Restoring hemostatic thrombin generation at the time of cutaneous wounding does not normalize healing in hemophilia B.
BACKGROUND
We recently reported that wound healing is abnormal in hemophilia B (HB) mice [1]. The wounds show abnormal histology: s.c. hematoma formation; delayed re-epithelialization; delayed macrophage influx; and an increase in wound site angiogenesis.


OBJECTIVE
To test the hypothesis that restoring a hemostatic level of thrombin generation at the time of wounding would allow formation of an adequate platelet/fibrin plug and correct abnormalities of wound healing in HB.


METHODS
We placed a 3-mm cutaneous wound on the back of each HB or wild-type (WT) mouse. Some HB mice were treated just prior to wounding with either human factor IX (FIX) or FVIIa in a dose sufficient to normalize bleeding in a tail bleed model.


RESULTS
The average wound size over time in treated HB animals was intermediate between those in WT and untreated HB mice. However, the time to complete skin closure was not improved by treatment. Hematoma formation was decreased and macrophage influx began earlier in treated than in untreated HB animals. However, treated HB mice had evidence of ongoing low-level bleeding near the wound site, even after closure of the skin defect. Treatment also did not normalize the increased angiogenesis observed in HB mice.


CONCLUSIONS
Restoring initial hemostasis can modulate some of the parameters of wound healing. However, an extended period of adequate hemostatic function is necessary to achieve normal healing, probably because the risk of hemorrhage is increased by vascular remodeling and angiogenesis during the healing process.
McDonald
A
A
Duke University, Durham Veterans Affairs and University of North Carolia Medical Centers, Durham, NC 27705, USA.
Hoffman
M
M
Hedner
U
U
Roberts
H R
HR
Monroe
D M
DM
D000818:Animals; D005164:Factor IX / Q000235:genetics* / Q000378:metabolism; D015942:Factor VIIa / Q000378:metabolism; D006467:Hemophilia A / Q000378:metabolism; D002836:Hemophilia B / Q000378:metabolism / Q000628:therapy*; D006470:Hemorrhage / Q000378:metabolism; D006487:Hemostasis; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D012867:Skin / Q000187:drug effects; D013917:Thrombin / Q000096:biosynthesis* / Q000378:metabolism; D014945:Wound Healing
D005164:Factor IX; D015942:Factor VIIa; D013917:Thrombin