Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

• Published in: Thrombosis research Vol. 116; no. 6; pp. 519 - 524
• Main Authors: Björkman, Jan-Arne E., Abrahamsson, Tommy I., Nerme, Viveca K., Mattsson, Christer J.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Ltd 2005; Elsevier Science
• Subjects: 3-Mercaptopropionic Acid - analogs & derivatives; 3-Mercaptopropionic Acid - therapeutic use; Animals; Biological and medical sciences; Blood and lymphatic vessels; Carboxypeptidase B2 - antagonists & inhibitors; Carboxypeptidase U; Cardiology. Vascular system; Coronary artery thrombosis; Coronary heart disease; Coronary Thrombosis - drug therapy; Coronary Thrombosis - physiopathology; Disease Models, Animal; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Dogs; Drug Therapy, Combination; Female; Fibrinolysis - drug effects; Fibrinolytic Agents - therapeutic use; Fundamental and applied biological sciences. Psychology; General aspects; Heart; Lysine Carboxypeptidase - antagonists & inhibitors; Male; Medical sciences; Plasminogen Activators - therapeutic use; Recombinant Proteins - therapeutic use; rt-PA; TAFIa; Thrombolysis; Thrombolytic Therapy; Tissue Plasminogen Activator - therapeutic use; Vertebrates: cardiovascular system; Carboxypeptidase U; Coronary artery thrombosis; Thrombolysis; rt-PA; TAFIa; Intravenous administration; Cardiovascular disease; t-Plasminogen activator; Arterial disease; Vascular disease; Reperfusion; Arterial pressure; Blood pressure; Dog; Human; Fissipedia; Carnivora; Serine endopeptidases; Enzyme; Coronary artery; Coronary heart disease; Blood flow; Heart rate; Peptidases; Vertebrata; Mammalia; Treatment; Animal; Lysis; Hydrolases; Hemodynamics; Artery occlusion; Metallocarboxypeptidases
• DOI: 10.1016/j.thromres.2005.02.009
• EISSN: 1879-2472
• ISSN: 0049-3848

The objective of this study was to test the hypothesis if thrombolysis induced by recombinant tissue-type plasminogen activator, (rt-PA) could be facilitated by inhibiting carboxypeptidase U (CPU, active Thrombin Activatable Fibrinolysis Inhibitor, TAFIa) activity. The efficacy of rt-PA alone, or in combination with the carboxypeptidase inhibitor MERGETPA, was compared in a dog model of coronary artery thrombosis. Twenty dogs were randomised in two groups, one received rt-PA, 1 mg kg
−1, as intravenous infusion over 20 min starting 30 min after thrombus formation, and the other group received rt-PA, 1 mg kg
−1, as group one with the addition of MERGEPTA 5 mg kg
−1 starting 25 min prior to coronary artery occlusion and followed by infusion of 5 mg kg
−1 h
−1 until the end of experiment. Efficacy was assessed by determination of time to lysis, duration of patency and blood flow during patency. Both groups had similar baseline characteristics with respect to haemodynamic parameters, i.e., heart rate, blood pressure and coronary artery blood flow. Coadministration of rt-PA and MERGETPA resulted in significant decrease in time to lysis (15±1.5 min vs. 20±1.7 min,
p=0.03), increased patency time (87±16 min vs. 46±12 min,
p=0.047) and increased coronary blood flow during patency (1131 mL h
−1 vs. 405 mL h
−1,
p=0.015), compared to rt-PA alone. These results indicate that an inhibitor of CPU activity may have a beneficial effect in patients undergoing thrombolytic therapy by attaining shorter time to reperfusion and improved coronary patency.