Title: Haemarthrosis of the ankle in haemophilia A and B: prevalence, impact and intervention
Funder: Health Education England

Abstract: Haemophilia impairs bleeding control because of an absence of clotting factor VIII (haemophilia A) or factor IX (haemophilia B)1 resulting in bleeding into muscles and joints2. Although treatment with artificial clotting factor has some effect on frequency of bleeds, most patients still experience ongoing spontaneous and traumatic bleeds in joints3. Prolonged exposure of joint structures to blood leads to cartilage, structural and functional damage, ultimately resulting in pain and disability2,3. Damage also leads to changes in joint function furthering the risk of subsequent mechanical joint and soft tissue haemorrhage. Ultimately, this vicious cycle results in cumulative and irreversible damage to joints with severe reduction in mobility4. Prevalence of these accumulative episodes of bleeding has yet to been evaluated in detail. The tibiotalar (ankle) joint is the most commonly affected joint in the lower limb, accounting for one in five haemophilia-related bleeds in the United Kingdom5,6. Functional changes in the joint lead to a reduction in ankle range of motion (ROM) in patients over 30 years of age by as much as 80%3.Treatment with artificial clotting factor at the Leeds Comprehensive Care Centre (CCC) costs up to 7800 per bleed incident (70kg male) in addition to standard prophylaxis costs. A review of eight adult cases at Leeds CCC conducted in preparation for this application found a reduction in incidence of lower limb bleeds over 12 months from a mean at baseline of 11.6 bleeds/year to only 2.4 bleeds/year over the subsequent 12 month period wearing a prototype Leeds Ankle Stable Enhanced Rocker (LASER) boot and foot orthoses. Manchester foot pain and disability scores also indicated an 18.5% improvement in patient reported pain and disability scores. The use of foot orthoses and footwear modifications in haemophilia has not been investigated thoroughly. In other diseases such as rheumatoid arthritis, there is good evidence that orthoses prevent foot deformity and provide stabilisation7. As yet however, there have been no rigorous studies to address potential benefits of footwear and foot orthoses in blood-induced haemophilic arthropathy8. In patients with limited ROM, rocker profile shoe's supplement the rocker function of the ankle allowing forward progression and reducing the potential anatomical stress that may occur at the ankle joint. Rocker profile shoes have been used in conditions such as neuropathy to reduce foot pressures at anatomical sites of high pressure9. In haemarthrosis ,a rocker profile shoe has the potential to compensate for the reduction in ankle ROM9. Hypothesis: Foot orthoses and footwear modification can reduce the impact of ankle haemarthrosis by controlling joint function and thereby reducing the frequency of ankle bleeds in haemophilia. Aims To estimate the prevalence and impact of chronic haemarthrosis of the ankle joint. To investigate the mechanism of action of the Leeds Ankle Stabilising Enhanced Rocker (LASER) boot on ankle function. To evaluate the feasibility of conducting a randomised controlled trial (RCT) in the management of ankle haemarthrosis to evaluate clinical and cost effectiveness of treatment. Methods Prevalence study using a national haemophilia database and an associated multicentre questionnaire to explore the impact of ankle haemarthrosis in people with haemophilia. Mechanism of action study exploring the properties of the novel LASER boot and foot orthoses. A study to establish the feasibility of conducting an effectiveness RCT. Potential Benefits- Improved pain, disability and function in patients with haemophilia. - Prolonged ankle joint health, and reduced mechanical burden on the joint. - Reduced NHS costs by reducing ankle bleeds, and subsequent extra factor and on-demand treatment. - Delayed need for resultant ankle joint surgery. - Improved efficiency of national CCCs and regional haemophilia treatment centres (HCs).

Lay abstract: Haemarthrosis (bleeding into a joint) is a painful and debilitating consequence of haemophilia. The ankle is the most commonly affected joint in the lower limb; however there are no evidence-based treatments to manage this condition. Aims of the researchThis research aims: to identify through a national survey how common haemarthrosis of the ankle is and how much it impacts on the lives of people with the condition; to explore how a novel mechanical treatment (the Leeds Ankle Stable Enhanced Rocker (LASER) boot) might benefit ankle function; and finally to determine the feasibility of conducting a future randomised controlled trial to compare the LASER boot against current care in patients with haemophilia and ankle haemarthrosis. Background to the researchThere are currently 6000 people with haemophilia A&B registered on the national haemophilia database. People with haemophilia have a reduction in blood clotting factor activity. Patients with less than 5% natural clotting factor (moderate and severe haemophilia) have a risk of spontaneous bleeding which persists even after taking artificial clotting factor. 80-90% of bleeds occur within the musculoskeletal system (muscles or joints), with the ankle being the most commonly affected joint of the lower limb. Each episode of bleeding can cost up to 7800 in extra factor, with UK ankle bleeds alone costing approximately 16.4M per year across the haemophilia population. Current evidence suggests that bleeds lead to irreversible changes in joint structure and function and more importantly increase pain and disability. These permanent changes in turn increase the risk of future spontaneous bleeds and this self-fulfilling cycle can result in severe reduction in patient mobility. In other diseases such as rheumatoid arthritis, there is good quality evidence to demonstrate that mechanical treatments such as footwear and orthoses can help prevent foot deformity and provide stabilisation to damaged joints. As yet there have been no rigorous studies that have addressed the potential benefits of footwear and orthoses in people with haemophilia-related joint damage. Current standard practice in the Leeds Comprehensive Care Centre involves the use of functional foot orthoses (mechanical insoles) in combination with footwear modifications. This approach has been prototyped as the Leeds Ankle Stabilising Enhanced Rocker (LASER) boot. Although no formal evaluations have yet been undertaken, early data from eight cases indicates a promising reduction in the number of ankle bleeds from 12 per year to 2-3 per year. Patient reported pain and disability scores also improved by 18.5%. Preliminary pilot work exploring the mechanical effects of the LASER boot approach also suggests that improvements may be achievable in symmetry, energy efficiency and pressure under the foot. This early evidence supports the need for a larger study to explore more fully how the LASER boot approach might work and whether it has the potential to help in haemarthrosis. Design and methods used A study using a national haemophilia database and an associated questionnaire to explore how frequent chronic ankle haemarthrosis is and to measure the impact on people with the condition. A mechanism of action study exploring the mechanical and functional properties of the LASER boot components using 3D gait and foot pressure analysis. A study to establish the feasibility of conducting a future definitive randomised controlled trial (RCT) comparing the new LASER boot approach to current care. Patient and public involvement (PPI) Patients and the public have been involved in all stages of the development of this application. A presentation to the Leeds PPI group, (a group of ~120 people with MSK conditions and including two patients with bleeding disorders), was conducted during the study protocol development phase. PPI members identified potential issues such as visit schedules and offered feedback which has reduced visit requirement. PPI will be included throughout the proposed research program in line with INVOLVE guidelines. Patient representatives will contribute at four levels: (i) study steering committee, (ii) reviewing all training materials, questionnaires and patient information, (iii) reviewing of reports targeted towards patients and the general public, (iv) strategy for patient and public involvement and assistance in engaging with the community.Dissemination During the course of this fellowship dissemination will follow traditional academic pathways through publication of research in peer reviewed journals and profession specific publications, as well as national and international conferences. Dissemination to patients, carers and the public will include summaries of the results, presentations at regional patient meeting events which will include the Yorkshire Bleeding Disorders & Haemophilia Group and NIHR OK to ask events. A brochure will also be produced to present research findings to NHS clinicians and managers.

Research activity codes: 6.3 MEDICAL DEVICES;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: BLOOD