OPTIMAL ANTAGONISM OF GPIIB IIIA FAVORS PLATELET-ADHESION BY INHIBITING THROMBUS GROWTH - AN EX-VIVO CAPILLARY PERFUSION CHAMBER STUDY IN THE GUINEA-PIG/

To evaluate the involvement of the glycoprotein (GP) IIb/IIIa-dependen t process in platelet deposition and thrombus growth on capillaries co ated with human type III collagen, the effects of incremental doses of Lamifiban, a potent specific synthetic GPIIb/IIIa antagonist, were st udied in ex vivo capillary perfusion chambers using guinea pig blood. In this model, nonanticoagulated blood was perfused for 4.5 minutes at three shear rates: 100, 650, and 1600 s(-1). Platelet deposition was quantified by computer-assisted morphometry and expressed as platelet adhesion (percentage of capillary surface covered with spread and cont act platelets and platelets implicated in thrombus), mean thrombus hei ght; and total thrombus cross-sectional area. In control untreated gui nea pigs, platelet adhesion and thrombus height were 63% and 2.5 mu m at 100 s(-1), 60.5% and 13.5 mu m at 650 s(-1), and 45% and 28.1 mu m at 1600 s(-1), respectively. At 100 s(-1), Lamifiban had no effect on platelet deposition at any of the three doses administered to the guin ea pigs (0.3, 1, and 3 mg/kg). At 0.3 mg/kg and shear rates of 650 and 1600 s(-1), Lamifiban had no effect on platelet adhesion or thrombus size, but at 1 and 3 mg/kg and shear rates of 650 and 1600 s(-1), it s ignificantly reduced thrombus size. At 1600 s(-1), 1 mg/kg Lamifiban s ignificantly increased platelet adhesion from 45% to 62.5%, whereas at 3 mg/kg it induced a significant overall decrease from 45% to 25% and qualitatively increased the ratio of contact to spread platelets. The se data suggest that at high shear rates, GPIIb/IIIa participates in p latelet spreading and that there is a balance between platelet involve ment in adhesion to the thrombogenic surface and the growth of the alr eady formed thrombus. This indicates that important clinical implicati ons of an optimal therapeutic degree of GPIIb/IIIa antagonism could be expected.