Gene Mutations and Inhibitor Formation in Patients with Hemophilia B

Abstract

The nature of the mutation in the factor IX gene is an important factor in determining whether a patient with hemophilia B will develop an inhibitor. In a series of 62 Swedish families with hemophilia B, including 30 with the severe form, approximately one third of the families exhibiting deletions or nonsense mutations contained one member who developed an inhibitor. The risk for inhibitor development in family members carrying missense mutations was virtually zero.

Human recombinant factor IX: safety and efficacy studies in hemophilia B patients previously treated with plasma-derived factor IX concentrates

“…32,33 The majority of patients who develop inhibitors have gross deletions or certain nonsense mutations in the F9 gene, whereas complete F9 gene deletions also confer the risk of anaphylaxis. [34][35][36][37] These observations support the hypothesis that a lack of circulating factor IX protein predisposes to an immune response following factor IX replacement therapy. Although missense mutations are less commonly associated with such immune responses, this patient had a signal peptide missense mutation that prevented secretion of his factor IX protein, resulting in his factor IX antigen-negative phenotype and increased risk of inhibitor development.…”

Functional mapping of anti-factor IX inhibitors developed in patients with severe hemophilia B

“…It has been established that such inhibitory antibodies (inhibitors) arise in 1% to 4% of the treated patients with severe hemophilia B (FIX activity Ͻ 0.01 IU/mL). [9][10][11][12] The mechanism involved in inhibitor development in hemophilia B remains poorly documented and understood compared with hemophilia A particularly with regard to inhibitor recognition sites and inhibitory properties. The present study was directed to gain more insight into these aspects of FIX inhibitors.…”

Factor VIII C1 domain residues Lys 2092 and Phe 2093 contribute to membrane binding and cofactor activity

“…However, such treatment can result in the production of specific antibodies that neutralize function of factor VIII in the circulation. 19,20 Some inhibitory antibodies block membraneinteractive epitope(s) of factor VIII, underscoring the importance of membrane binding for normal function. Indeed, these antibodies have helped to identify membrane-interactive motifs of factor VIII.…”