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

Abstract

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 (4h and 24h) after hemarthrosis, thrombin activity in WT mice quickly peaked at 4h, and returned to baseline after 1 week. In hemophilia B mice, there was no/minimal thrombin activity in joint tissues at 4h and 24h, whereas at 72h 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 600IU/kg FIX within the first 24h or the whole 2-week period. We concluded that timely (in the first 24h) and sufficient hemostasis correction is critical for a better protection against the development of hemophilic arthropathy.