Experimental models of thrombosis and atherosclerosis

Atherothrombosis is a complex disease which includes two different pathologies: atherosclerosis, the process of plaque formation in the arterial wall and thrombosis, the formation of a blood clot mostly at the site of a ruptured atherosclerotic lesion. Animal models for both pathologies have been useful to understand their aetiology and their evolution and they were used to evaluate the efficacy of new treatments. Numerous models to study venous and arterial thrombosis have been described. Thus in the rat, venous thrombosis induced by lesion/stasis, e.g. in the vena cava, and arterial thrombosis by lesioning of the vessel wall are frequently used. The resulting blood clot formation is measured either directly (weight of the thrombus) or indirectly (reduction in blood flow). More complex models have been developed in large animals such as dogs and pigs in order to examine coronary thrombosis; the principle always being the arterial lesion that causes the thrombus formation. The effect of the TP-receptor antagonist terutroban (S 18886) on different thrombosis models has been evaluated and this has allowed to conclude on the powerful anti-thrombotic effects of this agent and has contributed to its progression into clinical development. In the past the most frequently used model of atherosclerosis was the hypercholesterolemic rabbit; both plaque formation and its consequences on vascular, endothelial, function have been largely studied in this model. More recently genetically engineered mouse models of atherosclerosis have been introduced and they are now largely studied to characterize the disease and to evaluate new drugs. The two models mostly used are the ApoE(-/-) and the LDL receptor(-/-) mice. Studies with terutroban have illustrated that this TP-receptor antagonist prevents lesion formation in mouse and rabbit models illustrating its interesting anti-atherosclerotic properties and demonstrating the role played by endothelial TP-receptors in atherogenesis. In conclusion, experimental models to study atherosclerosis and thrombosis have been developed and used to study the etiology and the evolution of atherothrombotic disease. They have also been of great value to predict anti-thrombotic and/or anti-atherosclerotic properties of new substances such as terutroban, that may become novel treatments for this complex cardiovascular disease.