J I Loomans1, A S van Velzen1, C L Eckhardt1,2, M Peters1, A Mäkipernaa3, M Holmstrom4, P P Brons5, N Dors6, S Haya7, J Voorberg8, J G van der Bom9,10, K Fijnvandraat1,8. 1. Department of Pediatric Hematology, Emma Children's Hospital, Amsterdam, the Netherlands. 2. Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands. 3. Children's Hospital and Hematology, Comprehensive Cancer Center, Helsinki University Hospital, University of Helsinki, Helsinki, Finland. 4. Coagulation Unit, Hematology Center, Karolinska University Hospital and Department of Medicine Karolinska Inisitutet, Stockholm, Sweden. 5. Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands. 6. Catharina Hospital, Eindhoven, the Netherlands. 7. University Hospital la Fe, Valencia, Spain. 8. Department of Plasma Proteins, Sanquin-AMC Landsteiner Laboratory, Amsterdam, the Netherlands. 9. Leiden University Hospital, Leiden, the Netherlands. 10. Sanquin Research, Leiden, the Netherlands.
Abstract
Essentials Factor VIII levels vary in mild and moderate hemophilia A (MHA) patients with the same mutation. We aimed to estimate the variation and determinants of factor VIII levels among MHA patients. Age and genotype explain 59% of the observed inter-individual variation in factor VIII levels. Intra-individual variation accounted for 45% of the variation in the three largest mutation groups. SUMMARY: Background The bleeding phenotype in patients with mild/moderate hemophilia A (MHA) is inversely associated with the residual plasma concentration of factor VIII (FVIII:C). Within a group of patients with the same F8 missense mutation, baseline FVIII:C may vary, because, in healthy individuals, von Willebrand factor (VWF) levels, ABO blood group and age are also known to influence baseline FVIII:C. Our understanding of the pathophysiologic process of the causative genetic event leading to reduced baseline FVIII:C in MHA patients is still limited. Objectives To estimate the variation and determinants of baseline FVIII:C among MHA patients with the same F8 missense mutation. Methods Three hundred and forty-six patients carrying mutations that were present in at least 10 patients in the cohort were selected from the INSIGHT and the RISE studies, which are cohort studies including data of 3534 MHA patients from Europe, Canada, and Australia. Baseline FVIII:C was measured with a one-stage clotting assay. We used Levene's test, univariate and multivariate linear regression, and mixed-model analyses. Results For 59% of patients, the observed variation in baseline FVIII:C was explained by age and genotype. Compared to FVIII:C in patients with Arg612Cys, FVIII:C was significantly different in patients with eight other F8 missense mutations. Intra-individual variation explained 45% of the observed variance in baseline FVIII:C among patients with the same mutation. Conclusion Our results indicate that baseline FVIII:C levels are not exclusively determined by F8 genotype in MHA patients. Insights into other factors may provide potential novel targets for the treatment of MHA.
Essentials Factor VIII levels vary in mild and moderate hemophilia A (MHA) patients with the same mutation. We aimed to estimate the variation and determinants of factor VIII levels among MHApatients. Age and genotype explain 59% of the observed inter-individual variation in factor VIII levels. Intra-individual variation accounted for 45% of the variation in the three largest mutation groups. SUMMARY: Background The bleeding phenotype in patients with mild/moderate hemophilia A (MHA) is inversely associated with the residual plasma concentration of factor VIII (FVIII:C). Within a group of patients with the same F8 missense mutation, baseline FVIII:C may vary, because, in healthy individuals, von Willebrand factor (VWF) levels, ABO blood group and age are also known to influence baseline FVIII:C. Our understanding of the pathophysiologic process of the causative genetic event leading to reduced baseline FVIII:C in MHApatients is still limited. Objectives To estimate the variation and determinants of baseline FVIII:C among MHApatients with the same F8 missense mutation. Methods Three hundred and forty-six patients carrying mutations that were present in at least 10 patients in the cohort were selected from the INSIGHT and the RISE studies, which are cohort studies including data of 3534 MHApatients from Europe, Canada, and Australia. Baseline FVIII:C was measured with a one-stage clotting assay. We used Levene's test, univariate and multivariate linear regression, and mixed-model analyses. Results For 59% of patients, the observed variation in baseline FVIII:C was explained by age and genotype. Compared to FVIII:C in patients with Arg612Cys, FVIII:C was significantly different in patients with eight other F8 missense mutations. Intra-individual variation explained 45% of the observed variance in baseline FVIII:C among patients with the same mutation. Conclusion Our results indicate that baseline FVIII:C levels are not exclusively determined by F8 genotype in MHApatients. Insights into other factors may provide potential novel targets for the treatment of MHA.
Authors: Ángel Bernardo; Alberto Caro; Daniel Martínez-Carballeira; José Ramón Corte; Sonia Vázquez; Carmen Palomo-Antequera; Alfredo Andreu; Álvaro Fernández-Pardo; Julia Oto; Laura Gutiérrez; Inmaculada Soto; Pilar Medina Journal: J Clin Med Date: 2022-06-10 Impact factor: 4.964
Authors: Janneke I Loomans; Marieke J H A Kruip; Manuel Carcao; Shannon Jackson; Alice S van Velzen; Marjolein Peters; Elena Santagostino; Helen Platokouki; Erik Beckers; Jan Voorberg; Johanna G van der Bom; Karin Fijnvandraat Journal: Haematologica Date: 2018-01-05 Impact factor: 9.941
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