Pharmacologic inhibition of platelet vWF-GPIbα interaction prevents coronary artery thrombosis

James K. Hennan; Robert E. Swillo; Gwen A. Morgan; Courtney E. Leik; Jonathan M. Brooks; Gray D. Shaw; Robert G. Schaub; David L. Crandall; George P. Vlasuk

doi:10.1160/TH05-09-0640

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2006; 95(03): 469-475
DOI: 10.1160/TH05-09-0640

Platelets and Blood Cells

Schattauer GmbH

Pharmacologic inhibition of platelet vWF-GPIbα interaction prevents coronary artery thrombosis

Authors

James K. Hennan

¹Cardiovascular and Metabolic Disease Research, Wyeth Research, Collegeville, Pennsylvania
Robert E. Swillo

¹Cardiovascular and Metabolic Disease Research, Wyeth Research, Collegeville, Pennsylvania
Gwen A. Morgan

¹Cardiovascular and Metabolic Disease Research, Wyeth Research, Collegeville, Pennsylvania
Courtney E. Leik

¹Cardiovascular and Metabolic Disease Research, Wyeth Research, Collegeville, Pennsylvania
Jonathan M. Brooks

^*Cardiovascular and Metabolic Disease Research, Wyeth Research, Collegeville, Pennsylvania, Cambridge, Massachussetts, USA
Gray D. Shaw

^*Cardiovascular and Metabolic Disease Research, Wyeth Research, Collegeville, Pennsylvania, Cambridge, Massachussetts, USA
Robert G. Schaub

^*Cardiovascular and Metabolic Disease Research, Wyeth Research, Collegeville, Pennsylvania, Cambridge, Massachussetts, USA
David L. Crandall

¹Cardiovascular and Metabolic Disease Research, Wyeth Research, Collegeville, Pennsylvania
George P. Vlasuk

^*Cardiovascular and Metabolic Disease Research, Wyeth Research, Collegeville, Pennsylvania, Cambridge, Massachussetts, USA

Abstract

Summary

Under high shear arterial blood flow von Willebrand Factor (vWF) binds the platelet receptor glycoprotein (GP) Ibα, leading to platelet adhesion, activation and thrombosis. Blockade of vWF-GPIbα interactions by GPG-290 was investigated in a canine model of coronary artery thrombosis alone and in combination with clopidogrel. GPG-290 (100 µg/kg, n=6; 500 µg/kg, n=6) prolonged time to thrombotic occlusion (TTO) to 105±34 and 156±23 (p<0.05) min, respectively compared to the saline treated control group (32±6min, n=6). Patency of the injured vessel was sustained in 1/6 (100µg/kg) and 3/6 vessels (500 µg/kg) 4 hours after injury, in contrast to 0/6 in the control group. There was an increase in bleeding after the 500 µg/kg dose, but only at the 1 hr time point. Clopidogrel was studied in two dosing regimens representing either a clinical pretreatment regimen (PTR) of 4.3 mg/kg on day –2 followed by 1.1 mg/kg daily for2 days prior to the procedure or pre-procedural loading dose regimen (LDR) of 4.3 mg/kg 3 hr pre-procedure. The PTR and LDR clopidogrel treatments prolonged TTO to 98.2±30.0 min and 136.1±39.5 min (p<0.05), and sustained patency in 1/6 and 4/8 vessels, respectively. However, template bleeding time in the LDR clopidogrel group was sustained higher than the control group. The combination of PTR clopidogrel and GPG-290 (100 µg/kg) prolonged TTO equivalent to LDR clopidogrel alone (141.4±35.1 min) and sustained patency in 3/7 dogs, without increased bleeding while LDR clopidogrel combined with 100 µg/kg GPG-290 prevented occlusion in 5/8 dogs and further prolonged TTO (173.5±32.6 min) but was associated with increased bleeding compared to control. GPG-290 is an antithrombotic agent that may be combined with lower doses of clopidogrel to yield similar antithrombotic efficacy as higher loading doses.

Keywords

Glycoprotein (GP) Ibα - platelet adhesion - platelet agglutination - thrombosis - von Willebrand factor (vWF)

Full Text

References

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