Tranexamic acid is an active site inhibitor of urokinase plasminogen activator

Guojie Wu, Blake A. Mazzitelli, Adam J. Quek, Matthew J. Veldman, Paul J. Conroy, Tom T. Caradoc-Davies, Lisa M. Ooms, Kellie L. Tuck, Jonathan G. Schoenecker, James C. Whisstock, Ruby H. P. Law

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Lysine binding sites (LBSs) of plasminogen (Plg) are essential for maintaining a closed conformation in circulation and binding to fibrin and cell surface receptors.1,2 Upon binding to the targets, Plg is activated to plasmin (Plm) by the fibrin-bound tissue plasminogen activator (tPA) or the cell receptor–bound urokinase plasminogen activator (uPA). Tranexamic acid (TXA) is a lysine analog that binds to the LBSs of Plg with 1 high-affinity (1.1 μM) and 3 medium-affinity (∼0.75 mM) binding sites.1⇓-3 Accordingly, TXA at submicromolar concentrations significantly attenuates in situ Plm formation4 and is used frequently as an antifibrinolytic agent in trauma, as well as in major surgeries, including cardiac, orthopedic, and hepatic surgeries.5

The CRASH-26 and MATTERs7 clinical studies revealed that, when TXA is administered within 3 hours after injury, mortality is reduced by up to 20%.8 Recent reanalysis of the clinical data further showed that the survival benefit of TXA decreased by 10% for every 15 minutes of delayed administration, with no benefit obtained after 3 hours.9 This lack of efficacy outside of the “3-hour window” has been associated with the upregulation of plasma uPA postinjury.6,10,11

We have previously observed that a very high concentration (∼25 mM) of TXA inhibits Plm activity via binding to the primary catalytic (S1) pocket of the enzyme.12 However, because of the low affinity of TXA for Plm, we do not anticipate that TXA functions as a Plm inhibitor during clinical use.12 However, given these findings, we investigated whether TXA may have an inhibitory effect on other proteases in the Plg-activation system. Unexpectedly, our results revealed that TXA attenuates uPA activity with an inhibitory constant (Ki) of 2 mM. In contrast, similar efficacy is not observed in the presence of ε-aminocaproic acid (EACA; an alternative drug to TXA).
Original languageEnglish
Pages (from-to)729-733
Number of pages5
JournalBlood Advances
Volume3
Issue number5
DOIs
Publication statusPublished - 12 Mar 2019

Cite this

@article{c1457236da2d4e068a3a83d8c6df6e13,
title = "Tranexamic acid is an active site inhibitor of urokinase plasminogen activator",
abstract = "Lysine binding sites (LBSs) of plasminogen (Plg) are essential for maintaining a closed conformation in circulation and binding to fibrin and cell surface receptors.1,2 Upon binding to the targets, Plg is activated to plasmin (Plm) by the fibrin-bound tissue plasminogen activator (tPA) or the cell receptor–bound urokinase plasminogen activator (uPA). Tranexamic acid (TXA) is a lysine analog that binds to the LBSs of Plg with 1 high-affinity (1.1 μM) and 3 medium-affinity (∼0.75 mM) binding sites.1⇓-3 Accordingly, TXA at submicromolar concentrations significantly attenuates in situ Plm formation4 and is used frequently as an antifibrinolytic agent in trauma, as well as in major surgeries, including cardiac, orthopedic, and hepatic surgeries.5The CRASH-26 and MATTERs7 clinical studies revealed that, when TXA is administered within 3 hours after injury, mortality is reduced by up to 20{\%}.8 Recent reanalysis of the clinical data further showed that the survival benefit of TXA decreased by 10{\%} for every 15 minutes of delayed administration, with no benefit obtained after 3 hours.9 This lack of efficacy outside of the “3-hour window” has been associated with the upregulation of plasma uPA postinjury.6,10,11We have previously observed that a very high concentration (∼25 mM) of TXA inhibits Plm activity via binding to the primary catalytic (S1) pocket of the enzyme.12 However, because of the low affinity of TXA for Plm, we do not anticipate that TXA functions as a Plm inhibitor during clinical use.12 However, given these findings, we investigated whether TXA may have an inhibitory effect on other proteases in the Plg-activation system. Unexpectedly, our results revealed that TXA attenuates uPA activity with an inhibitory constant (Ki) of 2 mM. In contrast, similar efficacy is not observed in the presence of ε-aminocaproic acid (EACA; an alternative drug to TXA).",
author = "Guojie Wu and Mazzitelli, {Blake A.} and Quek, {Adam J.} and Veldman, {Matthew J.} and Conroy, {Paul J.} and Caradoc-Davies, {Tom T.} and Ooms, {Lisa M.} and Tuck, {Kellie L.} and Schoenecker, {Jonathan G.} and Whisstock, {James C.} and Law, {Ruby H. P.}",
year = "2019",
month = "3",
day = "12",
doi = "10.1182/bloodadvances.2018025429",
language = "English",
volume = "3",
pages = "729--733",
journal = "Blood Advances",
issn = "2473-9529",
publisher = "American Society of Hematology",
number = "5",

}

Tranexamic acid is an active site inhibitor of urokinase plasminogen activator. / Wu, Guojie; Mazzitelli, Blake A.; Quek, Adam J.; Veldman, Matthew J.; Conroy, Paul J.; Caradoc-Davies, Tom T.; Ooms, Lisa M.; Tuck, Kellie L.; Schoenecker, Jonathan G.; Whisstock, James C.; Law, Ruby H. P.

In: Blood Advances, Vol. 3, No. 5, 12.03.2019, p. 729-733.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Tranexamic acid is an active site inhibitor of urokinase plasminogen activator

AU - Wu, Guojie

AU - Mazzitelli, Blake A.

AU - Quek, Adam J.

AU - Veldman, Matthew J.

AU - Conroy, Paul J.

AU - Caradoc-Davies, Tom T.

AU - Ooms, Lisa M.

AU - Tuck, Kellie L.

AU - Schoenecker, Jonathan G.

AU - Whisstock, James C.

AU - Law, Ruby H. P.

PY - 2019/3/12

Y1 - 2019/3/12

N2 - Lysine binding sites (LBSs) of plasminogen (Plg) are essential for maintaining a closed conformation in circulation and binding to fibrin and cell surface receptors.1,2 Upon binding to the targets, Plg is activated to plasmin (Plm) by the fibrin-bound tissue plasminogen activator (tPA) or the cell receptor–bound urokinase plasminogen activator (uPA). Tranexamic acid (TXA) is a lysine analog that binds to the LBSs of Plg with 1 high-affinity (1.1 μM) and 3 medium-affinity (∼0.75 mM) binding sites.1⇓-3 Accordingly, TXA at submicromolar concentrations significantly attenuates in situ Plm formation4 and is used frequently as an antifibrinolytic agent in trauma, as well as in major surgeries, including cardiac, orthopedic, and hepatic surgeries.5The CRASH-26 and MATTERs7 clinical studies revealed that, when TXA is administered within 3 hours after injury, mortality is reduced by up to 20%.8 Recent reanalysis of the clinical data further showed that the survival benefit of TXA decreased by 10% for every 15 minutes of delayed administration, with no benefit obtained after 3 hours.9 This lack of efficacy outside of the “3-hour window” has been associated with the upregulation of plasma uPA postinjury.6,10,11We have previously observed that a very high concentration (∼25 mM) of TXA inhibits Plm activity via binding to the primary catalytic (S1) pocket of the enzyme.12 However, because of the low affinity of TXA for Plm, we do not anticipate that TXA functions as a Plm inhibitor during clinical use.12 However, given these findings, we investigated whether TXA may have an inhibitory effect on other proteases in the Plg-activation system. Unexpectedly, our results revealed that TXA attenuates uPA activity with an inhibitory constant (Ki) of 2 mM. In contrast, similar efficacy is not observed in the presence of ε-aminocaproic acid (EACA; an alternative drug to TXA).

AB - Lysine binding sites (LBSs) of plasminogen (Plg) are essential for maintaining a closed conformation in circulation and binding to fibrin and cell surface receptors.1,2 Upon binding to the targets, Plg is activated to plasmin (Plm) by the fibrin-bound tissue plasminogen activator (tPA) or the cell receptor–bound urokinase plasminogen activator (uPA). Tranexamic acid (TXA) is a lysine analog that binds to the LBSs of Plg with 1 high-affinity (1.1 μM) and 3 medium-affinity (∼0.75 mM) binding sites.1⇓-3 Accordingly, TXA at submicromolar concentrations significantly attenuates in situ Plm formation4 and is used frequently as an antifibrinolytic agent in trauma, as well as in major surgeries, including cardiac, orthopedic, and hepatic surgeries.5The CRASH-26 and MATTERs7 clinical studies revealed that, when TXA is administered within 3 hours after injury, mortality is reduced by up to 20%.8 Recent reanalysis of the clinical data further showed that the survival benefit of TXA decreased by 10% for every 15 minutes of delayed administration, with no benefit obtained after 3 hours.9 This lack of efficacy outside of the “3-hour window” has been associated with the upregulation of plasma uPA postinjury.6,10,11We have previously observed that a very high concentration (∼25 mM) of TXA inhibits Plm activity via binding to the primary catalytic (S1) pocket of the enzyme.12 However, because of the low affinity of TXA for Plm, we do not anticipate that TXA functions as a Plm inhibitor during clinical use.12 However, given these findings, we investigated whether TXA may have an inhibitory effect on other proteases in the Plg-activation system. Unexpectedly, our results revealed that TXA attenuates uPA activity with an inhibitory constant (Ki) of 2 mM. In contrast, similar efficacy is not observed in the presence of ε-aminocaproic acid (EACA; an alternative drug to TXA).

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U2 - 10.1182/bloodadvances.2018025429

DO - 10.1182/bloodadvances.2018025429

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JF - Blood Advances

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