Running title: Intrinsic Pathway and Thrombogenicity of Atherosclerotic Plaque

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 studie