Guidelines for the management of
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Synovitis 1. Following acute hemarthrosis, the synovium becomes inflamed, is hyperemic and extremely friable.
2. Failure to manage acute synovitis can result in repeated hemarthroses [1,2]. 3. During this stage, the joint requires protection with a removal splint or compressive bandaging. 4. Activities should be restricted until swelling and temperature of the joint return to baseline. 5. In some cases, COX-2 inhibitors may be useful. 6. Range of motion is preserved in the early stages. Differentiation between hemarthrosis and syno- vitis is made by performing a detailed physical examination of the joint. 7. The presence of synovial hypertrophy may be confirmed by ultrasonography or MRI. Plain radiographs and particularly MRI will assist in defining the extent of osteochondral changes. 8. With repeated bleeding, the synovium becomes chronically inflamed and hypertrophied, and the joint appears swollen (this swelling is usually not tense, nor is it particularly painful): this is chronic synovitis. 9. As the swelling continues to increase, articular damage, muscle atrophy, and loss of motion will progress to chronic hemophilic arthropathy. 10. The goal of treatment is to deactivate the synovium as quickly as possible and preserve joint function (Level 5) [3,4]. Options include: ■ factor concentrate replacement, ideally given with the frequency and at dose levels sufficient to prevent recurrent bleeding (Level 2) [5-8] ■ If concentrates are available in sufficient doses, short treatment courses (6-8 weeks) of secondary prophylaxis with intensive physiotherapy are beneficial. 6 COMPLICATIONS OF HEMOPHILIA GUIDELINES FOR THE MANAGEMENT OF HEMOPHILIA 56 ■ physiotherapy (Level 2) [9,10], including: ■ daily exercise to improve muscle strength and maintain joint motion ■ modalities to reduce secondary inflamma- tion, if available [11] ■ functional training [12] ■ a course of NSAIDs (COX-2 inhibitors), which may reduce inflammation (Level 2) [13,14] ■ functional bracing, which allows the joint to move but limits movement at the ends of range where the synovium can be pinched and which may prevent new bleeding [15]. ■ synovectomy Synovectomy 1. Synovectomy should be considered if chronic synovitis persists with frequent recurrent bleeding not controlled by other means. Options for synovectomy include chemical or radioisotopic synoviorthesis, and arthroscopic or open surgical synovectomy. (Level 4) [16,17] 2. Non-surgical synovectomy is the procedure of choice. 3. Radioisotopic synovectomy using a pure beta emitter (phosphorus-32 or yttrium-90) is highly effective, has few side effects, and can be accom- plished in an out-patient setting. (Level 4) [18,19] ■ A single dose of clotting factor is often suffi- cient for a single injection of the isotope. ■ Rehabilitation is less intense than after surgical synovectomy but is still required to help the patient regain strength, proprioception, and normal functional use of the joint. 4. If a radioisotope is not available, chemical synovi- orthesis with either rifampicin or oxytetracycline chlorhydrate is an appropriate alternative [20,21]. ■ Chemical synoviorthesis involves weekly injec- tions until the synovitis is controlled. ■ These painful injections require the administra- tion of intra-articular xilocaine a few minutes before injection of the sclerosing agent, oral analgesics (a combination of acetaminophen/ paracetamol and an opioid), and a dose of clot- ting factor concentrate prior to each injection. ■ The low cost of the chemical agent is offset by the need for multiple injections of factor concentrate. ■ Rehabilitation, as described for radioactive synovectomy, is recommended. 5. Surgical synovectomy, whether open or arthroscopic, requires a large supply of clotting factor for both surgery and the lengthy period of rehabilitation. The procedure must be performed by an experi- enced team at a dedicated hemophilia treatment centre. It is only considered when other less inva- sive and equally effective procedures fail. Chronic hemophilic arthropathy 1. Chronic hemophilic arthropathy can develop any time from the second decade of life (and sometimes earlier), depending on the severity of bleeding and its treatment. 2. The process is set in motion by the immediate effects of blood on the articular cartilage during hemarthrosis [1,2] and reinforced by persistent chronic synovitis and recurrent hemarthroses, resulting in irreversible damage. 3. With advancing cartilage loss, a progressive arthritic condition develops that includes: ■ secondary soft tissue contractures ■ muscle atrophy ■ angular deformities 4. Deformity can also be enhanced by contracture following muscle bleeds or neuropathy. 5. Loss of motion is common, with flexion contrac- tures causing the most significant functional loss. 6. Joint motion and weight bearing can be extremely painful. 7. As the joint deteriorates, swelling subsides due to progressive fibrosis of the synovium and the capsule. 8. If the joint becomes ankylosed, pain may diminish or disappear. 9. The radiographic features of chronic hemophilic arthropathy depend on the stage of involvement. ■ Radiographs will only show late osteochon- dral changes [22,23]. COMPLICATIONS OF HEMOPHILIA 57 ■ Ultrasound or MRI examination will show early soft tissue and osteochondral changes [24-26]. ■ Cartilage space narrowing will vary from minimal to complete loss. ■ Bony erosions and subchondral bone cysts will develop, causing collapse of articular surfaces that can lead to angular deformities. ■ Fibrous/bony ankylosis may be present [27]. 10. The goals of treatment are to improve joint function, relieve pain, and assist the patient to continue/resume normal activities of daily living. 11. Treatment options for chronic hemophilic arthropathy depend on: ■ the stage of the condition ■ the patient’s symptoms ■ the impact on the patient’s lifestyle and func- tional abilities ■ the resources available 12. Pain should be controlled with appropriate anal-
13. Supervised physiotherapy aiming to preserve muscle strength and functional ability is a very important part of management at this stage. Secondary prophylaxis may be necessary if recurrent bleeding occurs as a result of phys- iotherapy. (Level 2) [9,10] 14. Other conservative management techniques include: ■ serial casting to assist in correcting deformi- ties [28,29]. ■ bracing and orthotics to support painful and unstable joints [15]. ■ walking aids or mobility aids to decrease stress on weight-bearing joints. ■ adaptations to the home, school, or work envi- ronment to allow participation in community activities and employment and to facilitate activities of daily living [30]. 15. If these conservative measures fail to provide satisfactory relief of pain and improved func- tioning, surgical intervention may be considered. Surgical procedures, depending on the specific condition needing correction, may include: ■ extra-articular soft tissue release to treat contractures. ■ arthroscopy to release intra-articular adhe- sions and correct impingement [31]. ■ osteotomy to correct angular deformity. ■ prosthetic joint replacement for severe disease involving a major joint (knee, hip, shoulder, elbow) [32]. ■ elbow synovectomy with radial head excision [33].
■ arthrodesis of the ankle, which provides excel- lent pain relief and correction of deformity with marked improvement in function. Recent improvements in ankle replacement surgery may pose an alternative for persons with hemo- philia in the future [34,35]. 16. Adequate resources, including sufficient factor
1. Physiotherapists and occupational therapists and/ or physiatrists should be part of the core hemo- philia team. Their involvement with patients and their families should begin at the time of diag- nosis, and they remain important to the patient throughout their lifespan. 2. Their role in the management of the patient with hemophilia includes the following [9,39-41]: ■ Assessment ■ Determining the site of an acute bleed ■ Regular assessment throughout life ■ Pre-operative assessment ■ Education ■ Of the patient and family regarding muscu- loskeletal complications and their treatment ■ Of school personnel regarding suitable activities for the child, immediate care in case of a bleed, and modifications in activ- ities that may be needed after bleeds. ■ Treatment of acute bleeds, chronic synovitis, and chronic arthropathy using a variety of techniques including hydrotherapy, heat, ice, GUIDELINES FOR THE MANAGEMENT OF HEMOPHILIA 58 electrical nerve stimulation, pulsed diathermy, ultrasound as well as various orthoses for pain relief and restoration of function. Pseudotumours 1. The pseudotumour is a potentially limb and life- threatening condition unique to hemophilia that occurs as a result of inadequately treated soft tissue bleeds, usually in muscle adjacent to bone, which can be secondarily involved. It is most commonly seen in a long bone or the pelvis. 2. If not treated, the pseudotumour can reach enormous size, causing pressure on the adja- cent neurovascular structures and pathologic fractures. A fistula can develop through the over- lying skin. 3. Diagnosis is made by the physical finding of a localized mass. 4. Radiographic findings include a soft tissue mass with adjacent bone destruction. 5. A more detailed and accurate evaluation of a pseudotumour can be obtained with CT scan and MRI. 6. Management depends on the site, size, rate of growth, and effect on adjoining structures. Options include factor replacement and moni- toring, aspiration, and surgical ablation. ■ A six-week course of treatment with factor is recommended, followed by repeat MRI. If the tumour is decreasing, continue with factor and repeat MRI for three cycles. (Level 4) [42,43] ■ Proceed to surgery if necessary, which will be much easier if the tumour has shrunk. ■ Aspiration of the pseudotumour followed by injections of fibrin glue, arterial emboliza- tion, or radiotherapy may heal some lesions. Surgery may be needed for others. (Level 4) [44,45] ■ Surgical excisions, including limb amputations, may be necessary for large pseudotumours, particularly if they erode long bones. Large abdominal pseudotumours present a special challenge in surgical management of hemo- philia; surgery must only be performed by teams with experience in hemophilia. Fractures 1. Fractures are not frequent in people with hemo- philia, possibly due to lower levels of ambulation and intensity of activities [46]. However, a person with hemophilic arthropathy may be at risk for fractures around joints that have significant loss of motion and in bones that are osteoporotic. 2. Treatment of a fracture requires immediate factor concentrate replacement. (Level 4) [46-48] 3. Clotting factor levels should be raised to at least 50% and maintained for three to five days. (Level 4) [3,46-48] 4. Lower levels may be maintained for 10–14 days while the fracture becomes stabilized and to prevent soft tissue bleeding. 5. The management plan should be appropriate for the specific fracture, including operative treat- ment under appropriate coverage of clotting factor concentrates. 6. Circumferential plaster should be avoided;
7. Compound/infected fractures may require external fixators [49]. 8. Prolonged immobilization, which can lead to significant limitation of range of movement in the adjacent joints, should be avoided. (Level 4) [46,47] 9. Physiotherapy should be started as soon as the fracture is stabilized to restore range of motion, muscle strength, and function [39]. Principles of orthopedic surgery in hemophilia For important considerations related to performing surgical procedures in persons with hemophilia, please see “Surgery and invasive procedures”, on page 16. Specific issues in relation to orthopedic surgery include:
1. Orthopedic surgeons should have had specific training in surgical management of persons with hemophilia [3].
COMPLICATIONS OF HEMOPHILIA 59 2. Performing multiple site elective surgery in a simultaneous or staggered fashion to use clot- ting factor concentrates judiciously should be considered. (Level 3) [50] 3. Local coagulation enhancers may be used. Fibrin glue is useful to control oozing when operating in extensive surgical fields. (Level 3) [36,51,52] 4. Post-operative care in patients with hemophilia requires closer monitoring of pain and often higher doses of analgesics in the immediate post-operative period. (Level 5) [36] 5. Good communication with the post-operative rehabilitation team is essential [39]. Knowledge of the details of the surgery performed and intra- operative joint status will facilitate planning of an appropriate rehabilitation program. 6. Post-operative rehabilitation should be carried out by a physiotherapist experienced in hemo- philia management. 7. Rehabilitation may have to progress more slowly in persons with hemophilia. 8. Adequate pain control is essential to allow appro- priate exercise and mobilization. 9. These principles also apply to fixation of frac- tures and excision of pseudotumours. 6.2 Inhibitors 1. “Inhibitors” in hemophilia refer to IgG anti- bodies that neutralize clotting factors. 2. In the current era in which clotting factor concen- trates have been subjected to appropriate viral inactivation, inhibitors to FVIII or FIX are considered to be the most severe treatment- related complication in hemophilia. 3. The presence of a new inhibitor should be suspected in any patient who fails to respond clinically to clotting factors, particularly if he has been previously responsive. In this situation, the expected recovery and half-life of the transfused clotting factor are severely diminished. 4. Inhibitors are more frequently encountered in persons with severe hemophilia compared to those with moderate or mild hemophilia. 5. The cumulative incidence (i.e. lifetime risk) of inhibitor development in severe hemophilia A is in the range of 20-30% and approximately 5-10% in moderate or mild disease [53-54]. 6. In severe hemophilia A, the median age of inhibitor development is three years or less in developed countries. In moderate/mild hemo- philia A, it is closer to 30 years of age, and is often seen in conjunction with intensive FVIII expo- sure with surgery [55,56]. 7. In severe hemophilia, inhibitors do not change the site, frequency, or severity of bleeding. In moderate or mild hemophilia, the inhibitor may neutralize endogenously synthesized FVIII, thereby effectively converting the patient’s pheno- type to severe. 8. Bleeding manifestations in moderate/mild hemo- philia complicated by an inhibitor are more frequently reminiscent of those seen in patients with acquired hemophilia A (due to auto-anti- bodies to FVIII), with a greater predominance of mucocutaneous, urogenital, and gastrointes- tinal bleeding sites [57]. Consequently, the risk of severe complications or even death from bleeding may be significant in these patients. 9. Inhibitors are much less frequently encountered in hemophilia B, occurring in less than 5% of affected individuals [58]. 10. In all cases, inhibitors render treatment with replacement factor concentrates difficult. Patients on clotting factor therapy should therefore be screened for inhibitor development. 11. Confirmation of the presence of an inhibitor
GUIDELINES FOR THE MANAGEMENT OF HEMOPHILIA 60 12. For children, inhibitors should be screened once every five exposure days until 20 expo- sure days, every 10 exposure days between 21 and 50 exposure days, and at least two times a year until 150 exposure days. (Level 5) [61] 13. For adults with more than 150 exposure days, apart from a 6-12 monthly review, any failure to respond to adequate factor concentrate replace- ment therapy in a previously responsive patient is an indication to assess for an inhibitor. (Level 3) [56,62-64] 14. Inhibitor measurement should also be done in all patients who have been intensively treated for more than five days, within four weeks of the last infusion. (Level 4) [63,65] 15. Inhibitors should also be assessed prior to surgery or if recovery assays are not as expected, and when clinical response to treatment of bleeding is sub-optimal in the post-operative period. (Level 2) [53,63,66] 16. A low responding inhibitor is defined as an inhib- itor level that is persistently < 5 BU/ml, whereas a high responding inhibitor is defined by a level ≥ 5 BU/ml. 17. High responding inhibitors tend to be persis- tent. If not treated for a long period, titre levels may fall or even become undetectable, but there will be a recurrent anamnestic response in three to five days when challenged again with specific factor products. 18. Some low titre inhibitors may be transient, disappearing within six months of initial docu- mentation, despite recent antigenic challenge with factor concentrate. 19. Very low titre inhibitors may not be detected by the Bethesda inhibitor assay, but by a poor recovery and/or shortened half-life (T-1/2) following clotting factor infusions.
1. Management of bleeding in patients with inhib- itors must be in consultation with a centre experienced in their management. (Level 5) [63,67] 2. Choice of treatment product should be based on titre of inhibitor, records of clinical response to product, and site and nature of bleed. (Level 4) [63,68] 3. Patients with a low-responding inhibitor may be treated with specific factor replacement at a much higher dose, if possible, to neutralize the inhibitor with excess factor activity and stop bleeding. (Level 4) [63,68] 4. Patients with a history of a high responding inhibitor but with low titres may be treated similarly in an emergency until an anamnestic response occurs, usually in three to five days, precluding further treatment with concentrates that only contain the missing factor. (Level 4) [63,68] 5. Porcine factor VIII prepared from the plasma of pigs has been effective in halting bleeding in some patients. The plasma-derived preparation is being superceded by a recombinant porcine factor VIII concentrate currently in clinical trials. 6. With an inhibitor level > 5 BU, the likelihood is low that specific factor replacement will be effec- tive in overwhelming the inhibitor without ultra high dose continuous infusion therapy. 7. Alternative agents include bypassing agents such as recombinant factor VIIa (rFVIIa) and prothrombin complex concentrates (PCC), including the activated forms (APCC). 8. The efficacy of two doses of rFVIIa and one dose
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