Over the course of healing, the wounds also have abnormal histological features, including (i) reduced neutrophil influx and delayed macrophage influx; (ii) subcutaneous haematoma formation; (iii) an unexpected increase in wound site angiogenesis and (iv) persistent deposition of iron in

the wound bed and adjacent tissues. We found that temporarily restoring thrombin generation with a single dose of FIX replacement or high dose FVIIa restored neutrophil and macrophage influx. However, it did not correct delayed epithelial closure, excess angiogenesis or late rebleeding [23]. Thus, although formation of an adequate fibrin clot at the time of injury plays a role in tissue repair, the ability to generate thrombin and/or other activated coagulation factors remains important during the later phases of wound healing. Proper haemostatic function later in the healing process prevents bleeding at

the wound DAPT site and at adjacent sites of angiogenesis. This prevents deposition of additional iron in the wound area, which can promote inflammation that impedes healing [37]. Our data suggest that sites of angiogenesis are at high risk of rebleeding during wound healing [14]. Inhibition of angiogenesis does not further impair wound healing in haemophilia. Celecoxib, a non-steroidal anti-inflammatory agent, reduced angiogenesis in healing wounds in the haemophilia B mouse model, but did not further delay healing [4]. Inflammation alone does not seem to provoke Raf activation bleeding in haemophilic mice [38]. However, certain inflammatory mediators can drive angiogenesis and may possibly provoke bleeding at sites where inflammation is secondarily associated with angiogenesis. Although our studies have been conducted using skin wounds, we feel that they reveal general principles that likely apply to bleeding and healing in other tissues, such as joints. We believe that modulators of angiogenesis and inflammation hold promise as adjunctive therapies to reduce joint and soft tissue bleeding in haemophilia. Cartilage is composed of chondrocytes embedded in an extracellular

matrix. Chondrocytes are responsible for maintenance of the matrix. The cartilage matrix consists of two major components: collagen, which provides shape and tensile strength, and proteoglycans, which are responsible for the negative 上海皓元医药股份有限公司 charge. This causes high osmotic pressure, thereby attracting water and with that resisting compressive forces in a joint. Previous in vitro research showed that a single blood-exposure of cartilage leads to persistent damage [39]. It was demonstrated that monocytes/macrophages and red blood cells, as present in blood, are responsible for the irreversible inhibition of cartilage matrix synthesis [40]. This is caused by induction of chondrocyte apoptosis due to formation of hydroxyl radicals in the vicinity of chondrocytes [41]. Small amounts of interleukin (IL)-1β, produced by activated monocytes/macrophages, increase production of hydrogen peroxide by chondrocytes.