SearchPublisher and Institutes
You are here: Home :: Area NEM :: Medical science :: Human medicine
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
Pharmacologic inhibition of platelet vWF-GPIb interaction prevents coronary artery thrombosis
Keywords: Glycoprotein (GP) Iba, platelet adhesion, platelet agglutination, thrombosis, von Willebrand factor (vWF)
Under high shear arterial blood flow von Willebrand Factor (vWF) binds the platelet receptor glycoprotein (GP) Ib, leading to platelet adhesion, activation and thrombosis. Blockade of vWF-GPIb interactions by GPG-290 was investigated in a canine model of coronary artery thrombosis alone and in combination with clopidogrel. GPG-290 (100 g/kg, n = 6; 500 g/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 6 min, n = 6). Patency of the injured vessel was sustained in 1/6 (100 g/kg) and 3/6 vessels (500 g/kg) 4 hours after injury, in contrast to 0/6 in the control group. There was an increase in bleeding after the 500 g/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 for 2 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 g/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 g/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.
Thrombosis and Haemostasis, Schattauer
Print ISSN: 0340-6245
Volume: 95, 03/2006
Pages: 469 - 475