Unravelling the effect of blood group on FVIII:C levels and response to DDAVP in 20 males with a single genotype (Twillingate Variant) causing Haemophilia A.

INTRODUCTION: The genetic variant responsible for haemophilia A (HA) significantly impacts endogenous coagulant factor VIII (FVIII:C) level, thus impacting DDAVP responsiveness. Blood group (BG) also impacts FVIII:C levels, but this is difficult to evaluate in a genetically heterogeneous population. Canada has a large cohort of mild-moderate HA due to a single point variant: c.6104T>C, p.Val2035Ala-the Twillingate variant. AIM: To evaluate the impact of BG on endogenous FVIII:C levels and DDAVP responsiveness in a single genotype of mild-moderate HA. METHODS: This was a retrospective, single-centre study. BG and FVIII:C levels were obtained for males with the Twillingate variant. One-hour absolute and fold increases in FVIII:C post-DDAVP were calculated. T-tests and Mann-Whitney U tests were used to compare FVIII:C levels and DDAVP challenge variables between individuals according to BGs (O vs. non-O). RESULTS: Twenty males were included. There were significant differences between BGs (O vs. non-O) in their lowest FVIII:C level at age <12 years (medians: 0.05 vs. 0.08 IU/mL; P = .05). Fifteen subjects underwent DDAVP challenges. Mean 1-h FVIII:C were 0.29 (O BG) versus 0.41 IU/mL (non-O BG); P = .04. There were no significant differences between BGs (O vs. non-O) in mean absolute FVIII:C increase (0.20 vs. 0.27 IU/mL; P = .10) and FVIII:C fold increase (3.3-fold vs. 3.8-fold; P = .51). CONCLUSION: In HA subjects with an identical genotype, BG significantly impacts baseline FVIII:C levels and FVIII:C levels post-DDAVP, but does not impact absolute and fold increases in FVIII:C with DDAVP.

Face validity of the Kids' ITP Tools (KIT) in the era of thrombopoietin receptor agonists.

The Kids' ITP Tools (KIT) is a questionnaire to assess quality of life of children with immune thrombocytopenia (ITP). The aim of this study was to update this previously validated tool to align with changes in clinical practice, specifically, treatment with thrombopoietin receptor agonists (TPO-RAs). Children aged 1-18 with ITP and/or their families were recruited to participate in interviews to review the KIT. Twenty-six interviews were conducted. Based on interview data from children and families, current guidelines, and expert opinion, five changes were made to the KIT in order to improve its face validity.

Genetic determinants of VWF clearance and FVIII binding modify FVIII pharmacokinetics in pediatric hemophilia A patients.

Factor VIII (FVIII) pharmacokinetic (PK) properties show high interpatient variability in hemophilia A patients. Although previous studies have determined that age, body mass index, von Willebrand factor antigen (VWF:Ag) levels, and ABO blood group status can influence FVIII PK, they do not account for all observed variability. In this study, we aim to describe the genetic determinants that modify the FVIII PK profile in a population of 43 pediatric hemophilia A patients. We observed that VWF:Ag and VWF propeptide (VWFpp)/VWF:Ag, but not VWFpp, were associated with FVIII half-life. VWFpp/VWF:Ag negatively correlated with FVIII half-life in patients with non-O blood type, but no correlation was observed for type O patients, suggesting that von Willebrand factor (VWF) half-life, as modified by the ABO blood group, is a strong regulator of FVIII PK. The FVIII-binding activity of VWF positively correlated with FVIII half-life, and the rare or low-frequency nonsynonymous VWF variants p.(Arg826Lys) and p.(Arg852Glu) were identified in patients with reduced VWF:FVIIIB but not VWF:Ag. Common variants at the VWF, CLEC4M, and STAB2 loci, which have been previously associated with plasma levels of VWF and FVIII, were associated with the FVIII PK profile. Together, these studies characterize the mechanistic basis by which VWF clearance and ABO glycosylation modify FVIII PK in a pediatric population. Moreover, this study is the first to identify non-VWF and non-ABO variants that modify FVIII PK in pediatric hemophilia A patients.

Patterns of joint damage in severe haemophilia A treated with prophylaxis.

OBJECTIVE: The primary objective of this study was to assess whether there are different patterns (classes) of joint health in young boys with severe haemophilia A (SHA) prescribed primary tailored prophylaxis. We also assessed whether age at first index joint bleed, blood group, FVIII gene abnormality variant, factor VIII trough level, first-year bleeding rate and adherence to the prescribed prophylaxis regimen significantly predicted joint damage trajectory, and thus class membership. METHODS: Using data collected prospectively as part of the Canadian Hemophilia Primary Prophylaxis Study (CHPS), we implemented a latent class growth mixture model technique to determine how many joint damage classes existed within the cohort. We used a multinomial logistic regression to predict the odds of class membership based on the above predictors. We fitted a survival model to assess whether there were differences in the rate of dose escalation across the groups. RESULTS: We identified three distinct classes of trajectory: persistently low, moderately increasing and rapidly increasing joint scores. By multinomial regression, we found that only age at first index joint bleed predicted rapidly increasing joint scores. The rapidly increasing joint score class group moved through dose escalation significantly faster than the other two groups. CONCLUSIONS: Using tailored prophylaxis, boys with SHA follow one of three joint health trajectories. By using knowledge of disease trajectories, clinicians may be able to adjust treatment according to a subject's predicted long-term joint health and institute cost-effective programmes of prophylaxis targeted at the individual subject level.

Genotype-phenotype correlation in children with hereditary spherocytosis.

Hereditary spherocytosis (HS) is a common inherited haemolytic anaemia attributed to disturbances in five different red cell membrane proteins. We performed a retrospective study of 166 children with HS and describe the clinical phenotype according to the genotype. In 160/166 (97%) children with HS a disease-causing mutation was identified. Pathogenic variants in ANK1, SPTB, SLC4A1 and SPTA1 were found in 49%, 33%, 13% and 5% of patients. Children with SLC4A1-HS had the mildest phenotype, showing the highest haemoglobin (P < 0·001), lowest reticulocyte counts (P < 0·001) and lowest unconjugated bilirubin levels (P = 0·006), and none required splenectomy in childhood (P < 0·001). Conversely, children with autosomal recessive SPTA1-HS had the most severe clinical phenotype, with almost all patients undergoing splenectomy in early childhood. Patients with ANK1 and SPTB variants showed a similar clinical phenotype. Within each gene, variant type or location did not predict disease severity or likelihood of splenectomy. Among patients with a genetic diagnosis, 47 (29%) underwent splenectomy (23 partial; 24 total) while 57 (36%) underwent cholecystectomy. Total splenectomy led to greater improvements in haemoglobin (P = 0·02). Select use of genetic testing (especially in patients without a family history) may help predict clinical phenotype in childhood and guide family counselling.

Measuring the impact of changing from standard half-life (SHL) to extended half-life (EHL) FVIII prophylaxis on health-related quality of life (HRQoL) in boys with moderate/severe haemophilia A: Lessons learned with the CHO-KLAT tool.

INTRODUCTION: In many countries, there is a shift from standard half-life (SHL) to extended half-life (EHL) clotting factor concentrates (CFCs). AIM: To describe the experience of switching from SHL to an EHL FVIII CFC and the impact of this on frequency of infusions, factor consumption, bleeding rates and HRQoL using the Canadian Hemophilia Kids' Life Assessment Tool (CHO-KLAT). METHODS: A retrospective chart review was conducted at a single haemophilia treatment centre in 2018 that included boys (ages: 4-18 years) with moderate/severe haemophilia A, without inhibitors, who switched from a SHL to an EHL FVIII CFC in the previous 2 years and for whom HRQoL data were available. RESULTS: The study cohort comprised 38 boys [mean (SD) age: 11.0 (3.4) years] with moderate (n = 5)/severe (n = 33) haemophilia A. The switch was associated with a 33% reduction in the number of weekly infusions from a median of 3.5 to 2.3 (P < .0001) and a 17% reduction in median FVIII consumption from 103 IU/kg/wk to 85.5 IU/kg/wk (P = .004). There was no significant change in annualized joint bleed rates or in CHO-KLAT scores. CONCLUSIONS: Despite documenting several benefits of switching to EHL FVIII (less infusions, lower factor consumption with no increase in bleeding), our study did not demonstrate any improvement in HRQoL. We conclude that either the current CHO-KLAT tool is not optimized to measure burden of treatment administration in boys with low bleed rates switching from SHL to EHL FVIII CFCs or that a reduction of 1.2 infusions/week does not result in a meaningful change in HRQoL.

Use of ultrasound for assessment of musculoskeletal disease in persons with haemophilia: Results of an International Prophylaxis Study Group global survey.

AIM: The objective of this survey was to understand the global trends of imaging assessments in persons with haemophilia, focusing on point-of-care ultrasound (POCUS). Insights into the barriers impeding its widespread proliferation as a frontline imaging modality were obtained. METHODS: The survey opened in September of 2017 and closed in May of 2018. Haemophilia Treatment Centres (HTCs) treating both paediatric/adult patients were the population of interest. A REDCap survey of 25 questions was disseminated to 232 clinical staff in 26 countries. RESULTS: The majority of respondents (88.3%, 91/103) reported that POCUS is most useful to confirm or rule out a presumed acute joint bleed. European HTCs reported the highest routine use of POCUS at 59.5% (22/37) followed by HTCs in the "Other" countries of the world at 46.7% (7/15) and North American HTCs at 43.9% (25/57). At the time of the survey, physiotherapists were identified as the clinical staff who perform POCUS 52.8% (28/53) of the time, in contrast with nurses/nurse practitioners who represent only 5.7% (3/53) of users. The greatest perceived barriers to the implementation of POCUS are the lack of trained healthcare professionals who can perform POCUS at 69.2% (74/107) and the overall time commitment required at 68.2% (73/107). CONCLUSION: Despite POCUS being used in 49.5% (54/109) of sampled HTCs, it is still utilized almost 30% less globally than full diagnostic ultrasound. A list of barriers has been identified to inform HTCs which challenges they will likely need to overcome should they choose to incorporate this imaging modality into their practice.

Health-related quality of life in children with chronic immune thrombocytopenia treated with eltrombopag in the PETIT study.

The PETIT (Eltrombopag in Pediatric Patients with Thrombocytopenia from Chronic ITP) trial showed that in children aged 1-17 years with chronic or persistent immune thrombocytopenia (ITP), eltrombopag improved platelet counts, decreased clinically significant bleeding and reduced rescue medication need. We report the health-related quality of life (HRQoL) results from the PETIT study using the Kids' ITP Tools (KIT). A limitation was that PETIT was not powered for the HRQoL analysis. Eltrombopag did not impact children's HRQoL assessed by the KIT. Although median KIT scores in children treated with eltrombopag with platelet responses were numerically higher compared with non-responders in some age groups, the interquartile ranges overlapped.

Long-term treatment with romiplostim and treatment-free platelet responses in children with chronic immune thrombocytopenia.

Children with immune thrombocytopenia for ≥6 months completing a romiplostim study received weekly subcutaneous romiplostim (1-10 µg/kg targeting platelet counts of 50-200×109/L) in this extension to examine romiplostim's long-term safety and efficacy. Sixty-five children received romiplostim for a median of 2.6 years (range: 0.1-7.0 years). Median baseline age was 11 years (range: 3-18 years) and platelet count was 28×109/L (range: 2-458×109/L). No patient discontinued treatment for an adverse event. Median average weekly dose was 4.8 mg/kg (range: 0.1-10 mg/kg); median platelet counts remained >50×109/L, starting at week 2. Nearly all patients (94%) had ≥1 platelet response (≥50×109/L, no rescue medication in the previous 4 weeks), 72% had responded at ≥75% of visits, and 58% had responded at ≥90% of visits. Treatment-free response (platelets ≥50×109/L ≥24 weeks without immune thrombocytopenia treatment) was seen in 15 of 65 patients while withholding romiplostim doses. At onset of treatment-free response, the nine girls and six boys had a median immune thrombocytopenia duration of four years (range: 1-12 years) and had received romiplostim for two years (range: 1-6 years). At last observation, treatment-free responses lasted for a median of one year (range: 0.4-2.1 years), with 14 of 15 patients still in treatment-free response. Younger age at first dose and platelet count >200×109/L in the first four weeks were associated with treatment-free responses. In this 7-year open-label extension, three-quarters of the patients responded ≥75% of the time, and romiplostim was well tolerated, with no substantial treatment-related adverse events. Importantly, 23% of children maintained treatment-free platelet responses while withholding romiplostim and all other immune thrombocytopenia medications for ≥6 months. (Registered at clinicaltrials.gov identifier: 01071954).

Validation of the school age self-administered pediatric bleeding questionnaire (Self-PBQ) in children aged 8-12 years.

BACKGROUND: In the pediatric population, pathologic bleeding is often challenging to identify. The pediatric bleeding questionnaire (PBQ) was developed as a screening tool for von Willebrand disease (VWD) but was designed to be self-completed by children above 12 years of age. The study objective was to determine whether a modified Self-PBQ could be completed by 8- to 12-year-old children with adult assistance. PROCEDURE: The initial phase involved seven children who underwent cognitive debriefing to identify problems in the questionnaire, resulting in modifications to wording and response options. In phase 2, children completed the modified Self-PBQ independently or with assistance from their parent at five Canadian treatment centers. Parents filled out the Self-PBQ separately to serve as a comparison. Bleeding scores derived from the child self-report were compared to those of the parent proxy. RESULTS: Twenty-nine out of 31 patient/parent pairs successfully completed the Self-PBQ. Child and parent scores demonstrated a high level of agreement with an intraclass correlation (ICC) of 0.825. In the age subgroup analysis, the ICC was 0.834 and 0.824 for the 8- to 9-year-old and 10- to 12-year-old groups, respectively. The ICC was also determined in children with type 1 VWD (ICC = 0.829) versus those with more severe bleeding disorders (ICC = 0.802). Thus, age and disease severity had no significant effect on degree of agreement. CONCLUSIONS: Our study shows that agreement was maintained even in younger children aged 8-9 years and in children with varying bleeding phenotypes. This supports the administration of the modified Self-PBQ to 8- to 12-year-old children.

Severity and Features of Epistaxis in Children with a Mucocutaneous Bleeding Disorder.

OBJECTIVE: To use standardized bleeding questionnaires to compare the severity and patterns of epistaxis in children with a mucocutaneous bleeding disorder and control children. STUDY DESIGN: The epistaxis sections of the Pediatric Bleeding Questionnaire (PBQ) administered to pediatric patients with von Willebrand disease or a platelet function disorder and healthy control children were reviewed. Scores and features of epistaxis (frequency, duration, onset, site, seasonal correlation, and need for medical/surgical intervention) were recorded. A PBQ epistaxis score ≥2 was defined as clinically significant. The Katsanis epistaxis scoring system was administered to eligible patients, ie, with ≥5 episodes of epistaxis per year. RESULTS: PBQ epistaxis scores were obtained for 66 patients, median age 12 years (range 0.6-18.3 years), and 56 control children. The median PBQ epistaxis score in patients was 2 vs 0 in control children (P <.0001). All of the features of epistaxis, except spontaneous onset, occurred in a significantly greater proportion of patients than control children with epistaxis. A total of 50% of the patients were graded as having severe epistaxis by the Katsanis epistaxis scoring system, and 30 of these (91%) had a clinically significant PBQ epistaxis score. CONCLUSION: Standardized bleeding questionnaires are useful in the assessment of epistaxis severity and pattern and may help to distinguish children with and without a mucocutaneous bleeding disorder.

A Quality Improvement Bundle to Improve Informed Choice for Children With Typical, Newly Diagnosed Immune Thrombocytopenia.

IVIG has been the predominant therapy for the initial management of children with newly diagnosed immune thrombocytopenia at our hospital. With current guidelines supporting more conservative management, we undertook a quality improvement initiative to lead practice change. Over a 2-year time period (2013 to 2015), we strove to decrease use of hospital resources (use of IVIG, length of stay) while optimizing family satisfaction. An interdisciplinary working group was struck and a quality improvement bundle was implemented. The bundle comprised a patient information sheet; an evidence-informed, consensus-based protocol; and promotion of shared decision-making via stakeholder engagement and education. Data were collected prospectively; baseline data from a 2007 to 2009 audit were used for comparison. In total, 27 patients were included. Mean initial platelet count was 4×10/L. Bleeding was classified as none or mild in 56% of patients. IVIG use decreased from 88% to 55% of patients, corticosteroid prescription increased from 6% to 15%, and observation increased from 6% to 30% of patients. Hospital length of stay decreased from 47 to 36 hours. Family satisfaction was stable across treatment groups. Through introduction of a quality improvement initiative, we were able to improve family-centered care and decrease use of hospital resources.

Romiplostim in children with immune thrombocytopenia: a phase 3, randomised, double-blind, placebo-controlled study.

BACKGROUND: The thrombopoietin receptor agonist romiplostim could be an effective treatment in symptomatic children with persistent or chronic immune thrombocytopenia. We aimed to assess whether romiplostim is safe and effective in children with immune thrombocytopenia of more than 6 months' duration. METHODS: In this phase 3 double-blind study, eligible participants were children with immune thrombocytopenia aged 1 year to 17 years and mean platelet counts 30 × 10(9)/L or less (mean of two measurements during the screening period) with no single count greater than 35 × 10(9)/L, and were recruited from 27 sites in the USA, Canada, and Australia. Participants were randomly assigned (2:1) through the interactive voice response system to receive weekly romiplostim or placebo for 24 weeks stratified by age (1 year to <6 years, 6 years to <12 years, 12 years to <18 years), adjusting the dose weekly from 1 µg/kg to 10 µg/kg to target platelet counts of 50-200 × 10(9)/L. Patients and investigators were blinded to the treatment assignment. The primary analysis included all randomised patients and the safety analysis included all randomised patients who received at least one dose of investigational product. The primary endpoint, durable platelet response, was defined as achievement of weekly platelet responses (platelet counts ≥50 × 10(9)/L without rescue drug use in the preceding 4 weeks) in 6 or more of the final 8 weeks (weeks 18-25). This study is registered with ClinicalTrials.gov, NCT 01444417. FINDINGS: Between Jan 24, 2012, and Sept 3, 2014, 62 patients were randomly assigned; 42 to romiplostim and 20 to placebo. Durable platelet response was seen in 22 (52%) patients in the romiplostim group and two (10%) in the placebo group (p=0·002, odds ratio 9·1 [95% CI 1·9-43·2]). Durable platelet response rates with romiplostim by age were 38% (3/8) for 1 year to younger than 6 years, 56% (10/18) for 6 years to younger than 12 years, and 56% (9/16) for 12 years to younger than 18 years. One (5%) of 19 patients in the placebo group had serious adverse events compared with 10 (24%) of 42 patients in the romiplostim group. Of these serious adverse events, headache and thrombocytosis, in one (2%) of 42 patients in the romiplostim group, were considered treatment related. No patients withdrew due to adverse events. INTERPRETATION: In children with chronic immune thrombocytopenia, romiplostim induced a high rate of platelet response with no new safety signals. Ongoing romiplostim studies will provide further information as to long-term efficacy, safety, and remission in children with immune thrombocytopenia. FUNDING: Amgen Inc.

Generation and optimization of the self-administered pediatric bleeding questionnaire and its validation as a screening tool for von Willebrand disease.

OBJECTIVE: Our objective was to generate, optimize, and validate a self-administered pediatric bleeding questionnaire (Self-PBQ) as a screening tool for von Willebrand disease (VWD) in children referred to the hematology clinic for the first time. STUDY DESIGN: The Self-PBQ was generated by combining the validated expert-administered PBQ and the International Society on Thrombosis and Hemostasis (ISTH) bleeding assessment tool (BAT). Medical terminology was translated into lay language requiring a grade 4 reading level. In Phase 1, the Self-PBQ was optimized and the level of agreement between the Self-PBQ and the expert-administered PBQ was determined. Phase 2 established the normal range of bleeding scores (BSs) of the Self-PBQ. Phase 3 examined the Self-PBQ as a screening tool for first-time referrals to the hematology clinic. RESULTS: The Self-PBQ is a reliable surrogate for the expert-administered PBQ with an excellent intraclass correlation (ICC) of 0.917. The Self-PBQ was scored with the PBQ and the ISTH-BAT scoring systems, for which its normal BS ranges are -1 to 2 or 0 to 2, respectively. A positive Self-PBQ BS (≥3) had a sensitivity of 78%, a specificity of 37%, a positive predictive value of 0.18, and a negative predictive value of 0.91 for identifying VWD in children being investigated by a hematologist for a bleeding disorder. CONCLUSION: The Self-PBQ generates comparable BSs to the expert-administered PBQ and is a reliable, reasonably sensitive screening tool to incorporate into the assessment of children presenting to a hematologist for the investigation of an inherited bleeding disorder.

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Determine the Effect of Romiplostim on Health-Related Quality of Life in Children with Primary Immune Thrombocytopenia and Associated Burden in Their Parents.

BACKGROUND: Chronic immune thrombocytopenia (ITP) in children can negatively impact their health-related quality of life (HRQoL) and impose a burden on their parents. This study sought to examine the effect of romiplostim on HRQoL and parental burden in children with primary ITP. PROCEDURE: This was a phase 3, randomized, double-blind, placebo-controlled study. Children aged <18 years with ITP ≥6 months were randomly assigned to receive romiplostim or placebo for 24 weeks. The Kids' ITP Tool (KIT) was used to measure HRQoL and was administered to patients and/or their parents at baseline and weeks 8, 16, and 25. Mean KIT scores at each assessment and mean changes in KIT scores from baseline were calculated overall by treatment group and platelet response status. Psychometric properties of the KIT were evaluated and the minimally important difference (MID) was estimated for different KIT versions. RESULTS: Sixty-two patients (42 romiplostim and 20 placebo) were enrolled. Changes in KIT scores by treatment group showed numerically greater and more often statistically significant improvements from baseline to each assessment for children receiving romiplostim versus placebo. Mixed-effects analysis demonstrated statistically significantly greater reduction in parental burden from baseline in the romiplostim group versus placebo. Ranges for the MID were estimated as 9-13 points for the Child Self-Report version and 11-13 points for the Parent Impact version. CONCLUSIONS: The treatment with romiplostim may be associated with improved HRQoL in children with primary ITP and reduced burden to their parents.

Definitions in hemophilia: resolved and unresolved issues.

Definitions of clinical events and end points of care are important for disease characterization as well as documentation of outcomes in clinical practice and trials. Until recently, the only definitions in hemophilia that were provided through an international scientific organization related to disease severity and levels of inhibitors. Recently, the Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis, through its Factor VIII and IX subcommittee, published consensus definitions for several other aspects of hemophilia management, including classification of disease severity; inhibitors; bleeding (and rebleeding) into muscles and joints; target joints; different forms of factor replacement therapy; and response to therapy for joint bleeding and surgical hemostasis. These definitions should help to bring greater uniformity in the documentation of critical clinical events and laboratory data that are reported both from clinical trials as well as real-world practice. This article describes these definitions in greater detail than the SSC short report and also addresses some of the unresolved issues. Wide dissemination of these concepts and definitions and their acceptance by relevant leading scientific societies, drug regulators, industry, and patient organizations will go a long way in ensuring their acceptance and use globally.

Bleeding manifestations and management of children with persistent and chronic immune thrombocytopenia: data from the Intercontinental Cooperative ITP Study Group (ICIS).

Long-term follow-up of children with immune thrombocytopenia (ITP) indicates that the majority undergo remission and severe thrombocytopenia is infrequent. Details regarding bleeding manifestations, however, remain poorly categorized. We report here long-term data from the Intercontinental Cooperative ITP Study Group Registry II focusing on natural history, bleeding manifestations, and management. Data on 1345 subjects were collected at diagnosis and at 28 days, 6, 12, and 24 months thereafter. Median platelet counts were 214 × 10(9)/L (interquartile range [IQR] 227, range 1-748), 211 × 10(9)/L (IQR 192, range 1-594), and 215 × 10(9)/L (IQR 198, range 1-598) at 6, 12, and 24 months, respectively, and a platelet count <20 × 10(9)/L was uncommon (7%, 7%, and 4%, respectively). Remission occurred in 37% of patients between 28 days and 6 months, 16% between 6 and 12 months, and 24% between 12 and 24 months. There were no reports of intracranial hemorrhage, and the most common site of bleeding was skin. In patients with severe thrombocytopenia we observed a trend toward more drug treatment with increasing number of bleeding sites. Our data support that ITP is a benign condition for most affected children and that major hemorrhage, even with prolonged severe thrombocytopenia, is rare.

Validation and reliability of a disease-specific quality of life measure (the TranQol) in adults and children with thalassaemia major.

This study aimed to demonstrate the validity, reliability and responsiveness of a new disease-specific quality of life (QoL) questionnaire for children and adults with thalassaemia major, the Transfusion-dependent QoL questionnaire (TranQol). 106 participants (51 adults and 55 children) were recruited from six North American thalassaemia treatment centres with a mean age of 20·7 years (standard deviation [SD] 9, range 7-51 years). The mean total TranQol score was 71 (SD 17, 32-97) on a scale of 0-100. Patients with co-morbidities had significantly lower scores (63 vs. 75, P = 0·001). TranQol scores showed substantial agreement (P < 0·001) with the Health Utilities Index Mark 3 (all patients, r = 0·65), the Pediatric QoL (children, r = 0·77) and the Short Form (36) physical (adults, r = 0·69) and mental summary scores (r = 0·76). In the subgroup who rated their QoL as better, there was a 4·0 point (SD 9·0) improvement in TranQol scores, from baseline of 67·1-71·1 one week later (P = 0·008). Test-retest reliability was excellent (intra-class correlation coefficient, 0·93). The TranQol was valid, with acceptable correlation for all administered measures and was reliable and responsive to change. The TranQol can be incorporated into future studies of thalassaemia major.

Population pharmacokinetics of recombinant factor VIII: the relationships of pharmacokinetics to age and body weight.

Comparison of the pharmacokinetics (PK) of a coagulation factor between groups of patients can be biased by differences in study protocols, in particular between blood sampling schedules. This could affect clinical dose tailoring, especially in children. The aim of this study was to describe the relationships of the PK of factor VIII (FVIII) with age and body weight by a population PK model. The potential to reduce blood sampling was also explored. A model was built for FVIII PK from 236 infusions of recombinant FVIII in 152 patients (1-65 years of age) with severe hemophilia A. The PK of FVIII over the entire age range was well described by a 2-compartment model and a previously reported problem, resulting from differences in blood sampling, to compare findings from children and adults was practically abolished. The decline in FVIII clearance and increase in half-life with age could be described as continuous functions. Retrospective reduction of blood sampling from 11 to 5 samples made no important difference to the estimates of PK parameters. The obtained findings can be used as a basis for PK-based dose tailoring of FVIII in clinical practice, in all age groups, with minimal blood sampling.

Shared decision making in the management of children with newly diagnosed immune thrombocytopenia.

This study aimed to examine the treatment decision-making process for children hospitalized with newly diagnosed immune thrombocytopenia (ITP). Using focus groups, we studied children with ITP, parents of children with ITP, and health care professionals, inquiring about participants' experience with decision support and decision making in newly diagnosed ITP. Data were examined using thematic analysis. Themes that emerged from children were feelings of "anxiety, fear, and confusion"; the need to "understand information"; and "treatment choice," the experience of which was age dependent. For parents, "anxiety, fear, and confusion" was a dominant theme; "treatment choice" revealed that participants felt directed toward intravenous immune globulin (IVIG) for initial treatment. For health care professionals, "comfort level" highlighted factors contributing to professionals' comfort with offering options; "assumptions" were made about parental desire for participation in shared decision making (SDM) and parental acceptance of treatment options; "providing information" was informative regarding modes of facilitating SDM; and "treatment choice" revealed a discrepancy between current practice (directed toward IVIG) and the ideal of SDM. At our center, families of children with newly diagnosed ITP are not experiencing SDM. Our findings support the implementation of SDM to facilitate patient-centered care for the management of pediatric ITP.