Research Article: Risk stratification integrating genetic data for factor VIII inhibitor development in patients with severe hemophilia A

Date Published: June 13, 2019

Publisher: Public Library of Science

Author(s): Delphine Bachelet, Thilo Albert, Cyprien Mbogning, Signe Hässler, Yuan Zhang, Stephan Schultze-Strasser, Yohann Repessé, Julie Rayes, Anna Pavlova, Behnaz Pezeshkpoor, Kerstin Liphardt, Julie E. Davidson, Agnès Hincelin-Méry, Pierre Dönnes, Sébastien Lacroix-Desmazes, Christoph Königs, Johannes Oldenburg, Philippe Broët, Pablo Garcia de Frutos.


Replacement therapy in severe hemophilia A leads to factor VIII (FVIII) inhibitors in 30% of patients. Factor VIII gene (F8) mutation type, a family history of inhibitors, ethnicity and intensity of treatment are established risk factors, and were included in two published prediction tools based on regression models. Recently investigated immune regulatory genes could also play a part in immunogenicity. Our objective is to identify bio-clinical and genetic markers for FVIII inhibitor development, taking into account potential genetic high order interactions. The study population consisted of 593 and 79 patients with hemophilia A from centers in Bonn and Frankfurt respectively. Data was collected in the European ABIRISK tranSMART database. A subset of 125 severely affected patients from Bonn with reliable information on first treatment was selected as eligible for risk stratification using a hybrid tree-based regression model (GPLTR). In the eligible subset, 58 (46%) patients developed FVIII inhibitors. Among them, 49 (84%) were “high risk” F8 mutation type. 19 (33%) had a family history of inhibitors. The GPLTR model, taking into account F8 mutation risk, family history of inhibitors and product type, distinguishes two groups of patients: a high-risk group for immunogenicity, including patients with positive HLA-DRB1*15 and genotype G/A and A/A for IL-10 rs1800896, and a low-risk group of patients with negative HLA-DRB1*15 / HLA-DQB1*02 and T/T or G/T for CD86 rs2681401. We show associations between genetic factors and the occurrence of FVIII inhibitor development in severe hemophilia A patients taking into account for high-order interactions using a generalized partially linear tree-based approach.

Partial Text

For severe hemophilia A (HA) patients, the current standard of care includes regular prophylactic infusions of factor VIII (FVIII) products in order to prevent spontaneous bleeds or on demand infusions to treat bleeds. The main concern nowadays is the development of inhibitors that neutralize the activity of the FVIII molecule, which occurs mainly in the first 20 days of exposure for approximately 30% of the patients. In this context, the search for risk factors for immunogenicity of FVIII products is of primary concern in order to understand the mechanisms leading to the development of inhibitors and ultimately to prevent their development.

The selection of patients for the different analyses is described in a flowchart in Fig 1.

The dataset comprised 593 and 79 patients with severe HA from the Bonn and the Frankfurt databases respectively. Univariate analyses for well-established risk factors were performed separately. A pooled analysis was performed when results exhibited the same trend.

In this study, we investigated the association of bio-clinical and genetic markers with the development of FVIII inhibitor taking into account potential genetic high order interactions.

The present study investigates the relationship between genetic factors and FVIII inhibitor development in severe hemophilia A patients, together with F8 mutation type, a family history of inhibitors and FVIII product type. It relies on a hybrid tree-based model which is well suited to investigate high-order interactions. The final optimal tree distinguishes two groups of patients: a high-risk group for immunogenicity with positive HLA-DRB1*15 and IL-10 genotype G/A and A/A, a low-risk group for immunogenicity with negative HLADRB1*15/ HLADQB1*02 and CD86 genotype T/T and G/T.