# F8 Variants and Inhibitor Development in a Multiethnic Cohort of Nonsevere Haemophilia A

## TL;DR

This study identifies F8 gene variants linked to inhibitor development in a diverse group of people with mild hemophilia A, showing these variants are common and not tied to race.

## Contribution

The study expands the known F8 variants associated with inhibitor development in a multiethnic cohort, offering actionable insights for clinical management.

## Key findings

- Inhibitors developed in 7.9% of the NSHA cohort, linked to 70 F8 variants.
- Most inhibitor-associated F8 variants (95.7%) were missense mutations.
- Race or ethnicity was not associated with inhibitor development in this multiethnic cohort.

## Abstract

Neutralising antibodies (inhibitors) against factor VIII can result in severe bleeding in persons with nonsevere haemophilia A (NSHA). The INSIGHT study of 1112 persons with NSHA in a predominantly White population identified 19 different F8 missense variants that were associated with inhibitor development.

To describe the F8 variants and inhibitor development in persons with NSHA in a multiethnic cohort using the My Life, Our Future (MLOF) Research Repository and the American Thrombosis and Hemostasis Network dataset (ATHNdataset).

The MLOF Research Repository and ATHNdataset were queried for demographic, clinical and genotyping data.

A total of 1805 persons with NSHA with at least one reportable F8 variant and known inhibitor status were included in this study. Inhibitors were developed in 142 (7.9%) persons with NSHA. Inhibitor development occurred in seventy F8 variants, of which the majority (n = 67, 95.7%) were missense variants. These 70 F8 variants were identified in a total of 1006 (55.7%) persons with NSHA. Race or ethnicity was not associated with inhibitors in persons with NSHA.

The MLOF Research Repository identified additional F8 variants where inhibitor development occurred in a multiethnic cohort of NSHA. Identification of these F8 variants can inform both physicians and persons with NSHA to adopt measures to reduce the risk of inhibitor development.