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Increased urokinase and consumption of ?₂ -antiplasmin as an explanation for the loss of benefit of tranexamic acid after treatment delay.

ABSTRACT: 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. ?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 IC₅₀ values for antifibrinolytic activity of TXA varied from < 10 to > 1000 ?mol 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 ?₂ -antiplasmin. No clot formed with plasma containing 40% normal ?₂ -antiplasmin after short incubation with TXA + uPA. Adding purified ?₂ -antiplasmin progressively restored clotting. Plasmin could be inhibited by aprotinin, IC₅₀ = 530 nmol L^-1 , in plasma. Conclusions Tranexamic acid protects fibrin but stimulates uPA activity and slows inhibition of plasmin by ?₂ -antiplasmin. Plasmin proteolytic activity digests fibrinogen and disrupts coagulation, exacerbated when ?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.

SUBMITTER: Longstaff C

PROVIDER: S-EPMC6334274 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Increased urokinase and consumption of α<sub>2</sub> -antiplasmin as an explanation for the loss of benefit of tranexamic acid after treatment delay.

Longstaff C C Locke M M

Journal of thrombosis and haemostasis : JTH 20181213 1

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<sub>2</sub> -Antiplasmin consumption with ongoing fibrinolysis increases plasmin-induced coagulopathy. SUMMARY: Background Tranexamic acid (TXA) is an effective antifibrinolytic agent with a proven safety record. Howe ...[more]

PMID: 30451372

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Project description:Plasmin inhibition by alpha 2-antiplasmin (alpha 2AP) is regulated by the vascular components fibrin(ogen) fragments, plasminogen and lipoprotein (a). Kinetic analysis demonstrates that CNBr-derived fibrinogen fragments completely protect plasmin from alpha 2AP. Plasminogen and 6-aminohexanoic acid decrease the rate of inhibition by 5- and 10-fold respectively. These studies show that CNBr-derived fibrinogen fragments and 6-aminohexanoic acid bind plasmin kringle(s) with binding constants of 2 micrograms/ml and 120 microM respectively, and that plasminogen binds to alpha 2AP with an affinity of 0.5 nM. The unmodulated inhibition is not effected by the presence of lipoprotein (a), but in the presence of protective CNBr-derived fibrinogen fragments the rate of inhibition is increased by the presence of the lipoprotein. The kinetics demonstrate that lipoprotein (a) binds to CNBr-derived fibrinogen fragments with an affinity of 4 nM, displacing plasmin from the protective surface. In addition, tissue-type plasminogen activator and trypsin inhibition by alpha 2AP is not slowed by the presence of CNBr-derived fibrinogen fragments or plasminogen (Pg), respectively. These kinetics suggest that the initial reversible interaction between plasmin and alpha 2AP is mediated by binding of the inhibitor to the kringle 1 domain of plasmin, with a reversible inhibition constant (Ki) of 5.0 x 10(-10) M. Under conditions where this kringle-inhibitor interaction is blocked, the reversible inhibition still occurs between the plasmin and alpha 2AP, but the initial Ki is increased to 5.0 x 10(-9) M. These data suggest that, in the circulation, plasmin inhibition by alpha 2AP may be down-regulated by fibrin, fibrin(ogen) fragments and Pg, but up-regulated by lipoprotein (a) in the presence of fibrin or fibrin(ogen) fragments. The lipoprotein (a)-mediated promotion of plasmin inhibition may provide an additional mechanism by which the lipoprotein impairs fibrinolysis and promotes atherosclerosis.

Dataset Information

Increased urokinase and consumption of ?₂ -antiplasmin as an explanation for the loss of benefit of tranexamic acid after treatment delay.

Publications

Increased urokinase and consumption of α<sub>2</sub> -antiplasmin as an explanation for the loss of benefit of tranexamic acid after treatment delay.

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Dataset Information

Increased urokinase and consumption of ?2 -antiplasmin as an explanation for the loss of benefit of tranexamic acid after treatment delay.

Publications

Increased urokinase and consumption of α<sub>2</sub> -antiplasmin as an explanation for the loss of benefit of tranexamic acid after treatment delay.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Increased urokinase and consumption of ?₂ -antiplasmin as an explanation for the loss of benefit of tranexamic acid after treatment delay.