Tranexamic Acid Mediates Pro- and Anti-Inflammatory Signaling via Complement C5a Regulation in a Plasminogen Activator-Dependent Manner

Background Both tPA in the circulation and urokinase (uPA) in tissues cleave plasminogen to plasmin to promote clot lysis. TXA blocks both the tPA-dependent generation of plasmin on blood clots as well as active plasmin binding to polymerized fibrin, and is commonly administered for bleeding in trauma to limit fibrinolysis. In addition to lysing clots, however, active plasmin also cleaves Complement proteins, potentially enhancing inflammation. Because TXA does not block uPA-dependent plasmin generation from plasminogen and instead augments it, we hypothesized that administration of TXA could enhance or inhibit pro-inflammatory C5a formation in a plasminogen activator-dependent manner. Methods Citrate platelet-poor plasma (PPP) and PPP depleted of Complement Protein C3 or plasminogen (PLG) were obtained from healthy donors and commercial sources. PPP was treated ex vivo with -/+TXA and either -/+tPA or -/+uPA. Clotting was then induced by calcium and thrombin in clotted PPP experiments, while unclotted PPP experiments were treated with vehicle controls. C5a levels were measured via ELISA. Data were expressed as mean -/+SEM. Results Plasmin-mediated fibrinolysis by tPA in clotted PPP led to a ~3-fold increase in C5a production (p

from Emergency Medicine via xlomafota13 on Inoreader https://ift.tt/2P27chk