Search

Introduction: Contemporary haemophilia management recommends sport and physical activity in children with haemophilia. Assessment of subjective physical functioning requires standardized and validated instruments. Aims: To adapt and psychometrically test the adult Haemophilia & Exercise Project‐Test‐Questionnaire (HEP‐Test‐Q) for children (aged 6‐17 years). Methods: In discussion rounds with children, single items of the adult HEP‐Test‐Q were reformulated to make them understandable without changing the item concept. The validation of the child‐adapted version in children with haemophilia (n = 228) included pre‐testing with feasibility testing, cognitive interviewing (n = 34), pilot‐testing of the revised version in the EIS Study (n = 67) and field‐testing in the SO‐FIT Study (n = 127). Results: Pre‐testing revealed a completion time of 8.2 ± 4.1 minutes and children liked the instrument. Cognitive interviews demonstrated that most items were easy to understand; 9 items were reformulated. Pilot‐testing demonstrated good psychometric characteristics in terms of reliability (α = .94 Total Score) and validity. Convergent validity testing showed moderate correlations with the Haemo‐QoL (r = −.491), but low correlations with the Petrini Score (r = −.293). Known groups' validity revealed significant differences in clinical subgroups; chronic pain (P < .002) and target joints (P < .021). Field‐testing confirmed psychometric characteristics; Cronbach's alpha ranged from α = .80 ("endurance") to α = .94 (Total Score). The child‐adapted HEP‐Test‐Q showed moderate correlations with the PedHAL (r = .634, P < .0001) and the Haemo‐QoL SF (r = −.575, P < .0001). Known groups' validity testing proved that the HEP‐Test‐Q could discriminate between clinical subgroups. Conclusion: The child‐adapted HEP‐Test‐Q is a short, practical and acceptable instrument for the assessment of subjective physical functioning. Outcomes can be compared to adults because item concepts are identical to the adult version. [ABSTRACT FROM AUTHOR]

Background Prophylactic replacement with factor concentrate is the optimal treatment for persons with severe haemophilia to avoid or minimize bleeding. This ultimately prevents or reduces joint disease and improves life expectancy and quality of life towards values matching those in the normal population. However, uncertainty still exists around the optimal regimens to be prescribed for prophylaxis. An increasing number of treating physicians and patients are showing interest in patient-tailored approaches to prophylaxis, which aim to harmonize the prophylaxis regimen with the patients' bleeding phenotype, levels of physical activity and a variety of other variables. Methods A modified Delphi technique was adopted to generate consensus. The expert panel met in person to set the objectives, be trained on the Delphi technique and agree on the desired level of consensus. Three iterations were used to identify the targets, the scenarios and their combinations. Results Twenty-eight scenarios and eight target levels were identified and used to issue recommendations. The panel reached the desired level of consensus on positive or negative recommendations. Areas where consensus was not reached were identified and proposed as areas for future research. Prospective assessment of the validity of most of the proposed targets is recommended. Conclusions We have generated, by expert consensus, target plasma levels of factor concentrate to be used to tailor treatment for persons with haemophilia. [ABSTRACT FROM AUTHOR]

Introduction We previously showed that pharmacokinetic-guided prophylaxis ( PKP) allows the dosing interval to be extended while maintaining a specific trough level. However, the associations of peak factor VIII ( FVIII) levels and area under the curve ( AUC) with breakthrough bleeding have not been investigated. Aim The aim of this study was to analyse data from the PKP arm to determine whether peak FVIII levels, AUC and time with FVIII levels in a haemostatically effective range are independent predictors of bleeding during prophylaxis. Methods Post hoc analysis of the association of FVIII levels and AUC with annualized bleeding rate in 34 patients on PKP. Results During 1 year of PKP, 131 bleeding episodes occurred in 24/34 patients. Average peak FVIII levels ranged from 24 to 168 IU dL−1, with higher values associated with a decreased risk for all bleeding (joint and non-joint; P < 0.01) and joint bleeding ( P < 0.01). Following rFVIII infusion, median percent of time spent with FVIII levels >20 IU dL−1 was 22%; median AUC was 1363. Both values were significantly associated with a lower ABR when targeting a 1% trough at 72 h. Conclusion When PKP was administered every third day, higher peak FVIII levels, higher AUC and more time spent per week with FVIII levels >20 IU dL−1 provided increased protection from joint and non-joint bleeding. These data highlight the potential impact of variability in individual pharmacokinetic and bleeding risk and support the need for high peak levels and AUC in some patients treated every third day. The findings do not necessarily apply to alternate-day or other prophylactic dosing regimens. [ABSTRACT FROM AUTHOR]

Inhibitor development in haemophilia patients is challenging especially when undergoing surgical procedures. The development of an inhibitor precludes using factor VIII (FVIII) therapy thereby requiring a bypassing agent ( BPA) for surgical bleeding prophylaxis if the FVIII inhibitor titre >5 BU. Concomitant use of anti-inhibitor coagulant complex ( AICC) and tranexamic acid has been reported in the literature as a beneficial treatment for this population. Anti-inhibitor coagulant complex is known to cause an increase in thrombin generation and tranexamic acid inhibits fibrinolysis. Hence, the combined used of AICC and tranexamic acid has been limited due to safety concerns over possibilities of increased risk of thrombotic events and disseminated intravascular coagulation. However, the rationale for concomitant therapy is to obtain a potential synergistic effect and to increase clot stability. We conducted a literature review of past studies and individual case reports of concomitant use of AICC and tranexamic acid, which was extensively used during dental procedures. Evidence also exists for concomitant use of the combined therapy in orthopaedic procedures, control of gastrointestinal bleeding, epistaxis and cerebral haemorrhages. Some patients who received the combined therapy had failed monotherapy with a single BPA prior to combined therapy. There were no reports of thrombotic complications related to the concomitant therapy and haemostasis was achieved in all cases. Anti-inhibitor coagulant complex and tranexamic acid therapy was found to be safe, well-tolerated and effective therapy in haemophilia patients with inhibitors. Additional randomized controlled studies should be performed to confirm these findings. [ABSTRACT FROM AUTHOR]

Introduction Prophylaxis is effective in reducing the number of bleeding episodes in patients with severe or moderately severe haemophilia A and B, including those with inhibitors. However, data, predominantly from observational studies, suggest more equivocal effects on health-related quality of life ( HRQoL). Aim To examine the impact of prophylaxis on HRQoL from prospective clinical trials. Methods We performed a systematic literature review of clinical trials evaluating the efficacy of prophylaxis with factor VIII, FIX or bypassing agents. Trials assessing HRQoL via validated instruments were selected and summarized. Results Thirteen trials (haemophilia A [ n = 8]; haemophilia B [ n = 2]; inhibitors [ n = 3]) met all inclusion criteria. HRQoL instruments included the EQ-5D, SF-36, Haem-QoL-A, Haem-A-QoL, Haemo-QoL and CHO- KLAT. Improvements in HRQoL following prophylaxis were observed with the EQ- VAS, SF-36 and haemophilia-specific instruments in adult patients and were associated with reduced pain, fewer restrictions in physical activities and better general health. Prophylaxis led to statistically significant or clinically meaningful HRQoL improvement in six trials and non-significant improvement in four trials; two trials found no improvement and one reported no data. Despite study differences, consistent trends suggested that patients previously treated solely on-demand and those who experienced marked reductions in the frequency of bleeding with prophylaxis had a greater improvement in HRQoL. Conclusion Contrary to findings of observational studies, the results from the majority of prospective trials using validated instruments showed positive trends for improved HRQoL with prophylaxis in adults. [ABSTRACT FROM AUTHOR]

Many paediatric patients with haemophilia who might benefit from radiosynovectomy ( RS) for the control of synovitis do not undergo the procedure as there is controversy in the literature regarding the safety of radiation exposure after two cases of acute lymphocytic leukaemia in children with haemophilia treated with 32P RS were reported. The purpose of this review was to analyse the safety of RS in paediatric patients with haemophilia and provide a risk-benefit assessment, which practitioners could apply to their patients. Children undergoing knee RS receive a radiation dose of approximately 0.74 mSv (90 megabecquerels-MBq) and elbow and ankle RSs a dose of approximately 0.32 mSv (30-40 MBq). The radiation dose from natural sources is approximately 2 mSv and the recommended limit for patients (apart from natural sources) is 1 mSv per year. The lifetime cancer risk increases about 0.5% per 100 mSv per year. Considering the risks and benefits of RS, the authors recommend that clinicians consider this procedure in children with inhibitors or in patients without inhibitors when bleeding is recurrent and persistent despite aggressive factor replacement. [ABSTRACT FROM AUTHOR]

Prophylaxis prevents joint and other bleeding episodes in patients with haemophilia A. Development of new factor concentrates with longer circulating half-lives may encourage patients to start, continue or resume prophylaxis. The aim of this study was to compare the pharmacodynamic effect of a PEGylated full-length recombinant factor VIII ( rFVIII) concentrate with that of an unmodified rFVIII concentrate with respect to the duration of prophylactic efficacy in a murine model of haemophilic joint bleeding. Mice were pretreated with BAX 855 or unmodified rFVIII at specified times before right knee puncture to induce haemarthrosis; left knee joints served as controls. Joint bleeding was evaluated using a combination of visual and histological assessments. Administration of a single dose of unmodified rFVIII before joint puncture prevented haemarthrosis in mice up to 24 h, whereas pretreatment with BAX 855 protected the joint from bleeding up to 48 h. This pharmacodynamic study showed prolonged efficacy of BAX 855 compared to ADVATE in a haemophilia A mouse joint bleeding model. This finding supports the possibility of using BAX 855 to increase FVIII trough levels and/or extend the dosing interval in patients with haemophilia A on prophylaxis, which may potentially improve prophylactic efficacy and long-term adherence. [ABSTRACT FROM AUTHOR]

Neonatal circumcision in patients with severe haemophilia has not been well studied. We performed a survey of paediatric haematologists from Hemophilia Treatment Centers ( HTC) across the United States to better understand the attitudes toward and management of neonatal circumcision in haemophilia patients. Response rate to our survey was 40% ( n = 64/159). Thirty-eight percent of respondents ( n = 24) said that they would allow this procedure in the newborn period but in many cases this was against medical advice. The most reported concern regarding neonatal circumcision in haemophilia patients was the risk of development of an inhibitor ( n = 25; 39%) followed by the concern for bleeding ( n = 22; 34%) and issues related to vascular access in the neonate ( n = 11; 17%). All respondents recommended at least one preprocedure dose of factor replacement. Twenty-two percent ( n = 14) of respondents did not use more than one dose of factor replacement but 32% ( n = 21) used 1-2 postoperative doses. The remainder of paediatric haematologists surveyed recommended between 3-5 (16%; n = 10) and 6-10 (3%, n = 2) additional days postoperatively. There was wide variation in both techniques of circumcision as well as adjuvant haemostatic agents used. Only 22% of respondents said that they had an established protocol for management of circumcision in the newborn haemophilia patient. These survey results highlight the need for evidence-based guidelines regarding the optimal management of circumcision in neonates with severe haemophilia. [ABSTRACT FROM AUTHOR]

Prophylaxis is considered optimal care for children and adults with severe haemophilia A because of its proven ability to reduce joint and other bleeding episodes. However, a ‘one size fits all’ approach to prophylaxis is not ideal, potentially leading to over-treatment in some individuals and under-treatment in others. Moreover, a generic plan fails to take into account a patient’s lifestyle and personal preferences. This article reviews the factors contributing to bleeding risk and joint damage and uses case studies to illustrate how these contributors can be weighed to individualize the prophylactic regimen, thereby increasing the likelihood of therapeutic success. [ABSTRACT FROM AUTHOR]

The phenotypic variability in haemophilia is well documented; however, the biological basis beyond factor VIII and IX activities to explain the differing clinical pictures of the disease remains unclear. It has therefore been of interest to explore other modulators of the disease's variability. Furthermore, a scoring system that reflects the multiple facets of haemophilia symptoms would be useful to compare patients via a comprehensive assessment tool. To this end, Schulman et al., created a measure known as the Haemophilia Severity Score ( HSS) as one way to compare phenotypic severity. The aim of this study was to document the differing symptomatology of haemophilia patients using the HSS. Clinical data for 178 haemophilia patients without inhibitors were reviewed and annual incidence of haemarthrosis, orthopaedic joint scores and annual factor usage calculated. Each parameter was then entered into the formula to create the HSS for haemophilia A and B patients with mild, moderate and severe factor deficiencies. Variability in the HSS for patients with the same baseline level of factor was observed for all three deficiency levels and both haemophilia types. In addition, we found that moderate and severe haemophilic B patients tended to have more morbidity based on the above calculations than the haemophilic A counterparts. The HSS is a comprehensive tool that allows for easy numerical comparison of haemophilic patients and elucidates the variable clinical presentation of the disease. The HSS could be used to stratify patients via other possible modulators of haemophilia and discover other aetiologies of the disease. [ABSTRACT FROM AUTHOR]

Repeated haemarthroses and the consequences of blood in the joint contribute to blood induced joint disease ( BIJD) in people with haemophilia ( PWH). Prevention of bleeding, through medical management, is the standard of care in developed countries, but is not universally available due to financial and other barriers. Ice application, as part of R.I.C.E. (Rest, Ice, Compression, Elevation) or alone, is commonly recommended as an adjunct treatment to decrease bleeding, pain, tissue metabolism, oedema, and inflammation. This article will review evidence regarding local cooling by commonly used ice application methods, to decrease the temperature of the skin and intra-articular ( IA) joint space and the resultant effects on haemostasis and coagulation. The general literature was reviewed for articles in English describing temperatures achievable in the skin and IA space using clinically relevant ice protocols, and the effect of cooling on haemostasis and coagulation. The literature demonstrates that typical methods of ice application can cool both the skin and IA space. Published, general literature studies have also consistently demonstrated that experimental cooling of blood and/or tissue, both in vitro and in vivo in humans and in animal models, can significantly impair coagulation and prolong bleeding. In PWH with acute haemarthrosis, ice application has potential to increase haemorrhage morbidity by further impairing coagulation and haemostasis. Ice has not been shown to improve overall outcome, stop bleeding nor swelling from haemarthrosis. Although ice can help manage acute, haemarthrosis-related pain, there are other available interventions that will not impair coagulation and haemostasis. [ABSTRACT FROM AUTHOR]

. Blood in the joint causes a number of physiological and pathological events that eventually lead to haemophilic arthropathy. Animal models show that blood in the joint induces inflammation that continues long after blood has been cleared [1]. TNF-alpha, IL-1beta and IL-6 are inflammatory mediators that increase following haemarthrosis in haemophilic mice [2]. Conventional anti-inflammatory drugs have failed to demonstrate a lasting effect in preventing haemophilic arthropathy. A new TNF-alpha antagonist has shown promising results in haemophilic mice [3]. Similarly, the use of cyclo-oxygenase-2 inhibitors may reduce angiogenesis associated with the healing process following bleeding and the associated tissue damage [4]. Animal models are useful for studying the pathophysiology of haemarthropathy, however, when applying results from animals to humans, the differences in matrix turnover rate, thickness of cartilage and joint biomechanics must be kept in mind [5]. In people with haemophilia, there is a variable response to haemarthrosis as demonstrated by magnetic resonance imaging (MRI). Up to 30% of subjects have normal MRI despite having three or more haemarthroses into the same joint [6]. Once bone damage is present, little can be done to restore anatomic integrity. Several molecules, including members of the bone morphogenic protein subfamily, have been injected into bone defects in non-haemophilic subjects with some evidence of benefit [7]. To achieve the primary goal of reducing blood in the joint and the negative sequelae, it is questionable to use ice to treat haemarthrosis. Indeed low temperature is associated with impairment of coagulation enzyme activity and platelet function [8]. [ABSTRACT FROM AUTHOR]

. Advances in therapy have improved life expectancy and quality of life of patients with haemophilia A. Due to the chronic and complex management of this disease, particularly, the development of inhibitors, little is known about their health resource utilization in the real-life setting over time. The aim was to assess the distribution and trend of healthcare resource utilization among US haemophilia A patients with and without inhibitors. The MarketScan® Database, was queried to identify individuals with ≥1 year continuous enrolment, two medical diagnoses of haemophilia A and claims for factor VIII or bypassing agent (to infer inhibitor status) during 2001-2007. Haemophilia-related cost was estimated from inpatient, outpatient and pharmacy claims. Annual cost differences were assessed by age and over a 4-year period for those with continuous enrolment. Among 51 million covered lives, 1044 haemophilia patients were identified, of whom 981 (94%; mean age = 21.2 years) did not have an inhibitor. The median haemophilia-related cost for these patients was $63,935 per patient per year. When normalized by weight, annual cost was stable (no statistically significant differences) among 312 non-inhibitor patients (mean age = 21.8 years) with 4-year continuous data. While there was a wide distribution of haemophilia-related cost among the 63 individuals with an inhibitor (mean age = 15.4 years), only 0.6% of the total haemophilia patients had costs exceeding $1 million per patient per year. This study indicated that most haemophilia A patients were inhibitor-free with relatively stable annual costs over time. There was a wide distribution of haemophilia-related cost for inhibitor patients, while the proportion of patients who incurred extreme high cost was low. [ABSTRACT FROM AUTHOR]

. Haemophilia has been recognized as the most severe among the inherited disorders of blood coagulation since the beginning of the first millennium. Joint damage is the hallmark of the disease. Despite its frequency and severity, the pathobiology of blood-induced joint disease remains obscure. Although bleeding into the joint is the ultimate provocation, the stimulus within the blood inciting the process and the mechanisms by which bleeding into a joint results in synovial inflammation (synovitis) and cartilage and bone destruction (arthropathy) is unknown. Clues from careful observation of patient material, supplemented with data from animal models of joint disease provide some clues as to the pathogenesis of the process. Among the questions that remain to be answered are the following: (i) What underlies the phenotypic variability in bleeding patterns of patients with severe disease and the development of arthropathy in some but not all patients with joint bleeding? (ii) What is the molecular basis underlying the variability? (iii) Are there strategies that can be developed to counter the deleterious effects of joint bleeding and prevent blood-induced joint disease? Understanding the key elements, genetic and/or environmental, that are necessary for the development of synovitis and arthropathy may lead to rational design of therapy for the targeted prevention and treatment of blood-induced joint disease. [ABSTRACT FROM AUTHOR]

Prophylactic infusion of factor concentrates is a safe, effective intervention for preventing arthropathy in patients with haemophilia; on-demand treatment is insufficient to prevent the orthopaedic complications and subsequent haemophilic arthropathy that stem from recurrent joint haemorrhages. The usefulness of prophylaxis in haemophilia patients without inhibitors suggests that patients with haemophilia and inhibitors could derive similar benefits. In patients with haemophilia and high-titre (>5 BU mL−1) inhibitors, bleeding episodes are treated with bypassing agents such as activated prothrombin complex concentrates (APCCs) and recombinant activated factor VII (rFVIIa, NovoSeven®; Novo Nordisk A/S, Bagsvaerd, Denmark). It is possible to administer bypassing therapy regularly to prevent haemorrhages, with the goal of limiting arthropathy and serious life- and limb-threatening bleeding. The data evaluating the efficacy and safety of this approach in patients with inhibitors are limited, consisting of results from one prospective trial and retrospective case reports. This report describes our experience with the prophylactic use of the APCC Factor Eight Inhibitor Bypassing Activity, Anti-Inhibitor Coagulant Complex, Vapor Heated (FEIBA™; Baxter AG, Vienna, Austria). Data from patients at one treatment centre were retrospectively evaluated. Case records of six patients with haemophilia A or B and high-titre inhibitors were identified. When APCC was administered regularly, most patients exhibited a reduction in the numbers of haemorrhages, an improvement in orthopaedic status, and an improvement in quality of life. Prophylaxis with APCC can reduce haemorrhages and halt further joint deterioration in patients with haemophilia and inhibitors. [ABSTRACT FROM AUTHOR]

Preservation of normal joint function in patients with haemophilia is a goal of modern therapy. Regular injections of anti-haemophilic factor concentrate reduce the risk of joint bleeding, the optimal regimen for which remains under investigation. The goals of the experiment described here are: (i) to assess the capacity of a murine model of severe haemophilic arthropathy to predict the likelihood of success of a test product to prevent joint bleeding and the complications that follow and (ii) to compare the effectiveness of recombinant human activated factor VII (rFVIIa) to recombinant human factor VIII (rFVIII) to prevent acute joint bleeding in the mouse model of haemarthrosis. Mice lacking expression of FVIII received a single intravenous injection of human rFVIII (280 U kg−1), rFVIIa (10 mg kg−1) or vehicle prior to blunt trauma injury to the knee joint. Mice receiving rFVIII and rFVIIa developed less injury-induced joint bleeding, swelling and loss of range of motion compared to mice pretreated with vehicle. Despite the reduction in clinical symptoms, synovial hyperplasia was evident in all groups after 7 days although less pronounced in mice receiving rFVIII and rFVIIa. The data under these experimental conditions demonstrate: (i) that this model can be used to evaluate novel therapies designed to prevent joint bleeding (prophylaxis) and (ii) both rFVIII and rFVIIa reduced acute haemarthrosis but did not completely prevent synovitis, the sequelae of blood induced joint injury. [ABSTRACT FROM AUTHOR]

Haemophilic arthropathy, which shares some clinical and biological injury characteristics with rheumatoid arthritis, is characterized by two main features: chronic proliferative synovitis and cartilage destruction. It is the consequence of repeated extravasation of blood into joint cavities, but its exact pathogenesis, particularly with regard to early changes in the joint, is still incompletely understood. This review presents recent findings obtained in experiments performed in vitro and using animal models, which have improved our knowledge of the pathogenesis of haemophilic arthropathy. These experimental studies show that haemophilic arthropathy is a multifactorial event in which the deposit of iron in the joints appears to exert a central role. First, iron may promote the apoptosis of chondrocytes by catalysing the formation of oxygen metabolites; this may explain the fact that intra-articular blood exerts a directly harmful effect on cartilage before, and independent of synovial changes. Secondly, iron may also act on the synovial membrane by favouring its proliferation through the induction of proto-oncogenes involved in cellular proliferation and stimulation of inflammatory cytokines as well as abrogation of apoptosis. These two processes, one degenerative and cartilage-mediated, the other inflammatory and synovium-mediated could occur in parallel or sequentially. Overall, it may be expected that these experimental results will yield new therapeutic strategies capable of effectively preventing the occurrence of this still serious and common complication in patients with severe haemophilia. [ABSTRACT FROM AUTHOR]

Recurrent haemarthrosis results in chronic synovitis and destructive arthropathy. The long-term effect of a single haemorrhage is not known. To investigate the histopathological changes following a single, but major joint haemorrhage, an animal model of massive haemarthrosis without mechanical trauma was developed and is described in this manuscript. The knee joint capsule of mice deficient in coagulation factor VIII or IX and non-haemophilic wild type mice was punctured to induce a one time, but massive haemorrhage. The single joint puncture resulted in acute haemarthrosis in both types of haemophilic mice but not in wild type mice. Subsequent to injury, the changes in the knee joints were analysed using gross, histological and radiographic assessments and compared with the uninjured knee. In addition, a novel imaging modality, micro-computed tomography, was used to document the structural damage to the joint. Our results indicate that the long-term changes classically observed in patients with advanced haemophilic arthropathy are evident following a single massive haemarthrosis. This model will allow a thorough investigation of the pathobiology of blood-induced joint disease and will be useful to test the efficacy of innovative therapeutic strategies to prevent haemophilic synovitis and arthropathy. [ABSTRACT FROM AUTHOR]

Haemophilia is a congenital disorder that commonly results in musculoskeletal bleeding and orthopaedic complications. After an acute joint haemorrhage, an increase in intra-articular pressure and inflammation cause pain, swelling and limited motion. Blood in the joint space provokes a proliferative disorder known as haemophilic synovitis. Overgrowth of the synovial membrane causes mechanical dysfunction. Eventually, there is destruction of the articular surface and underlying bone. The aim of this project was to test the hypothesis that a minimum number of haemarthroses negatively impacts on joint function and that this would be reflected by decreased physical performance of experimental animals. Mice deficient in factor VIII coagulant activity were trained to ambulate on a rotating rod then injured three times at weekly intervals. Their ability to walk was then compared to a group of uninjured mice. Cohorts of mice were killed after 1, 2 or 3 months and the knee joints examined by gross and histological methods. The results supported the following conclusions: (i) haemophilic mice can be trained to ambulate on a rotating rod; (ii) acute hemarthrosis temporarily impairs their ability to ambulate and (iii) following recovery from acute injury, mice developing synovitis demonstrated inferior physical ability compared to mice not developing synovitis. This is the first description of a quantitative assay to monitor joint function in experimental animals and should be useful to evaluate the efficacy of new therapies developed to prevent and treat bleeding and to test strategies to counter the devastating effects of synovitis. [ABSTRACT FROM AUTHOR]

Prophylaxis is paramount to try to avoid the development of haemophilic synovitis. The best treatment for synovitis in patients with inhibitors is radioactive synoviorthesis (rhenium for ankle and elbows, yttrium for knees). With both methods (prohylaxis and radioactive synoviorthesis), we can delay the development of severe haemophilic arthropathy, that eventually will require major orthopaedic surgery. [ABSTRACT FROM AUTHOR]

Hemarthrosis is a common manifestation of haemophilia, and joint arthropathy remains a frequent complication. Even though the exact mechanisms related to blood-induced joint disease have not yet been fully elucidated, it is likely that iron deposition in the synovium induces an inflammatory response that causes not only immune system activation but also stimulates angiogenesis. This process ultimately results in cartilage and bone destruction. Investigating the processes that occur in the early stages of blood-induced joint disease in humans has been very limited. Therefore, the use of haemophilic animal models is critical to augment the understanding of this phenomenon. This article discusses three cellular regulators (p53, p21 and TRAIL) induced in synovial tissue that are important for iron metabolism. A cartilage remodelling programme induced by the release of cytokines and growth factors that result in articular damage is also discussed. Full elucidation of the pathogenesis of haemophilic joint disease is required to identify new avenues for prevention and therapy. [ABSTRACT FROM AUTHOR]

Recurrent spontaneous haemarthrosis are commonly seen in patients affected by haemophilia. The knee and the elbow are most commonly affected and both are amenable to arthroscopic treatment. Arthroscopic synovectomy is indicated after failure of appropriate medical management with recurrent bleeding. Many patients also demonstrate motion loss and functional deterioration. The benefits of arthroscopic synovectomy include the ability to perform adequate synovial debridement, but also concomitant lysis of adhesion and capsular release to regain range of motion. Results of arthroscopic synovectomy demonstrate a significant decrease in episodes of haemarthrosis, and significant improvement in pain, range of motion and function. The primary predictor of outcome is degree of pre-existing degenerative changes within the joint. In more severe cases, the results of arthroscopic synovectomy are unpredictable and serious consideration should be given to primary arthroplasty. [ABSTRACT FROM AUTHOR]

Arthropathy remains a major cause of morbidity in patients with haemophilia. Frequent bleeding into the joints leads to joint damage with resultant contractures, joint deformities and arthritis. This in turn leads to muscle atrophy, limited physical activity, osteoporosis and disability. Even though several studies of prophylactic factor replacement for persons with severe haemophilia demonstrate improved joint function, this therapy is still not readily available to most people with haemophilia around the world and a universal treatment protocol has not been used. In this article, we discuss key issues in the treatment of severe haemophilia: the optimal timing of initiation and termination of therapy, dosing options and goals of therapy. The options for countries where prophylaxis is not readily available are also discussed. Most studies are small and not randomized making consensus treatment recommendations difficult to formulate. Randomized, clinical trials are needed to provide the answers regarding the optimal treatment of patients with severe haemophilia. [ABSTRACT FROM AUTHOR]

Orthopaedic complications are among the most disabling sequelae occurring in patients with haemophilia and inhibitors. Recurrent or refractory joint bleeds can lead to joint damage, limiting mobility and causing permanent disability. Activated prothrombin complex concentrates (aPCCs) are effective in controlling acute, intraoperative and postoperative bleeding in patients with haemophilia and inhibitors. The relatively long, dosing interval and safety profile distinguish aPCCs as a well-suited option for prophylaxis. Therefore, it is postulated that long-term routine aPCC administration will decrease the frequency of recurrent bleeds, prevent damage to normal joints, and slow the progression of existing joint disease in patients with inhibitors. To test this hypothesis, a retrospective chart audit was performed. In four treatment centres, five patients were identified who received aPCC [Factor Eight Inhibitor Bypassing Activity, Anti-Inhibitor Coagulant Complex (FEIBA®); Baxter AG, Vienna, Austria] prophylactically for ≥6 months to prevent or reduce further joint deterioration, reduce bleeding and prevent postsurgical bleeding. Median treatment duration was 15 months and included administration of >1300 doses of aPCC. Dosages ranged from 50 to 75 U kg−1 three times per week in four patients; one patient received 100 U kg−1 daily. Orthopaedic status was maintained in four patients and improved in one; the frequency of bleeding episodes was reduced in all patients. No adverse events or thrombotic complications were reported. This case series demonstrates that routine aPCC administration may be used safely and effectively to reduce the occurrence of bleeding episodes and to maintain or improve clinical joint status in some patients. [ABSTRACT FROM AUTHOR]

Haemophilia is a congenital disorder that results in frequent bleeding into joints, in which a chronic and debilitating arthritis develops. The presence of blood evokes an inflammatory and proliferative synovial reaction. Although the molecular mechanisms and biochemical pathways which underlie this disorder are not known, significant advances have been made by studying a murine model of human haemophilic synovitis. In order to better understand and correlate the pathological, molecular and biochemical changes, it has become necessary to grade the histological changes observed. Despite a search of the literature and review of relevant publications, none of the currently utilized schemes were appropriate, and therefore a novel grading scheme was developed. After review of over 1000 histological sections, six characteristic changes were identified: (i) synovial hyperplasia; (ii) vascularity; (iii) discolouration by haemosiderin; (iv) the presence of blood (erythrocytes); (v) villus formation; and (vi) cartilage erosion. Synovial hyperplasia and vascularity were present in variable amounts and were quantitatively scored (0–3), while the other changes were qualitatively scored as absent or present (0 or 1). Application of the grading scheme was tested and a high interobserver correlation (greater than 80%) was found. The scheme was easy to learn even by novices, with no prior experience. The availability of the histological grading scheme for murine synovitis will allow for precise evaluation of the pathological changes following joint bleeding, and facilitate correlations with molecular and biochemical changes that lead to these changes. [ABSTRACT FROM AUTHOR]

The development of pseudotumors represents one of the most challenging complications facing physicians who care for patients with hemophilia. The successful removal of the giant pseudotumor described in this case report was acheived by a multidisciplinary team and demonstrates that this approach, albeit associated with significant risk, may be curative. [ABSTRACT FROM AUTHOR]

Recurrent joint bleeding is the most common musculoskeletal manifestation of haemophilia and leads to a target joint and synovitis. The pathobiology of haemophilic synovitis (HS) is not well understood. Here the histopathological changes that occur following haemarthrosis were examined in an animal model for human HS. After two haemarthrosis, there was soft tissue and joint swelling and histological changes of acute synovitis included infiltration of the sub-synovial layer by mononuclear cells and neutrophils, thickening of the synovial membrane with villus formation, and hyperplasia of blood vessels. Subacute changes were evident after three haemarthrosis; muscle atrophy was present and an intense mononuclear cell infiltrate filled the sub-synovial space. There was destruction of articular surfaces and loss of cartilage. Seventeen months after three haemarthrosis, chronic joint changes included gross deformity and loss of congruence due to dense fibrotic tissue filling the joint space. The mononuclear inflammatory cell infiltrate and thickened synovial membrane persisted. Pits and erosions of articular surfaces and sub-chondral cysts were present. There was fibro-cartilage and new bone formation. This model of human HS should be useful to fully evaluate the biochemical and molecular changes that occur following joint bleeding and to test novel therapeutics to prevent HS. [ABSTRACT FROM AUTHOR]

Haemophilia is a genetic disease as a result of the deficiency of blood coagulation factor VIII or IX. Bleeding is common, especially into joints where an inflammatory, proliferative synovitis develops resulting in a debilitating arthritis, haemophilic arthropathy. The pathogenesis of blood-induced haemophilic synovitis (HS) is poorly understood. The gross, microscopic and ultrastructural changes that occur in the synovial membrane following human and experimental hemarthrosis have been described. Repeated episodes of bleeding induce synoviocyte hypertrophy and hyperplasia, an intense neovascular response and inflammation of the synovial membrane. The component(s) in blood that initiates these changes is(are) not known, although iron is often proposed as one possibility. Here, we describe a novel murine model of human haemophilia A, which facilitates the examination of large number of animals and tissue specimens. The effects of hemarthrosis on the physical, gross and microscopic changes evoked following joint bleeding are described. Controlled, blunt trauma to the knee joint consistently resulted in joint swelling because of a combination of bleeding and inflammation. Hemosiderin was found in the synovial membrane. Similar to hemarthrosis in human haemophilia, joint bleeding resulted in acute morbidity evidenced by inactivity, weight loss and immobility. With time the animals recovered. The model of experimental murine HS described here has utility in the study of the pathogenesis of HS. This is the first of a series of articles, which will discuss the pathophysiology and characterize the model, with comparison of his model to others which have been published previously. It should provide a useful model to test potential therapeutic interventions. [ABSTRACT FROM AUTHOR]

The complex process underlying the development of blood-induced joint disease remains mysterious. Novel technologies such as matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) to examine protein signatures may provide clues into the process. [ABSTRACT FROM AUTHOR]