Correlation between phenotype and genotype in a large unselected cohort of children with severe hemophilia A

Carção, Manuel; Berg, H. M. Van Den; Ljung, Rolf; Mancuso, Maria Elisa

doi:10.1182/blood-2012-11-469403

Cited by 69 publications

(82 citation statements)

References 23 publications

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“… Defined by intron 22 and intron 1 inversions, nonsense mutations, large deletions, small deletions/insertions outside poly‐A runs, or splice‐site mutations involving conserved nucleotides …”

Section: Resultsmentioning

confidence: 99%

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

Dover

Blanchette

Wrathall

et al. 2020

Research and Practice in Thrombosis and Haemostasis

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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 (P < 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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Section: Resultsmentioning

confidence: 99%

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

Dover

Blanchette

Wrathall

et al. 2020

Research and Practice in Thrombosis and Haemostasis

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“…[1][2][3][4][5] Determination of the causative genetic variant in families affected by hemophilia is important for use in reproductive planning, for use in pregnancy and neonatal management, and also to inform risks of neutralizing antibody (inhibitor) formation and bleeding severity. [6][7][8][9][10][11][12] Therapies targeted to specific mutations have been studied and are likely to become more common in the future. 13 In 2012, 2 separate surveys, 1 distributed to hemophilia providers through the American Thrombosis Hemostasis Network (ATHN) and the other distributed to the patient community through the National Hemophilia Foundation, found that only ;20% of the hemophilia patients in the United States had had their genotype determined.…”

Section: Introductionmentioning

confidence: 99%

Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative

et al. 2017

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• MLOF used an innovative approach to genotype 3000 hemophilia patients identifying likely causative variants in 98.4% of patients.• Hemophilia genotyping should include structural variation, F8 inversions (for hemophilia A), and consideration of gene-wide approaches.Hemophilia A and B are rare, X-linked bleeding disorders. My Life, Our Future (MLOF) is a collaborative project established to genotype and study hemophilia. Patients were enrolled at US hemophilia treatment centers (HTCs). Genotyping was performed centrally using nextgeneration sequencing (NGS) with an approach that detected common F8 gene inversions simultaneously with F8 and F9 gene sequencing followed by confirmation using standard genotyping methods. Sixty-nine HTCs enrolled the first 3000 patients in under 3 years.Clinically reportable DNA variants were detected in 98.1% (2357/2401) of hemophilia A and 99.3% (595/599) of hemophilia B patients. Of the 924 unique variants found, 285 were novel.Predicted gene-disrupting variants were common in severe disease; missense variants predominated in mild-moderate disease. Novel DNA variants accounted for ;30% of variants found and were detected continuously throughout the project, indicating that additional variation likely remains undiscovered. The NGS approach detected .1 reportable variants in 36 patients (10 females), a finding with potential clinical implications. NGS also detected incidental variants unlikely to cause disease, including 11 variants previously reported in hemophilia. Although these genes are thought to be conserved, our findings support caution in interpretation of new variants. In summary, MLOF has contributed significantly toward variant annotation in the F8 and F9 genes. In the near future, investigators will be able to access MLOF data and repository samples for research to advance our understanding of hemophilia.

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“…Hemophilia A is an X‐chromosome‐linked coagulation disorder that primarily affects males, and occurs in approximately 1 per 10,000 live births . It is caused by mutations and/or deletions in the F8 gene, resulting in a deficiency of factor VIII (FVIII) activity . Severe hemophilia A is defined as a coagulation activity of FVIII in plasma (FVIII:C) level <1% (<1 IU/dL), and individuals with this severe form of the disease experience recurrent spontaneous bleeding, primarily into the muscles and joints, leading to joint damage and severe disability .…”

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confidence: 99%

Population pharmacokinetics of recombinant factor VIII Fc fusion protein

Nestorov

Neelakantan

Ludden³

et al. 2014

Clinical Pharm in Drug Dev

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Population pharmacokinetics (PK) of FVIII activity-time profiles following recombinant factor VIII Fc fusion protein (rFVIIIFc) and recombinant factor VIII (rFVIII) dosing were evaluated in previously treated patients with severe hemophilia A (from two clinical trials). Potential covariates that may be determinants of variability in FVIII activity were identified. A 2-compartment model adequately described the PK of both compounds. von Willebrand Factor (VWF) concentration was the major covariate for rFVIIIFc clearance, reflecting its protective role in FVIII activity clearance. The effect of body weight and hematocrit on the central volume of distribution of rFVIIIFc was minor. The results of these analyses confirmed that rFVIIIFc clearance (1.65 dL/h) is much lower than that of rFVIII (2.53 dL/h), while the steady state volumes of distribution were similar. The strong positive correlations between the PK parameters of rFVIIIFc and rFVIII suggest that individuals who have high time-related PK characteristics with rFVIII are likely to have comparable characteristics with rFVIIIFc. Steady-state activity-time profiles for selected rFVIIIFc dosing regimens were simulated accounting for uncertainty in model parameters. These population PK analyses and simulations provide a comprehensive characterization of the PK of rFVIIIFc and rFVIII and may be useful for designing dosing regimens.

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Correlation between phenotype and genotype in a large unselected cohort of children with severe hemophilia A

Cited by 69 publications

References 23 publications

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

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

Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative

Population pharmacokinetics of recombinant factor VIII Fc fusion protein

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