OBJECTIVE: 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. APPROACH AND RESULTS: Ex vivo thrombus formation was assessed in the Badimon chamber at low and high shear rates in 2 double-blind randomized cross-over studies of 20 healthy volunteers duringextracorporeal 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). These increases were accompanied by an increase in plasma D-dimer concentration (P<0.005 for all versus saline) and, in the presence of enalapril, a reduction in thrombus area in the low shear (16±5; P=0.03) and a trend toward a reduction in the high shear chamber (13±7%; P=0.07). CONCLUSIONS: Using a well-characterized 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 are warranted.
RCT Entities:
OBJECTIVE: 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. APPROACH AND RESULTS: Ex vivo thrombus formation was assessed in the Badimon chamber at low and high shear rates in 2 double-blind randomized 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). These increases were accompanied by an increase in plasma D-dimer concentration (P<0.005 for all versus saline) and, in the presence of enalapril, a reduction in thrombus area in the low shear (16±5; P=0.03) and a trend toward a reduction in the high shear chamber (13±7%; P=0.07). CONCLUSIONS: Using a well-characterized 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 are warranted.
Authors: Jack P M Andrews; Christophe Portal; Tashfeen Walton; Mark G Macaskill; Patrick W F Hadoke; Carlos Alcaide Corral; Christophe Lucatelli; Simon Wilson; Ian Wilson; Gillian MacNaught; Marc R Dweck; David E Newby; Adriana A S Tavares Journal: Eur Heart J Cardiovasc Imaging Date: 2020-06-01 Impact factor: 6.875
Authors: Mohammed N Meah; Jennifer Raftis; Simon J Wilson; Vidya Perera; Samira M Garonzik; Bindu Murthy; J Gerry Everlof; Ronald Aronson; Joseph Luettgen; David E Newby Journal: Arterioscler Thromb Vasc Biol Date: 2020-09-10 Impact factor: 8.311
Authors: Claire S Whyte; Hadj Ahmed Mostefai; Kim M Baeten; Andrew J Lucking; David E Newby; Nuala A Booth; Nicola J Mutch Journal: Int J Mol Sci Date: 2021-02-20 Impact factor: 6.208