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.

Platelet Rich Plasma for Chronic Synovitis Treatment in Patients with Haemophilia.

INTRODUCTION: Haemophilic synovitis is caused by chronic accumulation of blood in the joint. Conservative treatment is insufficient to solve this pathology. Platelet-rich plasma (PRP) has a high concentration of growth factors (GFs) that play a key role in regulation and stimulation of healing processes. The aim of this study was to describe the effect of PRP injection in chronic synovitis of the joints in patients with haemophilia (PWH). PATIENTS AND METHODS: Nineteen patients with 28 joints were treated at our centre in Buenos Aires, Argentina between December 2014 and December 2015. Eighteen were Haemophilia type A (17 severe, one mild) and one was type B severe. Mean age was 26 years old. Chronic synovitis was present in two ankles, seven elbows and 19 knee joints. All affected joints were evaluated for range of motion (ROM), perimeter, Haemophilia Joint Health Score (HJHS), number of bleedings episodes and Visual Analogue Scale (VAS). Evaluations were before treatment and 3 and 6 months after treatment. RESULTS: A mean volume of 4 mL of PRP was injected into the joint cavity. The statistical analysis before and after treatments revealed a statistically significant (P < 0.001) decrease in the HJHS score. Decrease in joint bleeding episodes was also statistically significant (P < 0.001). All patients reported pain relief and VAS scores were statistically significant (P < 0.001). Joint perimeter also showed a statistically significant difference (P < 0.001). No complications were observed in any of the patients, either during blood collection or during PRP injection, even for inhibitor patients. CONCLUSION: Platelet-rich plasma is a useful, safe, and inexpensive treatment for chronic haemophilic synovitis.

Knee flexion contracture treated with botulinum toxin type A in patients with haemophilia (PWH).

INTRODUCTION: Knee flexion contracture (KFC) remains a common complication of haemoarthrosis in children and young adults with haemophilia. If the KFC is not treated properly it produces disability, postural and gait abnormalities. OBJECTIVE: Evaluate the effectiveness of conservative treatment of KFC with Botulinum toxin type A (BTX-A) in PWH. METHODS: Seventeen patients were treated, with 21 affected knees. Mean age was 26 years. The mean follow up was 12 months. We evaluated flexion and KFC pretreatment BTX-A and up to 12 months posttreatment. BTX-A application was in hamstring and calf muscles. To evaluate the function, a questionnaire about different activities was made, and it was checked 3, 6 and 12 months after BTX-A. According to the degree of KFC, knees were divided into 3 groups: Group 1: -10° to -30° (n = 10), Group 2: -31° to -45° (n = 6) Group 3: -46° or more (n = 5). RESULTS: The average KFC improved from -38° to -24°. The improvement was 14° (P < 0.001). The average KFC improvement was 9° in group 1, 17° in group 2, and 23° in group 3. There was a high correlation between the improvement in KFC and the total score of the questionnaire R = 0.77. CONCLUSIONS: Treatment of KFC with BTX-A improves knee-related functional activities, with the advantage of being a low-cost procedure and easy to apply.

Is it possible to use autologous adipose graft for wound repair in patients with coagulation disorders?

INTRODUCTION: Wound healing is an intricate process whereby the skin repairs itself after injury according to a specific sequence: haemostasis, inflammation, proliferation and remodelling. Cell therapy has the potential to improve wound healing conditions and can be applied in both acute and chronic wounds. Normal healing requires adequate haemostatic function. Patients with coagulation disorders whose haemostatic function is altered may not heal naturally. AIM: The aim of this study was to show a simple, safe and inexpensive minimally invasive technique for wound repair in patients with coagulation disorders which involves the use of concentrated autologous adipose cells. PATIENTS AND METHOD: Six patients were enrolled in this study at the Foundation of Haemophilia, in Buenos Aires, Argentina. Five patients had severe haemophilia type A and one had severe von Willebrand diseases. The average age was 37.5 years old. One patient had a retractile scar (RS) and five patients had cutaneous fistulas (CF). Suction was used to obtain autologous adipose graft from subcutaneous abdominal tissue. The graft was centrifuged and, the adipose cell concentrate was transferred to a syringe and injected in the edge of the lesion. RESULTS: One adipose suction in each patient was performed. There were no intraoperative or postoperative complications in any of the six patients. CONCLUSIONS: The application of autologous adipose graft is a simple and safe treatment for complicated wound repair in patients with coagulation disorders.

Treatment of subchondral cysts in patients with haemophilia.

INTRODUCTION: The haemophilic arthropathy is a disabling disease that causes chronic pain and functional limitation, due to recurrent intra-articular bleeding, with impaired quality of life. OBJECTIVE: The aim of this work is to present our 24-year experience in the treatment of subchondral cysts filled with hydroxyapatite coralline in patients with haemophilia. PATIENTS AND METHOD: Thirty-seven male patients with forty-nine cystic lesions were treated and evaluated between 1990 and 2014. Thirty four patients were haemophilia type A, three were haemophilia type B, two patients had inhibitors to factor VIII. The average age was 23.6 years. The average follow-up was 10 years. The lesions were located: twenty-four in the tibia (49%), six in the talus (12.2%), seven in the ulna (14.4%), five in the humerus (10.2%), five in the femur (10.2%) and two in the distal radius (4%). In all patients' radiographs, Computed Tomography and Magnetic Resonance Imaging were performed before surgery. The lesions were treated when the injury was greater than 15% of the joint area, and when the joint area was greater than 1 cm of diameter. Surgical technique consisted of aspirating the cyst contents and refilling it with hydroxyapatite coralline. RESULTS: In forty-eight cysts, restitution of bone structure was achieved by impaction of hydroxyapatite coralline. The average time of bone restoration was 10 months. Only one patient required a second intervention. CONCLUSION: The treatment of subchondral cyst in PWH by aspiration and filling with hydroxyapatite coralline allows bone restoration and delays deterioration of the joint treated.

Epidemiology of fractures in patients with haemophilia.

INTRODUCTION: Haemophilia is an X-chromosome linked inherited bleeding disorder characterised by an anomaly synthesis of coagulation factor VIII (Haemophilia A) or factor IX (Haemophilia B). There is very little information on the magnitude and management of fractures in PWH in the literature regards the advance on replacement therapy. The purpose of this paper is to present our 28 years experience treating PWH who suffered fractures and evaluate the impact of access to treatment. MATERIALS AND METHODS: In the period 1986-2013, 151 fractures in 141 PWH were treated, 125 patients type A (88.7%), 12 type B (8.5%) and 4 (2.8%) with von Willebrand's disease. For the sake of analysis we divided the fractures in five groups: 1986-1990: 25, 1991-1995: 35, 1996-2001: 33, 2002-2007: 31, and 2008-2013: 27; and classified the fractures in lower limb (LL) and upper limb (UL). We also considered the age at which the fractures occurred. RESULTS: However the incidence of presentation of the fractures of the upper limb and lower limb changed through the years, being more frequent in the LL in the first period analysed (76% LL vs. 24% UL) and in the UL in the latter one (63% UL vs. 37% LL), the difference was statically significant (p=0.0168). In the relation with the age, the 1986-1990 cohort vs. 2008-2013 cohort reached statistical significance (p: 0.035). Regarding treatment, 121 fractures were treated in a non invasive way, the others 30 fractures, were treated with internal fixation. The patient treated with internal fixation had less mal-alignment, and delay consolidation. DISCUSSION: This is the largest series of fractures in PWH published. We show a higher incidence of LL fractures in the first period analysed (1986-1990), over time, the ratio LL/UL changed as UL fractures became more frequent. This change is due to the access of the treatment and specifically to the prophylaxis. CONCLUSION: Fractures in PWH have changed their pattern, becoming more common in the UL than in the LL, lowering the age at which they occur and being less frequent. We believe that the advent of new and accessibly treatments, decreased the development of orthopaedic complications and favours the improvement in quality of life of PWH.

Haemophilia pseudotumours in patients with inhibitors.

Development of inhibitors against factor VIII (FVIII) or FIX is the most serious complication of replacement therapy in patients with haemophilia. Haemophilic pseudotumours in a patient with inhibitors can lead to devastating consequences. The aim of this study is to show our experience in the treatment of 10 pseudotumours in 7 patients with inhibitors who were treated by the same multidisciplinary team in the period between January 2000 and March 2013. Seven severe haemophilia A patients were treated at the Haemophilia Foundation in Buenos Aires, Argentina, for 10 pseudotumours. Eight were bone pseudotumours and two soft tissue. All patients underwent imaging studies at baseline to assess the size and content of the lesion. The patients received Buenos Aires protocol as conservative treatment of their pseudotumours for 6 weeks, after which they were evaluated. Only one patient responded to conservative treatment. Surgery was performed on the others six patients, since their pseudotumours did not shrink to less than half their original size. Any bleeding in the musculoskeletal system must be treated promptly in order to prevent pseudotumours. When pseudotumours do appear in inhibitor patients, they can be surgically removed when patients received proper haemostatic coverage, improving the quality of life of these patients.

Hemophilic chronic synovitis: therapy of hemarthrosis using endovascular embolization of knee and elbow arteries.

PURPOSE: Congenital hemophilia is a hereditary bleeding disorder that affects 1 in 5,000 males and is characterized by repetitive musculoskeletal bleeding episodes. Selective embolization of the knee and elbow arteries can prevent bleeding episodes. To evaluate the long-term efficacy of these procedures, we assessed the outcomes of 30 procedures performed in our center. METHODS: We performed 30 procedures in 27 hemophilic patients, including 23 knee, and 7 elbow procedures. To evaluate the efficacy of selective embolization of knee and elbow arteries in people with hemophilia, we analyzed the number of bleeding episodes during 12 months before the procedure compared with the amount of episodes that occurred 3, 6, and 12 months after embolization. RESULTS: Twenty-nine of 30 procedures were classified as successful. The median of 1.25 episodes per month (range 0-3) observed before the procedure was reduced to 0 (range 0-1.67; p < 0.001) at 3 months, 0.17 (range 0-1.67; p < 0.001) at 6 months, and 0.33 (range 0-1.67; p = 0.024) at 12 months. Three patients remained free of bleeding events for more than 6 months. Additionally, after the procedure there was a significant reduction in factor FVIII usage that sustained up to 12 months after the procedures. No serious adverse events were observed. CONCLUSIONS: Selective angiographic embolization of knee and elbow arteries is a feasible procedure that can prevent repetitive bleedings, which would translate in better joint outcomes for these patients.

Musculoskeletal problems in persons with inhibitors: how do we treat?

Inhibitors are a serious complication, considerably increasing the morbidity, mortality and cost of treatment in this patient group. The challenge of treating people with haemophilia (PWH) with inhibitors can be met by a well-coordinated multidisciplinary team specialized in haemophilia. Each treatment centre must run a screening programme to detect inhibitors within their population and develop protocols to treat these patients. The treatment centre in Buenos Aires developed a screening programme that tests all our patients twice a year, ensuring early detection of inhibitors and early treatment of complications. In 2006, we analysed the quality of life (QOL) of non-inhibitor patients and compared it with inhibitor patients detected by this programme and found no differences in QOL measured by the SF36 questionnaire and no differences in school absenteeism. When diagnosis of the inhibitor does not come from a screening programme, its presence is suspected upon a lack of response to conventional replacement therapy for musculoskeletal bleeding, losing the 'golden moment' of treatment. This complication is much more serious when facing a traumatic bleed. In this situation, the lack of early diagnosis can lead to permanent damage or even death. Due to the cost of bypassing factors and the lack of experience of the medical team in the treatment of patients with inhibitors, many treatments that would improve the QOL of patients are instituted in an insufficient manner. Therefore, patients with haemophilia and inhibitors are often untreated or undertreated in their community. Orthopaedic surgeons and physiotherapists play a key role in the treatment of these patients and should be included in therapeutic decision making and most specifically in the postoperative treatment of patients with haemophilia and inhibitors. It is important that these patients have quick access to a trained therapeutic team in order to obtain an early diagnosis and treatment plan to prevent the evolution of the pathological process. Early treatment is cost-effective in maintaining and improving the QOL of patients. Experience in patients with haemophilia and inhibitors is not very extensive. Today, this situation is changing, with several treatment centres beginning to perform surgeries in these most complex patients, giving them a chance to improve their QOL. This article presents the experience of experts from various fields involved in treating patients with inhibitors from a developed and developing world perspective.

Elective orthopaedic surgery for haemophilia patients with inhibitors: single centre experience of 40 procedures and review of the literature.

With the introduction of safe and effective factor VIII/IX-bypassing agents--recombinant activated factor VII (rFVIIa) and plasma-derived activated prothrombin complex concentrates (pd-APCC)--elective orthopaedic surgery (EOS) is a viable option for haemophilia patients with inhibitors. We report a series of patients with haemophilia and inhibitors undergoing EOS between 1997 and 2008 using bypassing agents to provide haemostatic cover. All inhibitor patients undergoing EOS and receiving rFVIIa, plasma-derived prothrombin complex concentrates (pd-PCC) or pd-APCC as haemostatic cover were included. Patients were operated on by the same surgeon and were managed by the same haemophilia treatment centre. Forty procedures (25 minor and 15 major) were conducted in 18 patients. Twenty-one minor cases were covered using rFVIIa, three with pd-PCC, and one with pd-APCC; all major cases were covered using rFVIIa. Bleeding was no greater than expected compared with a non-haemophilic population in all 25 minor procedures. In the major procedure group, there was no excessive bleeding in 40% of cases (6/15) and bleeding completely stopped in response to rFVIIa. For the remaining nine cases, bleeding response to rFVIIa was described as 'markedly decreased' or 'decreased' in 4/15 cases and 'unchanged' in 5/15 cases. Overall, efficacy of rFVIIa, based on final patient outcome, was 85%. One death occurred as a result of sepsis secondary to necrotizing fasciitis. Good control of haemostasis can be achieved with bypassing agents in haemophilia patients with inhibitors undergoing minor EOS; rFVIIa was used as an effective bypassing agent, enabling EOS in patients undergoing minor and major procedures.

Orthopaedic management of haemophilia arthropathy of the ankle.

Joint bleeding, or haemarthrosis, is the most common type of bleeding episode experienced by individuals with haemophilia A and B. This leads to changes within the joints, including synovial proliferation, which results in further bleeding and chronic synovitis. Blood in the joint can also directly damage the cartilage, and with repeated bleeding, there is progressive destruction of both cartilage and bone. The end result is known as haemophilic arthropathy. The joints most commonly affected are the knees, elbows and ankles, although any synovial joint may be involved. In the ankle, both the tibiotalar and subtalar joints may be affected and joint bleeding and arthropathy can lead to a number of deformities. Haemophilic arthropathy can be prevented through regular factor replacement prophylaxis and implementing physiotherapy. However, when necessary, there are multiple surgical and non-surgical options available. In early ankle arthropathy with absent or minimal joint changes, both radioisotopic and chemical synoviorthesis can be used to reduce the hypertrophied synovium. These procedures can decrease the frequency of bleeding episodes, minimizing the risk of articular cartilage damage. Achilles tendon lengthening can be performed, in isolation or in combination with other surgical measures, to correct Achilles tendon contractures. Both arthroscopic and open synovectomies are available as a means to remove the friable villous layer of the synovium and are often indicated when bleeding episodes cannot be properly controlled by factor replacement therapy or synoviorthesis. In the later stages of ankle arthropathy, other surgical options may be considered. Debridement may be indicated when there are loose pieces of cartilage or anterior osteophytes, and can help to improve the joint function, even in the presence of articular cartilage damage. Supramalleolar tibial osteotomy may be indicated in patients with a valgus deformity of the hindfoot without degenerative radiographic findings. Joint fusion, or arthrodesis, is the treatment of choice in the advanced stages of ankle arthropathy although total ankle replacement is currently available. Early ankle replacement components were associated with a poor outcome, but as implant designs have improved, there have been successful outcomes achieved. As the ankle is a commonly affected joint in many individuals with haemophilia, it is important to add to the knowledge base to validate indications and timing of surgical and non-surgical interventions in ankle arthropathy.

Tissue engineering in musculoskeletal problems related to haemophilia.

This article is a review of how advances in tissue engineering can be applied to the musculoskeletal pathology of patients with haemophilia. This article will also explain the theory that the deterioration of joints in patients with haemophilia is due to biological and mechanical causes. Current concepts of tissue engineering would be to replace the degenerated and damaged tissue by live cells, using them as a biological implant. However, before these new technologies are applied, an appropriate control of their indication and results is required.

Elective orthopedic surgery for hemophilia patients with inhibitors: New opportunities.

We report a series of 108 elective orthopedic surgical procedures in hemophilia patients with inhibitors, comprising 88 cases in which radiosynoviorthesis was performed and 20 cases in which major orthopedic procedures were carried out. Hemostatic cover was provided by recombinant factor VIIa (rFVIIa, NovoSeven(R), Novo Nordisk, Bagsvaerd, Denmark) in 17 cases, and by FVIII anti-inhibitor product (FEIBA, Baxter Corp, Toronto, Canada) in the remaining three procedures. A total of 51 patients from nine centers worldwide were included. The results of the procedures were characterized as good (82 procedures), fair (15), or poor (11). Postoperative bleeding complications requiring further surgical intervention occurred in three (15%) of the 20 major orthopedic procedures; all three procedures used rFVIIa as a hemostatic agent. Despite these complications, however, our study has shown that rFVIIa allows hemophilic patients with high inhibitor titers to undergo elective orthopedic surgery (EOS) with a greater expectation of success, leading to an improved quality of life. Thorough analysis of each case as part of a multidisciplinary team will help to identify further inhibitor patients in whom EOS can be performed both safely and effectively.

Elective orthopaedic surgery for inhibitor patients.

We report on a series of 108 elective orthopaedic surgical procedures. It includes 88 radiosynoviortheses and 20 major orthopaedic procedures, performed on 51 patients at nine centres worldwide. The average age of patients was 28.5 years (range 5-40 years), and the average follow-up time was 2 years (range 1-5 years). There were 82 good results, 15 fair and 11 poor. In the synoviorthesis group (41 patients, 88 synoviortheses) the average age was 14.3 years (range 5-40 years) and the average follow-up was 6.5 years (range 1-10 years). There were 66 good results, 14 fair and eight poor. There were no complications. In the group of major orthopaedic procedures, the average age of the 10 patients was 32.5 years (range 27-40 years), and the average follow-up was 2.3 years (range 1-5 years). There were 16 good results, one fair and three poor. Postoperative bleeding complications occurred in three of the 20 major orthopaedic procedures performed (15% complications rate). They occurred in three patients treated with insufficient doses of recombinant activated factor VII. Despite such complications, the study has shown that haemophilic patients with inhibitors requiring elective orthopaedic surgery (EOS) can undergo such procedures with a high expectation of success. In other words, EOS is now possible in haemophilic patients with inhibitors, leading to an improved quality of life for these patients. Thorough analysis of each case as part of a multidisciplinary team will allow us to perform elective orthopaedic procedures in patients with inhibitors.

Intra-articular hyaluronic acid in the treatment of haemophilic chronic arthropathy.

We report our preliminary experience with the use of hyaluronic acid (Synvisc) in 29 joints from 25 different haemophilic patients (17 knees, six shoulders, four ankles, one elbow and one hip). All the joints were grade III of our classification, characterized by synovial thickening, axial deformities and muscle atrophy (chronic arthropathy). In view of the very satisfactory results obtained with this procedure, we have substituted Synvisc for the previous use of intra-articular long-standing corticosteroids that we had been used for some years. This method is theoretically more physiological and does not destroy the joint cartilage further, as corticosteroids can.

Haemophilic pseudotumours of the limbs and their percutaneous treatment.

The percutaneous treatment of limb pseudotumours is a nonaggressive method of treating haemophilic pseudotumours. However, efforts should be directed to the prevention of such pseudotumours by ensuring that all patients receive adequate treatment of their bleeding episodes through education and the elimination of geographical or social barriers that prevent access to such treatment. Prevention of pseudotumours by means of early substitution treatment of muscular bleeding episodes is the best treatment.

Chemical synoviorthesis with rifampicin in haemophilia.

Rifampicin is an antibiotic that has been currently used for the treatment of noninfectious articular lesions with satisfactory results. The first experience was performed with patients who presented rheumatoid arthritis, and later with haemophilic patients. The clinical experience of three haemophilia centres which used rifampicin for the treatment of chronic haemophilic synovitis is presented here. The protocols were different. It was observed that rifampicin is more effective when it is used in small joints (elbows and ankles), than when used in bigger ones (knees), and that a high number of injections predicts failure. Mention is also made of experimental studies in animals where it was shown that the healing pattern of rifampicin is similar to that of NSAIDs.

On the safety of synoviorthesis in haemophilia.

One of the best procedures to prevent haem-arthrosis has been radioactive synovectomy (synoviorthesis). Since the first report of radioactive synovectomy in haemophilia of Ahlberg in 1971 [1], many centres adopted this procedure as the one of choice, through fibrosing the synovial membrane, prevent further haemarthrosis. Since 1976 we have performed 104 such radioactive synoviorthesis in 97 patients, age ranging from 6 to 40 years with a mean of 10 years. Sixty-five of these patients were under 12 years of age. The knees were injected in 61 cases, elbow in 26 cases, ankles in 14 cases and shoulders in three cases. The clinical results of this procedure show 80% of excellent results with no further bleeding. In case of failure, a new injection can be given in the same joint at a 6-month interval, or an injection for the same purpose in other joint. One of the criticisms against this method is the possible chromosomal damage induced by the radioactive material. In our centre, four studies have been carried out in order to see whether these changes, when they occur, are everlasting; all have demonstrated that chromosomal changes are reversible. The radioactive material used in the two first studies was Gold-189 (189Au). In 1978, 354 metaphases were studied with 61 ruptures, 17.23% (nonpremalign) and six structural changes, considered premalign (1.69%). Any number below 2% is considered not to be dangerous. A further study was done in 1982, in the same group of patients with a result of 21 ruptures (3.34%) and no structural changes. This demonstrated that the possible premalign changes disappeared with time. A third study was performed in a series of 13 patients that sustained radioactive synoviorthesis with Rhenium-186 (186Re) in November 1991. For comparison, we carried out a chromosomal study just before and 6 months after the radioactive material injection. The results confirmed that changes that could be linked to the radiation, appeared equally in nonirradiated patients, and those changes due to the radiation disappear with time, never reaching the dangerous zone of 2%. In the group treated with 186Re we studied an additional number of 130 metaphases with identical results and no structural changes. In a study on patients where 90Y was the radiocolloid, no premalign change was found before or after the synoviorthesis. It seems, in view of these results, that radioactive synovectomy is safe and gives great benefits to the haemophilic patients.

Problemas ortopédicos del niño hemofílico / Orthopaedic problems of hemophilic children

En este artículo se revisan los principales problemas del niño hemofílico, especialmente los hemartros, los hematomas musculares y los quistes hemofílicos (pseudotumores). La sinoviortesis con rifampicina y el tratamiento percutáneo de los pseudotumores son dos de los métodos fundamentalmente analizados en este artículo (AU)