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Prepublished online as a Blood First Edition Paper on April 17, 2002; DOI 10.1182/blood-2001-11-0140.
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Blood, 15 June 2002, Vol. 99, No. 12, pp. 4475-4485
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Intrinsic pathway of blood coagulation contributes to
thrombogenicity of atherosclerotic plaque
Natalya M. Ananyeva,
Diana
V. Kouiavskaia,
Midori Shima, and
Evgueni L. Saenko
From the Holland Laboratory, American Red Cross,
Rockville, MD and Nara Medical University, Kashihara, Nara,
Japan.
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.
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