Genotype-Phenotype relationships in Hemophilia. Genetic basis of inhibitor development, immune-tolerance induction response and discordant FVIII:C assays.

In hemophilia A and B (HA and HB), the hemophilic phenotype is mainly determined by the F8 and F9 genotype, respectively, with severe, moderate and mild forms of expression, depending on the activity of the clotting factor. However, there are other modifying factors of the clinical-biochemical phenotype, depending on ethnicity and geographic region that more severely condition the quality of life of people with hemophilia. In this scenario, predisposing genetic factors are investigated for the development of replacement therapy inhibitor antibody in patients with Hemophilia in more than 600 Argentine families, through the characterization and analysis of causal pathogenic variants of HA and HB, and other modifying genetic factors of the phenotype (estimation of the gene admix and individual ancestry) accompanied by a statistical case / control study in patients stratified by causal variant, to locally estimate the risk factors for inhibitor in our population. The first exploratory study of the whole exome (WES) will be carried out in patients with HA and inhibitors and discordant immunological tolerance induction (ITI) results.

Additionally, many patients with mild HA have a discrepancy between FVIII: C levels determined by one-stage and two-stage biochemical assays; likewise, clinical manifestations and the laboratory phenotype are frequently confused with Type 2N von Willebrand disease, these data could lead to a misclassification of the severity and diagnosis of HA, for this the molecular basis of the discrepancy is explored and performed the differential diagnosis of other coagulopathies.