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Introduction: People with haemophilia (PWH) not administered primary haematological prophylaxis since childhood, that is, those treated haematologically on demand or not treated at all, often experience the degeneration of the ankles, leading to pain and functional impairment., Aim: To analyse the outcomes and complications of arthroscopic ankle surgery performed on PWH., Methods: For this narrative review of the literature, a search was conducted in PubMed on 2, December 2023, using the keywords "haemophilia", "ankle" and "arthroscopy". Of the 29 articles identified, 15 specifically related to ankle arthroscopy in PWH were selected (inclusion criterion). The remaining articles did not meet this requirement (exclusion criterion) and were therefore eliminated., Results: Arthroscopic procedures (arthroscopic synovectomy, debridement and arthrodesis of the ankle) are increasingly used in the surgical treatment of haemophilic ankle arthropathy. Although arthroscopic ankle surgery offers good outcomes in patients with haemophilia, the procedure is not free of complications, which range from 7.9% for arthroscopic ankle debridement to 13.1% in arthroscopic ankle synovectomy and 17.8% in arthroscopic ankle arthrodesis, respectively. The non-union rate of arthroscopic ankle arthrodesis is 7.1% (2/28)., Conclusion: Although arthroscopic interventions in the haemophilic ankle (synovectomy, debridement, arthrodesis) offer good functional outcomes, they are associated with a non-negligible rate of complications. Arthroscopic ankle surgery in PWH is major surgery and should be treated as such., (© 2024 John Wiley & Sons Ltd.)

Background: The ability of clinical tools to identify early joint changes is limited. Synovitis is a fundamental finding in understanding haemophilia activity and the response to its therapies; thus, there is a need for sensitive methods to better diagnose subclinical synovitis early., Purpose: Our aim was to compare the frequency with which clinical assessment and ultrasound detected synovial hypertrophy in the most frequently affected joints in patients with haemophilia (elbows, knees and ankles)., Methods: We analysed patients with haemophilia older than 16 years who came to the haemophilia centre for routine follow-up. From the clinical assessment carried out in the consultation, the swelling, pain and history of haemarthrosis were evaluated and compared with the findings of synovial hypertrophy detected by ultrasound. This comparison was also analysed independently for elbows, knees and ankles., Results: A total of 203 joints of 66 patients with haemophilia (mean age 34 years), most of them on secondary, tertiary prophylaxis or on demand treatment, were included. In joints with swelling, pain and history of haemarthrosis, 78% of the joints showed synovial hypertrophy on ultrasound. However, in joints with no swelling, no pain and no history of haemarthrosis, 40% presented subclinical synovial hypertrophy on ultrasound. This percentage was higher in elbows than in knees and ankles., Conclusion: In adults with haemophilia, physical examination and point-of-care ultrasound study provide complementary data on their joint disease. However, without ultrasound, the ability to detect subclinical synovitis is considerably reduced, especially in the elbows., (© 2021 John Wiley & Sons Ltd.)

Introduction: Emicizumab-kywh (ACE910) is a recombinant, humanized, asymmetric bispecific antibody that functions to bring activated FIX (FIXa) and zymogen FX into an appropriate steric conformation to medicate the activation of FX to FXa thereby mimicking the cofactor function of FVIIIa., Aim: The objective of this manuscript was to review the development and potential role for emicizumab in the treatment of patients with haemophilia A with and without inhibitors., Methods: A Cochrane Library and PubMed (MEDLINE) search focusing on emicizumab in haemophilia was conducted., Results: In total, 37 citations were retrieved and serve as the database for the literature reviewed herein. Once-weekly subcutaneous injection of emicizumab at three dose levels has been shown to be effective as prophylaxis to prevent bleeding in a majority haemophilia A patients with inhibitors to FVIII. Likewise, prevention of bleeding was also observed in more than two thirds of patients without inhibitors to FVIII. One antidrug antibody to emicizumab has been reported in over 600 treated patients, two have developed thromboembolic events and three thrombotic microangiopathy. These thrombotic complications have occurred in conjunction with FVIII-bypassing agents, and none have been observed following recommendations from the manufacturer regarding concomitant use of bypassing agents. The median annual treated bleeding rates were decreased in patients with as well as those without an inhibitor to FVIII., Conclusion: The principal advantage of emicizumab is subcutaneous administration and effectiveness irrespective of the presence of inhibitors. Emicizumab could conceivably represent a new epoch in the treatment of people with haemophilia A., (© 2018 John Wiley & Sons Ltd.)

Planning and undertaking elective surgery in people with haemophilia (PWH) is most effective with the involvement of a specialist and experienced multidisciplinary team (MDT) at a haemophilia treatment centre. However, despite extensive best practice guidelines for surgery in PWH, there may exist a gap between guidelines and practical application. For this consensus review, an expert multidisciplinary panel comprising surgeons, haematologists, nurses, physiotherapists and a dental expert was assembled to develop practical approaches to implement the principles of multidisciplinary management of elective surgery for PWH. Careful preoperative planning is paramount for successful elective surgery, including dental examinations, physical assessment and prehabilitation, laboratory testing and the development of haemostasis and pain management plans. A coordinator may be appointed from the MDT to ensure that critical tasks are performed and milestones met to enable surgery to proceed. At all stages, the patient and their parent/caregiver, where appropriate, should be consulted to ensure that their expectations and functional goals are realistic and can be achieved. The planning phase should ensure that surgery proceeds without incident, but the surgical team should be ready to handle unanticipated events. Similarly, the broader MDT must be made aware of events in surgery that may require postoperative plans to be changed. Postoperative rehabilitation should begin soon after surgery, with attention paid to management of haemostasis and pain. Surgery in patients with inhibitors requires even more careful preparation and should only be undertaken by an MDT experienced in this area, at a specialized haemophilia treatment centre with a comprehensive care model., (© 2018 The Authors Haemophilia Published by John Wiley & Sons Ltd.)

Introduction: Advanced haemophilic arthropathy of the elbow can be a devastating manifestation of severe haemophilia with significant implications for activities of daily living., Aim: To summarize the currently available data on total elbow arthroplasty (TEA) for haemophilic arthropathy of the elbow, to draw comparisons to TEA for other indications, and to outline some considerations regarding TEA in this unique population., Methods: A narrative review of the literature has been performed., Results: The scant data regarding outcomes of TEA for haemophilic arthropathy are limited to small case series and case reports. A review of the available literature shows that, while pain relief and patient satisfaction are promising, variable outcomes with significant complications and infection rates may discourage routine use of TEA for haemophilic arthropathy of the elbow., Conclusion: While patients with severe haemophilic arthropathy of the elbow are likely to make gains in terms of pain control and range of motion following TEA, there are insufficient data to routinely recommend its use. Complication and infection rates are concerning, and the lack of survival analysis data makes it difficult to quantify the benefit to the patient in light of the risks and resources involved in the procedure., (© 2018 John Wiley & Sons Ltd.)

Introduction: Haemophilic arthropathy of the ankle is rare disorder caused by recurrent haemarthorses beginning in early adulthood., Aim: Our aim was to evaluate the fusion rate of various techniques of hindfoot fusion using internal fixation for the treatment of haemophilic arthropathy of the hindfoot., Methods: We have evaluated the fusion rate of various techniques of hindfoot (tibiotalar and subtalar joints) fusion for the treatment of haemophilic arthropathy of the hindfoot. Twenty-eight patients underwent a total of 41 procedures. Thirty-four ankle (tibiotalar) fusions were performed, seven were done arthroscopically, six using a minimal access approach and 21 with an open approach. There were two isolated subtalar fusions, three combined tibiotalar and subtalar fusions, one of which included a talonavicular fusion at the second operation. There was one peritalar ankle fusion (tibiotalar, subtalar and talonavicular). The mean age at operation was 40.3 years (SD, 12.3; range, 18.7-65.7 years). The mean time to last follow-up was 77 months (SD, 50.4; range, 7-190)., Results: The overall non-union rate was 9.7%. All non-unions occurred in tibiotalar fusions (there were no non-unions in cases of subtalar or talonavicular fusion). A single deep infection (2.4%) occurred in an arthroscopically fused ankle. The revision rate was 4.8% (2 cases) and was carried out for non-unions. Both revisions were successful., Conclusion: Hindfoot arthrodesis in patients with haemophilic ankle arthropathy provides a high fusion rate with few complications. Arthroscopic tibiotalar fusion did not result in shorter hospital stays. Revision surgery for the haemophilic hindfoot is successful, and fusion of the entire hindfoot can be achieved without complications., (© 2016 John Wiley & Sons Ltd.)

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., (© 2015 John Wiley & Sons Ltd.)

Introduction: As the population of patients with haemophilia (PWH) ages, healthcare providers are required to direct greater attention to age-related co-morbidities. Low bone mineral density (BMD) is one such co-morbidity where the incidence not only increases with age, but also occurs with greater frequency in PWH., Aim: To review risk factors for low BMD, and strategies to promote bone health and identify patients who would benefit from screening for osteoporosis and subsequent treatment., Methods: A narrative review of the literature was performed in MEDLINE with keywords haemophilia, bone density, osteoporosis and fracture. Reference lists of retrieved articles were also reviewed., Results: Low BMD occurs more commonly in PWH than the general population and is most likely the result of a combination of risk factors.  Steps to promote bone health include preventing haemarthrosis, encouraging regular exercise, adequate vitamin D and calcium intake, and avoiding tobacco and excessive alcohol intake. Adults 50 years of age and older with haemophilia and those younger than 50 years with a fragility fracture or increased fracture risk based on FRAX (The Fracture Risk Assessment Tool), regardless of haemophilia severity, should be screened for low BMD using dual x-ray absorptiometry (DXA). Once osteoporosis is diagnosed based on DXA, fracture risk should guide treatment. Currently, treatment is similar to those without haemophilia and most commonly includes bisphosphonates., Conclusion: Haemophilia care providers should promote adequate bone formation during childhood and reduce bone loss during adulthood as well as identify patients with low BMD that would benefit from therapy., (© 2015 John Wiley & Sons Ltd.)

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 (32) P 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., (© 2015 John Wiley & Sons Ltd.)

A growing number of publications have described the efficacy and safety of FEIBA as a first-line haemostatic agent for surgical procedures in haemophilia A patients with high-responding FVIII inhibitors. The aim of this study was to provide practical guidance on patient management and selection and also to communicate a standardized approach to the dosing and monitoring of FEIBA during and after surgery. A consensus group was convened with the aims of (i) providing an overview of the efficacy and safety of FEIBA in surgery; (ii) sharing best practice; (iii) developing recommendations based on the outcome of (i) and (ii). To date there have been 17 publications reporting on the use of FEIBA in over 210 major and minor orthopaedic and non-orthopaedic surgical procedures. Haemostatic outcome was rated as 'excellent' or 'good' in 78-100% of major cases. The reporting of thromboembolic complications or anamnestic response to FEIBA was very rare. Key to the success of FEIBA as haemostatic cover in surgery is to utilize the preplanning phase to prepare the patient both for surgery and also for rehabilitation. Haemostatic control with FEIBA should be continued for an adequate period postoperatively to support wound healing and to cover what can in some patients be an extended period of physiotherapy. Published data have demonstrated that FEIBA can provide adequate, well tolerated, peri and postoperative haemostatic cover for a variety of major and minor surgical procedures in patients with haemophilia A. The consensus recommendations provide a standardized approach to the dosing and monitoring of FEIBA., (© 2012 Blackwell Publishing Ltd.)

Due to improvements in the treatment and medical care of haemophilia, the life expectancy of individuals with haemophilia has approached that of the general population. To review the main co-morbidities of the musculoskeletal system in elderly persons with haemophilia, we have performed a review of the literature on the musculoskeletal problems of elderly haemophiliacs. Chronic arthropathy is the main co-morbidity in the ageing person with haemophilia. Age-related orthopaedic co-morbidities include degenerative joint changes, osteoporosis, muscle atrophy or sarcopenia, muscle weakness and disturbance of gait and balance. Increased pain, muscle weakness and atrophy along with an increased risk of falling are key features of advanced haemophilic arthropathy and ageing. An ageing haemophilia population in which arthropathy continues to be the primary co-morbidity is a current challenge for those responsible for their care. Exercise programmes undertaken two to three times per week for at least 12 weeks seem most effective in reducing the impact of age-related changes on the musculoskeletal system. Establishing effective exercise programmes and strategies to identify individuals who would benefit from early surgical intervention together with presurgical physiotherapy prehabilitation is a priority for future research., (© 2012 Blackwell Publishing Ltd.)

Current treatment of joint cartilage lesions is based either on conventional techniques (bone marrow stimulation, osteochondral autograft or allograft transplantation) or on newly developed techniques (chondrocyte implantation and those based on cell therapy that use bioreactors, growth factors, mesenchymal stem cells [MSCs] and genetically modified cells). The aim of this article is to review the therapeutic strategies above mentioned and to determine whether the chondral damage seen in haemophilia could benefit from any of them. The different conventional techniques have shown similar results whereas autologous chondrocyte implantation, which is in common use at the present time, has not been shown to produce any conclusive results or to lead to the formation of hyaline cartilage. MSCs hold promise for the repair of joint cartilage given their differentiation capacity and the therapeutic effect. The use of bioreactors and growth factors, which stimulate cartilage formation, may optimize such strategies in the context of reimplantation of chondrocytes, differentiated MSCs and cartilage progenitor cells. The aim of cell therapy is restoration of function through the repair of damaged tissue or the stimulation of growth factor synthesis. Implantation of autologous chondrocytes or MSCs was up to now able to address only highly localized chondral lesions. Adequate control of the differentiation process as well as the use of growth factors and appropriate bioreactors could transform cell-based therapies into a more efficient and longer term treatment even for patients with haemophilia. Nevertheless, raising false expectations in these patients should be avoided. There are a number of approaches to cartilage restoration in haemophilic arthropathy, which are currently being explored for other joint related degenerative disorders. If it can be proven to be effective for the disorders in which clinical trials are ongoing and costs could be limited, it might be an useful palliative approach to haemophilic arthropathy. However, we still have a long way to go for use in haemophilic arthropathy., (© 2012 Blackwell Publishing Ltd.)

Animal experiments have shown that a number of bleeding disorders may affect wound healing (WH), including haemophilia B, deficiency of factor XIII and abnormalities of fibrinogen. Therefore, normal healing requires adequate haemostatic function for the appropriate time frame (up to 4 weeks in the clean and uncontaminated wound). Many factors may affect WH, including impaired haemostasis, diabetes, poor nutrition, insufficient oxygenation, infection, smoking, alcoholism, old age, stress and obesity. The gold standard for the correct care of surgical wounds in patients with bleeding disorders includes wound dressing and comprehensive standard care (haemostasis, nutritional support, treatment of co-morbidities, offloading, reperfusion therapy and compression). Although complications of surgical wounds healing in patients with bleeding disorders are uncommon, a low level of the deficient factor for an insufficient period of time could cause WH complications such as haematomas, infection, and skin necrosis and dehiscence. Clinical experience and animal experiments appear to indicate that, to get a satisfactory healing of surgical wounds and avoid potential complications of WH, a good level of haemostasis is necessary for 2-3 weeks after surgery. However, many treaters would regard this recommendation at odds with (i.e. more aggressive than) current standards. Unfortunately no additional clinical evidence for this recommendation can be provided., (© 2012 Blackwell Publishing Ltd.)

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

If continuous prophylaxis is not feasible due to expense or lack of venous access, we must aggressively treat major haemarthroses (including arthrocentesis) to prevent progression to synovitis, recurrent joint bleeds, and ultimately end-stage osteoarthritis (haemophilic arthropathy). For the treatment of chronic haemophilic synovitis, radiosynovectomy should always be indicated as the first procedure. If, after three procedures with 6-month interval, radiosynovectomy fails, an arthroscopic synovectomy must be indicated. Between the second and fourth decades, many haemophilic patients develop joint destruction (arthropathy). At this stage possible treatments include alignment osteotomy, arthroscopic joint debridement, arthrodesis (joint fusion) and total joint arthroplasty. For the hip press-fit uncemented components (hemispherical acetabulum, flanged femoral stem, metal-to-polyethylene) are recommended whilst for the knee a posterior-stabilized (PS) cemented design is advised. Muscular problems must not be underestimated in haemophilia due to their risk of developing compartment syndromes (which will require surgical decompression) and pseudotumours (which will require surgical removal or percutaneous treatment). Regarding patients with inhibitors, the advent of APCCs and rFVIIa has made major orthopaedic surgery possible, leading to an improved quality of life for haemophilia patients. Concerning local fibrin seal, it is not always necessary to achieve haemostasis in all surgical procedures performed in persons with haemophilia. However, it could be a good adjunct therapy, mainly when a surgical field potentially will bleed more than expected (i.e. patients with inhibitors), and also in some orthopaedic procedures (mainly the surgical removal of pseudotumours)., (© 2011 Blackwell Publishing Ltd.)

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)., (© 2011 Blackwell Publishing Ltd.)

Haemarthroses (intra-articular haemorrhages) are a frequent finding typically observed in patients with haemophilia. Diagnosis and treatment of these bleeding episodes must be delivered as early as possible. Additionally, treatment should ideally be administered intensively (enhanced on-demand treatment) until the resolution of symptoms. Joint aspiration plays an important role in acute and profuse haemarthroses as the presence of blood in the joint leads to chondrocyte apoptosis and chronic synovitis, which will eventually result in joint degeneration (haemophilic arthropathy). Ultrasonography (US) is an appropriate diagnostic technique to assess the evolution of acute haemarthrosis in haemophilia, although magnetic resonance imaging remains the gold standard as far as imaging techniques are concerned. Some patients experience subclinical haemarthroses, which eventually tend to result in some degree of arthropathy, especially in the ankles. Nowadays, the most effective way of protecting these patients is primary prophylaxis, which in practice changes severe haemophilia into moderate haemophilia, preventing or at least minimizing the occurrence of haemarthrosis. If primary prophylaxis is, for whatever reason not an option, secondary prophylaxis and enhanced on demand treatment should be considered. Two alternatives are available for inhibitor patients: (i) control of haemostasis using by-passing agents (rFVIIa or aPCCs) either as enhanced on demand treatment or secondary prophylaxis, as appropriate, following the same basic principles used for non-inhibitor patients and (ii) immune tolerance induction (ITI) to eradicate the inhibitor., (© 2011 Blackwell Publishing Ltd.)

We report on a series of 92 surgical procedures (90 patients). It includes 35 orthopaedic procedures (33 patients) and 57 non-orthopaedic procedures (57 patients). The orthopaedic procedures include 27 radiosynovectomies (minor surgery) and eight major orthopaedic procedures. The non-orthopaedic procedures include 52 minor interventions and five major procedures. The average age of patients was 34 years (range: 8-56), and the average follow-up time was 3 years (range: 1-6). Of the 92 surgical procedures, 42 were performed with activated prothrombin complex concentrates [factor eight inhibitor bypassing agent (FEIBA)] and 47 with recombinant-activated factor VIIa (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark). Regarding FEIBA treatment in minor surgery, the initial dose was 100 IU kg(-1). After 6 h, we continued with 50 IU kg(-1) every 12 h for at least 4 days (radiosynovectomies). In minor non-orthopaedic procedures, the dose was continued until day 14. In patients who underwent surgery with the haemostatic control achieved by means of rFVIIa, the initial dose of rFVIIa in minor procedures (both orthopaedic and non-orthopaedic) was 90-120 microg kg(-1). In postoperative days 1-5, the dose was 2-4 x 90-120 microg kg(-1) q3-6 h for 24 h. In major procedures (both orthopaedic and non-orthopaedic), the dose was 120 microg kg(-1) pre-operatively, 120 microg kg(-1) q 3 h day 2/day 3-5, and then 90-120 microg kg(-1) q 6 h until day 14. There were 87 good results, four fair results and one poor result. Our study has shown that haemophilic patients with inhibitors requiring surgery can undergo orthopaedic and non-orthopaedic procedures with a high expectation of success. In other words, surgery (orthopaedic and non-orthopaedic) is now possible in haemophilia patients with inhibitors, leading to an improved quality of life for these patients.

The incidence of haemarthrosis as a result of a spontaneous periarticular aneurysm in haemophilia is very low. In these circumstances, angiographic embolization might be considered as a promising therapeutic and coagulation factor saving option in joint bleeds not responding to replacement of coagulation factor to normal levels. Moreover, embolization should be considered as a possible treatment for postoperative pseudoaneurysms complicating total knee arthroplasty in haemophilia. However, the pathological process of aneurysmal bleeding and clotting factor replacement is entirely different. While embolization is the treatment of choice for some periarticular complications that may occur, it is by no means a panacea for all resistant periarticular bleeds in haemophilia or for postoperative bleeding which usually settles with clotting factor replacement. Another use of arterial embolization is for the treatment of haemophilic tumours of the pelvis, because they can act as a focus for infection and cause cutaneous fistulas. When they present perforations and infections of endogenous origin, their course is usually fatal. Suitable treatment has been investigated on numerous occasions, most of the literature agreeing that the only curative treatment is surgical resection. However, surgical resection after performing arterial embolization to reduce the vascularization of the pseudotumour is a good alternative, thereby reducing the size of the pseudotumour and the risk of bleeding complications during surgery. It is important to bear in mind that despite its efficacy, arterial embolization is an invasive procedure with a reported rate of complications up to 25% (16% minor, 7% serious, 2% death).

The haemophilic pseudotumour is an expanding destructive haematoma, which is associated with a considerable amount of morbidity in haemophilic patients. Its prevention is paramount. In fact, this goal can be achieved by primary prophylaxis to avoid muscle haematomas and by adequate and long-term haematological treatment of muscle haematomas in case they appear. At the moment, surgical excision of pseudotumour is the preferred treatment by many authors. However, there are instances that surgical extraction of the lesion is not feasible. In such situations, radiotherapy and arterial embolization should be considered either alone or as an adjunct to surgery. Conservative management using a combination of radiotherapy and replacement therapy should be considered for treating haemophilic bone pseudotumours, which are located in the skull or in the distal parts of the limbs, especially in conditions where some impediments to surgical excision exist. In fact, the radiation should be delivered to the lesion site in small fragments of 2 Gy or less to a total dosage of 6-23.5 Gy, which is the most recommended radiation dosage, at the moment. Therapeutic arterial embolization of haemophilic pseudotumours should be considered in lesions of large size, especially in pseudotumours of pelvic region, as it may effectively reduce its size and decrease the risk of bleeding complications during surgery. Nevertheless, in view of its temporary effect, embolization may better be performed, as a preparatory procedure, at best about 2 weeks prior to surgery. This time lapse will allow for mass shrinkage but is insufficient for vessel restoration.

Prophylaxis is the ideal manner to treat haemophilia patients without inhibitors. In fact, it can prevent the orthopaedic complications that commonly bedevil haemophilia patients without inhibitors in the absence of such prophylaxis or when they are only managed by on-demand treatment. Currently, there are two agents that allow us to control haemostasis in patients with inhibitors, i.e. recombinant factor VIIa (rFVIIa) and activated prothrombin complex concentrate (APCC). Both agents can be used for arthropathy prevention, or for intensive on-demand treatment in haemophilia patients with inhibitors. In this paper, we have tried to find an answer to the question of which bypassing agents (rFVIIa or APCC) could be used in children and adults.

We recommend prophylaxis in haemophilic children with an inhibitor as a way of preventing the musculoskeletal impairment that is likely to affect them. This approach has been used for children without inhibitors with excellent results. If prophylaxis is not feasible, we suggest that intensive on-demand treatment should be given. Two agents, recombinant activated FVII (rFVIIa) and activated prothrombin complex concentrates (aPCC), are currently used to control haemostasis either for prophylaxis or intensive on-demand treatment. As it is recombinant, rFVIIa would seem more appropriate to be employed in children. aPCC could be used in adults, or in the event of an unsatisfactory response to rFVIIa. We recommend prophylaxis or, at least, intensive on-demand treatment in haemophilia children with inhibitors. Both rFVIIa and aPCC are being used for this purpose. It would seem that rFVIIa might be more appropriate for children as it is a recombinant product. Nevertheless, after skeletal maturity (in adults), both agents could be used indistinctively (taking into consideration that FEIBA is a plasma-derived product). We still need more well-designed comparative studies in order to be able to assert that our consensus-based conclusion is evidence based. In orthopaedic surgery, both aPCC and rFVIIa have been reported to be effective in controlling perioperative haemostasis, although in practice most centres have so far used rFVIIa for their orthopaedic procedures. We recommend rehabilitation programmes for all patients with inhibitors in order to mitigate the disabling and handicapping impact of their condition and thereby enable them to achieve social integration. Programmes for haemophilic children without inhibitors can be applied to children with inhibitors but should be individually tailored.

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 with inhibitor have a higher level of arthropathy and more severe joint morbidity than patients without inhibitors. In recent years, interest has grown in the possibility that bypassing agent regimens could prevent bleeding and, consequently, arthropathy in inhibitor patients. Nevertheless, doubts about efficacy, complications and cost exist, questioning the justification of an uncertain prophylaxis in patients with inhibitors. Activated prothrombin complex concentrate (aPCC) has been used in more than 70 haemophilia patients with inhibitors in different clinical situations. aPCC prophylaxis seems to be safe and effective for the reduction of bleeding episodes in some patients. Recombinant activated factor VII (rFVIIa) has been employed prophylactically in over 44 haemophilia patients with inhibitors; 22 patients were included in the only randomized, prospective clinical trial of bypassing agents in prophylaxis. Bleeding frequency was reduced and this reduction was maintained during the postprophylaxis period. No thromboembolic events were reported during prophylaxis with rFVIIa. Although the effect of aPCC can last longer than that of rFVIIa, their efficacy rates are similar, suggesting that the biological effect of rFVIIa is actually much longer than indicated by its short plasma half-life. aPCC contains residual factor VIII antigen and may cause an anamnestic response in the inhibitor titre. This is crucial when immune tolerance induction is postponed to allow the inhibitor titre to decline to <10 Bethesda Units. In this setting, aPCC is not recommended as a first-line prophylaxis because of its potential to protract anamnesis, and rFVIIa is the preferred agent.

Various conservative options are available to treat ankle problems in haemophilia, which achieve a high rate of satisfactory results in the majority of cases. They are usually employed in combination and include the use of patellar tendon bearing (PTB) orthoses and radiosynoviorthesis. The effect of the PTB orthoses is that it allows the patient to walk without weight bearing of the ankle. Radiosynoviorthesis can be performed in cases of haemophilic arthropathy of the ankle, provided there is at least a minimal degree of synovitis within the joint, with a 75% of satisfactory results. If the conservative options fail, surgical intervention can be indicated. Alternatives to total ankle arthroplasty or arthrodesis include arthroscopic debridement, removal of osteophytes of the anterior aspect of the distal tibia and peri-articular osteotomies to correct angular, rotational or translational malalignment. Ankle arthrodesis is the standard technique for end-stage ankle arthropathy. Arthroscopic debridement of the ankle with haemophilic arthropathy can offer temporary relief; however, it is important to stress to patients that the degree of improvement is limited. The complication rate in ankle arthroscopy is high compared with other joints, which is especially true for neurological complications and postoperative infections. Orthopaedic procedures are not very frequent in the haemophilic ankle, because the majority of problems can be solved satisfactorily by conservative means (radiosynoviorthesis and PTB orthosis).

In this paper, the most recent developments on arthropathy and inhibitors in haemophilia are reviewed. Firstly, early long-term prophylaxis is strongly recommended in children with severe haemophilia. Secondly, in joint bleeds not responding to substitution of factor VIII to normal factor VIII levels angiographic embolization might be considered as a promising therapeutic option. Thirdly, recent data indicate disruption of normal development for adolescents with inhibitors. Fourthly, some case reports indicate the benefit of secondary prophylaxis with recombinant factor VIIa (rFVIIa) or factor eight inhibitor bypassing activity (FEIBA) in patients with severe haemophilia A and inhibitors. Finally, surgical procedures in haemophilia patients with factor inhibitors can be accomplished safely and effectively with FEIBA and/or rFVIIa, although the risk of complications is higher than in haemophilia patients without inhibitors.

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.

Chronic synovitis is a serious complication of haemophilia that should be understood to avoid or minimize its consequences (articular damage and joint degeneration). Haematological prophylaxis and treatment are paramount during the life of people with haemophilia. However, as about 80% of bleedings in haemophilia affect the musculo-skeletal system, the role of orthopaedic surgeons, rehabilitation physicians and physiotherapists is very important in the context of the multidisciplinary team. Synovitis can firstly be prevented and/or controlled with medical treatment and then be treated by synoviorthesis or surgical synovectomy. In this article, the author reviews some current basic principles on the prevention and treatment of haemophilic synovitis to avoid further development of joint destruction (haemophilic arthropathy).

In severely affected haemophilic patients knee and hip arthropathy is a common problem, which can leads to considerable pain and functional deficit. Surgical management, including total knee and hip arthroplasty, can be undertaken if conservative management fails. This paper reviews the functional outcome of arthroplasty in the knee and hip, the postoperative and long-term complications, and the impact of HIV. Although complications are commonly described and the surgery is technically demanding, the results of the author of this paper and the review of the literature suggest that arthroplasty of the hip and knee can be a valuable option in the management of severe haemophilic arthropathy.

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.

We report on a series of 27 orthopaedic surgical procedures. It includes 20 radiosynoviortheses and seven major orthopaedic procedures, performed on 26 patients. The average age of patients was 36 years (range: 8-53) and the average follow-up time was 2.5 years (range:1-5). There were 23 good results and four fair. In the synoviorthesis group (20 patients, 20 synoviortheses) the average age was 13.5 years (range: 9-26) and the average follow-up was 4.5 years (range: 1-7). There were 19 good results and one fair. All synoviortheses were done with activated prothrombin complex concentrates (FEIBA), all the responses being good except in one case (which had the final fair result). The total dose of FEIBA used was 600 IU kg(-1,) except in a patient that had a haemorrhagic complication. In fact, he required a prolongation of treatment up to a total dose of 2000 IU kg(-1). In the group of major orthopaedic procedures, the average age of the six patients was 30.5 years (range: 11-53) and the average follow-up was 2.5 years (range: 1-5). There were six good results and one fair. Postoperative bleeding complications occurred in one of the seven major orthopaedic procedures performed (arterial pseudoaneurym after a total knee arthroplasty). Despite such complication, which had the final fair result, our study has shown that haemophilic patients with high inhibitor titres requiring orthopaedic surgery can undergo such procedures with a high expectation of success. In other words, orthopaedic surgery is now possible in haemophilia patients with high-titre inhibitors, leading to an improved quality of life for these patients.

Pseudotumours are a rare complication of haemophilia. Surgery undertaken for pseudotumour on a lesion that is subsequently found to be malignant can be expected to adversely affect patient outcome. We present six case reports found from a literature search of patients with haemophilia who underwent surgery on what was a primary malignancy misdiagnosed as a pseudotumour and give a subsequent discussion.

In the era of contemporary orthopaedics, haematology and internal medicine, it is obvious that surgery can be indicated in human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfected haemophilia patients suffering from severe and painful musculoskeletal problems. However, the expected high risk of infection and other postoperative complications is a concern due to the poor health status that many of these patients present. In a HIV and HCV coinfected haemophilia patient, the orthopaedic surgeon together with the multidisciplinary haemophilia team should weigh the risks and benefits carefully. Clinical and immunological status should be considered before suggesting a surgical procedure (specially a joint arthroplasty) in this group of patients. If a surgical procedure is contraindicated, conservative treatment could be an alternative, although many times with inferior results. Usually, surgical procedures can better relieve pain for several years and improve the quality of life in this cohort of patients. Regarding anaesthetics, drugs metabolized by the liver or the kidney should be avoided depending on every particular case. Rachianaesthesia is more recommendable than epidural anaesthesia in elderly patients in whom general anaesthesia sometimes could be dangerous, although in all ages we prefer general anaesthesia. The size of the needle should be small (size G-27), and we never use spinal catheters.

Radiation synoviorthesis is a very effective procedure that decreases both the frequency and the intensity of recurrent ankle bleeds related to ankle synovitis. The procedure should be performed as soon as possible to minimize the degree of articular cartilage damage. It can also be used in patients with inhibitors with minimal risk of complications. On average, the efficacy of the procedure ranges from 76% to 80%, and can be performed at any age. The procedure slows the cartilaginous damage which intra-articular blood tends to produce in the long term. After 30 years of using radiation synovectomy worldwide, no damage has been reported in relation to the radioactive materials. Radiation synovectomy is currently the preferred procedure when radioactive materials are available; however, chemical synoviorthesis is an effective alternative method if radioactive materials are not available. Personal experience and the general recommendation among orthopaedic surgeons and haematologists is that when three early consecutive synoviorthesis (repeated every 3 months) fail to halt synovitis, a surgical synovectomy (open or by arthroscopy) should be immediately considered. For advanced haemophilic arthropathy of the ankle, the best solution is an ankle arthrodesis. Primary prophylaxis and radioactive synoviorthesis are the best ways that we have today of protecting against haemophilic synovitis and arthropathy of the ankle joint.

A careful review of the available literature has shown with a moderate degree of evidence that surgery can be safely performed in haemophilic patients with either low-responding or high-responding inhibitors. Until recently, it was generally advised that surgery should be carried out in high responding haemophilic patients only if absolutely necessary, i.e. in emergency situations. Elective surgery was usually discouraged, with the exception of the placing of an indwelling catheter to carry out immune tolerance protocols. However, in reality elective surgery is often advisable in haemophilic patients with inhibitors because it may lead to an improved quality of life. At the present time, several options of treatment exist which appear to be sufficiently safe to assure haemostasis in different surgical procedures However, a more informed choice between different treatment options, based on estimation of advantages and risks linked to each treatment modality is desirable. Furthermore, the choice between different options has to be made taking into consideration costs of treatment. Ideally, randomised prospective studies are needed in order to provide a higher level of evidence of safety and efficacy of different treatment options and specifically comparing the two main bypassing options:activated prothrombin complex concentrates (aPCCs) and recombinant factor (rF)VIIa. In addition, such studies should be done with an adequate protocol, providing sufficient haematological data and an appropriate prolonged postoperative assessment.