The Influence of Hemophilia on Wound Healing.

Abstract SCI-21

Hemostasis is considered to be the first phase of wound healing, followed by inflammation, proliferation and remodeling of the reconstituted tissue. However, very little has been written on the overall effect of impaired hemostatic function on wound healing. Our group has studied the effects of hemophilia B and some other coagulation impairments on healing in a mouse skin punch biopsy model. In this model, a defect of the epidermis and dermis must be replaced. Normally a platelet and fibrin clot fills the defect and forms a framework for the repair process. In addition, growth factors and cytokines are released during hemostasis that influence cellular activities necessary for healing. However, hemophilia and other hemostatic defects delay healing and alter the histology of the process. In our punch biopsy model, the epidermal defect is closed in 8 days in wild type mice, and 10 days in hemophilia B (HB) mice. Histologically, the influx of neutrophils and monocytes is delayed and reduced in HB. This finding supports a key role for thrombin and/or fibrin in mediating the inflammatory response. While the ingrowth of fibroblasts and endothelial sprouts (angiogenesis) appears normal in tempo and histology in HB mice, there are greater numbers of new vessels in the granulation tissue iand much greater microvascular bleeding in HB mice. In addition, hematomas are found adjacent to the vessels from which angiogenic vessels sprout. While reconsitution of thrombin generation at the time of wounding restored clot structure and the initial inflammatory influx, it did not prevent later bleeding into the granulation tissue and hematoma formation. In the mouse model, 5 days of hemostatic therapy (replacement or bypassing) were needed to restore normal healing. Thus, we conclude that adequate hemostatic function is required for an extended period of time to assure normal wound healing. Angiogenesis during healing predisposes to bleeding which can lead to a cycle of inflammation, enhanced angiogenesis and recurrent bleeding. A better understanding of the roles played by hemostasis in the subsequent response to injury holds the promise of improving the management of patients with hemophilia, as well as improving tissue recovery after trauma or surgery.