Antithrombotic effect of a recombinant von Willebrand factor, VCL, on nitrogen laser-induced thrombus formation in guinea pig mesenteric arteries.
To assess the antithrombotic effectiveness of blocking the platelet glycoprotein (GP) Ib/IX receptor for von Willebrand factor (vWF), the antiaggregating and antithrombotic effects were studied in guinea pigs using a recombinant fragment of vWF, Leu 504-Lys 728 with a single intrachain disulfide bond linking residues Cys 509-Cys 695. The inhibitory effect of this peptide, named VCL, was tested in vitro on ristocetin- and botrocetin-induced platelet aggregation and compared to the ADP-induced platelet aggregation. In vivo, the antithrombotic effect of VCL was tested in a model of laser-injured mesentery small arteries and correlated to the ex vivo ristocetin-induced platelet aggregation. In this model of laser-induced thrombus formation, five mesenteric arteries were studied in each animal, and the number of recurrent thrombi during 15 min, the time to visualization and time to formation of first thrombus were recorded. In vitro, VCL totally abolished ristocetin- and botrocetin-induced platelet aggregation, but had no effect on ADP-induced platelet aggregation. Ex vivo, VCL (0.5 to 2 mg/kg) administered as a bolus i.v. injection inhibits risocetin-induced platelet aggregation with a duration of action exceeding 1 h. The maximum inhibition was observed 5 min after injection of VCL and was dose related. The same doses of VCL had no significant effect on platelet count and bleeding time.(ABSTRACT TRUNCATED AT 250 WORDS)
Azzam
K
K
Institut des Vaisseaux et du Sang, Paris, France.
Garfinkel
L I
LI
Bal dit Sollier
C
C
Cisse Thiam
M
M
Drouet
L
L
D000595:Amino Acid Sequence; D000818:Animals; D001760:Bleeding Time; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007834:Lasers; D008297:Male; D008638:Mesenteric Arteries; D008641:Mesenteric Vascular Occlusion / Q000188:drug therapy* / Q000209:etiology; D008969:Molecular Sequence Data; D009584:Nitrogen; D010446:Peptide Fragments / Q000494:pharmacology*; D010976:Platelet Count / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D013927:Thrombosis / Q000188:drug therapy* / Q000209:etiology; D014841:von Willebrand Factor / Q000494:pharmacology*
D010446:Peptide Fragments; D011994:Recombinant Proteins; D014841:von Willebrand Factor; C090953:von Willebrand factor (504-728); D009584:Nitrogen