Blood flow and antithrombotic drug effects

This paper reviews the importance of blood flow phenomena in models of experimental thrombosis used for measuring antithrombotic drug efficacy. The characteristics of these systems and their application for studies with human blood and in animal models are considered. Central to these investigations has been the development of various types of perfusion chambers in which a thrombogenic test surface is exposed to flowing blood under well-defined conditions of blood flow and device geometry. Such perfusion chambers, which have been used in vitro, ex vivo, and in vivo by insertion into arteriovenous shunts in various animal species, have allowed reproducible testing of both conventional and experimental agents. Shear-dependent antithrombotic effects have been observed with anticoagulants such as heparin and with selective inhibitors of thrombin, factor Xa, and factor VIIa. However, the degree of shear dependency depends on the chemical composition of the thrombogenic surface; for example, anticoagulant effects may be more pronounced on a tissue factor-rich surface than on a collagen-rich surface, particularly at venous or low arterial shear rates. Platelet inhibitors such as aspirin, thromboxane antagonists, or inhibitors of von Willebrand factor platelet interactions are also shear dependent, being more efficient at high shear rates. In contrast, inhibitors of adenosine diphosphate-dependent platelet reactions or antagonists of the platelet membrane glycoprotein IIb/IIIa complex are shear rate independent. At very high shear rates characteristic of severely stenotic arteries, aspirin loses its direct antithrombotic effect, whereas adenosine diphosphate pathway inhibitors and GP IIb/IIIa antagonists are still beneficial. In general, results obtained with many of these models have predicted antithrombotic efficacy in human beings when comparisons were possible. Therefore shear-dependent models of experimental thrombosis are routinely used in the evaluation of antithrombotic pharmacologic agents, both preclinically and clinically.