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Essentials    Delayed treatment with tranexamic acid results in loss of efficacy and poor outcomes.  Increasing urokinase activity may account for adverse effects of late tranexamic acid treatment.  Urokinase + tranexamic acid produces plasmin in plasma or blood and disrupts clotting.  α 2 ‐Antiplasmin consumption with ongoing fibrinolysis increases plasmin‐induced coagulopathy.Summary   Background  Tranexamic acid ( TXA ) is an effective antifibrinolytic agent with a proven safety record. However, large clinical trials show  TXA  becomes ineffective or harmful if treatment is delayed beyond 3 h. The mechanism is unknown but urokinase plasminogen activator ( uPA ) has been implicated.    Methods  Inhibitory mechanisms of  TXA  were explored in a variety of clot lysis systems using plasma and whole blood. Lysis by tissue plasminogen activator ( tPA ),  uPA  and plasmin were investigated. Coagulopathy was investigated using  ROTEM  and activated partial thromboplastin time ( APTT ).    Results  IC 50  values for antifibrinolytic activity of  TXA  varied from < 10 to > 1000 μmol L −1  depending on the system, but good fibrin protection was observed in the presence of  tPA ,  uPA  and plasmin. However, in plasma or blood, active plasmin was generated by  TXA  +  uPA  (but not  tPA ) and coagulopathy developed leading to no or poor clot formation. The extent of coagulopathy was sensitive to available α 2 ‐antiplasmin. No clot formed with plasma containing 40% normal α 2 ‐antiplasmin after short incubation with  TXA  +  uPA . Adding purified α 2 ‐antiplasmin progressively restored clotting. Plasmin could be inhibited by aprotinin ,  IC 50  = 530 nmol L −1 , in plasma.    Conclusions  Tranexamic acid protects fibrin but stimulates  uPA  activity and slows inhibition of plasmin by α 2 ‐antiplasmin. Plasmin proteolytic activity digests fibrinogen and disrupts coagulation, exacerbated when α 2 ‐antiplasmin is consumed by ongoing fibrinolysis. Additional direct inhibition of plasmin by aprotinin may prevent development of coagulopathy and extend the useful time window of  TXA  treatment.

Increased urokinase and consumption of α 2 ‐antiplasmin as an explanation for the loss of benefit of tranexamic acid after treatment delay