title: Pharmacologic inhibition of platelet vWF-GPIb alpha interaction prevents coronary artery thrombosis.
abstract: 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.
authors.affiliation: Cardiovascular and Metabolic Disease Research, Philadelphia, PA 19101, USA. hennanj@wyeth.com
authors.forename: James K
authors.initials: JK
authors.lastname: Hennan
authors.forename: Robert E
authors.initials: RE
authors.lastname: Swillo
authors.forename: Gwen A
authors.initials: GA
authors.lastname: Morgan
authors.forename: Courtney E
authors.initials: CE
authors.lastname: Leik
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Brooks
authors.forename: Gray D
authors.initials: GD
authors.lastname: Shaw
authors.forename: Robert G
authors.initials: RG
authors.lastname: Schaub
authors.forename: David L
authors.initials: DL
authors.lastname: Crandall
authors.forename: George P
authors.initials: GP
authors.lastname: Vlasuk
mesh_terms: D000818:Animals; D001760:Bleeding Time; D000077144:Clopidogrel; D003328:Coronary Thrombosis / Q000517:prevention & control*; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D000077542:Eptifibatide; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010455:Peptides / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors; D014654:Vascular Patency / Q000187:drug effects; D014841:von Willebrand Factor / Q000037:antagonists & inhibitors
chemical_list: D005343:Fibrinolytic Agents; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D019038:Platelet Glycoprotein GPIb-IX Complex; D011993:Recombinant Fusion Proteins; C023592:glycocalicin; D014841:von Willebrand Factor; D000077144:Clopidogrel; D000077542:Eptifibatide; D013988:Ticlopidine