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

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 microg/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.