The development of pharmacologic agents that inhibit platelet performance could not have proceeded without a fundamental knowledge of normal biology and a clear understanding of the laws that govern cellular events in the circulatory system. The adhesion of platelets to a site of vessel wall injury is mediated by von Willebrand factor (vWF), which binds to the platelet glycoprotein (GP) Ib/IX-V complex receptor (and the GPIIb/IIIa receptor under high shear stress conditions). Monoclonal antibodies to vWF have been developed and tested in animal models, as has aurintricarboxylic acid (Strony et al., 1990), a triphenylmethyl compound that inhibits vWF binding. To date, investigation in humans has not taken place, perhaps because of concerns regarding the potential risk for hemorrhagic complications. Nevertheless, the scientific community remains interested in vWF and its platelet surface receptor as potential pharmacology-directed targets. Although the GPIIb/IIIa receptor antagonists are best known for their ability to inhibit platelet aggregation, under high shear stress conditions vWF can also bind the GPIIb/IIIa receptor, facilitating adhesion. As a result, GPIIb/IIIa antagonists may have an impact on both platelet adhesion and aggregation. As previously discussed, platelet activation is followed by a series of intracellular events that culminate in the release of calcium and substances that augment platelet aggregation and support coagulation protease binding. Thus, pharmacologic agents that inhibit initial surface receptor–mediated activation may also impair platelet aggregation. Several natural prostanoids (prostaglandin [PG] E1 and PGI2) can inhibit platelet activation and aggregation by elevating cyclic adenosine monophosphate (cAMP) levels. Although the mechanism is complex, the primary mode of inhibition is through the activation of adenylate cyclase (with a subsequent rise in cAMP concentrations), which in turn prevents calcium mobilization. The clinical application of PGE1 and PGI2 has been limited by their effect on vascular tone, producing substantial systemic hypotension (Emmons et al., 1967; Terres et al., 1989), and by extensive first-pass metabolism in the lungs (70% of the active compound is rapidly cleared) (Kleiman et al., 1994).
5065Platelet desialylation induced by high shear-stress mechanical circulatory support