Search

Background: Both one‐stage (OSA) and chromogenic substrate assays (CSA) are used to measure factor VIII (FVIII) activity. Factors explaining analytical variation in FVIII activity levels are still to be completely elucidated. Aim: The aim of this study was to investigate and quantify the analytical variation in OSA and CSA. Methods: Factors determining analytical variation were studied in sixteen lyophilized plasma samples (FVIII activity <0.01‐1.94 IU/mL) and distributed by the ECAT surveys. To elucidate the causes of OSA variation, we exchanged deficient plasma between three company set‐ups. Results: On average, 206 (range 164‐230) laboratories used the OSA to measure FVIII activity and 30 (range 12‐51) used CSA. The coefficient of variation of OSA and CSA increased with lower FVIII levels (FVIII <0.05 IU/mL). This resulted in misclassification of a severe haemophilia A sample into a moderate or mild haemophilia A sample in 4/30 (13.3%) of CSA measurements, while this was 37/139 (26.6%) for OSA. OSA measurements performed with reagents and equipment from Werfen showed slightly lower FVIII activity (0.93, IQR 0.88‐0.98 IU/mL) compared to measurements with Stago (1.07, IQR 1.02‐1.14 IU/mL) and Siemens (1.03, IQR 0.97‐1.07 IU/mL). Part of this difference is explained by the value of the calibrator. For CSA, the measured FVIII levels were similar using the different kits. Conclusions: In the lower range (<0.05 IU/mL), analytical variation of FVIII measurements is high in both OSA and CSA measurements. The variation in FVIII activity levels was partly explained by specific manufacturers. Further standardization of FVIII measurements and understanding of analytical variation is required. [ABSTRACT FROM AUTHOR]

Introduction: Care for adolescents with haemophilia is transferred from paediatric to adult care around the age of 18 years. Transition programs help to prepare adolescents for this transfer and prevent declining treatment adherence. Evaluating transition readiness may identify areas for improvement. Objective: Assess transition readiness among Dutch adolescents and young adults with haemophilia, determine factors associated with transition readiness, and identify areas of improvement in transition programs. Methods: All Dutch adolescents and young adults aged 12–25 years with haemophilia were invited to participate in a nationwide questionnaire study. Transition readiness was assessed using multiple‐choice questions and was defined as being ready or almost ready for transition. Potential factors associated with transition readiness were investigated, including: socio‐demographic and disease‐related factors, treatment adherence, health‐related quality of life, and self‐efficacy. Results: Data of 45 adolescents and 84 young adults with haemophilia (47% with severe haemophilia) were analyzed. Transition readiness increased with age, from 39% in 12–14 year‐olds to 63% in 15–17 year‐olds. Nearly all post‐transition young adults (92%, 77/84) reported they were ready for transition. Transition readiness was associated with treatment adherence, as median VERITAS‐Pro treatment adherence scores were worse in patients who were not ready (17, IQR 9–29), compared to those ready for transition (11, IQR 9–16). Potential improvements were identified: getting better acquainted with the adult treatment team prior to transition and information on managing healthcare costs. Conclusions: Nearly all post‐transition young adults reported they were ready for transition. Improvements were identified regarding team acquaintance and preparation for managing healthcare costs. [ABSTRACT FROM AUTHOR]

Publications on the exposure‐effect relationships of factor concentrates for hemophilia treatment are limited, whereas such analyses give insight on treatment efficacy. Our objective was to examine the relationship between the dose, factor VIII (FVIII) levels and bleeding for rFVIII‐SingleChain (lonoctocog alfa, Afstyla). Data from persons with severe hemophilia A on rFVIII‐SingleChain prophylaxis from three clinical trials were combined. The published rFVIII‐SingleChain population pharmacokinetic (PK) model was evaluated and expanded. The probability of bleeding was described with a parametric repeated time‐to‐event (RTTE) model. Data included 2080 bleeds, 2545 chromogenic stage assay, and 3052 one‐stage assay FVIII levels from 241 persons (median age 19 years) followed for median 1090 days. The majority of the bleeds occurred in joints (65%) and the main bleeding reason was trauma (44%). The probability of bleeding decreased during follow‐up and a FVIII level of 8.9 IU/dL (95% confidence interval: 6.9–10.9) decreased the bleeding hazard by 50% compared to a situation without FVIII in plasma. Variability in bleeding hazard between persons with similar FVIII levels was large, and the pre‐study annual bleeding rate explained part of this variability. When a FVIII trough level of 1 or 3 IU/dL is targeted during prophylaxis, simulations predicted two (90% prediction interval [PI]: 0–17) or one (90% PI: 0–11) bleeds per year, respectively. In conclusion, the developed PK‐RTTE model adequately described the relationship between dose, FVIII levels and bleeds for rFVIII‐SingleChain. The obtained estimates were in agreement with those published for the FVIII concentrates BAY 81‐8973 (octocog alfa) and BAY 94‐9027 (damoctocog alfa pegol), indicating similar efficacy to reduce bleeding. [ABSTRACT FROM AUTHOR]

The article discusses the current recommendations for the diagnosis and management of haemophilia, a hereditary disorder of haemostasis associated with prolonged and excessive bleeding. Basic knowledge of the inheritance and management of haemophilia is essential for healthcare workers, because severe or even life threatening bleeding can be prevented if the condition is diagnosed and promptly treated. The ways in which patients with haemophilia can be diagnosed are described. Prophylactic administration of factor VIII or factor IX concentrate is standard treatment for haemophilia. A safety amulet that makes patients with haemophilia easily recognizable and may be life saving is recommended. INSETS: A PARENT¿S PERSPECTIVE;TIPS FOR NON-SPECIALISTS.

We report two novel α2-globin gene mutations found in the same Surinamese family. The proband, a newborn presenting during neonatal screening with 21.3% Hb Bart's (γ4), proved to be a carrier of the common –α3.7 deletion and a novel codon 32 (A TG>A GG) transversion that we named Hb Rotterdam. The father carried the same point mutation with borderline hemoglobin (Hb), MCV and low MCH values. The mother presented with a significant microcytic hypochromic anemia and also carried the –α3.7 deletion and a second novel TA T>TA G transversion generating a stop codon at position 24. Shortly thereafter, Hb Rotterdam was again found in two unrelated adult females and in a Canadian newborn, all of African origin, suggesting that Hb Rotterdam could be a frequently occurring αT determinant in the Black population. Screening and characterization of the mutations, phenotype/genotype correlation and the issue of reporting newborn carriers of α-thalassemia (α-thal) are discussed. [ABSTRACT FROM AUTHOR]

Aim To study functional outcome in children aged 1 month to 18 years after paediatric arterial ischaemic stroke (PAIS) and to identify risk factors influencing their quality of life. Method In a consecutive series of 76 children (35 males 41 females, median age at diagnosis 2y 6mo, range 1mo–17y 2mo; median length of follow-up 2y 4mo, range [7mo–10y 6mo]) with PAIS diagnosed at the Erasmus Medical Centre Sophia Children's Hospital between 1997 and 2006, we collected clinical, biochemical, and radiological data prospectively. In 66 children surviving at least 1 year after PAIS, functional outcome could be evaluated with the World Health Organization’s International Classification of Impairments, Disabilities and Handicaps. Results Significant risk factors at presentation for a poor neurological outcome were young age, infarction in the right middle cerebral artery territory, and fever at presentation. Fifty-four % of children had severe neurological impairments at 12 months after PAIS, and at last follow-up more than half needed remedial teaching, special education, or institutionalization. Health-related quality of life (HRQOL) questionnaires showed a significantly lower HRQOL in all age groups. Children with a longer follow-up had a lower HRQOL in the cognitive functioning domain. Interpretation Our study shows significant morbidity and mortality and a reduced HRQOL after PAIS depending on age, fever at presentation, and infarction in the right middle cerebral artery territory. [ABSTRACT FROM AUTHOR]

In population pharmacokinetic (PK) models, interindividual variability is explained by implementation of covariates in the model. The widely used forward stepwise selection method is sensitive to bias, which may lead to an incorrect inclusion of covariates. Alternatives, such as the full fixed effects model, reduce this bias but are dependent on the chosen implementation of each covariate. As the correct functional forms are unknown, this may still lead to an inaccurate selection of covariates. Machine learning (ML) techniques can potentially be used to learn the optimal functional forms for implementing covariates directly from data. A recent study suggested that using ML resulted in an improved selection of influential covariates. However, how do we select the appropriate functional form for including these covariates? In this work, we use SHapley Additive exPlanations (SHAP) to infer the relationship between covariates and PK parameters from ML models. As a case‐study, we use data from 119 patients with hemophilia A receiving clotting factor VIII concentrate peri‐operatively. We fit both a random forest and a XGBoost model to predict empirical Bayes estimated clearance and central volume from a base nonlinear mixed effects model. Next, we show that SHAP reveals covariate relationships which match previous findings. In addition, we can reveal subtle effects arising from combinations of covariates difficult to obtain using other methods of covariate analysis. We conclude that the proposed method can be used to extend ML‐based covariate selection, and holds potential as a complete full model alternative to classical covariate analyses. [ABSTRACT FROM AUTHOR]

Nonlinear mixed effect (NLME) models are the gold standard for the analysis of patient response following drug exposure. However, these types of models are complex and time‐consuming to develop. There is great interest in the adoption of machine‐learning methods, but most implementations cannot be reliably extrapolated to treatment strategies outside of the training data. In order to solve this problem, we propose the deep compartment model (DCM), a combination of neural networks and ordinary differential equations. Using simulated datasets of different sizes, we show that our model remains accurate when training on small data sets. Furthermore, using a real‐world data set of patients with hemophilia A receiving factor VIII concentrate while undergoing surgery, we show that our model more accurately predicts a priori drug concentrations compared to a previous NLME model. In addition, we show that our model correctly describes the changing drug concentration over time. By adopting pharmacokinetic principles, the DCM allows for simulation of different treatment strategies and enables therapeutic drug monitoring. [ABSTRACT FROM AUTHOR]

Background: Glanzmann thrombasthenia (GT) and Bernard‐Soulier syndrome (BSS) patients require frequent platelet transfusions and hence have an increased risk for alloimmunization against donor Human Leukocyte Antigens (HLA) when no HLA‐matching is performed. Knowing that Human Platelet Antigens (HPA) are located on the platelet glycoproteins that can be absent in these patients, preventive HPA‐matching may also be considered. Uniform recommendations on this topic lack in transfusion guidelines making standard practice unclear, therefore, we aimed to provide a framework for matched platelet transfusions. Study Design and Methods: We conducted a targeted literature search and a national survey of Dutch (pediatric) hematologists from July to September 2021. Results: We found 20 articles describing platelet transfusion policies in 483 GT‐patients and 29 BSS‐patients, both adults and children. Twenty surveys were returned for full analysis. All responders treated patients with platelet disorders, including GT (n = 36 reported) and BSS (n = 29 reported). Of respondents, 75% estimated the risk of antibody formation as "likely" for HLA and 65% for HPA. Formation of HLA antibodies was reported in 5 GT and in 5 BSS‐patients, including one child. Fifteen respondents gave preventive HLA‐matched platelets in elective setting (75%). Three respondents additionally matched for HPA in GT‐patients (15%). Main argument for matched platelet transfusions was preventing alloimmunization to safeguard the effectivity of 'random' donor‐platelets in acute settings. Conclusion: Elective HLA‐matching for GT and BSS‐patients is already conducted by most Dutch (pediatric) hematologists. HPA‐matching is mainly applied when HPA‐antibodies are formed. Based on the current literature and the survey, recommendations are proposed. [ABSTRACT FROM AUTHOR]

Determines the prevalence of endocrinologic disorders in children with neurofibromatosis type 1 (NF1). Relationship of the disorders and cerebral abnormalities with magnetic resonance imaging; Prevalence of central precocious puberty and growth hormone deficiency in the presence of chiasma glioma; Diagnosis of the disorders; Endocrine manifestations of NF1.

Introduction: Non‐severe haemophilia A patient can be treated with desmopressin or factor VIII (FVIII) concentrate. Combining both may reduce factor consumption, but its feasibility and safety has never been investigated. Aim: We assessed the feasibility and safety of combination treatment in nonsevere haemophilia A patients. Methods: Non‐severe, desmopressin responsive, haemophilia A patients were included in one of two studies investigating peri‐operative combination treatment. In the single‐arm DAVID study intravenous desmopressin (0.3 μg/kg) once‐a‐day was, after sampling, immediately followed by PK‐guided FVIII concentrate, for maximally three consecutive days. The Little DAVID study was a randomized trial in patients undergoing a minor medical procedure, whom received either PK‐guided combination treatment (intervention arm) or PK‐guided FVIII concentrate only (standard arm) up to 2 days. Dose predictions were considered accurate if the absolute difference between predicted and measured FVIII:C was ≤0.2 IU/mL. Results: In total 32 patients (33 procedures) were included. In the DAVID study (n = 21), of the FVIII:C trough levels 73.7% (14/19) were predicted accurately on day 1 (D1), 76.5% (13/17) on D2. On D0, 61.9% (13/21) of peak FVIII:C levels predictions were accurate. In the Little DAVID study (n = 12), on D0 83.3% (5/6) FVIII:C peak levels for both study arms were predicted accurately. Combination treatment reduced preoperative FVIII concentrate use by 47% versus FVIII monotherapy. Desmopressin side effects were mild and transient. Two bleeds occurred, both despite FVIII:C > 1.00 IU/mL. Conclusion: Peri‐operative combination treatment with desmopressin and PK‐guided FVIII concentrate dosing in nonsevere haemophilia A is feasible, safe and reduces FVIII consumption. [ABSTRACT FROM AUTHOR]

Introduction: Bleeding disorders (BDs) may influence health‐related quality of life (HRQoL) in children and caregivers. Measuring HRQoL gives insight into domains requiring support and provides an opportunity to evaluate the effects of novel therapies. Aim: To gain insight in the current body of literature on HRQoL in children with BDs in order to identify knowledge gaps for research and further development of this field. Methods: Scoping review. Results: We included 53 articles, describing studies mainly performed in Europe and North–America (60.4%) and mostly within the last ten years. Only 32% studies included children <4 years. Almost all studies (47/53, 88.7%) were performed in boys with haemophilia, pooling haemophilia A and B (n = 21) and different disease severities (n = 20). Thirteen different generic and five disease‐specific HRQoL‐questionnaires were applied; all questionnaires were validated for haemophilia specifically. Six (11,3%) combined generic and disease‐specific questionnaires. Self‐reports were most frequently applied (40/53, 75.5%), sometimes combined with proxy and/or parent‐reports (17/53, 32.1%). Eleven studies used a reference group (20.8%). Statistical analyses mostly consisted of mean and SD (77.4%). Conclusion: HRQoL‐research is mainly performed in school‐aged boys with haemophilia, treated in developed countries. Pitfalls encountered are the pooling of various BDs, subtypes and severities, as well as the application of multiple generic questionnaires prohibiting comparison of results. More attention is needed for broader study populations including other BDs, young children, feminine bleeding issues and platelet disorders, as well as the use of HRQoL as an effect‐measurement tool for medical interventions, and more thorough statistical analysis. [ABSTRACT FROM AUTHOR]

The potential of using ChatGPT in pharmacometrics was explored in this study, with a focus on developing a population pharmacokinetic (PK) model for standard half‐life factor VIII. Our results demonstrated that ChatGPT can be utilized to accurately obtain typical PK parameters from literature, generate a population PK model in R and develop an interactive Shiny application to visualize the results. ChatGPT's language generation capabilities enabled the development of R codes with minimal programming knowledge and helped to identify as well fix errors in the code. While ChatGPT presents several advantages, such as its ability to streamline the development process, its use in pharmacometrics also has limitations and challenges, including the accuracy and reliability of AI‐generated data, the lack of transparency and reproducibility regarding codes generated by ChatGPT. Overall, our study demonstrates the potential of using ChatGPT in pharmacometrics, but researchers must carefully evaluate its use for their specific needs. [ABSTRACT FROM AUTHOR]

Aims: Recombinant factor IX Fc fusion protein (rFIX‐Fc) is an extended half‐life factor concentrate administered to haemophilia B patients. So far, a population pharmacokinetic (PK) model has only been published for patients aged ≥12 years. The aim was to externally evaluate the predictive performance of the published rFIX‐Fc population PK model for patients of all ages and develop a model that describes rFIX‐Fc PK using real‐world data. Methods: We collected prospective and retrospective data from patients with haemophilia B treated with rFIX‐Fc and included in the OPTI‐CLOT TARGET study (NTR7523) or United Kindom (UK)‐EHL Outcomes Registry (NCT02938156). Predictive performance was assessed by comparing predicted with observed FIX activity levels. A new population PK model was constructed using nonlinear mixed‐effects modelling. Results: Real‐world data were obtained from 37 patients (median age: 16 years, range 2–71) of whom 14 were aged <12 years. Observed FIX activity levels were significantly higher than levels predicted using the published model, with a median prediction error of −48.8%. The new model showed a lower median prediction error (3.4%) and better described rFIX‐Fc PK, especially for children aged <12 years. In the new model, an increase in age was correlated with a decrease in clearance (P <.01). Conclusions: The published population PK model significantly underpredicted FIX activity levels. The new model better describes rFIX‐Fc PK, especially for children aged <12 years. This study underlines the necessity to strive for representative population PK models, thereby avoiding extrapolation outside the studied population. [ABSTRACT FROM AUTHOR]

Keywords: bleeding; bleeding disorder; desmopressin; haemophilia A; pharmacokinetics EN bleeding bleeding disorder desmopressin haemophilia A pharmacokinetics e506 e509 4 07/21/21 20210701 NES 210701 Haemophilia A is an X-linked bleeding disorder characterized by a deficiency of coagulation factor VIII (FVIII). They found similar desmopressin responses as reported in literature with weight-based dosing.13 Building on a potential benefit of decreased desmopressin exposure, we evaluated associations between desmopressin exposure and haemodynamic changes and no associations were found. This was necessary for desmopressin AUC, FVIII:C Cmax and delta FVIII:C. Transformation of duration of FVIII:C response did not lead to normally divided variables. Desmopressin concentrations were measured with a validated LC-MS/MS assay.9 In all patients, desmopressin concentrations before infusion were set at zero, also when no measurement was available. [Extracted from the article]

Introduction: Diagnostic evaluation of patients with a bleeding tendency remains challenging, as no disorder is identified in approximately 50% of patients. An impaired interplay of several haemostatic factors might explain bleeding phenotype in these patients. Objective: To investigate whether global haemostasis assays are able to identify haemostatic abnormalities in patients with a bleeding tendency unexplained by current diagnostic laboratory tests. Materials and methods: Patients of ≥12 years with a bleeding tendency were included from a tertiary outpatient clinic. Bleeding phenotype was assessed with the ISTH‐BAT. Patients were classified as having bleeding of unknown cause (BUC) or a mild bleeding disorder (MBD) based on abnormalities assessed by routine haemostatic tests. Global haemostasis tests (rotational thromboelastometry (ROTEM), thrombin generation test (TG) and plasma clot lysis time (CLT)) were measured in all patients. The results were compared with 76 controls. Results: One hundred and eighty‐one patients were included, and 60% (109/181) was classified as having BUC. BUC patients demonstrated a significantly prolonged lag time in TG (median 7.7 minutes, IQR 6.7‐8.7) and a significantly prolonged CLT (median 60.5 minutes, IQR 54.7‐66.1) compared to controls. No differences in ROTEM variables were found. Patients with MBD showed an impaired thrombin generation with a significantly decreased ETP (median 1024 nmol/L*min, IQR 776‐1355) and peak height (median 95 nmol/L, IQR 76‐138), compared to BUC patients and controls. Conclusion: No major differences were found in ROTEM and TG variables in BUC patients compared to controls. BUC patients did have a significantly prolonged clot lysis time. The underlying mechanism for this finding is unknown. [ABSTRACT FROM AUTHOR]

Harmonizing patient-reported outcome measurements in inherited bleeding disorders with PROMIS To achieve all advantages PROMIS has to offer to the field of inherited bleeding disorders, PROMIS needs to become the national and international standard for generic outcome measurement by persons with inherited bleeding disorders. In recent years, advances regarding novel therapeutic approaches in inherited bleeding disorders and other rare disease entities underline the need for systematic outcome measurement in healthcare and research.[1] Traditionally, haemophilia treatment centres have focused on clinical outcomes such as bleeding frequency, functional status and joint damage as well as health-related quality of life (HRQoL). Within the field of inherited bleeding disorders, forces were united to start a Dutch research group for PROMIS implementation in inherited bleeding disorders, which consists of a multidisciplinary team of representatives from multiple haemophilia treatment centres in the Netherlands. [Extracted from the article]

The host response to infection involves complex interplays between inflammation, coagulation, and fibrinolysis. Deregulation of hemostasis and fibrinolysis are major causes of critical illness and important determinants of outcome in severe sepsis. The hemostatic responses to infection vary widely between individuals, and are in part explained by polymorphisms in genes responsible for the protein C and fibrinolytic pathway. This review gives an overview of genetic polymorphisms in the protein C and fibrinolytic pathway associated with susceptibility and severity of pediatric sepsis. In addition, genetic polymorphisms associated with adult sepsis and other pediatric thromboembolic disorders are discussed, as these polymorphisms might be candidates for future molecular genetic research in pediatric sepsis. [ABSTRACT FROM AUTHOR]

Objective: To study whether the circadian variation of plasminogen-activator-inhibitor-1 (PAI-1) levels, with high morning levels, is associated with poor outcome of children with meningococcal sepsis presenting in the morning hours. Design: Retrospective analysis of prospectively collected clinical and laboratory data. Setting: Single center study at Erasmus MC-Sophia Children’s Hospital, Rotterdam, the Netherlands. Subjects: 184 patients aged 3 weeks to 18 years with meningococcal sepsis. In 36 of these children, PAI-1 levels at admission to the PICU were measured in plasma by ELISA. Interventions: None. Measurements and main results: Circadian variation was studied by dividing one day in blocks of 6 hours. Patients admitted between 6:00 am and 12:00 am had increased illness severity scores and higher PAI-1 levels (n = 9, median 6912 ng/mL, IQR 5808–15600) compared to patients admitted at night (P = 0.019, n = 9, median 3546 ng/mL, IQR 1668–6118) or in the afternoon (P = 0.007, n = 7, median 4224 ng/mL, IQR 1804–5790). In 184 patients, analysis of circadian variation in relation to outcome showed more deaths, amputations and need for skin grafts in patients admitted to the PICU between 6:00 am and 12:00 am than patients admitted during the rest of the day (P = 0.009). Conclusions: Circadian variation of PAI-1 levels is present in children with meningococcal sepsis and is associated with illness severity, with a peak level in the morning. Whether circadian variation is an independent risk factor for morbidity and mortality in meningococcal sepsis needs to be explored in future studies. [ABSTRACT FROM AUTHOR]

Disorders of the long arm of chromosome 11 (11q) are rare and involve various chromosomal regions. Patients with 11q disorders, including Jacobsen syndrome, often present with a susceptibility for bacterial and prolonged viral and fungal infections partially explained by hypogammaglobulinemia. Additional T lymphocyte or granular neutrophil dysfunction may also be present. In order to evaluate infectious burden and immunological function in patients with 11q disorders, we studied a cohort of 14 patients with 11q deletions and duplications. Clinically, 12 patients exhibited prolonged and repetitive respiratory tract infections, frequently requiring (prophylactic) antibiotic treatment (n = 7), ear-tube placement (n = 9), or use of inhalers (n = 5). Complicated varicella infections (n = 5), chronic eczema (n = 6), warts (n = 2), and chronic fungal infections (n = 4) were reported. Six patients were on immunoglobulin replacement therapy. We observed a high prevalence of low B lymphocyte counts (n = 8), decreased T lymphocyte counts (n = 5) and abnormal T lymphocyte function (n = 12). Granulocyte function was abnormal in 29% without a clinical phenotype. Immunodeficiency was found in patients with terminal and interstitial 11q deletions and in one patient with terminal 11q duplication. Genetically, FLI1 and ETS1 are seen as causative for the immunodeficiency, but these genes were deleted nor duplicated in 4 of our 14 patients. Alternative candidate genes on 11q may have a role in immune dysregulation. In conclusion, we present evidence that inborn errors of immunity are present in patients with 11q disorders leading to clinically relevant infections. Therefore, broad immunological screening and necessary treatment is of importance in this patient group. [ABSTRACT FROM AUTHOR]

Introduction: Desmopressin can be used to prevent bleeding in von Willebrand disease (VWD), but the relationship between desmopressin and von Willebrand factor activity (VWF:Act) has yet to be quantified. Aim: To quantify the relationship between desmopressin dose, its plasma concentration and the VWF:Act response in type 1 VWD patients. Methods: Forty‐seven VWD patients (median age 25 years, IQR: 19–37; median body weight 71 kg, IQR: 59–86) received an IV desmopressin dose of.3 mcg/kg. In total, 177 blood samples were available for analysis. We developed an integrated population pharmacokinetic‐pharmacodynamic (PK‐PD) model using nonlinear mixed effect modelling. Subsequently, we performed Monte Carlo simulations to investigate the efficacy of the current dosing regimen. Results: A one‐compartment PK model best described the time profile of the desmopressin concentrations. In the PD turnover model, the relationship between desmopressin plasma concentration and release of VWF:Act from the vascular endothelium was best described with an Emax model. Typically, VWF:Act increased 452% with an EC50 of.174 ng/ml. Simulations demonstrated that after.3 mcg/kg desmopressin intravenously, >90% patients with a VWF:Act baseline of ≥.20 IU/mL attain a VWF:Act >.5 IU/ml up to ≥4 h after administration. A capped dose of 30 mcg was sufficient in patients weighing over 100 kg. Conclusion: The relationship between desmopressin and VWF:Act was quantified in a PK‐PD model. The simulations provide evidence that recently published international guidelines advising an intravenous desmopressin dose of.3 mcg/kg with a capped dose of 30 mcg > 100 kg gives a sufficient desmopressin response. [ABSTRACT FROM AUTHOR]

Background: To account for interindividual variability in the pharmacokinetics (PK) of factor concentrates, PK‐guided dosing is increasingly implemented in haemophilia patients. Calculations are based on provided label potency, but legislation allows a potency difference of ±20% between label and actual potency. It is unknown if these differences affect PK guidance. Aim: Explore the effects of potency differences on individual factor VIII (FVIII) PK parameters and the prediction of FVIII trough levels of dosing regimens. Methods: We analyzed individual preoperative PK profiling data from severe and moderate haemophilia A patients included in the OPTI‐CLOT randomized controlled trial. Label and actual potency were compared, with data on potency provided by pharmaceutical companies. For both potencies, individual PK parameters were estimated and concentration‐time curves were constructed by nonlinear mixed‐effects modelling. Finally, we explored the effect of both the identified and the maximum legislated potency difference on predicted FVIII trough levels infused in a low and high dose regimen. Results: In 45/50 included patients, actual potency was higher than its label potency. The median potency difference was 6.0% (range ‐9.2% to 18.4%) and resulted in varying individual PK parameter estimates but practically identical FVIII concentration‐time curves. As expected, predicted FVIII trough levels were linearly correlated to the actual dose. Conclusion: It is not necessary to take potency differences into account when applying PK guidance of FVIII concentrates in haemophilia A patients. However, when the patient is switched to another FVIII batch after PK‐guided dosing, trough levels may deviate ±20% from calculations based on label dose. [ABSTRACT FROM AUTHOR]

Aims: Prophylactic treatment of haemophilia A patients with factor VIII (FVIII) concentrate focuses on maintaining a minimal trough FVIII activity level to prevent bleeding. However, due to differences in bleeding tendency, the pharmacokinetic (PK)‐guided dosing approach may be suboptimal. An alternative approach could be the addition of haemostatic pharmacodynamic (PD) parameters, reflecting a patient's unique haemostatic balance. Our aim was to develop a population PK/PD model, based on FVIII activity levels and Nijmegen Haemostasis Assay (NHA) patterns, a global haemostatic assay that measures thrombin/plasmin generation simultaneously. Methods: PK/PD measurements were collected from 30 patients treated with standard half‐life FVIII concentrate. The relationship between FVIII activity levels and the thrombin/plasmin generation parameters (thrombin potential, thrombin peak height and plasmin peak height), were described by sigmoidal Emax functions. Results: The obtained EC50 value was smallest for the normalized thrombin potential (11.6 IU/dL), followed by normalized thrombin peak height (56.6 IU/dL) and normalized plasmin peak height (593 IU/dL), demonstrating that normalized thrombin potential showed 50% of the maximal effect at lower FVIII activity levels. Substantial inter‐individual variability in the PD parameters, such as EC50 of thrombin potential (86.9%) was observed, indicating that, despite similar FVIII activity levels, haemostatic capacity varies significantly between patients. Conclusion: These data suggest that dosing based on patients' individual PK/PD parameters may be beneficial over dosing solely on individual PK parameters. This model could be used as proof‐of‐principle to examine the application of PK/PD‐guided dosing. However, the relation between the PD parameters and bleeding has to be better defined. [ABSTRACT FROM AUTHOR]

Summary: Von Willebrand disease (VWD) is a bleeding disorder caused by quantitative (type 1 or 3) or qualitative (type 2A/2B/2M/2N) defects of circulating von Willebrand factor (VWF). Circulating VWF levels not always fully explain bleeding phenotypes, suggesting a role for alternative factors, like platelets. Here, we investigated platelet factor 4 (PF4) in a large cohort of patients with VWD. PF4 levels were lower in type 2B and current bleeding phenotype was significantly associated with higher PF4 levels, particularly in type 1 VWD. Based on our findings we speculate that platelet degranulation and cargo release may play a role across VWD subtypes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: The negative impact of haemophilia on social participation is well established in previous studies, however, the impact of Von Willebrand disease (VWD) on social participation has not been studied. Aim: To compare the social participation of a large cohort of VWD patients in the Netherlands with the general Dutch population. In addition, to identify factors associated with social participation in VWD. Methods: Patients participating in the "Willebrand in the Netherlands" study completed an extensive questionnaire on educational level, absenteeism from school or work, and occupational disabilities. Results: Seven‐hundred and eighty‐eight VWD patients were included (mean age 38.9 years, 59.5% females), of whom 136 children < 16 years. Adult patients with type 3 VWD more often had a low educational level (52.9%) compared to type 1 (40.2%), type 2 VWD (36.8%) and the general population (36.4%) (p =.005). Moreover, in patients aged ≥16 years the days lost from school and/or work in the year prior to study inclusion differed significantly between the VWD types (p =.011). Using negative binomial regression analysis, the occurrence of bleeding episodes requiring treatment in the year preceding study inclusion was significantly associated with the number of days lost from school and/or work among patients aged ≥16 years. Multivariable logistic regression analysis showed that a higher total bleeding score, older age and presence of at least one comorbidity were significantly associated with occupational disability in patients aged ≥16 years. Conclusion: Our study shows that social participation was lower in type 3 VWD and VWD patients with a more severe bleeding phenotype. [ABSTRACT FROM AUTHOR]

Introduction: Haemophilia A patients require perioperative clotting factor replacement to limit excessive bleeding. Weight‐based dosing of Factor VIII (FVIII) does not account for inter‐individual pharmacokinetic (PK) variability, and may lead to suboptimal FVIII exposure. Aim: To perform an external validation of a previously developed population PK (popPK) model of perioperative FVIII in haemophilia A patients. Methods: A retrospective chart review identified perioperative haemophilia A patients at the University of North Carolina (UNC) between April 2014 and November 2019. Patient data was used to externally validate a previously published popPK model proposed by Hazendonk. Based on these validation results, a modified popPK model was developed to characterize FVIII PK in our patients. Dosing simulations were performed using this model to compare FVIII target attainment between intermittent bolus (IB) and continuous infusion (CI) administration methods. Results: A total of 521 FVIII concentrations, drawn from 34 patients, were analysed. Validation analyses revealed that the Hazendonk model did not fully capture FVIII PK in the UNC cohort. Therefore, a modified one‐compartment model, with weight and age as covariates on clearance (CL), was developed. Dosing simulations revealed that CI resulted in improved target attainment by 16%, with reduced overall FVIII usage by 58 IU/kg, compared to IB. Conclusion: External validation revealed a previously published popPK model of FVIII did not adequately characterize UNC patients, likely due to differences in patient populations. Future prospective studies are needed to evaluate our model prior to implementation into clinical practice. [ABSTRACT FROM AUTHOR]

Aims: Population pharmacokinetic (PK) models are increasingly applied to perform individualized dosing of factor VIII (FVIII) concentrates in haemophilia A patients. To guarantee accurate performance of a population PK model in dose individualization, validation studies are of importance. However, external validation of population PK models requires independent data sets and is, therefore, seldomly performed. Therefore, this study aimed to validate a previously published population PK model for FVIII concentrates administrated perioperatively. Methods: A previously published population PK model for FVIII concentrate during surgery was validated using independent data from 87 children with severe haemophilia A with a median (range) age of 2.6 years (0.03–15.2) and body weight of 14 kg (4–57). First, the predictive performance of the previous model was evaluated with MAP Bayesian analysis using NONMEM v7.4. Subsequently, the model parameters were (re)estimated using a combined dataset consisting of the previous modelling data and the data available for the external validation. Results: The previous model underpredicted the measured FVIII levels with a median of 0.17 IU mL−1. Combining the new, independent and original data, a dataset comprising 206 patients with a mean age of 7.8 years (0.03–77.6) and body weight of 30 kg (4–111) was obtained. Population PK modelling provided estimates for CL, V1, V2, and Q: 171 mL h−1 68 kg−1, 2930 mL 68 kg−1, 1810 mL 68 kg−1, and 172 mL h−1 68 kg−1, respectively. This model adequately described all collected FVIII levels, with a slight median overprediction of 0.02 IU mL−1. Conclusions: This study emphasizes the importance of external validation of population PK models using real‐life data. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: In well-resourced countries, comprehensive care programs have increased life expectancy of patients with sickle cell disease, with almost all infants surviving into adulthood. However, families affected by sickle cell disease are more likely to be economically disenfranchised because of their racial or ethnic minority status. As every individual child has the right to the highest attainable standard of health under the United Nations Convention on the Rights of the Child, it is essential to identify both barriers and facilitators with regard to the delivery of adequate healthcare. Optimal healthcare accessibility will improve healthcare outcomes for children with sickle cell disease and their families. Healthcare professionals in the field of sickle cell care have first-hand experience of the barriers that patients encounter when it comes to effective care. We therefore hypothesised that these medical professionals have a clear picture of what is necessary to overcome these barriers and which facilitators will be most feasible. Therefore, this study aims to map best practises and lessons learnt in order to attain more optimal healthcare accessibility for paediatric patients with sickle cell disease and their families.Methods: Healthcare professionals working with young patients with sickle cell disease were recruited for semi-structured interviews. An interview guide was used to ensure the four healthcare accessibility dimensions were covered. The interviews were transcribed and coded. Based on field notes, initial codes were generated, to collate data (both barriers and solutions) to main themes (such as "transportation", or "telecommunication"). Through ongoing thematic analysis, definitive themes were formulated and best practices were reported as recommendations. Quotations were selected to highlight or illustrate the themes and link the reported results to the empirical data.Results: In 2019, 22 healthcare professionals from five different university hospitals in the Netherlands were interviewed. Participants included (paediatric) haematologists, nurses and allied health professionals. Six themes emerged, all associated with best practices on topics related to the improvement of healthcare accessibility for children with sickle cell disease and their families. Firstly, the full reimbursement of invisible costs made by caregivers. Secondly, clustering of healthcare appointments on the same day to help patients seeing all required specialists without having to visit the hospital frequently. Thirdly, organisation of care according to shared care principles to deliver specialised services as close as possible to the patient's home without compromising quality. Fourthly, optimising verbal and written communication methods with special consideration for families with language barriers, low literacy skills, or both. Fifthly, improving the use of eHealth services tailored to users' health literacy skills, including accessible mobile telephone contact between healthcare professionals and caregivers of children with sickle cell disease. Finally, increasing knowledge and interest in sickle cell disease among key stakeholders and the public to ensure that preventive and acute healthcare measures are understood and safeguarded in all settings.Conclusion: This qualitative study describes the views of healthcare professionals on overcoming barriers of healthcare accessibility that arise from the intersecting vulnerabilities faced by patients with sickle cell disease and their families. The recommendations gathered in this report provide high-income countries with a practical resource to meet their obligations towards individual children under the United Nations Convention on the Rights of the Child. [ABSTRACT FROM AUTHOR]

Hemophilia A and B are bleeding disorders caused by a deficiency of clotting factor VIII and IX, respectively. Patients with severe hemophilia (< 0.01 IU mL−1) and some patients with moderate hemophilia (0.01–0.05 IU mL−1) administer clotting factor concentrates prophylactically. Desmopressin (d-amino d-arginine vasopressin) can be applied in patients with non-severe hemophilia A. The aim of administration of factor concentrates or desmopressin is the prevention or cessation of bleeding. Despite weight-based dosing, it has been demonstrated that factor concentrates still exhibit considerable pharmacokinetic variability. Population pharmacokinetic analyses, in which this variability is quantified and explained, are increasingly performed in hemophilia research. These analyses can assist in the identification of important patient characteristics and can be applied to perform patient-tailored dosing. This review aims to present and discuss the population pharmacokinetic analyses that have been conducted to develop population pharmacokinetic models describing factor levels after administration of factor VIII or factor IX concentrates or d-amino d-arginine vasopressin. In total, 33 publications were retrieved from the literature. Two approaches were applied to perform population pharmacokinetic analyses, the standard two-stage approach and non-linear mixed-effect modeling. Using the standard two-stage approach, four population pharmacokinetic models were established describing factor VIII levels. In the remaining 29 analyses, the non-linear mixed-effect modeling approach was applied. NONMEM was the preferred software to establish population pharmacokinetic models. In total, 18 population pharmacokinetic analyses were conducted on the basis of data from a single product. From all available population pharmacokinetic analyses, 27 studies also included data from pediatric patients. In the majority of the population pharmacokinetic models, the population pharmacokinetic parameters were allometrically scaled using actual body weight. In this review, the available methods used for constructing the models, key features of these models, patient population characteristics, and established covariate relationships are described in detail. [ABSTRACT FROM AUTHOR]

Background and Purpose: Silent cerebral infarcts (SCIs) are the most common neurological complication in children and adults with sickle cell disease (SCD). In this systematic review, we provide an overview of studies that have detected SCIs in patients with SCD by cerebral magnetic resonance imaging (MRI). We focus on the frequency of SCIs, the risk factors involved in their development and their clinical consequences.Methods: The databases of Embase, MEDLINE ALL via Ovid, Web of Science Core Collection, Cochrane Central Register of Trials via Wiley and Google Scholar were searched from inception to June 1, 2019.Results: The search yielded 651 results of which 69 studies met the eligibility criteria. The prevalence of SCIs in patients with SCD ranges from 5.6 to 80.6% with most studies reported in the 20 to 50% range. The pooled prevalence of SCIs in HbSS and HbSβ0 SCD patients is 29.5%. SCIs occur more often in patients with the HbSS and HbSβ0 genotype in comparison with other SCD genotypes, as SCIs are found in 9.2% of HbSC and HbSβ+ patients. Control subjects showed a mean pooled prevalence of SCIs of 9.8%. Data from included studies showed a statistically significant association between increasing mean age of the study population and mean SCI prevalence. Thirty-three studies examined the risk factors for SCIs. The majority of the risk factors show no clear association with prevalence, since more or less equal numbers of studies give evidence for and against the causal association.Conclusions: This systematic review and meta-analysis shows SCIs are common in patients with SCD. No clear risk factors for their development were identified. Larger, prospective and controlled clinical, neuropsychological and neuroimaging studies are needed to understand how SCD and SCIs affect cognition. [ABSTRACT FROM AUTHOR]

Introduction: Diagnosis, treatment monitoring and assessment of desmopressin effect in haemophilia A patients are performed by measurement of factor VIII activity (FVIII). The two assays commonly applied are the one‐stage assay and the chromogenic assay. Especially in non‐severe haemophilia A, discrepancies between these assays are common. It is still unestablished which assay corresponds best with bleeding phenotype and desmopressin effect. Aim: To correlate FVIII levels measured by the one‐stage assay and by the chromogenic assay with bleeding phenotype and, additionally, to compare FVIII assay discrepancies before and after desmopressin administration. Method: Factor VIII was measured in 130 non‐severe haemophilia A patients during routine visits to the outpatient clinic and/or during desmopressin testing. FVIII was measured by both the one‐stage assay and the chromogenic assay. Discrepancies between assays were defined as at least a twofold difference of FVIII or an absolute FVIII difference between measurements of ≥0.10 IU/mL. Bleeding phenotype was defined as annual number of treated bleedings (adjusted ABR). Results: Hundred and thirty non‐severe haemophilia A patients were included. In 31/130 patients, assay results were discrepant. However, FVIII measurements with both assays correlated adequately with adjusted ABR. In addition, in 27/130 patients FVIII measurements at baseline and after desmopressin administration were analysed. In 13/27 patients, all measurements were either equivalent or discrepant when results were compared. In 14/27 patients, this was not the case as both equivalent measurements and discrepant measurements at different time points within one patient were observed. Conclusion: Neither the one‐stage assay nor the chromogenic assay is superior in predicting bleeding phenotype. In addition, equivalent or discrepant FVIII results measured before desmopressin do not always predict FVIII assay results after desmopressin administration. [ABSTRACT FROM AUTHOR]

Background: In patients with haemophilia A (HA) perioperative dosing of factor VIII (FVIII) concentrate is based on body weight, historical FVIII level, in vivo recovery and FVIII level target values. In moderate and severe HA patients, this dosing regimen frequently leads to perioperative FVIII levels below and above target. This has not yet been evaluated in mild HA patients. Objectives: To evaluate perioperative FVIII concentrate treatment in mild HA patients and to assess the frequency of FVIII levels below or above target. Patients/Methods: This retrospective single‐centre study collected data from medical files of mild HA patients undergoing surgery and treated with FVIII concentrate. FVIII levels were compared to their target ranges and predictive factors for levels outside the target ranges were determined by logistic regression. Results: Fifty surgeries performed in 34 patients were evaluated. Median age was 47 years and median historical FVIII level was 0.14 IU/mL. Preoperative peak FVIII level was above or below the target range in 80% and 6.7% of surgeries, respectively. Postoperatively, the percentages above and below target trough ranges were 55.8% and 12.8%. Patients with blood group 0 had the highest risk on the preoperative peak FVIII level being above target. In addition, patients who had a preoperative baseline FVIII level of >0.10 IU/mL higher than their historical FVIII level had a higher preoperative peak FVIII level than patients without this increase. Conclusions: Dosing above FVIII target ranges with FVIII concentrates occurs frequently during perioperative treatment of mild HA patients. These results underline the necessity for better patient‐tailored treatment. [ABSTRACT FROM AUTHOR]

Introduction: Patients with bleeding disorders may experience limitations in sports participation and physical activity. Several studies on sports participation have been performed in haemophilia patients, but studies in patients with von Willebrand disease (VWD) are lacking. Aim: We assessed the sports participation and physical activity of a large cohort of VWD patients. Methods: Patients were included from the "WiN study." All patients completed a questionnaire on sports participation, physical activity, quality of life and bleeding symptoms (Tosetto bleeding score). Results: From the 798 included patients, 474 had type 1, 301 type 2 and 23 type 3 VWD. The mean age was 39 ± 20 (standard deviation) years. Five hundred and fifty‐two patients (69.3%) participated in various types of sports. Type 3 VWD patients more often did not participate in sports due to fear of bleeding and physical impairment, respectively, OR = 13.24 (95% CI: 2.45‐71.53) and OR = 5.90 (95% CI: 1.77‐19.72). Patients who did not participate in sports due to physical impairment had a higher bleeding score item for joint bleeds 1.0 (±1.6) vs 0.5 (± 1.1) (P = 0.036). Patients with type 3 VWD and patients with a higher bleeding score frequently had severe limitations during daily activities, respectively, OR = 9.84 (95% CI: 2.83‐34.24) and OR = 1.08 (95% CI: 1.04‐1.12). Conclusion: The majority of VWD patients participated in sports. Patients with type 3 VWD, a history of joint bleeds and a more severe bleeding phenotype frequently experienced limitations in sports participation and physical activities during daily life. [ABSTRACT FROM AUTHOR]

Summary: Some comorbidities, such as hypertension, are associated with higher von Willebrand factor (VWF) levels in the general population. No studies have been conducted to assess this association in patients with von Willebrand disease (VWD). Therefore, we studied this association in patients with type 1 (n = 333) and type 2 (n = 203) VWD from the ‘WiN” study. VWF antigen (VWF:Ag) was higher in type 1 VWD patients with hypertension [difference: 0·23 iu/ml, 95% confidence interval (CI): 0·11–0·35], diabetes mellitus (0·11 iu/ml, 95% CI: −0·02 to 0·23), cancer (0·14 iu/ml, 95% CI: 0·03–0·25) and thyroid dysfunction (0·14 iu/ml, 95% CI: 0·03–0·26) than in patients without these comorbidities (all corrected for age, sex and blood group). Similar results were observed for VWF collagen binding capacity (VWF:CB), VWF activity as measured by the VWF monoclonal antibody assay (VWF:Ab) and factor VIII (FVIII) coagulant activity (FVIII:C). In type 1 VWD, age was associated with higher VWF:Ag (0·03 iu/ml; 95% CI: 0·01–0·04), VWF:CB (0·02 iu/ml; 95% CI: 0·00–0·04), VWF:Ab (0·04 iu/ml; 95% CI: 0·02–0·06) and FVIII:C (0·03 iu/ml; 95% CI: 0·01–0·06) per decade increase. After adjustment for relevant comorbidities, these associations were no longer significant. Despite the higher VWF and FVIII levels, type 1 VWD patients with comorbidities had more bleeding episodes, particularly during surgery. There was no association between comorbidities and VWF/FVIII levels or bleeding phenotype in type 2 VWD patients. In conclusion, comorbidities are associated with higher VWF and FVIII levels in type 1 VWD and may explain the age‐related increase of VWF and FVIII levels. [ABSTRACT FROM AUTHOR]

Summary: Stroke risk in children with sickle cell disease (SCD) is currently assessed with routine transcranial Doppler ultrasound (TCD) measurements of blood velocity in the Circle of Willis (CoW). However, there is currently no biomarker with proven prognostic value in adult patients. Four‐dimensional (4D) flow magnetic resonance imaging (MRI) may improve risk profiling based on intracranial haemodynamics. We conducted neurovascular 4D flow MRI and blood sampling in 69 SCD patients [median age 15 years (interquartile range, IQR: 12–50)] and 14 healthy controls [median age 21 years (IQR: 18–43)]. We measured velocity, flow, lumen area and endothelial shear stress (ESS) in the CoW. SCD patients had lower haematocrit and viscosity, and higher velocity, flow and lumen area, with lower ESS compared to healthy controls. We observed significant age‐related decline in haemodynamic 4D flow parameters; velocity (Spearman's ρ = −0·36 to −0·61), flow (ρ = −0·26 to −0·52) and ESS (ρ = −0·14 to −0·54) in SCD patients. Further analysis in only adults showed that velocity values were similar in SCD patients compared to healthy controls, but that the additional 4D flow parameters, flow and lumen area, were higher, and ESS lower, in the SCD group. Our data suggest that 4D flow MRI may identify adult patients with an increased stroke risk more accurately than current TCD‐based velocity. [ABSTRACT FROM AUTHOR]

Background: Sickle cell disease (SCD) is endemic in non-Western countries. Due to migration, the prevalence of SCD in the Netherlands has increased. Adherence to medical treatment is recognized as a major problem area. Therefore, new effective interventions to increase adherence are urgently needed. Methods/design: The TEAM study is an ongoing randomized controlled trial (RCT) to compare protocolized individual medical appointments (IMA's; care-as-usual) with protocolized group medical appointments (GMA's; novel intervention) in pediatric (n = 40) and adult (n = 60) patients. The study aims to assess the effectiveness of GMA's (over a three year period) on patients' self-efficacy, adherence, quality of life, morbidity, hospital admissions and satisfaction with the treating professional; as well as to test the cost-effectiveness of GMA's. In both the IMA and GMA groups structured assessments will be performed at baseline (start of the study), after 1.5 and after 3 years. Discussion: This is the first RCT to investigate the effectiveness of GMA's on self-efficacy and adherence in pediatric and adult patients with SCD, including a cost-effectiveness analysis. [ABSTRACT FROM AUTHOR]

Prevention of bleeding and joint damage in severe haemophilia is dependent on adherence to prophylactic replacement therapy. The aim of this study was to assess adherence to prophylaxis, including associations with age, bleeding and clotting factor consumption ( CFC). In three Dutch haemophilia centres, semi-structured interviews about adherence to prophylaxis in the previous 2 weeks were conducted with patients or parents of a child with haemophilia. Patients were classified, according to pre-specified definitions, as adherent, sub-optimally adherent or non-adherent based on missing, timing, and dose of infusions. Association of annual bleeding rates, mean CFC, person performing the infusion (parents verus patients) with adherence categories were analysed. Overall, 241 patients with haemophilia using prophylaxis were studied. Parents were more adherent (66%; n = 48/73) than patients (43%; n = 72/168). Sub-optimal adherence occurred in 29% of parents and 37% of patients and was characterized by changes in timing of infusion (mostly from morning to evening), while missing <6% of infusions. Non-adherence occurred less often: in 5% of parents and 20% of patients. Reduced adherence was associated with lower CFC, but not with joint bleeding. In conclusion, non-adherence in haemophilia was relatively rare, yet 1/3 of patients struggled to administer prophylaxis at the appropriate time of day. [ABSTRACT FROM AUTHOR]

Sickle cell disease ( SCD) is complicated by silent cerebral infarcts, visible as white matter hyperintensities ( WMHs) on magnetic resonance imaging ( MRI). Both local vaso-occlusion, elicited by endothelial dysfunction, and insufficiency of cerebral blood flow ( CBF) have been proposed to be involved in the aetiology. We performed an explorative study to investigate the associations between WMHs and markers of endothelial dysfunction and CBF by quantifying WMH volume on 3·0 Tesla MRI. We included 40 children with Hb SS or HbSβ0thalassaemia, with a mean age of 12·1 ± 2·6 years. Boys demonstrated an increased risk for WMHs (odds ratio 4·5, 95% confidence interval 1·2-17·4), unrelated to glucose-6-phosphate dehydrogenase deficiency. In patients with WMHs, lower fetal haemoglobin (HbF) was associated with a larger WMH volume (regression coefficient = −0·62, R2 = 0·25, P = 0·04). Lower ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) levels were associated with lower CBF in the white matter (regression coefficient = 0·07, R2 = 0·15, P = 0·03), suggesting that endothelial dysfunction could potentially hamper CBF. The findings of our explorative study suggest that a high level of HbF may be protective for WMHs and that endothelial dysfunction may contribute to the development of WMHs by reducing CBF. [ABSTRACT FROM AUTHOR]

The ratios between von Willebrand factor propeptide (VWFpp) or factor VIII activity (FVIIkC) and VWF antigen (VWF:Ag) reflect synthesis, secretion, and clearance of VWF. We aimed to define the pathophysiology of 658 patients with type 1, 2, or 3 von Willebrand disease (VWD) with VWF levels ⩽30 U/dL from the Willebrand in The Netherlands (WiN) study using the VWFpp/VWFtAg and FVIII:C/VWF:Ag ratios. We evaluated the use of VWFpp in the classification and diagnosis of VWD. On the basis of the ratios, reduced VWF synthesis was observed in 18% of type 1 and only 2% of type 2 patients. A significant proportion of type 3 patients had detectable VWFpp (41%). These patients had a lower bleeding score than type 3 patients who had a complete absence of VWF:Ag and VWFpp (14.0 vs 19.5; P= .025). The majority of these patients had missense mutations with rapid VWF clearance, whereas type 3 patients with no VWFpp were homozygous for null alleles. In conclusion, VWFpp identified severe type 1 VWD with very low VWF levels in patients who had previously been classified as type 3 VWD. This study underlines the clinical significance of the VWFpp assay in the diagnosis and classification of VWD. [ABSTRACT FROM AUTHOR]

Sickle cell disease can be complicated by cerebral white matter hyperintensities ( WMHs), which are associated with diminished neurocognitive functioning. The influence of the total volume of WMHs on the degree of neurocognitive dysfunction has not yet been characterized. In our study of 38 patients (mean age 12·5 years) we demonstrated that a higher volume of WMHs was associated with lower full-scale intelligence quotient ( IQ), verbal IQ, Processing Speed Index and more fatigue. Our results suggest that volume of WMHs is an additional parameter to take into account when planning individual diagnostic and treatment options. [ABSTRACT FROM AUTHOR]

Neutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into account. In the INSIGHT study, we analyzed the association between F8 mutation and inhibitor development in patients with nonsevere hemophilia A (factor VIM 2-40 lU/dL). This analysis included 1112 non-severe hemophilia A patients from 14 centers in Europe and Australia that had genotyped at least 70% of their patients. Inhibitor risk was calculated as Kaplan-Meier incidence with cumulative number of exposure days as the time variable. During 44 800 exposure days (median, 24 exposure days per patient; interquartile range [IQR], 7-90), 59 of the 1112 patients developed an inhibitor; cumulative incidence of 5.3% (95% confidence interval [CI], 4.0-6.6) after a median of 28 exposure days (IQR, 12-71). The inhibitor risk at 50 exposure days was 6.7% (95% CI, 4.5-8.9) and at 100 exposure days the risk further increased to 13.3% (95% CI, 9.6-17.0). Among a total of 214 different F8 missense mutations 19 were associated with inhibitor development. These results emphasize the importance of F8 genotyping in nonsevere hemophilia [ABSTRACT FROM AUTHOR]