Tissue factor inhibition: Another approach reducing thrombosis after vascular injury

Abstract

Vascular injury induces haemostasis with subsequent thrombus formation. Accumulating evidence indicates that activation of the tissue factor (TF) pathway may play an important role in the pathophysiology of intravascular thrombus formation following arterial injury. A variety of cell types like monocytes, smooth muscle cells, foam cells and endothelial cells express TF in atherosclerotic lesions (1). In the plaque, TF is also present on microparticles within the necrotic core that are derived from apoptotic foam cells or macrophages, respectively. Moreover, the number of circulating TFpositive microparticles is increased in patients with acute coronary syndromes, endotoxaemia and cancer and may contribute to thrombotic events (2). Activation of the coagulation cascade consists of three overlapping phases: initiation, amplification and propagation. The initiation phase is localized to TF expressing surfaces that are exposed from the subendothelial tissue to flowing blood after vascular injury or plaque rupture. The proteolytic TF/factor (F)VIIa complex activates small amounts of FIX and FX. On TFexposing cells FXa then associates with FVa to form the prothombinase complex. In the amplification phase low concentrations of thrombin activate platelets to release FV. A positive feedback loop is generated whereby thrombin activates FV and FVIII. During the propagation phase the phospholipids surface of activated platelets acts as a cofactor for the generation of the FVIIIa-FIXa and of FVa-FXa which accelerate the generation of and FXa thrombin (3). Targeting the initiation phase may prevent thrombus formation more efficiently than at later stages, since the coagulation cascade is specifically blocked right from the beginning. The activity of the TF/FVIIa complex can be inhibited by TF antibodies, recombinant tissue factor pathway inhibitor (tifagosin), recombinant nematode anticoagulant (NAPc2) or active-site blocked FVIIa (ASIS). Experimental studies with these compounds in various vascular injury models suggest an effective reduction in thrombosis with a lower bleeding risk as compared to other types of coagulation inhibitors such as heparin or direct thrombin inhibitors (4). Recently, a chimeric mouse/human monoclonal antibody to TF (ALT836) has been developed. This antibody binds specifically to human TF at the FX binding site, thereby preventing formation of the TF:FVIIa–FX or TF=FVIIa-FIX complex. First clinical studies in subjects with stable coronary artery disease showed a dose-dependent anticoagulant effect with only minor bleeding (5). In the study by Jiao et al. (6) in this issue of Thrombosis and Haemostasis the authors describe that application of ALT836 after endatherectomy in chimpanzees results in a significant reduction in local thrombus formation, as assessed by platelet deposition and an improved 30 days vessel patency. This antithrombotic effect was not associated with an increase in bleeding time or surgical blood loss. These results indicate that early inhibition of the coagulation cascade using TF-inhibitory antibodies is effective in reducing thrombus formation after arterial injury. Since in the experiments by Jiao et al. the antibody was administered immediately before the restoration of blood flow, the prediction of efficacy in the clinical situation will need to be proven. Thus, ALT836 may Correspondence to: Prof. Dr. I. Ott 1. Med. Klinik, Klinikum Rechts Der Isar Der Technischen Universitat Munchen Ismaningerstr. 22, 81675 Munchen, Germany Tel.: +49 89 414