Cutaneous wound healing is impaired in hemophilia B

Abstract

We used a mouse model to test the hypothesis that the time course and histology of wound healing is altered in hemophilia B. Punch biopsies (3 mm) were placed in the skin of normal mice and mice with hemophilia. The size of the wounds was measured daily until the epidermal defect closed. All wounds closed in mice with hemophilia by 12 days, compared with 10 days in normal animals. Skin from the area of the wound was harvested at different time points and examined histologically. Hemophilic animals developed subcutaneous hematomas; normal animals did not. Macrophage infiltration was significantly delayed in hemophilia B. Unexpectedly, hemophilic mice developed twice as many blood vessels in the healing wounds as controls, and the increased vascularity persisted for at least 2 weeks. The deposition and persistence of ferric iron was also greater in hemophilic mice. We hypothesize that iron plays a role in promoting excess angiogenesis after wounding as it had been proposed to do in hemophilic arthropathy. We have demonstrated that impaired coagulation leads to delayed wound healing with abnormal histology. Our findings have significant implications for treatment of patients with hemophilia, and also highlight the importance of rapidly establishing hemostasis following trauma or surgery. (Blood. 2006; 108:3053-3060)

Factor VII Deficiency Impairs Cutaneous Wound Healing in Mice

“…Studies on wound healing in hemophilia B mice (FIX -/-) showed that macrophage infiltration and wound healing were delayed, potentially because of insufficient thrombin-mediated generation of fibrin degradation-based chemoattractant agents and insufficient fibrin scaffolding for reepithelialization of the wound area (20). Other studies have demonstrated that in FXIII -/-mice, a delay in reepithelialization of the wounded area occurs that is rescued with FXIII treatment (21).…”

Animal models of bleeding and tissue repair

“…The haemophilic mice exhibit delayed cutaneous wound closure with abnormal histology, including: (i) subcutaneous haematoma formation near the wound site; (ii) delayed macrophage influx; (iii) delayed reepithelialization; and (iv) a surprising increase in wound site angiogenesis [31].…”

“…However, it did lead to an earlier macrophage (MP) influx in both FIX-and FVIIa-treated HB animals compared with untreated HB mice. Thus, it appears that two major mechanisms operate to promote MP influx to a wound site: (i) thrombin plays an important role in promoting rapid MP influx in wild type (WT) mice; and (ii) haemorrhage promotes MP influx into the wound area in HB mice [31]. The pattern of MP influx in the treated HB mice is a composite of the pattern seen in WT and HB mice: an early influx of MP is related to thrombin generation during haemostasis and a late influx of MP occurs in response to recurrent haemorrhage.…”

The Frequency of Iron Deficiency among Patients with Hemophilia

“…With repeated bleeding, there is deposition of iron in synovial membrane. However the iron deposits are not physiologically functional as they are not readily available for haemoglobin synthesis but rather are pathological mediators of inflammatory changes leading to crippling synovitis and arthropathy [14].…”