Tissue factor as a therapeutic target in coronary syndromes

Abstract

T issue factor (TF), a low molecular weight (45kDa) membrane-bound glycoprotein, is a major regulator of coagulation and a critical determinant of thrombin generation in normal hemostasis and in atherothrombotic disease.1,2 Binding of TF to factor VIIa (FVIIa) is the first step in the extrinsic coagulation cascade. Normally, TF is located away from the luminal surface of blood vessels and outside the vasculature. The clinical consequences of inappropriately high intravascular expression of TFs are often catastrophic. Intraluminal TF activity can trigger the thrombogenic cascade that underlies the often-lethal thrombotic complications of atherosclerosis, the consumptive coagulopathy and hemorrhagic diathesis of systemic infections, and the prothrombotic state of cancer patients. In the uninjured vessel wall, TF is present on cells mainly in the adventitia and variably on cells of the media. It is usually not detectable on normal, healthy, endothelial cells.3 In human atherosclerotic vessels, TF is abundant, particularly within the acellular lipid core of the plaques and in the adjacent “shoulder region” close to the lumen where it is prominently expressed by monocyte-derived macrophages.3–5 Monocyte/macrophage-type cells play a major role in the development, progression, disruption, and thrombogenicity of atherosclerotic lesions.6 The relatively high TF content within the lipid-rich core is considered to be the principal underlying reason for the high thrombogenicity of this component of the plaque in human coronary arteries.7 Under “normal” conditions, intramural TF is not exposed to flowing blood. However, circumstances such as injury to the atherosclerotic arterial wall associated with disruption of the luminal surface and the fibrous cap results in exposure of TF to circulating factor VII/VIIa. The TF:FVIIa binding forms an enzymatic complex that proteolytically activates factor X to factor Xa, and factor IX to factor IXa, leading to thrombin generation followed by fibrin formation, platelet activation, and thrombosis. The proteolytic activity of this TF:FVIIa complex is tightly regulated by the endogenous inhibitor, TF pathway inhibitor (TFPI).8,9 TFPI forms a stable, inactive, quaternary complex consisting of TFPI, TF, FVIIa, and factor Xa, which inhibits the TF-dependent coagulation cascade.10 In normal arteries, the major pool of TFPI is found in the endothelium.11 Smooth muscle cells, megakaryocytes, platelets, freshly isolated monocytes, and macrophages also express TFPI.12,13 TFPI, although expressed predominantly in the normal vessel wall, is also enhanced in atherosclerotic vessels where it modulates TF activity.5 The complementary deoxyribonucleic acid of TFPI has been cloned and characterized, and TFPI has been synthesized by recombinant technology.14 The pathogenesis of restenosis after balloon angioplasty includes thrombosis at the site of vessel wall injury, acute elastic recoil, neointimal formation, and, in the long term, constrictive vessel wall remodeling. Thrombosis is the immediate consequence of angioplasty, stent implantation, or other forms of mechanical percutaneous coronary intervention. Similar in part to plaque erosion or rupture, deep arterial wall injury by the inflated balloon exposes subendothelial components to the flowing blood. Many of the exposed vessel wall components are thrombogenic, but in restenotic lesions, as with primary lesions, TF is probably the most thrombogenic. TF exposure and elaboration on the luminal surface, and factor X activation on the surface of platelets play pivotal roles in thrombus formation15,16 and thrombin generation, which facilitate smooth muscle cell proliferation, migration, and secretion of extracellular matrix—the principal pathogenetic components of neointima formation.17,18 Recently, it has been suggested that TF expression may play an important role in neointima formation not only through a coagulation-dependent mechanism, such as expansion of mural thrombus, but also through coagulation-independent mechanisms, such as direct acceleration of smooth muscle cell proliferation.19 Angioplasty is associated with a strikingly enhanced elevation of local TF expression in the adventitia and media during the first few days after injury.15,20 This has been shown to be persistent in some models even after 1 month.21 Balloon injury to the atherosclerotic arterial wall also has been shown to be associated with a marked increase in TF expression by circulating monocytes.22 Thrombus at the site of a disrupted atherosclerotic plaque is the principal cause of acute myocardial infarction, unstable angina, and sudden cardiac death. Plaque rupture has been shown to occur preferentially at sites of extensive lipid-rich pultaceous debris, which are separated from the lumen by a thin fibrous cap.23,24 The high TF content of the lipid-rich components is thought to account, in large part, for the high thrombogenicity of advanced lesions.4,25 From the Department of Cardiology, Bikur Cholim Hospital, and Department of Anatomy and Cell Biology, The Hebrew University–Hadassah Medical School, Jerusalem, Israel. Manuscript received August 2, 2000; revised manuscript received and accepted October 12, 2000. Address for reprints: Shmuel Banai, MD, Department of Cardiology, Bikur Cholim Hospital, P.O. Box 492, Jerusalem 91002, Israel. E-mail: banais@mail.netvision.net.il.