Contribution of thrombogenic factors to the pathogenesis of atherosclerosis

Abstract

H UMAN atherosclerosis can be defined as a disease process, caused by multiple pathogenic factors, which starts in childhood and decades later produces occlusive lesions and clinical symptoms. The intima is the cell layer principally involved in atherosclerosis although secondary changes are occasionally found in the media. According to McGill’ the earliest discernible change in human coronary arteries and aortas after birth is a diffuse thickening of the musculoelastic intima. In the later stages of life three different types of lesions can be identified: the fatty streak, the fibrous plaque and the complicated lesions.2,3 The fatty streak consists of a focal accumulation of a small number of intimal smooth muscle cells surrounded by deposits of lipids. The fibrous plaque protrudes into the lumen of the artery. It contains a number of lipid laden smooth muscle cells surrounded by lipid, collagen, elastic fibers and proteoglycans. The complicated lesion appears to be a fibrous plaque that has become altered as a result of hemorrhage, calcification, cell necrosis and mural thrombosis. This type of lesion often becomes associated with occlusive disease. Some pathologists also delineate “gelatinous lesions” or gelatinous thickening or focal intimal edema, which may be the precursors of fibrous plaques.4.” The thrombogenic theory of atherosclerosis was first proposed 130 years ago by Carl von Rokitansky6 who described atheroma as an excessive deposition of blood products, particularly fibrin on the lining membrane of the vessels. von Rokitansky’s views were opposed by Virchow in 1856’ who regarded atheroma as an inflammatory process, and the “thickening as the product of a reactive proliferation on the part of the intimal connective tissue cells.” Virchow’s concept of ceIlular proliferation appears to be very valid today. It is compatible with a theory of smooth muscle proliferation that follows injury to the vessel wall’ and with a “monoclonal hypothesis” of the pathogenesis of atherosclerosis which suggests that each lesion is derived from a single smooth muscle cell that serves as a progenitor for the remaining proliferative cells.8 In the light of modern research demonstrating promotion of cell proliferation by platelet proteins and coagulant factors, the early concepts of atherosclerosis appear to be complimentary rather than contradictory. It is generally accepted that an abnormal metabolism of lipoproteins and lipids contributes significantly to the development of atherosclerosis. At the beginning of this century Ignatowski’ and Anitchkow and Chalatow” produced experimental atherosclerosis in rabbits fed on a cholesterol-enriched diet. On the last two decades a number of models of experimental atherosclerosis in animals fed with a fat-rich diet have been developed.“-‘6 In 1954 Page” proposed a filtration concept of atherosclerosis which was based on the view that atherogenesis is due to the tissue reaction to substances filtered from plasma such as lipoproteins which are deposited in the intima as foreign lipids. Gero et al’* demonstrated by means of immunoelectrophoresis that /3-lipoprotein is indeed present within the human atherosclerotic lesion. This observation was confirmed later by a quantitative immunoelectrophoretic technique developed by Smith et a14,5,‘9-2’ who demonstrated that low density lipoprotein (LDL) is selectively accumulated in the atherosclerotic lesions. It is well established, particularly by the Framingham study,‘3.24 that elevation of LDL and very low density lipoproteins (VLDL) in plasma predisposes to premature atherosclerosis. The occurrence of premature atherosclerosis in familial hyperlipoproteinemias is also well established.‘j Brown et a12h demonstrated the absence of LDL receptors on libroblasts in patients with familial hypercholesteremia. These receptors