Abstract Number: OC 24.2
Meeting: ISTH 2021 Congress
Background: The most common complication in hemophilia A (HA) treatment is the development of alloimmune inhibitors that foreclose the ability of infused factor VIII (FVIII) to participate in coagulation. Inhibitors confer significant pathology and present major complexities in patient management. Inhibitors are more common in African American patients, and it has been hypothesized that this is a consequence of haplotype (H)-treatment product mismatch. F8 haplotypes H1-H5 are defined by nonsynonymous single-nucleotide polymorphisms encoding sequence variations at FVIII residues 1241, 2238 and 484. Haplotypes H2-H5 are more prevalent in individuals with black African ancestry, while >90% of the white population has the H1 haplotype.
Aims: (1) to test the hypothesis that three polymorphic FVIII sequence variations defining F8 haplotypes that are more prevalent in African Americans comprise immunodominant B-cell epitopes;
(2) To quantify neutralizing and non-neutralizing anti-FVIII antibodies in a representative cross-section of black and white U.S. HA subjects.
Methods: A validated Luminex-based assay was used to determine anti-FVIII antibody titers in plasma from 394 HA (188 black, 206 white) and 23 non-HA subjects, measuring their binding to recombinant full-length H1 and H2 and B-domain-deleted (BDD) H1/H2, H3/H5 and H4 FVIII proteins. Inhibitor titers were determined using a chromogenic assay and linear B-cell epitopes characterized using peptide microarrays.
Results: FVIII-reactive antibodies were readily detected in most HA subjects and controls, with higher titers in inhibitor subjects as expected. Neither total nor inhibitory antibody titers correlated with F8 haplotype mismatches, and peptides with D1241E and M2238V polymorphisms did not comprise linear B-cell epitopes. Interestingly, the BDD-FVIII proteins were markedly more reactive than the full-length FVIII products with plasma antibodies.
Conclusions: F8 haplotype mismatch is not a significant risk factor for inhibitor development. The stronger immunoreactivity of BDD-FVIII suggests that B-domain removal exposes novel B-cell epitopes, perhaps through conformational rearrangements of FVIII domains.
To cite this abstract in AMA style:Pratt KP, Gunasekera D, Vir P, Tan S, Pierce GF, Olsen C, Butenas S, Mann KG. Neutralizing and Non-neutralizing Anti-FVIII Antibodies in Black and White Hemophilia A Subjects: A Natural History Profile [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/neutralizing-and-non-neutralizing-anti-fviii-antibodies-in-black-and-white-hemophilia-a-subjects-a-natural-history-profile/. Accessed May 16, 2022.
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