Thrombosis develops on an atherosclerotic plaque either because of:

1. Erosion — the overlying endothelium undergoes denudation or
2. Rupture — the plaque tears open exposing the highly thrombogenic core to blood in the arterial lumen.

In 1) the thrombus is laid down on the surface of the plaque; in 2) there is an additional component of the thrombus which forms deep within the liquid core of the ruptured plaque.

1. Erosion: Small areas of endothelial erosion are very common and are unrelated to the degree of stenosis. Exposure of the subendothelial collagen matrix leads to adhesion of a monolayer of platelets to the denuded area. Such microthrombi are too small either to be visible on angiography or to cause symptoms directly. Larger areas of endothelial denudation may allow the build up of a platelet-rich thrombus and ultimately lead to occlusion.
2. Rupture: a complication of plaques that have large lipid cores, thin fibrous caps with low densities of smooth-muscle cells separating the cores from the arterial lumens, and high densities of macrophages. These plaques are at high risk for thrombosis. The risk of unstable angina or an acute myocardial infarction to a patient with CAD depends on how many vulnerable plaques are present.

Plaque rupture is a mechanical event that depends on an imbalance between the stress imposed on the plaque cap in systole and the innate strength (resistance to fracture) of the cap tissue. The cap is being recognized as a dynamic structure in which collagen synthesis is modulated by positive and negative growth factors produced by inflammatory cells and in which collagen is degraded by macrophages.
Both endothelial erosion and plaque rupture are currently regarded as sequelae of an inflammatory process, involving response of the activated macrophage to oxidized low-density lipoproteins.
Plaque rupture is more common than erosion as a cause of major thrombi by a ratio of 3 to 1. However, sex influences plaque morphology — more women who die suddenly have thrombi due to endothelial erosion.
Low levels of high-density lipoprotein and high levels of total plasma cholesterol are associated with the frequency of vulnerable plaque morphology.
"The conclusion is that in men the principal risk factor driving plaque toward vulnerability is elevated plasma lipids. The reduction in acute events following lipid lowering therapy is best explained by a reduction in plaque vulnerability."
The benefits of lowering plasma lipids are multiple: endothelial function improves rapidly; monocyte migration and activation decline. In the long term, treatment changes the plaque structurally, the lipid core is obliterated by smooth muscle cells making disruption impossible.
NEJM May 1, 1997;336: 1312-14 Editorial from St. Georges Hospital Medical School, London.
See also "Coronary Risk Factors and Plaque Morphology in Men With Coronary Disease Who Die Suddenly" NEJM May 1, 1997; 336: 1276-82: An acute plaque rupture consists of a luminal platelet-fibrin thrombus continuous with an underlying lipid-rich core. The connection between the thrombus and the lipid core is through a disrupted thin fibrous cap infiltrated by macrophages.
A plaque erosion is defined as an acute thrombus in direct contact with the intimal plaque without rupture of a lipid pool.
A vulnerable plaque is defined as a fibrous cap less than 65 um thick with an infiltrate of macrophages. [Illustrations pp 1278-79]
Cholesterol-lowering therapy reduces the risk of acute coronary events. Because the decrease in the luminal narrowing is not large, the benefits are assumed to be due to the stabilization of vulnerable plaques rather than plaque regression. A decrease in serum cholesterol may result in the stabilization of plaque by removing cholesterol from macrophage foam cells and decreasing the volume of the soft, cholesterol-ester-rich necrotic core.
Cigarette smoking in men is associated, independent of other risk factors, with coronary thrombosis in cases of sudden death from coronary disease. Smoking is associated with thrombosis regardless of whether the mechanism is thrombus formation on top of an erosion or a plaque rupture. It is not associated with the number of vulnerable plaques. The mechanism of coronary thrombosis in smokers may be related to increased platelet aggregation and plasma epinephrine concentrations.
"We propose that among men who die suddenly, hypercholesterolemia has predisposed them to rupture of vulnerable plaques, and cigarette smoking has predisposed them to acute thrombosis. Cholesterol lowering may be particularly beneficial to patients with vulnerable plaques, and antithrombotic therapy may be especially effective in cigarette smokers."

Comment:
The new pathophysiological concept had important clinical applications. It takes us away from the old gross anatomical (obstructive) concept of pathogenesis to the new concept of pathogenesis —plaque morphology. Our old approach to therapy was to try to reduce the chronic obstructive atherosclerotic lesions (which, if it occurred at all, was slow and minimal). Many occluding thrombi occur on plaques that are not producing significant luminal obstruction. Now, the concept is a more functional one, relating to stabilization of plaques. Stabilization occurs much more rapidly than regression and is much more certain for a given reduction in LDL-cholesterol. Thus treating elderly patients with hypercholesterolemia is reasonable. RTJ