Timely and large dose of clotting factor IX provides better joint wound healing after hemarthrosis in hemophilia B mice

Bleeding into the joints represents the major morbidity of severe hemophilia and predisposes it to hemophilic arthropathy (HA). In a reproducible hemarthrosis mouse model, we found distinct changes in thrombin activity in joint tissue homogenate following exposure of the joint to blood in wide type (WT) and hemophilic B mice. Specifically, at early time points (4 h and 24 h) after hemarthrosis, thrombin activity in WT mice quickly peaked at 4 h, and returned to baseline after 1 week. In hemophilia B mice, there was no/minimal thrombin activity in joint tissues at 4 h and 24 h, whereas at 72 h and thereafter, thrombin activity kept rising, and persisted at a higher level. Nevertheless, prothrombin had not decreased in both WT and hemophilia. The pattern was also confirmed by Western blotting and immunostaining. To optimize the protection against development of HA, we tested different treatment regimens by administration of clotting factor IX into hemophilia B mouse after hemarthrosis induction, including a total of 600 IU/kg FIX within the first 24 h or the whole 2-week period. We concluded that timely (in the first 24 h) and sufficient hemostasis correction is critical for a better protection against the development of hemophilic arthropathy.