Regulation of tissue factor coagulant activity on cell surfaces

Abstract

Summary Tissue factor (TF) is a transmembrane glycoprotein and an essential component of factor VIIa-TF enzymatic complex that triggers activation of the coagulation cascade. Formation of TF-FVIIa complexes on cell surfaces not only trigger the coagulation cascade but also transduce cell signaling via activation of protease-activated receptors. Tissue factor is expressed constitutively on cell surfaces of a variety of extravascular cell types, including fibroblasts and pericytes in and surrounding blood vessel walls and epithelial cells but generally absent on cells that come in contact with blood directly. However, TF expression could be induced in some blood cells, such as monocytes and endothelial cells, following an injury or pathological stimuli. Tissue factor is essential for hemostasis, but aberrant expression of TF leads to thrombosis. Therefore, a proper regulation of TF activity is critical for the maintenance of hemostatic balance and health in general. TF-FVIIa coagulant activity at the cell surface is influenced not only by TF protein expression levels but also independently by a variety of mechanisms, including alterations in membrane phospholipid composition and cholesterol content, thiol-dependent modifications of TF allosteric disulfide bond, and other post-translational modifications of TF. In this article, we critically review key literature on mechanisms by which TF coagulant activity is regulated at the cell surface in the absence of changes in TF protein levels with specific emphasis on recently published data and provide the authors’ perspective on the subject.

Hepatocyte tissue factor activates the coagulation cascade in mice

“…2 However, the TF:FVIIa complex can also exist in an encrypted state that has little or no PCA. 3 In this molecular state, TF could potentially be expressed on cells in contact with coagulation factors in the blood without triggering pathologic coagulation. Molecular events proposed to increase PCA of the TF:FVIIa complex include interaction of the TF:FVIIa complex with anionic phospholipids on the cell membrane and modification of allosteric disulfides in the TF molecule.…”

“…Molecular events proposed to increase PCA of the TF:FVIIa complex include interaction of the TF:FVIIa complex with anionic phospholipids on the cell membrane and modification of allosteric disulfides in the TF molecule. [3][4][5][6] However, the mechanism whereby the TF:FVIIa complex attains full PCA is not completely understood.…”

Application of High-Intensity Focused Ultrasound to the Study of Mild Traumatic Brain Injury

“…surface are a well-characterized phenomenon of vascular cell activation and injury (Kulik et al 2009;Rao and Pendurthi 2012;Rosenberg 2012). The fact that no change in infiltration was seen with IgG or IgM, however, suggests that although there was perturbation of the endothelium, there was no evidence that under these conditions, HIFU exposure resulted in a shearing injury or a significant breach of the blood-brain barrier that permitted the infiltration of macromolecules in the range of 150 kDa.…”

Biocompatibility and Biotolerability Assessment of Microspheres Using a Whole Blood Model

“…The extrinsic pathway is initiated by tissue factor (TF). TF is a transmembrane glycoprotein constitutively expressed on extravascular cells (like fibroblasts and pericytes surrounding blood vessels), while inducible expressed upon blood vessel injury [41,42], as well as in monocytes upon stimulation with LPS or bacteria's [43][44][45]. TF is also exposed on circulating cell-derived microparticles (MPs) [46].…”