Abstract
The risk of bleeding is one of the major clinical problems of anti-platelet agents such as aspirin and clopidogrel which modulate platelet aggregation induced by traditional chemical agonists. Targeting shear stress-induced platelet aggregation, primarily occurring under abnormally high shear stress in atherosclerotic lesion, may be an attractive alternative for the development of anti-thrombotic agents with reduced bleeding risk. Here we demonstrated novel anti-platelet and anti-thrombotic activities of protocatechuic acid (PCA), a bioactive component from herbal materials, through its selective inhibition of shear-induced platelet activation and aggregation. In isolated human platelets, PCA decreased high shear stress-induced platelet change including intracellular calcium mobilization, granular secretion, adhesion receptor expression, and aggregation. The inhibitory effect of PCA was mediated through blocking of the initial interaction between von Willerbrand factor (vWF) and platelet receptor GP Ib. Notably, PCA did not affect platelet aggregation induced by chemical agonists, demonstrating its selective protection against shear-induced platelet activation. In vivo relevancy was examined using rat arterial thrombosis model, where PCA showed significant anti-thrombotic activity. While aspirin and clopidogrel prolonged bleeding time in rat tail transection model, PCA did not change bleeding time suggesting the reduced risk of bleeding. With this study, we believe that novel therapeutic potential of PCA was elucidated, supporting its possible application as an anti-platelet and anti-thrombotic drug candidate.
