Anaphylactic response to factor IX replacement therapy in haemophilia B patients: complete gene deletions confer the highest risk

Abstract

Haemophilia B is an X-linked recessive coagulopathy due to mutations in the factor IX gene. Occasionally, patients receiving factor IX replacement therapy develop inhibiting antibodies to the factor IX protein, and it has been recently documented that a subset of these patients have had anaphylactic responses to factor IX replacement therapy in association with the development of inhibiting antibodies. To determine the relationship between mutation type and the risk of anaphylaxis, eight unrelated patients from families in whom anaphylaxis had occurred were genotyped. The mutations were compared to those in 550 haemophilia B patients and to those in 276 patients with clinically severe disease. Individuals with complete gene deletions were found to be at greatest risk for anaphylaxis, with an estimated risk of 26% or greater. Anaphylaxis was less likely to occur in patients with protein truncation mutations or partial gene deletions and least likely to occur with missense mutations. Genotypes can help physicians and patients anticipate the likelihood of anaphylaxis, a potentially life-threatening complication of factor IX replacement therapy. The very high risk of anaphylaxis associated with a complete gene deletion suggests that the lack of expression of a partial protein product may predispose to anaphylaxis and/or that the absence of a closely linked, codeleted gene enhances the anaphylactic immune response.

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.…”

Oral delivery of bioencapsulated coagulation factor IX prevents inhibitor formation and fatal anaphylaxis in hemophilia B mice

“…However, there are no protocols for preventing or suppressing IgE formation, nor has there been an animal model that mimics this aspect of hemophilia pathophysiology. Similar to observations in humans, the strain of mice we iden- tified as prone to anaphylactic reactions has an F9 gene deletion (8). A lack of prior reports on anaphylactic reactions to coagulation factors may be because protein replacement therapy has been largely studied using F.VIII infusions to hemophilia A mice (which, similar to human treatment, is less likely to cause anaphylaxis).…”

“…Importantly, studies found that up to 50% of patients with F.IX inhibitors may experience potentially life-threatening anaphylactic reactions to F.IX which also preclude the subject from home treatment and severely hinder ITI protocols (3). These acute severe and systemic type I hypersensitive allergic reactions, often attributed to IgE formation, have been reported for treatment of hemophilia A and B, lysosomal storage disorders, and others (4)(5)(6)(7)(8)(9). No prophylactic protocols are currently available for prevention of these pathogenic antibody responses.…”

The safety and efficacy of recombinant human blood coagulation factor IX in previously untreated patients with severe or moderately severe hemophilia B

“…This mutation has been associated with a high risk for inhibitor development 33,34 and anaphylactoid reactions following therapy with pdFIX. 35 Of interest, genotype analysis also revealed that 2 additional patients with the same mutation did not develop inhibitors. Because the 2 patients who developed inhibitors were unrelated, and 2 additional patients with the same mutation did not develop inhibitors, the existence of other immune response modifiers should be considered in addition to the contribution of the R29X mutation itself.…”