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.
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.
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).
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 (r = 0.56, P = .01), and a strong correlation between the CHO‐KLAT v3.0 parent‐proxy and PedsQL‐Core (r = .79, P = .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.
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.
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.
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.
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; P< .0001) and a moderate correlation for parents of boys aged <7 years (r = 0.64; P= .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; P= .04).
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.
Introduction
Diagnosing hemophilia B (HB) carrier status is important to manage bleeding in carriers and to prevent bleeding in potential offspring. Without a family history of hemophilia, diagnosing ...HB carrier status is challenging. Genetic testing is the gold‐standard, however it is reserved for individuals with a high suspicion of carrier status.
Aims
To describe the distribution of activated partial thromboplastin time (aPTT) and factor IX coagulant (FIX:C) levels in HB carriers and assess the ratio of FIX:C to other Vitamin K dependent factors (FII:C, FVII:C, FX:C) as an indicator of HB carrier status.
Methods
In this retrospective, single‐centre cohort study, subjects were included if they were obligate or genetically proven HB carriers. Distributions of aPTT and FIX:C were described and the relationship between FIX:C levels in carriers and severity of familial HB was analysed. Ratios of FIX:C to FII:C, FVII:C, FX:C were calculated.
Results
Seventy‐two female HB carriers (median age: 34 years; IQR 24–43) were included. Median aPTT and FIX:C levels were 33.0 s IQR 30.0–37.0 and 57 IU/dL IQR 43–74. Fifteen carriers (21%) had mild HB (FIX:C levels of 10–40 IU/dL). FIX:C levels trended higher in carriers of mild HB versus carriers of moderate/severe HB. In six carriers, the median ratio of FIX:C to other Vitamin K dependent factors was 0.44, with 92% of ratios being ≤ 0.75.
Conclusion
aPTT and FIX:C levels were unreliable in diagnosing HB carrier status. A low ratio of FIX:C to other Vitamin K dependent factors may be a useful marker of HB carrier status.
Introduction
The COVID‐19 pandemic has resulted in lifestyle changes for children. The aim of this study was to evaluate the impact of the pandemic on weight/BMI in children with severe bleeding ...disorders.
Methods
We conducted a retrospective review of patients age 3–18 years with severe bleeding disorders on prophylactic therapy treated at SickKids Hospital (Toronto, Canada) between February 01, 2018 and March 31, 2021. We evaluated the following pre‐ and post‐COVID variables: weight (kg), weight percentile, BMI (kg/m2), BMI percentile, HJHS score, and prophylactic dosing (units/kg).
Results
One hundred and four patients were included in the final analysis. Diagnoses were as follows: haemophilia A (n = 92; 70.8%), haemophilia B (n = 17; 13.1%), type 3 von Willebrand disease (n = 11; 8.5%), the remainder were diagnosed with rare factor deficiencies. Median interval time from pre‐COVID measurements to latest follow‐up was 12.4 months (IQR 10.32–14.52 months) during which there was a statistically significant increase in median weight percentile +5.75 centiles (from 63rdcentile to 68.75thcentile). There was a statistically significant increase in mean BMI of +1.03 kg/m2(P = < .001) while median BMI percentile increased +8.82 centiles (from 53.9thcentile to 62.72ndcentile) and mean BMI percentile increased 3.42 centiles (from 57.5 centile to 60.9 centile). The group that gained the most weight centiles, BMI and BMI centiles were 5–14 years old.
Conclusion
There was a trend to weight gain over the study period. More long‐term data is required to evaluate the impact of this increase in weight and BMI on children with bleeding disorders.
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.
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.
Persons with mild hemophilia A (HA) may use intranasal desmopressin prior to sports participation. Desmopressin is expensive and can cause vomiting, headache, palpitation, and occasionally seizures. ...Our group has previously documented a 2.3-fold increase in factor VIII activity (FVIII:C) in adolescents with mild HA after moderate-intensity aerobic exercise. Herein, we report principal findings of a randomized trial of intranasal desmopressin vs a standardized, moderate-intensity aerobic exercise regimen in adolescents with mild HA. Our primary objective was to compare the change in FVIII:C associated with these 2 interventions. We also examined changes in hemostatic parameters arising from their sequential administration. The study was conducted simultaneously at the Hospital for Sick Children, Canada, and Nationwide Children's Hospital, USA. Thirty-two eligible male adolescents (mean age ± standard deviation: 16.1 ± 2.6 years) with mild HA (mean baseline FVIII:C: 27.9% ± 18.4%) were randomized to 1 of 4 study arms (desmopressin followed by exercise, desmopressin alone, exercise followed by desmopressin, and exercise alone). Blood work was obtained at baseline and at 3 subsequent time-points. Participants randomized to exercise cycled on an ergometer for approximately 12 minutes, with the final 3 minutes at 85% of their predicted maximum heart rate. Standard weight-based dosing of desmopressin was used. Mean immediate increase in FVIII:C was 1.7-fold with exercise compared with 1.9-fold with desmopressin (noninferiority, P = .04). Exercise-induced improvement in hemostatic parameters including FVIII:C was brief compared with more sustained improvements seen with desmopressin. More than 60% of participants randomized to receive both exercise and desmopressin achieved normal (>50%) FVIII:C, 75 and 135 minutes into the study protocol.
Introduction
The paediatric Haemophilia Activities List (pedHAL) was developed to measure activities and participation in children and youth with haemophilia. Results from international studies ...provide an opportunity to determine which items are universally important.
Aim
The aim of this study was to determine which items of the pedHAL are redundant to construct a shorter version of the pedHAL.
Methods
This study is a cross‐sectional multicentre secondary analysis on pooled data of published studies using the pedHAL (7 domains, 53 items, optimum score: 100) in children with haemophilia A/B aged 4–18 years. To identify redundant items, the following aspects were evaluated: floor and ceiling effects, proportions of missing and ‘not applicable’ responses, inter‐item correlations, component loadings in an exploratory factor analysis, internal consistency and item‐total correlations.
Results
Data on 315 patients with haemophilia from 6 studies were evaluated. Median age was 12.2 years) (range 4.0–18.0), 87.3% had severe haemophilia and 80.3% received prophylaxis. Median (IQR) pedHAL sum score was 96.7 (88.0–100). After a stepwise procedure, 31 items were removed, resulting in a pedHALshort of 22 items, representing all original 7 domains. Most remaining items belonged to the domains ‘sitting/kneeling/standing’ and ‘functions of the legs’. The pedHALshort sum score was similar to the original pedHAL sum score, with small differences in 5 domains.
Conclusion
This clinimetric study resulted in >50% reduction of the length of the pedHAL. The 22‐item pedHALshort reduces patient burden and is expected to capture the information on activities and participation. The pedHALshort needs validation in other populations.
Introduction
Clearance of infused factor VIII (FVIII) varies approximately 2-fold between persons with severe hemophilia A. This results in significant interpatient differences in factor levels ...following an infusion of FVIII and contributes to potentially significant differences in protection against spontaneous musculoskeletal bleeding in patients on fixed dose prophylaxis regimens.
Aim
The aim of this study is to compare two PK protocols: 1) a 6-point PK protocol with a 72 hour washout; and 2) a 2-point, one clinic visit PK protocol with no washout using the following pharmacokinetic (PK) parameters: clearance (Cl) and time to FVIII:C of 1% above baseline (tt1%) in persons with severe hemophilia A.
Methods
Inhibitor negative males with severe hemophilia A (FVIII<2%) receiving a standard half-life recombinant FVIII (rFVIII) concentrate (ADVATE®) were consented into a research ethics board approved study. In the 6-point PK protocol, participants were infused with approximately 50 IU/kg rFVIII after a minimum washout of 72 hours and FVIII levels were measured pre-infusion and at 1, 3, 9, 24 and 48 hours post-infusion. The 2-point PK protocol consisted of a blood sample taken in clinic approximately 24 hours after the participant infused their prophylactic dose at home (15-50 IU/kg), followed by a 25 IU/kg dose given in clinic and a 3 hour post-infusion sample. Frozen plasma samples were sent to a central laboratory in Kingston, Ontario where one-stage and chromogenic FVIII assays were performed. PK parameters (Cl and tt1%) were estimated using the 2 compartmental models of PK programs Phoenix WinNonlin 7.0 (Certara USA Inc.) and myPKFiT version 3.0 (Baxalta US Inc). Intra-class correlations (ICCs) were used to compare the PK parameters derived from the two PK protocols using WinNonlin and myPKFiT.
Results
28 males (median age: 12 years, range: 2-69 years) participated. The frequency distribution of clearance and the median half-life (t1/2) generated using myPKFiT is presented in Figure 1. There was a substantial to almost perfect agreement observed when comparing the PK parameters derived from the 6-point PK protocol with washout using the two PK programs (Table 1). There was a moderate to almost perfect agreement observed when comparing the PK parameters derived from the 6-point PK protocol with washout to the 2-point PK protocol with no washout using the myPKFiT program (Table 2).
Conclusion
The 2-point, one clinic visit, PK protocol (24 and 3 hrs) with no washout offers a convenient and practical approach to generating clinically relevant PK parameters in persons with severe hemophilia A. It can provide information relevant to selection of personalized prophylaxis regimens that aim to reduce to a minimum/eliminate spontaneous joint bleeding.
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Blanchette:Shire: Other: Investigator-initiated research funding; Novo Nordisk: Other: Speaker's fees; Shire: Other: Speaker's fees; Bayer: Other: speaker's fees; Bioverativ: Other: Investigator-initiated research funding; Pfizer: Other: Speaker's fees. Jackson:Pfizer: Honoraria; Roche: Honoraria; Bayer: Honoraria; Novo Nordisk: Honoraria; Shire: Honoraria; Bioverativ: Other: Investigator initiated grant funding. Carcao:Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; LFB: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL-Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Khoo:Shire: Research Funding; Biogen Idec: Research Funding. Blatny:Shire, Pfizer, Roche: Consultancy, Speakers Bureau.
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