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Abnormal joint and bone wound healing in hemophilia mice is improved by extending factor IX activity after hemarthrosis

Junjiang Sun, Baolai Hua, Eric W. Livingston, Sarah Taves, Peter B. Johansen, Maureane Hoffman, Mirella Ezban, Dougald M. Monroe, Ted A. Bateman and Paul E. Monahan

Key Points

  • Joint and bone healing abnormalities are demonstrated in hemophilic mice that are not solely because of the amount of blood in their joints.

  • Following initial hemostasis, extended FIX activity is needed in the week after hemarthrosis to normalize osteochondral healing.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.

Abstract

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.

  • Submitted August 13, 2016.
  • Accepted December 19, 2016.
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