Blood-born tissue factor in cardiovascular disease: where are we now?

Abstract

Over the last decade, many clinical, pathological and laboratory data have been obtained indicating that, in the majority of cases, acute coronary thrombosis occurs upon rupture of the thin fibrous cap of a vulnerable atherosclerotic plaques, a result of a series of immuno-inflammatory processes. The inner content of the plaque becomes then exposed to the circulating blood leading to the deposition of thrombotic material into the lumen [1]. Our data, as well as that acquired by others, demonstrate that one of the major determinants of the thrombogenicity of the disrupted atheroma is tissue factor (TF),which triggers the activation of coagulation by binding to factor VII/VIIa. TF is particularly abundant in the lipid-rich necrotic core of the lesion, which is therefore the most thrombogenic component of atherosclerotic plaque [2]. The binding of TF to factor VIIa causes thrombin generation, which in turn induces platelet activation and fibrin formation leading to a partial or total thrombotic occlusion of the artery, and to the occurrence of an acute coronary syndrome (ACS) [1]. We also have demonstrated that the activation of the coagulation cascade within the coronary vessel at sites of atherosclerotic plaque rupture is largely TF-dependent, since a significant reduction in both platelet and fibrin deposition can be obtained by local pretreatment of atherosclerotic lesions with the recombinant analog of the physiologic tissue factor pathway inhibitor (rTFPI) or with a specific anti-TF antibody [3]. Instabilization and rupture of the plaque are mainly due to inflammatory processes that take place in the vessel wall. Experimental studies demonstrate that inflammatory cells such as macrophages, macrophage-derived lipid laden ‘foam cells’, and T lymphocytes are major constituents of plaques, and infiltrate areas of superficial erosion and the shoulder region of the coronary lesions where the fibrous cap usually breaks [4]. Macrophages and ‘foam cells’ are also the major source of TF within the lesions, and therefore this protein can be considered a product of the inflammatory processes of the atheroma [1]. The interplay between these cells results in the production and local secretion of several inflammatory cytokines and chemokines like interleukin (IL)-1, interferon-c and TNF-a, which, in turn, lead to the release of metalloproteinases (MMPs), particularly of MMP-9, which degrade extracellular matrix and particularly collagen, thus inducing plaque weakening and fracture[1, 5, 6].