Intrinsic pathway of blood coagulation contributes to thrombogenicity of atherosclerotic plaque

Thrombosis is the major mechanism underlying acute complications of atherosclerosis. Although thrombogenicity of atherosclerotic plaques has been ascribed to activation of the extrinsic pathway of blood coagulation, in the present study we investigated contribution of the intrinsic factor VIII (fVII...

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Bibliographic Details
Published in:Blood 2002-06, Vol.99 (12), p.4475-4485
Main Authors: Ananyeva, Natalya M., Kouiavskaia, Diana V., Shima, Midori, Saenko, Evgueni L.
Format: Article
Language:English
Subjects:
Aorta
Apoptosis - drug effects
Arteriosclerosis - blood
Arteriosclerosis - complications
Arteriosclerosis - pathology
Atherosclerosis (general aspects, experimental research)
Biological and medical sciences
Blood and lymphatic vessels
Blood Coagulation Factors - metabolism
Blood Coagulation Factors - physiology
Cardiology. Vascular system
Cysteine Endopeptidases - metabolism
Cysteine Endopeptidases - physiology
Endothelium, Vascular - cytology
Endothelium, Vascular - drug effects
Factor IXa - metabolism
Factor VIII - metabolism
Factor VIIIa - metabolism
Humans
Kinetics
Lipoproteins, LDL - pharmacology
Macrophages - drug effects
Medical sciences
Muscle, Smooth, Vascular - cytology
Muscle, Smooth, Vascular - drug effects
Neoplasm Proteins
Thrombin - metabolism
Thromboplastin - metabolism
Thrombosis - blood
Thrombosis - etiology
Thrombosis - pathology
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Summary:Thrombosis is the major mechanism underlying acute complications of atherosclerosis. Although thrombogenicity of atherosclerotic plaques has been ascribed to activation of the extrinsic pathway of blood coagulation, in the present study we investigated contribution of the intrinsic factor VIII (fVIII)–dependent pathway. We found that in vitro exposure of human macrophages and smooth muscle cells (SMCs) to atherogenic oxidized low-density lipoprotein (oxLDL) enhances their ability to support activity of 2 major complexes of the intrinsic pathway, Xase and prothrombinase, leading to a 20- and 10-fold increase in thrombin formation, respectively. In contrast, human aortic endothelial cells were less responsive to oxLDL. The increase in the intrinsic procoagulant activity was related to formation of additional fVIII binding sites due to enhanced translocation of phosphatidylserine to the outer surface of oxLDL-treated cells and a 5-fold higher affinity of interaction between components of the Xase complex, activated factors VIII and IX. Processes occurring at early apoptotic stages, including changes in the cell membrane induced by free radicals, may be related to activation of the intrinsic pathway as suggested by effects of inhibitors of early apoptosis on thrombin formation. Immunohistochemical studies on human atherectomy specimens revealed the presence of fVIII in the vicinity of macrophages and SMCs in atheromatous regions with massive deposits of oxLDL, supporting the possible involvement of the intrinsic pathway in thrombus formation in vivo. Our data predict that the intrinsic pathway significantly enhances thrombogenicity of atherosclerotic lesions after removal of the endothelial layer and exposure of SMCs and macrophages to blood flow.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2001-11-0140