The role of tissue factor and factor VIIa in hemostasis

Abstract

Tissue factor (TF) is a transmembrane receptor for Factor VII/VIIa (FVII/VIIa). It is constitutively expressed by cells surrounding blood vessels. The endothelium physically separates this potent "activator" from its circulating ligand FVII/FVIIa and prevents inappropriate activation of the clotting cascade. Breakage of the endothelial barrier leads to exposure of extravascular TF and rapid activation of the clotting cascade. TF is also expressed in certain tissues, such as the heart and brain, and provides additional hemostatic protection to these tissues. Small amounts of TF are also present in blood in the form of microparticles, which are small membrane vesicles derived from activated and apoptotic cells. Levels of microparticle TF increase in a variety of diseases, such as sepsis and cancer, and this so-called "blood-borne" TF may contribute to thrombosis associated with these diseases. Recombinant FVIIa has been developed as an effective hemostatic drug for the treatment of hemophilia patients with inhibitory antibodies. In addition, it is used for patients with bleeding that do not respond to conventional therapy. However, the mechanism by which recombinant FVIIa restores hemostasis has not been clearly defined. In conclusion, the TF:FVIIa complex is essential for hemostasis and recombinant FVIIa is an effective hemostatic drug.

Figure 1

Simplified version of the clotting cascade. Tissue factor (TF) and FVIIa comprise the extrinsic pathway. FXIIa, FXIa, FIXa, and FVIIIa are members of the intrinsic pathway. The common pathway is made up of FVa, FXa, and thrombin. Thrombin cleaves fibrinogen, activates FXIII, and activates platelets (Plt). The clotting cascade is regulated by three major pathways: TF pathway inhibitor (TFPI) that inhibits the TF:FVIIa complex; activated protein C (APC) that cleaves and inactivates FVa and FVIIIa; and antithrombin (AT) that inhibits thrombin and other proteases in the cascade. For simplicity only activated proteases and cofactors are shown.

Figure 2

Tissue factor (TF) expression in the vessel wall. TF staining (brown color) in the wall of a mouse arteriole. Original magnification ×400. The picture was kindly provided by Dr. M. Hoffman, Duke University, North Carolina.

Figure 3

Models for idling of the clotting cascade in normal individuals. (A) The extravascular tissue factor (TF) model. It is proposed that the smaller clotting factors leak into the vessel wall and this generates low levels of thrombin. Diffusion of thrombin back into the blood would allow cleavage of low levels of fibrinogen and the release of Fibrinopeptide A. Alternatively, subclinical vessel injury may expose extravascular TF and lead to the generation of low levels of TF. (B) The intravascular TF model. TF on the surface of microparticles generates low levels of FXa and thrombin.

Figure 4

Model for tissue-specific hemostasis. It is proposed that the extrinsic pathway mediates hemostasis in tissues that express high levels of tissue factor (TF), whereas the intrinsic pathway mediates hemostasis in tissues that express low levels of TF.