Abstract-Atherosclerotic cardiovascular disease results in Ͼ19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of

Arterial thrombosis is considered to arise from the interaction of tissue factor (TF) in the vascular wall with platelets and coagulation factors in circulating blood. According to this paradigm, coagulation is initiated after a vessel is damaged and blood is exposed to vessel-wall TF. We have examined thrombus formation on pig arterial media (which contains no stainable TF) and on collagen-coated glass slides (which are devoid of TF) exposed to f lowing native human blood. In both systems the thrombi that formed during a 5-min perfusion stained intensely for TF, much of which was not associated with cells. Antibodies against TF caused Ϸ70% reduction in the amount of thrombus formed on the pig arterial media and also reduced thrombi on the collagencoated glass slides. TF deposited on the slides was active, as there was abundant fibrin in the thrombi. Factor VII ai , a potent inhibitor of TF, essentially abolished fibrin production and markedly reduced the mass of the thrombi. Immunoelectron microscopy revealed TF-positive membrane vesicles that we frequently observed in large clusters near the surface of platelets. TF, measured by factor X a formation, was extracted from whole blood and plasma of healthy subjects. By using immunostaining, TF-containing neutrophils and monocytes were identified in peripheral blood; our data raise the possibility that leukocytes are the main source of blood TF. We suggest that blood-borne TF is inherently thrombogenic and may be involved in thrombus propagation at the site of vascular injury.Tissue factor (TF) present in the arterial wall has been considered to be responsible for the initiation of the coagulation cascade and thrombus formation (1). The role of vascular TF in acute thrombosis and atherosclerosis has been proposed based on our previous studies (2-5). To investigate the role of circulating TF in thrombogenesis, we have used a system in which pig aortic media or collagen-coated slides were mounted in a laminar flow chamber and perfused with native human blood. We noted that when stained either with derivatized factor VII a (FVII a ) or with specific anti-TF antibodies, the thrombi contained large amounts of TF staining, whereas the media and collagen-coated slides were essentially negative. Thus, we surmised that the TF came from the blood; accordingly, we examined whole blood and plasma for TF activity that we have extracted and assayed. We conclude that there is circulating, potentially active TF in normal subjects. We present evidence that this pool is thrombogenic in model flow systems. We also present evidence suggesting the TF comes from leukocytes and hypothesize that the cell-surface TF is completely encrypted (6-8) but becomes available during thrombosis. METHODSReagents. Human recombinant FVII a was a gift from NovoNordisk, Copenhagen. Factor X was purified from human plasma (9). Affigel-15 was purchased from Bio-Rad. The phospholipids used for relipidation of TF consisted of 30% 1,2-dioleoyl-sn-glycero-3-phosphatidylserine and 70% 1,2-dioleoyl-sn-gl...

Atherothrombosis is a complex disease in which cholesterol deposition, inflammation, and thrombus formation play a major role. Rupture of high-risk, vulnerable plaques is responsible for coronary thrombosis, the main cause of unstable angina, acute myocardial infarction, and sudden cardiac death. In addition to rupture, plaque erosion may also lead to occlusive thrombosis and acute coronary events. Atherothrombosis can be evaluated according to histologic criteria, most commonly categorized by the American Heart Association (AHA) classification. However, this classification does not include the thin cap fibroatheroma, the most common form of high-risk, vulnerable plaque. Furthermore, the AHA classification does not include plaque erosion. As a result, new classifications have emerged and are reviewed in this article. The disease is asymptomatic during a long period and dramatically changes its course when complicated by thrombosis. This is summarized in five phases, from early lesions to plaque rupture, followed by plaque healing and fibrocalcification. For the early phases, the role of endothelial dysfunction, cholesterol transport, high-density lipoprotein, and proteoglycans are discussed. Furthermore, the innate and adaptive immune response to autoantigens, the Toll-like receptors, and the mechanisms of calcification are carefully analyzed. For the advanced phases, the role of eccentric remodeling, vasa vasorum neovascularization, and mechanisms of plaque rupture are systematically evaluated. In the final thrombosis section, focal and circulating tissue factor associated with apoptotic macrophages and circulatory monocytes is examined, closing the link between inflammation, plaque rupture, and blood thrombogenicity.

Background-Growth of atherosclerotic plaques is accompanied by neovascularization from vasa vasorum microvessels extending through the tunica media into the base of the plaque and by lumen-derived microvessels through the fibrous cap. Microvessels are associated with plaque hemorrhage and may play a role in plaque rupture. Accordingly, we tested this hypothesis by investigating whether microvessels in the tunica media, the base of the plaque, and the fibrous cap are increased in ruptured atherosclerotic plaques in human aorta. Methods and Results-Microvessels, defined as CD34-positive tubuloluminal capillaries recognized in cross-sectional and longitudinal profiles, were quantified in 269 advanced human plaques by bicolor immunohistochemistry. Macrophages/T lymphocytes and smooth muscle cells were defined as CD68/CD3-positive and ␣-actin-positive cells. Total microvessel density was increased in ruptured plaques when compared with nonruptured plaques (Pϭ0.0001). Furthermore, microvessel density was increased in lesions with severe macrophage infiltration at the fibrous cap (Pϭ0.0001) and at the shoulders of the plaque (Pϭ0.0001). In addition, microvessel density was also increased in lesions with intraplaque hemorrhage (Pϭ0.04) and in thin-cap fibroatheromas (Pϭ0.038). Logistic regression analysis identified plaque base microvessel density (Pϭ0.003) as an independent correlate to plaque rupture. Conclusions-Thus, neovascularization as manifested by the localized appearance of microvessels is increased in ruptured plaques in the human aorta. Furthermore, microvessel density is increased in lesions with inflammation, with intraplaque hemorrhage, and in thin-cap fibroatheromas. Microvessels at the base of the plaque are independently correlated with plaque rupture, suggesting a contributory role for neovascularization in the process of plaque rupture. (Circulation.

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The effects of homologous plasma HDL and VHDL fractions on established atherosclerotic lesions were studied in cholesterol-fed rabbits. Atherosclerosis was induced by feeding the animals a 0.5% cholesterol-rich diet for 60 d (group 1). Another group of animals were maintained on the same diet for 90 d (group 2). A third group was also fed the same diet for 90 d but received 50 mg HDL-VHDL protein per wk (isolated from normolipemic rabbit plasma) during the last 30 d (group 3). Aortic atherosclerotic involvement at the completion of the study was 34±4% in group 1, 38.8±5% in group 2, and 17.8±4% in group 3 (P < 0.005). Aortic lipid deposition was also significantly reduced in group 3 compared with group 1 (studied at only 60 d) and group 2. This is the first in vivo, prospective evidence of the antiatherogenic effect of HDL-VHDL against preexisting atherosclerosis. Our results showed that HDL plasma fractions were able to induce regression of established aortic fatty streaks and lipid deposits. Our results suggest that it may be possible not only to inhibit progression but even to reduce established atherosclerotic lesions by HDL administration. (J. Clin. Invest. 1990.

Our results show that tissue factor is present in lipid-rich human atherosclerotic plaques and suggest that it is an important determinant of the thrombogenicity of human atherosclerotic lesions after spontaneous or mechanical plaque disruption.

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