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Prepublished online as a Blood First Edition Paper on April 17, 2002; DOI 10.1182/blood-2001-11-0140. This Article Full Text (PDF) All Versions of this Article: 2001-11-0140v1 99/12/4475    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ananyeva, N. M Articles by Saenko, E. L Search for Related Content PubMed PubMed Citation Articles by Ananyeva, N. M Articles by Saenko, E. L Social Bookmarking                   What's this? Submitted November 30, 2001 Accepted February 7, 2002 Intrinsic pathway of blood coagulation contributes to thrombogenicity of atherosclerotic plaque Natalya M Ananyeva, Diana V Kouiavskaia, Midori Shima, and Evgueni L Saenko* Holland Laboratory, American Red Cross, Rockville, MD, USA Nara Medical University, Kashihara, Nara, Japan * Corresponding author; email: saenko{at}usa.redcross.org. Thrombosis is the major mechanism underlying acute complications of atherosclerosis. While 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 (SMC) to atherogenic oxidized low density lipoprotein (oxLDL) enhances their ability to support activity of two 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 free radicals-induced changes in the cell membrane, 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 presence of fVIII in the vicinity of macrophages and SMC 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 SMC and macrophages to blood flow. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: L. Hu, L.S.M. Boesten, P. May, J. Herz, N. Bovenschen, M.V. Huisman, J.F.P. Berbee, L.M. Havekes, B.J.M. van Vlijmen, and J.T. Tamsma Macrophage Low-Density Lipoprotein Receptor-Related Protein Deficiency Enhances Atherosclerosis in ApoE/LDLR Double Knockout Mice Arterioscler Thromb Vasc Biol, December 1, 2006; 26(12): 2710 - 2715. [Abstract] [Full Text] [PDF] J. Khallou-Laschet, G. Caligiuri, E. Tupin, A.-T. Gaston, B. Poirier, E. Groyer, D. Urbain, S. Maisnier-Patin, R. Sarkar, S.V. Kaveri, et al. Role of the Intrinsic Coagulation Pathway in Atherogenesis Assessed in Hemophilic Apolipoprotein E Knockout Mice Arterioscler Thromb Vasc Biol, August 1, 2005; 25(8): e123 - e126. [Abstract] [Full Text] [PDF] P S Gilmour, E R Morrison, M A Vickers, I Ford, C A Ludlam, M Greaves, K Donaldson, and W MacNee The procoagulant potential of environmental particles (PM10) Occup. Environ. Med., March 1, 2005; 62(3): 164 - 171. [Abstract] [Full Text] [PDF] V. Llorente-Cortes, M. Otero-Vinas, S. Camino-Lopez, O. Llampayas, and L. Badimon Aggregated Low-Density Lipoprotein Uptake Induces Membrane Tissue Factor Procoagulant Activity and Microparticle Release in Human Vascular Smooth Muscle Cells Circulation, July 27, 2004; 110(4): 452 - 459. [Abstract] [Full Text] [PDF] S. M. S. Espirito Santo, N. M. M. Pires, L. S. M. Boesten, G. Gerritsen, N. Bovenschen, K. W. van Dijk, J. W. Jukema, H. M. G. Princen, A. Bensadoun, W.-P. Li, et al. Hepatic low-density lipoprotein receptor-related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol Blood, May 15, 2004; 103(10): 3777 - 3782. [Abstract] [Full Text] [PDF]

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