National Institute for Social Services) has published scales that can be used to establish disability levels. The elbow functional unit accounts for 70% of upper extremity function. As far as mobility is concerned, flexion–extension represents 60% and pronosupination accounts for 40%. It is not difficult to imagine the degree of disability caused by impaired elbow mobility for such basic activities as personal hygiene (reaching the different parts of the body); getting food to the mouth (in the presence of limited elbow flexion); and sticking into and cutting food (when pronosupination is disturbed). Performance of multiple activities of daily living is usually impacted by the loss of lower upper mobility [9]. As mentioned above, sensory and pain-related deficiencies are also evaluated, which requires identification of the dermatomic area. Alterations of muscle forces around the elbow also result in obvious disability. The score used to evaluate muscle forces around joints is similar to the well known Hemophilia Joint Health Score (HJHS) used for symptomatic evaluation of hemophilic patients [10]. The scale assigns 0–4 points, in which 4 denotes the greatest severity, that is absence of muscle contraction. Kendall's and Daniels and Wortingham's scales, which are the most frequently used by rehabilitators and physical therapists, assign up to 5 points and, unlike the HJHS score, the higher the score the less severe the disability. As in the upper limb, anatomic and functional methods are used to evaluate permanent impairment (sequelae) of the lower limb. In addition to the four indicators used by elbow scores, knee and ankle scores take into account axial deviations (varus, valgus) and length discrepancies. Moreover, these knee and ankle lesions may – and do – affect the hip and the spine giving rise to pain in those structures, which may be exacerbated by the dysfunction itself. Alterations in the standing posture as well as in balance and gait are the sequelae that most severely affect the activities of daily living. The different scores used for clinically evaluating hemophilic arthropathy, including HJHS, also contemplate gait disturbances. In countries where factor replacement therapy is available, the ultimate goal should be that of zero bleeds. Nonetheless, as nobody is immune to accidental trauma and therefore to musculoskeletal injury, and even injury to the central nervous system, the acute and chronic disorders caused by hemophilia are inescapable and are usually associated with the need of rehabilitation and physical therapy. Age-related degenerative processes are inescapable and deteriorate a person's physical condition, inevitably causing disability. Appropriate care of patients with coagulopathies will probably require measures such as specific hematologic care and, undoubtedly, physical therapy. Acknowledgements Conflicts of interest There are no conflicts of interest.