Limited value of testing for factor XIII and α2-antiplasmin deficiency in patients with a bleeding disorder of unknown cause.

INTRODUCTION: In patients with an increased bleeding tendency, extensive diagnostic blood testing is often performed. When results of tier 1 assays of primary haemostasis are normal, protocols recommend additional testing to rule out rare disorders including coagulation factor XIII (FXIII) and α2-antiplasmin (α2AP) deficiency. AIM: To evaluate the added diagnostic value of FXIII and α2AP levels in patients with a bleeding disorder of unknown cause (BDUC). METHODS: A retrospective monocentre cohort study between August 2011 and August 2023 was conducted. In all patients with bleeding tendencies and normal diagnostic tests for von Willebrand disease and platelet function, FXIII and α2AP were measured. RESULTS: We included 158 consecutive patients; mean ISTH-BAT scores were 8.2 (SD ± 3.7) in children, 6.2 (SD ± 2.1) in men and 10.6 (SD ± 3.3) in women. Median age was 37 (range 5-79) years, 88.6% of patients were female. Patients displayed median FXIII activity of 111% (IQR = 97-131) and median α2AP activity of 112% (IQR = 103-119). Three (1.9%) patients had FXIII levels < 50%, respectively 43%, 45% and 46%. Corresponding ISTH-BAT scores were 7, 12 and 14. No α2AP levels < 60% was observed. No significant association was found between FXIII levels and ISTH-BAT scores. CONCLUSION: In our cohort of BDUC patients, no clinical relevant FXIII deficiencies were detected; absolute values were well above the 30% cutoff considered adequate for normal haemostasis. No α2AP deficiencies were detected. These data suggest that in BDUC patients, measuring FXIII or AP activity is of limited value.

No immunological changes after factor VIII product switch: An in depth analysis in haemophilia A patients.

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.

Functional decline in persons with haemophilia and factors associated with deterioration.

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 (R2 adj : .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.

Proof of concept and feasibility of a blended physiotherapy intervention for persons with haemophilic arthropathy.

BACKGROUND: Regular physiotherapy with a physiotherapist experienced in the field is not feasible for many patients with haemophilia. We, therefore, developed a blended physiotherapy intervention for persons with haemophilic arthropathy (HA) (e-Exercise HA), integrating face-to-face physiotherapy with a smartphone application. AIM: The aim of the study was to determine proof of concept of e- Exercise HA and to evaluate feasibility. METHODS: Proof of concept was evaluated by a single-case multiple baseline design. Physical activity (PA) was measured with an accelerometer during a baseline, intervention and post-intervention phase and analysed using visual inspection and a single case randomisation test. Changes in limitations in activities (Haemophilia Activities List [HAL]) and a General Perceived Effect (GPE) were evaluated between baseline (T0), post-intervention (T1) and 3 months post-intervention (T2) using Wilcoxson signed rank test. Feasibility was evaluated by the number of adverse events, attended sessions and open-ended questions. RESULTS: Nine patients with HA (90% severe, median age 57.5 (quartiles 50.5-63.3) and median HJHS 32 (quartiles 22-36)) were included. PA increased in two patients. HAL increased mean 15 (SD 9) points (p = .001) at T1, and decrease to mean +8 points (SD 7) (p = .012) at T2 compared to T0. At T1 and T2 8/9 participants scored a GPE > 3. Median 5 (range 4-7) face-to-face sessions were attended and a median 8 out of 12 information modules were viewed. No intervention-related bleeds were reported. CONCLUSION: A blended physiotherapy intervention is feasible for persons with HA and the first indication of the effectiveness of the intervention in decreasing limitations in activities was observed.

Liver-related complications before and after successful treatment of chronic hepatitis C virus infection in people with inherited bleeding disorders.

INTRODUCTION: With availability of direct-acting antivirals (DAA), most persons with inherited bleeding disorders are currently cured of hepatitis C virus (HCV) infection. The risk of liver-related complications following HCV cure has not been reported for this population. AIM: Reporting liver-related complications during long-term chronic HCV infection and following sustained virological response (SVR) in this population. METHODS: Retrospective follow-up of a prospective single-centre cohort of HCV antibody-positive persons with inherited bleeding disorders. Primary endpoint was liver-related complications [hepatocellular carcinoma (HCC), decompensated cirrhosis, bleeding gastroesophageal varices]. Liver-related complications were reported separately during chronic HCV and following SVR, stratified for interferon-based and DAA-based SVR. RESULTS: In total 309/381 (81%) HCV antibody-positive individuals developed chronic HCV infection. Median follow-up was 44 years [interquartile range (IQR): 34-50]. Liver-related complications occurred in 36/309 (12%) of individuals with chronic HCV infection after median 31 years of chronic infection. Of 199 individuals with SVR, 97 were cured with interferon-based regimens and 102 with DAA after median infection durations of 29 and 45 years, respectively. At end of follow-up, respectively, 21% and 42% had advanced fibrosis or cirrhosis. Post-SVR, seven (4%) individuals had a liver-related complication, mainly HCC (n = 4). Incidence of liver-related complications per 100 patient-years post-SVR follow-up was .2 for interferon-cured and 1.0 for DAA-cured individuals (p = .01). CONCLUSION: Successful HCV treatment does not eliminate the risk of liver-related complications in persons with inherited bleeding disorders. Due to higher baseline risk, incidence was higher after DAA than interferon-based SVR. We advise continuing HCC surveillance post-SVR in all with advanced fibrosis or cirrhosis.

Clotting factor activity levels and bleeding risk in people with haemophilia playing sports.

BACKGROUND: Improved treatment options for people with haemophilia (PWH) have increased the possibilities for sports participation, but the risk of sports-induced bleeding (SIB) is still considered considerable by many. AIM: To assess sports associated injury- and bleeding risk in PWH and to assess clotting levels associated with safe sports participation. METHODS: Sports injuries and SIBs were prospectively collected for 12 months in PWH aged 6-49 without inhibitors playing sports at least once weekly. Injuries were compared according to factor levels, severity, joint health, sports risk category and sports intensity. Factor activity at the time of injury was estimated using a pharmacokinetic model. RESULTS: 125 participants aged 6-49 (41 children, 90% haemophilia A; 48% severe, 95% severe on prophylaxis) were included. Sports injuries were reported by 51 participants (41%). Most participants (62%) reported no bleeds at all and only 16% reported SIBs. SIBs were associated with factor levels at time of injury (OR: 0.93/%factor level (CI 0.88-0.99); p = .02), but not with haemophilia severity (OR: 0.62 (CI 0.20-1.89); p = .40), joint health, sports risk category or sports intensity. PWH with factor levels <10% during sports injury had a bleeding risk of 41% versus 20% in those with higher (>10%) factor levels. CONCLUSION: The results of this study emphasize the importance of clotting factor levels in prevention of bleeds. This information is vital for patient counselling and tailoring prophylactic treatment with clotting factors and non-replacement therapy.

Structural changes after ankle joint distraction in haemophilic arthropathy: an explorative study investigating biochemical markers and 3D joint space width.

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.

Subclinical synovial proliferation in patients with severe haemophilia A: The value of ultrasound screening and biochemical markers.

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.

Menstrual problems in chronic immune thrombocytopenia: A monthly challenge - a cohort study and review.

Immune thrombocytopenia (ITP) may cause menstrual problems. This cross-sectional study assessed menstrual problems in premenopausal chronic ITP women by several questionnaires, including the pictorial bleeding assessment calendar (PBAC; score ≥100 indicates heavy menstrual bleeding [HMB]), and the menorrhagia multiattribute scale (MMAS). Spearman was used for assessing correlations. A literature review was performed in Pubmed. The cohort comprised 37 women (mean age 31 ± 9). A total of 29/37 (78%) had experienced clinical menstrual problems in the present or past. Of the 33 patients who returned the PBAC, 13 (39%) had a score of ≥100. The median MMAS score was 79 (IQR 60-95). The PBAC scores correlated with the MMAS. Both questionnaires were unrelated to the platelet count. Patients with a levonorgestrel intrauterine device (LNG-IUD) had lower PBAC scores than patients with other or no hormonal therapy. MMAS scores were correlated with fatigue. The review identified 14 papers. HMB occurred in 6%-55% at ITP diagnosis and 17%-79% during disease. Menstrual symptoms influenced the quality of life, particularly in patients with a low platelet count. This explorative study suggested that HMB is frequent in women with chronic ITP despite management and platelet counts >50 *109 /l. An LNG-IUD seemed to reduce blood loss significantly.

Prevalence, burden and treatment effects of vaginal bleeding in women with (suspected) congenital platelet disorders throughout life: a cross-sectional study.

Congenital platelet disorders (CPDs) are rare bleeding disorders that are associated with mucocutaneous bleeds. However, data on vaginal bleeding in women with CPDs are scarce. A set of generic and bleeding-specific questionnaires were used to evaluate the prevalence of vaginal bleeding, its impact on quality of life (QoL) and sexual functioning and the consequences for pregnancy, miscarriage and delivery in a cohort of women who were referred for diagnostic evaluation for CPDs. A total of 78 women included in the study were either diagnosed with a CPD (n = 35) or were clinically suspected of a CPD (n = 43). Heavy menstrual bleeding (HMB) was reported by a large proportion of women, which mainly started at menarche. In all, 76% of women received any kind of HMB treatment, often leading to surgical prodecures. HMB was shown to have a high impact on QoL, which improved upon treatment. Even though women reported that vaginal bleeding affects sexuality, this topic is not frequently discussed with physicians. Heavy blood loss frequently occurred after miscarriage/delivery, often requiring treatment. Women with (suspected) CPDs frequently encounter HMB, negatively impacting daily life and sexual functioning. Together with peripartum bleeding, these data highlight the burden of vaginal bleeding in CPDs and importance of adequate treatment.

Patient-reported outcomes in autosomal inherited bleeding disorders: A systematic literature review.

AIM: Currently, it is unknown which patient-reported outcomes are important for patients with autosomal inherited bleeding disorders. Therefore, the purpose of this study is to systematically review the available literature assessing patient-reported outcomes and their measurement methods in autosomal inherited bleeding disorders. METHODS: The Embase, Medline ALL, Web of Science Core Collection, Cochrane Central Register of Controlled Trails and Google Scholar databases were searched from inception until 14 August 2020. Studies on patient-reported outcomes in patients with von Willebrand disease, inherited platelet function disorders and coagulation factor deficiencies were included. RESULTS: Twenty-one articles met the inclusion criteria. Three studies were assessed as having poor quality, and therefore a high risk of bias. Nineteen studies had fair quality rating. Different measurements methods were used, ranging from predefined to self-developed questionnaires. The majority of included studies focused on von Willebrand disease. Patients with von Willebrand disease reported lower health-related quality of life compared to the general population. Overall, this trend was especially visible in the following domains: vitality, physical and social functioning and pain. Women with inherited bleeding disorders scored lower on health-related quality of life compared to men, especially women with heavy menstrual bleeding. Patients with joint bleeds or heavy menstrual bleeding reported an increased level of pain. CONCLUSION: Patients with autosomal inherited bleeding disorders report lower health related quality of life, especially those with joint bleeds or heavy menstrual bleeding. Numerous measurement methods are used in patients with autosomal inherited bleeding disorders, highlighting the need for studies using established, standardized measurement methods.

Zero incidence of factor VIII inhibitors and successful haemostatic response in previously factor VIII-treated patients with haemophilia A switching to turoctocog alfa in a noninterventional study.

INTRODUCTION: Turoctocog alfa (NovoEight® ) is a B-domain-truncated recombinant factor VIII (FVIII) approved for patients with haemophilia A. AIM: To investigate the long-term safety and efficacy of turoctocog alfa in routine clinical practice. METHODS: Guardian 5 was a prospective, multinational, non-interventional, post-authorisation safety study. Male previously treated patients (> 150 exposure days [EDs]) of any age with severe/moderately severe haemophilia A (FVIII ≤ 2%) and a negative inhibitor test prior to first dosing (independent of FVIII-inhibitor history) were included to receive prophylaxis or on-demand treatment. The primary endpoint was the proportion of patients developing FVIII inhibitors (≥.6 Bethesda Units [BU]) after baseline visit, measured as per routine practice of each study site during clinic visits. Secondary endpoints included haemostatic effect, annualised bleeding rate (ABR), and adverse reactions assessment. The study concluded when 50 patients reached 100 EDs/patient minimum. RESULTS: Seventy patients were screened and 68 exposed to turoctocog alfa; 63 (92.6%) were on prophylaxis and five received on-demand treatment. Six (8.8%) patients reported a history of positive inhibitors. During the study, patients were exposed to turoctocog alfa for a mean (standard deviation) of 131.9 (99.0) days/patient. Fifty-five of 58 patients who completed the study were tested for FVIII inhibitors; no positive tests were reported. Overall success rate of turoctocog alfa for treatment of bleeds was 87.3%. Among patients receiving prophylaxis, median (range) ABR was 1.97 (.0-25.5) bleeds/year; estimated ABR (negative binomial model) was 3.65 (95% confidence interval: 2.53-5.25). CONCLUSION: Turoctocog alfa was safe and efficacious for haemophilia A treatment in routine clinical practice.

Ankle joint distraction is a promising alternative treatment for patients with severe haemophilic ankle arthropathy.

INTRODUCTION: Haemophilic ankle arthropathy (HAA) causes major morbidity. When conservative treatment fails, major surgical interventions are indicated. An alternative treatment to maintain joint mobility and postpone these interventions is desired. AIM: To gather prospective data on clinical/structural changes after ankle joint distraction (AJD) in HAA. METHODS: This study includes patients with severe HAA insufficiently responding to conservative treatment. AJD was performed during 8-10 weeks by use of an external frame. Questionnaires, physical examination and radiology were used to evaluate pain, function and structural changes before and 6, 12, 24 and 36 months after distraction. Mixed effect models were used for analysis. RESULTS: This study includes eight cases (21-53 years). The fixed effects estimates of the visual analogue score (0-10) improved from 7.5 at baseline to 3.4 (p = .023) 3 years after distraction. The Haemophilia Activities List (HAL, 0-100) for basic/complex lower extremities functions improved from respectively 29.6 and 31.5 to 54.3 (p = .015) and 50.7 (p = .031). Joint mobility was maintained. Magnetic resonance imaging (MRI) showed thickened cartilage and reduced bone marrow oedema and subchondral cysts. Pin tract infections (n = 6) were effectively treated and no adverse bleeding events occurred. At 3-year follow-up, in none of the patients the originally indicated arthrodesis was performed. CONCLUSION: This first prospective study showed that AJD in HAA results in decreased pain, improved function and decreased arthropathy-related MRI findings in the majority of patients for prolonged time. Although the study population is small and follow-up is relatively short, AJD may be promising to postpone invalidating interventions and might be a breakthrough treatment.

Alternatives for Vitamin K Antagonists as Thromboprophylaxis for Mechanical Heart Valves and Mechanical Circulatory Support Devices: A Systematic Review.

The holy grail of anticoagulation in patients with intracardiac devices, such as mechanical heart valves (MHVs) and left ventricular assist devices (LVADs), comprises safe prevention of thrombosis without interrupting normal hemostasis. Device-induced thrombosis and anticoagulant-related bleeding problems are dreaded complications that may cause a significantly reduced quality of life and increased morbidity and mortality. Vitamin K antagonists are the current standard for oral anticoagulation therapy in patients with MHVs and LVADs. Even within the therapeutic range, hemorrhage is the primary complication of these drugs, which emphasizes the need for safer anticoagulants for the prevention of device-induced thrombosis. Device-induced thrombosis is a complex multifactorial phenomenon that likely requires anticoagulant therapy targeting multiple pathways. Here, we review the preclinical and clinical data describing the efficacy of a variety of anticoagulants as thromboprophylaxis after implantation of intracardiac devices.

Coordinating physiotherapy care for persons with haemophilia.

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.

Shortening the Haemophilia Activities List (HAL) from 42 items to 18 items.

INTRODUCTION: The Haemophilia Activities List (HAL) was developed to measure activities and participation in persons with haemophilia (PWH). Shortening the questionnaire may facilitate use of the HAL. AIM: The aim of this study was to determine which items of the HAL are redundant, to construct a shorter version of the HAL, and to determine the construct validity of the HALshort . METHODS: A secondary analysis was performed on pooled data of two published studies using the HAL (seven domains, 42 items, optimum score: 100) in adults with haemophilia A/B. Data were divided into a derivation (62%) and a validation set (38%). Redundant items were identified by evaluation of: floor and ceiling effects, proportions of missing and 'not applicable' responses, inter-item correlations, component loadings in an exploratory factor analysis, internal consistency, and item-total correlations. Correlations with the SF-36 and EQ-5D-5L were used to determine construct validity of the HALshort . RESULTS: Data on 680 PWH were evaluated. In the derivation dataset (n = 420), median age was 30 years (range 18-80), 43% had severe haemophilia and 61% received prophylaxis. Median (IQR) HAL sum score was 65.0 (55.7-88.8). The stepwise procedure resulted in a HALshort of 18 items with a median sum score of 63.3 (54.4-86.7). Construct validity was similar for the HAL and HALshort in the validation dataset (n = 260). CONCLUSION: This clinimetric study resulted in a >50% shortening of the HAL. The 18-item HALshort reduces patient burden and is expected to capture the information on activities and participation. The HALshort needs further validation.

On-demand treatment with the iron chelator deferasirox is ineffective in preventing blood-induced joint damage in haemophilic mice.

INTRODUCTION: Early intervention in the devastating process of haemophilic arthropathy (HA) is highly desirable, but no disease-modifying therapy is currently available. Considering the pivotal role of iron in the development of HA, iron chelation is considered a promising therapeutic approach. A previous study in haemophilic mice demonstrated that treatment with the iron chelator deferasirox (DFX) 8 weeks before joint bleed induction, attenuated cartilage damage upon blood exposure. However, in haemophilia patients this approach is not opportune given the unpredictable occurrence of hemarthroses. AIM: To evaluate the effectiveness of on-demand DFX treatment, initiated immediately after joint bleed induction. METHODS: A joint bleed was induced in 66 factor VIII-deficient mice by infra-patellar needle puncture. Mice were randomly assigned to treatment with either placebo (drinking water) or DFX (dissolved in drinking water) throughout the study. Five weeks after joint bleed induction, inflammation and cartilage damage were assessed histologically. Joints of ten bleed naive haemophilic mice served as controls. RESULTS: A joint bleed resulted in significant inflammation and cartilage damage in the blood-exposed joint compared with those of control animals, in both the placebo and DFX group (all p = <.05). No differences in tibiofemoral or patellar inflammation (p = .305 and p = .787, respectively) nor cartilage damage (p = .265 and p = .802, respectively) were found between the blood-exposed joints of both treatment groups. CONCLUSION: On-demand treatment with DFX does not prevent joint damage following blood exposure in haemophilic mice. DFX seems unable to reach the joint in time to exert its effect before the irreversible harmful process is initiated.

Adherence to prophylaxis and its association with activation of self-management and treatment satisfaction.

INTRODUCTION: Prophylactic replacement therapy (prophylaxis) in patients with haemophilia (PWH) requires lifelong, frequent (self)infusions. Prophylaxis effectiveness depends on adherence, and the drivers of treatment adherence among PWH are unclear. AIM: To quantify prophylaxis adherence and associations between adherence and patients' treatment attitudes and satisfaction in a large cohort of children and adults with haemophilia. METHODS: In a nationwide, cross-sectional, questionnaire-based study, PWH with complete information currently using prophylaxis were selected. Validated Hemophilia Regimen Treatment Adherence Scale-Prophylaxis (VERITAS-Pro; normalised score range: 0-100, optimum 0) measured treatment adherence; the Patient Activation Measure (PAM-13; total score range 0-100, optimum 100) measured activation of self-management; Hemophilia Patient Satisfaction Scale (Hemo-Sat; range 0-100, optimum 0) measured treatment satisfaction. Groups were compared according to age (children: <12 years; adolescents: 12-18 years; adults >18 years) and adherence levels using non-parametric tests, and correlations were assessed using Spearman's rho. RESULTS: Among 321 participants (median age 33 years, interquartile range [IQR]:15-54 years), adherence was high (median VERITAS-Pro total score 17, 89% adherent) but worsened with age, with median scores of 5, 14 and 20 in children, adolescents, adults, respectively (p < .001). Attitudes towards treatment (median 66 vs. 68) participants and treatment satisfaction (12 vs. 10) were similar between adherent and non-adherent patients. The VERITAS-Pro total score was moderately correlated with PAM-13 (r = .41) but not with Hemo-Sat (r = -.11). DISCUSSION: Prophylaxis adherence was high (89%) but decreased significantly with age and was not correlated with treatment attitude or treatment satisfaction.

Dosing of factor VIII concentrate by ideal body weight is more accurate in overweight and obese haemophilia A patients.

AIMS: Under- and, especially, overdosing of replacement therapy in haemophilia A patients may be prevented by application of other morphometric variables than body weight (BW) to dose factor VIII (FVIII) concentrates. Therefore, we aimed to investigate which morphometric variables best describe interindividual variability (IIV) of FVIII concentrate pharmacokinetic (PK) parameters. METHODS: PK profiling was performed by measuring 3 FVIII levels after a standardized dose of 50 IU kg-1 FVIII concentrate. A population PK model was constructed, in which IIV for clearance (CL) and central volume of distribution (V1) was quantified. Relationships between CL, V1 and 5 morphometric variables (BW, ideal BW [IBW], lean BW, adjusted BW, and body mass index [BMI]) were evaluated in normal weight (BMI < 25 kg m-2 ), overweight (BMI 25-30 kg m-2 ) and obese haemophilia A patients (BMI > 30 kg m-2 ). RESULTS: In total, 57 haemophilia A patients (FVIII≤0.05 IU mL-1 ) were included with median BW of 83 kg (range: 53-133) and median age of 48 years (range: 18-77). IBW best explained observed variability between patients, as IIV for CL and V1 was reduced from 45.1 to 37.6 and 26.% to 14.1%, respectively. CL, V1 and half-life were similar for all BMI categories. The national recommended dosing schedule did not result in adequate trough levels, both in case of dosing based on BW and IBW. However, dosing based on IBW prevented unnecessary high FVIII peaks. CONCLUSION: IBW is the most suitable morphometric variable to explain interindividual FVIII PK variability and is more appropriate to dose overweight and obese patients.

Treatment of acquired hemophilia A, a balancing act: results from a 27-year Dutch cohort study.

Acquired hemophilia A (AHA) is a severe auto-immune bleeding disorder. Treatment of AHA is burdensome and optimal management is still unresolved. Therefore a retrospective nationwide multi-center cohort study (1992-2018) was performed to evaluate clinical presentation and treatment efficacy and safety of AHA in the Netherlands. Multivariate logistic and Cox regression analysis was used to study independent associations between patient characteristics and clinical outcomes. A total of 143 patients (median age 73 years; 52.4% male) were included with a median follow-up of 16.8 months (IQR 3.6-41.5 months). First-line immunosuppressive treatment was mostly steroid monotherapy (67.6%), steroids/cyclophosphamide (11.9%) and steroids/rituximab (11.9%), with success rates of 35.2%, 80.0% and 66.7% respectively, P < .05. Eventually 75% of patients achieved complete remission (CR). A high anti-FVIII antibody titer, severe bleeding and steroid monotherapy were associated with lower CR rates. Infections, the most important adverse event, occurred significantly more often with steroid combination therapy compared to steroids alone (38.7% vs 10.6%; P = .001). Overall mortality was 38.2%, mostly due to infections (19.2%) compared to 7.7% fatal bleeds. Advanced age, underlying malignancy and ICU admission were predictors for mortality. This study showed that AHA is characterized by significant disease-related and treatment-related morbidity and mortality. A high anti-FVIII titer, severe bleeding and steroid monotherapy were associated with a lower CR rate. The efficacy of steroid combination therapies however, was overshadowed by higher infection rates and infections represented the most important cause of death. The challenging and delicate balance between treatment effectivity and safety requires ongoing monitoring of AHA and further identification of prognostic markers.