BACKGROUND

Both tissue plasminogen activator (tPA) in the circulation and urokinase (uPA) in tissues cleave plasminogen (PLG) to plasmin to promote clot lysis. Tranexamic acid (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 PLG and instead augments it, we hypothesized that administration of TXA could enhance or inhibit proinflammatory C5a formation in a PLG activator–dependent manner.

METHODS

Citrate platelet-poor plasma (PPP) and PPP depleted of complement protein C3 or PLG were obtained from healthy donors and commercial sources. Platelet-poor plasma was treated ex vivo with or without TXA and either with or without tPA or with or without 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 enzyme–linked immunosorbent assay. Data were expressed as mean±SEM.

RESULTS

Plasmin-mediated fibrinolysis by tPA in clotted PPP led to an approximately threefold increase in C5a production (p< 0.0001), which was significantly inhibited by TXA (p< 0.001). Paradoxically, when fibrinolysis was induced by uPA, TXA treatment led to further increases in C5a production beyond uPA alone (p< 0.0001). Furthermore, clotting was not required for C5a generation from uPA+ TXA. C3 depletion had no effect on C5a production, while depletion of PLG eliminated it.

CONCLUSIONS