Targets of autoantibodies in acquired hemophilia A are not restricted to factor VIII: data from the GTH-AH 01/2010 study

Abstract

The root cause of autoantibody formation against factor VIII (FVIII) in acquired hemophilia A (AHA) remains unclear. We aimed to assess whether AHA is exclusively associated with autoantibodies towards FVIII, or whether patients also produce increased levels of autoantibodies against other targets. A case-control study was performed enrolling patients with AHA and age-matched controls. HEp-2 immunofluorescence was applied to screen for anti-nuclear (ANA) and anti-cytoplasmic autoantibodies. Screening for autoantibodies against extractable nuclear antigens (ENA) was performed by enzyme immunoassay (EIA) detecting SSA/Ro, SSB/La, U1RNP (70 kDa, A, C), Scl-70, JO-1, centromere B, Sm, double-stranded DNA, and alpha-fodrin (AF). AHA patients were more often positive for ANA than control patients (64% vs. 30%, odds ratio [OR] 4.02, 1.98-8.18) and had higher ANA titers detected than controls. Cytoplasmic autoantibodies and anti-AF IgA autoantibodies were also more frequent in AHA patients compared to controls. Autoantibodies against any target other than FVIII were found in 78% of AHA patients compared to 46% of controls (OR 4.16, 1.98-8.39). Results were similar preforming sensitivity analyses (excluding either subjects with autoimmune disorders, cancer, pregnancy, or immunosuppressive medication at baseline) and in multivariable binary logistic regression. To exclude that autoantibody staining was merely a result of cross-reactivity of anti-FVIII autoantibodies, we tested a mix of 7 well-characterized monoclonal anti-FVIII antibodies. These antibodies did not stain HEp-2 cells used for ANA detection. In conclusion, a diverse pattern of autoantibodies is associated with AHA, suggesting that a more general breakdown of immune tolerance might be involved in its pathology.

Genetics and Epigenetics in Acquired Hemophilia A: From Bench to Bedside

“…Patients with AHA were found to be more frequently positive for antinuclear antibodies (ANAs), cytoplasmic autoantibodies, and anti-α-fodrin (AF) immunoglobulin A autoantibodies compared with the controls. The GTH-AH 01/2010 study presented that autoantibodies in patients with AHA are not only specific for FVIII but for other immune targets (ANA WITH human epithelial cell (HEp-2) immunofluorescence, AF nuclear, and cytoplasmic) (78% produced antibodies for any other target than FVIII compared with 46% of controls, OR 4.16, 1.98-8.39) [50].…”

“…The direct inhibition of FVIII by binding to functional regions or the enhancement of catabolism and clearance are the main mechanisms involved in the inactivation of FVIII in patients with AHA [51]. Autoantibodies in AHA are not specific only for FVIII [50]. The autoantibodies against FVIII can interplay with the factor via hydrolysis or proteolysis [52,53].…”

Risk factors, treatment and survival rates of late‐onset acquired haemophilia A: A cohort study from the Shizuoka Kokuho Database

“…In addition, AHA is known to occur more frequently in the elderly 4–6,9,10,13 . Dysfunction of the immune system caused by aging can contribute to the loss of self‐tolerance and potentially increase the risk of developing AHA 14 . Since immune mechanisms are thought to be involved in its pathogenesis, 2 it makes sense that background immune abnormalities are highly prevalent.…”

“…[4][5][6]9,10,13 Dysfunction of the immune system caused by aging can contribute to the loss of self-tolerance and potentially increase the risk of developing AHA. 14 Since immune mechanisms are thought to be involved in its pathogenesis, 2 it makes sense that background immune abnormalities are highly prevalent. However, if autoimmune abnormalities are the only triggers, as in systemic lupus erythematosus and Graves' disease, they would be more common in younger patients than in older patients.…”