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 microg/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-alpha, 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.
Bezuhly
Michael
M
Halifax, Nova Scotia, Canada From the Division of Plastic Surgery, the Department of Anatomy and Neurobiology, the Department of Pathology, and the Department of Medicine, Dalhousie University, Queen Elizabeth II Health Sciences Centre.
Morris
Steven F
SF
Juskevicius
Ridas
R
Currie
R William
RW
West
Kenneth A
KA
Liwski
Robert S
RS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D005169:Factor VIII / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D053583:Interleukin-1beta / Q000235:genetics; D007511:Ischemia / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D008297:Male; D009336:Necrosis; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D011486:Protein C / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013524:Surgical Flaps / Q000098:blood supply / Q000473:pathology / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D053583:Interleukin-1beta; D011486:Protein C; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D005169:Factor VIII