Tissue Factor and Tissue Factor Pathway Inhibitor as Key Regulators of Global Hemostasis: Measurement of Their Levels in Coagulation Assays

Abstract

The tissue factor (TF)/factor (F)VIIa complex is the primary initiator of coagulation in vivo. Tissue factor pathway inhibitor (TFPI) is the physiological inhibitor of the TF/FVIIa complex. Deficiencies of either TF or TFPI have not been reported in humans, and a complete absence of either of these two proteins in mice is embryonically lethal. To maintain normal hemostasis, levels of TF and TFPI need to be balanced. Increased levels of TF can overwhelm the inhibitory capacity of TFPI, resulting in thrombosis. Decreased levels of TF are associated with bleeding. Global assays of coagulation are defined as tests capable of evaluating all components of the clotting cascade that are present in plasma. In these tests the thrombogenic surface is either provided by platelets or exogenous phospholipids. Clotting assays currently used in clinical practice are not designed to measure endogenous levels of TF and TFPI. Therefore, there is a need to develop sensitive and specific assays for measuring levels of functional TF and TFPI in whole blood and plasma. These assays could be useful in patient management in many scenarios. KeywordsTissue factor; tissue factor pathway inhibitor; thrombosis; thromboelastography Significant progress has been made over the last decade in understanding the many complex interactions involved in the process of blood coagulation. The care ofpatientswithdisordersofthrombosisisalsoentering a new era with many new treatment modalities in varying stages of development, including new oral anticoagulants, aptamers targeted against coagulation factors and the use of natural anticoagulants. 1,2 In addition, hemophilia patients with inhibitors can be treated with recombinant factor (F)VIIa, and possibly in the future with drugs that interfere with the activity of anticoagulant proteins, such as tissue factor pathway inhibitor (TFPI). In keeping with these advances, ongoing efforts are aimed at improving our ability to identify at-risk patients, such as those at risk for bleeding or those at risk for venous thromboembolism (VTE). Successful risk stratification has the advantage of both improving outcomes and decreasing the number of patients exposed to unnecessary interventions. This review briefly discusses the role of tissue factor (TF) and TFPI in hemostasis and the measurement of endogenous levels of these proteins in whole blood and plasma. TF is constitutively expressed by perivascular cells, which ensures rapid activation of coagulation at sites of vascular damage. TF is also constitutively expressed in the brain, heart, lung, kidney, and placenta, where it provides additional tissue-specific hemostatic protection to these vital organs. The importance of TF in these organs is underscored by the development of hemorrhages in the brain, lung, and heart in mice expressing low levels of TF or FVIIa. A genetic deficiency of TF has not been described in humans, and a complete absence of TF is embryonically lethal in mice. 4 TF expression can also be induced in a variety of cells, such as monocyt...

Hemoconcentration and Hemostasis During Acute Stress: Interacting and Independent Effects

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“…Further showing the importance of platelets in CHD are epidemiologic studies showing the increased levels of platelet markers (i.e., BTG and PF4) and PLAs in patients with acute coronary syndromes, unstable angina, and stable CHD (for reviews, see [5,92]). In the vast majority of studies, platelet markers and PLAs have a positive relationship with CHD.…”

Indoleamine 2,3‐dioxygenase 1 in coronary atherosclerotic plaque enhances tissue factor expression in activated macrophages

“…Thrombi produced on disrupted plaques comprise aggregated platelets and considerable amount of fibrin; therefore, a tissue factor‐mediated coagulation pathway plays a critical role in thrombus formation that leads to the onset of ACS 2, 3, 4. Tissue factor (TF) expression by macrophages and smooth muscle cells in plaques5, 6 is induced by proinflammatory cytokines such as interferon‐γ (IFNγ), tumor necrosis factor‐alpha (TNFα), lipopolysaccharide, as well as hypoxia,5, 6, 7 and its procoagulant activity is inhibited by TF pathway inhibitor (TFPI) 8…”

Effects of Melatonin and Luzindole on plasma levels of tissue factor, tissue factor Pathway inhibitor and Von Willebrand factor in rats

“…Tissue factor (TF), also known as plasma factor III, is a transmembrane glycoprotein which plays an initiating role for blood coagulation in the extrinsic pathway (1,2). It is widely present in all tissues but is expressed mostly in subendothelial cells, adventitial fibroblasts, alveolar cells, cardiomyocytes, astrocytes, trophoblasts, and others (3,4,5).…”

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