Haemophilic arthropathy: basic protocols for clinical examination and imaging.

In haemophilia, screening protocols in the prevention and treatment of common lesions still require unification of criteria. Patients with haemophilia seek medical consultation exclusively for two reasons: because they have requested an appointment for a routine check-up (1-2 times a year in case of severe haemophilia) or because they have developed acute bleeding that requires treatment. The purpose of this paper is to emphasize the importance of an early differential diagnosis of joint damage and to review the techniques that allow an effective evaluation. The World Federation of Haemophilia recommends the 'Primary Prophylaxis' treatment modality, and today, severe haemophilia patients adhering to that factor VIII/IX therapy have significantly reduced common injuries: haematomas, haemarthrosis, synovitis, and haemophilic arthropathy. The basic protocols and minimum data for the control of musculoskeletal health are described. In summary, the primary goal of the haematologist-led multidisciplinary care team treating patients with haemophilia is likely to restore and/or preserve joint and musculoskeletal health, which is essential to promoting quality of life. Appropriate factor replacement regimens are required to prevent bleeding, these should be combined with physical activity and a physiotherapy program, in accordance with the recommendations of the World Health Organization for the general population.

Bayesian pharmacokinetic-guided prophylaxis with recombinant factor VIII in severe or moderate haemophilia A.

INTRODUCTION: Personalised pharmacokinetics (PK) using Bayesian analysis with limited sampling is assumed to help to optimise prophylaxis in haemophilia A (HA) patients. MATERIALS AND METHODS: Our prospective, observational study analysed the influence of PK parameters on clinical variables (bleeding rates, joint status, adherence, and consumption) using myPKFiT® in a cohort of twenty-one severe and moderate HA patients on prophylaxis with recombinant FVIII (Advate®) in two periods of one year, the first before PK-based tailoring and the second after PK-guided prophylaxis. Intra-individual and inter-individual coefficients of variation (CV) of half-life (t1/2) were calculated. RESULTS: A total of 73 PK estimations were performed in both periods, resulting in 17.2% inter-individual CV in mean t1/2, and 4.9% intra-individual CV. Before PK-based tailoring a significant association between joint bleeds and t1/2 was found (P = 0.010), especially in patients with short t1/2. This finding was reproduced (P = 0.013) after withdrawal of two patients with bleeding phenotype related to their advanced arthropathy but normal t1/2 and trough levels. Patients with joint bleeds weighed less (P = 0.039) and required higher doses (P = 0.032) than patients with zero joint bleeds. These associations were not observed in the second period after the adoption of PK-guided prophylaxis. There were no differences between the two periods, although a tendency to fewer spontaneous bleeds was suggested after PK-based tailoring. CONCLUSIONS: PK-guided prophylaxis facilitates an adequate level of bleeding control in patients with HA, maintaining clinical variables and patient convenience in an integrative manner, without increasing FVIII consumption.

Effect of radiosynoviorthesis on the progression of arthropathy and haemarthrosis reduction in haemophilic patients.

INTRODUCTION: Repeated haemarthrosis is widely accepted as the triggering cause of synovitis and haemophilic arthropathy. A first-line treatment of chronic synovitis is radiosynoviorthesis (RS). The aim of this study was to evaluate the RS effects on the progression of arthropathy and on a reduction in bleeding in patients with haemophilia. METHODS: An observational-retrospective study was performed. Bleeding episodes in the 12 months following and in the 12 months preceding RS was compared. The arthropathy was clinically and radiologically analysed by age range, joint and subject, comparing those undergoing RS (Radiosynoviorthesis Group, RSG) against those not undergoing this treatment (Non-Radiosynoviorthesis Group, Non-RSG). RESULTS: One hundred and seventy-four RS were performed in 71 patients (90 Y in Knees and 186 Re in elbows/ankles/shoulder). RS resulted in significant reduction in bleeding (582 preintervention and 168 postintervention, P < .001). In general, the level of arthropathy measured clinically and radiologically was greater with age increase in both groups (RSG and Non-RSG), especially in the 25-40 age range. A significant increase (P < .05) in the progression of arthropathy was also observed, both globally by patient and specifically for each joint, in non-RSG and RSG group. CONCLUSION: RS is an effective method to reduce the number of haemarthrosis episodes in chronic synovitis. Moreover, RS can positively affect arthropathy by slowing down its progression. However, the results obtained suggest that arthropathy may be conditioned by the subject's age, regardless of whether or not the joint has undergone RS.

Sensory strategies of postural sway during quiet stance in patients with haemophilic arthropathy.

INTRODUCTION: The sensory strategies of postural control in adult haemophilic arthropathy patients are still poorly understood. AIM: To determine sensorial posture-control strategies through postural sway frequency analysis when in a bipedal quiet stance with and without visual stimulus deprivation in healthy subjects and patients with haemophilic arthropathy. Secondarily, to determine the irregularity of postural balance control through sample entropy (SampEn). METHODS: A triaxial accelerometer attached at the L3 level determined the displacement and acceleration of the centre of mass (DCoM and ACoM, respectively) under open- and closed-eyes conditions. Sensorial strategies were studied by spectral analysis of the DCoM signal, divided into low, medium and high frequencies for visual/vestibular, cerebellum and somatosensory strategies respectively. DCoM irregularity was also analysed by SampEn. RESULTS: Fifteen young, healthy subjects and fifteen young, haemophilia patients were included. The mediolateal DCoM and anteroposterior ACoM differed between groups. During the open-eyes condition, haemophiliacs presented limited high and medium frequencies, and more low frequency bands as compared to non-haemophiliacs (P<.05). In the closed-eyes condition, haemophiliacs had a minor percentage of high frequencies but an elevated percentage of low frequencies as compared to non-haemophiliacs (P<.05). Non-haemophiliacs had higher SampEn than haemophiliacs in the mediolateral axis with open- and closed-eyes (P<.05 and <.001, respectively). CONCLUSIONS: The presented results indicate that patients with haemophilic arthropathy, as compared to healthy subjects, have less postural control irregularity and poor somatosensory system contributions that are compensated by more vestibular inputs.

Balance evaluation in haemophilic preadolescent patients using Nintendo Wii Balance Board®.

INTRODUCTION: Alterations in the musculoskeletal system, especially in the lower limbs, limit physical activity and affect balance and walking. Postural impairments in haemophilic preteens could increase the risk of bleeding events and deteriorate the physical condition, promoting the progression of haemophilic arthropathy. AIM: This study aims to evaluate static postural balance in haemophilic children, assessed by means of the Wii Balance Board® (WBB). METHODS: Nineteen children with haemophilia and 19 without haemophilia aged 9-10 years, have participated in this study. Postural balance was assessed by performing four tests, each one lasting 15 s: bipodal eyes open (BEO), bipodal eyes closed (BEC), monopodal dominant leg (MD) and monopodal non-dominant leg (MND). Two balance indices, standard deviation of amplitude (SDA) and standard deviation of velocity (SDV) were calculated in the anterior-posterior (AP) and medial-lateral (ML) directions. RESULTS: Index values were higher in haemophilic group and the differences were statistically significant (P < 0.05) in only six (SDAAP in BEO, BEC and MD conditions, SDAML in BEO, SDVAP in BEO and SDVML in MND condition) of 16 parameters analysed. CONCLUSION: Tests performed indicate a poorer static postural balance in the haemophilic cohort compared to the control group. Accordingly, physiotherapy programmes, physical activity and sports should be designed to improve the postural balance with the aim of preventing joint deterioration and improving quality of life.

Haemophilia Experiences, Results and Opportunities (HERO) study: treatment-related characteristics of the population.

The HERO (Haemophilia Experiences, Results and Opportunities) quantitative surveys collected information on characteristics and perceptions of adult persons with haemophilia (PWH) and parents of children with haemophilia. The aim of this article is to describe the perceptions of PWH and parents on psychosocial aspects related to treatment. Two online surveys (one for PWH, one for parents) were conducted in 10 countries. Among 675 PWH respondents, 77% reported having responsibility for their own care; 72% of 561 parent respondents had the main responsibility for their son. PWH were most commonly treated on demand (45% of 648 adults using factor concentrate), with 32% on regular prophylaxis and 23% treated on demand with short-term prophylaxis (e.g. for sports/physiotherapy). Children were most often treated with prophylaxis (65% of 549 children using factor concentrate), with 26% treated on demand and 8% treated on demand with short-term prophylaxis. Factor was generally used as instructed at home. Some respondents (41% PWH; 30% parents) had difficulties/concerns with factor availability/affordability. PWH reported more bleeds in the last 12 months than parents reporting their son's bleeds (mean 17.8 vs. 8.7). Both PWH and parents generally perceived that overall, their (their son's) haemophilia was well controlled. Results differed by country. The HERO study captured new, patient-based data regarding many facets of life relevant to PWH, including treatment. The information conveyed in this article largely represents new insights regarding perceptions of treatment and provides initial benchmark statistics for further research.

Secondary prophylaxis vs. on-demand treatment to improve quality of life in severe adult haemophilia A patients: a prospective study in a single centre.

BACKGROUND: Retrospective publications show a decrease in the bleeding frequency and an improvement in the quality of life (QoL) in severe adult haemophilia A (SAHA) after switching from the on-demand treatment (DT) to secondary prophylaxis (SP). But there are no prospective studies which demonstrate, using a haemophilia-specific questionnaire, an improvement in the QoL after such treatment change. The main objective of this study is to prospectively compare the QoL and the musculoskeletal assessment after switching from DT to SP in SAHA using the A36 Hemofilia-QoL(®) . As secondary objective, we compare the haemarthrosis frequency and factor VIII consumption in DT and SP during a similar period of time (12 months) after switching. MATERIALS AND METHODS: We have designed a prospective study including SAHA who have been under DT and were changed to a protocol, which combines SP (biweekly administration of factor VIII) with individualized physiotherapy programme. RESULTS: Twelve months after switching to SP, the QoL was significantly improved (P = 0·005). Musculoskeletal assessment of pathologic irreversible joints and joints with a reversible alteration was generally improved, although in only a few joints, this improvement was statistically significant. Haemarthrosis was strongly reduced (12·60-1·42, P < 0·001). CONCLUSIONS: This prospective study has demonstrated a statistically significant improvement in the QoL after 1 year from switching patients from DT to SP. The musculoskeletal assessment after 1 year was maintained similar or slightly improved. When we compared retrospective DT and prospective SP, haemarthrosis where strongly reduced requiring a slight increase in the consumption of factor VIII concentrates.

The role of ultrasonography in the diagnosis of the musculo-skeletal problems of haemophilia.

Recurrent haemarthrosis is the final cause of haemophilic arthrosic disease in haemophilia patients. Therefore, it is essential to diagnose it early, both clinically and by imaging. In addition, haemophilia patients experience chronic synovitis, joint degeneration, muscle haematoma and pseudotumours. The objective of this article is to highlight the value of ultrasounds in the diagnosis and control of the evolution of musculo-skeletal problems in haemophilia patients. To this end, we have performed a literature search in the PubMed, Web of Science(®) (WOS) and SciVerse bases, using the following keywords: hemophilia or haemophilia and ultrasonography (US), ultrasound, echography and sonography. The search was limited to studies published in English between the years 1991 and 2011, finding a total of 221 references. After reviewing the title or abstract for evidence of the use of US for the diagnosis of musculo-skeletal lesions in haemophilia, we selected 24 of these references. We added data collected from our experience to the most important data found in the references. Our main conclusion is that US is highly valuable for the diagnosis of musculo-skeletal diseases in haemophilia. It is a fast, effective, safe, available, comparative, real-time technique that can help us confirm the clinical examination. It is particularly important in acute haemarthrosis, as it can be used to objectively identify the presence of blood in the joints, measure its size, pinpoint its location, assess its evolution and confirm its complete disappearance.

Psychosocial aspects of haemophilia: a systematic review of methodologies and findings.

Psychosocial factors have a significant impact on quality of life for patients with chronic diseases such as haemophilia. Interventions to support the psychosocial needs of patients and their families, such as offering information and assistance, clarifying doubts, and teaching coping strategies to minimize the impact of disabilities, may help to maximize patient outcomes and improve quality of life for their families. The aim of this study was to evaluate the current literature on psychosocial aspects of haemophilia. Literature searches were performed using the PubMed database to identify studies evaluating psychosocial stressors in persons with haemophilia. Articles pertaining to the HIV epidemic were excluded from the analysis, as were those published before 1997. The literature reviews identified 24 studies, covering a range of different populations, generally with small cohorts (n < 100). Most studies were questionnaire based, with almost no overlap in terms of the instruments used. Only one study combined questionnaire techniques with qualitative methods. Except for two European studies, all publications reported data from a single country. Overall, studies tended to show that quality of life is reduced in persons with haemophilia, with a potential impact on education and employment, particularly when prophylactic treatment is not available. Carrier status in women may have a psychosocial impact and affect reproductive choices. Data on psychosocial aspects of the haemophilia life cycle are lacking in the published literature, along with data from developing countries. There is a need for more international, multifaceted research to explore and quantify the social and psychological aspects of life with haemophilia.

Joint protection in haemophilia.

Haemarthroses (intra-articular haemorrhages) are a frequent finding typically observed in patients with haemophilia. Diagnosis and treatment of these bleeding episodes must be delivered as early as possible. Additionally, treatment should ideally be administered intensively (enhanced on-demand treatment) until the resolution of symptoms. Joint aspiration plays an important role in acute and profuse haemarthroses as the presence of blood in the joint leads to chondrocyte apoptosis and chronic synovitis, which will eventually result in joint degeneration (haemophilic arthropathy). Ultrasonography (US) is an appropriate diagnostic technique to assess the evolution of acute haemarthrosis in haemophilia, although magnetic resonance imaging remains the gold standard as far as imaging techniques are concerned. Some patients experience subclinical haemarthroses, which eventually tend to result in some degree of arthropathy, especially in the ankles. Nowadays, the most effective way of protecting these patients is primary prophylaxis, which in practice changes severe haemophilia into moderate haemophilia, preventing or at least minimizing the occurrence of haemarthrosis. If primary prophylaxis is, for whatever reason not an option, secondary prophylaxis and enhanced on demand treatment should be considered. Two alternatives are available for inhibitor patients: (i) control of haemostasis using by-passing agents (rFVIIa or aPCCs) either as enhanced on demand treatment or secondary prophylaxis, as appropriate, following the same basic principles used for non-inhibitor patients and (ii) immune tolerance induction (ITI) to eradicate the inhibitor.

Transdermal nitroglycerine treatment of shoulder tendinopathies in patients with spinal cord injuries.

STUDY DESIGN: A clinical blind study was conducted to determine the efficacy of transdermal nitroglycerine treatment on the awareness of shoulder pain. OBJECTIVE: This study aims to determine the effects of transdermal nitroglycerine on shoulder pain and on functional shoulder movement in patients with spinal cord injuries and shoulder tendinopathies. A second aim is to establish the side effects of the treatment. SETTING: Hospital "La Fe" in Valencia, Spain. METHODS: A total of 45 spinal cord injury patients, all of whom are wheelchair users with shoulder tendinopathy, were randomly divided into two groups: placebo (n=12) and experimental (n=33). The experimental group (EG) received transdermal treatment for 6 months in the form of a 1.25 mg nitroglycerine (NT) patch on the greater tubercle. A placebo patch was used with the placebo subjects. Functional shoulder movements were assessed by articular range of motion and pain, using a visual analogical scale. RESULTS: NT treatment reduced the awareness of shoulder pain and increased the functional movement and range of articular motion in the shoulders of the EG members (P<0.05). CONCLUSIONS: We conclude that transdermal NT is an efficient method for treating shoulder tendinopathies in wheelchair users with spinal cord injuries.

Comparison of physical activity and sedentary behaviours between young haemophilia A patients and healthy adolescents.

In recent studies, adolescent haemophilia A patients and healthy adolescents have been encouraged to participate in physical activity (PA) based on its many established health benefits. However, none of the studies to date has used objective measures of PA and sedentary behaviour. The aims of the current study included: (i) to determine the amount and intensity of habitual PA among haemophilia A and healthy adolescents, and in haemophilia A patients with and without bleeding episodes in the previous year, and (ii) to identify the type and determine the time spent in sedentary activities in which both groups participate to obtain a broadened view of their daily activities. A total of 41 adolescent haemophiliacs and 25 healthy adolescents, between the ages of 8 and 18 years, participated in this cross-sectional study. A triaxial accelerometer was used to measure PA and the Adolescent Sedentary Activity Questionnaire to assess sedentary behaviours among members of both groups. Adolescent haemophilia A patients showed a higher daily mean time engaged in light, moderate and moderate-to-vigorous PAs relative to their healthy counterparts (P < 0.001). Patients who had experienced bleeding episodes during the previous year also spent more time participating in vigorous PAs than healthy adolescents (P = 0.002). With regard to sedentary behaviours, healthy adolescents spent more time listening to music than haemophilia A adolescents (P = 0.003), whereas haemophilia A adolescents spent more time watching TV (P < 0.001) and playing videogames (P = 0.003) than healthy counterparts. Findings suggest that increased participation in moderate intensity PAs and reduced sedentary behaviours should be recommended among adolescents with haemophilia A.

Influence of aquatic training on the motor performance of patients with haemophilic arthropathy.

Thirteen patients with haemophilia A took part in this study voluntarily. They underwent an aquatic training programme over a 9-week period (27 sessions; three sessions per week; 1 h per session). Their motor performance was assessed by the following cardio-respiratory and mechanical variables before and after the training programme: oxygen uptake (VO(2), mL min(-1)), relative oxygen uptake (rel VO(2), mL min(-1).kg(-1)), carbon dioxide (CO(2), mL min(-1)), respiratory quotient (R), heart rate (bpm) and the distance covered in 12 min (the Cooper test, m). Nine patients successfully completed the intervention and measurement protocols without bleeding or other adverse events. After the proposed training programme, significant differences between the pre-test and post-test were observed. Patients' aerobic capacity increased considerably, and their oxygen uptake improved by 51.51% (P < 0.05), while their relative oxygen uptake went up by 37.73% (P < 0.05). Their mechanical capacity also increased considerably (14.68%, P < 0.01). Our results suggest that 27 specially designed aquatic training sessions for our patients with haemophilia A had a positive effect on their motor performance and considerably improved their aerobic and mechanical capacity without causing adverse effects.

Exercise and sport in the treatment of haemophilic patients: a systematic review.

In haemophiliacs, the physical condition, muscular strength, aerobic resistance, anaerobic resistance and proprioception have all diminished. Muscle atrophy and instability, being more vulnerable to stressful motor demands, increase the risk of lesion and establish a vicious circle that is hard to break: pain, immobility, atrophy, articular instability and repeated bleeding episodes. In haemophilia, physical and/or sporting activities were not recommended until the seventies. Nowadays, the overall policy is to recommend certain physical activities, especially swimming, to improve the patient's quality of life, thanks to prophylaxis programmes. The objective of this study is to perform a systematic review of the exercise and sporting activities recommended for haemophiliacs. Experimental and observational studies and clinical assays about rehabilitation for haemophiliacs with exercise and sporting activities have been included. The relevant studies were identified in Medline, Cinahl, Embase and SportDiscus, and key words were: haemophilia, exercise and sport (with no language restrictions). Works were independently analysed by reviewers and the following were identified: of 3603 studies, 103 were included in this review: 29 (28.15%) were experimental, 27 (26.21%) were observational and 47 (45.63%) were clinical. Physiotherapy, physical activity and sport are basic elements to improve quality of life and the physical condition, increase strength and resistance and to reduce the risk of musculoskeletal lesions and to prevent haemophilic atrophy. In general, professionals in haemophilia believe that regular exercise and rehabilitation with physiotherapy is fundamental, particularly in countries where replacement therapy is not readily available.

Posturographic analysis of balance control in patients with haemophilic arthropathy.

Musculoskeletal disorders in haemophiliacs represent the highest percentage of lesions, giving rise to haemophilic arthropathy (HA) which predominantly affects lower limbs, influencing postural control, standing and walking. Leading a sedentary lifestyle seems to influence strength and muscular resistance in haemophiliacs which, in turn, are related to articular stability and the prevention of articular degenerative processes. The objective of this work was to study alterations in balance to subsequently evaluate the appropriate therapeutics and how this influences the development of arthropathy. Twenty-five haemophiliacs with HA, 25 haemophiliacs without HA (NHA) and 25 healthy control subjects (CTL) took part in this study. Tests were performed on a force platform and the subjects remained as still as possible for 30 s under different conditions: (i) bilateral stance with eyes open; (ii) bilateral stance with eyes closed; (iii) right unilateral stance; and (iv) left unilateral stance. The results of these tests indicated significant differences (P < 0.05) between the groups HA, NHA and CTL. The HA group presented worse results for both unilateral and bilateral stance when compared with the other two cohorts. Surprisingly, the NHA group displayed a worse balance than the controls. A single calculated parameter (mean frequency) did not show significant differences. This apparently indicates the absence of pathology in the nervous system in relation to postural control. The results suggest that our patients should participate in physical exercise programmes, rehabilitation and physiotherapy to improve their postural control.

Clinical and echographical control protocol of haemarthrosis in haemophilia patients with inhibitors: evaluation of the efficacy of recombinant factor VIIa in the evolution process (EFFISEVEN protocol).

The intention of the 'clinical and echographical protocol of evaluation the efficacy of recombinant activated factor VII in the haemarthrosis' (EFFISEVEN protocol) was to provide an extensive study of the evolution of haemarthrosis, and second, of its repercussions on the degenerative process of joints. The clinical evaluation of haemarthroses and their evolution is based on a well-established methodology, although very few studies have sought to determine the correlation between pain, mobility and the objective data regarding the haemorrhage. We believe that it is necessary to unify criteria and that the EFFISEVEN protocol may contribute data that improve standards which, in turn, will influence the degenerative process of joints, and consequently affect the quality of life of haemophilia patients with inhibitors. Echographical control of haemarthrosis is an objective method that allows control over how the haemorrhage evolves and also helps in the identification of rebleeding. Therefore, its use adds a new dimension to patient management strategies. Techniques used to monitor recombinant activated factor VII (rFVIIa) treatment require further study, although preliminary results guarantee their efficacy.