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Introduction Haemophilic arthropathy (osteoarthritis secondary to haemophilia) of the ankle may result in painful hindfoot malalignment. Purpose To analyse hindfoot alignment in subjects with haemophilic arthropathy of the ankle and evaluate the response (improvement of pain, function and alignment) to the orthotic treatment prescribed in patients with malalignment. Methods The study included 163 patients with haemophilia, all of them over 16 years of age. Hindfoot alignment and footprint were analysed in patients with and without haemophilic arthropathy of the ankle (as determined by the Pettersson score). Response to the use of an orthosis was evaluated at 6 months by means of the AOFAS Ankle-Hindfoot Scale. Results Fifty-six (59.5%) patients with haemophilic arthropathy presented with concomitant hindfoot malalignment. The most common abnormality was a valgus alignment combined with a neutral footprint. In 14 cases, valgus was associated with a pes planus or a pes cavus. Only 5 patients without haemophilic arthropathy (7.2%) presented with some form of malalignment. The differences between the groups were statistically significant. The probability of having malalignment increased with the degree of arthropathy. Patients with haemophilic arthropathy and malalignment were treated with an orthosis, with insoles as the most commonly used alternative (86%). Such treatment significantly improved patients' pain and function-related scores on the AOFAS Ankle-Hindfoot Scale. Conclusion Given the high rates of valgus malalignment in subjects with haemophilic arthropathy of the ankle, and the good response rates obtained following individualised orthotic treatment, it seems reasonable to routinely evaluate hindfoot alignment in this group of patients.

Aim The use of musculoskeletal ultrasound (MSK-US) following protocols for haemophilic arthropathy and the Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) score can help standardize monitoring in haemophilia. This study evaluated the joint status (elbows, knees and ankles) of patients with haemophilia B (HB) in Spain using MSK-US and the HEAD-US score. Methods Haemophilia B patients ≥14 years old were included in this observational, multicentre, cross-sectional study, regardless of their clinical condition, HB severity and treatment received. Two blinded observers were involved in image acquisition and scoring in each centre. Results Eighty-two patients from 12 centres were enrolled: 27% mild HB, 23% moderate, 50% severe HB. Mean age was 38.9 ± 16.4 years, 60% were treated on demand (OD) and 40% were on prophylaxis. HEAD-US was zero in all joints in 28.6% OD patients and 36.4% on prophylaxis. Mean scores significantly worsened with HB severity, except for the left knee. Patients on primary and secondary prophylaxis had significantly better joint health vs OD patients in all joints, except the right ankle. Among OD patients, those with severe disease presented significantly worse scores in all HEAD-US items related to permanent damage. Conclusion Joint status of HB patients in Spain is influenced by severity and treatment modality, related to the development of arthropathy, which appears prevalent in OD patients with severe HB. Routine assessment with an imaging tool such as ultrasound and HEAD-US system may help to improve joint health by personalizing and adjusting treatment in this population.

Summary Monitoring recombinant activated factor VII (rFVIIa) treatment outcomes remains challenging. Thromboelastography (TEG) and the thrombin generation assay (TGA), measure coagulation dynamics over time and are being assessed as potential methods for evaluating and monitoring haemophilia treatment. Lack of standardized TEG/TGA methods makes it difficult to compare results and to establish a correlation with clinical outcomes. Aims To compare the pharmacokinetics (PK) of rFVIIa after 3×90 μg kg−1 doses vs a single dose (270 μg kg−1) in haemophilia patients and to evaluate TEG/TGA results postdosing to determine how these assays relate to PK findings. Methods Patients in this open-label, single-centre, randomized, crossover trial received one injection of 270 μg kg−1 rFVIIa crossed over with three injections of 90 μg kg−1 rFVIIa in a non-bleeding state. For TEG, kaolin and tissue factor were used as activators; TGA was performed on frozen platelet-rich and platelet-poor plasma, with and without corn trypsin inhibitor. FVIIa activity was evaluated using in vivo samples. Results TGA showed a dose-dependent effect of rFVIIa on thrombin generation; TEG revealed lower dose-dependent effects. Both showed some differences between single-/multiple-dose rFVIIa; both supported the PK findings. Conclusion While TEG and TGA are not yet clinically predictive, both supported the PK results. Data suggest that, while a single dose of 270 μg kg−1 rFVIIa provides slightly higher haemostatic potential than the multiple-dose regimen of 3×90 μg kg−1, the latter results in prolonged activity levels compared with a higher single dose.

Prophylaxis is considered the optimal treatment regimen for patients with severe haemophilia, and may be especially important in the prevention of joint disease. Novel coagulation factor concentrates with prolonged half-lives promise to improve patient treatment by enabling prophylaxis with less frequent dosing. With the call to individualize therapy in haemophilia, there is growing awareness of the need to use pharmacokinetic (PK) assessments to tailor prophylaxis. However, for new factor concentrates, it is not yet known which PK values will be most informative for optimizing prophylaxis. This topic was explored at the Eighth Zurich Haemophilia Forum. On the basis of our clinical experience and a discussion of the literature, we report key issues relating to the PK assessment of new coagulation factors and include suggestions on the implementation of PK data to optimize therapy. As both inter- and intra-individual variability in factor half-life have been reported, we suggest that frequent PK assessments should be conducted. However, to diminish the burden of more frequent sampling, sparser sampling strategies and the use of population modelling should be considered. Guidelines on how to assay new factor concentrates, and which PK parameters should be measured, are needed. Concerns were raised regarding the possibility of breakthrough bleeding, and current thinking on how to prevent breakthrough bleeding may no longer be appropriate. Finally, as treatment adherence may be more important to ensure that a therapeutic level of a new coagulation factor concentrate is maintained, behavioural techniques could be implemented to help to improve treatment adherence.

The incidence of haemarthrosis as a result of a spontaneous periarticular aneurysm in haemophilia is very low. In these circumstances, angiographic embolization might be considered as a promising therapeutic and coagulation factor saving option in joint bleeds not responding to replacement of coagulation factor to normal levels. Moreover, embolization should be considered as a possible treatment for postoperative pseudoaneurysms complicating total knee arthroplasty in haemophilia. However, the pathological process of aneurysmal bleeding and clotting factor replacement is entirely different. While embolization is the treatment of choice for some periarticular complications that may occur, it is by no means a panacea for all resistant periarticular bleeds in haemophilia or for postoperative bleeding which usually settles with clotting factor replacement. Another use of arterial embolization is for the treatment of haemophilic tumours of the pelvis, because they can act as a focus for infection and cause cutaneous fistulas. When they present perforations and infections of endogenous origin, their course is usually fatal. Suitable treatment has been investigated on numerous occasions, most of the literature agreeing that the only curative treatment is surgical resection. However, surgical resection after performing arterial embolization to reduce the vascularization of the pseudotumour is a good alternative, thereby reducing the size of the pseudotumour and the risk of bleeding complications during surgery. It is important to bear in mind that despite its efficacy, arterial embolization is an invasive procedure with a reported rate of complications up to 25% (16% minor, 7% serious, 2% death).

We recommend prophylaxis in haemophilic children with an inhibitor as a way of preventing the musculoskeletal impairment that is likely to affect them. This approach has been used for children without inhibitors with excellent results. If prophylaxis is not feasible, we suggest that intensive on-demand treatment should be given. Two agents, recombinant activated FVII (rFVIIa) and activated prothrombin complex concentrates (aPCC), are currently used to control haemostasis either for prophylaxis or intensive on-demand treatment. As it is recombinant, rFVIIa would seem more appropriate to be employed in children. aPCC could be used in adults, or in the event of an unsatisfactory response to rFVIIa. We recommend prophylaxis or, at least, intensive on-demand treatment in haemophilia children with inhibitors. Both rFVIIa and aPCC are being used for this purpose. It would seem that rFVIIa might be more appropriate for children as it is a recombinant product. Nevertheless, after skeletal maturity (in adults), both agents could be used indistinctively (taking into consideration that FEIBA is a plasma-derived product). We still need more well-designed comparative studies in order to be able to assert that our consensus-based conclusion is evidence based. In orthopaedic surgery, both aPCC and rFVIIa have been reported to be effective in controlling perioperative haemostasis, although in practice most centres have so far used rFVIIa for their orthopaedic procedures. We recommend rehabilitation programmes for all patients with inhibitors in order to mitigate the disabling and handicapping impact of their condition and thereby enable them to achieve social integration. Programmes for haemophilic children without inhibitors can be applied to children with inhibitors but should be individually tailored.

We report on a series of 27 orthopaedic surgical procedures. It includes 20 radiosynoviortheses and seven major orthopaedic procedures, performed on 26 patients. The average age of patients was 36 years (range: 8-53) and the average follow-up time was 2.5 years (range:1-5). There were 23 good results and four fair. In the synoviorthesis group (20 patients, 20 synoviortheses) the average age was 13.5 years (range: 9-26) and the average follow-up was 4.5 years (range: 1-7). There were 19 good results and one fair. All synoviortheses were done with activated prothrombin complex concentrates (FEIBA), all the responses being good except in one case (which had the final fair result). The total dose of FEIBA used was 600 IU kg(-1,) except in a patient that had a haemorrhagic complication. In fact, he required a prolongation of treatment up to a total dose of 2000 IU kg(-1). In the group of major orthopaedic procedures, the average age of the six patients was 30.5 years (range: 11-53) and the average follow-up was 2.5 years (range: 1-5). There were six good results and one fair. Postoperative bleeding complications occurred in one of the seven major orthopaedic procedures performed (arterial pseudoaneurym after a total knee arthroplasty). Despite such complication, which had the final fair result, our study has shown that haemophilic patients with high inhibitor titres requiring orthopaedic surgery can undergo such procedures with a high expectation of success. In other words, orthopaedic surgery is now possible in haemophilia patients with high-titre inhibitors, leading to an improved quality of life for these patients.