title: Intrinsic pathway of blood coagulation contributes to thrombogenicity of atherosclerotic plaque.
abstract: 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.
authors.affiliation: Holland Laboratory, American Red Cross, Rockville, MD 20855, USA.
authors.forename: Natalya M
authors.initials: NM
authors.lastname: Ananyeva
authors.forename: Diana V
authors.initials: DV
authors.lastname: Kouiavskaia
authors.forename: Midori
authors.initials: M
authors.lastname: Shima
authors.forename: Evgueni L
authors.initials: EL
authors.lastname: Saenko
mesh_terms: D001011:Aorta; D017209:Apoptosis / Q000187:drug effects; D001161:Arteriosclerosis / Q000097:blood / Q000150:complications* / Q000473:pathology; D001779:Blood Coagulation Factors / Q000378:metabolism / Q000502:physiology*; D003546:Cysteine Endopeptidases / Q000378:metabolism / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D015949:Factor IXa / Q000378:metabolism; D005169:Factor VIII / Q000378:metabolism; D015944:Factor VIIIa / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D009363:Neoplasm Proteins; D013917:Thrombin / Q000378:metabolism; D013925:Thromboplastin / Q000378:metabolism; D013927:Thrombosis / Q000097:blood / Q000209:etiology* / Q000473:pathology
chemical_list: D001779:Blood Coagulation Factors; D008077:Lipoproteins, LDL; D009363:Neoplasm Proteins; C099252:oxidized low density lipoprotein; D015944:Factor VIIIa; D005169:Factor VIII; D013925:Thromboplastin; D015949:Factor IXa; D013917:Thrombin; D003546:Cysteine Endopeptidases; C030910:cancer procoagulant