Hemophilia A and B: An Overview
ARTHROPATHY
Before the advent of factor products for the treatment of hemophilia, hemarthrosis was one of the leading causes of morbidity. Today, the routine use of prophylactic treatment has resulted in a significant improvement in the lifestyle, quality of life, and life expectancy of these patients. However, despite best efforts, some patients will have severe joint destruction as a result of repeated articular bleeding episodes during their early years. This leads to pain and significant functional disability, thus impairing the quality of life. The basic pathology behind hemophilic arthropathy is chronic synovitis.
It is common to observe a pattern of repeated bleeding (chronic hemarthrosis), especially in patients with severe hemophilia, that can lead to chronic synovitis, inflammatory arthritis, and progressive arthropathy. Therefore, the key to preventing hemophilic arthropathy is aggressive management of the initial hemarthrosis. This is generally accomplished with the use of clotting factor replacement, restorative physiotherapy, and close clinical follow-up. If chronic synovitis develops, synovectomy may be considered in order to slow the progression of the hemophilic arthropathy and to prevent the development of major articular surface erosions that can lead to end-stage arthropathy.83 Primary prophylaxis is discussed earlier and is the mainstay of prevention of chronic hemophilic arthropathy.
SYNOVECTOMY
The emergence of chronic hemophilic hemarthrosis is incited by a hypertrophic and highly vascular synovium. Removal of the synovium prevents further joint damage,84 and can be accomplished through surgical and nonsurgical procedures.
,Surgical excision of the hypertrophic synovium can be performed through open or arthroscopic procedures. The open approach has largely been replaced by arthroscopic synovectomies. Regardless of the approach, these patients need prolonged hospitalization, extensive factor replacement, and exhaustive physiotherapy. Moreover, patients with inhibitors are usually not considered candidates for surgical synovectomy.
Chemical and radioactive agents injected intra-articularly can decrease the volume and activity of the synovial tissue. Due to the minimally invasive nature of these procedures, nonsurgical synovectomies are of special importance for hemophilic patients with inhibitors to clotting factors.
Chemical Synovectomy
Chemical synovectomies, using thiotepa, osmic acid, D-penicillamine and other agents, have been used in the distant past. Rifampicin, which is used an antibiotic, is now the most commonly used chemical for the purpose of synovectomy, and the one that has shown better results in terms of decreasing hemarthrosis.85 Each one of the injections should be accompanied by prophylactic administration of clotting factor concentrate. Excellent results (no synovitis and restoration of previous function) have been reported in up to 83% of patients at an average of 2.4 years after the intra-articular injection of rifampicin. As the pathology of the joint becomes more severe, however, the number of injections required to achieve improvement increases. Younger patients and smaller joints benefit more from this procedure.
Radiation Synovectomy
Radiosynovectomy (RS) and radiosynoviorthesis are common terms used to describe the synovial ablation accomplished by intra-articular injection of radioisotopes. Isotopes of gold, yttrium, rhenium, and dysprosium have been used to perform radiation synovectomies in patients with hemophilia. Yttrium-90, a pure beta emitter with adequate particle size and depth penetration, has been used successfully for the treatment of hemophilic synovitis.
The local (growth plate and articular cartilage) and remote effects of radiation are a concern. There have been no reported cases of growth plate disturbance after radiosynovectomy, even after the use of beta emitters such as gold-198.86 Articular cartilage is highly resistant to radiation, and although damage is theoretically possible, none has been reported. Progressive degeneration of treated joints does occur, but the rate is slower than that expected without radiosynovectomy. The principal concern is the potential for late, radiation-induced neoplasia. However, the safety of intra-articular radioisotopes is supported by a long-term follow-up study of more than 5000 RS procedures performed for rheumatoid arthritis, which found no reported radiation-induced malignancies.87
One review analyzed the safety of RS in pediatric patients with hemophilia to provide a risk-benefit assessment. During knee RS, patients receive a radiation dose of approximately 0.74 mSv, and during elbow and ankle RS, a dose of approximately 0.32 mSv. The radiation dose from natural sources is approximately 2 mSv per year 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.88 External-beam radiation has been extensively studied and carries a small risk of osteosarcoma induction.
ACQUIRED INHIBITORS TO FACTOR VIII
Acquired hemophilia (AH) has an estimated prevalence of 1.48 cases per million per year, and a reported mortality between 9% and 22%.89,90 AH is uncommon in children younger than 16 years (prevalence estimated at 0.045/million/year), and may be underdiagnosed in persons older than age 85 (prevalence estimated at 14.7/million/year).89 In the largest published population series, 50% to 60% of diagnosed individuals were previously healthy with no identified underlying disease state.90–91 Underlying conditions consistently associated with AH include pregnancy, evolving or pre-existing autoimmune or malignant disorders, and rarely medications. Primary among the autoimmune disorders are collagen vascular disorders, including systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis, multiple sclerosis, and autoimmune hemolytic anemia. Most antibodies are mixtures of polyclonal IgG1 and IgG4 immunoglobulins, with the IgG4 molecules mainly responsible for inhibiting clotting activity. The clinical picture of AH is characterized by acute onset of severe bleeding in individuals who previously had no history of bleeding diathesis. Patients generally present with mucocutaneous bleeding (eg, epistaxis and gastrointestinal bleeding), as well as soft tissue bleeding (eg, extensive ecchymoses and hematomas).
The 2 major goals of treatment of AH are the immediate control of acute and chronic bleeding and the long-term suppression/eradication of the autoantibody inhibitor. For patients with an inhibitor titer < 5 BU/mL, administration of desmopressin and concentrates of human recombinant factor VIII may raise the factor VIII activity levels in plasma. If the inhibitor titer is > 5 BU/mL, or if bleeding persists despite infusions of factor VIII concentrates, then factor VIII bypassing agents, such as aPCCs or rFVIIa, are indicated. Local measures for treatment of mucosal hemorrhage, such as antifibrinolytic agents or topical fibrin glues, are helpful.
The primary aim in long-term management of AH is to eradicate the factor VIII autoantibodies so that further bleeding can be averted. Although in some clinical situations (postpartum women and drug-related AH) factor VIII antibodies may remit spontaneously, most published guidelines and algorithms recommend early initiation of eradication therapy. This is usually achieved through immunosuppressive medications or immunomodulation. Successful immunosuppression regimens in AH have most frequently used corticosteroids as the cornerstone, either as a single agent or in combination with cyclophosphamide. In a prospective randomized trial involving 31 participants treated with prednisone 1 mg/kg/day for 3 weeks, 32% achieved complete remission. In participants with antibody persistence after 3 weeks, switching to oral cyclophosphamide 2 mg/kg/day as second-line therapy appeared more effective than continuing prednisone (complete remission rate 50% versus 42%).92
Other immunosuppressive medications have been employed for eradication of refractory autoantibody inhibitors, including azathioprine, cyclosporine, tacrolimus, mycophenolate motefil, and sirolimus. Controlled studies have not been performed to confirm their comparative safety and efficacy in sufficiently large populations. Anti-CD20 antibody has been used to treat inhibitors in patients with both congenital and acquired hemophilia.93,94 Other less frequently used treatment options include administration of intravenous immunoglobulins (IVIG) in large doses. IVIG by itself rarely is able to induce a complete remission, but may be useful adjunctive therapy along with immunosuppressants, as part of an ITI regimen, or with extracorporeal plasmapheresis.
