The Inhibitor Antibody Response Is More Complex in Hemophilia A Patients Than in Most Nonhemophiliacs With Factor VIII Autoantibodies

Abstract

Approximately 25% of hemophilia A patients infused with factor VIII (fVIII) mount an immune response, which leads to its inactivation. Anti-fVIII autoantibodies are also seen rarely in individuals with normal fVIII. We have previously demonstrated that some anti-A2 and anti-C2 domain antibodies are fVIII inhibitors and that many patients have additional inhibitors with a fVIII light chain (LCh) epitope outside C2. Because the contribution of the different antibodies to the plasma inhibitor titer had been examined in a limited number of patients (14), we report in this study a more extensive analysis of 55 plasmas. The dominant inhibitors in 62% (13 of 21) of autoantibody plasmas were directed only against C2 or A2, but not both, whereas this pattern was found in only 15% (5 of 34) of hemophilic plasmas. In addition, anti-A2 inhibitors were present in 71% (24 of 34) of hemophilic plasmas, but only 33% (7 of 21) of autoantibody plasmas. These results demonstrated that the inhibitor response in hemophiliacs was more complex and the epitope specificity was somewhat different. A comparison of hemophiliacs treated only with plasma fVIII or recombinant fVIII showed no significant differences in the complexity of the inhibitor response, as ≥ 2 different inhibitor antibodies were present in 78% (18 of 23) of the former and 82% (9 of 11) of the latter. In contrast, the major inhibitors in 35% (8 of 23) of hemophiliacs treated with plasma fVIII were directed against C2 and another LCh epitope within residues 1649-2137, but not A2, while none (0 of 11) treated with recombinant fVIII had this pattern.

Successful steroid pulse treatment in childhood acquired haemophilia with nephrotic syndrome

“…We could not examine IgG 1 antibodies because of non-specific binding reactions, but it was supposed that the FVIII antibody seen in the present case was an inhibitor that inhibited the FVIII activity mainly via light chain recognition. This finding matches the report by Prescot et al [22]. In convalescent phase, only IgG 4 antibody was detected by the ELISA method and IgG 4 antibody recognized mainly heavy chains in immunoblotting analysis, although its inhibitor activity was unclear.…”

Immunological aspects of inhibitor development

“…This suggests different mechanisms of inhibitor formation, which is expected given that inhibitors are a consequence of an alloimmune response in congenital haemophilia A patients and an autoimmune response in acquired haemophilia patients. This finding is also consistent with the observation that inhibitor-binding epitopes in congenital and acquired haemophilia patients may differ [26].…”

Epitope mapping of factor VIII inhibitor antibodies of Chinese origin

“…There was no data to differentiate the exact fraction of their findings that recognized a3 from those that recognized A3-C1. Human antibodies directed to the a1 region are rare, occurring only at an incidence of 1´8±7% (Fulcher et al, 1987;Lubahn et al, 1989;Scandella et al, 1989;Prescott et al, 1997). We found 14´3% (4 out of 28) for a1, which is the highest number reported; however, explanations for this high incidence are not clear.…”

“…Using a synthetic peptide of residues 1687±1695 in competitive RIA (radioimmunoassay), Tiarks et al (1992) reported a 46% (38 out of 82) positive rate for a3 occurring in patients with haemophilia A. Prescott et al (1997) reported a 29% positive rate for spontaneous inhibitors, recognizing an epitope of a broader region of a3-A3-C1. There was no data to differentiate the exact fraction of their findings that recognized a3 from those that recognized A3-C1.…”