Radioisotope synovectomy with rhenium186 in haemophilic synovitis for elbows, ankles and shoulders

Summary. We have performed 221 radioisotope synovectomy (RS) in more than 150 children and young adults with haemophilia, age ranging 3–30 years (mean 15) in Ege Hemophilia Center, Izmir, Turkey for last 7 years. We always preferred to use Yttrium 90 (Y⁹⁰) for knees; however, since 2005, we started using rhenium 186 (Re¹⁸⁶) for medium‐sized joints with respect to safety. In this article, we have evaluated long‐term experience ranging from 6 months to 3 years (mean 18 months) with Re¹⁸⁶ for elbows (n = 35), ankles (n = 26) and shoulders (n = 2) in total of 63 RS procedures for 49 patients. Their age range was 3–30 years and mean age was 15.5. Two mCi of Re¹⁸⁶ intra‐articularly injected for treating target joints and chronical synovitis. After RS, joint bleedings were decreased for all patients. The best results were obtained for all joints in patients with grade‐II synovitis as like earlier experience with Y⁹⁰. Excellent rates (no bleeding) were observed in grade‐II synovitis in 81% and 46% for elbows vs. 86% and 57% for ankles after 6 months and after 1 year follow‐up of patients, respectively. In grade‐III synovitis, excellent rates were 53% and 25% for elbows and 44% and 29% for ankles, respectively. In five joints for five patients, repeated injections were needed for better outcome. No adverse events such as radioisotope leakage, local inflamatory reactions or malignancy development were observed during and after RS. For medium‐sized joints, RS with Re¹⁸⁶ seems to be either effective or safe treatment method. Our results confirm those previously published by others on the value of Re¹⁸⁶ synoviorthesis in medium‐sized joints in haemophilia patients. After this experience, we changed our protocol and we use Re¹⁸⁶ for all medium‐sized joints for treating chronical synovitis.     

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

Summary. 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 Yttrium90 citrate 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 Yttrium⁹⁰ citrate (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‐Y⁹⁰ at 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‐Y⁹⁰ represents 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.     

Surgical synovectomy combined with yttrium 90 in patients with recurrent joint synovitis

Radiation synovectomy (RS) is one of many therapeutic options used for recurrent joint synovitis. Our aim was to analyze the effect of the surgical synovectomy combined with yttrium 90 (⁹⁰Y) in the treatment for recurrent joint synovitis. A surgical combined RS procedure was used on 32 knees of 30 patients. They were divided into two groups. Group 1 consisted of 7 knees of 7 patients (5 women and 2 men) with a mean age of 40.7 years in whom RS was combined with the open synovectomy. Group 2 consisted of 25 knees of 23 patients (21 men and 2 women) with a mean age of 45.5 years in whom RS was combined with the arthroscopic synovectomy. Arthroscopic synovectomy or open surgery biopsy was carried out for all cases who diagnosed of having synovitis. A scintigraphic examination was conducted within 24 h after the RS procedure to investigate the systemic leakage of ⁹⁰Y in all patients. The outcome of treatment was assessed based on self-reporting using the visual analogue scale (VAS) of night pain, rest pain, activity pain, effusion, and satisfactory scores. The average follow-up period was 4.15 years. There was a significant difference between before and after treatment in terms of outcome parameters’ VAS scores in both groups (p < 0.05). But there was no statistically significant difference between open and arthroscopic synovectomy groups in terms of outcome parameters (p > 0.05). Satisfactory outcome was excellent in 3 patients (42.8 %) in group 1 and 8 patients (32 %) in group 2. Surgical synovectomy with combined ⁹⁰Y could treat recurrent joint synovitis successfully. There was no statistically significant difference between open and arthroscopic synovectomy techniques combined with RS procedure.     

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

Summary. 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.     

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 ³²P 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.     

A retrospective study on chemical and radioactive synovectomy in severe haemophilia patients with recurrent haemarthrosis

Between 1970 and 1994, 116 chemical and 90 radioactive synovectomies were performed in 107 patients with severe haemophilia and two with type 3 von Willebrand's disease. The products used were osmic acid (OA) in 100 cases, 90-Yttrium in 35 cases, 186-Rhenium in 48, 169-Erbium in two, hexacetonide triamcinolone in 16 and radioactive gold in five cases. The use of radioactive colloids is not allowed in France in patients under 15 years of age. Twenty-nine patients had more than one synovectomy per joint. All patients were evaluated for 6 months post-synovectomy, using both a clinical and a radiological score. Six months after synovectomy, a good or excellent result was obtained for 81% of the joints treated with isotopes, compared with 44% of those treated with OA, P<0.001. This superiority of isotopes over osmic acid was still observed after 6 months for the 89 joints that were re-evaluated, with follow-up ranging from 1 to 9 years. It was possible to calculate a radiological score in 84 cases. With OA the best results were from the joints with the lowest scores pre-synovectomy (<7). No correlation could be established between the clinical and the radiological scores, due to the small size of the sample. In summary: (1) chemical and radioactive synovectomy are simple and safe procedures for haemophilic arthropathy, (2) in our series, after 6 months the efficacy of isotopic synovectomy was greater than that of chemical synovectomy, and this benefit seems to persist after 6 months, and up to 9 years in the group of patients with longer-term follow-up.     

Radioactive synovectomy with 90yttrium and 153samarium hydroxyapatite in haemophilic joints: preliminary study on radiation safety

Most countries still do not achieve 1 IU of factor VIII/capita sufficient for survival. Although primary prophylaxis prevents synovitis, is not universally used. Chronic synovitis is treated with arthroscopy at expense of considerable amount of coagulation factors, and specialized surgeons. Radioactive synovectomy (RS) is a minimally invasive and cost effective alternative to arthroscopy, often considered first the option for persistent synovitis. Even without established causation with cancer, RS is avoided by some, due to this concern. We aim contributing to the understanding of RS safety regarding malignancy, presenting a large number of treated patients, and a single case of cancer. Three centres in Brazil applied RS with ⁹⁰Yttrium Citrate, ⁹⁰Yttrium hydroxyapatite or ¹⁵³Samarium hydroxyapatite in haemophilic joints and performed a survey addressing cancer in these patients. Four hundred and eighty eight patients (ages 3–51) received 1–3 RS (total 842) and follow‐up was 6 months to 9 years. One patient aged 14 years presented Ewing sarcoma, 11 months after RS. The tumour was treated successfully with surgery and chemotherapy. Causality of cancer by RS is improbable in this case. Accordingly, latency here is far below minimum 5–10 years for radio‐induction of solid tumours. Moreover, ES is not a typically radio‐induced tumour, even at high doses. In agreement with others, though recognizing limitations, this study suggests RS is safe regarding cancer induction. Synovitis is a known burden for patients. The decision of making reasonable usage of RS should be outweighed with the risks of leaving synovitis untreated.     

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

Summary. 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).     

Clinical observation on safety and efficacy of a plasma‐ and albumin‐free recombinant factor VIII for on‐demand treatment of Chinese patients with haemophilia A

Summary. Recombinant FVIII (rFVIII) has become the best choice for treating bleeding of haemophilia A patients. A plasma‐ and albumin‐free recombinant FVIII (rAHF‐PFM, ADVATE^®), as the third generation rFVIII, virtually eliminates the risk of blood‐borne disease transmission by excluding all human blood derived additives throughout cell culture, purification and formulation. In this multicentre prospective clinical study we evaluated the efficacy, safety and immunogenicity of ADVATE^® in Chinese patients with haemophilia A. Fifty‐eight patients enrolled and received ADVATE^® treatment. Of the patients enrolled, eight (13.79%) had severe haemophilia, 45 (77.59%) had moderate haemophilia and five (8.62%) had mild haemophilia. Fifty‐four patients completed 6 months of observation. A total of 781 bleeds occurred in these 58 subjects, all evaluable per‐protocol. A total of 984 infusions were administered with a mean of 17.0 ± 11.1 infusions per patient. On average, each patient received a mean of 15030.2 ± 7972.7 IU ADVATE^® (median 13 625 IU, range 9500–19 750 IU) during 6 months. The majority of bleeding episodes (95.9%) were successfully treated with one or two infusions of ADVATE^®. Overall, response to the first ADVATE^® treatment was rated as either ‘excellent’ (82.8%) or ‘improved’ (17.2%) in all subjects. All patients tolerated ADVATE^® infusions well. One patient (1/58, 1.7%) developed an inhibitor of 4 Betheseda units at day 180 visit. The results of this clinical observational study support that ADVATE^® is efficacious, safe and well tolerated in the treatment of Chinese patients with haemophilia A.     

Comparison of the effect of knee synovectomy in haemophilic patients with 153Sm‐ and 90Y ‐labelled hydroxyapatite 1 year after

To compare the use of 740 Mbq (20 mCi) of ¹⁵³Sm and 185 Mbq (5mCi) of ⁹⁰Y, both labelling hydroxyapatite (HA), for knee synovectomy in haemophilic patients, 1 year after the intervention. Thirty three men (36 knees) were studied, divided into two groups: 1 – treatment using 740 Mbq of ¹⁵³Sm‐HA: 20 knees of 18 patients, with mean age of 21.4 ± 13.3 years (ranging from 7 to 56 years) and mean Pettersson score of 5.3; 2 – treatment using 185 Mbq of ⁹⁰Y‐HA: 16 knees of 15 patients, with mean age of 26.3 ± 10.3 (ranging from 7 to 51 years) and mean Pettersson score of 6.3. The following criteria were adopted for the evaluation before and 1 year after synovectomy: reduction in haemarthrosis episodes and pain using a visual analogue scale, as well as improved joint mobility. The occurrence of adverse events in the treatment was also considered. The chi‐square, Wilcoxon and Mann–Whitney tests were used with P ≤ 0.05 set as significant. The occurrence of haemarthrosis declined by 65.7% with the use of ¹⁵³Sm‐HA and 82.6% for ⁹⁰Y‐HA, with no statistical difference between the groups (P = 0.632); pain reduction was 42.5% in group 1 and 30.7% in group 2, once again with no statistical difference (P = 0.637). Improvement in joint mobility was not significant for both groups. Two cases of mild reactive synovitis were observed in group 1 and one in group 2, which cleared up without medical intervention. Although the beta energy from ⁹⁰Y is the gold standard for knee synovectomy, higher activities of ¹⁵³Sm may be used in places which have only production of this material.     

A retrospective cohort study of cancer incidence among patients treated with radiosynoviorthesis

Summary. Radiosynoviorthesis (RS) is an intra-articular injection of a radioactive colloid for the treatment of synovitis administered most often to patients with rheumatoid arthritis or haemophilia. Although highly cost-effective in comparison with surgical or arthroscopic synovectomy, the risk of cancer associated with this treatment is not well known. We evaluated the incidence of cancer in a group of patients treated with RS. A cohort of 2412 adult patients with a variety of underlying conditions (mainly rheumatoid arthritis) and treated with at least one RS between January 1976 and December 2001, was recruited from two centres in Montréal. Cancer incidence and mortality data for cohort members over that time period were obtained from regulatory agencies using linkage. Background rates for all and specific types of cancer were obtained for the provincial (Québec) and national (Canada) population according to age, gender and calendar period categories. Category-specific rates in the cohort were compared with rates in similar categories from the general population generating standardized incidence ratios (SIR). The effects of specific isotope doses and of number of RS treatments were analysed using a Cox-regression model. No increase in the risk of cancer was observed (SIR 0.96; 95% confidence interval 0.82-1.12). There was no dose-response relationship with the amount of radioisotope administered or number of RS treatments. The study provides some indication for the safety of the procedure but homogenous diagnostic groups of younger patients (such as haemophilic patients) receiving RS will need more evaluation.     

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.     

Surgery in patients with haemophilia and high responding inhibitors: Izmir experience

Summary. This report evaluates the haemostatic efficacy of recombinant factor VIIa (rFVIIa) and activated prothrombin complex concentrate (APCC) in patients with haemophilia and high responding inhibitors who underwent major and minor surgery. Data pertaining to surgeries from 2001 to 2009 at a single centre were retrospectively analysed. During this period, 53 surgical procedures were performed in 30 haemophiliacs with high responding inhibitors. Mean age was 16.2 ± 9.4 years. Eleven major surgeries in 4 patients, 41 radioisotope synovectomies (RS) and one circumcision classified as minor surgery in 28 patients were performed. Among the major surgery procedures, four were treated with rFVIIa, five with APCC and two with sequential use of APCC and rFVIIa. We used rFVIIa at the dosage of 80–120 μg kg^?1 every 2 h and APCC 100 IU kg^?1 every 12 h for the major surgery. When performing RS, we used rFVIIa in 18 patients with 26 target joints and APCC in 9 patients with 15 target joints. Three consecutive doses of rFVIIa (90 μg kg^?1) were used at 2‐h intervals followed by additional three doses at 6‐h intervals. The initial dose of APCC was 75 IU kg^?1 followed by a second and third dose of 50 IU kg^?1 at 12‐h intervals. APCC and rFVIIa demonstrated excellent efficacy in our major and minor surgical interventions [100% (22/22) and 94% (31/33), respectively]. We had only two bleeding complications with rFVIIa. There were no thromboembolic complications. APCC and rFVIIa provide an effective and safe first line haemostatic therapy for inhibitor‐positive haemophiliacs, allowing both major and minor surgery to be successfully performed.     

Lessons from a systematic literature review of the effectiveness of recombinant factor VIIa in acquired haemophilia

To conduct a systematic review of the literature reporting efficacy and safety of recombinant factor VIIa (rFVIIa) for the treatment of bleeding in acquired haemophilia and, if data permitted, undertake a meta-analysis of the current evidence. MEDLINE^®, Embase^®, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched for all studies on rFVIIa treatment in acquired haemophilia. Heterogeneity of included studies was measured using the inconsistency index (I²). Of the 2353 publications screened, 290 potentially relevant references were identified: 12 studies published in 32 publications met inclusion criteria. In total, 1244 patients and 1714 bleeds were included (671 patients received rFVIIa treatment for 1063 bleeds). In seven of 12 studies, the initial dose of Recombinant FVIIa was 90?±?10 μg/kg. Recombinant FVIIa was used as first-line therapy in the majority of cases. Median number of doses administered ranged from 10 to 28. Between 68 and 74% of bleeds were spontaneous, whereas 4–50% were traumatic. Thirty-nine to 90% of bleeds were severe. Haemostatic effectiveness was >?90% in 5/6 studies for both patient and bleed level. Recombinant FVIIa had a favourable safety profile with low risk of general adverse events and thromboembolic-associated events. The heterogeneity of the studies and data precluded a meta-analysis. Recombinant FVIIa demonstrated effectiveness for the treatment of bleeds and had a good safety profile. It is apparent from these data that there is a need for more standardised measures of clinical effectiveness in acquired haemophilia to enable comparison and pooling of results in the future.     

Factor VIIa in the treatment of haemophilia

Recombinant FVIIa is being developed for treatment of haemophiliacs with antibodies against FVIII/FIX. rFVIIa was shown to be haemostatically active in haemophilia A and B dogs as well as in 20 haemophilia patients (one haemophilia B and 19 haemophilia A patients). Thirteen patients were treated for life-threatening bleedings and nine at surgery (dose: 60-90 micrograms/kg q 3-4 h). One patient underwent synovectomy in a knee joint under the cover of rFVIIa as the sole coagulation factor without any problems. One patient with FXI deficiency was successfully treated at an orchidectomy. The haemophilia B patient was treated in association with a compartment syndrome (surgical fasciotomy) with a complete haemostasis. He later uneventfully underwent skin grafting. Two CNS bleeds, a severe mouth bleed were treated as well as an extensive nasopharyngeal bleed in a patient with an acquired inhibitor against FVIII. Shortening of the prothrombin time as well as of the APTT was seen. No side-effects were observed. It is speculated whether FVIIa in complex with not only tissue factor but also phospholipids exposed at the site of injured cells directly activates FXa and thereby the final common pathway of the coagulation cascade.     

Single 270 μg kg−1-dose rFVIIa vs. standard 90 μg kg−1-dose rFVIIa and APCC for home treatment of joint bleeds in haemophilia patients with inhibitors: a randomized comparison

Summary. Evidence suggests greater doses of recombinant activated factor VII (rFVIIa; NovoSeven^®, Novo Nordisk A/S, Bagsværd, Denmark) than currently administered may result in enhanced haemostasis and convenience for patients with haemophilia A and B with inhibitors. This study evaluated efficacy and safety of rFVIIa and an activated prothrombin complex concentrate (APCC; Factor Eight Inhibitor Bypassing Activity [FEIBA]^®, Baxter AG, Vienna, Austria) for controlling joint bleeds in a home‐treatment setting. Patients received each of three treatments in one of six possible sequences: 270 μg kg^?1 rFVIIa at hour 0 + placebo at hours 3 and 6, 90 μg kg^?1 rFVIIa at hours 0, 3 and 6, and 75 U kg^?1 APCC at hour 0. Efficacy was assessed by the requirement for additional haemostatics within 9 h and by a novel global response algorithm. The percentage of rFVIIa 270 μg kg^?1 group patients requiring additional haemostatics within 9 h (8.3%) was significantly lower than that for the APCC group (36.4%, P = 0.032). The percentage of rFVIIa 90 × 3 μg kg^?1 group patients requiring such rescue medication (9.1%) was also lower compared to the APCC group. This result approached, but did not reach statistical significance (P = 0.069). Both rFVIIa treatment groups showed similar use of rescue medication (8.3% and 9.1% of episodes for rFVIIa 270 μg kg^?1 and rFVIIa 90 × 3 μg kg^?1 groups respectively). No significant differences in treatment response were observed with the global response algorithm (P = 0.173). No safety issues were identified. A single dose of rFVIIa 270 μg kg^?1 is as safe and effective as rFVIIa 90 × 3 μg kg^?1 dosing, and may be considered a potentially more effective alternative to APCCs for the management of joint bleeding in this population.     

Safety and efficacy of turoctocog alfa (NovoEight®) during surgery in patients with haemophilia A: results from the multinational guardian™ clinical trials

Recombinant factor VIII (rFVIII) products provide a safe and efficacious replacement therapy for prevention and treatment of bleeding episodes in patients with haemophilia A. The present investigations from the multinational, open‐label guardian^? clinical trials assessed the haemostatic response of turoctocog alfa (NovoEight^®), a rFVIII product, in patients with severe haemophilia A (FVIII ≤ 1%) undergoing surgery. All patients had a minimum of 50 exposure days to any FVIII product prior to surgery and no history of inhibitors. A total of 41 procedures (13 orthopaedic, 19 dental and 9 general) were performed in 33 patients aged 4–59 years. Of the 41 procedures, 15 were major surgeries in 13 patients and 26 were minor surgeries in 21 patients. The success rate for haemostatic response was 100% (success was defined as ‘excellent’ or ‘good’ haemostatic outcome). Turoctocog alfa consumption on the day of surgery ranged from 27 to 153 IU kg^?1. The mean daily dose declined over time, while retaining adequate FVIII coverage as measured by trough levels. Overall, no safety issues were identified. No thrombotic events were observed and none of the patients developed FVIII inhibitors. In conclusion, the present results show that turoctocog alfa was effective in controlling blood loss by obtaining a sufficient haemostatic response in patients with severe haemophilia A undergoing surgery.     

The impairment in daily life of obese haemophiliacs

Summary. Obesity is a major health concern not only in the general population but also in patients with haemophilia. Little is known about the consequences of obesity for haemophilia patients. As obesity is an important risk factor for osteoarthritis, these effects may be even more pronounced in haemophilia patients who are prone to joint damage. The association between obesity and limitations in daily activities as well as the frequency of bleeds and use of factor VIII (FVIII) concentrate in obese and normal weight haemophilia patients was assessed. Fifteen obese (BMI ≥ 30 kg m^?2) and fifteen normal weight (BMI ≤ 25 kg m^?2) haemophilia A patients matched for severity and age were analysed. The Hemophilia Activities List (HAL) was used to assess the impairment in daily activities. Compared with the normal weight haemophilia patients, obese haemophiliacs had a significantly lower sum score (88/100 and 98/100, respectively, P = 0.02), which was mainly caused by an impaired lower limb function. All other components of the HAL also showed lower scores in the obese patients, but did not reach statistical significance. A higher frequency of bleeds requiring treatment with FVIII concentrate occurred in the obese haemophiliacs (17 bleeds in eight individuals) compared with the controls (three bleeds in three individuals) (P = 0.045). Compared with non‐obese haemophilia patients, obese haemophiliacs had more joint bleeds and a lower overall HAL score, which was driven by a lower limb function score. Prevention of overweight and weight reduction requires special attention from physicians treating haemophilia patients.     

Similar bleeding phenotype in young children with haemophilia A or B: a cohort study

The bleeding phenotype has been suggested to differ between haemophilia A and B. More knowledge on the bleeding phenotype at initiation of treatment is important to optimize patient care. The aim of this study was to investigate the severity of the bleeding phenotype and the variation in bleeding in children with severe or moderate haemophilia A and B. Consecutive, previously untreated patients with severe or moderate haemophilia A and B (factor VIII or IX activity <0.01 or 0.01–0.05 IU mL^?1 respectively) born between January 1st 2000 and January 1st 2010 were included. Primary outcome was severity of bleeding tendency. Secondary outcome was variation in bleeding pattern. A total of 582 patients with severe haemophilia A and 76 with severe haemophilia B did not differ in age at first exposure to clotting factor (0.81 vs. 0.88 years, P = 0.20), age at first bleed (0.82 vs. 0.88 years, P = 0.36), and age at first joint bleed (1.18 vs. 1.20 years, P = 0.59). Patients with moderate haemophilia were older compared to patients with severe haemophilia. In patients with moderate haemophilia there were no clear differences between haemophilia A and B. Severity and variation in bleeding phenotype are similar during the early stage of treatment in patients with severe and moderate haemophilia A and B respectively. The findings imply that children with haemophilia B should be observed and treated as vigilantly as those with haemophilia A.