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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
1   Department of BioResources
,
Dianne Sako
2   Department of Cardiovascular and Metabolic Diseases
,
Gray D. Shaw
2   Department of Cardiovascular and Metabolic Diseases
,
Robert G. Schaub
2   Department of Cardiovascular and Metabolic Diseases
,
Qin Wang
3   Department of Discovery Pharmacokinetics and
,
Boris Tchernychev
2   Department of Cardiovascular and Metabolic Diseases
,
Jin Xu
4   Department of Characterization and Analytical Development, Wyeth Research, Cambridge, Massachusetts, USA
,
Thomas J. Porter
4   Department of Characterization and Analytical Development, Wyeth Research, Cambridge, Massachusetts, USA
,
Qinheng Huang
2   Department of Cardiovascular and Metabolic Diseases
› Author Affiliations
Further Information

Publication History

Received 11 October 2006

Accepted after resubmission 13 May 2007

Publication Date:
28 November 2017 (online)

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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
 

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