Acquired
hemophilia is a rare
bleeding disorder characterized by the spontaneous occurrence of inhibitory
antibodies against endogenous
factor VIII (FVIII).
IgG from some patients with acquired
hemophilia hydrolyze FVIII. Because of the complex etiology of the disease, no clinical parameter, including the presence of FVIII-hydrolyzing
IgG, has been associated with patient's survival or death. Here, we demonstrate the presence of anti-FIX
antibodies in acquired
hemophilia patients.
IgG from some patients were found to hydrolyze FIX. In most cases,
IgG-mediated FIX-hydrolysis resulted in FIX activation.
IgG-mediated hydrolysis of FIX thus led to the significant generation of activated FIX in 25 of 65 patients. Based on the estimated kinetic parameters, patients'
IgG activated up to 0.3nM FIX in 24 hours, an amount that restored
thrombin generation in vitro provided the presence of more than or equal to 3% residual FVIII activity in plasma. This work identifies proteolytic
IgG as novel molecules able to activate FIX under pathologic conditions.
IgG-mediated FIX activation is a prevalent phenomenon among acquired
hemophilia patients. The presence of FIX-activating
IgG may partly compensate for the antibody-mediated inhibition of endogenous FVIII in restoring
thrombin generation. This clinical trial was registered at www.clinicaltrials.gov as #NCT00213473.