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Thrombus Formation on Atherosclerotic Plaques: Pathogenesis and Clinical Consequences

Ursula Rauch, MD; Julio I. Osende, MD; Valentin Fuster, MD, PhD; Juan J. Badimon, PhD; Zahi Fayad, PhD; and James H. Chesebro, MD
[+] Article and Author Information

From the Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York.


Grant Support: By the National Institutes of Health SCOR on Thrombosis (P50 HL54469).

Requests for Single Reprints: James H. Chesebro, MD, The Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, Box 1030, New York, NY 10029; e-mail, james.chesebro@mssm.edu.

Current Author Addresses: Dr. Rauch: Benjamin Franklin Clinic, Department of Cardiology, Free University of Berlin, Berlin, Germany.

Drs. Osende, Fuster, Badimon, Fayad, and Chesebro: The Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, Box 1030, New York, NY 10029.


Ann Intern Med. 2001;134(3):224-238. doi:10.7326/0003-4819-134-3-200102060-00014
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Purpose: To describe the characteristics of thrombus formation on atherosclerotic plaques, the clinical expression of atherothrombosis in vascular disease, and some of the most recent therapeutic approaches in cardiovascular disease.

Data Sources: MEDLINE search for English-language articles on thrombosis and atherosclerosis published up to January 2000. Abstracts of recent international meetings on new aspects of thrombus formation and new therapeutic options were reviewed, and references from identified articles were selected and reviewed.

Study Selection: Experimental, basic, clinical, and epidemiologic studies related to the pathophysiology of thrombosis on atherosclerotic lesions. Therapeutic approaches were obtained from experimental studies and large clinical investigations.

Data Extraction: Arterial vessel wall substrate, rheologic conditions, and blood thrombogenicity influence the process of thrombus formation in arteries. Thrombus formation on disrupted atherosclerotic plaques or arterial erosions frequently causes acute coronary syndromes. Severe atherosclerosis of the aorta has been identified as an important morphologic indicator of an increased risk for thromboembolism. Current antithrombotic therapies available as long-term treatment for patients with cardiovascular disease are often not effective enough to prevent acute thrombotic events and deterioration of atherosclerosis.

Data Synthesis: Improved understanding of the pathophysiology of thrombus formation on atherosclerotic plaques has led to the development of new therapeutic approaches. Glycoprotein IIb/IIIa, tissue factor, factor Xa, and thrombin inhibitors as well as combined antithrombotic therapy, such as aspirin plus a thienopyridine plus warfarin, are being evaluated as new possible options for the treatment of arterial thrombosis.

Conclusions: Long-term treatment with potent antithrombotic drugs, such as tissue factor or factor Xa inhibitors, that effectively block thrombosis without causing bleeding complications could help reduce death from cardiovascular disease.

Figures

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Figure 1.
Relation of lesion morphologic characteristics and phases of progression of coronary atherosclerosis to clinical findings.(8, 11)

An early lesion (phase 1) can become an atheromatous or fibrolipid plaque (phase 2). Phase 2 can progress into an acute phase (phase 3 or 4). Formation of thrombosis or hematoma may cause angina pectoris (phase 3) or an acute coronary syndrome due to occlusive thrombosis (phase 4). Phase 3 and 4 lesions can evolve into a fibrotic phase (phase 5) characterized by more stenotic plaques that may progress to occlusive lesions. Stenosis and myocardial ischemia can induce the growth of collateral vessels. Patients may have angina or silent vessel occlusions in phase 5. White indicates lipid accumulation, gray indicates thrombosis and hemorrhage, and black indicates fibrous tissue. Roman numerals indicate the lesion types. I–III = early lesions with isolated macrophage–foam cells (I), multiple foam-cell layers (II), or isolated extracellular lipids (III); IV–Va = advanced lesions (atheromatous or fibrolipid plaques with confluent extracellular lipid pools [atheroma] [IV] or fibromuscular tissue layers and atheroma [Va]); VI = advanced lesions (complicated plaques with surface defects, hemorrhage, or thrombi deposition); Vb–Vc = advanced lesions with calcifications (Vb) or fibrous tissue (Vc). Reproduced with permission from Fuster and colleagues .

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Figure 2.
The tissue factor pathway activation of coagulation.
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Figure 3.
Activation and amplification of coagulation by activator complexes (generating thrombin for platelet activation[78]and fibrin formation) and thrombus formation on disrupted atherosclerotic plaques.vWFIbIa(79)23IIb/IIIa(4)

Exposure of subendothelium and plaque contents to circulating blood activates the hemostatic system and generates thrombin. Platelets recognize von Willebrand factor ( ) by glycoprotein Ib ( ) and collagen by platelet glycoprotein Ia ( ) . The binding of platelets to these arterial structures leads to intracellular signaling, ion currents, protein kinase activation, polymerization of the platelet cytoskeleton, and arachidonic acid metabolism. Constitutively expressed integrin (glycoprotein IIb/IIIa [ ] complex) changes its steric conformation and exposes the high-affinity binding site for fibrinogen. The cross-bridging of circulating activated platelets to fibrinogen results in platelet aggregation. Thrombin generated at the blood–plaque interface in association with cellular membranes on cells and platelets converts fibrinogen to fibrin, activates platelets and coagulation factors V and VIII, and stabilizes the growing thrombus by cross-linking fibrin. Thrombin activity and continued generation are necessary for maintaining platelet cohesion within mural thrombi and thrombus growth . TF = tissue factor.

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