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    I am studying haematology and have an essay title that I am just really confused and cannot find anything worth while writing about...

    The essay title: Haemostasis: Discuss current ideas of the mechanism(s) by which tissue factor becomes activated?

    Tissue factor is the cell surface and is activated by factor 7a which activates 10a
    but that is literally it. I don't understand what does it mean by current ideas of the mechanism?

    Hi, various processes in human physiology have complex cellular level or even molecular level mechanisms many of which have been elucidated in the last several years. For example, certain prostaglandin class members have actions on thrombolysis or thrombogenesis, respectively, which can be turned on or off or modulated by gene activation or suppression. These effects on gene activity may be translated into cellular events via protein synthesis, whereby certain proteins or small peptides produce the desired effect.

    Firstly, let me oint out that my knowledge of the blood clotting mechanism is very basic, only what i learnt in physiology as a medic. If you are doing a degree in haematology, you will be covering this in much more detail.

    I would suggest you look up the references below (the abstracts therein at the very least) and plan your essay based on the info you derive from them, but also expanding on relevant parts by following other references cited in these papers.

    Hope this helps.

    (Panteleev, Zarnitsina et al. 2002)
    (Riewald and Ruf 2001)
    (Camici and Sagripanti 1999)
    (Monroe, Hoffman et al. 1998)
    (Carmeliet and Collen 1998)
    (Kazama 1997)
    (Kondo, Noguchi et al. 1987)
    Camici, M. and A. Sagripanti (1999.

    "Tissue factor pathway inhibitor." Minerva Med 90(1-2): 25-32. The role of Tissue Factor (TF, thromboplastin) as the major factor in initiation of the blood coagulation process has been known for more than 100 years. Its importance for the development of clinical thrombosis, be it venous or arterial, and the complexity of the cell biology of TF, have however been increasingly appreciated over the past 15-20 years. Acting as a cofactor for coagulation factor VIIa, it is now clear that TF is able to activate factor IX. Aberrant expression of TF seems to play a major role in the intravascular coagulations disorders linked to endotoxemia, malignancies, immunological diseases and atherosclerosis. Tissue Factor Pathway Inhibitor (TFPI) is the natural direct inhibitor of TF/FVIIa complex. In this study the physiological role, mechanism of action and pharmacological potential of TFPI are discussed.

    Carmeliet, P. and D. Collen (1998). "Tissue factor." Int J Biochem Cell Biol 30(6): 661-667. Tissue factor is the primary cellular initiator of blood coagulation via interaction with coagulation factor VII. Aberrant expression of tissue factor is responsible for thrombosis during septic shock, atherosclerosis and cancer. However, recent evidence has accumulated that tissue factor may have functions beyond controlling fibrin-dependent hemostasis. It is expressed as an immediate early gene by growth factors and cytokines, it transduces intracellular signals via its cytosolic domain, triggers production of growth factors and has been implicated in immune function, smooth muscle migration and metastasis, the latter via mechanisms requiring intracellular signaling as well as the proteolytic activity of the tissue factor-factor VIIa complex. Further evidence for a possible alternative role of tissue factor has been provided from tissue factor gene inactivation studies, indicating that tissue factor controls vascular integrity by affecting the maturation of the muscular wall around endothelial cell lined channels. Surprisingly, however, deficiency of factor VII does not affect vascular integrity and tissue factor may act independently of fibrin formation during embryogenesis. Elucidation of the mechanism of its action may provide insights for selective interference with the hemostatic versus morphogenic properties of tissue factor.

    Kazama, Y. (1997). "The importance of the binding of factor Xa to phospholipids in the inhibitory mechanism of tissue factor pathway inhibitor: the transmembrane and cytoplasmic domains of tissue factor are not essential for the inhibitory action of tissue factor pathway inhibitor." Thromb Haemost 77(3): 492-497. To investigate the inhibitory mechanism of tissue factor pathway inhibitor (TFPI), an attempt was made to examine the inhibitory activity of TFPI toward the factor VIIa-truncated tissue factor (TF1-219) complex, which lacks its transmembrane and cytoplasmic domains. Factor VIIa-TF1-219 activity was significantly inhibited by TFPI-factor Xa complex in the presence of phospholipids, but was not in the absence of phospholipids. In addition, TFPI did not inhibit factor VIIa-TF1-219 activity in the presence of gamma-carboxyglutamic acid-domainless factor Xa. The ability of TFPI-factor Xa complex to inhibit factor VIIa-TF1-219 activity was totally dependent on the presence of phospholipids and was neutralized by prothrombin fragment 1 in a dose-dependent manner. These results indicate that the transmembrane and cytoplasmic domains of tissue factor are not essential for the inhibitory mechanism of TFPI and confirm that the binding of factor Xa to phospholipids through its gamma-carboxyglutamic acid domain is essential for this reaction.

    Kondo, S., M. Noguchi, et al. (1987). "Inhibition of human factor VIIa-tissue factor activity by placental anticoagulant protein." Thromb Res 48(4): 449-459. Previous studies indicated that human placental anticoagulant protein, a member of the lipocortin family, prolonged the clotting time of normal plasma when clotting was induced by brain thromboplastin or by kaolin in the presence of cephalin and calcium. Using a two-stage amidolytic assay to assess factor X activation and a tritiated peptide release assay to assess factor IX activation, we have examined the ability of purified preparations of placental anticoagulant protein (Mr = 36.5 kDa) to inhibit the activation of either factor X or factor IX by a complex of human factor VIIa-tissue factor. Placental anticoagulant protein markedly inhibits factor X and factor IX activation by factor VIIa-tissue factor in a non-competitive manner with Ki values of 40 nM and 70 nM, respectively. Placental anticoagulant protein had no effect on factor Xa amidolytic activity, and its inhibitory activity was not diminished by prior incubation with antibody raised against partially purified plasma extrinsic pathway inhibitor. Binding of placental anticoagulant protein to phospholipid vesicles, crude tissue factor and purified, relipidated human brain tissue factor apoprotein was observed only in the presence of calcium ions. These results indicate that placental anticoagulant protein is a potent factor VIIa-tissue factor inhibitor and suggests that its mechanism of action involves binding to the phospholipid portion of the tissue factor lipoprotein.

    Monroe, D. M., M. Hoffman, et al. (1998). "A possible mechanism of action of activated factor VII independent of tissue factor." Blood Coagul Fibrinolysis 9 Suppl 1: S15-20. We have used a cell-based model system to examine some aspects of coagulation. Unactivated platelets and tissue factor (TF)-bearing cells were mixed with plasma levels of zymogen factors IX (FIX), FVIII, FX, FV, and prothrombin, as well as coagulation inhibitors antithrombin III and TF pathway inhibitor. Reactions were initiated with plasma levels (0.2 nmol/l) of activated factor VII (FVIIa). We were able to measure platelet activation and subsequent thrombin generation in this system and have established parameters for the normal amount of thrombin generation and the range of values seen with different individuals. If FIX or FVIII were not added to this system, platelet activation but not thrombin generation was seen. We have used this system to examine the mechanism of action of high-dose FVIIa. If platelets were activated with the thrombin receptor agonist peptide SFLLRN and incubated with inhibitors and zymogen factors X, V, and prothrombin, no thrombin generation was observed. Addition of increasing amounts of FVIIa gave increasing amounts of thrombin generation. At the FVIIa concentrations present in the plasma of patients given 60 microg/kg recombinant FVIIa (NovoSeven, Novo Nordisk, Bagsvaerd, Denmark), 10-40 nmol/l, thrombin generation in the model system approached the normal amount seen in the TF-initiated model system. When FIX and FVIII were included in the above reaction, FVIIa could initiate thrombin generation at levels three to four times the amount seen in the TF-initiated model system. We speculate that this platelet-localized thrombin generation may, in part, account for the clinical efficacy of high-dose FVIIa.

    Panteleev, M. A., V. I. Zarnitsina, et al. (2002). "Tissue factor pathway inhibitor: a possible mechanism of action." Eur J Biochem 269(8): 2016-2031. We have analyzed several mathematical models that describe inhibition of the factor VIIa-tissue factor complex (VIIa-TF) by tissue factor pathway inhibitor (TFPI). At the core of these models is a common mechanism of TFPI action suggesting that only the Xa-TFPI complex is the inhibitor of the extrinsic tenase activity. However, the model based on this hypothesis could not explain well all the available experimental data. Here, we show that a good quantitative description of all experimental data could be achieved in a model that contains two more assumptions. The first assumption is based on the hypothesis originally proposed by Baugh et al. [Baugh, R.J., Broze, G.J. Jr & Krishnaswamy, S. (1998) J. Biol. Chem. 273, 4378-4386], which suggests that TFPI could inhibit the enzyme-product complex Xa-VIIa-TF. The second assumption proposes an interaction between the X-VIIa-TF complex and the factor Xa-TFPI complex. Experiments to test these hypotheses are suggested.

    Riewald, M. and W. Ruf (2001). "Mechanistic coupling of protease signaling and initiation of coagulation by tissue factor." Proc Natl Acad Sci U S A 98(14): 7742-7747. The crucial role of cell signaling in hemostasis is clearly established by the action of the downstream coagulation protease thrombin that cleaves platelet-expressed G-protein-coupled protease activated receptors (PARs). Certain PARs are cleaved by the upstream coagulation proteases factor Xa (Xa) and the tissue factor (TF)--factor VIIa (VIIa) complex, but these enzymes are required at high nonphysiological concentrations and show limited recognition specificity for the scissile bond of target PARs. However, defining a physiological mechanism of PAR activation by upstream proteases is highly relevant because of the potent anti-inflammatory in vivo effects of inhibitors of the TF initiation complex. Activation of substrate factor X (X) by the TF--VIIa complex is here shown to produce enhanced cell signaling in comparison to the TF--VIIa complex alone, free Xa, or Xa that is generated in situ by the intrinsic activation complex. Macromolecular assembly of X into a ternary complex of TF--VIIa--X is required for proteolytic conversion to Xa, and product Xa remains transiently associated in a TF--VIIa--Xa complex. By trapping this complex with a unique inhibitor that preserves Xa activity, we directly show that Xa in this ternary complex efficiently activates PAR-1 and -2. These experiments support the concept that proinflammatory upstream coagulation protease signaling is mechanistically coupled and thus an integrated part of the TF--VIIa-initiated coagulation pathway, rather than a late event during excessive activation of coagulation and systemic generation of proteolytic activity.
    • Thread Starter

    Thank you so much! I did not expect a response quite like this. This is amazing I will look into every source and plan my essay. I am studying a degree in biomedical science.

    Thanks once again!
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