Hanson S R, Sakariassen K S
Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Am Heart J. 1998 May;135(5 Pt 2 Su):S132-45. doi: 10.1016/s0002-8703(98)70241-8.
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.
本文综述了血流现象在用于测量抗血栓药物疗效的实验性血栓形成模型中的重要性。考虑了这些系统的特性及其在人体血液研究和动物模型中的应用。这些研究的核心是开发各种类型的灌注室，在其中，在明确的血流条件和装置几何形状下，使血栓形成测试表面暴露于流动的血液中。这种灌注室已在体外、离体和体内使用，通过插入各种动物物种的动静脉分流中，使得对传统药物和实验药物都能进行可重复的测试。已观察到肝素等抗凝剂以及凝血酶、因子Xa和因子VIIa的选择性抑制剂具有剪切依赖性抗血栓作用。然而，剪切依赖性的程度取决于血栓形成表面的化学成分；例如，抗凝作用在富含组织因子的表面可能比在富含胶原蛋白的表面更明显，特别是在静脉或低动脉剪切速率下。阿司匹林、血栓素拮抗剂或血管性血友病因子与血小板相互作用的抑制剂等血小板抑制剂也具有剪切依赖性，在高剪切速率下更有效。相比之下，二磷酸腺苷依赖性血小板反应抑制剂或血小板膜糖蛋白IIb/IIIa复合物拮抗剂与剪切速率无关。在严重狭窄动脉特有的非常高的剪切速率下，阿司匹林失去其直接抗血栓作用，而二磷酸腺苷途径抑制剂和GP IIb/IIIa拮抗剂仍然有益。一般来说，当可以进行比较时，许多这些模型所获得的结果已经预测了在人类中的抗血栓疗效。因此，实验性血栓形成的剪切依赖性模型在临床前和临床评估抗血栓药物时经常使用。
