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)

C. Mattsson; J. A. Björkman; T. Abrahamsson; V. Nerme; K. Schatteman; J. Leurs; S. Scharpé; D. Hendriks

doi:10.1055/s-0037-1613049

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2002; 87(04): 557-562
DOI: 10.1055/s-0037-1613049

In Focus

Schattauer GmbH

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)

C. Mattsson

¹AstraZeneca, Mölndal, Sweden

,

J. A. Björkman

¹AstraZeneca, Mölndal, Sweden

,

T. Abrahamsson

¹AstraZeneca, Mölndal, Sweden

,

V. Nerme

¹AstraZeneca, Mölndal, Sweden

,

K. Schatteman

²Laboratory of Medical Biochemistry, University of Antwerp, Belgium

,

J. Leurs

²Laboratory of Medical Biochemistry, University of Antwerp, Belgium

,

S. Scharpé

²Laboratory of Medical Biochemistry, University of Antwerp, Belgium

,

D. Hendriks

²Laboratory of Medical Biochemistry, University of Antwerp, Belgium

› Author Affiliations

Abstract

Summary

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.

Keywords

TAFI - thrombolysis - thrombin inhibitor - melagatran - CPU assay

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References

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