Profiling of Anti-FVIII Antibodies in Acquired Haemophilia A: 'Insights into Domain Specificity, Isotype Variability, and Clinical Correlations'.

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

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

Methods: 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.

Results: 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).

Conclusion: 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.