Haemophilic Synovitis Research Articles

Musculo-Skeletal Complications of Hemophilia

Prophylactic treatment from ages 2 to 18 years could avoid the development of hemophilic arthropathy if the concentration of the patient’s deficient factor is prevented from falling below 1% of normal. A review of the literature on the musculo-skeletal complications of hemophilia has been performed. Early treatment is of paramount importance because the immature skeleton is very sensitive to the complications of hemophilia; severe structural deficiencies may develop quickly. Major hemarthrosis (including joint aspiration) and chronic hemophilic synovitis should be treated aggressively to prevent hemophilic 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. When advanced hemophilic arthropathy is present with severe disability, the aim should be to restore function. Arthroscopic joint debridement is an effective method to achieve this goal and can be considered to be an alternative to total joint arthroplasty in the younger age groups. Finally total joint arthroplasty can usually be relied upon to restore both mobility and function in a diseased joint. The potential benefits of joint arthroplasty must though always be weighed up against the long term sequelae, especially loosening and consequent revision surgery. A correct surgical haemostasis must be achieved by the infusion of factor concentrate at the right dose. Prophylactic treatment from ages 2 to 18 years could avoid the development of hemophilic arthropathy if the concentration of the patient ’s deficient factor is prevented from falling below 1% of normal. Major hemarthrosis, chronic hemophilic synovitis and the initial stages of hemophilic arthropathy should be treated aggressively to prevent hemophilic arthropathy. Finally total joint arthroplasty can usually be relied upon to restore both mobility and function in a diseased joint. A correct surgical haemostasis must be achieved by the infusion of factor concentrate at the right dose. doi:10.4021/jh18e

Radiosynovectomy in hemophilia: quantification of its effectiveness through the assessment of 10 articular parameters

Radiosynovectomy (RS) can reduce the number of hemarthroses in chronic hemophilic synovitis. The purpose of this study was to quantitatively assess the effectiveness of RS in terms of the objective improvement of ten articular parameters. One-hundred and fifty-six radiosynovectomies were performed in 104 joints of 78 hemophiliacs diagnosed with chronic synovitis. The mean patient age was 18 years. The RS was carried out with either yttrium-90 or rhenium-186 (1-3 injections with a 6-month interval between them). RS resulted in significant improvement in nine of the 10 variables studied, namely in the number of episodes of hemarthrosis, articular pain, range of motion (ROM) in flexion. ROM in extension, muscle strength (MS) in flexion, MS in extension, the degree of synovitis detected on clinical examination, the size of the synovium as measured by means of imaging techniques (in millimeters), the clinical scale developed by the World Federation of Haemophilia (WFH), and the radiologic scale of the WFH. The tenth parameter, the WFH radiologic score, showed no improvement. The other nine parameters studied improved independently for each one of the intra-articular injections of the radioisotope. Categorization of the variables with regard to the degree of improvement achieved showed that the number of episodes of hemarthrosis and the severity of pain were the variables associated with the greatest improvement, with a 70% decrease in the amount of bleeding and in the level of pain experienced by the patient. The reduction of articular bleeding after RS was 67.6% when RS-1 was used, 62.1% with RS-2 and 61.2% with RS-3. Synovial hypertrophy as assessed clinically and by imaging techniques also showed a reduction of 30% and 39%, respectively. The WFH clinical scale revealed an improvement of around 19%. MS also improved in flexion and extension (7.9% and 8.2% improvement, respectively). ROM showed a slight but non-significant improvement.

What patient, joint and isotope characteristics influence the response to radiosynovectomy in patients with haemophilia?

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).

Aspects of current management: orthopaedic surgery in haemophilia

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).

Radiosynovectomy in patients with chronic haemophilic synovitis: when is more than one injection necessary?

One hundred and fifty-six radiosynovectomies (RSs) were performed in 104 joints of 78 haemophilic patients diagnosed with chronic haemophilic synovitis. Mean patient age was 18 yr. Previous studies on the same group of patients indicated that RS is an effective procedure for treating chronic haemophilic synovitis, which may require the performance of 1-3 injections (RS-1, RS-2, RS-3), with a 6-month interval between them. Those studies also revealed that the parameters showing the greatest improvement after RS were pain and haemarthrosis, followed by the World Federation of Haemophilia (WFH) clinical score and muscle strength and range of motion. Such studies also demonstrated that the improvement achieved further to RS is independent of the patient's age, the type and severity of haemophilia, the previous haematologic treatment regime administered (on demand or prophylactic), the presence or absence of a circulating inhibitor, the patients' previous level or activity (or inactivity), the presence or absence of previous arthropathy (joint degeneration), of the isotope used (yttrium-90 or rhenium-186) and of the appearance or otherwise of RS-derived complications. In this study, we looked into the potential relationship between the type of joint treated and the degree of synovitis present with the need of one or more further RSs, and we found that the knee requires more injections than the elbow or the ankle and that the more severe synovites require a higher number of RS procedures.

90Yttrium‐hydroxyapatite: a new therapeutic option for radioactive synovectomy in haemophilic synovitis

Recurrent haemarthroses often lead to chronic synovitis in patients with haemophilia and von Willebrand disease. Radioactive synovectomy with yttrium-90 (⁹⁰Y) citrate is frequently used to treat this complication, usually with good results. Since 2006, the Nuclear Energy Research Institute (IPEN, Sao Paulo, Brazil) has produced hydroxyapatite particles labelled with ⁹⁰Y for radioactive synovectomy. The aim of this study was to compare the results achieved by both forms of ⁹⁰Y in the treatment of haemophilic synovitis. We included 221 joints from 136 patients (age range: 6-20 years), treated by one of the two radiopharmaceuticals, at the Hemocenter of Mato Grosso, Brazil. The outcomes analysed were the annual frequency of haemarthrosis, articular pain and joint range of motion before and 1 year after RS. Similar results were achieved regardless of whether ⁹⁰Y hydroxyapatite or ⁹⁰Y citrate was used, and results were independent of the joint type, age, gender, radiologic stage and presence of inhibitors. ⁹⁰Y hydroxyapatite appears to be equivalent to the reference product ⁹⁰Y citrate in the treatment of chronic synovitis associated with bleeding disorders.

Neoangiogenesis contributes to the development of hemophilic synovitis

AbstractJoint arthropathy secondary to recurrent hemarthroses remains a debilitating complication of hemophilia despite the use of prophylactic factor concentrates. Increased vascularity and neoangiogenesis have been implicated in the progression of musculoskeletal disorders and tumor growth. We hypothesized that de novo blood vessel formation could play a major role in the pathogenesis of hemophilic joint disease (HJD). We observed a 4-fold elevation in proangiogenic factors (vascular endothelial growth factor-A [VEGF-A], stromal cell–derived factor-1, and matrix metalloprotease-9) and proangiogenic macrophage/monocyte cells (VEGF+/CD68+ and VEGFR1+/CD11b+) in the synovium and peripheral blood of HJD subjects along with significantly increased numbers of VEGFR2+/AC133+ endothelial progenitor cells and CD34+/VEGFR1+ hematopoietic progenitor cells. Sera from HJD subjects induced an angiogenic response in endothelial cells that was abrogated by blocking VEGF, whereas peripheral blood mononuclear cells from HJD subjects stimulated synovial cell proliferation, which was blocked by a humanized anti-VEGF antibody (bevacizumab). Human synovial cells, when incubated with HJD sera, could elicit up-regulation of HIF-1α mRNA with HIF-1α expression in the synovium of HJD subjects, implicating hypoxia in the neoangiogenesis process. Our results provide evidence of local and systemic angiogenic response in hemophilic subjects with recurrent hemarthroses suggesting a potential to develop surrogate biologic markers to identify the onset and progression of hemophilic synovitis.

Synoviorthesis induced by rifampicin in hemophilic arthropathy: a report of 24 treated joints

Intra-articular hemorrhage is the clinical hallmark of hemophilia. Synoviorthesis, the intra-articular injection of chemical or radioactive substances in order to produce fibrosis of the hypertrophied synovium, has proved effective in the treatment of chronic hemophilic synovitis. Between December 2006 and July 2007, we treated 21 patients with hemophilic arthropathy by synoviorthesis with rifampicin once a week. The procedures were performed on 14 knees, five elbows, four ankles, and one shoulder (24 joints and 113 injections). The mean age was 16.7 years (range, 7-49 years). According to the Fernandez-Palazzi classification, synoviorthesis was considered satisfactory (excellent or good) in 21 (87.5%) joints and unsatisfactory (fair or poor) in three (12.5%). A mean reduction of 6.3 bleeding episodes per month was obtained (P < 0.0001). The mean pain score was reduced from 2.62 (range, 2-3; SD, 0.49) before treatment to 0.79 (range, 0-2; SD, 0.65) after treatment. The mean World Federation of Hemophilia (WFH) score was 5.45 (range, 2-8) before synoviorthesis and 3.5 (range, 1-7) after treatment. This method effectively reduced hemarthrosis and pain and also improved the range of motion in patients with hemophilic arthropathy. Chemical synoviorthesis with rifampicin appears to be efficient, inexpensive, and simple and also especially practical in developing countries where radioactive agents are not easily available.

Haemophilia and joint disease: pathophysiology, evaluation, and management.

In patients with haemophilia, regular replacement therapy with clotting factor concentrates (prophylaxis) is effective in preventing recurrent bleeding episodes into joints and muscles. However, despite this success, intra-articular and intramuscular bleeding is still a major clinical manifestation of the disease. Bleeding most commonly occurs in the knees, elbows, and ankles, and is often evident from early childhood. The pathogenesis of haemophilic arthropathy is multifactorial, with changes occurring in the synovium, bone, cartilage, and blood vessels. Recurrent joint bleeding causes synovial proliferation and inflammation (haemophilic synovitis) that contribute to end-stage degeneration (haemophilic arthropathy); with pain and limitation of motion severely affecting patients' quality of life. If joint bleeding is not treated adequately, it tends to recur, resulting in a vicious cycle that must be broken to prevent the development of chronic synovitis and degenerative arthritis. Effective prevention and management of haemophilic arthropathy includes the use of early, aggressive prophylaxis with factor replacement therapies, as well as elective procedures, including restorative physical therapy, analgesia, aspiration, synovectomy, and orthopaedic surgery. Optimal treatment of patients with haemophilia requires a multidisciplinary team comprising a haematologist, physiotherapist, orthopaedic practitioner, rehabilitation physician, occupational therapist, psychologist, social workers, and nurses. Journal of Comorbidity 2011;1:51-59.

The Hemophilic Joints

Recurrent hemarthroses in childhhood before the initiation of primary prophylaxis will result in joint damage after a decade or later. The best way that we have today to protecting against hemophilic arthropathy is primary prophylaxis. The decision to institute early full prophylaxis by means of a port (central venous access device) has to be balanced against the child’s bleeding tendency, the family’s social situation and the experience of the specific hemophilia center. The reported complication rates for infection and thrombosis have varied considerably from center to center. Risk of infection can be reduced by repeated education of patients and staff, effective surveillance routines and limitations on the number of individuals allowed to use the device. In discussing options for early therapy, the risks and benefits should be thoroughly discussed with the parents. From a practical point of view, primary prophylaxis together with synovectomy (radioactive, chemical, arthroscopic, or open) to avoid joint bleeding, can help halt hemophilic synovitis. Radiosynovectomy is a relatively simple, virtually painless and inexpensive treatment for chronic hemophilic synovitis, even in patients with inhibitors and must be the best choice for patients with persistent synovitis (which must be confirmed by US and/or MRI). Arthroscopic joint debridement may be indicated in younger hemophiliacs when there is relative preservation of the joint architecture and congruity, after the failure of three radiosynovectomies with a 6-month interval, and when joint replacement is not considered to be a viable alternative. Total joint arthroplasty should be indicated in hemophiliacs with severe joint pain and disability, including those who are HIV-positive. Hemophilia is a risk factor for infection after total joint arthroplasty. An extended period (2-3 weeks) of adequate hemostatic function is necessary to achieve normal healing after orthopedic procedures in hemophilia.

Haemophilic arthropathy: the usefulness of intra-articular oxytetracycline (synoviorthesis) in the treatment of chronic synovitis in children

Synoviorthesis is already widely used in the treatment of chronic haemophilic synovitis. The aim of this study was evaluate the effectiveness of oxytetracicline synoviorthesis on the frequency of haemarthrosis in haemophilic children with chronic synovitis and its impact on joint function. Between January 2001 and October 2006, we performed 34 synoviorthesis in 28 paediatric patients (6-16 years old) with diagnosis of haemophilic arthropathy stage I-II. At each joint were administered five doses of oxytetracycline for five consecutive weeks at doses of 100 mg in elbow and ankle and 250 mg in the knee. The frequency of haemarthrosis and range of joint mobility were evaluated before and after of treatment. The results were analysed with Student t-test and descriptive statistics. Thirty-four joints were treated, including 20 knees (58.8%), eight elbows (23.5%) and six ankles (17.6%). Median follow-up was 46.3 months (range 12-71 months). The frequency of haemarthrosis was recorded before treatment 47.3 year(-1) (range 12-96, P < 0.0001) and decreased to 3.5 year(-1) (range 0-15, P = 0.0119) after treatment. The range of joint motion in flexion-extension before treatment was 84.9°, while after this was 97.5° (P = 0.0119). The synoviorthesis with oxytetracycline has shown a favourable effect in the treatment of chronic haemophilic synovitis in reducing the frequency of haemarthrosis and improvement was observed consistently in the range of motion.

The effectiveness of radioisotope synovectomy for chronic synovitis in Turkish paediatric haemophiliacs: Ankara experience

Between January 2006 and December 2009, 37 radioisotope synovectomy (RS) in 18 severe haemophilic patients (factor 8<1%) have been performed at our centre. The distribution of joint injected was as follows: rhenium-186 [Re186], 19 joints (ankles, 8 and elbows, 11) and yttrium-90 [Y90] 18 joints (knees, 18). Their mean age was 12 years (range: 8-20 years). Mean follow-up period after procedure was 22.6 months. We preferred to use Y90 for all large joints and Re186 for small joints. Haemophilic patients with grade-II or III synovitis were selected for RS in our study. Radioisotope synovectomy was performed in eight ankles for seven patients, 11 elbows for seven patients and 18 knees for 13 patients. Mean bleeding counts before the procedure and after the procedure were as follows: Ankles, 3.43 vs. 0.62 (P=0.002); elbows, 3.12 vs. 0.55 (P=0.000); and 3.83 vs. 0.62 (P=0.011). No major complications requiring secondary treatments were observed. In summary, an early RS is the best way to halt the evolution of chronic haemophilia synovitis to devastating haemophilic arthropathy. Radioisotope synovectomy is very effective and safe in the treatment of chronic synovitis of children with haemophilia. Our data confirm the efficacy of RS for the treatment of chronic haemophilic synovitis, which has been previously published by many authors around the world. We highly recommend this procedure for developing countries to prevent joint disabilities. For a better and a healthier generation, RS has to be introduced in all the developing countries.

Radioactive synovectomy with Yttrium90citrate in haemophilic synovitis: Brazilian experience

Summary. Recurrent haemarthroses leading to chronic synovitis and arthropathy remain a major cause of morbidity in patients with haemophilia. Radioactive synovectomy (RS) is considered the first choice of treatment for chronic haemophilic synovitis. The aim of this study was to evaluate the effect of RS with Yttrium90citrate (C‐Y90) in the joints of patients with chronic haemophilic synovitis. From 2003 to 2007, 245 joints (118 knees, 76 elbows, 49 ankles and two shoulders) of 190 patients with haemophilia or von Willebrand disease were submitted to RS with C‐Y90at Hemocentro de Mato Grosso, Brazil. Forty joints had radiographic Pettersson scores above 8. There were 36 joints of 22 patients with inhibitors to factor VIII. The procedure was safe with low occurrence of adverse events. The main effect was the overall reduction in joint bleeding frequency, from 19.8 to 2.6 per year post‐RS. Similar results were obtained in cases with high radiographic scores and in inhibitor patients. Pain reduction was observed in most cases. Average range of motion was maintained or increased 1 year post‐RS in most joints. Extension was stable or increased in 88.2% of the knees and 86.5% of the elbows. Ankle plantarflexion was stable or increased in 90.9%, whereas dorsiflexion was maintained or increased in 87.9%. Worsening of the range of motion, when present, ranged from 14 to 17 degrees. We concluded that RS with C‐Y90represents an important resource for the treatment of chronic haemophilic synovitis, markedly reducing joint bleeding frequency and pain, irrespective of the radiographic stage and inhibitor status.

IL‐1β, IL‐6, KC and MCP‐1 are elevated in synovial fluid from haemophilic mice with experimentally induced haemarthrosis

The hallmark of haemophilia is the joint morbidity resulting from haemarthrosis that accounts for the majority of the bleeds. The exact mechanisms underlying changes are not fully elucidated. Cytokines are speculated to be involved in the progression and in vitro studies have confirmed the presence of elevated levels of cytokines in synovial tissue and cartilage from patients with haemophilic synovitis. In this study, the presence of selected cytokines in synovial fluid from haemophilia A mice with experimentally induced haemarthroses treated with rFVIII, rFVIIa and an rFVIIa analogue were investigated. Ten cytokines previously shown to be involved in arthritic syndromes were evaluated. Interleukin (IL)-1 beta, IL-2, IL-4, IL-6, IL-10, IL-17, Tumor Necrosis Factor-alpha (TNF- alpha), keratinocyte-derived chemokine (KC), Regulated upon Activation, Normal T cell Expressed and Secreted (RANTES) and monocyte chemotactic protein-1 (MCP-1) were included. In this article, we demonstrate, for the first time, that bleeding in knee joints of haemophilia A mice resulted in correlated increased levels of the pro-inflammatory cytokines: IL-1 beta, IL-6, KC and the MCP-1 in synovial fluid. These results suggest an important role of MCP-1 in the recruitment of monocytes and furthermore that the inflamed synovium releases IL-1 beta, IL-6 and KC, which in turn might contribute to further progression of the inflammatory process.

Extra‐vascular clotting factor VIII protein protects against development of haemophilic synovitis in the presence of pre‐existing anti‐factor VIII inhibitor

Objective: Progressive destruction of joints resulting from recurrent intra‐articular haemorrhage represents the major morbidity resulting from haemophilia A or B. In addition to systemic clotting factor replacement, therapies localized to haemophilic joints may provide adjunctive protection. In a factor VIII‐/‐ mice model, we investigated if extra‐vascular delivery of recombinant human clotting factor VIII (rhFVIII) via intra‐articular (IA) injection can prevent bleeding‐induced joint damage, and also examined the possibility that IA delivery of FVIII carries greater risk of developing anti‐rhFVIII inhibitor antibody.Methods: FVIII‐/‐ mice received rhFVIII by inserting a 30.5 G needle into the left knee joint, along with a range doses of FVIII(100, 25 and 5 IU kg−1) in 5 μL, normal saline as the control. Comparison group received the same needle injury and intravenous (IV) rhFVIII (100, 25 and 5 IU kg−1). 14 days after injury, both knee joints were collected for histological examination. To exclude the possibility that IA clotting factor was entering into circulation, mice received 100 IU kg−1 rhFVIII IA, and FVIII activity was measured by aPTT. To see if IA rhFVIII delivery can carry greater risk of developing anti‐FVIII antibody, mice were treated with a total dose of 300 IU kg−1 rhFVIII over 10 days, either by IA or IV. 14 days after exposure, anti‐FVIII was detected. After induction of anti‐FVIII antibody by IV rhFVIII, mice were subjected either to needle puncture under coverage of bypassing agent (FEIBA) 100 IU kg−1 or 100 IU kg−1 IV rhFVIII, or needle puncture with 25 IU kg−1 rhFVIII. Control mice received needle puncture with normal saline. Two weeks later, knee joints were collected for histological examination.Summary: Mice receiving only saline at the time of needle puncture developed synovitis (mean score 5.0 ± 0.5). Mice treated with 25 IU kg−1 IA rhFVIII developed better protection than mice treated with 100 IU kg−1 IV rhFVIII (lower pathology score for IA, 0.733 ± 0.278 vs. IV 2.57 ± 1.70) and even better protection was achieved by the dose of 100IU IU kg−1 IA (Pathology score of 0.25 ± 0.31). IA injection of 100 IU kg−1 rhFVIII did not lead to increased circulating FVIII activity at any time point up to 48 h. In IV‐treated mice, 100% of mice developed anti‐FVIII antibody (8.06BU), while only 50% of mice developed anti‐FVIII inhibitor at the lowest detection limit (0.61BU). In the presence of inhibitory antibody, only 46% of mice receiving IV FVIII survived the needle injury, 58% with FEIBA and 100% of mice survived with 25 IU kg−1 FVIII IA injection. In the saline‐injected control mice, needle injury led to a mean pathology score of 6.8. Neither IV FVIII nor FEIBA provided effective protection, with pathology scores of 6.3 and 5.4, respectively. Surprisingly, 25 IU kg−1 IA rhFVIII produced a pathology score of only 1.7.Conclusion: Extravascular rhFVIII in the joint space can contribute protection against bleeding‐induced joint damage. Intra‐articular rhFVIII delivery did not induce greater risk of inhibitory antibody formation in FVIII knockout mice than circulating factor VIIII challenge; in fact, a lower incidence was observed. In the presence of anti‐FVIII inhibitory antibodies, IA delivery of FVIII still can offer protection from bleeding‐induced joint damage.

Power Doppler Sonography in the Diagnosis of Hemophilic Synovitis

Ultrasound Quarterly: March 2009 - Volume 25 - Issue 1 - p 27-28 doi: 10.1097/01.ruq.0000347536.98538.14

Intraarticular factor IX protein or gene replacement protects against development of hemophilic synovitis in the absence of circulating factor IX

AbstractHemophilic bleeding into joints causes synovial and microvascular proliferation and inflammation (hemophilic synovitis) that contribute to end-stage joint degeneration (hemophilic arthropathy), the major morbidity of hemophilia. New therapies are needed for joint deterioration that progresses despite standard intravenous (IV) clotting factor replacement. To test whether factor IX within the joint space can protect joints from hemophilic synovitis, we established a hemophilia B mouse model of synovitis. Factor IX knockout (FIX−/−) mice received a puncture of the knee joint capsule with a needle to induce hemarthrosis; human factor IX (hFIX) was either injected through the needle into the joint space (intraarticularly) or immediately delivered IV. FIX−/− mice receiving intraarticular FIX protein were protected from synovitis compared with mice receiving same or greater doses of hFIX IV. Next, adeno-associated virus (AAV) gene transfer vectors expressing hFIX were injected into knee joints of FIX−/− mice. Joints treated with 1010 vector genomes (vg)/joint AAV2-, AAV5-, or AAV8-hFIX or 2.5 × 109 vg/joint AAV5-hFIX developed significantly fewer pathologic changes 2 weeks after injury compared with the pathology of control injured contralateral hind limbs. Extravascular factor activity and joint-directed gene transfer may ameliorate hemophilic joint destruction, even in the absence of circulating FIX.

Radial Head Excision and Synovectomy in Patients with Hemophilia

Chronic hemophilic synovitis of the elbow usually leads to enlargement and erosion of the radial head, resulting in mechanical blockage of forearm rotation, synovial impingement, recurrent hemarthrosis, and pain. The purpose of the present study was to evaluate the intermediate-term results of radial head excision and synovectomy in a large group of patients with hemophilia who had been managed at a single institution. Information on forty radial head excision and synovectomy procedures that had been performed at our institution from 1969 to 2004 was retrospectively collected. All but one of the operations had been performed in patients with severe hemophilia. The mean age of the patients at the time of the procedure was thirty-three years. Pain, limited range of motion, and bleeding were the indications for surgery. The mean duration of follow-up was 7.7 years. Only one postoperative complication was observed: a posterior interosseous nerve palsy that fully resolved by six months. No additional surgical intervention for bleeding was required in sixteen of the nineteen elbows in which bleeding was one of the indications for surgery. Of the forty elbows, seven required a secondary surgical procedure at a mean of five years after the excision of the radial head. Examination of the mean range of motion at the time of the latest follow-up demonstrated a 63 degrees increase in the pronation-supination arc (p < 0.00001) but only a 2 degrees increase in the flexion arc. Radial head excision in patients with hemophilia is an effective procedure for improving forearm rotation and reducing pain and bleeding frequency, with a low risk of complications.

Experimental haemophilic arthropathy in a mouse model of a massive haemarthrosis: gross, radiological and histological changes

Recurrent haemarthrosis results in chronic synovitis and destructive arthropathy. The long-term effect of a single haemorrhage is not known. To investigate the histopathological changes following a single, but major joint haemorrhage, an animal model of massive haemarthrosis without mechanical trauma was developed and is described in this manuscript. The knee joint capsule of mice deficient in coagulation factor VIII or IX and non-haemophilic wild type mice was punctured to induce a one time, but massive haemorrhage. The single joint puncture resulted in acute haemarthrosis in both types of haemophilic mice but not in wild type mice. Subsequent to injury, the changes in the knee joints were analysed using gross, histological and radiographic assessments and compared with the uninjured knee. In addition, a novel imaging modality, micro-computed tomography, was used to document the structural damage to the joint. Our results indicate that the long-term changes classically observed in patients with advanced haemophilic arthropathy are evident following a single massive haemarthrosis. This model will allow a thorough investigation of the pathobiology of blood-induced joint disease and will be useful to test the efficacy of innovative therapeutic strategies to prevent haemophilic synovitis and arthropathy.

Blood-Induced Joint Disease: The Confluence of Dysregulated Oncogenes, Inflammatory Signals, and Angiogenic Cues

Hemophilia is a congenital disorder that commonly results in musculoskeletal bleeding and orthopedic complications. After an acute joint hemorrhage, there is pain, swelling, and limited motion due to an increase in intra-articular pressure and inflammation. Increases in intra-articular pressure induce mechanical signals that lead to cartilage cell apoptosis. Repeated bleeding results in development of a target joint, which is characterized by painless swelling and limited motion. Blood in the joint space provokes a proliferative disorder termed hemophilic synovitis (HS), with characteristics resembling those of malignant tumors. It has been suspected that one or more of the many components of blood, particularly iron, may be responsible for initiating and sustaining the inflammatory and synovial/vascular cell proliferation response associated with recurrent joint hemorrhages. In this paper, we review the pathogenesis of HS and present experimental data from mice deficient in factor VIII or IX activity in order to clarify the pathways by which blood in the joint space results in arthropathy. Understanding these pathways and cataloguing their key components may identify new targets for therapy of HS.