Cytotoxicity and effect on wound re-epithelialization after topical administration of tranexamic acid

Background Topical administration of tranexamic acid (TXA) reduces bleeding from surgical wounds similarly to intravenous use, but with negligible risk of adverse systemic events. Topical use is expanding, but is off-label. Surgeons lack guidelines regarding safe topical dosages and modes of administration. The effects of topical TXA on skin cells and wound healing are unknown. This study investigated whether topical TXA might be cytotoxic or affect wound re-epithelialization. Methods Human keratinocytes and fibroblast cell cultures and an ex vivo human skin wound model were subjected to both short (limited) and long (chronic) exposure to various clinically relevant concentrations of TXA to mimic different modalities of topical administration. Cytotoxicity and effects on wound re-epithelialization were evaluated. Results In cell culture, toxicity from chronic exposure was associated with increasing concentration and exposure time. Limited exposure to TXA did not cause significant cytotoxicity even at high concentrations. Re-epithelialization was completely absent in wounds chronically exposed to TXA concentrations of 25 mg/ml or above, and 50-100 mg/ml induced epidermolysis of normal epithelium, possibly by a non-toxic mechanism. Wound re-epithelialization was slightly delayed, but not impaired, by limited exposure to 100 mg/ml or chronic exposure to 6 center dot 25 mg/ml. Conclusion Although short exposure to even high concentrations of topical TXA seems well tolerated in vitro, prolonged exposure can be cytotoxic and may affect wound re-epithelialization. Surgeons should adjust the TXA concentration to the planned mode of topical administration in clinical practice.Surgical relevance Topical tranexamic acid (TXA) may reduce bleeding from surgical wounds similarly to intravenous administration without the risk of systemic effects. Little is known, however, regarding the adverse effects of TXA on exposed tissues. We exposed in vitro human keratinocytes and fibroblasts and an ex vivo human skin wound model to TXA at various concentrations and time intervals and found that short exposure to even high concentrations or prolonged exposure to low concentrations of TXA was well tolerated. Prolonged exposure to increasing concentrations increased keratinocyte and fibroblast toxicity, and TXA concentrations of 25 mg/ml or above completely prevented wound-re-epithelialization. Prolonged exposure to high concentrations of topical TXA may exert unwanted local tissue effects. This study suggests that surgeons should adjust TXA concentration to the planned mode of topical administration in clinical practice.