Haemophilia (2017), 1–10 DOI: 10.1111/hae.13201 REVIEW ARTICLE Guidelines for the management of acute joint bleeds and chronic synovitis in haemophilia A United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO) guideline J. HANLEY,* A. MCKERNAN,† M. D. CREAGH,‡ S. CLASSEY,§ P. MCLAUGHLIN,¶ N. GODDARD,¶ P. J. BRIGGS,* S. FROSTICK,** P. GIANGRANDE,†† J. WILDE,‡‡ J. THACHIL§§ and P. CHOWDARY¶ ON BEHALF OF THE MUSCULOSKELETAL WORKING PARTY OF THE UKHCDO *Haemophilia Centre, Royal Victoria Infirmary, Newcastle upon Tyne; †Department of Haematology, Derby Hospitals NHS Foundation Trust, Derby; ‡Haemophilia Centre, Royal Cornwall Hospitals NHS Trust, Truro; §Haemophilia Centre, Guys and St. Thomas’ NHS Foundation Trust, London; ¶Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital, London; **Institute of Translational Medicine, University of Liverpool, Liverpool; ††Haemophilia Centre, Churchill Hospital, Oxford; ‡‡Haemophilia Centre, Queen Elizabeth Hospital Birmingham, Birmingham; and §§Haemophilia Centre, Manchester Royal Infirmary, Manchester, UK Keywords: arthropathy, haemarthrosis, haemophilia, radioactive synovectomy, synovitis Introduction Although the exact pathogenesis of haemophilic arthropathy has not been elucidated, several in vitro ani- Prior to the availability of clotting factor concentrates, mal and human experiments have demonstrated blood- the natural history of arthropathy in severe haemophilia induced changes in all the ‘components’ of large synovial was well described, with recurrent bleeds into joints joints including the synovium itself, cartilage and the leading to progressive joint damage and ultimate subchondral bone. The two major changes in the syn- destruction with associated functional problems. The ovium are hypertrophy and hypervascularity. The key prophylactic use of factor concentrates has dramatically stimulant for these changes is iron released into the syn- modified the natural history of haemophilic arthropa- ovial fluid, which is both pro-inflammatory and proan- thy. The early use of prophylaxis can prevent joint giogenic [2–4]. The consequence of neovascularisation bleeding and avoid the cycle of damage associated with in the synovium is predisposition to more bleeding since recurrent haemarthrosis. Children who are treated on these new vessels are friable. This leads to a vicious circle prophylaxis schedules often reach skeletal maturity of bleeding, iron accumulation, synovial hypertrophy with well-preserved joint function. However, in addi- and hypervascularization leading to further bleeding tion to the clinically obvious bleeds, recurrent subclini- and ultimately progressive joint damage. Interventions cal episodes may also contribute to joint damage [1]. aimed at preventing or breaking this cycle are key strate- Once joint arthropathy is established, prophylactic gies for the preservation of joint function in people with treatment may not prevent further joint deterioration. haemophilia. Bleeding is particularly problematic in the diarthrodial-hinged joints such as the knee, elbow and ankle. It is therefore important that acute bleeds in Correspondence: John Hanley, Haemophilia Centre, Royal Vic- patients on either ‘on demand’ or ‘prophylaxis’ regimens toria Infirmary, Queen Victoria Road, Newcastle upon Tyne are treated optimally with the aim of minimizing the NE1 4LP, UK. synovial proliferation secondary to bleeding which is Tel.: 0191 282 4159; fax: 0191 282 0814; central to the pathogenesis of arthropathy. e-mail: [email protected] A recent survey has shown significant variation in Accepted after revision 24 January 2017 practice in the UK [5], which suggests that there is a © 2017 John Wiley & Sons Ltd 1 2 J. HANLEY et al. need for guidelines as a framework for best practice. The objective of initial factor replacement therapy is Evidence-based guidelines were developed summariz- to improve haemostasis in order to arrest bleeding. ing best practice for the assessment and management Subsequent treatment aims to prevent recurrent bleed- of acute joint bleeds and chronic synovitis in persons ing and the onset and progression of joint damage. with haemophilia. This guideline does not include sur- Prompt treatment of bleeding is important and as it gical procedures such as surgical synovectomy, has the advantage of potentially preventing permanent arthrodesis and arthroplasty. damage and this is best achieved with home therapy and patients have been traditionally advised to treat Materials and methods any early symptoms and signs of bleeding. The advan- tages of home therapy include significant decreases in The information contained in this guideline was days lost from work and school, days hospitalized and gathered from an appropriate and pertinent literature hospital visits [8]. In those with established arthropa- search in relation to UK practice. The writing group thy, it may be difficult to distinguish early bleeds from produced the draft guideline, which was subsequently flares of arthritic pain [9,10]. revised by consensus by members of the United Kingdom Haemophilia Centre Doctors’ Organisation Haemostatic management of patients with (UKHCDO) Advisory Board. The ‘GRADE’ system Haemophilia A and B was used to quote levels and grades of evidence, details of which can be found at: http://www. Dose of initial therapy. Early bleeds in patients who gradeworkinggroup.org. Strong recommendations are on prophylaxis are usually adequately treated by a (grade 1, ‘recommended’) are made when there is single dose with resumption of usual prophylaxis there- confidence that the benefits either do or do not out- after. Early studies attempted to investigate the opti- weigh the harm and costs of treatment. Where the mum treatment for bleed resolution. The interpretation magnitude of benefit or not is less certain, a weaker of these studies is complicated by the variable severity grade 2 recommendation (‘suggested’) is made. Grade of the bleeds included and the lack of standardized 1 recommendations can be applied uniformly to assessment criteria. Prior to the availability of factor most patients, whereas grade 2 recommendations concentrates, it was demonstrated that doses of cryo- require a more individualized application. The qual- precipitate achieving FVIII plasma levels of 28%, 35% ity of evidence is graded as high (A), based on high and 53% correlated with successful treatment in 90%, quality randomized clinical trials, moderate (B), low 95% and 99% of bleeding episodes respectively [11]. (C) or very low (D). Many early studies demonstrated that prompt, low doses of factor were equally effective in resolution of Management of acute haemarthrosis bleeds [12–14] but more rapid improvements were demonstrated with higher factor levels [15]. Prophylaxis is the current standard of care, although There are few randomized trials which have com- individual patients continue with on-demand treat- pared different initial doses of factor. One study found ment [6]. In patients receiving on-demand treatment, À that an initial treatment with factor VIII 28 IU kg 1 spontaneous and traumatic bleeds are common [7]. À was no more effective than 14 IU kg 1 in terms of For those receiving prophylaxis, trauma is often the time to symptom resolution and requirement for fur- major precipitant of bleeding but inadequate trough ther treatment [16]. However, the beneficial effect of levels, missed doses, underlying synovitis or estab- a higher initial dose has been demonstrated where lished joint damage may be contributory factors. The patients with levels of 40% compared to 20% had signs and symptoms associated with joint bleeds are shorter time to full functional recovery [17]. Pivotal shown in Table 1. A re-bleed is defined as worsening studies of recombinant factor VIII and Factor IX con- of the condition either on treatment or within 72 h centrates, including studies of extended half-life after stopping treatment [7]. Table 1. Symptoms and signs of joint bleeds. Bleed type Symptoms Signs References Early bleed A sensation of fullness, stiffness, Normal motion [7,73] discomfort, pain or tingling at the end of range of movement in the absence of trauma. Often described as aura by patients and at times can be difficult to distinguish from arthritic pain Moderate Pain Some swelling. Restriction of movement Severe Severe pain Marked swelling. Almost complete restriction [11] of movement ‘Joint immobilizing bleeds’ [16] Haemophilia (2017), 1--10 © 2017 John Wiley & Sons Ltd JOINT BLEEDS AND SYNOVITIS IN HAEMOPHILIA 3 products, have shown variation in the doses used, and there is inadequate response in the first 36 to 48 h the median dose used for bleed resolution was around (1C). À 30 IU Kg 1 in most studies, with 90 to or -95% of the bleeds requiring one or two infusions for complete Haemostatic management of patients with resolution [12,18–21]. In a retrospective study factor, À inhibitors to Factor VIII and IX doses of 25 to –40 IU kg 1 per bleeding episode were inferior only to prophylaxis in terms of reducing the Patients with inhibitors do not necessarily have an progression of arthropathy [22]. increased frequency of spontaneous joint and soft tissue bleeds compared to non-inhibitor patients but do have Subsequent factor treatment. Subsequent factor ther- a higher tendency to develop target joints, which can apy depends on the severity of the bleed. Serial ultra- be difficult to manage. Many inhibitor patients are now sounds of joint bleeds show a persistent effusion for a well established