Acquired hemophilia A (AHA) is an autoimmune disease caused by the development of inhibitory autoantibodies against factor VIII (FVIII) resulting in severe hemorrhages. Associated pathologies, such as autoimmune disease, malignancy and pregnancy are observed in approximately 50% of patients.
To elucidate the relationship between an underlying disease, the bleeding tendency and patients immunological profile the characteristics of anti-FVIII autoantibodies in AHA patients with (n=6) and without an underlying disease (n=9) were determined.
The median age of this cohort (n=15) was 71 years with two-thirds older than 70 years. Treatment parameters were analysed and patients were classified according to there bleeding tendency into a mild, moderate and severe phenotype. FVIII domain specificity of anti-FVIII autoantibodies was analysed in ELISA by binding to (i) FVIII fragments (heavy (HC) and light chain (LC), A2 and C2 domain) and (ii) single human domain hybrid human/porcine FVIII proteins. The amount of FVIII-specific IgGs was measured by ELISA and their relative contribution to the total amount of anti-FVIII IgG was calculated from standard curves for FVIII-specific IgG1, IgG2, IgG3, and IgG4.
All but one patient were treated with bypassing agents including activated FVII, activated prothrombin complex concentrate or porcine FVIII. All patients received immunosuppressive treatments. 14/15 achieved initial complete remission with 6 patients experiencing another episode of inhibitors. Characteristics of anti-FVIII autoantibodies in AHA patients with or without an underlying disease were similar: FVIII-specific autoantibodies targeted primarily the FVIII LC with a dominance of epitopes located C2 domain compared to the C1 domain. FVIII-specific antibodies belonged to the subclasses IgG1, IgG2, and IgG4. The individual IgG subclass levels did not correlate with the total amount of anti-FVIII antibodies or inhibitory anti-FVIII antibodies in Bethesda units. IgG1 and 2 vs IgG4 levels did not correlate with bleeding tendency. Patients with a mild bleeding phenotype only recognized the C2 domain, whereas other patients had antibodies against C2 and or other domains. Although lower levels of FVIII activity (FVIII:C) were observed in disease-associated AHA patients with a median FVIII:C of 0.5% (range, 0-6%) compared to 1.5% (range, 0-10%) in idiopathic AHA patients, this difference was not statistically significant. FVIII:C levels and FVIII inhibitor titers at clinical presentation did not correlate to the severity of bleeds: the median FVIII:C level in patients who had strong bleeds was 0.5% (range, 0-10%), moderate bleeds 3.6% (range, 0-6%), and mild bleeds 1.2% (range, 1-6%). The FVIII inhibitor titer at presentation was similar in patients who had mild, moderate and severe bleeding tendency with a median of 35 BU/mL (range, 29-55 BU/mL), 49.5 BU/mL (range, 9-156 BU/mL), and 17.3 BU/mL (range, 2.2-614 BU/mL), respectively.
The presented data challenges the view from other small cohorts that differential immunological profiles exist between disease-associated and idiopathic AHA patients. Data on the influence of epitopes and IgG subclasses on outcome in AHA patients remains conflicting and needs further study.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.