Circulating factor IX antigen-inhibitor complexes in hemophilia B- following infusion of a factor IX concentrate

Abstract

A persistent low-titer factor IX inhibitor was discovered in a patient with severe hemophilia B . The inhibitor was very likely an immunoglobulin, since it was present in serum, was not dialyzable, retained its potency after heating to 56°C, and was bound by staphylococcal protein A (SPA). When the hemophilia B patient with the inhibitor was given therapeutic infusions of factor IX concentrate, the survival of factor IX antigen (IXAg) was markedly prolonged (t½ approximately 60 hr) compared to the survival of IXAg in infused hemophilia B patients lacking an inhibitor (t½ 5 hr). The prolonged survival of IXAg suggested the possibility of circulating immune complexes composed of IXAg and factor IX inhibitor (IX***Inh). Since immunoglobulins bind to SPA via the Fc portion of the molecule, the Fab region is free to bind to antigen. If immune complexes were formed in vivo after a factor IX concentrate infusion, IXAg would be retained by SPA-sepharose due to the linking of IXAg with the inhibitor molecule. As expected, postinfusion plasma from the inhibitor patient (but not from other hemophilia B patients) showed binding of IXAg to the SPA-sepharose. Further evidence for circulating complexes was provided by crossed Immunoelectrophoresis using an antibody to purified factor IX. Preparations containing factor IX alone showed a single fast-moving peak in the gel, whereas postinfusion plasma from the inhibitor patient as well as mixtures in vitro of IXAg and IX***Inh showed an additional slow-moving peak. These studies document the presence of circulating factor IX antigen-inhibitor complexes in a patient with hemophilia B- and a persistent low-titer factor IX inhibitor. To date, clinical evidence of immune complex disease has not been observed.