Frequency and epitope specificity of anti-factor VIII C1 domain antibodies in acquired and congenital hemophilia A

Frequency and epitope specificity of anti-factor VIII C1 domain antibodies in acquired and congenital hemophilia A
Inhibitor development is the most challenging treatment-related complication in congenital Hemophilia, and autoantibody development in adults is associated with the equally challenging acquired Hemophilia A. Earlier studies suggested that the majority of both allo- and auto-antibodies were directed against the A2 and C2 domains of Factor VIII (F.VIII), with the autoantibody more likely to be restricted to a particular domain. Recently, inhibitors developing in a patient with mild Hemophilia A were found to target the C1 domain. Subsequent studies identified anti-C1 antibodies in up to 60% of inhibitors, and the response was greater to human than porcine F.VIII.
This study analyzed the frequency and epitope specificity of anti-C1 antibodies in patients with both acquired and congenital hemophilia.178 patients (63 congenital, 115 acquired) were studied by a variety of protein based and molecular methods. Human and porcine protein sources were studied in tandem, primarily because of the potential role of porcine replacement factor in patients with inhibitors and those with acquired hemophilia A.
The median inhibitor titre of the population was 5.4 BU (ranging from 1.9-20). C1-specific antibodies were found to contribute significantly to the total population of cross-reactive (human and porcine sequence) anti-F.VIII IgG. The C1 domain was noted to be important in binding to phospholipid membranes, F.V, and von Willebrand Factor, which could explain its impact in coagulation.
As a primary in vitro study, it is difficult to determine the true in vivo impact of these antibodies, or to compare them to the effects of antibodies against other epitopes. Some patients may also have antibodies to multiple epitopes, particularly in congenital hemophilia, with a more complex impact on coagulation and treatment.
Recent studies are highlighting both treatment and patient-related risk factors for inhibitor development. Given the clinical importance of inhibitor development, a better understanding of the nature and variability of inhibitors should contribute to the ability to better prevent and eradicate them with new approaches.