Protein S Antibody as an Adjunct Therapy for Hemophilia B.

Hemophilia B (HB) is caused by an inherited deficiency of plasma coagulation Factor IX (FIX). Approximately sixty percent of pediatric patients with HB possess the severe form of FIX deficiency (<1% FIX activity). Treatment typically requires replacement therapy by the administration of FIX. However, exogenous FIX has a limited functional half-life, and the natural anticoagulant Protein S (PS) inhibits activated FIX (FIXa). Protein S ultimately limits thrombin formation, which limits plasma coagulation. This regulation of FIXa activity by PS led us to test whether inhibiting PS would extend the functional half-life of FIX, and thereby prolong FIX-based HB therapy. We assayed clotting times and thrombin generation to measure the efficacy of a PS antibody for increasing FIX activity in commercial and pediatric patient HB plasmas. We included eleven pediatric patients who lacked additional comorbidities and coagulopathies. In vivo, we assessed thrombus formation in HB mice in the presence of FIXa ± PS antibody. We found an accelerated rate of clotting in the presence of PS antibody. Similarly, the peak thrombin formed was significantly greater in the presence of the PS antibody, even in plasma from patients with severe HB. Further, HB mice injected with PS antibody and FIX had a 4.5-fold higher accumulation of fibrin at the thrombus induction site compared with mice injected with FIX alone. Our findings imply that a PS antibody would be a valuable adjunct to increase the effectiveness of FIX replacement therapy in pediatric patients who have mild, moderate, and severe HB.