Purpose: Fibrinolysis inhibits thrombus propagation on the surface of unstable atherosclerotic plaques. Using a clinical model of deep arterial injury, we assessed the ability of exogenous and endogenous tissue Plasminogen Activator (t-PA) to limit acute in situ thrombus formation. Methods and results: Ex vivo thrombus formation was assessed in the Badimon Chamber at low and high shear rates in two double-blind randomised cross-over studies of 20 healthy volunteers during extracorporeal administration of recombinant t-PA (0, 40, 200 and 1000 ng/mL) or during endogenous t-PA release stimulated by intra-arterial bradykinin infusion in the presence or absence of oral enalapril. Recombinant t-PA caused a dose-dependent reduction in thrombus area under low and high shear conditions (p<0.001 for all). Intra-arterial bradykinin increased plasma t-PA concentrations in the chamber effluent (p<0.01 for all versus saline) that was quadrupled in the presence of enalapril (p<0.0001 versus placebo) (Figure 1, panel A). These increases were accompanied by an increase in plasma D-dimer concentration (p<0.005 for all versus saline) (Figure 1, panel B) and, in the presence of enalapril, a reduction in thrombus area in the low shear (16%±5%, p=0.03) (Figure 1, panel C) and a trend towards a reduction in the high shear chamber (13%±7%, p=0.07) (Figure 1, panel D). ![Figure][1] Figure 1 Conclusions: Using a well-characterised clinical model of coronary arterial injury, we demonstrate that endogenous t-PA released from the vascular endothelium enhances fibrinolysis and limits in situ thrombus propagation. These data support a crucial role for the endogenous fibrinolytic system in vivo and suggest that continued exploration and manipulation of its therapeutic potential is warranted. [1]: pending:yes