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The treatment landscape for haemophilia is changing rapidly, creating opportunities for personalized treatment. As major morbidity is still caused by haemophilic arthropathy, understanding the factors affecting joint damage and joint damage progression might lead to more individualized treatment regimens. We investigated the association of HFE mutations or HMOX1 polymorphisms affecting iron/heme handling with radiographic joint damage in 252 haemophilia patients (severe and moderate). Although iron levels and transferrin saturation were significantly increased in the 95 patients with an HFE mutation, neither carrying this mutation nor the HMOX1 polymorphism was associated with radiographic joint damage, and the same was true after adjustment for well-known factors associated with arthropathy. In conclusion, this study does not support the hypothesis that HFE mutations or HMOX1 polymorphisms can be used to predict the development of haemophilic arthropathy. [ABSTRACT FROM AUTHOR]

Aim: Subclinical bleeding and inflammation play a role in progression of haemophilic arthropathy. Synovial proliferation is predictive of joint bleeding and its early detection may guide treatment changes and prevent arthropathy progression. This study evaluated the prevalence of active and inactive subclinical synovial proliferation and investigated potential biochemical blood/urine markers to identify patients with active subclinical synovial proliferation. Methods: This cross‐sectional study included patients with severe haemophilia A born 1970–2006 who were evaluated during routine clinic visits. Patients with (a history of) inhibitors or recent joint bleeding were excluded. Elbows, knees and ankles were examined for subclinical synovial proliferation by ultrasound and physical examination. Active synovial proliferation was distinguished from inactive synovial proliferation using predefined criteria. Blood/urine biochemical markers (serum osteopontin, sVCAM‐1, Coll2‐1, COMP, CS846, TIMP, and urinary CTX‐II) were compared individually and as combined indexes between patients with and without active synovial proliferation. Results: This cohort consisted of 79 patients with a median age of 31 years (range 16.5–50.8 years) with 62/79 (78%) of the patients using continuous prophylaxis. The annualized joint bleeding rate over the last 5 years was.6 (.2–1.1). Active (17/79, 22%) and inactive subclinical synovial proliferation (17/79, 22%) were both prevalent in this cohort. Biochemical markers were not correlated with active subclinical synovial proliferation. Conclusion: Subclinical synovial proliferation, both active and inactive, was prevalent in patients with severe haemophilia A with access to prophylaxis and would be overlooked without routinely performed ultrasounds. Biochemical markers were unable to identify patients with active subclinical synovial proliferation. [ABSTRACT FROM AUTHOR]

Background: A challenging complication in the treatment of haemophilia A is the formation of neutralizing anti‐FVIII antibodies (inhibitors). There is ongoing debate on the effect of FVIII product and inhibitor risk, rendering patients and physicians reluctant to switch FVIII‐products. Aim: This study aimed to evaluate changes in the immune profile of haemophilia A patients after switching FVIII products and their possible relation to inhibitor development. Secondary, FVIII efficacy after switching were assessed. Methods: Patients, who switched FVIII‐products between 2017–2019, were included in this single centre cohort study. Prospective comparison of immunoregulatory cells and markers by flow‐cytometry before and after the switch was performed in a subgroup. For the total cohort clinical data regarding inhibitor development and FVIII efficacy 1 year before and after switching were retrospectively collected. Results: One‐hundred patients (including 39 with prospective immunological assessment) were analyzed, of which 31% switched from plasma‐derived (pdFVIII) to recombinant standard half‐life FVIII (SHL‐rFVIII), 47% between different SHL‐rFVIII, and 22% from pdFVIII/SHL‐rFVIII to rFVIII‐Fc. No remarkable changes in immunoregulatory cell functions were observed after switching, regardless the type of switch. None of the patients developed an inhibitor. FVIII efficacy, that is, FVIII usage, half‐life and annual bleeding rate (ABR), was similar before and after switch for the SHL products, whereas rFVIII‐Fc associated with a longer half‐life (13.1 vs. 15.0 h) and lower ABR (3.0 vs. 1.0). Conclusions: Switching to a different FVIII product was not associated with inhibitor development, nor with differences in the immune profile. Switching to rFVIII‐Fc lead to lower ABR. [ABSTRACT FROM AUTHOR]

Introduction: Ankle joint distraction (AJD) is a promising treatment for patients with severe haemophilic ankle arthropathy (HAA). However, some patients showed no clinical improvement after AJD and these differences may be related to structural differences. Aim: Primarily to quantify the structural changes after AJD in patients with HAA by the use of 3D joint space width (JSW) measurements and biochemical markers and secondarily to correlate these findings with clinical pain/function. Methods: Patients with haemophilia A/B who underwent AJD were included for this study. Bone contours on MRI (performed before and 12 and 36 months after AJD) were drawn manually and percentage change in JSW was calculated. Blood/urine (before and 6, 12, 24 and 36 months after AJD) was collected for biomarker measurement (COMP, CS846, C10C, CALC2, PRO‐C2, CTX‐II) and combined indexes of markers were calculated. Mixed effects models were used for analyses on group level. Structural changes were compared with clinical parameters. Results: Eight patients were evaluated. On group level, percentage changes in JSW showed a slight decrease after 12 months followed by a non‐statistically significant increase in JSW after 36 months compared to baseline. Biochemical marker collagen/cartilage formation also showed an initial decrease, followed by a trend towards net formation 12, 24 and 36 months after AJD. On individual patient level, no clear correlations between structural changes and clinical parameters were observed. Conclusion: Cartilage restoration activity on group level in patients with HAA after AJD was in concordance with clinical improvements. Correlating structural modifications with clinical parameters in the individual patient remains difficult. [ABSTRACT FROM AUTHOR]

Introduction: The World Haemophilia Federation advises regular musculoskeletal assessment covering all International Classification of Functioning and Health (ICF) domains, including limitations in activities and participation in persons with haemophilia (PWH). This enables clinicians to detect changes early and enable adjustments in personalized healthcare when needed. However, data on the course of physical functioning and occurrence of decline is lacking. The aim of this study is to describe changes in perceived limitations in activities of PWH and to identify factors associated with a change. Methods: Data were collected from medical health records of regular check‐up visits of adults with moderate and severe haemophilia in two time periods. Perceived limitations in activities was measured with the Haemophilia Activities List (HAL). Association between variables (e.g., age, body mass index, bleeding rate and synovitis) and change in perceived limitations was assessed using a generalized linear model. Results: A total of 104 PWH were included. At T0, the median HAL sum score was 79.5 (IQR 62.1–93.6) and at T1 the median HAL sum score was 74.2 (IQR 57.5–88.3). A functional decline was found in 35.6% of PWH, 55.8% remained stable and 8.7% improved. Among other variables, a BMI > 30 kg/m2 appeared to be an important factor that negatively influenced the change in perceived functioning in adult PWH. With the included factors we could only explain a small part of this decline (R2adj:.12). Conclusion: The majority of PWH remained stable in their perceived functional ability over mid‐long term (median 3.5 years). However, about a third showed a clinical relevant decline in their functional ability. [ABSTRACT FROM AUTHOR]

Introduction: Physiotherapy is highly recommended for persons with haemophilia (PWH), to regain functioning after bleeding and to maintain functioning when dealing with haemophilic arthropathy. However, many PWH live too far from their Haemophilia Comprehensive Care Centre (HCCC) to receive regular treatment at their HCCC. Physiotherapists in primary care may have limited experience with a rare disease like haemophilia. Aim: To explore experiences of stakeholders with primary care physiotherapy for PWH and develop recommendations to optimize physiotherapy care coordination. Methods: A RAND approach was used, consisting of a Delphi procedure with e‐mailed questionnaires and a consensus meeting. Included stakeholders were PWH, physiotherapists from HCCC's and primary care physiotherapists. HCCC physiotherapists approached patients from their centre and primary care physiotherapists from their network to fill in the questionnaires. Purposive sampling was used to select participants from the survey sample for the consensus meeting. Results: Ninety‐six primary care physiotherapists, 54 PWH and eight HCCC physiotherapists completed the questionnaire. Subsequently, four PWH, three primary care physiotherapists and four HCCC physiotherapists participated in the consensus meeting. The questionnaires yielded 33 recommendations, merged into a final list of 20 recommendations based on the consensus meeting. The final rank‐order consists of 13 recommendations prioritized by at least one stakeholder. Conclusion: Commitment to a formal network is considered not feasible for a rare disease like haemophilia. Development of a practice guideline, easy‐accessible information and contact details, two‐way and open communication between HCCC and primary care and criteria to refer back to the HCCC are recommended. [ABSTRACT FROM AUTHOR]

Recombinant activated factor VII ( rFVIIa) is a haemostatic agent that is used for the treatment of haemophilia A patients with inhibitors. However, clinical response to rFVIIa is variable and unpredictable with currently available assays. We investigated the anti-fibrinolytic effects of rFVIIa in relation to thrombin generation ( TG) and other haemostatic parameters in haemophilia A patients with inhibitors. After addition of rFVIIa to plasma, the clot-lysis assay, TF-dependent TG, TF-independent TG and parameters involved in coagulation, anticoagulation and fibrinolysis were assessed. The clot-lysis test distinguished two groups of patients: a group with a normal and a group with impaired anti-fibrinolytic response to rFVIIa. Our results showed a dose-dependent increase in TF-dependent TG and TF-independent TG in all individuals. There was a significant difference in TF-independent TG parameters between the normal and impaired response groups. In addition, there was a difference between the normal and impaired response group in prothrombin time, which could be explained by significantly higher levels of coagulation factors in the normal response group, and soluble thrombomodulin. In conclusion, we observed different in vitro responses following rFVIIa addition in plasma of patients with haemophilia A and inhibitors, which could be partially attributed to levels of procoagulant proteins and soluble thrombomodulin. [ABSTRACT FROM AUTHOR]