• Richard A Jacobson, Ashley J Williamson, Kiedo Wienholts, Sara Gaines, Sanjiv Hyoju, Harry van Goor, Alexander Zaborin, Benjamin D Shogan, Olga Zaborina, and John C Alverdy.
• Rush University Medical Center Department of Surgery, Chicago, IL.
• Ann. Surg. 2021 Dec 1; 274 (6): e1038-e1046.

ObjectiveTo investigate the role of bacterial- mediated plasminogen (PLG) activation in the pathogenesis of anastomotic leak (AL) and its mitigation by tranexamic acid (TXA).BackgroundAL is the most feared complication of colorectal resections. The pathobiology of AL in the setting of a technically optimal procedure involves excessive submucosal collagen degradation by resident microbes. We hypothesized that activation of the host PLG system by pathogens is a central and targetable pathway in AL.MethodsWe employed kinetic analysis of binding and activation of human PLG by microbes known to cause AL, and collagen degradation assays to test the impact of PLG on bacterial collagenolysis. Further, we measured the ability of the antifibrinolytic drug TXA to inhibit this process. Finally, using mouse models of pathogen-induced AL, we locally applied TXA via enema and measured its ability to prevent a clinically relevant AL.ResultsPLG is deposited rapidly and specifically at the site of colorectal anastomoses. TXA inhibited PLG activation and downstream collagenolysis by pathogens known to have a causal role in AL. TXA enema reduced collagenolytic bacteria counts and PLG deposition at anastomotic sites. Postoperative PLG inhibition with TXA enema prevented clinically and pathologically apparent pathogen-mediated AL in mice.ConclusionsBacterial activation of host PLG is central to collagenolysis and pathogen-mediated AL. TXA inhibits this process both in vitro and in vivo. TXA enema represents a promising method to prevent AL in high-risk sites such as the colorectal anastomoses.Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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