Argatroban enhances fibrinolysis by differential inhibition of thrombin-mediated activation of thrombin activatable fibrinolysis inhibitor and factor XIII

Vance G Nielsen, James K. Kirklin

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Direct thrombin inhibitors enhance fibrinolysis more efficiently than heparin. Direct thrombin inhibitors and heparin enhance fibrinolysis by inhibition of activation of thrombin activatable fibrinolysis inhibitor (TAFI); however, the role played by other thrombin-activated proteins [e.g., factor XIII (FXIII)] in fibrinolysis remained to be elucidated. Our goal was thus to define the roles of TAFI and FXIII in direct thrombin inhibitor-mediated fibrinolysis enhancement Plasma was exposed to argatroban or heparin, with coagulation initiated with kaolin/tissue factor and fibrinolysis initiated with tissue plasminogen activator. Additional experiments utilized TAFI and FXIII-deficient plasmas. Coagulation/fibrinolysis kinetics were monitored with thrombelastography. Argatroban (1.25, 2.5 μg/ml) significantly decreased clot lysis time and increased the maximum rate of lysis compared with unexposed plasma, whereas heparin exposure only diminished clot lysis time. When changes in maximum rate of lysis were related to changes in the maximum rate of thrombus generation, argatroban was associated with a greater increase in maximum rate of lysis per decrease in maximum rate of thrombus generation compared with heparin. Experiments with TAFI-deficient and FXIII-deficient plasma demonstrated a sparing of thrombin-mediated FXIII activation with concurrent inhibition of TAFI activation. The mechanism by which argatroban more efficiently enhanced fibrinolysis was via a differential inhibition of thrombin-mediated activation of TAFI and FXIII.

Original languageEnglish (US)
Pages (from-to)793-800
Number of pages8
JournalBlood Coagulation and Fibrinolysis
Volume19
Issue number8
DOIs
StatePublished - Dec 2008
Externally publishedYes

Fingerprint

Carboxypeptidase B2
Factor XIII
Fibrinolysis
Thrombin
Heparin
Antithrombins
Fibrin Clot Lysis Time
Thrombosis
Thrombelastography
Kaolin
Thromboplastin
Tissue Plasminogen Activator
argatroban

Keywords

  • Argatroban
  • Fibrinolysis
  • Heparin
  • Thrombelastography
  • Thrombin activatable fibrinolysis inhibitor
  • Tissue-type plasminogen activator

ASJC Scopus subject areas

  • Hematology

Cite this

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abstract = "Direct thrombin inhibitors enhance fibrinolysis more efficiently than heparin. Direct thrombin inhibitors and heparin enhance fibrinolysis by inhibition of activation of thrombin activatable fibrinolysis inhibitor (TAFI); however, the role played by other thrombin-activated proteins [e.g., factor XIII (FXIII)] in fibrinolysis remained to be elucidated. Our goal was thus to define the roles of TAFI and FXIII in direct thrombin inhibitor-mediated fibrinolysis enhancement Plasma was exposed to argatroban or heparin, with coagulation initiated with kaolin/tissue factor and fibrinolysis initiated with tissue plasminogen activator. Additional experiments utilized TAFI and FXIII-deficient plasmas. Coagulation/fibrinolysis kinetics were monitored with thrombelastography. Argatroban (1.25, 2.5 μg/ml) significantly decreased clot lysis time and increased the maximum rate of lysis compared with unexposed plasma, whereas heparin exposure only diminished clot lysis time. When changes in maximum rate of lysis were related to changes in the maximum rate of thrombus generation, argatroban was associated with a greater increase in maximum rate of lysis per decrease in maximum rate of thrombus generation compared with heparin. Experiments with TAFI-deficient and FXIII-deficient plasma demonstrated a sparing of thrombin-mediated FXIII activation with concurrent inhibition of TAFI activation. The mechanism by which argatroban more efficiently enhanced fibrinolysis was via a differential inhibition of thrombin-mediated activation of TAFI and FXIII.",
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AU - Kirklin, James K.

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N2 - Direct thrombin inhibitors enhance fibrinolysis more efficiently than heparin. Direct thrombin inhibitors and heparin enhance fibrinolysis by inhibition of activation of thrombin activatable fibrinolysis inhibitor (TAFI); however, the role played by other thrombin-activated proteins [e.g., factor XIII (FXIII)] in fibrinolysis remained to be elucidated. Our goal was thus to define the roles of TAFI and FXIII in direct thrombin inhibitor-mediated fibrinolysis enhancement Plasma was exposed to argatroban or heparin, with coagulation initiated with kaolin/tissue factor and fibrinolysis initiated with tissue plasminogen activator. Additional experiments utilized TAFI and FXIII-deficient plasmas. Coagulation/fibrinolysis kinetics were monitored with thrombelastography. Argatroban (1.25, 2.5 μg/ml) significantly decreased clot lysis time and increased the maximum rate of lysis compared with unexposed plasma, whereas heparin exposure only diminished clot lysis time. When changes in maximum rate of lysis were related to changes in the maximum rate of thrombus generation, argatroban was associated with a greater increase in maximum rate of lysis per decrease in maximum rate of thrombus generation compared with heparin. Experiments with TAFI-deficient and FXIII-deficient plasma demonstrated a sparing of thrombin-mediated FXIII activation with concurrent inhibition of TAFI activation. The mechanism by which argatroban more efficiently enhanced fibrinolysis was via a differential inhibition of thrombin-mediated activation of TAFI and FXIII.

AB - Direct thrombin inhibitors enhance fibrinolysis more efficiently than heparin. Direct thrombin inhibitors and heparin enhance fibrinolysis by inhibition of activation of thrombin activatable fibrinolysis inhibitor (TAFI); however, the role played by other thrombin-activated proteins [e.g., factor XIII (FXIII)] in fibrinolysis remained to be elucidated. Our goal was thus to define the roles of TAFI and FXIII in direct thrombin inhibitor-mediated fibrinolysis enhancement Plasma was exposed to argatroban or heparin, with coagulation initiated with kaolin/tissue factor and fibrinolysis initiated with tissue plasminogen activator. Additional experiments utilized TAFI and FXIII-deficient plasmas. Coagulation/fibrinolysis kinetics were monitored with thrombelastography. Argatroban (1.25, 2.5 μg/ml) significantly decreased clot lysis time and increased the maximum rate of lysis compared with unexposed plasma, whereas heparin exposure only diminished clot lysis time. When changes in maximum rate of lysis were related to changes in the maximum rate of thrombus generation, argatroban was associated with a greater increase in maximum rate of lysis per decrease in maximum rate of thrombus generation compared with heparin. Experiments with TAFI-deficient and FXIII-deficient plasma demonstrated a sparing of thrombin-mediated FXIII activation with concurrent inhibition of TAFI activation. The mechanism by which argatroban more efficiently enhanced fibrinolysis was via a differential inhibition of thrombin-mediated activation of TAFI and FXIII.

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KW - Tissue-type plasminogen activator

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