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Thrombosis Research May 2012Blood clotting is triggered when the plasma serine protease factor VIIa binds to the cell-surface protein, tissue factor (TF); the resulting TF:FVIIa complex activates... (Review)
Review
Blood clotting is triggered when the plasma serine protease factor VIIa binds to the cell-surface protein, tissue factor (TF); the resulting TF:FVIIa complex activates factors IX (FIX) and X (FX) by limited proteolysis. FVIIa, FIX and FX all bind reversibly to membranes via their gamma-carboxyglutamate-rich (GLA) domains, while TF is an integral membrane protein. Removing these proteases from the membrane surface is known to render them thousands of times less active, although the mechanisms by which blood clotting proteins bind to membranes-and the contributions of membranes to catalysis-remain very incompletely understood. Our recent and ongoing studies use a combination of nanoscale membrane bilayers (Nanodiscs), solid-state NMR and all-atom molecular dynamics (MD) simulations, enabling detailed insights into how GLA domains bind to phospholipid bilayers and how specific phospholipids enhance the catalytic activity of the TF:FVIIa complex.
Topics: Cell Membrane; Factor VIIa; Humans; Models, Molecular; Thromboplastin
PubMed: 22417943
DOI: 10.1016/j.thromres.2012.02.019 -
Blood Jan 1988
Review
Topics: Amino Acid Sequence; Animals; Blood Coagulation Tests; Factor IX; Factor VII; Factor X; Hemostasis; Humans; Mice; Molecular Sequence Data; Phospholipids; Protein Binding; Thromboplastin
PubMed: 3275472
DOI: No ID Found -
Canadian Medical Association Journal Jan 1969
Topics: Humans; Hypoprothrombinemias; Male; Prothrombin Time; Thromboplastin
PubMed: 5762237
DOI: No ID Found -
Stem Cells Translational Medicine Oct 2018Clinical cellular therapeutics (CCTs) have shown preliminary efficacy in reducing inflammation after trauma, preserving cardiac function after myocardial infarction, and...
Clinical cellular therapeutics (CCTs) have shown preliminary efficacy in reducing inflammation after trauma, preserving cardiac function after myocardial infarction, and improving functional recovery after stroke. However, most clinically available cell lines express tissue factor (TF) which stimulates coagulation. We sought to define the degree of procoagulant activity of CCTs as related to TF expression. CCT samples from bone marrow, adipose, amniotic fluid, umbilical cord, multi-potent adult progenitor cell donors, and bone marrow mononuclear cells were tested. TF expression and phenotype were quantified using flow cytometry. Procoagulant activity of the CCTs was measured in vitro with thromboelastography and calibrated thrombogram. Fluorescence-activated cell sorting (FACS) separated samples into high- and low-TF expressing populations to isolate the contribution of TF to coagulation. A TF neutralizing antibody was incubated with samples to demonstrate loss of procoagulant function. All CCTs tested expressed procoagulant activity that correlated with expression of tissue factor. Time to clot and thrombin formation decreased with increasing TF expression. High-TF expressing cells decreased clotting time more than low-TF expressing cells when isolated from a single donor using FACS. A TF neutralizing antibody restored clotting time to control values in some, but not all, CCT samples. CCTs demonstrate wide variability in procoagulant activity related to TF expression. Time to clot and thrombin formation decreases as TF load increases and this procoagulant effect is neutralized by a TF blocking antibody. Clinical trials using CCTs are in progress and TF expression may emerge as a safety release criterion. Stem Cells Translational Medicine 2018;7:731-739.
Topics: Adipose Tissue; Amniotic Fluid; Blood Coagulation; Bone Marrow Cells; Cell- and Tissue-Based Therapy; Fetal Blood; Humans; Mesenchymal Stem Cells; Thrombelastography; Thrombin; Thromboplastin
PubMed: 30070065
DOI: 10.1002/sctm.18-0015 -
Thrombosis Research May 2012Tissue factor (TF) is a transmembrane protein which, in complex with factor (F)VIIa, initiates blood coagulation. Numerous studies have determined TF epitopes and... (Review)
Review
Tissue factor (TF) is a transmembrane protein which, in complex with factor (F)VIIa, initiates blood coagulation. Numerous studies have determined TF epitopes and individual amino acids which play an important role in the TF/FVIIa complex formation and its activity towards natural substrates. However the subject of cell-surface TF activity remains controversial. It has been almost commonly accepted that TF on the cell surface has low (if any) activity, i.e. is encrypted and requires specific conditions/reagents to become active, i.e. decrypted. One of the leading theories suggests that cell membrane lipid composition plays a crucial role in TF decryption, whereas another assigns the key role to the formation of the Cys(186)-Cys(209) disulfide bond. Despite a number of studies published from several laboratories, the role of this bond in the activity of the TF/FVIIa complex remains elusive and controversial. One of the causes of this controversy could be related to the lack of specificity of the reagents used for the cell treatment leading to possible alterations in other cell surface proteins and cell membrane environment. In conclusion, the influence of the Cys(186)-Cys(209) this bond on cell surface TF function remains unclear.
Topics: Factor VIIa; Factor Xa; Humans; Thromboplastin
PubMed: 22401800
DOI: 10.1016/j.thromres.2012.02.022 -
Blood Advances Jun 2023Cancer enhances the risk of venous thromboembolism, but a hypercoagulant microenvironment also promotes cancer progression. Although anticoagulants have been suggested...
Cancer enhances the risk of venous thromboembolism, but a hypercoagulant microenvironment also promotes cancer progression. Although anticoagulants have been suggested as a potential anticancer treatment, clinical studies on the effect of such modalities on cancer progression have not yet been successful for unknown reasons. In normal physiology, complex formation between the subendothelial-expressed tissue factor (TF) and the blood-borne liver-derived factor VII (FVII) results in induction of the extrinsic coagulation cascade and intracellular signaling via protease-activated receptors (PARs). In cancer, TF is overexpressed and linked to poor prognosis. Here, we report that increased levels of FVII are also observed in breast cancer specimens and are associated with tumor progression and metastasis to the liver. In breast cancer cell lines, tumor-expressed FVII drives changes reminiscent of epithelial-to-mesenchymal transition (EMT), tumor cell invasion, and expression of the prometastatic genes, SNAI2 and SOX9. In vivo, tumor-expressed FVII enhanced tumor growth and liver metastasis. Surprisingly, liver-derived FVII appeared to inhibit metastasis. Finally, tumor-expressed FVII-induced prometastatic gene expression independent of TF but required a functional endothelial protein C receptor, whereas recombinant activated FVII acting via the canonical TF:PAR2 pathway inhibited prometastatic gene expression. Here, we propose that tumor-expressed FVII and liver-derived FVII have opposing effects on EMT and metastasis.
Topics: Humans; Female; Breast Neoplasms; Signal Transduction; Thromboplastin; Tumor Microenvironment
PubMed: 36920782
DOI: 10.1182/bloodadvances.2022008455 -
Frontiers in Bioscience (Elite Edition) Jan 2012It is generally believed that only a small fraction of the tissue factor (TF) found on cell surfaces is active whereas the vast majority is cryptic in coagulation. It is... (Review)
Review
It is generally believed that only a small fraction of the tissue factor (TF) found on cell surfaces is active whereas the vast majority is cryptic in coagulation. It is unclear how cryptic TF differs from the coagulant active TF or potential mechanisms involved in transformation of cryptic TF to the coagulant active form. Exposure of phosphatidylserine (PS) in response to various chemical or pathophysiological stimuli has been considered as the most potent inducer of TF decryption. In addition to PS, TF self-association and association with specialized membrane domains may also play a role in TF decryption. It has been suggested recently that protein disulfide isomerase regulates TF decryption through its oxidoreductase activity by targeting Cys186-Cys209 disulfide bond in TF extracellular domain or regulating the PS equilibrium at the plasma membrane. However, this hypothesis requires further validation to become an accepted mechanism. In this article, we critically review literature on TF encryption/decryption with specific emphasis on recently published data and provide our perspective on this subject.
Topics: Factor VIIa; Humans; Membrane Proteins; Signal Transduction; Thromboplastin
PubMed: 22201972
DOI: 10.2741/477 -
Anaesthesia May 2004The classical 'cascade/waterfall' hypothesis formulated to explain in vitro coagulation organised the amplification processes into the intrinsic and extrinsic pathways.... (Review)
Review
The classical 'cascade/waterfall' hypothesis formulated to explain in vitro coagulation organised the amplification processes into the intrinsic and extrinsic pathways. Recent molecular biology and clinical data indicate that tissue factor/factor-VII interaction is the primary cellular initiator of coagulation in vivo. The process of blood coagulation is divided into an initiation phase followed by a propagation phase. The discovery of tissue factor pathway inhibitor further supports the revised theory of coagulation. Tissue factor is also a signalling receptor. Recent evidence has shown that blood-borne tissue factor has an important procoagulant function in sepsis, atherosclerosis and cancer, and other functions beyond haemostasis such as immune function and metastases.
Topics: Animals; Blood Coagulation; Humans; Lipoproteins; Signal Transduction; Thromboplastin; Thrombosis
PubMed: 15096242
DOI: 10.1111/j.1365-2044.2004.03679.x -
Seminars in Thrombosis and Hemostasis Oct 2015Tissue factor (TF), the main trigger of blood coagulation, is essential for normal hemostasis. Over the past 20 years, heightened intravascular levels and activity of TF... (Review)
Review
Tissue factor (TF), the main trigger of blood coagulation, is essential for normal hemostasis. Over the past 20 years, heightened intravascular levels and activity of TF have been increasingly perceived as an entity that significantly contributes to venous as well as arterial thrombosis. Various forms of the TF protein in the circulation have been described and proposed to be thrombogenic. Aside from cell and vessel wall-associated TF, several forms of non-cell-associated TF circulate in plasma and may serve as a causative factor in thrombosis. At the present time, no firm consensus exists regarding the extent, the vascular setting(s), and/or the mechanisms by which such TF forms contribute to thrombus initiation and propagation. Here, we summarize the existing paradigms and recent, sometimes paradigm-shifting findings elucidating the structural, mechanistic, and pathophysiological characteristics of plasma-borne TF.
Topics: Animals; Humans; Protein Isoforms; Thromboplastin; Thrombosis
PubMed: 26408917
DOI: 10.1055/s-0035-1556049 -
Thrombosis Research Apr 2010Coagulation processes under flow conditions are fundamentally different when compared to whole blood clotting in a tube. Due to red blood cell migration toward the... (Review)
Review
Coagulation processes under flow conditions are fundamentally different when compared to whole blood clotting in a tube. Due to red blood cell migration toward the center of the vessel, platelet concentrations are elevated several-fold in the plasma layer near the wall or thrombus. Evaluation of platelet function, coagulation proteases, and pharmacological agents can utilize closed systems of constant volume that lack flow (eg. intracellular calcium measurement, automated calibrated thrombography) or include flow (eg. aggregometry or cone-and-plate viscometry). However, these laboratory approaches fail to recreate the fact that intravascular thrombosis is an open system where blood is continually flowing over a thrombotic site. In open systems, the rapid accumulation of platelets at a surface leads to platelet concentrations greatly exceeding those found in whole blood and the delivery/removal of species by convection may impact the efficacy of pharmacological agents. During a clotting event under flow, platelets can accumulate via adhesion receptors to concentrations that are 10 to 50-fold higher than that of platelet-rich plasma. Using controlled in vitro perfusions of whole blood, it is possible to determine the critical level of surface tissue factor needed to trigger full scale coagulation on collagen. Such in vitro perfusion systems also allow a determination of the potency of anti-platelet agents as a function of wall shear rate.
Topics: Blood Coagulation; Blood Platelets; Cell Movement; Collagen; Erythrocytes; Humans; Inhibitory Concentration 50; Kinetics; Microfluidic Analytical Techniques; Oligonucleotide Array Sequence Analysis; Platelet Adhesiveness; Stress, Mechanical; Thromboplastin; Thrombosis
PubMed: 20149924
DOI: 10.1016/j.thromres.2010.01.029