Atherothrombosis: Plaque instability and thrombogenesis,☆☆

https://doi.org/10.1053/pcad.2002.123469Get rights and content

Abstract

Hemostasis involves a carefully regulated balance between circulating and endothelium-derived prothrombotic and antithrombotic factors. The unstable or vulnerable plaque facilitates thrombosis, clinically manifest as an acute coronary syndrome (ACS), by creating an environment that favors thrombus formation over prevention of lysis. Endothelial cell dysfunction is integral to both the development of the atherosclerotic lesion as well as its destabilization. The transformation of a stable plaque to an unstable one involves complex interactions among T lymphocytes, macrophages, endothelial cells, and smooth muscle cells. Degradation of the fibrous cap of the atherosclerotic lesion as well as the overexpression of prothrombotic and underexpression of antithrombotic factors by cells within the plaque precede thrombus formation. Accordingly, pharmacological interventions for the treatment of ACS are directed against the initiation and propagation of thrombosis, as well as toward improvement of endothelial function. Copyright 2002, Elsevier Science (USA). All rights reserved.

Section snippets

Normal endothelial function

Normal endothelial function involves the expression of a host of surface proteins and secreted substances that maintain both vascular tone as well as a nonthrombogenic milieu. This local environment results, in part, from the physical barrier provided by an intact endothelial cell (EC) monolayer that protects circulating blood from exposure to prothrombotic subendothelial matrix proteins. An intact endothelium affords a smooth laminar surface that facilitates blood flow. The endothelium also

Plaque development, destabilization, and thrombosis

Atherosclerosis can be regarded as a chronic inflammatory process during which monocytes and lymphocytes migrate into the subintimal space of the arterial wall. Progressive expansion of this lesion, owing partly to lipid accumulation, leads to luminal narrowing and a reduction in blood flow. A fibrous cap composed of matrix proteins and smooth muscle cells characterizes the surface of the developing atherosclerotic lesion. Disruption of this fibrous cap (destabilization) promotes thrombosis

Future directions

The ability of clinicians to recognize an ACS and differentiate it from other noncardiac causes of chest pain syndromes remains a formidable challenge in the treatment of cardiovascular disease. As atherothrombosis is a form of chronic inflammation with plaque rupture and thrombosis in the setting of a superimposed acute inflammatory process, it follows that markers of acute inflammation may be indicators of an underlying unstable plaque phenotype. Indeed, although recent work has demonstrated

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    Supported in part by NIH grants HL55993, HL58976, HL61795, and HL04399.

    ☆☆

    Address reprint requests to Joseph Loscalzo, MD, 715 Albany St., W-507, Boston, MA 02118-2526.

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