A novel inhibitor of activated thrombin activatable fibrinolysis inhibitor (TAFIa) – Part II: Enhancement of both exogenous and endogenous fibrinolysis in animal models of thrombosis

Yi-Xin Wang; Valdeci da Cunha; Jon Vincelette; Lei Zhao; Mariko Nagashima; Kohichi Kawai; Shendong Yuan; Kumar Emayan; Imadul Islam; Junko Hosoya; Mark E. Sullivan; William P. Dole; John Morser; Brad O. Buckman; Ronald Vergona

doi:10.1160/TH06-09-0552

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2007; 97(01): 54-61
DOI: 10.1160/TH06-09-0552

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

A novel inhibitor of activated thrombin activatable fibrinolysis inhibitor (TAFIa) – Part II: Enhancement of both exogenous and endogenous fibrinolysis in animal models of thrombosis

Authors

Yi-Xin Wang

¹Berlex Bioscience, Richmond, California, USA
Valdeci da Cunha

¹Berlex Bioscience, Richmond, California, USA
Jon Vincelette

¹Berlex Bioscience, Richmond, California, USA
Lei Zhao

¹Berlex Bioscience, Richmond, California, USA
Mariko Nagashima

¹Berlex Bioscience, Richmond, California, USA
Kohichi Kawai

¹Berlex Bioscience, Richmond, California, USA
Shendong Yuan

¹Berlex Bioscience, Richmond, California, USA
Kumar Emayan

¹Berlex Bioscience, Richmond, California, USA
Imadul Islam

¹Berlex Bioscience, Richmond, California, USA
Junko Hosoya

¹Berlex Bioscience, Richmond, California, USA
Mark E. Sullivan

¹Berlex Bioscience, Richmond, California, USA
William P. Dole

¹Berlex Bioscience, Richmond, California, USA
John Morser

¹Berlex Bioscience, Richmond, California, USA
Brad O. Buckman

¹Berlex Bioscience, Richmond, California, USA
Ronald Vergona

¹Berlex Bioscience, Richmond, California, USA

Abstract

Summary

We have discovered a novel small-molecule TAFIa inhibitor, BX 528, which is potent, highly selective against other carboxypeptidases and safe. The present study was to determine if BX 528 can enhance exogenous and endogenous thrombolysis in four different animal models. In the first three models, a thrombus was induced by FeCl₂ (dogs) or laser (rats) injury of the femoral artery, or formed ex vivo and implanted in the jugular vein in rabbits. A low dose of exogenous t-PA was given to induce a lowlevel thrombolysis on an established thrombus. Co-treatment with BX 528 further enhanced the thrombolytic effects induced by the exogenous t-PA and, thus, r educed thrombosis in all three animal models. In a second rat model, fibrin deposition in the lungs was induced by batroxobin, which was spontaneously resolved in 30 minutes due to the activation of endogenous fibrinolysis. Pre-treatment with lipopolysaccharide (LPS) attenuated this spontaneous fibrinolysis. Co-treatment with 10 mg/kg BX 528 prevented the LPS-induced attenuation of endogenous fibrinolysis. Thus, these studies demonstrated that inhibition ofTAFIa by BX 528, our newly discovered small-molecule TAFIa inhibitor, enhanced both the exogenous (induced by a low dose of t-PA) and endogenous (LPS-induced resistance) thrombolysis without increasing the bleeding risk in four different animal models of thrombosis in different species (rat, dog and rabbit) employing different thrombogenic stimuli (FeCl₂, laser, ex vivo and batroxobin) to induce thrombus formation in different tissues (artery, vein and lung microcirculation).

Keywords

TAFI - fibrinolysis - thombolysis - thrombosis - bleeding - rat - dog - rabbit

Full Text

References

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