Evaluation of EC50 of factor VIII as predictor of prophylaxis efficacy in patients with severe haemophilia A.

Trough factor (F) VIII level is a not reliable bleeding risk indicator to predict prophylaxis efficacy in severe haemophilia A (SHA), therefore, accurate biomarkers are much needed. Thrombelastography (TEG) monitors both thrombin and clot formation addressing the global haemostatic status but its usefulness to tailor prophylaxis in haemophilia has been poorly evaluated. In this study, correspondence between individual pharmacodynamic/pharmacokinetic profile of FVIII and joint condition, physical activity and bleeding phenotype of SHA patients under prophylactic treatment was assessed. Nineteen SHA patients < 18 years old on long-term prophylaxis treatment with FVIII were studied in an observational cross-sectional study. Whole blood was withdrawn before FVIII administration and at five time-points after infusion for a TEG-based pharmacodynamic- and pharmacokinetic-study. Type of prophylaxis and joint condition at inclusion and physical activity as well as onset of treated spontaneous bleeding events in the previous two years were retrospectively assessed. Six patients had suffered at least one treated spontaneous bleeding event and were named as "bleeders". The rest were named as "non-bleeders". Only the half maximal effective concentration of FVIII (FVIII-EC50) for TEG parameters R-time, K-time and α-angle correlated with the bleeding phenotype being significantly higher in bleeders suggestive of a poorer response to FVIII. Poorer joint condition, trough FVIII levels or type of prophylaxis were not definitive predicting variables of bleeding phenotype. In conclusion, this study reveals FVIII-EC50 for the first time as a valuable biomarker to anticipate individual efficacy of prophylaxis in SHA.

The ICF (International Classification of Functioning, Disability and Health) developed by the WHO for measuring function in hemophilia.

INTRODUCTION: Assessment of the disease in people with hemophilia (PWH) must include an analysis of functioning. Researchers have done a lot of work over the last two decades in developing disease specific assessment tools in hemophilia - some of them based on the ICF (International Classification of Functioning, Disability and Health). AREAS COVERED: This article is a narrative review of the ICF developed by the World Health Organization (WHO) in the context of hemophilia. Expert commentary: The WFH has developed a website with a 'compendium of assessment tools' based on the ICF. The ICF developed by the WHO makes it possible to propose an approach that prioritizes capacities over difficulties. This article is intended to motivate physicians who treat PWH to incorporate the ICF into their assessments. A generalized use of the ICF will provide a common communication context. The ICF developed by the WHO should be used in hemophilia.

Radiosynovectomy in haemophilic synovitis of elbows and ankles: Is the effectiveness of yttrium-90 and rhenium-186 different?

BACKGROUND: Radiosynovectomy (RS) reduces the number of haemarthroses and the synovial size in chronic haemophilic synovitis. The purpose of this study was to quantitatively compare the effectiveness of two types of RS (yttrium-90 vs. rhenium-186) in terms of the objective improvement of haemarthroses and synovial size. METHODS: Seventy RSs were performed in 70 joints (44 elbows, 26 ankles) of 70 haemophiliacs diagnosed with chronic synovitis. Yttrium-90 was used in 21 joints and rhenium-186 was used in 49 joints. The mean patient age was 20.61 years. RESULTS: RS resulted in significant improvement in the three variables studied (six months before RS vs. six months after RS), namely in the number of episodes of haemarthrosis (67.8% improvement); the size of the synovium as measured by means of a clinical scale (43.8% improvement) and imaging techniques in millimetres (26.7% improvement). We did not find significant statistical differences between yttrium-90 and rhenium-186 regarding their efficacy. No correlation was found between the results and other variables: age, joint (ankle or elbow), presence or absence of radiological involvement, type of haemophilia (A or B), grade of haemophilia (mild, moderate or severe), previous haematological treatment (on demand or prophylaxis), and the presence or absence of inhibitor CONCLUSIONS: Yttrium-90 RS and rhenium-186 RS were equally effective in reducing the number of haemarthroses and the size of the synovium in ankles and elbows in the short-term (6 months). No correlation was found between the results and other patients' characteristics.

The current role of orthoses in treating haemophilic arthropathy.

INTRODUCTION: Haemophilic arthropathy (HA) is an inevitable consequence of repeated haemarthroses in people with haemophilia, and principally affects their ankles, knees and elbows. It is advisable that haematological treatment be complemented with rehabilitation therapy and surgery. Orthoses are devices that are used within the framework of rehabilitation, in order to change the functional or structural characteristics of the neuromusculoskeletal system. MATERIALS AND METHODS: This article reviews the design, the materials and characteristics of orthoses and the indications for the various orthoses used in HA. Ankle, knee, elbow orthoses, insoles, footwear modifications and orthopedic shoes are discussed. RESULTS: Orthoses can control or prevent joint movement, stabilise a specific joint or relieve the load or stress on it. These devices must be prescribed by a physician within the framework of rehabilitation. Recommendations for the proper selection and use of orthoses are highly complex. DISCUSSION: To maximise the benefits of this mode of therapy, a profound understanding of anatomy and biomechanics is crucial, as is an understanding of the devices available for the various joints that may be affected by HA (ankles-feet, knees, elbows). CONCLUSIONS: Orthotic devices can reduce pain and improve quality of life of people with HA, delaying surgery in many cases.

Radiosynovectomy in haemophilia: long-term results of 500 procedures performed in a 38-year period.

BACKGROUND: Radiosynovectomy (RS) can reduce the number of haemarthroses in chronic haemophilic synovitis. The purpose of this study was to assess the effectiveness of RS in terms of the objective improvement of five parameters (number haemarthroses, articular pain, degree of clinical synovitis, clinical score of the World Federation of Haemophilia (WFH), and radiological score of the WFH. METHODS: In a 38-year period (1976-2013), five hundred radiosynovectomies were performed in 443 joints of 345 patients with haemophilia diagnosed with chronic synovitis. The mean patient age was 23.7 years (range, 6-53). The mean follow-up was 18.5 years (range: 6 months-38 years). The RS was carried out with either yttrium-90 or rhenium-186. We performed 1 to 3 injections (RS-1, RS-2, RS-3), with a 6-month interval between them. RESULTS: RS resulted in significant improvement in all the parameters studied, except in the WFH radiologic score that showed no improvement. On average, the number of haemarthroses decreased by 64.1% and articular pain decreased by 69.4%. The degree of synovitis showed a reduction of 31.3%. The WFH clinical score revealed an improvement of 19%. The WFH radiological score showed no improvement. There were four complications (0.9%) of RS. Twenty-eight (6.3%) joints eventually had to be subjected to arthroscopic synovectomy or total knee replacement (TKR). No cancer was observed in this group of patients during the 38-year period. CONCLUSIONS: Radiosynovectomy (RS) is an effective, safe, minimally invasive, well tolerated procedure in the long-term for the treatment of chronic haemophilic synovitis. Moreover, it is very easy to perform. The knee required more injections than the elbow or the ankle and more severe synoviums required a higher number of RS procedures.

Is radiosynovectomy (RS) effective for joints damaged by haemophilia with articular degeneration in simple radiography (ADSR)?

BACKGROUND: Radiosynovectomy (RS) is known to be effective in the treatment of chronic haemophiliac synovitis. Its effectiveness may, however, be different when the joint treated shows articular degeneration in simple radiography (ADSR). PURPOSE: The purpose of this study was to investigate the effectiveness or otherwise of RS in the presence of ADSR. To this end, the objective improvement in five joint parameters (haemarthrosis, joint pain, range of motion, muscle strength and synovial size) has been analysed with respect to the pre-existence or otherwise of ADSR in the articulation treated. MATERIALS AND METHODS: An observational retrospective cohort study was conducted. Between January 1993 and December 2006, RS was performed on 78 people with haemophilia. Their average age was 18 (range 7-51). RS procedures were performed on 104 different joints; some joints required more than one injection (a maximum of 3 were given, with a 6-month interval between them), which we refer to respectively as RS-1, RS-2, RS-3, resulting in a total of 156 procedures. The isotopes used were (90)Y on 107 occasions and (186)Re in 49 injections. RESULTS: RS treatment reduced the frequency of haemarthroses, reduced joint pain and reduced synovial size, and resulted in improved muscle strength and range of motion both in joints with ADSR (N=86) and in those without ADSR (N=18). However, no articulation without ADSR required RS-3. CONCLUSION: The five parameters studied improved to an equal degree in joints with ADSR and without ADSR. No joint without ADSR required RS-3; this was the only difference our study found between joints without ADSR and those with ADSR at the time of the RS.

What patient, joint and isotope characteristics influence the response to radiosynovectomy in patients with haemophilia?

The literature describes radiosynovectomy (RS) as a good non-surgical option for reducing synovial membrane size and thus the number of haemarthrosis episodes. However, there are still many aspects concerning the beneficial effects of RS that have not been quantified. A total of 156 radiosynovectomies (RS) were performed in 104 joints corresponding to 78 haemophiliacs (yttrium-90, rhenium-186). The mean patient age was 18 years. In another study involving the same group of patients, the parameters that improved most after RS were pain and haemarthrosis, followed by the World Federation of Hemophilia clinical score, muscle strength and range of movement (ROM). Following RS, improvement was seen to be independent of patient age, haemophilia type and grade, previous haematological treatment, the presence or absence of circulating inhibitor, synovial membrane size, the type of joint (elbow, knee and ankle), previous physical activity or lack of activity, the prior presence or absence of radiographic signs of joint degeneration (arthropathy) or the isotope used. RS is effective in treating haemophilic synovitis and may require 1-3 injections (RS-1, RS-2 and RS-3) spaced 6 months apart. Following RS-1, the knee had a 3.4- and 3.2-fold greater risk of not improving in terms of pain, compared with the elbow and ankle, respectively. Regarding ROM, lesser improvement was recorded after RS-1 in cases of severe haemophilia and the ankle. In other words, severe haemophilia implies a 2.1-fold greater risk of no improvement in ROM compared with mild and moderate haemophilia. In addition, the ankle presented a 6-fold greater risk of not improving in terms of ROM compared with the elbow and knee. RS affords effective treatment of chronic haemophilic synovitis. RS is effective in all patient groups, independently of the presence of circulating inhibitor antibody, the type of joint involved, the degree of synovial membrane hypertrophy and the presence of radiographic findings of joint degeneration (arthropathy).

Radiosynovectomy in hemophilia: quantification of its effectiveness through the assessment of 10 articular parameters.

BACKGROUND: Radiosynovectomy (RS) can reduce the number of hemarthroses in chronic hemophilic synovitis. The purpose of this study was to quantitatively assess the effectiveness of RS in terms of the objective improvement of ten articular parameters. METHODS: One-hundred and fifty-six radiosynovectomies were performed in 104 joints of 78 hemophiliacs diagnosed with chronic synovitis. The mean patient age was 18 years. The RS was carried out with either yttrium-90 or rhenium-186 (1-3 injections with a 6-month interval between them). RESULTS: RS resulted in significant improvement in nine of the 10 variables studied, namely in the number of episodes of hemarthrosis, articular pain, range of motion (ROM) in flexion. ROM in extension, muscle strength (MS) in flexion, MS in extension, the degree of synovitis detected on clinical examination, the size of the synovium as measured by means of imaging techniques (in millimeters), the clinical scale developed by the World Federation of Haemophilia (WFH), and the radiologic scale of the WFH. The tenth parameter, the WFH radiologic score, showed no improvement. The other nine parameters studied improved independently for each one of the intra-articular injections of the radioisotope. CONCLUSIONS: Categorization of the variables with regard to the degree of improvement achieved showed that the number of episodes of hemarthrosis and the severity of pain were the variables associated with the greatest improvement, with a 70% decrease in the amount of bleeding and in the level of pain experienced by the patient. The reduction of articular bleeding after RS was 67.6% when RS-1 was used, 62.1% with RS-2 and 61.2% with RS-3. Synovial hypertrophy as assessed clinically and by imaging techniques also showed a reduction of 30% and 39%, respectively. The WFH clinical scale revealed an improvement of around 19%. MS also improved in flexion and extension (7.9% and 8.2% improvement, respectively). ROM showed a slight but non-significant improvement.

Radioactive synoviorthesis for the treatment of haemophilic synovitis.

Radioactive synoviorthesis, with (90)Y (knees) and (186)Rh (elbows and ankles) is a highly effective procedure that decreases both the frequency and the severity of recurrent intra-articular bleeds related to joint synovitis. The procedure should be performed as soon as possible to minimize the degree of articular cartilage damage, which based on many studies is irreversible. It can also be used in patients with inhibitors. On average, radioactive synoviorthesis has a 75-80% satisfactory outcome in the long-term. From the clinical standpoint, such efficacy can be measured by the decrease in the number of haemarthroses, with complete cessation for several years in some cases. One should bear in mind that in 20-25% of cases, radioactive synoviorthesis fails to control haemarthroses. In such cases, it can be repeated. Personal experience and the general recommendation among orthopaedic surgeons and haematologists is that when three early consecutive radioactive synoviortheses (repeated every three months) fail to halt synovitis, a surgical synovectomy (open or by arthroscopy) should be immediately considered.