Inhibitor treatment in haemophilias A and B: inhibitor diagnosis

Abstract

The clinical diagnosis and quantitative measurement of polyclonal IgG inhibiting antibodies are the subjects of this review. Inhibitors in congenital haemophilia are usually diagnosed either as part of a routine surveillance schedule or following a bleeding episode that responds poorly to standard specific replacement therapy. Routine surveillance schedules for paediatric haemophilia A patients during high-risk incidence periods are variable and the subject of ongoing discussion. There have never been any published recommendations for following haemophilia B patients at high risk for inhibitor development. The Factor VIII/IX Subcommittee of the International Society on Thrombosis and Haemostasis scientifically endorsed the Nijmegen method for inhibitor measurement in 1996. However, there are many unresolved issues surrounding inhibitor diagnosis using these assays. These issues include: (i) questions of accuracy and inter-assay variability inherent to the one-stage clotting assay; (ii) lack of consensus regarding the assay cut-off for negative determination; (iii) lack of assay standardization and (iv) the clinical importance of capturing non-neutralizing antibodies currently not measured in the functional assays. Ongoing efforts to resolve these issues will be discussed.

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

“…In a subset of patients, humoral immune responses to the functional protein develop and pose a serious complication for factor replacement therapy. In hemophilia A, formation of inhibitory antibodies (inhibitors) directed against factor VIII (F.VIII), a helper-T-cell-dependent response, occurs in 20-30% of patients (1). There is much progress in the risk assessment of inhibitor formation in patients early in therapy, using a combination of genotyping (e.g., determination of the underlying F.VIII mutation and polymorphisms in the promoters of the cytokine genes IL-10 and TNFα), family history of inhibitor formation, ethnicity, and intensity of early treatment (2).…”

Chloroplast-Derived Therapeutic and Prophylactic Vaccines

“…Replacement therapy with intravenous delivery of recombinant human factor IX results in the development of inhibitory antibodies in 9-23% of patients, potentiating life threatening anaphylactic reactions to this therapeutic (DiMichele 2006 ) . Expression of recombinant human Factor IX in transplastomic tobacco led to expression of CTB-FIX or CTB-FFIX (engineered Furin cleavage site) at 3.8% TSP (Verma et al 2010b ) .…”

In vivo induction of regulatory T cells for immune tolerance in hemophilia

“…Presently, treatment is based on periodical intravenous administration of the deficient coagulation factor. The currently most problematic complication is the development of neutralizing antibodies (inhibitors), which compromise therapy, may create immune toxicity, and increase the cost of treatment [1]. The incidence of inhibitor formation is about 20–30% in hemophilia A, and further elevated in African-American and Latino patients [1, 2].…”

“…The currently most problematic complication is the development of neutralizing antibodies (inhibitors), which compromise therapy, may create immune toxicity, and increase the cost of treatment [1]. The incidence of inhibitor formation is about 20–30% in hemophilia A, and further elevated in African-American and Latino patients [1, 2]. Although inhibitor formation occurs only in approximately 1.5–3% of the hemophilia B cases, it is more prevalent in severe hemophilia B patients, often with additional consequences.…”