Prevention of Anastomotic Leak Via Local Application of Tranexamic Acid to Target Bacterial-mediated Plasminogen Activation

Abstract

Objective: To investigate the role of bacterial-mediated plasminogen (PLG) activation in the pathogenesis of anastomotic leak (AL) and its mitigation by tranexamic acid (TXA). Background: AL 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. Methods: We 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. Results: PLG 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. Conclusions: Bacterial 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.

Antibiotic Bowel Decontamination in Gastrointestinal Surgery—A Single-Center 20 Years’ Experience

“…The concept of perioperative antibiotic bowel decontamination in gastrointestinal surgery based on the use of a (modified) SDD regimen may be able to improve patient safety and surgical outcome in gastrointestinal oncologic surgery in a routine clinical setting. Based on new experimental data, agents other than antibiotics, such as polyphosphates or protease inhibitors, may be an alternative in the future but have not yet been introduced into clinical practice ( 64 , 65 ).…”

New understanding of gut microbiota and colorectal anastomosis leak: A collaborative review of the current concepts

“…Bacterial-mediated plasminogen (PLG) activation also plays an essential role in the pathogenesis of AL ( Jacobson et al., 2021 ). Interestingly, P. aeruginosa and E. faecalis have developed the ability to get the host PLG system up to a high level, leading to collagen lysis ( Lahteenmaki et al., 2005 ).…”

“…Tranexamic acid (TXA) is an antifibrinolytic lysine analog that inhibits PLG from binding to bacterial cellular receptors. The pharmacological application of TXA successfully prevented AL by targeting the pathogen-induced PLG activation ( Jacobson et al., 2021 ).…”

The Benefits of Robotic Surgery: Are They Technical or Molecular?

“…For example, the recent discovery that elements with the coagulation system (i.e., plasminogen/plasmin) play a role in anastomotic leak pathogenesis may offer a molecular explanation for lower bleeding and leak rates with robotic surgery. 6 , 7…”