Wound healing requires interactions between coagulation,
inflammation, angiogenesis, cellular migration, and proliferation. Healing in dermal
wounds of
hemophilia B mice is delayed when compared with hemostatically normal wild-type (WT) mice, with abnormal persistence of
iron deposition,
inflammation, and neovascularity. We observed healing following induced joint
hemorrhage in WT and
factor IX (FIX) knockout (FIX-/-) mice, examining also parameters previously studied in an excisional skin
wound model. Hemostatically normal mice tolerated this joint
bleeding challenge, cleared blood from the joint, and healed with minimal pathology, even if additional autologous blood was injected intra-articularly at the time of wounding. Following
hemarthrosis, joint wound healing in
hemophilia B mice was impaired and demonstrated similar abnormal histologic features as previously described in hemophilic dermal
wounds. Therefore, studies of pathophysiology and
therapy of hemophilic joint
bleeding performed in hemostatically normal animals are not likely to accurately reflect the healing defect of
hemophilia. We additionally explored the hypothesis that the use of a FIX replacement
protein with extended circulating FIX activity could improve synovial and osteochondral wound healing in hemophilic mice, when compared with treatment with unmodified recombinant FIX (rFIX) in the established joint
bleeding model. Significantly improved synovial wound healing and preservation of normal osteochondral architecture are achieved by extending FIX activity after
hemarthrosis using glycoPEGylated FIX when compared with an equivalent dose of rFIX. These results suggest that treating joint
bleeding only until hemostasis is achieved may not result in optimal joint healing, which is improved by extending factor activity.