Arthroscopic ankle surgery in people with haemophilia.

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.

Clinical assessment and point of care ultrasonography: How to diagnose haemophilic synovitis.

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.

Concomitant use of bypassing agents with emicizumab for people with haemophilia A and inhibitors undergoing surgery.

INTRODUCTION: Surgery in people with haemophilia and factor VIII inhibitors is typically managed with perioperative administration of haemostatic agents to prevent or control the occurrence of bleeding events. Practical experience of surgery in patients with inhibitors who are receiving treatment with emicizumab is growing; however, the novelty of the situation means that standardised guidelines are lacking with regard to the concomitant administration of haemostatic agents, including dose and laboratory monitoring. AIM: To review approaches to haemostatic management during major and minor invasive procedures in patients with haemophilia A and inhibitors, and to provide recommendations for controlling bleeding events. METHODS: A search was conducted, limited to the past 4 years (January 2016-April 2020), pertaining to published evidence of surgery for patients receiving emicizumab. Publications identified from the search were manually reviewed to determine studies and case reports relevant for inclusion. RESULTS: Identified literature and practical experience of the authors were used to build a consensus of practical recommendations for the concomitant administration of haemostatic agents during the perioperative period for elective surgery in patients with inhibitors who are receiving emicizumab. CONCLUSIONS: The current evidence base indicates that surgery can be successfully performed in patients with inhibitors who are receiving emicizumab and that bypassing agents can be used concomitantly. Data from prospective studies are required to further support recommendations for haemostatic management of surgery in patients receiving emicizumab.

Gene Therapy in Hemophilia: Recent Advances.

Hemophilia is a monogenic mutational disease affecting coagulation factor VIII or factor IX genes. The palliative treatment of choice is based on the use of safe and effective recombinant clotting factors. Advanced therapies will be curative, ensuring stable and durable concentrations of the defective circulating factor. Results have so far been encouraging in terms of levels and times of expression using mainly adeno-associated vectors. However, these therapies are associated with immunogenicity and hepatotoxicity. Optimizing the vector serotypes and the transgene (variants) will boost clotting efficacy, thus increasing the viability of these protocols. It is essential that both physicians and patients be informed about the potential benefits and risks of the new therapies, and a register of gene therapy patients be kept with information of the efficacy and long-term adverse events associated with the treatments administered. In the context of hemophilia, gene therapy may result in (particularly indirect) cost savings and in a more equitable allocation of treatments. In the case of hemophilia A, further research is needed into how to effectively package the large factor VIII gene into the vector; and in the case of hemophilia B, the priority should be to optimize both the vector serotype, reducing its immunogenicity and hepatotoxicity, and the transgene, boosting its clotting efficacy so as to minimize the amount of vector administered and decrease the incidence of adverse events without compromising the efficacy of the protein expressed.

The role of six biomarkers in diagnosis of hemophilic arthropathy: review of the literature.

The aim of our narrative review of the literature is to identify the role of six important biomarkers: synovial fluid thrombomodulin, fibroblast-like synoviocytes, synovial tissue growth factor , vascular endothelial growth factor in synovium and peripheral blood, urinary C-terminal telopeptide of type II collagen, and synovial fluid tumor necrosis factor alpha. These urinary, serum and synovial biomarkers illustrated should be evaluated in patients with hemophilic arthropathy for early diagnosis of hemophilic arthropathy, because they have important implications in the development of arthrofibrosis, altered inflammatory response and bleeding. Moreover, better knowledge of their biological activity is important to identify possible new biological treatment options.

Emicizumab: Review of the literature and critical appraisal.

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.

Total elbow arthroplasty in haemophilia.

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.

Recommendations on multidisciplinary management of elective surgery in people with haemophilia.

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.

External Fixation vs Intramedullary Nailing for Knee Arthrodesis After Failed Infected Total Knee Arthroplasty: A Systematic Review and Meta-Analysis.

BACKGROUND: The aim of this study is to compare intramedullary nailing with external fixation for knee arthrodesis after failed infected total knee arthroplasty (TKA). Primary outcome is radiographic union. Secondary outcomes include recurrent deep infection, revision arthrodesis, and amputation. METHODS: Systematic review and meta-analysis of studies comparing outcomes from intramedullary nailing and external fixation in patients with infected TKA undergoing arthrodesis procedures was performed. Randomized controlled trials and cohort studies were included. RESULTS: Intramedullary nailing achieves a significantly higher rate of radiographic union compared with external fixation (odds ratio [OR] 5.17, 95% confidence interval [CI] 2.74-9.75, P < .00001) at a mean follow-up of 44.22 months. There is no significant difference in the rate of recurrent deep infection (OR 0.91, 95% CI 0.38-2.15, P = .83) or amputation (OR 0.94, 95% CI 0.23-3.84, P = .93). The rate of revision arthrodesis procedures is significantly lower for intramedullary nailing compared with external fixation (OR 0.28, 95% CI 0.08-0.93, P = .04). CONCLUSION: Intramedullary nailing is more effective than external fixation with respect to several clinically important outcomes. Therefore, we recommend intramedullary nailing for achieving knee arthrodesis as a salvage procedure for infected TKA in the absence of specific indications for external fixation.

Role of the Δ Resonance in the Population of a Four-Nucleon State in the

The ^{54}Fe nucleus was populated from a ^{56}Fe beam impinging on a Be target with an energy of E/A=500 MeV. The internal decay via γ-ray emission of the 10^{+} metastable state was observed. As the structure of this isomeric state has to involve at least four unpaired nucleons, it cannot be populated in a simple two-neutron removal reaction from the ^{56}Fe ground state. The isomeric state was produced in the low-momentum (-energy) tail of the parallel momentum (energy) distribution of ^{54}Fe, suggesting that it was populated via the decay of the Δ^{0} resonance into a proton. This process allows the population of four-nucleon states, such as the observed isomer. Therefore, it is concluded that the observation of this 10^{+} metastable state in ^{54}Fe is a consequence of the quark structure of the nucleons.

Hindfoot fusion in haemophilic arthropathy: 6-year mean follow-up of 41 procedures performed in 28 adult patients.

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.

Safety of radiation exposure after radiosynovectomy in paediatric patients with haemophilia.

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.

Bone health in persons with haemophilia.

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.

The current role of orthoses in treating haemophilic arthropathy.

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

Managing Haemophilia for Life: 5th Haemophilia Global Summit.

The 5th Haemophilia Global Summit was held in Barcelona, Spain, in September 2014. The programme was designed by an independent Scientific Steering Committee of haemophilia experts and explored issues relevant to the practical management of haemophilia, as well as key opportunities and challenges for care in the future. The topics outlined in this supplement were selected by the Scientific Steering Committee for their relevance to improving haemophilia care globally. In this supplement from the meeting, Gerry Dolan explores pharmacokinetics and dynamics in haemophilia, and Gerry Dolan and Ian Jennings jointly address the role of the laboratory in haemophilia care. The potential benefits of low-dose prophylaxis regimens for people with haemophilia in the developing world are reviewed by Jerzy Windyga, and the question of whether 'Future haemophilia research should be undertaken in the developing world' is debated by Jerzy Windyga and Cedric Hermans. Management strategies for ankle arthropathy are discussed by Sébastien Lobet and E. Carlos Rodríguez-Merchán, and the use of ultrasound for the early detection of haemophilic arthropathy is addressed by Matteo Nicola Dario Di Minno and Víctor Jiménez-Yuste. Finally, the role of patients in the future of haemophilia care is reviewed by Brian O'Mahony.

Hemophilic arthropathy of the elbow: prophylaxis, imaging, and the role of invasive management.

Hemophilia is an X-linked recessive deficiency of clotting factor VIII (hemophilia A) or IX (hemophilia B) that can result in hemarthrosis of various joints, including the elbow. Left unchecked, this can lead to progressive joint destruction and significant morbidity. Appropriate management of the elbow joint through prophylactic measures, accurate imaging, and timely intervention is essential. Replacing or supplementing deficient factor with a plasma-derived or recombinant factor concentrate can minimize bleeding episodes. Joints should be routinely monitored for damage. Plain films offer an inexpensive window into bone disease and joint space changes but lack soft tissue detail and may not detect early changes. Magnetic resonance imaging provides a high level of detail but may be limited by its cost and need for sedation in younger patients. Ultrasound may not achieve the same level of resolution as magnetic resonance imaging, but it is increasingly used as a convenient, effective, and relatively inexpensive alternative. Patients who experience hemarthrosis of the elbow with joint damage often require more invasive treatment. Radiosynovectomy and arthroscopic synovectomy are effective at minimizing pain and preventing future bleeding episodes, whereas extensive joint damage may necessitate total elbow replacement.

Re-revision Total Knee Arthroplasty: Causes, Risk Factors and Results.

The rate of re-revision total knee arthroplasty (TKA) ranges between 4% and 10%, depending on the cause of the procedure. Periprosthetic joint infection (PJI) and periprosthetic fracture are the main causes of re-revision TKA. The likelihood of implant survival of re-revision TKA diminishes with each subsequent revision, with PJI being the main cause of multiple revisions. Acute early aseptic revision TKA (within 90 days of surgery) involves a high risk of re-revision at 2 years and a high risk of subsequent PJI. The use of antibiotic-loaded cement is associated with lower risk of re-revision. Patients younger than 50 years experiencing aseptic revision TKA have a 1 in 3 risk of re-revision. Patients revised for instability or having prior TKA revisions have the highest risk of re-revision at 10 years. Patients younger than 55 years experiencing revision TKA have a 5-year revision-free survival of 80%.

Total Hip Arthroplasty in Hemophilic Patients: are their Results Similar to those of Nonhemophilic Patients?

Total hip arthroplasty (THA) is the mainstay therapy for patients with terminal hemophilic arthropathy of the hip. However, the largest case series published between 2017 and 2023 in the literature on THA in patients with hemophilia have found a higher 1-year infection rate (8.1% versus 3.4%) in hemophilia patients than in the general population, a higher rate of in-hospital bleeding complications (38.7% versus 16.1%), a higher length of stay (6 days versus 3 days) and a higher 30-day readmission rate (22.6% versus 4.1%). Finally, a lower 5-year survival rate has also been observed in hemophilia patients than in the general population (91.9% versus 95.3%). In the last decade there have been dramatically positive improvements in implant designs and hematological treatment, and therefore it does not seem that THA in hemophilia is so far from that in osteoarthritic patients.

Primary Total Knee Arthroplasty in Hemophilia and Allied Disorders: Revision Rates and Their Causes.

When patients with hemophilia and allied disorders (von Willebrand disease and other congenital bleeding disorders) do not receive adequate primary hematologic prophylaxis from infancy, their joints will suffer knee joint degeneration; when such joint degeneration becomes very advanced (painful and disabling) despite previous conservative treatment, the only way to alleviate the problem will be to implant a primary total knee arthroplasty (TKA). The literature has shown that twenty years after implantation, 71% of primary TKAs are still functional; on the other hand, 18% have to be revised as a consequence of periprosthetic joint infection (PJI). The main causes of revision total knee arthroplasty are PJI and aseptic loosening (39% each).