Local proCPU (TAFI) activation during thrombolytic treatment in a dog model of coronary artery thrombosis can be inhibited with a direct, small molecule thrombin inhibitor (melagatran).

Abstract

To test the hypothesis that the direct thrombin inhibitor, melagatran is able to inhibit local pro-carboxypeptidase U (proCPU) activation that occurs during thrombolytic treatment, t-PA alone, or in combination with melagatran, was given to dogs with a coronary artery thrombosis. Blood samples from the great cardiac vein and aorta were collected at baseline, during thrombus formation, throughout the t-PA+/-melagatran infusion and during the patency period, for analysis of CPU activity using a novel assay. A higher CPU activity in venous compared to arterial blood (V-A difference) indicates CPU activation in coronary vessels. Efficacy was assessed by determination of time to lysis, duration of patency and blood flow during patency. Dogs (n = 26) were randomized to receive either 1) t-PA, 1 mg/kg as an intravenous 20-min infusion; 2) t-PA as in group 1, +melagatran bolus, 0.3 mg/kg, followed by a 3-h infusion (0.15 mg/kg per h); 3) sham-operated but no coronary thrombus, and administered t-PA as for Group 1. All groups had similar baseline characteristics. Significant increases in CPU activity were observed in Groups 1 and 2 during thrombus formation, with V-A differences of 5.5 and 4.5 U/L, respectively. No significant V-A difference was observed in the sham-operated group. CPU activity increased in Group 1 during the t-PA infusion (V-A difference 15.9 U/L), whereas the V-A difference in Group 2 decreased to 2.6 U/L following melagatran treatment. These results demonstrate that melagatran attenuates generation of CPU in the coronary circulation. The mechanism is probably indirect, via inhibition of thrombin-mediated activation of proCPU.

• Authors: C Mattsson, J A Björkman, T Abrahamsson, V Nerme, K Schatteman, J Leurs, S Scharpé, D Hendriks
• Journal: Thrombosis and haemostasis (Thromb Haemost) Vol. 87 Issue 4 Pg. 557-62 (Apr 2002) ISSN: 0340-6245 [Print] Germany
• PMID: 12008935 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Azetidines
• Benzylamines
• Enzyme Precursors
• Fibrinolytic Agents
• melagatran
• Carboxypeptidase B2
• Thrombin
• Tissue Plasminogen Activator
• Glycine

Topics

• Animals
• Aorta
• Azetidines
• Benzylamines
• Carboxypeptidase B2 (antagonists & inhibitors, blood, physiology)
• Coronary Circulation (drug effects)
• Coronary Thrombosis (blood, drug therapy, enzymology)
• Dogs
• Enzyme Activation (drug effects)
• Enzyme Precursors (antagonists & inhibitors, blood)
• Female
• Fibrinolytic Agents (pharmacology)
• Glycine (analogs & derivatives, pharmacology)
• Male
• Models, Animal
• Random Allocation
• Thrombin (antagonists & inhibitors)
• Thrombolytic Therapy
• Tissue Plasminogen Activator (pharmacology)
• Veins