Erythropoietin and Soft Tissue Flap Survival: A Systematic Review

BACKGROUND: Erythropoietin (EPO) has emerging tissue-protective roles, including anti-apoptotic, anti-inflammatory, and pro-angiogenic effects. In reconstructive surgery, where flap necrosis remains a significant challenge, EPO has been investigated as an agent to enhance flap survival. Currently, no pharmacological agent has consistently improved flap survival, underscoring the need for novel therapeutics. METHODS: A systematic review was conducted in accordance with PRISMA guidelines. PubMed, Embase, and CENTRAL databases were searched from inception to September 2025. Eligible studies investigated the effect of EPO on surgical flap survival in animal or human models compared with placebo/no treatment, reporting percentage flap necrosis. Secondary outcomes included perfusion, histological and molecular parameters, and safety. RESULTS: Nine animal studies met the pre-defined inclusion criteria (mice, n = 139; rats, n = 196) using random-pattern dorsal, musculocutaneous, and TRAM flap models. All studies evaluated the effect of recombinant human EPO with a variety of different doses, routes, and time applications. Across all studies, EPO was associated with reduced flap necrosis versus controls, with the greatest benefit observed from short-course, low-dose peri-operative regimes. High-dose or prolonged schedules were less effective and occasionally detrimental. EPO improved perfusion (capillary density, arteriolar flow), enhanced microvascularity and tissue preservation, and upregulated vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (NOS) with reduced oxidative stress. No thrombotic events or treatment-related mortality were reported. CONCLUSION: EPO improves flap survival in experimental animal models. Short-term, low-dose preconditioning appears most effective, while higher doses raise safety concerns. Translation to clinical practice requires optimization of dosing strategies and rigorous clinical trials.