The von Willebrand factor antagonist (GPG-290) prevents coronary thrombosis without prolongation of bleeding time

Michael Wadanoli; Dianne Sako; Gray D. Shaw; Robert G. Schaub; Qin Wang; Boris Tchernychev; Jin Xu; Thomas J. Porter; Qinheng Huang

doi:10.1160/TH06-10-0582

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2007; 98(02): 397-405
DOI: 10.1160/TH06-10-0582

Cardiovascular Biology and Cell Signalling

Schattauer GmbH

The von Willebrand factor antagonist (GPG-290) prevents coronary thrombosis without prolongation of bleeding time

Michael Wadanoli

¹Department of BioResources

,

Dianne Sako

²Department of Cardiovascular and Metabolic Diseases

,

Gray D. Shaw

²Department of Cardiovascular and Metabolic Diseases

,

Robert G. Schaub

²Department of Cardiovascular and Metabolic Diseases

,

Qin Wang

³Department of Discovery Pharmacokinetics and

,

Boris Tchernychev

²Department of Cardiovascular and Metabolic Diseases

,

Jin Xu

⁴Department of Characterization and Analytical Development, Wyeth Research, Cambridge, Massachusetts, USA

,

Thomas J. Porter

⁴Department of Characterization and Analytical Development, Wyeth Research, Cambridge, Massachusetts, USA

,

Qinheng Huang

²Department of Cardiovascular and Metabolic Diseases

› Author Affiliations

Abstract

Summary

The interaction between von Willebrand factor (VWF) and platelet glycoprotein Ibα (GPIbα) is a critical step that allows platelet adhesion, activation and subsequent thrombus formation to the injured vessel wall under high-shear conditions. In this study, we sought to investigate 1) whether GPG-290, a recombinant human GPIbα chimeric protein, would prevent thrombosis in a canine model of coronary thrombosis by blocking VWFGPIbα interaction; and 2) whether desmopressin (DDAVP), a VWF release stimulant, could reduce the prolonged bleeding time caused by a 10x efficacious dose of GPG-290. The antithrombotic efficacy of GPG-290 was evaluated by the in-vivo ability to prevent cyclic flow reductions (CFRs) and ex-vivo inhibition of platelet adhesion/aggregation reflected by prolongation of Platelet Function Analyzer (PFA-100^®) collagen /ADP closure time. The anti-hemostatic effect was assessed by template bleeding time. GPG-290 at doses of 25, 50 and 100 μg/kg abolished CFRs in 67%,100% and 100% of the treated dogs without bleeding time prolongation, respectively; GPG-290 dose-dependently prolonged the ex-vivo collagen/ADP-closure time, while it had no effects on plasma VWF antigen level (VWF:Ag) and VWF-collagen binding activity (VWF:CB); the prolonged template bleeding time caused by 500 μg/kg of GPG-290 was prevented by intravenous infusion of DDAVP (0.3 μg/kg). In conclusion, GPG-290 appears to be an effective agent for treating arterial thrombosis without bleeding time prolongation.

Keywords

Glycoprotein (GP) Ibα - DDAVP - vonWillebrand factor - thrombosis - platelet adhesion/activation

Full Text

References

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