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Increased urokinase and consumption of α 2 ‐antiplasmin as an explanation for the loss of benefit of tranexamic acid after treatment delay
Author(s) -
Longstaff C.,
Locke M.
Publication year - 2019
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.14338
Subject(s) - tranexamic acid , plasmin , antifibrinolytic , aprotinin , fibrinolysis , fibrin , urokinase , pharmacology , plasminogen activator , chemistry , coagulopathy , medicine , biochemistry , immunology , blood loss , surgery , enzyme
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.