Researchers assessed the manner in which physicochemical properties affect severity and protein functionality in 5 human factor VIII (FVIII) variants that cause hemophilia A and published their results in Computer Methods and Programs in Biomedicine.

They employed the Delphi web server tool to determine that a range of measures regarding the nature and position of the variants are relevant to physicochemical changes in the variants and therefore the ultimate severity of hemophilia A.

“Regular prediction tools do not include structural elements and their physiological significance, which hampers our ability to functionally link variants to disease phenotype, opening an ample field for investigation,” the authors said. “The present study aims to elucidate how physicochemical changes generated by substitutions in different protein domains relate to [hemophilia A], and which of these features are more consequential to protein function and its impact on [hemophilia A] phenotype.”

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A total of 71 variants of FVIII, obtained from patients with various hemophilia phenotypes (mild, moderate, and severe) were analyzed through an in silico technology.

Physicochemical aspects such as electrostatic potential, disulfide disruptions, hydrophobicity, solvent-accessible/excluded surface areas, and substitution indexes were analyzed using homology modeling. The team then applied hierarchical clustering analysis and principal component analysis to investigate each aspect’s contribution to functional changes in the variants.

Every property evaluated was shown to have an impact on determining disease severity, which suggests the possibility of developing more precise tools to predict phenotypic outcomes in the near future. The research team’s bioinformatics approach offers new insights into hemophilia A variants and potentially other Mendelian disorders, and could eventually also be implemented in genetic counseling to help guide clinical decision-making.


Meireles MR, Stelmach LH, Bandinelli E, et al. Unveiling the influence of factor VIII physicochemical properties on hemophilia A phenotype through an in silico methodology. Comput Methods Programs Biomed. Published online March 25, 2022. doi:10.1016/j.cmpb.2022.106768