u that begins with fatty streaks and culminates in high-grade stenosis has been modified. Thrombotic occlusion is, in fact, frequently the result of thrombus induced by rupture of vulnerable plaques that were themselves not highly obstructive. Thus, as many as two-thirds of lesions responsible for acute coronary syndromes are minimally obstructive (less than 50% stenotic) immediately before plaque rupture. Conversely, asymptomatic disruption of lipid-rich plaques associated with limited, nonocclusive thrombosis appears to be responsible for intermittent, often clinically silent, plaque growth.

Thrombi can contribute to plaque growth by direct incorporation. Exposure of vessel wall constituents to clot-associated mitogens and cytokines can accelerate neointimalization and proliferation of vascular smooth muscle cells. Mural accumulation of fibrin and fibrin degradation products promotes the migration of vascular smooth muscle cells and monocytes into the neointima. Thrombin itself and growth factors released from platelet alpha granules such as platelet-derived growth factor and transforming growth factor beta activate smooth muscle cells potentiating their migration and proliferation.

The extent of thrombosis in response to plaque rupture depends upon factors potentiating thrombosis (prothrombotic factors), platelet reactivity, factors limiting thrombosis (antithrombotic factors), and the local capacity of the fi-brinolytic system reflecting a balance between activity of plasminogen activators and their primary physiological inhibitor, plasminogen activator inhibitor type 2. Activity of plasminogen activators leads to the generation of plasmin, an active serine proteinase, from plasminogen, an enzymatically inert circulating zymogen present in high concentration (~2 |M) in blood. The activity of plasmin is limited by inhibitors such as a2-antiplasmin and a2-macroglobulin.

When thrombosis is limited because of plasmin-dependent fibrinolysis at the time of rupture of a plaque, plaque growth may be clinically silent. When thrombosis is exuberant because of factors such as limited fibrinolysis, the thrombus may become occlusive and precipitate an acute coronary syndrome (acute myocardial infarction, unstable angina, or sudden cardiac death).

The rupture of an atherosclerotic plaque initiates coagulation and adhesion of platelets because of exposure to blood of luminal surfaces denuded of endothe-lium and hence to constituents such as collagen. The coagulation cascade in arterial thrombotic events is initiated by tissue factor, a cell-membrane-bound glycoprotein that binds circulating coagulation factor VII/VIIa to form the coagu- -o lation factor ''tenase'' complex that activates both circulating coagulation factors |

IX and X expressed on activated macrophages and monocytes as well as fibro- S

blasts and endothelium in response to cytokines at the site of plaque rupture. Initiation of thrombin-generating activity may reflect release of platelet coagulation factor V/Va, contained in alpha granules, which is a cofactor for coagulation factor Xa. Subsequent assembly of the ''prothrombinase'' complex comprising J

prothrombin, coagulation factors Xa and Va, calcium, and membrane surface

& u on platelet and other phospholipid membranes leads to generation of thrombin. Thrombin in turn cleaves fibrinogen to form fibrin. The generation of thrombin is amplified initially by its activation of circulating coagulation factors VIII (a cofactor for activated coagulation factor IX) and V (a cofactor for factor X) with consequent activation of the so-called intrinsic pathway of the coagulation cascade. Thrombin generation is sustained by activation by thrombin of other components in the intrinsic pathway including factor XI with consequent activation of coagulation factor IX. Platelets are activated by thrombin. Activated platelets markedly amplify generation of thrombin by releasing procoagulants and providing a potentiating surface replete with coagulation factor Va and Xa binding proteins.

A complex feedback system limits generation of thrombin. The tissue factor (extrinsic) pathway becomes inhibited by tissue factor pathway inhibitor (TFPI) previously called lipoprotein-associated coagulation inhibitor (LACI). Paradoxically, high concentrations of thrombin attenuate coagulation by binding to throm-bomodulin on the surface of endothelial cells. This complex activates protein C (to yield protein Ca) that, in combination with protein S, cleaves (inactivates) coagulation factors Va and VIIIa.

Exposure of platelets to the subendothelium as a result of plaque rupture leads to adherence mediated by collagen and von Willebrand factor multimers within the vessel wall. The exposure of platelets to agonists including collagen, von Willebrand factor, ADP (released by damaged red blood cells and activated platelets), and thrombin leads to accelerated activation of platelets. Activation is a complex process. It entails shape change (pseudopod extension that increases the surface area of the platelet); activation of surface glycoprotein IIb/IIIa; release of products from dense granules such as calcium, ADP, and serotonin and from alpha granules such as fibrinogen, factor V/Va, growth factors, and platelet factor 4, which inhibits heparin; and a change in the conformation of the platelet membrane that promotes binding of coagulation factors to phospholipids and their assembly.

Activation of surface glycoprotein IIb/IIIa entails a conformational change that exposes a binding site for fibrinogen on the activated conformer. Each molecule of fibrinogen can bind two platelets, thereby leading to aggregation. After activation, the plasma membranes of platelets express negatively charged phos-pholipids on the outer surface that facilitate the assembly of protein constituents and subsequent activity of the tenase and prothrombinase complexes. Thus, plate- |

lets participate in thrombosis by: (1) forming a hemostatic plug (shape change, £

adherence to the vascular wall, and aggregation); (2) supplying coagulation fac- g tors and calcium (release of alpha and dense granule contents); and (3) providing a surface for the assembly of coagulation factor complexes. In addition, activation Ja leads to vasoconstriction mediated by release of thromboxane and other vaso-active substances.

Both local and systemic factors can influence the extent of thrombosis occurring in association with plaque rupture. Local factors involve the morphology and biochemical composition of the plaque. Atheromatous plaques with substantial lipid content are particularly prone to initiate thrombosis. The severity of vascular injury and the extent of plaque rupture influence the extent to which blood is exposed to the subendothelium and consequently throm-bogenicity.

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