Methods and models to evaluate shear-dependent and surface reactivity-dependent antithrombotic efficacy

The purpose of the present communication is to evaluate the importance of b lood flow and surface reactivity for measurement of antithrombotic drug act ivity or efficacy in selected model systems of thrombus formation. Such inf ormation is essential for proper evaluation of antithrombotic drug profiles . The continuous development of flow-dependent thrombosis models for in vit ro (anticoagulated blood) and ex vivo (native blood) studies and their appl ication in in vivo animal models from the early 1970s and onwards are brief ly considered. Central to this process was the development of various types of perfusion chambers in which a thrombogenic surface is exposed to flowin g blood. Such perfusion chambers have been inserted into arteriovenous (AV) shunts in baboon, pig, dog, and rabbit. These approaches have allowed repr oducible testing of traditional and novel experimental antithrombotic drugs , and studies on novel drug strategies under well-defined shear conditions and surface reactivity. Shear-dependent anti-thrombotic efficacy in these m odels is observed with anticoagulants such as unfractionated heparin, low-m olecular weight heparins, or selective inhibitors of thrombin, Factor Xa, o r Factor VIIa. However, the degree of shear dependency depends on the natur e of the thrombogenic surface, e.g., the inhibition is more pronounced on a tissue factor (TF)-rich surface than on a collagen-rich surface, particula rly at venous or low arterial shear. Platelet antagonists such as the COX-1 inhibitor aspirin, inhibitors of thromboxane A2 (TxA2) synthetase, the TxA 2 platelet receptor, and of von Willebrand factor (vWf) are shear dependent also, being more efficient at high arterial shear. In contrast, the platel et ADP antagonist clopidogrel, or antagonists to the active platelet membra ne glycoprotein IIb-IIIa complex (GPIIb-IIIa) are shear independent. At ext remely high arterial shear, which activates platelets and elicit aggregates of circulating platelets, aspirin looses its antithrombotic effect, wherea s ADP and GPIIb-IIIa antagonists still interrupt thrombus formation. In gen eral, results obtained with these models mimic and predict antithrombotic e fficacy in man when comparison is possible. Information on antithrombotic e fficacy in flow devices with various thrombogenic surfaces is now sufficien tly available to suggest recommendations for experimental conditions, parti cularly with regard to blood flow and reactive surfaces. (C) 2001 Elsevier Science Ltd. All rights reserved.