# Profiling of Anti‐FVIII Antibodies in Acquired Haemophilia A: ‘Insights into Domain Specificity, Isotype Variability, and Clinical Correlations’

## TL;DR

This study examines the types of antibodies in a rare blood disorder, showing IgG4 is common and linked to severe symptoms, and highlights a specific protein region involved.

## Contribution

The study provides new insights into antibody isotype and domain specificity in acquired haemophilia A.

## Key findings

- IgG4 is the most common anti-FVIII subclass and correlates with higher inhibitor levels.
- C1C2 domain-targeting antibodies are more prevalent in AHA than in congenital haemophilia A.
- IgM positivity is associated with higher mortality in AHA patients.

## Abstract

Acquired haemophilia A (AHA) is a rare autoimmune disorder caused by autoantibodies against coagulation factor VIII (FVIII), resulting in significant bleeding risks.

To characterize the anti‐FVIII antibody profile in AHA patients by assessing isotypes, subclasses, and correlations with key clinical parameters.

Eighty AHA patients were retrospectively analysed by assessing FVIII inhibitor levels, antibody isotypes (IgG, IgA, IgM), IgG subclasses, and domain specificity using a bead‐based assay. Clinical data were correlated with antibody profiles. IgG domain profiles were compared with a congenital haemophilia A (CHA) cohort.

The cohort had a median age of 74 years, with 60% males. Idiopathic cases accounted for 67%, and 17% had bleeding linked to medical interventions. Major bleeding sites were musculoskeletal/retroperitoneal (45%) and skin (36%). Within six months, 18% of patients died, mostly from sepsis. Anti‐FVIII IgG antibodies were present in all patients, with IgG4 (96%) and IgG3 (60%) being the most common subclasses. IgM and IgA anti‐FVIII antibodies were detected in 17.5% and 18.8% of patients, respectively, with IgM positivity associated with higher mortality (33%). IgG4 subclass correlated significantly with inhibitor titres (r
s = 0.54; p < 0.001). Compared to CHA, AHA showed a higher prevalence of C1C2 domain‐targeting antibodies (49% vs. 77%), associated with NBA levels (r
s = 0.51; p < 0.001).

Anti‐FVIII antibody profiling reveals distinct patterns in AHA, with IgG4 linked to higher inhibitor levels. The C1C2 domain specificity of the anti‐FVIII antibodies suggests a potential role of this FVIII domain in the immunopathology of AHA patients, warranting further investigation to improve prognostic tools.