Activated protein C improves ischemic flap survival and modulates proangiogenic and antiinflammatory gene expression

BACKGROUND: Flap necrosis remains a major complication in reconstructive surgery. The authors evaluated whether systemic activated protein C, a natural serum anticoagulant with anti-inflammatory, proangiogenic, and cytoprotective properties, can improve ischemic skin flap survival. METHODS: Cranially based dorsal cutaneous flaps were elevated on 44 rats. Animals received intravenous injections of activated protein C (25 μg/kg) or saline. Rats were divided into three groups depending on the timing of the first injection: postoperative (45 minutes postoperatively, n = 12), late preoperative (45 minutes preoperatively, n = 5), and early preoperative (3 hours preoperatively, n = 5). In all groups, second and third injections were performed at 3 and 24 hours postoperatively. Flap survival was measured on day 7. Histological and real-time polymerase chain reaction specimens were collected on days 2 and 7 and at 3 and 24 hours, respectively. RESULTS: Postoperative activated protein C improved flap survival (68.9 ± 4.3 percent) compared with control treatment (39.3 ± 1.5 percent; p < 0.001). Late preoperative treatment produced diffuse flap hemorrhage. Early preoperative activated protein C injection produced near-complete flap survival (96.1 ± 1.1 percent for activated protein C versus 50.1 ± 3.3 percent for control; p < 0.001). Significantly fewer inflammatory cells, improved muscle viability, and increased blood vessel density were observed in activated protein C-treated versus control rats. Activated protein C treatment significantly reduced mRNA levels of intercellular adhesion molecule-1 and tumor necrosis factor-α, while increasing levels of Egr-1, vascular endothelial growth factor receptor 2, and Bcl-2. CONCLUSIONS: Systemic activated protein C modulates genes involved in angiogenesis, inflammation and apoptosis and improves ischemic flap survival.