Development of anaphylactic shock in haemophilia B patients with inhibitors

The development of inhibitor antibody is a serious complication of haemophilia in young children. The incidence of factor IX (FIX) inhibitors in haemophilia B patients is five- to 10-times less common (1.5-3%) than the incidence of FVIII inhibitors in haemophilia A (15-30%). Inhibitors are commonly associated with the total absence of FIX antigen due to total deletions or other major derangements of the FIX gene. Unlike those with haemophilia A, patients with haemophilia B often experience anaphylactic reactions to FIX concentrates at the time of inhibitor development. Although the reasons for anaphylaxis at the time of inhibitor development are not yet clear, several hypotheses can be considered. One relates to the smaller molecular size of FIX compared with FVIII. With a molecular size of 55000, FIX diffuses into extravascular spaces more readily. Secondly, since the normal plasma FIX concentration is much higher compared with FVIII (5 microg/ml versus 0.1 microg/ml), haemophilia B patients are exposed to higher amounts of exogenous protein when a standard dose of 40-80 units/kg FIX is used. The routine exposure of haemophilia B patients to such large amounts of exogenous protein without any endogenous FIX antigen may contribute to the development of hypersensitivity. A third reason to consider is the absence of tolerance. Whether the lack of tolerance is due to the total absence of any FIX antigen or co-deletion of neighbouring genes that modulate the immune system is unknown. Management of bleeding in patients with inhibitors and anaphylaxis is complicated because the only readily available products for treatment are the FIX-containing prothrombin complex concentrates or activated prothrombin complex concentrates, the very same products that induce anaphylaxis. Recently, recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) has been used effectively in several of these children, but in the USA rFVIIa is only available on a compassionate basis for the treatment of life- or limb-threatening bleeding. Eradication of the inhibitor by immune tolerance induction (ITI) has only been minimally successful in haemophilia B patients with inhibitors and anaphylaxis. Despite initial successful desensitization, the majority of these patients have had recurrent allergic reactions to FIX requiring administration of antihistamines and steroids. Recently, the development of nephrotic syndrome has been reported as a serious complication of ITI in these patients. Since inhibitor antibody is seen in association with complete gene deletions or major derangements of the FIX gene, it may be possible to select those patients with the highest risk for close monitoring during the early period of treatment by obtaining molecular diagnosis at the time of presentation.