title: The von Willebrand factor antagonist (GPG-290) prevents coronary thrombosis without prolongation of bleeding time.
abstract: The interaction between von Willebrand factor (VWF) and platelet glycoprotein Ibalpha (GPIbalpha) 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 GPIbalpha chimeric protein, would prevent thrombosis in a canine model of coronary thrombosis by blocking VWF-GPIbalpha 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 microg/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 microg/kg of GPG-290 was prevented by intravenous infusion of DDAVP (0.3 microg/kg). In conclusion, GPG-290 appears to be an effective agent for treating arterial thrombosis without bleeding time prolongation.
authors.affiliation: Department of BioResources, Wyeth Research, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Wadanoli
authors.forename: Dianne
authors.initials: D
authors.lastname: Sako
authors.forename: Gray D
authors.initials: GD
authors.lastname: Shaw
authors.forename: Robert G
authors.initials: RG
authors.lastname: Schaub
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.forename: Boris
authors.initials: B
authors.lastname: Tchernychev
authors.forename: Jin
authors.initials: J
authors.lastname: Xu
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Porter
authors.forename: Qinheng
authors.initials: Q
authors.lastname: Huang
mesh_terms: D000818:Animals; D001760:Bleeding Time; D003328:Coronary Thrombosis / Q000188:drug therapy / Q000517:prevention & control*; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000627:therapeutic use*; D015539:Platelet Activation / Q000187:drug effects*; D010979:Platelet Function Tests; D019038:Platelet Glycoprotein GPIb-IX Complex; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D014841:von Willebrand Factor / Q000032:analysis / Q000037:antagonists & inhibitors*
chemical_list: C523730:GPG-290 protein; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D019038:Platelet Glycoprotein GPIb-IX Complex; D011993:Recombinant Fusion Proteins; C094990:adhesion receptor; D014841:von Willebrand Factor; D003894:Deamino Arginine Vasopressin