The impact of ankle haemarthropathy in patients with moderate haemophilia

Moderate haemophilia has traditionally been associated with less complications than severe haemophilia. Changes in treatment recommendations have highlighted the burden of moderate haemophilia with a subset of patients with a severe bleeding phenotype. The ankle joint is disproportionally affected by ankle haemarthropathy however the impact has not been evaluated in moderate haemophilia, nor the effect on health related quality of life (HRQoL) or foot and ankle outcomes.


INTRODUCTION
Haemarthropathy is an inherent clinical feature of severe haemophilia. 1 Clinically moderate haemophilia is less severe in presentation however, those with a bleeding phenotype are reported to have similar or higher bleed rates than patients with severe haemophilia. European studies of treatment in moderate haemophilia report median annual bleed rate 2-8 compared to 1-4 in severe haemophilia. 2,3 In addition, examination of annual joint bleed rates (AJBR) from the United Kingdom Haemophilia's Doctors Organisation (UKHCDO) national haemophilia database report patients with moderate haemophilia had median AJBR between 1 and 5. 2 In the UK treatment of moderate haemophilia has been placed on the clinical burden of haemarthrosis in moderate haemophilia. [4][5][6] Recently published recommendations by the UKHCDO now endorse the initiation of haemostatic management with prophylaxis treatment regimens if moderate haemophilia patients experience haemarthrosis or clinically significant bleeding. 7 Despite this advancement in treatment recommendations prevention of joints disease is paramount in delaying or halting joint disease.
In adults with severe haemophilia AJBR of the most affected joints of the ankles, elbows and knees are similar, however the ankle joint is disproportionally affected by haemarthropathy. 8 It is not fully understood why the ankle is disproportionately affected by haemarthropathy. Haemarthrosis has been shown to cause synovitis and functional joint change resulting in articular cartilage degeneration, bone damage, loss of joint space which leading to chronic end-stage haemarthropathy. [9][10][11] Changes to ankle joint structure and function are thought to expose the ankle joint to high contact and shearing forces, however no definitive evidence has been established for this hypothesis. [12][13][14] The advancements in novel factor and nonfactor treatments are yet to be utilised or realised in the management of moderate haemophilia, and therefore the risk of joint disease remains an inherent clinical feature of their haemophilia status. 7 Health related quality of life (HRQoL) of patients with moderate haemophilia is comparable to the general population in Netherlands, however a subset of patients (23%/ n = 39) have been identified who have more frequent episodes of bleeding and haemarthrosis. 3 Worse orthopaedic complications were reported in27% (n = 46) of patients who reported joint impairment, chronic pain (n = 26 /15%) and the need for orthopaedic aids (n = 41 /24%). 3 Similarly a recent Nordic study of joint health and treatment modalities in moderate haemophilia identified generally good joint health, but a proportion (n = 36 /25%) of patients with moderate haemophilia had severe haemarthropathy. 6 In adults with severe haemophilia the ankle joint is often cited as the main site of haemarthropathy and pain when compared to the most commonly affected joints of the elbows and knees. The impact of ankle haemarthropathy on overall musculoskeletal health, including foot and ankle outcomes in moderate haemophilia has not been reported. [16][17][18][19] A subset of patients experience worse outcomes than the general moderate haemophilia population and the ankle is disproportionately affected by haemarthropathy in patients with severe haemophilia. Therefore, it was the aim of this paper to quantify the impact of ankle haemarthropathy of patients with moderate haemophilia investigating health related quality of life (HRQoL) and foot and ankle patientreported outcome measures (PROMs). Secondly, we aimed to report the clinical measures of ankle haemarthropathy, ankle AJBR and levels of patient reported chronic ankle pain.

METHODS
A cross-sectional multi-centre questionnaire was distributed to 18 national sites consisting of 13 haemophilia comprehensive care centres (CCC) and five haemophilia treatment centres (HC). concerns. 20,21 Higher scores indicate better health, with raw scores combined to produce a total score with 0 indicating worst health and 100 best possible health. 22 The MOxFQ (foot and ankle) is a PROM used to evaluate foot and ankle pain, consisting of three domains of walking/ standing pain and social interactions. A higher total index score (0-100) indicates worse severity. [23][24][25][26] Demographic details including disease characteristics (haemophilia type, severity), ankle pain status over six months using a numerical pain rating scale (NPRS) (Pain in your ankle over the last 6 months; How painful has your ankle been over the past six months? 0 = No Pain, 10 = Pain as bad as you can imagine) 27

DATA ANALYSIS
Data were analysed using Statistical Package for the Social Sciences

RESULTS
A total of 29 patients with moderate haemophilia were recruited from 11 haemophilia centres across the United Kingdom. Distribution amongst centres consisted of one participant at three centres, two participants at three centres and above three at five centres. Patient characteristics are presented in Table 1

HRQoL and PROMs
The individual domain scores of the HAEMO-QoL-A and MOxFQ are presented in Figures 1 and 2, respectively. Patients with mod-erate haemophilia appear to report low scores across the domains of role function, worry and consequence of bleeding and treatment concerns.
The MOxFQ (foot and ankle) PROM ( Figure 2) report higher scores for the walking/ standing domain indicating worse physical function followed by pain.
Total and index scores of the HAEMO-QoL-A and MOxFQ are presented in Table 3.   severely affected by haemarthrosis, disability and reduced HRQoL. 28 Måseide et al also identified a subgroup of patients with more severe joint haemarthropathy in Nordic haemophilia patients with moderate haemophilia A and B. 6 In this impact study we aimed to recruit this proportion of patients with ankle haemarthropathy, therefore it would be expected that they would represent a more affected cohort with poor HRQoL and Foot and ankle PROMs than previously reported.
The foot and ankle PROMs of patients in this study were equivalent to OA cohorts awaiting ankle fusion and arthroplasty surgery MOXFQ total scores and individual domains of walking/ standing pain and social interactions indicating chronic joint pain and disability. 32 There are few studies that report specific foot and ankle PROMs in haemophilia and patients with moderate haemophilia only reported in one study with a small number of moderate patients (n = 3). 12 Both studies report that moderate levels of haemarthropathy correlated with moderate impact using a recognised foot and ankle PROM. 16,17 In the presence of established joint haemarthropathy has been reported to "burn out" as the levels of joint disease become chronic and the rates of joint haemarthrosis decline. 33 In this study the median ankle HJHS were Ankle joint pain in problematic in clinical practice accounting for 45% of joint pain in haemophilia and multi-joint haemarthropathy. 18 Unlike the other affected joints of the knees and elbows the complexities of the ankle expose the joint to high forces during the loading phase of the gait cycle with ground reaction forces up to five times the patient's body weight. 34 The high ground reaction forces combined with limitations in ankle range of motions caused by ankle haemarthropathy make offloading difficult during ADL. 16,34 It is now recommended that patients with moderate haemophilia should be offered prophylaxis if they experience clinically significant bleeds or joint bleeding to prevent joint haemarthropathy. 35,36 Similarly in the UK it is recommended that patients with moderate haemophilia are assessed by a specialist physiotherapist at the same frequency as those with severe haemophilia to detect joint pathology in children, monitor joint health in adults and direct prophylaxis treatment. 35 The ankle joint is clinically difficult to assess with only access to the anterior and posterior margins with the HJHS reported to only moderate correlate with pathological changes identified using magnetic resonance imaging (MRI). 37 At the ankle it is recommend that where a patient presents with early ankle joint disease and a HJHS of less than 3 additional imaging such as MRI or musculoskeletal ultrasound (US) imaging should be considered. 37 The use of imaging modalities such as point of care US provides a cheap and repeatable addition to clinical assessment and have been shown to be effective at identifying early joint changes at the most affected joints of the ankles, elbows and knees. 38 The study findings advocate the need for targeted pharmacological and non-pharmacological interventions in moderate haemophilia.
A recent systematic review of pain management highlighted that studies involving physiotherapy interventions lacked methodological trial designs to make any conclusive recommendations for pain management. 39 Similarly, there is some low-quality evidence that the use of foot orthoses and footwear interventions reduce pain, however currently, there is no conclusive evidence sufficient to change clinical management and guidance. 40

LIMITATIONS
This study is limited by the sample size, whist patients were recruited from multiple sites our finding suggest only a small proportion of patients report ankle haemarthropathy, however we aimed to recruit patients with ankle haemarthropathy and our sample size is similarly to subsets in other studies with patients who have worse haemarthropathy. 3,6 Trough levels and treatment levels were not reported in this study which may have provided further clinical relevance to findings, however the patient reported in this study already have haemarthropathy and compilations related to haemarthrosis. The finding of this study do however, support recently published recommendations on the initiation of primary and secondary prophylaxis treatment of moderate haemophilia to prevent haemarthrosis and prevent or delay the progression of haemarthropathy. 7

CONCLUSION
Moderate haemophilia with a bleeding phenotype displays similarities to severe haemophilia in the development of haemarthropathy.
This study demonstrates that a subset of patients with moderate haemophilia and ankle haemarthropathy who report poor HRQoL, marked increase in foot and ankle PROMs, and ankle pain similar to patients with severe haemophilia A. AJBR remain similar to the UK THUNDER study and whist levels of joint damage are lower than severe haemophilia, the age of the patients in this study suggest joint disease is delayed and driven by repeated haemarthrosis. The findings of this study highlight the need for early initiation of pharmacological treatment regimens, closer monitoring of joint health in moderate haemophilia and target pharmacological and non-pharmacological interventions for the management of ankle haemarthropathy in haemophilia.

AUTHOR CONTRIBUTIONS
The study was conceived by RAW, AR, GC and HS. Analysis was undertaken by RAW and RW. The manuscript was written by RAW.
Subsequent drafts were edited and approved by all authors.