Pharmacologic inhibition of platelet vWF-GPIb alpha interaction prevents coronary artery thrombosis

• Published in: Thrombosis and haemostasis Vol. 95; no. 3; p. 469
• Main Authors: Hennan, James K, Swillo, Robert E, Morgan, Gwen A, Leik, Courtney E, Brooks, Jonathan M, Shaw, Gray D, Schaub, Robert G, Crandall, David L, Vlasuk, George P
• Format: Journal Article
• Language: English
• Published: Germany 01.03.2006
• Subjects: Animals; Bleeding Time; Coronary Thrombosis - prevention & control; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fibrinolytic Agents - pharmacology; Fibrinolytic Agents - therapeutic use; Peptides - pharmacology; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - pharmacology; Platelet Aggregation Inhibitors - therapeutic use; Platelet Glycoprotein GPIb-IX Complex - genetics; Platelet Glycoprotein GPIb-IX Complex - pharmacology; Platelet Glycoprotein GPIb-IX Complex - therapeutic use; Recombinant Fusion Proteins - pharmacology; Recombinant Fusion Proteins - therapeutic use; Ticlopidine - analogs & derivatives; Ticlopidine - pharmacology; Ticlopidine - therapeutic use; Time Factors; Vascular Patency - drug effects; von Willebrand Factor - antagonists & inhibitors
• ISSN: 0340-6245
• DOI: 10.1160/TH05-09-0640

Under high shear arterial blood flow von Willebrand Factor (vWF) binds the platelet receptor glycoprotein (GP) Ibalpha, leading to platelet adhesion, activation and thrombosis. Blockade of vWF-GPIb alpha interactions by GPG-290 was investigated in a canine model of coronary artery thrombosis alone and in combination with clopidogrel. GPG-290 (100 microg/kg, n=6; 500 microg/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 microg/kg) and 3/6 vessels (500 microg/kg) 4 hours after injury, in contrast to 0/6 in the control group. There was an increase in bleeding after the 500 microg/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 microg/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 microg/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.