RELATIVE INVOLVEMENT OF GPIB IX-VWF AXIS AND GPIIB/IIIA IN THROMBUS GROWTH AT HIGH-SHEAR RATES IN THE GUINEA-PIG/

The relative involvement of the glycoprotein (GP) Ib/IX-von Willebrand factor (vWF) axis and GPIIb/IIIa in thrombus growth al high shear rat es was assessed and compared by testing the pharmacological effects of VCL, a recombinant GPIb-binding fragment of vWF (residues 504-728), a urintricarboxylic acid (ATA), which binds to the 509-695 disulfide loo p of VWF, and lamifiban, a specific synthetic GPIIb/IIIa antagonist. I n vivo, their effects were evaluated in guinea pig mesenteric arteries , in a model of a laser-induced cyclic thrombotic process, and ex vivo , at a shear rate of 1800 s(-1), in a capillary perfusion chamber mode l, in which collagen-adherent platelets are exposed to nonanticoagulat ed guinea pig blood. In vivo, VCL, ATA, and lamifiban administered 2 m inutes after intimal injuries stopped thrombus growth, prevented the c yclic thrombotic process, and induced gradual thrombus dissolution. Ex vivo, at 1800 s(-1), collagen exposure to untreated blood for 2 minut es, 4 minutes, or two consecutive periods of 2 minutes each resulted i n similar platelet adhesion, 56%, 59%, and 61%, respectively, with an average thrombus volume of 6, 19, and 17.5 mu m(3)/mu m(2), respective ly, without any fibrin formation. This indicated that the two consecut ive perfusions did not affect the dynamic process of thrombus growth. When collagen-adherent platelets deposited after the first 2-minute pe rfusion were perfused for 2 minutes with VCL-, ATA-, or lamifiban-trea ted blood, thrombus growth was prevented and platelet adhesion remaine d unchanged, but fibrin formation increased on and around the predepos ited platelets. These results suggest that both the GPIb/IX-vWF axis a nd GPIIb/IIIa are involved in in vivo platelet-to-platelet interaction s at high shear rates in the guinea pig.