Publications by authors named "Victor S Blanchette"

66 Publications

Magnetic resonance imaging in boys with severe hemophilia A: Serial and end-of-study findings from the Canadian Hemophilia Primary Prophylaxis Study.

Res Pract Thromb Haemost 2021 Oct 16;5(7):e12565. Epub 2021 Oct 16.

Department of Medical Imaging University of Saskatchewan Saskatoon SK Canada.

Background: This study examined the structural outcomes for joints of boys with severe hemophilia A receiving frequency/dose-escalated primary prophylaxis using magnetic resonance imaging (MRI), and the importance of interval MRI changes.

Methods: Forty-six subjects (27 with interval studies) were evaluated by radiographs (X-rays) and mid- and end-of-study MRIs (using the International Prophylaxis Study Group scale), as part of the Canadian Hemophilia Prophylaxis Study. The primary outcome was the presence of MRI osteochondral findings.

Results: The median (range) time on study at the end-of-study MRI examination was 9.6 (4.8-16.0) years, during which 18 of 46 subjects (39%) had osteochondral changes in at least one joint. An interval change in MRI score of at least 1 point was observed in 44% of joints (43 ankles, 21 elbows, 4 knees); at least one joint showed this change in all 27 subjects. Self-reported interval hemarthrosis was associated with a higher likelihood of interval osteochondral change (odds ratio [OR], 1.49; 95% confidence interval [CI] = 1.08-2.06). Presence of synovial hypertrophy or hemosiderin on interval MRIs was associated with an OR of 4.71 (95% CI, 1.92-11.57) and 5.25 (95% CI, 2.05-13.40) of later osteochondral changes on MRI.

Discussion: MRI changes were seen in 39% of subjects. Interval index joint bleeding was associated with an increased risk of later MRI changes, and earlier soft-tissue changes were associated with subsequent osteochondral changes.
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http://dx.doi.org/10.1002/rth2.12565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8520573PMC
October 2021

Significant reduction in hemarthrosis in boys with severe hemophilia A: The China hemophilia individualized low-dose secondary prophylaxis study.

Res Pract Thromb Haemost 2021 Aug 18;5(6):e12552. Epub 2021 Sep 18.

Department of Pediatrics Laboratory Medicine and Pathology Division of Hematology and Oncology University of Ottawa Children Hospital of Eastern Ontario Ottawa ON Canada.

Introduction: In countries with restricted access to clotting factor concentrates, early implementation of low-dose prophylaxis is recommended over episodic treatment.

Objective: The objective of this 1-year prospective secondary prophylaxis study was to evaluate the efficacy of a dose/frequency escalating protocol in young boys with hemophilia A in China.

Methods: Boys were started on a low-dose protocol (minimum 10-15 IU/kg of factor VIII [FVIII] twice weekly). Escalation was based on index joint bleeding, swelling/persistent joint swelling, and serial ultrasound (gray scale and color Doppler) examinations of index joints.

Results: Thirty-three boys, median age 4.8 years (interquartile range, 3.8-6.1) were enrolled in a 3-month observation period that preceded a 1-year prophylaxis phase. A significant reduction in total bleeding events (43.0%, = .001), index joint bleeds (53.2%, = .002), and target index joint bleeds (70.0%, = 0.02) was observed during the prophylaxis phase. During the prophylaxis period, 40% of target joints resolved. The percentage of boys with zero index joint bleeds increased significantly (= .004) from 51.5% during the observation phase to 81.8% in last quarter of the prophylaxis phase (months 10-12). There was no progression of arthropathy based on physical examination (Hemophilia Joint Health Score), X-ray, and ultrasound obtained at entry into the prophylaxis phase and at study exit. The median FVIII consumption over the prophylaxis phase was 1786 IU/kg/y.

Conclusion: A low-dose, individualized prophylaxis protocol, guided by individual bleeding profiles and serial assessment of joint status, enables escalation of treatment intensity in boys with severe hemophilia A, leading to a significant reduction in bleeding events and reduction in target joint bleeding.
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http://dx.doi.org/10.1002/rth2.12552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449287PMC
August 2021

A semiquantitative color Doppler ultrasound scoring system for evaluation of synovitis in joints of patients with blood-induced arthropathy.

Insights Imaging 2021 Sep 25;12(1):132. Epub 2021 Sep 25.

Department of Diagnostic Imaging, Research Institute, The Hospital for Sick Children, University of Toronto, 555 University Ave, Toronto, ON, M5G 1X8, Canada.

Background: Intra-articular bleeds in patients with inherited bleeding disorders lead to active synovitis which may progress to a chronic state over time. We explored the diagnostic value of color Doppler ultrasound in detecting synovitis in boys with bleeding disorders.

Results: Sixty boys with hemophilia and 3 boys with type 3 von Willebrand disease aged 5 to 18 years (median 12.3 years) were imaged by gray-scale and color Doppler ultrasound (US) in three centers (Beijing, China [n = 22], Guangzhou, China [n = 12] and Toronto, Canada [n = 29])) in this observational study. Images were independently reviewed by two radiologists blinded to clinical data using a subjective semi-quantitative scoring system and objective measurements of synovial thickness and vascularity. Inter-reader reliability for using subjective versus objective color Doppler US methods for assessing synovial vascularity was excellent for the subjective method and moderate/lower range of substantial for the objective method. Agreement between degree of vascularity on color Doppler and extent of synovial hypertrophy on gray-scale US was overall poor for Canada data and moderate for China data. Correlations between degree of vascularity on color Doppler and synovial hypertrophy on gray-scale US, and clinical constructs (total and itemized HJHS scores and total Pettersson X-ray scores) for assessment of blood-induced arthropathy were all poor.

Conclusion: Color Doppler US is a valuable scoring method for evaluating reactive synovitis in joints of subjects with inherited bleeding disorders and holds potential for assessing post-bleed reactive synovitis once further information on its association with timing of the joint bleed becomes available in the literature.
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http://dx.doi.org/10.1186/s13244-021-01043-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8464640PMC
September 2021

Musculoskeletal ultrasound in hemophilia: Results and recommendations from a global survey and consensus meeting.

Res Pract Thromb Haemost 2021 Jul 10;5(5):e12531. Epub 2021 Jul 10.

School of Rehabilitation Science Faculty of Health Science Hamilton Niagara Regional Hemophilia Program Hamilton Health Sciences McMaster University Hamilton ON Canada.

Introduction: For persons with hemophilia, optimization of joint outcomes is an important unmet need. The aim of this initiative was to determine use of ultrasound in evaluating arthropathy in persons with hemophilia, and to move toward consensus among hemophilia care providers regarding the preferred ultrasound protocols for global adaptation.

Methods: A global survey of hemophilia treatment centers was conducted that focused on understanding how and why ultrasound was being used and endeavored to move toward consensus definitions of both point-of-care musculoskeletal ultrasound (POC-MSKUS) and full diagnostic ultrasound, terminology to describe structures being assessed by ultrasound, and how these assessments should be interpreted. Next, an in-person meeting of an international group of hemophilia health care professionals and patient representatives was held, with the objective of achieving consensus regarding the acquisition and interpretation of POC-MSKUS and full diagnostic ultrasound for use in the assessment of musculoskeletal (MSK) pathologies in persons with hemophilia.

Results: The recommendations were that clear definitions of the types of ultrasound examinations should be adopted and that a standardized ultrasound scoring/measurement system should be developed, tested, and implemented. The scoring/measurement system should be tiered to allow for a range of complexity yet maintain the ability for comparison across levels.

Conclusion: Ultrasound is an evolving technology increasingly used for the assessment of MSK outcomes in persons with hemophilia. As adoption increases globally for clinical care and research, it will become increasingly important to establish clear guidelines for image acquisition, interpretation, and reporting to ensure accuracy, consistency, and comparability across groups.
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http://dx.doi.org/10.1002/rth2.12531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271584PMC
July 2021

Patient-relevant health outcomes for hemophilia care: Development of an international standard outcomes set.

Res Pract Thromb Haemost 2021 May 6;5(4):e12488. Epub 2021 Mar 6.

Department of Clinical Epidemiology Leiden University Medical Center Leiden The Netherlands.

Background: Patient-relevant health outcomes for persons with hemophilia should be identified and prioritized to optimize and individualize care for persons with hemophilia. Therefore, an international group of persons with hemophilia and multidisciplinary health care providers set out to identify a globally applicable standard set of health outcomes relevant to all individuals with hemophilia.

Methods: A systematic literature search was performed to identify possible health outcomes and risk adjustment variables. Persons with hemophilia and multidisciplinary health care providers were involved in an iterative nominal consensus process to select the most important health outcomes and risk adjustment variables for persons with hemophilia. Recommendations were made for outcome measurement instruments.

Results: Persons with hemophilia were defined as all men and women with an X-linked inherited bleeding disorder caused by a deficiency of coagulation factor VIII or IX with plasma activity levels <40 IU/dL. We recommend collecting the following 10 health outcomes at least annually, if applicable: (i) cure, (ii) impact of disease on life expectancy, (iii) ability to engage in normal daily activities, (iv) severe bleeding episodes, (v) number of days lost from school or work, (vi) chronic pain, (vii) disease and treatment complications, (viii) sustainability of physical functioning, (ix) social functioning, and (x) mental health. Validated clinical as well as patient-reported outcome measurement instruments were endorsed. Demographic factors, baseline clinical factors, and treatment factors were identified as risk-adjustment variables.

Conclusion: A consensus-based international set of health outcomes relevant to all persons with hemophilia, and corresponding measurement instruments, was identified for use in clinical care to facilitate harmonized longitudinal monitoring and comparison of outcomes.
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http://dx.doi.org/10.1002/rth2.12488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117824PMC
May 2021

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

Haemophilia 2021 Jul 20;27(4):666-673. Epub 2021 May 20.

Institute of Health Policy, Management & Evaluation, The Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.

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.
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http://dx.doi.org/10.1111/hae.14345DOI Listing
July 2021

Measuring the impact of hemophilia on families: Development of the Hemophilia Family Impact Tool (H-FIT).

Res Pract Thromb Haemost 2021 May 7;5(4):e12519. Epub 2021 May 7.

Division of Pediatric Hematology/Oncology Department of Pediatrics IWK Health Centre Dalhousie University Halifax NS Canada.

Introduction: This study aimed to assess the impact of hemophilia on families, in the context of current and emerging hemostatic therapies, and explore the need for a hemophilia-specific tool targeted at parents of boys aged <4 years. A secondary aim was to develop and validate the new tool.

Methods: Focus groups were conducted with parents of boys with hemophilia and hemophilia health care providers at Canadian hemophilia treatment centers (HTCs) to review the relevance of the Pediatric Quality of Life Family Impact Module (PedsQL-FIM); a novel questionnaire was developed by identifying core themes expressed. This questionnaire, the Hemophilia Family Impact Tool (H-FIT) was validated in a sample of parents of boys with hemophilia relative to the PedsQL-FIM.

Results: Seven focus groups were conducted at four HTCs, generating themes specific to hemophilia not covered by the PedsQL-FIM, suggesting that a new tool be developed (the H-FIT). In the validation phase, 54 parents completed the H-FIT and PedsQL-FIM. The H-FIT had a strong correlation with the PedsQL-FIM across all ages (r = 0.79; < .0001) and a moderate correlation for parents of boys aged <7 years (r = 0.64; = .0007). There was a significant difference between the mean H-FIT scores for parents of boys using extended half-life factor (68.1; standard deviation [SD]=14.2) compared to standard half-life factor (54.7; SD=18.4; = .04).

Conclusion: A novel, disease-specific tool, the H-FIT, has been developed to measure the impact of hemophilia on families. The H-FIT has good preliminary measurement properties and may be responsive to changes in therapy associated with a decreased burden of administration.
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http://dx.doi.org/10.1002/rth2.12519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114030PMC
May 2021

Updating the Canadian Hemophilia Outcomes-Kids' Life Assessment Tool (CHO-KLAT) in the era of extended half-life clotting factor concentrates.

Res Pract Thromb Haemost 2021 Mar 27;5(3):403-411. Epub 2021 Mar 27.

Child Health Evaluative Sciences The Hospital for Sick Children Research Institute Toronto ON Canada.

Introduction: The purpose of this study was to review and update the content of the Canadian Hemophilia Outcomes-Kids' Life Assessment Tool version 2.0 (CHO-KLAT), in the context of extended half-life (EHL) factor concentrates (FCs) and to establish the validity and reliability of the updated CHO-KLAT.

Methods: Focus groups were conducted with boys with hemophilia, their parents, and health care providers across Canada to review the CHO-KLAT v2.0 and determine if any modifications were required. The validity of the revised CHO-KLAT (version 3.0) was then determined in a sample of boys with hemophilia and their parents by calculating its correlation with the Pediatric Quality of Life Core Module (PedsQL-Core). Test-retest reliability was assessed using an intraclass correlation coefficient (ICC).

Results: Thirteen focus groups at 5 pediatric hemophilia treatment centers (HTCs) (n = 71) resulted in 19 changes to the CHO-KLAT v2.0, generating a revised 40-item CHO-KLAT, the CHO-KLAT v3.0. Thirty-five boys with hemophilia (median age, 14; range, 7-17 years) and 47 parents participated in the validation of the CHO-KLAT v3.0. There was a moderate correlation between the CHO-KLAT v3.0 child self-report and PedsQL-Core ( = 0.56,  = .01), and a strong correlation between the CHO-KLAT v3.0 parent-proxy and PedsQL-Core ( = .79,  = .0007). The test-retest reliability ICC was 0.90 for the child self-report CHO-KLAT v3.0 and 0.68 for the parent-proxy CHO-KLAT v3.0.

Conclusion: The CHO-KLAT v3.0 is a reliable and valid child-centric tool that effectively measures health-related quality of life in boys with hemophilia who are receiving standard half-life or EHL FCs.
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http://dx.doi.org/10.1002/rth2.12498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035800PMC
March 2021

A Practical, One-Clinic Visit Protocol for Pharmacokinetic Profile Generation with the ADVATE myPKFiT Dosing Tool in Severe Hemophilia A Subjects.

Thromb Haemost 2021 Oct 27;121(10):1326-1336. Epub 2021 Jan 27.

Faculty of Medicine, Masaryk University, Brno, Czech Republic.

Standard pharmacokinetic (PK) assessments are demanding for persons with hemophilia A, requiring a 72-hour washout and 5 to 11 timed blood samples. A no-washout, single-clinic visit, sparse sampling population PK (PPK) protocol is an attractive alternative. Here, we compared PK parameters obtained with a traditional washout, 6-sampling time point PPK protocol with a no-washout, single-clinic visit, reverse 2-sampling time point PPK protocol in persons with severe hemophilia A (SHA) receiving ADVATE. A total of 39 inhibitor-negative males with SHA (factor VIII activity [FVIII:C] < 2%) were enrolled in a prospective sequential design PK study. Participants completed a washout, 6-sampling time point PPK protocol as well as a no-washout, reverse 2-sampling time point protocol, with samples taken during a single 3-hour clinic visit 24 hours post home infusion of FVIII and then 3 hours post infusion in clinic. FVIII:C levels were analyzed by one-stage and chromogenic assays; blood group and von Willebrand factor antigen (VWF:Ag) were determined; and PK parameters were analyzed using the ADVATE myPKFiT dosing tool. There was moderate to almost perfect agreement for the PK parameters obtained with the 2- and the 6- point PPK protocols using a one-stage FVIII:C assay and a substantial to almost perfect agreement using a chromogenic FVIII:C assay. Significant associations between specific PK parameters and blood group and VWF:Ag were observed. The no-washout, single-clinic visit, reverse 2-sampling time point PPK protocol can be used in the routine clinical setting since it demonstrates sufficient accuracy compared with the more demanding and less practical washout, 6-sampling time point PPK protocol in persons with SHA receiving ADVATE.
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http://dx.doi.org/10.1055/a-1376-0970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494515PMC
October 2021

Clinical outcomes in hemophilia: Towards development of a core set of standardized outcome measures for research.

Res Pract Thromb Haemost 2020 May 9;4(4):652-658. Epub 2020 Apr 9.

Child Health Evaluative Sciences The Hospital for Sick Children Toronto ON Canada.

Introduction: A lack of uniformity in the choice of outcome measurement in hemophilia care and research has led to studies with incomparable results. We identified a need to define core outcome measures for use in research and clinical care of persons with hemophilia.

Objective: To move toward a core set of outcome measures for the assessment of persons with hemophilia in research and practice.

Methods: A modified nominal groups process was conducted with an international group of hemophilia experts, including persons with hemophilia as follows. Step 1: item generation for all potential outcome measures. Step 2: survey where respondents voted on the relative importance and usefulness of each item. Steps 3/4: 2-day meeting where attendees voted for items they valued, followed by open discussion and a second round of voting. Step 5: survey where respondents selected their top five items from those with >50% agreement at the meeting.

Results: The highest ranked items for the pediatric core set (% agreement) are treatment satisfaction (92.7%), joint health (83.3%), a measure of access to treatment (82.5%), a measure of treatment adherence (72.5%), and generic performance based physical function (72.1%). The highest ranked items for the adult core set (% agreement) are total bleeding events (88.1%), EuroQol five dimensions (85.4%), treatment adherence (82.1%), joint health (79.1%), and number/location of bleeds per unit time (78.6%).

Conclusion: This process generated a list of preferred outcome measures to consider for assessment in persons with hemophilia. This information now requires refinement to define optimal core sets for use in different clinical/research contexts.
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http://dx.doi.org/10.1002/rth2.12331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292657PMC
May 2020

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

Haemophilia 2020 Jul 22;26(4):685-693. Epub 2020 May 22.

Department of Medical Imaging, University of Saskatchewan and Saskatchewan Health Authority Saskatoon City Hospital, Saskatoon, SK, Canada.

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.
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http://dx.doi.org/10.1111/hae.14006DOI Listing
July 2020

Genotype-phenotype correlation in children with hereditary spherocytosis.

Br J Haematol 2020 11 20;191(3):486-496. Epub 2020 May 20.

Department of Paediatrics, Division of Haematology/Oncology, Hospital for Sick Children, Toronto, Ontario, Canada.

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.
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http://dx.doi.org/10.1111/bjh.16750DOI Listing
November 2020

IVMP+IVIG raises platelet counts faster than IVIG alone: results of a randomized, blinded trial in childhood ITP.

Blood Adv 2020 04;4(7):1492-1500

Division of Haematology/Oncology, Department of Paediatrics, Hospital for Sick Children and University of Toronto, Toronto, ON, Canada.

Children with immune thrombocytopenia (ITP) rarely suffer from life-threatening bleeds (eg, intracranial hemorrhage). In such settings, the combination of IV methylprednisolone (IVMP) with IV immune globulin (IVIG) is used to rapidly increase platelet counts (PCs). However, there are no controlled data to support using combination therapy over IVIG alone. We conducted a randomized, double-blind, placebo-controlled study to evaluate the rapidity of the PC increment and associated adverse events (AEs) between 2 regimens: A (IV placebo) and B (IVMP 30 mg/kg), both given over 1 hour, followed in both cases by IVIG (Gamunex 10%) 1 g/kg over 2-3 hours in children 1-17 years old with primary ITP and PCs <20 × 109/L in whom physicians had decided to treat with IVIG. Thirty-two children (ages: median, 8 years; range, 1.2-17.5 years) with a mean baseline PC of 9.2 × 109/L participated. Eighteen were randomized to regimen A and 14 to regimen B. By 8 hours after initiating therapy, 55% of all children had a PC ≥20 × 109/L (no group difference). By 24 hours, mean PCs were 76.9 × 109/L (B) vs 55 × 109/L (A) (P = .06; P = .035 when adjusted for intergroup differences in patient ages). No patient experienced severe bleeding/unexpected severe AEs. There were statistically fewer IVIG-related headaches in the group receiving combination therapy (P = .046). Our findings show a rapid response to IVIG with/without steroids and provide evidence to support the use of IVMP+IVIG in life-threatening situations. This trial was registered at www.clinicaltrials.gov as #NCT00376077.
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http://dx.doi.org/10.1182/bloodadvances.2019001343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160294PMC
April 2020

Hemophilia prophylaxis adherence and bleeding using a tailored, frequency-escalated approach: The Canadian Hemophilia Primary Prophylaxis Study.

Res Pract Thromb Haemost 2020 Feb 29;4(2):318-325. Epub 2020 Jan 29.

Child Health Evaluative Sciences The Hospital for Sick Children Toronto ON Canada.

Background: Standard of care for persons with severe hemophilia A includes regular replacement of factor VIII (FVIII). Prophylaxis regimens using standard half-life (SHL) FVIII concentrates, while effective, are costly and require frequent intravenous infusions.

Aim: This study evaluated the adherence of 56 boys with severe hemophilia A to tailored, frequency-escalated prophylaxis with an SHL recombinant FVIII concentrate.

Methods: We reviewed the factor infusion and bleeding logs of study subjects. Adherence to the prescribed regimen was calculated on a weekly basis, and bleeding rates were determined from self/proxy-reported bleeding logs. The primary outcome was adherence to the prescribed prophylaxis regimen.

Results: The median (range of values [ROV]) weekly adherence to prophylaxis was 85.7% (37.4%-99.8%). The median (ROV) adherent weeks on steps 1 (weekly), 2 (twice weekly), and 3 (alternate-day) were 92.9% (50%-100%), 80.3 (32%-96%), and 72.6% (14%-98%); relative to step 1, subjects were less likely to be adherent on steps 2 and 3 ( < 0.00). On step 1, our cohort had higher adherence than previously reported rates. The median (ROV) adherence to the breakthrough bleeding protocol was 47.1% (0%-100%). At any given time, bleeding risk was reduced by 15% for each 10% increase in adherence during the preceding 12 weeks (hazard ratio, 0.85; 95% confidence interval, 0.81-0.90).

Conclusion: This cohort had high rates of adherence to the prescribed prophylaxis regimen. Initiating prophylaxis with once-weekly infusions facilitated adherence to the prophylaxis regimen in this cohort of boys with severe hemophilia A started on primary prophylaxis at a very young age.
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http://dx.doi.org/10.1002/rth2.12301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040543PMC
February 2020

Bleeding assessment tools to predict von Willebrand disease: Utility of individual bleeding symptoms.

Res Pract Thromb Haemost 2020 Jan 30;4(1):92-99. Epub 2019 Oct 30.

Department of Medicine Queen's University Kingston ON Canada.

Background: Bleeding assessment is part of the diagnostic workup of von Willebrand disease (VWD). Bleeding assessment tools (BATs) have standardized obtaining this information but have been criticized because they are time consuming.

Objective: To use our legacy data to determine which questions from BATs are the strongest predictors of a VWD diagnosis.

Patients/methods: Bleeding score data from 3 different BATs were used. Patients aged <12 years were excluded. Questions on BATs relate to different bleeding symptoms, and each symptom is scored by severity. Scores for each symptom were sorted based on whether they indicated clinically significant bleeding, and nonsignificant scores were set as the reference category. Multivariable logistic regression was used to determine the symptoms that were the strongest predictors of a laboratory-confirmed VWD diagnosis.

Results: A total of 927 participants were included; 144 (16%) were patients with VWD, and 783 (84%) were healthy controls. The top 3 symptoms for which a clinically significant positive response increased the likelihood of VWD were hemarthrosis (odds ratio [OR], 19.2; 95% confidence interval [CI], 3.7-100.4), postsurgical bleeding (OR, 15.2; 95% CI, 5.9-38.9), and menorrhagia (OR, 10.3; 95% CI, 4.9-21.9). With each increase in number of bleeding symptom categories with clinically significant scores, subjects had a stepwise increase in odds of a VWD diagnosis.

Conclusions: Our results suggest that most of the bleeding symptoms on BATs are significant predictors of VWD, and there is value in assessing multiple bleeding symptoms when eliciting a bleeding history. Certain bleeding symptoms are more useful predictors than others. Future BAT revisions may consider adding a relative weighting to each symptom.
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http://dx.doi.org/10.1002/rth2.12256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971303PMC
January 2020

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.

Haemophilia 2020 Jan 22;26(1):73-78. Epub 2019 Dec 22.

Child Health Evaluative Sciences, The Hospital for Sick Children Research Institute, Toronto, ON.

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.
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http://dx.doi.org/10.1111/hae.13905DOI Listing
January 2020

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

Blood 2019 09 26;134(11):880-891. Epub 2019 Jul 26.

Department of Pathology and Molecular Medicine and.

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 , , and 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- and non- variants that modify FVIII PK in pediatric hemophilia A patients.
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http://dx.doi.org/10.1182/blood.2019000190DOI Listing
September 2019

Comparative pharmacokinetics of two extended half-life FVIII concentrates (Eloctate and Adynovate) in adolescents with hemophilia A: Is there a difference?

J Thromb Haemost 2019 07 2;17(7):1085-1096. Epub 2019 Jun 2.

Division of Haematology/Oncology, Department of Paediatrics and Child Health Evaluative Sciences, Research Institute, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.

Essentials The PK parameters of Eloctate vs Adynovate were compared using one-stage and chromogenic assays in 25 boys (12-18 years). The FVIII levels were taken at 3, 24, 48, and 72 hours following a dose of either FVIII; levels analyzed by WAPPS PK program. The PK profiles (half-life, clearance, and time to 5%, 3%, and 1%) were not statistically different for the two EHL FVIIIs. The significant interpatient variability in PK is mainly related to VWF levels (and blood group).

Background: A head-to-head comparison of the pharmokinetcs (PK) of extended half-life (EHL) factor VIII (FVIII) concentrates in the same subjects has not been reported. Recently, boys (ages 12-18 years) with hemophilia A in Canada were required to switch from Eloctate to Adynovate.

Objectives: Compare the PK profiles of Eloctate vs Adynovate in the same boys.

Methods: Boys switching from Eloctate to Adynovate prophylaxis had FVIII levels sampled at 3, 24, 48, and 72 hours following a regular prophylactic infusion of Eloctate and then 1-3 months later, of Adynovate. Testing was done by one-stage assay (OSA) and chromogenic assay (CA). The PK parameters were determined with the Web Accessible Population Pharmacokinetic Service (WAPPS)-Hemo PK tool.

Results: Twenty-five boys (mean age 15.3 years; range: 12.1-18.4; 9 O blood group) underwent switching. Mean (range) terminal half-lives with the OSA were 16.1 hours (10.4 to 23.4; Eloctate) and 16.7 hours (11.0 to 23.6; Adynovate) (NS). With the CA, these were 18.0 hours (12.0 to 25.5; Eloctate) and 16.0 hours (10.3 to 22.9; Adynovate) (P = 0.001). There were no significant differences between the two EHL-FVIIIs in clearance, area under the concentration vs time curve (AUC), Vss, or time for FVIII levels to drop to 5%, 3%, and 1%. At the 72-h time point, mean observed FVIII levels following a mean dose of 39.3 IU/kg of Eloctate were 4.4% (OSA) and 4.4% (CA). For Adynovate, these were 5.1% (OSA) and 5.3% (CA) following similar doses. There was considerable interpatient variation in PK, mainly explained by differences in blood group/von Willebrand factor (VWF) levels.

Conclusions: Eloctate and Adynovate have almost identical PK parameters. When switching from one to another no prophylaxis regimen change is needed.
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http://dx.doi.org/10.1111/jth.14469DOI Listing
July 2019

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

Pediatr Blood Cancer 2019 06 22;66(6):e27709. Epub 2019 Mar 22.

Department of Pediatrics, Division of Hematology/Oncology, Children's Hospital of Eastern Ontario, Ottawa, Canada.

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.
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http://dx.doi.org/10.1002/pbc.27709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643750PMC
June 2019

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

Haematologica 2019 11 7;104(11):2283-2291. Epub 2019 Mar 7.

Amgen Inc., Thousand Oaks, CA, USA.

Children with immune thrombocytopenia for ≥6 months completing a romiplostim study received weekly subcutaneous romiplostim (1-10 μg/kg targeting platelet counts of 50-200×10/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 28×10/L (range: 2-458×10/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 >50×10/L, starting at week 2. Nearly all patients (94%) had ≥1 platelet response (≥50×10/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 ≥50×10/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 >200×10/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 ).
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http://dx.doi.org/10.3324/haematol.2018.202283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821612PMC
November 2019

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

Br J Haematol 2019 04 27;185(1):102-106. Epub 2018 Dec 27.

Department of Pediatrics, Division of Hematology/Oncology, Weill Cornell Medicine, New York, NY, USA.

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.
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http://dx.doi.org/10.1111/bjh.15732DOI Listing
April 2019

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

J Pediatr Hematol Oncol 2018 11;40(8):e537-e543

Division of Pediatric Medicine.

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.
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http://dx.doi.org/10.1097/MPH.0000000000001247DOI Listing
November 2018

Pharmacokinetic Studies of Factor VIII in Chinese Boys with Severe Hemophilia A: A Single-Center Study.

Chin Med J (Engl) 2018 Aug;131(15):1780-1785

Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics, Ministry of Education, Beijing 100045, China.

Background: Although much attention has been paid to the pharmacokinetics (PKs) of different factor VIII (FVIII) concentrates in persons with hemophilia A (HA), limited information is available in young boys with severe HA. In this study, we aimed to assess the PK parameters of FVIII products in boys with severe HA in China.

Methods: A total of 36 boys (plasma-derived [pd]-FVIII, n = 15; recombinant [r] FVIII, n = 21) were enrolled between January 2015 and May 2016 in Beijing Children's Hospital. PK characteristics of FVIII products were studied according to a reduced 4-sampling time point design (1 h, 9 h, 24 h, and 48 h postinfusion).

Results: The mean FVIII half-life (t) was 10.99 ± 3.45 h (range 5.52-20.02 h), the mean in vivo recovery (IVR) was 2.01 ± 0.42 IU/dl per IU/kg (range 1.24-3.02 IU/dl per IU/kg) and mean clearance (CL) of FVIII is 4.34 ± 1.58 ml·kg·h (range 2.29-7.90 ml·kg·h). We also analyzed the influence of several parameters that potentially modulate FVIII PK. The age was closely associated with FVIII half-life (R = 0.32, P < 0.01). The tof FVIII increased by 0.59 h per year. Besides age, von Willebrand factor antigen (VWF:Ag) also was associated with FVIII half-life (R = 0.52, P < 0.01). Patients with blood Group O had a shorter FVIII half-life than patients with non-O blood group (9.40 ± 0.68 h vs. 12.3 ± 0.79 h, t = 2.70, P = 0.01). The FVIII IVR correlated with age (R = 0.21, P < 0.01) and VWF:Ag level (R = 0.28, P < 0.01). CL rates were faster in young patients and in those with low-VWF:Ag levels. CL rates of FVIII are higher in blood Group O versus non-blood Group O persons (5.02 ± 0.38 vs. 4.00 ± 0.32 ml·kg·h, t = 2.53, P = 0.02).

Conclusions: Chinese boys with severe HA have similar PK values to other ethnic groups and large differences in FVIII PK between individual patients. Age, blood group, and VWF:Ag levels are important determining factors for FVIII CL.
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http://dx.doi.org/10.4103/0366-6999.233604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071451PMC
August 2018

Tailored frequency-escalated primary prophylaxis for severe haemophilia A: results of the 16-year Canadian Hemophilia Prophylaxis Study longitudinal cohort.

Lancet Haematol 2018 Jun 3;5(6):e252-e260. Epub 2018 May 3.

Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Child Health Evaluative Sciences, The Hospital for Sick Children Research Institute, Toronto, ON, Canada; Department of Pediatrics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.

Background: Severe haemophilia A has high morbidity, and treatment, while effective, is very expensive. We report the 16-year follow-up of the Canadian Hemophilia Prophylaxis Study, which examined the effectiveness of tailored frequency-escalated primary prophylaxis with a focus on health outcomes within the domains of body structures and functions, and activities and participation (according to the WHO International Classification of Functioning, Disability and Health [WHO-ICF] framework) and a view to reducing consumption of costly clotting factor, which accounts for more than 90% of the cost of care of severe haemophilia.

Methods: In this longitudinal study, boys with severe haemophilia A from 12 Canadian centres were enrolled at age 1·0-2·5 years. They were treated with standard half-life recombinant factor VIII (SHL-rFVIII), beginning as once-weekly prophylaxis with 50 IU/kg and escalating in frequency (with accompanying dose adjustments) in response to breakthrough bleeding as determined by the protocol. The primary endpoint for this analysis was joint health, as measured by the modified Colorado Child Physical Examination Scores (CCPES) at study end. All analyses were done by intention to treat. The trial is complete, and is registered with ClinicalTrials.gov, number NCT01085344.

Findings: Between June 26, 1997, and Jan 30, 2007, 56 boys were enrolled. They were followed for a median of 10·2 years (to a maximum of 16·1 years). Median rFVIII usage was about 3600 IU/kg per year. The median end-of-study CCPES physical examination score was 1 (IQR 1-3; range 0-12) for the left ankle and 1 (1-2; 0-12) for the right ankle, with all other joints having a median score of 0. No treatment-related safety events occurred over the duration of the study, including central venous catheter infections. The median annualised index joint bleeding rate was 0·95 per year (IQR 0·44-1·35; range 0·00-13·43), but 17 (30%) patients had protocol-defined unacceptable breakthrough bleeding at some point during the study.

Interpretation: Tailored frequency-escalated prophylaxis leads to very little arthropathy and very good health outcomes within the WHO-ICF domains, and only uses a moderate amount of expensive clotting factor as compared with standard prophylaxis protocols. Some sequelae of bleeding were observed in our cohort, and future studies should consider a more stringent protocol of escalation.

Funding: This study was initially funded by grants from the Medical Research Council of Canada/Pharmaceutical Manufacturers Association of Canada Partnership Fund and the Bayer/Canadian Blood Services/Hema-Quebec Partnership Fund. Subsequent renewals were funded by Bayer.
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http://dx.doi.org/10.1016/S2352-3026(18)30048-6DOI Listing
June 2018

Identifying Children with HEreditary Coagulation disorders (iCHEC): a protocol for a prospective cohort study.

BMJ Open 2018 05 3;8(5):e020686. Epub 2018 May 3.

Pediatric Hematology, Academic Medical Center - Emma Children's Hospital, Amsterdam, The Netherlands.

Introduction: It is challenging to obtain a reliable bleeding history in children who are referred for a suspected inherited bleeding disorder. Bleeding symptoms may be subtle as children face fewer haemostatic challenges compared with adults. In order to standardise bleeding histories, questionnaires have been developed, called bleeding assessment tools (BATs). Although it has been shown that high bleeding scores are associated with the presence of a mucocutaneous bleeding disorder, these BATs lack sensitivity, efficiency and flexibility in the paediatric setting. We developed a new BAT (the iCHEC (identifying Children with HEreditary Coagulation disorders) BAT) to improve on these characteristics. We aim to evaluate the diagnostic accuracy of the iCHEC BAT as a screening tool for children who are suspected for having a bleeding disorder.

Methods And Analysis: This is a prospective cohort study. Children (age 0-18 years) suspected for a bleeding disorder who present at tertiary haematology clinics, and/or their parents/guardians, will be asked to complete the iCHEC BAT. Sensitivity was increased by inclusion of paediatric-specific bleeding symptoms and novel qualitative questions per bleeding symptom. Efficiency was improved by developing a self-administered (online) version of the questionnaire. Flexibility for changes in the bleeding phenotype of developing children was improved by including questions that define when the bleeding symptoms occurred in the past. The diagnostic accuracy of the specific bleeding items will be evaluated by receiver operator characteristic curves, using classification based on the results from laboratory assessment as the reference standard. Analysis of the discriminative power of individual bleeding symptoms will be assessed.

Ethics And Dissemination: The study has been approved by the medical ethics committees of all participating centres in the Netherlands, Canada and the UK. All paediatric subjects and/or their parents/guardians will provide written informed consent. Study results will be submitted for publication in peer-reviewed journals.
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http://dx.doi.org/10.1136/bmjopen-2017-020686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5942417PMC
May 2018

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

J Pediatr 2018 02 1;193:183-189.e2. Epub 2017 Dec 1.

Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada; Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada; Departments of Laboratory Medicine & Pathobiology and Biochemistry, University of Toronto, Toronto, Ontario, Canada. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jpeds.2017.09.082DOI Listing
February 2018

Glanzmann thrombasthenia platelets compete with transfused platelets, reducing the haemostatic impact of platelet transfusions.

Br J Haematol 2018 05 3;181(3):410-413. Epub 2017 May 3.

Division of Haematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.

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http://dx.doi.org/10.1111/bjh.14623DOI Listing
May 2018

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

Pediatr Blood Cancer 2017 Oct 28;64(10). Epub 2017 Apr 28.

Queen's University, Kingston, Canada.

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.
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http://dx.doi.org/10.1002/pbc.26588DOI Listing
October 2017
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