Anti‐fibrinolytic agent tranexamic acid suppresses the endotoxin‐induced expression of Tnfα and Il1α genes in a plasmin‐independent manner

• Published in: Transfusion (Philadelphia, Pa.) Pa.), 2023-05, Vol.63 (S3), p.S168-S176
• Main Authors: Kacer, Doreen, Machnitzky, Eva, Fung, Angus, Greene, Autumn, Carter, Damien, Rappold, Joseph, Prudovsky, Igor
• Format: Article
• Language: English
• Subjects: Animals; Antifibrinolytic agents; Antifibrinolytic Agents - pharmacology; Cytokines; Edema; endotoxin; Endotoxins; Fibrin; Fibrinolysin; Fibrinolytic Agents; Heart; Hemorrhage; Inflammation; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Mice; Mitochondrial DNA; Molecular modelling; Orthopedics; Plasmin; plasminogen; Plasminogen - genetics; Plasminogen - metabolism; Polymerase chain reaction; proinflammatory cytokines; tranexamic acid; Tranexamic Acid - pharmacology; Trauma; Tumor Necrosis Factor-alpha - genetics
• ISSN: 0041-1132; 1537-2995
• DOI: 10.1111/trf.17353

Introduction Tranexamic acid (TXA) is widely used as an antifibrinolytic agent in hemorrhagic trauma patients. The beneficial effects of TXA exceed the suppression of blood loss and include the ability to decrease inflammation and edema. We found that TXA suppresses the release of mitochondrial DNA and enhances mitochondrial respiration. These results allude that TXA could operate through plasmin‐independent mechanisms. To address this hypothesis, we compared the effects of TXA on lipopolysaccharide (LPS)‐induced expression of proinflammatory cytokines in plasminogen (Plg) null and Plg heterozygous mice. Methods Plg null and Plg heterozygous mice were injected with LPS and TXA or LPS only. Four hours later, mice were sacrificed and total RNA was prepared from livers and hearts. Real time quantitative polymerase chain reaction with specific primers was used to assess the effects of LPS and TXA on the expression of pro‐inflammatory cytokines. Results LPS enhanced the expression of Tnfα in the livers and hearts of recipient mice. The co‐injection of TXA significantly decreased the effect of LPS both in Plg null and heterozygous mice. A similar trend was observed with LPS‐induced Il1α expression in hearts and livers. Conclusions The effects of TXA on the endotoxin‐stimulated expression of Tnfα and Il1α in mice do not depend on the inhibition of plasmin generation. These results indicate that TXA has other biologically important target(s) besides plasminogen/plasmin. Fully understanding the molecular mechanisms behind the extensive beneficial effects of TXA and future identification of its targets may lead to improvement in the use of TXA in trauma, cardiac, and orthopedic surgical patients.