Consensus recommendations for the use of FEIBA(®) in haemophilia A patients with inhibitors undergoing elective orthopaedic and non-orthopaedic surgery.

A growing number of publications have described the efficacy and safety of FEIBA as a first-line haemostatic agent for surgical procedures in haemophilia A patients with high-responding FVIII inhibitors. The aim of this study was to provide practical guidance on patient management and selection and also to communicate a standardized approach to the dosing and monitoring of FEIBA during and after surgery. A consensus group was convened with the aims of (i) providing an overview of the efficacy and safety of FEIBA in surgery; (ii) sharing best practice; (iii) developing recommendations based on the outcome of (i) and (ii). To date there have been 17 publications reporting on the use of FEIBA in over 210 major and minor orthopaedic and non-orthopaedic surgical procedures. Haemostatic outcome was rated as 'excellent' or 'good' in 78-100% of major cases. The reporting of thromboembolic complications or anamnestic response to FEIBA was very rare. Key to the success of FEIBA as haemostatic cover in surgery is to utilize the preplanning phase to prepare the patient both for surgery and also for rehabilitation. Haemostatic control with FEIBA should be continued for an adequate period postoperatively to support wound healing and to cover what can in some patients be an extended period of physiotherapy. Published data have demonstrated that FEIBA can provide adequate, well tolerated, peri and postoperative haemostatic cover for a variety of major and minor surgical procedures in patients with haemophilia A. The consensus recommendations provide a standardized approach to the dosing and monitoring of FEIBA.

Absorption spectroscopy in microfluidic flow cells using a metal clad leaky waveguide device with a porous gel waveguide layer.

Broadband absorption spectroscopy is advantageous because the full spectral profile of an analyte can permit identification of species. This work for the first time investigates the feasibility of a metal clad leaky waveguide (MCLW) device to obtain an absorption spectrum of an analyte of interest, methylene blue, using a white light source in a microfluidic flow cell. The MCLW device comprises a porous low refractive index gel, agarose, deposited on a titanium coated glass slide. The device was capable of detecting 2.3 µM of methylene blue at a wavelength of 650 nm. The corresponding minimum detectable absorbance is 1.6 × 10(-1) cm(-1). In comparison to commonly used detection devices the MCLW is simpler, robust, easier to fabricate and can be easily interfaced to microfluidic devices. It was also possible to store the MCLW devices dry for up to a year and rehydrate them in 30 s to a working condition.

Factor IX replacement to cover total knee replacement surgery in haemophilia B: a single-centre experience, 2000-2010.

Total knee replacement (TKR) is a well recognized treatment for haemophilic arthropathy. Successful haemostasis can be achieved by bolus doses or continuous infusion (CI) using either recombinant (r) or plasma-derived (pd) factor IX (FIX). We retrospectively analysed our experience of factor replacement to cover TKR in haemophilia B patients and explored factors related to FIX use during surgery. Between 2000 and 2010, 13 primary TKRs were performed in 11 haemophilia B patients. Operations were performed by the same surgeon using standard techniques. Median age was 58 years (42-79). An adjusted CI protocol was used for 5 days followed by bolus doses. FIX:C was maintained at 100 IU dL(-1) in the immediate postoperative period. There was no excess haemorrhage. There was no evidence of thrombosis or infection. All patients received mechanical thromboprophylaxis and only one chemical. CI was used in seven cases. Ten patients received pdFIX. Median hospital stay was 14 days (8-17). Median factor usage was 999 IU kg(-1) (768-1248). During CI, factor consumption was 695 IU kg(-1), 691 IU kg(-1) and 495 IU kg(-1) for BeneFix®, Replenine® and Haemonine, respectively. Clearance of both pdFIX and rFIX reduced during CI. All operations were uncomplicated. The decreased clearance in the CI setting reduced the amount of FIX required to maintain a therapeutic level. This reduction was greater with pdFIX and may be related to pharmacokinetic differences between pdFIX and rFIX. Given the excellent safety profile of the pdFIX products, CI of FIX and particularly pdFIX is safe, efficacious and convenient.

Perioperative clotting factor replacement and infection in total knee arthroplasty.

Total knee arthroplasty, or replacement (TKR), is now the most commonly performed surgical procedure performed in adults with haemophilia. It is indicated when end-stage haemophilic arthropathy results in intractable pain and reduced function. In patients with haemophilia, however, there has always been a concern about the high risk of infection, which carries with it potentially catastrophic consequences. The aims of this study were to review the case series of TKR for haemophilic arthropathy published in the medical literature, comparing the published infection rates and the differing clotting factor replacement regimes employed. Nineteen retrospective case series were identified; representing 556 TKR's in 455 patients with an overall infection rate of 7.9%. Case series which maintained a high level of clotting factor replacement throughout the first two postoperative weeks, however, had an infection rate of 2.15%, significantly lower than that of case series using the clotting factor replacement regime currently recommended in the World Federation of Hemophilia guidelines (9.22% P = 0.00545). We believe this study supports the use of a high level clotting factor replacement regime, replacing clotting factors to maintain them at a higher level for a longer period of time than currently recommended in international guidelines.

Total knee replacement in patients with end-stage haemophilic arthropathy: 25-year results.

Haemophilia is an x-linked inherited bleeding disorder which can cause severe arthropathy. We have reviewed the results of 70 primary total knee replacements (TKR) performed in 57 haemophilic patients between 1983 and 2007. The functional results were assessed using the Hospital for Special Surgery (HSS) knee scoring system and Kaplan-Meier survivorship analysis. Six patients died. HSS scores were available for 60 TKRs at a mean follow-up of 9.2 years (2 to 23); 57 (95%) had good or excellent results. Deep infection was recorded in one patient. Kaplan-Meier analysis using infection and aseptic loosening as endpoints showed the survival rate at 20 years to be 94.0%. A reduction in infection, spontaneous haemarthrosis and improvement in the quality of life were noted to justify surgery in our series of patients with a mean age of 43 (25 to 70). We have found that using the latest techniques of continuous infusion of clotting Factor have significantly helped to reduce the complication rates and have achieved results which match those of the non-haemophilic population undergoing TKR.

Current approaches in haemophilic arthropathy of the hip.

The hip is considered to be one of the main load bearing joints of the body. In the haemophilic patient joint bleeds can be catastrophic, leading to long-term joint degeneration and accompanying arthritis. In this review we explore the mechanisms of joint destruction, with particular consideration of the anatomy of the hip and how it may influence disease progression. We also review current strategies for treatment including hip replacement in the haemophilic patient and describe our experiences as a unit. Finally we evaluate future prospects in the management of hip disease in haemophilia.

Consensus protocol for the use of recombinant activated factor VII [eptacog alfa (activated); NovoSeven] in elective orthopaedic surgery in haemophilic patients with inhibitors.

Patients with haemophilia complicated by inhibitors have a significant burden of joint disease, which is associated with a negative impact on their quality of life. Successful elective orthopaedic surgery can result in decreased bleed frequency into a new joint, less time spent in hospital, increased mobility and improved well being. This paper describes a new protocol for use of recombinant activated factor VII (rFVIIa) in elective orthopaedic surgery, based on a review of published data as well as the personal experience of a group of expert physicians. The protocol offers guidance on the planning of the surgery and preoperative testing as well as the bolus schedule for rFVIIa and advice on the concomitant use of antifibrinolytic agents and fibrin sealants. A total of 10 operations involving 13 procedures in eight patients in five comprehensive care centres have been undertaken until now using the protocol, which employs an initial bolus dose of rFVIIa in the range of 120-180 microg kg(-1) to cover surgery. The clinical experience reported here encompasses all cases of elective orthopaedic surgery using rFVIIa as initial treatment carried out in the UK and Republic of Ireland over the last 2 years. In all cases, there was good control of haemostasis during surgery and the final outcome was rated as 'excellent' or 'extremely satisfactory' by the reporting clinicians. Although the initial cost of product to cover surgery such as arthroplasty is high, it needs to be borne in mind that this may be offset in subsequent years by savings resulting from avoidance of bleeding episodes in the affected joint.

Ankle arthropathy in the haemophilic patient: a description of a novel ankle arthrodesis technique.

The ankle joint is well known to show early involvement in severe haemophilia. We describe a novel operative technique developed by the senior author. This combines a medial approach to the ankle, medial malleolar osteotomy, bone graft and compression with staples. All patients had excellent pain relief and improvement in function with 100% achieving bony union. There was a significant improvement in Mazur ankle scores following ankle fusion (P < 0.01). This surgical technique gives good results which are reproducible in this patient population.

The impact of haemophilia on the success of total hip arthroplasty.

We present the results of 34 total hip arthroplasties performed, on haemophiliac patients, between 1983 and 2005. The haematological diagnoses and management are discussed, emphasizing their impact on keeping complication levels to a minimum. The orthopaedic diagnoses and treatment methods are also highlighted, discussing the survivorship and reasons for their failures.

Diagnosis of haemophilic synovitis.

The pathophysiology of haemophilic synovitis is complex and not as well understood on a molecular level as we have thought. The repeated bleeding episodes and synovial hypertrophy occurring within the joint. Iron and other red-cell debris are phagocytized, and hydrolytic enzymes are produced leading to the destruction of articular cartilage is a simplistic model. However, how iron stimulates this destructive cascade remains speculative and poorly understood. Diagnostic options include radiographic examination using horizontal beam technique, which may reveal a fat blood fluid level, and computed tomography scanning or magnetic resonance imaging.

An outline of the current orthopaedic management of haemophilic disease of the upper limb.

There remains a relative paucity in the literature regarding upper limb manifestations of haemophilic arthropathy. Haemophilia has a wide range of clinical manifestations, often presenting with orthopaedic complications. These arise from multiple haemarthroses which exact a cumulative toll on the fabric of the joints. Although the lower limbs are predominantly affected due to their load-bearing nature, upper limb disease is common. This arises from the mechanical demands on the upper limb as the elbow and shoulder become partially weight bearing on use of walking aids such as elbow crutches.

Primary malignancies mistaken for pseudotumours in haemophilic patients.

Pseudotumours are a rare complication of haemophilia. Surgery undertaken for pseudotumour on a lesion that is subsequently found to be malignant can be expected to adversely affect patient outcome. We present six case reports found from a literature search of patients with haemophilia who underwent surgery on what was a primary malignancy misdiagnosed as a pseudotumour and give a subsequent discussion.

Optical leaky waveguide biosensors for the detection of organophosphorus pesticides.

Organophosphorus (OP) pesticides can be rapidly detected by integrating organophosphorus hydrolase with an optical leaky waveguide biosensor. This enzyme catalyses the hydrolysis of a wide range of organophosphorus compounds causing an increase in the pH. Thus, the direct detection of OP is possible by monitoring of the pH changes associated with the enzyme's activity. This article describes the use of an optical, leaky waveguide clad with absorbing materials for the detection of OP pesticides by measuring changes in refractive index, absorbance and fluorescence. In the most effective configuration, a thick sensing layer was used to increase the amount of immobilized enzyme and to increase the light interaction with the sensing layer, resulting in a greatly enhanced sensitivity. The platforms developed in this work were successfully used to detect paraoxon and parathion down to 4 nM concentrations.

Heterotropic bone formation as a complication of elective joint replacement in haemophilic patients - a case report and literature review.

We report two cases of this rare postoperative condition. Both patients having undergone extensive surgery to their hips, developed increased bone growth in the soft tissue of the hip, accounting for the reduced range of movement, pain and stiffness. Plain x-rays taken confirmed the presence of heterotopic ossification, also known as a variant of myositis ossificans. We review the literature and discuss treatment options of this rare condition in patients with end-stage haemophilic arthropathy.

Haemophilic arthropathy of the elbow.

Patients affected by haemophilia commonly have recurrent intra-articular bleeding which leads to progressive destruction and instability of joints. Severe arthropathy of the elbow is complicated by pain, stiffness and loss of function which can be debilitating. Conservative measures such as analgesics, physiotherapy and orthotics are commonly used in the management of these patients. Surgery is considered when conservative measures fail to control the symptoms. Total elbow replacement is now increasingly performed with the advances made in factor replacement therapy and evolution of better implants and techniques of total elbow arthroplasty. The pathogenesis, clinical features and radiological changes of haemophilic arthropathy of the elbow are described in this review article.

Novel variable volume injector for performing sample introduction in a miniaturised isotachophoresis device.

A microdevice design furnished with a novel sample injector, capable of delivering variable volume samples, for miniaturised isotachophoretic separations is presented. Micromachining by direct milling was used to realise two flow channel network designs on poly(methyl methacrylate) chips. Both designs comprised a wide bore sample channel interfaced, via a short connection channel, to a narrow bore separation channel. Superior injection performance was observed with a connection channel angled at 45 degrees to the separation channel compared to a device using a channel angled at 90 degrees. Automated delivery of electrolytes to the microdevice was demonstrated with both hydrostatic pumping and syringe pumps; both gave reproducible sample injection. A range of different sampling strategies were investigated. Isotachophoretic separations of model analytes (metal ions and an anionic dye) demonstrated the potential of the device. Separations of ten metal cations were achieved in under 475 s.

Elective orthopaedic surgery for inhibitor patients.

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

Integrated moulded polymer electrodes for performing conductivity detection on isotachophoresis microdevices.

The feasibility of using integrated injection moulded polymer electrodes as drive and detection electrodes for performing miniaturised isotachophoresis (ITP) separations with conductivity detection has been demonstrated. Injection moulded electrodes were produced from three different grades of carbon-filled polymer. Two of the electrode designs were found to be suitable for performing on-chip conductivity detection. The high-voltage characteristics of the microdevices were found to be suitable for performing ITP, with a power dissipation up to 1.4 W m(-1) being achieved. Three model separations are presented to demonstrate the separation capability of the miniaturised injection moulded devices. Three anionic dyes, two inorganic anions and a mixture of eight alkaline earth, transition and lanthanide metal cations were analysed.