Tissue Factor encryption and decryption: Facts and controversies

Center for Biomedical Research, The University of Texas Health Science Center at Tyler, Tyler, TX, USA.
Thrombosis Research (Impact Factor: 2.43). 03/2012; 129 Suppl 2:S13-7. DOI: 10.1016/j.thromres.2012.02.021
Source: PubMed

ABSTRACT Tissue factor (TF)-initiated coagulation plays a critical role in both hemostasis and thrombosis. It is generally believed that most of the tissue factor expressed on cell surfaces is maintained in a cryptic, i.e., coagulantly inactive state and an activation step (decryption) is required for the expression of maximum TF procoagulant activity. However, what exactly constitutes cryptic or procoagulant TF, molecular differences between these two forms and mechanisms that are responsible for transformation from one to the other form are not entirely clear and remain highly controversial, thus are a matter of ongoing debate. This brief review discusses pertinent literature on TF encryption/decryption with specific emphasis on the role of membrane phospholipids and reduction/oxidation of the TF Cys186-Cys209 disulfide bond in regulating TF activity at cell surfaces.

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    ABSTRACT: Tissue factor (TF) is a transmembrane glycoprotein and an essential component of the 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 is generally absent on cells that come into 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 bonds, and other post‐translational modifications of TF. In this article, we critically review the 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.
    Journal of Thrombosis and Haemostasis 11/2012; 10(11). DOI:10.1111/jth.12003 · 5.55 Impact Factor
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    ABSTRACT: BACKGROUND: Tissue factor (TF) encryption plays an important role in regulating TF coagulant activity. Potential differences in experimental cell model systems and strategies hampered our understanding of the TF encryption mechanisms. OBJECTIVE: To characterize procoagulant activity status of TF in different cell types, and to determine whether increased TF procoagulant activity following the activation stems from transformation of the cryptic TF to active form. METHODS: Simultaneous kinetic analyses of TF-FVIIa activation of FX and FVIIa binding to cell surface TF were performed under identical experimental conditions in fibroblast (WI-38), cancer cell (MDA-231), endothelial cell (HUVEC), and monocytic cell (THP-1) model systems. These data were then utilized to estimate TF coagulant specific activity and percentages of active and cryptic TF present in these cell types. RESULTS: MDA-231 and WI-38 cells express 10 to 100-times more TF on their cell surfaces compared to perturbed HUVEC and THP-1 cells. TF specific activity on cell surfaces of MDA-231, WI-38, and THP-1 cells was very similar. Nearly, 80-90% of the TF in MDA-231, WI-38, and THP-1 cells was cryptic. A plasma concentration of FVII would be sufficient to bind both active and cryptic TF on cell surfaces. Increased TF activity following cell activation stems from decryption of cryptic TF rather than increasing the coagulant activity of the active TF. CONCLUSIONS: Our data demonstrate that TF encryption is not limited to a specific cell type, and unlike previously thought, majority of the TF expressed in cancer cells is not constitutively procoagulant. This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 04/2013; 11(7). DOI:10.1111/jth.12272 · 5.55 Impact Factor
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    ABSTRACT: Highly elevated microparticle (MP)-associated tissue factor (TF) activity was found in patients with pancreatic cancer, one of the most prothrombotic malignancies. It remains to be elucidated whether MP-TF activity reflects the prothrombotic state in these patients. MP-TF activity levels and the TF-dependent and -independent effect of MPs on fibrin clot formation were determined in patients with metastatic pancreatic cancer (n = 27) and in healthy individuals (n = 10). These parameters were also investigated in plasma samples from lipopolysaccharide (LPS)-stimulated blood (LPS-plasma), which is rich in monocyte-derived TF-bearing MPs. The median MP-TF activity was 1.06 pg/mL (range, from 0.19 to 10.34 pg/mL) in patients with pancreatic cancer, 0.61 pg/mL (range, from 0.36 to 0.79 pg/mL) in LPS-plasma, and 0.18 pg/mL (range, from 0.04 to 0.39 pg/mL) in healthy individuals. MPs derived from LPS-plasma had the strongest impact on fibrin clot formation time (median, 157.6 seconds; range, from 149.5 to 170.4 seconds). Fibrin clot formation occurred significantly later in MPs derived from patients with pancreatic cancer (median, 273.4 seconds; range, from 146.6 to 354.4 seconds; P < 0.001) and in healthy individuals (median, 299.0 seconds; range, from 261.1 to 417.9 seconds; P < 0.001). Only in MPs derived from LPS-plasma did the fibrin clot formation time depend strongly on TF (median prolongation after TF blockade: 68% in LPS-plasma, 10% in patients with pancreatic cancer, and 4% in healthy individuals). In conclusion, highly elevated MP-TF activity was found in patients with metastatic pancreatic cancer, but TF-bearing MPs had a small effect on fibrin clot formation. TF-bearing MPs might not be the main mediators of the prothrombotic state associated with pancreatic cancer. However, the small but significant increase in coagulation potential by TF-bearing MPs might contribute to the multifactorial pathogenesis of venous thromboembolism in pancreatic cancer.
    08/2013; DOI:10.1016/j.trsl.2013.06.009

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