Catalytic activity of antibodies against factor VIII in patients with hemophilia A

Hemophilia A is an X chromosome-linked recessive disorder resulting in defe ctive or deficient factor VIII (FVIII) molecules, which, in its severe form , is a life-threatening and crippling hemorrhagic disease. Infusion of homo logous FVIII to patients with severe hemophilia A results, in 25% of patien ts, in the emergence of alloantibodies against FVIII (inhibitors)(ref. 1) t hat inhibit FVIII procoagulant activity by steric hindrance of the interact ion of FVIII either with stabilizing molecules(2), with molecules essential for its activity(3,4) Or With activating molecules(5). Here, we report on the proteolysis of FVIII by alloantibodies of two patients with severe hemo philia A, demonstrating a previously unknown mechanism by which FVIII inhib itors may prevent the pro-coagulant function of FVIII. The kinetic paramete rs of FVIII hydrolysis indicate a functional role for the catalytic immune response in the inactivation of FVIII in vivo. The characterization of allo antibodies against FVIII as site-specific proteases may provide new approac hes to the treatment of FVIII inhibitors.