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Introduction: Early diagnosis of joint damage is pivotal in haemophilia to prevent the occurrence and progression of haemophilic arthropathy thus providing optimal personalised management. The haemophilia joint health score version 2.1 (HJHS) is based on a physical examination of the mainly affected joints. Musculoskeletal ultrasound has demonstrated the capability to detect early changes in terms of synovitis and osteochondral damage. The haemophilia early detection with ultrasound (HEAD-US) score has been proposed as a simple and reliable evaluation tool., Aim: This study aims to investigate the correlation between the HJHS and the HEAD-US scores performed by two independent operators (physical therapist and musculoskeletal ultrasound expert) for the evaluation of the joint health status of patients with haemophilia., Methods: Consecutive adult patients independent of the severity degree were included. Elbows, knees and ankles were evaluated by a physical therapist by HJHS and by a musculoskeletal ultrasound expert following the HEAD-US protocol., Results: We observed a good positive correlation between HJHS and HEAD-US (Spearman's rho 0.72). The main discrepancy in conceptually similar domains was found between the HJHS swelling and the HEAD-US synovitis (rho 0.17), as ultrasound was able to detect even mild synovitis when HJHS swelling was scored 0 in up to 40% of cases., Conclusions: The HJHS and HEAD-US correlate well even when performed by two independent operators. Musculoskeletal ultrasound is particularly useful for the early detection of synovitis. The routine assessment of both scores helps clinicians define the stage and extension of joint involvement and set up a personalised treatment., (© 2024 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction/aim: To evaluate whether patients with haemophilia (PwH) can be enabled to perform ultrasonography (US) of their knees without supervision according to the Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) protocol and whether they would be able to recognize pathologies., Methods: Five PwH (mean age 29.6 years, range 20-48 years) were taught the use of a portable US device and the HEAD-US protocol. Subsequently, the patients performed US unsupervised at home three times a week for a total of 6 weeks with a reteaching after 2 weeks. All images were checked for mapping of the landmarks defined in the HEAD-US protocol by a radiologist. In a final test after the completion of the self-sonography period, participants were asked to identify scanning plane and potential pathology from US images of other PwH., Results: On the images of the self-performed scans, 82.7% of the possible anatomic landmarks could be identified and 67.5% of the requested images were unobjectionable, depicting 100% of the required landmarks. There was a highly significant improvement in image quality following reteaching after 2 weeks (74.80 ± 36.88% vs. 88.31 ± 19.87%, p < .001). In the final test, the participants identified the right scanning plane in 85.0% and they correctly identified pathology in 90.0% of images., Conclusion: Appropriately trained PwH can perform the HEAD-US protocol of their knee with high quality and are capable to identify pathologic findings on these standardized images. Asynchronous tele-sonography could enable early therapy adjustment and thereby possibly reduce costs., (© 2024 The Author(s). Haemophilia published by John Wiley & Sons Ltd.)

Objectives: Early detection of bleeding into a joint is crucial in patients with haemophilia. This study was designed to evaluate the sensitivity of ultrasonography (USG) and magnetic resonance imaging (MRI) to detect the presence of blood in small concentrations in a simulated model to mimic joint bleeding., Materials and Methods: Different concentrations of blood in plasma, varying from 0.1% to 45%, were collected in 10-ml plastic syringes and imaged using 12 and 18 MHz USG transducers and with 1.5T and 3T MRI scanners, at different intervals of time following dilution. The images were scored for the presence of blood by four experienced radiologists who were blinded to the concentration of blood., Results: Within the first 2 h, the 18 MHz transducer was able to detect blood consistently up to 0.5%, whereas the 12 MHz transducer could consistently identify blood up to 1.4%. After the first 12 h, both transducers were able to detect blood up to 0.5% concentration. However, at concentrations below 0.5%, there was discordance in the ability to detect blood, with both transducers. There was no correlation between the signal intensities of MRI images and concentration of blood, at different time intervals, irrespective of the magnetic field strength., Conclusions: Detection of blood using the USG is dependent on variables such as the concentration of blood, frequency of the transducer used and timing of the imaging. As the concentration of blood decreases below 0.5%, the discordance between the observers increases, implying that the detection limit of USG affects its reliability at lower concentrations of blood. Caution is urged while interpreting USG imaging studies for the detection of blood in symptomatic joints., (© 2021 John Wiley & Sons Ltd.)

Aim: We previously reported the outcome of chromic phosphate-32( 32 P) colloid synoviorthesis in 53 haemophilic patients with an average follow-up of 31 months. The purpose of the present study was the long-term follow-up of the same cohort on both clinical and radiographic features., Materials: Nine patients failed to attend the recall appointment. The mean follow-up for the remaining 44 patients (52 procedures) was 15 years (range, 14.6-15.5). The mean age at the time of reassessment was 31 years (range, 18-43)., Results: The haemarthrosis frequency was not statistically significant at the latest follow-up years compared with 31 months (0.8 vs 0.4 per week, P = .3). There was no significant change in the clinical severity of haemophilic arthropathy (P = .5). Most of the treated joints still are in stage III of Fernandez-Palazzi and Caviglia classification. There was a trend towards the radiologic deterioration of arthritis with nearly 50% of patients at Arnold-Hilgartner Stage V. 13% of patients underwent a total knee arthroplasty (TKA). The age at which the initial radiosynovectomy was performed was significantly higher in patients who had a TKA than those who had not (22 vs 15 years, P < .002)., Conclusion: The bleeding control effect of 32P on the target joint remains over time; however, it did not appear to halt the progression of radiographic changes in haemophiliacs. It could delay the need for TKA if it performs at the right time., (© 2019 John Wiley & Sons Ltd.)

Aim: Using diffusional kurtosis imaging (DKI) to assess the impact of emotional disorders on microstructural changes of the brain in children with haemophilia A., Materials and Methods: Diffusional kurtosis imaging was acquired from haemophilia A (n = 22) and controls (n = 22) using a 3T scanner. A regression analysis of frontal, cingulate, hippocampus, insula and amygdala regions of interest (ROIs) was conducted. Clinical data and results of psychological tests were collected. A paired t-test was used to analyse the differences between the two groups' ROIs, and the Spearman test was used to analyse the correlation between ROIs and psychological tests or clinical data., Results: Fractional anisotropy (FA) in the left middle cingulate and right hippocampus; mean diffusion (MD) in the frontal lobe, right anterior cingulate and right middle cingulate showed varying degrees of increase in the ROI compared to controls (P < 0.003). MD in the frontal lobe and the course of disease (P < 0.05), FA in the right hippocampus and the social score of the self-consciousness scale (P < 0.01) had a positive correlation., Conclusion: Our study is the first to evaluate the relationship between emotion disorders and cognitive changes in the microstructure of the brain in children with haemophilia A, suggesting that DKI provides more information about tissue microstructural changes than do the conventional image method and traditional psychological tests., (© 2017 John Wiley & Sons Ltd.)

Introduction: A major complication of haemophilia is haemophilic arthropathy (HA), a debilitating disorder with an incompletely defined pathobiology. High-resolution imaging may provide new knowledge about onset and progression of HA, and thereby support identification of new treatment opportunities. Recently, a F8 -/- rat model of HA was developed. The size of the rat allows for convenient and high resolution imaging of the joints, which could enable in vivo studies of HA development., Aim: To determine whether HA in the F8 -/- rat can be visualized using ultrasonography (US) and micro-computed tomography (μCT)., Methods: Sixty F8 -/- and 20 wild-type rats were subjected to a single or two induced knee bleeds. F8 -/- rats were treated with either recombinant human FVIII (rhFVIII) or vehicle before the induction of knee bleeds. Haemophilic arthropathy was visualized using in vivo US and ex vivo μCT, and the observations correlated with histological evaluation., Results: US and μCT detected pathologies in the knee related to HA. There was a strong correlation between disease severity determined by μCT and histopathology. rhFVIII treatment reduced the pathology identified with both imaging techniques., Conclusion: US and μCT are suitable imaging techniques for detection of blood-induced joint disease in F8 -/- rats and may be used for longitudinal studies of disease progression., (© 2016 John Wiley & Sons Ltd.)

Introduction and Objectives: Intra-articular corticosteroid injections are standard of care for managing joint pain secondary to osteoarthritis or rheumatoid arthritis but are rarely used in haemophilic arthropathy. We have introduced and evaluated the efficacy and safety of ultrasound-guided corticosteroid injections for pain relief in patients with haemophilic arthropathy., Patients and Methods: Ultrasound-guided intra-articular injections performed on haemophilia patients at UCSD between March 2012 and January 2016 were analysed. Needle placement and injection (40 mg triamcinolone; 3-5 mL lidocaine) were performed with musculoskeletal ultrasound and Power Doppler. Analysis included patient demographics, joint-specific parameters such as tissue hypervascularity and effusions, pain relief, and procedure-associated complications., Results: Forty-five injections (14 ankles, 13 elbows, 18 knees) were administered in 25 patients. Advanced arthropathy with hypervascularity and/or effusions was present in 91% and 61% of joints, respectively. Ninety-one per cent of injections resulted in pain relief which was significant in 84% (>30% reduction). Median pain score was reduced from 7 of 10 to 1 of 10 (P < 0.001), usually within 24 h. Median duration of pain relief was 8 weeks (range 1-16 weeks). Haemophilia B patients experienced longer periods of relief, and high Pettersson scores were associated with shorter duration of relief. There were no procedure-associated complications. Repeat ultrasound of eight joints within 4 weeks of injection demonstrated nearly complete resolution of hypervascularity., Conclusions: Point-of-care ultrasound enabled intra-articular corticosteroid injections that provided highly effective, safe, and relatively long-lasting pain relief in haemophilic arthropathy. This approach should be used to improve pain management in haemophilic arthropathy., (© 2016 John Wiley & Sons Ltd.)

Little objective information exists about musculoskeletal bleeding patterns in haemophilic arthropathy. Bleeding is assumed to be the cause of painful joints or muscles. Clotting factor treatment is provided empirically, but often does not alleviate pain. We hypothesized that perception of pain aetiology is unreliable, and introduced point-of-care high-resolution musculoskeletal ultrasound (MSKUS) to differentiate intra-articular bleeds vs. joint inflammation, and intra-muscle bleeds vs. other regional pain syndromes. To assess painful musculoskeletal episodes in adult haemophiliacs, we used rapid MSKUS, employing grey scale and power Doppler examination. Forty episodes in 30 adult haemophiliacs were evaluated. Thirty three of the 40 episodes were patient-reported as 'bleeding', five as 'arthritis-type' pain and two as 'undecided'. Of the 33 bleeding reports, only 12 were confirmed by MSKUS; the other episodes revealed other pathology. In contrast, three of five perceived arthritis flares were reclassified as bleeds. Similarly, physician assessment was incorrect in 18 of 40 instances. Swelling and warmth were present in approximately half of confirmed bleeding and non-bleeding episodes, and therefore not useful clinically. Few of the painful episodes were symptom controlled at the time of MSKUS. Management changed based on objective imaging findings in >70% of episodes, which resulted in symptom improvement >60% of the time. Significant discrepancies exist between MSKUS findings and patient/physician-perceived pain classification as bleeding or other musculoskeletal symptoms. Current practice of prescribing clotting factor or conservative measures based on pain perception seems inadequate and suggests that point-of-care imaging should be included into modern haemophilia care., (© 2013 John Wiley & Sons Ltd.)

Most countries still do not achieve 1 IU of factor VIII/capita sufficient for survival. Although primary prophylaxis prevents synovitis, is not universally used. Chronic synovitis is treated with arthroscopy at expense of considerable amount of coagulation factors, and specialized surgeons. Radioactive synovectomy (RS) is a minimally invasive and cost effective alternative to arthroscopy, often considered first the option for persistent synovitis. Even without established causation with cancer, RS is avoided by some, due to this concern. We aim contributing to the understanding of RS safety regarding malignancy, presenting a large number of treated patients, and a single case of cancer. Three centres in Brazil applied RS with (90) Yttrium Citrate, (90) Yttrium hydroxyapatite or (153) Samarium hydroxyapatite in haemophilic joints and performed a survey addressing cancer in these patients. Four hundred and eighty eight patients (ages 3-51) received 1-3 RS (total 842) and follow-up was 6 months to 9 years. One patient aged 14 years presented Ewing sarcoma, 11 months after RS. The tumour was treated successfully with surgery and chemotherapy. Causality of cancer by RS is improbable in this case. Accordingly, latency here is far below minimum 5-10 years for radio-induction of solid tumours. Moreover, ES is not a typically radio-induced tumour, even at high doses. In agreement with others, though recognizing limitations, this study suggests RS is safe regarding cancer induction. Synovitis is a known burden for patients. The decision of making reasonable usage of RS should be outweighed with the risks of leaving synovitis untreated., (© 2013 John Wiley & Sons Ltd.)

Patients with bleeding disorders may be exposed to ionizing radiation during medical care. We hypothesized that children with severe haemophilia may have higher radiation exposure than those with mild bleeding disorders (MBDs). To compare medical radiation exposure rates between children with severe haemophilia and MBDs. Charts of 35 pediatric patients with severe haemophilia were randomly selected from a database of active male patients followed in our bleeding disorders clinic from 2000 to 2010. Case patients were age and sex matched with two control patients with MBDs [Type 1 von Willebrand disease (VWD) or mild platelet function defect (PFD)]. By retrospective review, data on radiation exposure in millisieverts (mSv) was collected from radiological studies performed within Emory/CHOA. The rates of exposure between cohorts were compared using the Mann-Whitney Test. Case patients had a mean of 11.3 (median 8, IQR = 29) radiographic studies compared with 1.8 (median 1, IQR = 11) for controls (P < 0.001). The mean effective dose of radiation per patient per year of study was two mSv for case patients (median 0.4, IQR = 3) and 0.4 mSv for control patients (median 0.01, IQR = 0.3) (P < 0.001). Overall, 1.4% of controls and 31.4% of cases accumulated high to very high levels of exposure ( > 20 mSv). Case patients with severe hemophilia accumulated significantly more medical radiation exposure than controls. While the use of ionizing radiation is often necessary for management of these patients, avoidance of unnecessary exposure along with exploration of alternative imaging techniques and low dose protocols should be considered whenever possible., (© 2012 Blackwell Publishing Ltd.)

Children with haemophilia are at risk of suboptimal bone mass accrual and low bone mineral density (BMD). We recently demonstrated that although BMD in Finnish children with haemophilia was within the normal range, their whole body BMD was significantly lower and hypercalciuria more prevalent than in controls. This study sought to determine the bone structure and strength in physically active children with haemophilia. To investigate the underlying mechanisms in this group, we conducted a case-control study to assess bone structure and strength by peripheral quantitative computed tomography (pQCT) at the radius. The study group comprised 29 patients (mean age 12.2 years) and 46 age-matched controls. Children with haemophilia had decreased total BMD Z-score at the distal radius (P ≤ 0.001), but increased cortical bone density at the proximal radius (P ≤ 0.001). Total bone area at the proximal radius was significantly lower in children with haemophilia (P = 0.002), whereas there were no differences in cortical bone area or in polar Strength-Strain Index, a parameter of bone strength, between the patients and controls. Patients with mild to moderate haemophilia and on-demand treatment had inferior bone strength compared to those with moderate to severe haemophilia and prophylaxis. Our findings suggest altered skeletal development in patients with haemophilia in the radius, resulting in smaller bone size and higher cortical bone density. Importantly, bone strength at the radius appears equal to healthy children. Prophylactic treatment seems to have a beneficial effect on bone health., (© 2012 Blackwell Publishing Ltd.)

Evaluation of prophylactic treatment of haemophilia requires sensitive methods. To design and test a new magnetic resonance imaging (MRI) scale for haemophilic arthropathy, two scales of a combined MRI scoring scheme were merged into a single scale which includes soft tissue and osteochondral subscores. Sixty-one joint MRI's of 46 patients with haemophilia were evaluated by four radiologists using the new and older scales. Forty-six of the joints were evaluated using two X-ray scales. For all MRI scores, interreader agreement and correlations with X-ray scores and lifetime number of haemarthroses were analysed. The interreader agreement intraclass correlation coefficient was 0.82, 0.89 and 0.88 for the soft tissue and osteochondral subscores and the total score, as evaluated according to the new MRI scale, compared to 0.80 and 0.89 as for the older scales. The total score and osteochondral subscore according to the new scale, as well as scores according to the older scales were correlated (P < 0.01) with number of haemarthroses (Spearman correlation 0.35-0.68) and with the X-ray scores (Spearman correlation 0.40-0.76), but no correlation (P > 0.05) was found between the soft tissue subscore of the new MRI scale and the X-ray scores. The new MRI scale is simpler to apply than the older and has similar reader reliability and correlation with lifetime number of haemarthroses, and by separating soft tissue and osteochondral changes it gives additional information. The new scale is useful for analyses of early and moderate stages of arthropathy, and may help to evaluate prophylactic haemophilia treatment., (© 2012 Blackwell Publishing Ltd.)

The functional independence score in haemophilia (FISH) is a performance-based instrument used to assess musculoskeletal function in patients with haemophilia. We aimed to evaluate the functional independence of haemophilia A adolescents and its correlation to radiological joint scores. A cross-sectional study was carried out on 50 adolescent haemophilia A patients. Musculoskeletal function was assessed using the FISH and individual joints were assessed radiologically using the Pettersson score and MRI scale. The mean age of our patients was 16 ± 1.1 with a mean FISH of 23.32 ± 4.69 (range 13-28) and a mean Pettersson score of 2.32 ± 3.09 (range 0-13) for the knees, 1.86 ± 2.67 (range 0-11) for ankles and 1.42 ± 2.17 (range 0-10) for elbows. The mean MRI score for the knees was 3.92 ± 2.74 (range 0-10) while that for ankles was 3.16 ± 2.64 (range 0-10) and for elbows was 2.34 ± 2.63 (range 0-10). There was highly significant correlation between both radiological joint scores and FISH and between degree of factor VIII deficiency and each of FISH, Pettersson score and MRI score. MRI was superior to conventional radiography in detection of subchondral cyst formation and erosions at joint margins. Given the highly significant correlation with both radiological joint scores, FISH appears to be a reliable tool for assessment of functional independence in adolescents with haemophilia A. MRI is more sensitive than conventional radiography in detection of early joint abnormalities., (© 2011 Blackwell Publishing Ltd.)

Haemarthrosis triggers haemophilic arthropathy (HA) because bleeding starts synovitis immediately, damages cartilage and leads to loss of function and disability. The aim of our study was to investigate the capacity of ultrasonography (US) in detecting bleeding and joint damage in HA. The joints of 62 patients (pts) with haemophilia A or haemophilia B were consecutively evaluated and scored (score ranging from 0 to 21) for effusion (E), bone remodelling (BR), cartilage damage (CD), synovial hypertrophy (SH), haemosiderin (H), osteophytes (O), haemarthrosis (Hae), erosion (Er) and fibrotic septa (FS) with US. X-rays [Pettersson Score (PXS)] were performed in 61 patients and clinical evaluation [World Federation Haemophiliac orthopaedic score (WFHO)] was performed in all patients. A total of 20 healthy subjects and 20 patients affected by Rheumatoid Arthritis (RA) were used as controls. Power Doppler US (PDUS) was performed in all patients on the knee, ankle and elbow joints. A total of 83 joints were studied (50 knees; 12 elbows and 21 ankles). US showed effusion in 57 joint, bone remodelling in 62, cartilage damage in 64, synovial hypertrophy in 45, haemosiderin in 39, osteophytes in 30, haemarthrosis in 24, erosion in 5 and fibrotic septa in 3. The X-rays score showed remodelling in 47 joints, narrowing joint space in 44, displacement/angulation in 39, osteoporosis in 42, subchondral irregularity in 44, subchondral cyst formation in 37, osteophytes in 36 and erosions in 25. The US score in healthy subjects was always ≤ 5 (range 0 to 4). In haemophiliacs, 34 of 83 joints showed US score ≤ 5, and 49 US score > 5. Joints with US score ≤ 5 had a low PXS (SRCC = 0.375, P < 0.01) and joints with US score > 5 showed a high PXS (SRCC = 0.440, P < 0.01). A significant correlation between US score and PXS for bone remodelling [Spearman's rho Correlation Coefficient (SRCC) = 0.429, P < 0.01] and for osteophytes (SRCC = 0.308, P < 0.05) was found. The correlation between the US score and number of bleedings in 83 joints was very significant (SRCC = 0.375, P < 0.01). A total of 24 bleeding joints were identified and verified with aspiration of haematic fluid. US may detect bone and cartilage alterations and synovitis. Indeed, PDUS identified bleeding also in asymptomatic joints and was able to show different entity of haemarthrosis. US may be a feasible and reliable tool to evaluate joint modifications in HA., (© 2010 Blackwell Publishing Ltd.)

To evaluate the inter-observer reliability of radiological assessment systems for haemophilic arthropathy, three senior orthopaedic surgeons with expertise in haemophilia independently evaluated a total of 527 joint radiographs of adult haemophilia patients, without any knowledge of the clinical data. This study was the largest study to evaluate the reliability of radiological assessment systems. As for the results, the Arnold-Hilgartner staging system showed moderate reliability (kappa value: κ = 0.44, P = 0.000), and the De Palma grading system and the Pettersson scoring system showed fair reliability (κ = 0.40, P = 0.000) and slight reliability (κ = 0.12, P = 0.000) respectively. As for the reliability of the eight findings in the Pettersson scoring system, three findings, which were 'narrowing of joint space' (κ = 0.70 P = 0.000), 'irregular subchondral surface' (κ = 0.58, P = 0.000) and 'erosion of joint margins' (κ = 0.56, P = 0.000), showed substantial or moderate reliability. Other findings showed fair or less reliability. The traditional radiological assessment systems showed poor inter-observer reliability. Both progressive scales showed higher reliability than the additive scale, and the three findings in the Pettersson scoring system showed good reliability. These results suggested that the progressive scale, including the three reliable radiological findings, might be a more reliable radiological assessment system., (© 2010 Blackwell Publishing Ltd.)

Summary: In spite of the fact that the diagnosis of haemophilia is essentially clinical and laboratory-based, imaging has become an important tool for the evaluation of complications, diagnostic confirmation and/or complementation and therapeutic follow-up in haemophilic arthropathy. Radiography remains the workforce horse in the diagnosis and follow-up of haemophilic arthropathy. The radiographical findings in arthropathy follow an expected sequence of events and are overall similar in different joints. Magnetic resonance imaging (MRI) has advantages over radiography based on its capability of visualizing soft tissue and cartilage changes in haemophilic joints. The recent development and standardization of MRI scoring systems for measuring soft tissue and cartilage abnormalities may enable the comparison of pathological joint findings in clinical trials conducted at different institutions across the world. The implementation of high-frequency transducers and colour/power Doppler capabilities has provided new insights for clinical applications of ultrasonography (US) in haemophilic arthropathy. In spite of the imaging modality's technical challenges such as operator-dependency, US has advantages over MRI. One of these advantages is its ability of differentiating synovium hypertrophy and hemosiderin deposition, which is not possible with MRI given the presence of susceptibility artefacts from extracellular hemosiderin on gradient-echo MR images. In addition to the aforementioned conventional imaging modalities, novel imaging techniques (blood oxygen level dependent, ultrasmall superparamagnetic iron-oxide contrast-enhanced, and T1 and T2 mapping MRI, ultrasound biomicroscopy, microbubble contrast-enhanced US and positron emission tomography, among others) hold promise for early assessment of haemophilic arthropathy in the future upon completion of their clinical validation.

Total hip arthroplasty (THA) in haemophilic arthropathy is reported to be less successful than in non-haemophilic indications. Although preliminary results are encouraging, the survival and functional outcome of cementless THA in haemophilia are not known. The aim of this study was to analyse mid-term results of cementless THA in haemophilia. Twenty-seven consecutive cementless THAs with 23 patients performed between June 1995 and June 2003 were reviewed. Mean age at time of operation was 36 years and mean follow-up period was 92 months (range, 60-156). Radiographic assessment was done for fixation of components, loosening, osteolysis, wear and bone responses around the implants. The factor requirements, amount of transfusion and complications associated with bleeding were studied. The mean preoperative Harris hip score changed from 57 to 95.9 at the latest follow-up. The survival at mean follow-up was 95.2%. One patient with osteolysis around acetabular cup was re-operated with bone-grafting and change of polyethylene liner. One loose cup was revised with a cemented cup. All other components were deemed stable at the latest follow-up. A standardized management protocol and dedicated team approach comprising of haematologist, physicians, physical therapist, nurses and coordinators is needed for excellent results. The present retrospective study shows that the functional results of cementless THA in haemophilia are satisfactory as it happens in osteoarthritic patients according to the current literature, mainly the younger. Thus, taking into account that the majority of haemophilia patients requiring a THA are relatively young, cementless THA is currently recommended.

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

Haemophilia patients with inhibitors commonly present much more severe musculoskeletal problems than patients without inhibitors. With haematological advances using recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrate (aPCC), it is now possible to perform orthopaedic procedures in these patients with a high rate of success. In Spain, the healthcare system sets no financial limits for the treatment of haemophilia, and children with haemophilia today have a much better musculoskeletal status than 30 years ago. However, the children of 30 years ago are now adults and are afflicted by severe articular deformities that frequently require the intervention of an orthopaedic surgeon. Our view is that the well-known concepts of prophylaxis in patients without inhibitors should be followed and applied to patients with inhibitors. In fact, prophylaxis seems to be the only way to prevent the development of haemophilic arthropathy in patients with haemophilia. Until this goal can be achieved, major and minor orthopaedic procedures will be necessary in patients with inhibitors more frequently than in patients without inhibitors.

Haemophilia patients may develop cardiovascular diseases, suggesting that their clotting defect does not protect them completely from atherosclerosis and its complications. We aimed to evaluate cardiovascular risk factors and, for the first time, the presence of endothelial dysfunction in middle-aged haemophilia patients. We studied 40 patients with haemophilia A and B (24 with moderate-severe disease and 16 with mild disease), and 40 healthy controls. Flow-mediated dilation (FMD), carotid ultrasound (US) intima media thickness (IMT), arterial blood pressure, body mass index (BMI), cholesterol, triglycerides, glucose, insulin, lipoprotein(a) and homocysteine levels were measured, and PAI-1 and t-PA levels before and after venous occlusion (VO), and antibodies to HIV, HBV and HCV were assayed. At least one cardiovascular risk factor was detected in 87.5% of patients, and 2 or more in 47.5% of cases. At US exam, none of the patients had significant carotid stenosis or significant differences in IMT compared to controls. In contrast, all the patients had a significant FMD impairment, associated with a reduced t-PA release after VO in 70% of cases. PAI-1 levels significantly correlated with BMI, triglycerides and insulin values. Fifteen haemophilia patients with chronic viral hepatitis and/or HIV infection showed a significantly lower FMD than patients without active infection. We found an endothelial dysfunction with impaired FMD and t-PA release in our haemophilia patients, usually associated with cardiovascular risk factors. Other pathogenic mechanisms, such as chronic viral infections, are likely to be involved in this endothelial damage, however.

New imaging techniques are valuable for the care of patients with haemophilia. On angiography it is shown that some bleedings in severely damaged joints or after implantation of prostheses are arterial. Effect of clotting factor is often poor. Selective catherization with embolization of the bleeding artery stops the bleed and is clinically effective. From 31 patients with severe haemophilia A or B, 62 knee radiographs were scored according to the Pettersson-scoring system as well as with Knee Digital Image Analysis (KIDA). Using KIDA, good correlation was found for osteoporosis, irregular subchondral surface, narrowing of the joint space, deformity and incongruence. For each of the parameters within one point in the Pettersson score a large variation existed in KIDA grading. MRI is accurate for diagnosis of soft and osteochondral tissue. Nevertheless, it is costly and not very accessible. The use of parallel imaging is more feasible for assessment of multiple joints within a relatively short period of time. Although ultrasonography also holds the potential for being an adjunct to MRI it has the disadvantage that it is operator-dependent. In a cohort of 124 chronically HCV infected haemophilia patients transient elastography was performed to measure liver stiffness. 57 (46%) had no or mild fibrosis, 18 (14.5%) moderate fibrosis and 49 severe or cirrhotic fibrosis. Transient elastography is safe and helpful to refer patients to antiviral therapy.

Although the severity of haemophilic arthropathy is commonly assessed using established radiographic scoring systems, there is limited available information about their inter- and intra-observer reliability. The purpose of the present study was to establish the inter-observer reliability (IEOR) and intra-observer reliability (IAOR) of three different methods available for the classification of haemophilic arthropathy, including the Arnold and Hilgartner classification, a modification to the Arnold and Hilgartner system described by Luck et al., and the classification described by Pettersson et al. Antero-posterior and lateral radiographs of 54 haemophilic joints were included for the analysis. To determine the IEOR for each one of the three radiographic systems, the radiographs were randomly evaluated by four observers, including two orthopaedic surgeons, one orthopaedic resident and one haematologist. For the determination of IAOR, all four reviewers repeated the assessment in a similar fashion, after a period of at least 2 weeks. IEOR and IAOR for the three classification systems was established using kappa (kappa) statistics. A Spearman rank correlation was used to determine the similarities between each reviewer's own interpretative scales. The IEOR was low for the Arnold and Hilgartner system (kappa = 0.35, P < or = 0.001) and the Luck system (kappa = 0.38, P < or = 0.001), but even lower for the Pettersson system (kappa = 0.06, P = 0.1). For the Pettersson system, particularly low kappa values were observed for the presence or absence of osteoporosis (kappa = 0.11, P = 0.0027), enlarged epiphysis (kappa = 0.10, P = 0.0039), erosion of joint margins (kappa = 0.11, P = 0.0018), and joint deformity (kappa = 0.16, P = 0.00001). However, a relatively high Spearman rank correlation for all three scales [r(s) = 0.75 (P < 0.001) for Arnold and Hilgartner system, r(s) = 0.74 (P < 0.001) for the Luck system and r(s) = 0.81 (P < 0.001) for Pettersson system] indicated an overall, general agreement among the reviewers with regard to the severity of the haemophilic arthropathy. There was a moderate IAOR value for both, the Arnold and Hilgartner system (kappa = 0.57, P = 0.00001) and the Luck system (kappa = 0.62, P = 0.00001) with a low IAOR value for the Pettersson system [kappa = 0.22, P = 0.00001). Currently available radiographic scoring systems for haemophilic arthropathy have low inter- and intra-observer reliability rates. Improvements, either through education or modification of the scoring systems, are critical in an era where correlations between clinical and radiographic scores have received significant attention.

We assessed the reliability and construct validity of the Compatible MRI scale for evaluation of elbows, and compared the diagnostic performance of MRI and radiographs for assessment of these joints. Twenty-nine MR examinations of elbows from 27 boys with haemophilia A and B [age range, 5-17 years (mean, 11.5)] were independently read by four blinded radiologists on two occasions. Three centres participated in the study: (Toronto, n = 24 examinations; Atlanta, n = 3; Cuiaba, n = 2). The number of previous joint bleeds and severity of haemophilia were reference standard measures. The inter-reader reliability of MRI scores was substantial (ICC = 0.73) for the additive (A)-scale and excellent (ICC = 0.83) for the progressive (P)-scale. The intrareader reliability was excellent for both P-scores (ICC = 0.91) and A-scores (ICC = 0.93). The total P- and A-scores correlated poorly (r = 0.36) or moderately (r = 0.54), but positively, with clinical-laboratory measurements. The total MRI scores demonstrated high accuracy for discrimination of presence or absence of arthropathy [P-scale, area-under-the-curve (AUC) = 0.94 +/- 0.05; A-scale, AUC = 0.89 +/- 0.06], as did the soft tissue scores of both scales (P-scale, AUC = 0.90 +/- 0.06; A-scale, AUC = 0.86 +/- 0.06). Areas-under-the-curve used to discriminate severe disease demonstrated high accuracy for both P-MRI scores (AUC = 0.83 +/- 0.09) and A-MRI scores (AUC = 0.87 +/- 0.09), but non-diagnostic ability to discriminate mild disease. Similar results were noted for radiographic scales. In conclusion, both MRI scales demonstrated substantial to excellent reliability and accuracy for discrimination of presence/absence of arthropathy, and severe/non-severe disease, but poor to moderate convergent validity for total scores and non-diagnostic discriminant validity for mild/non-mild disease. Compared with radiographic scores, MRI scales did not perform better for discrimination of severity of arthropathy.

We tested the reliability and construct validity of the Compatible magnetic resonance imaging (MRI) scale for the evaluation of haemophilic knees and ankles and compared the diagnostic performance of MRI and plain film radiographs. Sagittal and coronal gradient-echo 1.5-T MR images of knees (n=22) and ankles (n=23) were obtained from boys (age range 4-16 years; mean 11 years) in two centres (Toronto, n=26; Europe, n=19). The MR images were independently read by four blinded radiologists on two occasions. Number of previous joint bleedings and laboratory level of severity of haemophilia were the reference standards for imaging assessment. Both components of the MRI scale demonstrated high inter- and intrareader intraclass correlation coefficients (progressive (P) scale, 0.91 and 0.94; additive (A) scale, 0.81 and 0.92 respectively). The correlation between the osteochondral domain of the MRI scale and patient's age was moderate. Otherwise, correlations between A- and P-scales and clinical laboratory measurements were weak. The areas under the curve (AUCs) used for discrimination of disease severity were similar for the A- and P-scales (AUCs used for mild disease, A-scale, 0.72+/-0.07; P-scale, 0.69+/-0.08; P=0.23; AUCs for severe disease, A-scale, 0.93+/-0.05; P-scale, 0.87+/-0.08; P=0.05). No differences were noted between the AUCs of the MRI and radiographic scales used for discrimination of late osteoarticular changes; MRI scales performed better for discrimination of early changes. In conclusion, both MRI scales demonstrated excellent reliability, poor convergent validity, and moderate and excellent validity for discrimination of mild and severe diseases respectively. Compared with radiographic scores, the MRI scales performed better for discrimination of early osteoarticular changes.

To evaluate joints alterations, we performed clinical examination, X-rays and magnetic resonance imaging (MRI) (Denver score) in 165 joints of 40 children with severe (n, 32) or moderate (n, 8) haemophilia A or B. All investigated joints had a history of more than three bleeds. At evaluation, 25 of 40 haemophilic patients were on prophylaxis for the last 1-8 years (mean: 3.5 years). MRI revealed chronic synovitis in 55.4% and 50% of joints, which were diagnosed, as normal by the clinical scale and plain radiography respectively. Moreover, MRI unmasked more profound alterations than those observed by plain radiography in 70% of cases. Statistical analysis showed that the clinical and Pettersson scores in contrast to the Denver score provide an underestimation of arthritic changes. Besides, Denver score did not provide resolution in differentiating stages of arthropathy, because of its inherent nature; however, a score of 6 expressing severe synovitis seemed to be the cut-off value for the distinction of severe cases. Based on MRI findings we intensified prophylaxis in nine children and initiated it in another nine children. Five children, who were already on prophylaxis complied with our recommendations and eliminated haemorrhages. Finally, three boys with severe haemophilic arthropathy in knees underwent successful chemical synovectomy with rifampicin.

Since 2001 we have performed 105 radioisotope synovectomy (RS) in 65 children and young adults, age ranging from 3 to 25 years with a average of 15 years in Ege University Hospital, Izmir, Turkey. One fourth of cases were below 10 years of age. All patients had severe haemophilia A and B. Ten patients (17 joints) had high responder inhibitor. We prefer to use Yttrium 90 for all joints (5 mCi for knees; 2 mCi for others). The knees were injected in 56 cases, elbows in 24 cases, ankles in 23 cases and shoulders in two cases. Steroid injections were not preferred as the principle drug of choice. Mean follow-up period after procedure was 2 years (range: 6 months to 3.5 years). All inhibitor patients had satisfactory results. The best results were obtained in elbows than knees and ankles. Excellent rates (no bleeding) were observed in grade-II synovitis 84% for knees, 93% for elbows and 50% for ankles. Because of the excellent and good response (bleeding reduction to 75%), rates were 100% for knees and elbows and 92% for ankles. In six cases, repeated injections were given at 6-month interval and all of them had good results. The grading of synovitis seems to be an important parameter than the age of the patient. Even in patients below 10 years of age, outcomes are not satisfactory in all joints with grade-III vs. grade-II synovitis (12% vs. 73%). No serious complications were observed during and after procedure except two cases. A mild and transient inflammatory reaction was observed in the ankle. There was a minimal radioisotope leakage to superficial skin in the elbow. RS seems to be a safe and effective treatment for chronic synovitis causing recurrent joint bleedings.

Patients affected by haemophilia commonly have recurrent intra-articular bleeding which leads to progressive destruction and instability of joints. Severe arthropathy of the elbow is complicated by pain, stiffness and loss of function which can be debilitating. Conservative measures such as analgesics, physiotherapy and orthotics are commonly used in the management of these patients. Surgery is considered when conservative measures fail to control the symptoms. Total elbow replacement is now increasingly performed with the advances made in factor replacement therapy and evolution of better implants and techniques of total elbow arthroplasty. The pathogenesis, clinical features and radiological changes of haemophilic arthropathy of the elbow are described in this review article.

Although prophylactic treatment is advised for all children with severe haemophilia, the optimal regimen is still under discussion. Should all joint bleeds be prevented, or can a limited amount of arthropathy be tolerated in adulthood without loss of quality of life? To answer this question, the effect of haemophilic arthropathy on health-related quality of life (HRQoL) needs to be quantified. In a retrospective study, the effect of arthropathy on HRQoL and socio-economic parameters was assessed in a single-centre cohort of 96 patients with severe and moderate haemophilia with a minimum age of 13 years. Arthropathy was measured by the radiological Pettersson score of the elbows, knees and ankles (maximum: 78 points). HRQoL was assessed by the Short Form 36 (SF36), measuring eight domains of health. Labourforce participation and medical consumption were assessed using a separate questionnaire. Patients were studied at a mean age of 28.6 years (range: 13-54), the mean time between evaluation and the last Pettersson score was 0.4 years (SD: 1.1). The overall median Pettersson score was 13 (range: 0-78). There was a trend towards lower quality of life with increasing Pettersson scores and age, especially in the physical domains of the SF36. An age-adjusted analysis showed that arthropathy had a small but significant effect on HRQoL in the domain of 'physical function' of the SF36, but not on its other domains, or on labourforce participation and medical consumption. Thus suggesting that the SF36 can be used to assess the effects of haemophilic arthropathy, especially in the domain of 'physical function'.

Participants in an international conference on prophylactic therapy for severe haemophilia developed a consensus summary of the findings and conclusions of the conference. In the consensus, participants agreed upon revised definitions for primary and secondary prophylaxis and also made recommendations concerning the need for an international system of pharmacovigilance. Considerations on starting prophylaxis, monitoring outcomes, and individualizing treatment regimens were discussed. Several research questions were identified as needing further investigation, including when to start and when to stop prophylaxis, optimal dosing and dose interval, and methods for assessment of long-term treatment effects. Such studies should include carefully defined cohorts, validated orthopaedic and quality-of-life assessment instruments, and cost-benefit analyses.

To assess the risk of deep vein thrombosis in haemophiliacs with long-term central venous catheters, we studied haemophiliacs followed at our centre with implantable venous access devices (ports) in place for > 6 months. Medical records were reviewed for a history of catheter-related complications. Each patient was examined for physical stigmata of thrombosis. Patency of the vessels was evaluated by contrast venography. Of 21 males with ports, 19 had factor VIII deficiency and two factor IX deficiency. Nineteen ports were evaluable (i.e. were in place for > 6 months). Seventeen patients have their original ports in place; two ports were replaced for mechanical dysfunction (1) and recurrent infection (1). Difficulty withdrawing or infusing occurred with three ports, two of which were cleared with urokinase. Physical examination was normal on all 19 patients. Venograms were performed in 13 of 19 patients. Parents of the remaining six patients refused venography because of the need for peripheral venipuncture. One patient had a small nonocclusive thrombus on the same side as his functioning catheter, and another had minimal narrowing of the subclavian vein at the site of a prior catheter. The overall prevalence of clinically relevant upper venous system thrombosis identifiable by contrast venography was zero (95% CI, 0-23%). We conclude that haemophiliacs do not have as high a risk of thrombosis as other populations of patients with central venous catheters. The theoretical risk of thrombosis should not preclude use of central venous catheters in patients with haemophilia.