Vascular Thrombosis

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In most instances, thrombosis occurring in the arterial system is composed of platelets and fibrin in a tightly packed network (white thrombus). By contrast, venous thrombi consist of a tightly packed network of erythrocytes, leukocytes, and fibrin (red thrombus).

The process of vascular thrombosis, particularly in the arterial system, is dynamic, with clot formation and dissolution occurring almost simultaneously. The overall extent of thrombosis and ensuing circulatory compromise is therefore determined by the predominant force that shifts the delicate balance. If local stimuli exceed the vessel's own thromboresistant mechanisms, thrombosis will occur. If, on the other hand, the stimulus toward thrombosis is not particularly strong and the intrinsic defenses are intact, clot formation of clinical importance is unlikely. In some circumstances, systemic factors contribute to or magnify local prothrombotic factors, shifting the balance toward thrombosis (68).

Overall, the site, size, and composition of thrombi forming within the arterial circulatory system is determined by: (i) alterations in blood flow; (ii) thrombogenicity of cardiovascular surfaces; (iii) concentration and reactivity of plasma cellular components; and (iv) effectiveness of physiologic protective mechanisms.

Defining Steps

Platelet Deposition

Platelets attaching to nonendothelialized or disrupted surfaces undergo adherence by activation and distribution along the involved area and subsequent recruitment to form a rapidly enlarging platelet mass.

The process of platelet deposition involves: (i) platelet attachment to collagen or exposed surface adhesive proteins; (ii) platelet activation and intracellular signaling; (iii) the expression of platelet receptors for adhesive proteins; (iv) platelet aggregation; and (v) platelet recruitment mediated by thrombin, thromboxane A2, and adenosine diphosphate.

Coagulation Factor Activation

Thrombin is rapidly generated in response to vascular injury. It also plays a central role in platelet recruitment and the formation of an insoluble fibrin network. The thrombotic process is localized, amplified, and modulated by a series of biochemical reactions driven by the reversible binding of circulating proteins (coagulation factors) to damaged vascular cells, elements of exposed subendothelial connective tissue (especially collagen), platelets (which also express receptor sites for coagulation factors), and macrophages. These events lead to an assembly of enzyme complexes that increases local concentrations of procoagulant material; in this way, a relatively minor initiating stimulus can be amplified greatly to yield a thrombus.

Fibrin Formation

The final phase in thrombus formation involves the generation of a stable fibrin network that provides the structural support for the circulating blood's cellular elements and the scaffolding for vascular remodeling. In this pivotal process, thrombin cleaves two small peptides, fibrinopeptide A and fibrinopeptide B, to form fibrin monomers, which in turn polymerize to form soluble fibrin strands. An orderly assembly, branching, and lateral association of fibrillar strands follows, terminating with factor XIII-mediated covalent crosslinking to form a mature fibrin network (mature thrombus).

Pathology of Thrombotic Events

There is evidence that the growth of atheromatous plaques occurs in a stepwise yet dynamic fashion in response to vascular injury. The clinical expression of a broad potential of pathobiologic events ranges from asymptomatic plaque growth to complete coronary arterial occlusion with a fatal outcome (Fig. 7).

James Herrick (1912) (69) is credited with describing the association between acute coronary thrombosis and acute MI, paving the way toward a greater understanding of acute coronary syndromes. Support for the disrupted plaque theory as a precipitant or nidus for coronary thrombosis can be traced to the work of Saphir et al. (1735) (70), followed by the observations of Chapman (1965) (71), Constantindines (1966) (72), Bouch and Montgomery (1970) (73), Ridolfi and Hutchins (1977) (74), Falk (1983) (75), and

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Fig. 7. Pathobiology-based natural history and clinical expression of acute coronary syndromes.

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Fig. 7. Pathobiology-based natural history and clinical expression of acute coronary syndromes.

Davies and Thomas (1985) (76). Additional support for the role of thrombosis-mediated processes in clinical events can be found in autopsy-based series that have revealed coronary microthrombi among patients with sudden cardiac death (75,76).

Theory of Dynamic Plaque Disruption and Arterial Thrombosis

Despite early views, the evidence suggests that plaque disruption and coronary arterial thrombosis are not random events in atherosclerosis, rather the process is sudden and dynamic. In a series of 42 patients undergoing coronary angiography before and after MI, Little and colleagues (1988) (43) found that most had a stenosis of <50% of the infarct-related vessel prior to the event. Similar findings were reported by Taeymans. Computer-based modeling also supports the dynamic nature of coronary occlusion (77). Comparing a rigid stenosis and a dynamic stenosis in which proximal vessel constriction and distal collapse were simulated, the latter model (with an added potential for vasoconstriction and passive collapse) required a much smaller thrombus burden for complete occlusion.

Atherosclerotic Plaque Imaging

The fine structure and composition of an atherosclerotic plaque rather than the degree of stenosis determines the likelihood of future clinical events. As a result, imaging modalities capable of characterizing the plaques internal environment have strong appeal. Having information on both plaque composition and luminal features may also be useful during atherosclerosis coronary interventions.

A majority of imaging modalities are catheter-based; however, more generalizable techniques are being developed and studied. High frequency intravascular ultrasound (20-40 MHz) provides tomographic images of the arterial wall and is able to quantitate luminal and plaque area as well as morphologic features including calcification and inti-

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Fig. 8. (A) Angioscopic image of the left anterior descending artery in a patient with acute MI demonstrating yellow plaque. (B,C,D) Intravascular ultrasound images as depicted in lesion A demonstrating compensatory enlargement. (B) At the defined proximal reference site the external elastic membrane (EEM) cross-sectional area (CSA) was 11.8 mm2. (C) At the culprit lesion, EEM CSA was 13.5 mm2. (D) At the distal reference site, EEM CSA was 9.6 mm2. The remodeling ratio (RR) was 1.26. (E) Angioscopic image of the left anterior descending artery in a patient with stable angina demonstrating white plaque. (F,G,H) Intravascular ultrasound images at the same lesion as E demonstrating paradoxical shrinkage. (F) At the proximal reference site, EEM CSA was 17.1 mm2. (G) At the culprit lesion EEM CSA was 10.1 mm2. (H) At the distal reference site, EEM CSA was 15.3 mm2. The RR was 0.62 (79).

Fig. 8. (A) Angioscopic image of the left anterior descending artery in a patient with acute MI demonstrating yellow plaque. (B,C,D) Intravascular ultrasound images as depicted in lesion A demonstrating compensatory enlargement. (B) At the defined proximal reference site the external elastic membrane (EEM) cross-sectional area (CSA) was 11.8 mm2. (C) At the culprit lesion, EEM CSA was 13.5 mm2. (D) At the distal reference site, EEM CSA was 9.6 mm2. The remodeling ratio (RR) was 1.26. (E) Angioscopic image of the left anterior descending artery in a patient with stable angina demonstrating white plaque. (F,G,H) Intravascular ultrasound images at the same lesion as E demonstrating paradoxical shrinkage. (F) At the proximal reference site, EEM CSA was 17.1 mm2. (G) At the culprit lesion EEM CSA was 10.1 mm2. (H) At the distal reference site, EEM CSA was 15.3 mm2. The RR was 0.62 (79).

mal dissection (78). Axial resolution to approximately 150 mHz is possible, permitting identification of lipid-rich regions and features of the plaques' fibrous cap.

Intervascular ultrasound with elastography is a unique method which allows both visual characterization of the plaque and its mechanical properties. Tissue components compare differently in response to applied pressure allowing determination of mechanical and structural integrity (79) (Fig. 8).

Coronary angioscopy, although not used frequently in North American catheteriza-tion laboratories, is a sensitive means to detect atherosclerotic plaques, grossly approximate their lipid composition, determine the presence of fibrous cap disruption and identify associated thrombosis formation (80).

Magnetic resonance imaging (MRI) (high resolution fast spin echo) represents a promising tool for studying the progression and regression of atherosclerosis over time. In addition, recently developed intravascular techniques can accurately assess plaque size and vulnerability (for rupture) (81).

A variety of innovative imaging modalities under development include optical coherence tomography, nuclear scintigraphy, thermometry, and Raman spectroscopy (82).

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