A new role for P-selectin in shear-induced platelet aggregation.

Abstract

P-selectin, expressed on platelets on activation, mediates rolling of platelets on endothelial cells, but its role in shear-induced platelet aggregation is not known. Platelets were exposed to either a single pulse (30 seconds) or 3 pulses (10 seconds) of high shear stress (150 to 200 dynes/cm(2)) each followed by low shear stress (10 dynes/cm(2)) for 4.5 minutes or 90 seconds, respectively, at 37 degrees C to resemble more closely in vivo conditions such as those in stenotic arteries. Under these conditions, platelet aggregation was significantly increased compared with low or high shear stress alone. Monoclonal anti-P-selectin antibodies inhibited shear-induced platelet aggregation, especially when induced by the combination of high and low shear stress, by approximately 70% and had an additive effect on the inhibition by abciximab (anti-glycoprotein (GP) IIb/IIIa antibody). However, anti-P-selectin antibody inhibited shear-induced platelet aggregation only at 37 degrees C, not at 22 degrees C, whereas abciximab inhibited shear-induced platelet aggregation at both 22 degrees C and 37 degrees C. This differential effect of anti-P-selectin antibody is explained by the finding that shear-induced P-selectin expression on platelets was observed mainly at 37 degrees C. These results indicate that pulsatile shear stress, which resembles flow conditions in stenotic arteries, induces significantly more platelet aggregation at 37 degrees C than monophasic shear stress. Under these conditions, we show a novel role for P-selectin in platelet aggregation distinct from that of GP IIb/IIIa, which may be of importance in the initiation of thrombosis associated with atherosclerotic lesions.