Coagulation is initiated by contact between blood and Tissue Factor. Vascular cells articulate TF and provide a haemostatic boundary to limit blood loss after vessel injury. The activation of Factor X and factor IX is initiated by this bimolecular complex, which initiates blood coagulation and leads to the generation of thrombin, fibrin deposition and the activation of platelets. The initiator of coagulation factor TF/FVII complex is inhibited by kunitz type protease inhibitor called tissue factor pathway inhibitor (TFPI).
Tissue factor is an essential membrane protein with a molecular weight of approximately 43,000 situated on the plasma membrane of most vascular cells. TF is a receptor and cofactor for factors FVII and FVIIa, which are necessary for the initiation of blood coagulation via extrinsic pathway. TF is composed of 263 amino acids and consists of a 219 amino acid N- terminal the extracellular domain, a 23 residue transmembrane portion and a 21 residue intracytoplasmic C terminal domain, which contains palmitate and stearate bound through a thioester bond to a cysteine residue (Ronald et al 2005). The location of TF gene is on chromosome 1p21-p22 and it's about 12.4 Kb in length and is composed of six exons and 5 introns. Tissue factor is expressed constitutively on many extravascular tissues.TF expression can also be induced on blood monocytes and vascular endothelial cells by bacterial products, inflammatory cytokines and engagement of p-selectine glycoprotein ligand-1 on monocytes. Expression of intravascular TF may contribute to the procoagulant state associated with inflammatory or infection (Ernest etal 2001).
Activation and Activity
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The factor VIIa/TF complex is thought to be the major physiologic initiator of blood coagulation. The process of coagulation is initiated when an injury ruptures a vessel and allows blood to come into contact with extravascular TF. When circulating factor VII binds to TF, it is rapidly converted to the active protease, factor VIIa. The factor VIIa/TF complex can activate both factor IX (FIX) and factor X (FX). The binding of factor VIIa to TF enhances its proteolitic activity by almost three orders of magnitude. FVII binding to tissue factor is calcium dependant and the affinity of the interaction is only slightly enhanced by the presence of anionic phospholipid. Therefore the cleavage of factor IX or X by FVIIa/TF is enhanced by anionic phospholipid. This effect is due to enhanced binding of the substrate rather than to any effect of phospholipid on the catalytic efficiency of the factor VIIa/TF complex. Binding of TF to FVIIa is reconstituted into synthetic phospholipid vesicles always results in enhanced factor VIIa proteolytic activity. However, binding of FVIIa to cellular sources of TF does not correlate with enhanced enzymatic activity. This illustrates that cells can regulate the cofactor activity of TF in a manner that is not reduced by synthetic phospholipid vesicles. TF does not require proteolytic activation to express its activity. However it appears that TF can occur in encrypted form, that is TF detected as antigen on the cell surface may not express cofactor activity. Hypothesis suggests that, TF could form dimmers that block access to the substrate binding site on TF. Dimerized TF could still bind to FVII but would be inactive because it could not bind factor IX or X. The physiologic regulators that control TF encryption is not clear and it remains to be determined whether this is an important regulatory mechanism in vivo (Susan et al 2008).
The role of tissue factor
The goal of haemostasis is to produce fibrin clot to seal a site of injury or rupture in the blood vessel wall. The factor VIIa/TF complex localised by cells to the site of injury and the activation of factor X to factor Xa and activation of factor IX to IXa leads separate functions in the process of blood coagulation. The factor Xa formed on the TF bearing cell interacts with cofactor Va to form a prothrombinase complex sufficient to generate very small amount of thrombin in the surrounding area of the TF cells. However, the quantity of thrombin generated is inadequate to clot fibrinogen; nevertheless, it is satisfactory to initiate the clotting system for a subsequent burst of thrombin generation. The small amounts of thrombin generated on the TF bearing cells are capable of accomplishing, the activation of platelets, activation of factor V, FVIII from Von Willebrand factor (vWF) and activation of FXI. The activity of FXa is restricted by the TF bearing cell. FXa is rapidly inhibited by Tissue Factor pathway inhibited (TFPI) or antithrombin (ATIII). However, FXa can diffuse to adjacent cell surfaces without inhibited by TFPI, nevertheless, it is inhibited much more slowly by ATIII than Xa. (Nigel 2005)
The role of activated platelets and TF
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Platelets also play a major role in localising clotting reactions to the site of injury since they adhere and aggregate at the same sites where TF is exposed. Platelets localisation and activation are mediated by vWF, thrombin, platelet receptors and vessel wall components such as collagen.TF on platelets may could be articulated by mechanisms, such as, ''fusion of TF containing microparticles (MPs) with the membrane of activated platelets, storage in α- granules with exocytosis to the cell surface platelet activation and novo synthesis of TF by activated platelets following the splicing of TF pre mRNA'' (Nigel 2008). Polymorphonuclear neutrophils (PMNs) transport TF containing MPs to platelet adherent to collagen by the interaction of CD15 on the MP and TF. The CD15 binds to p-selectin (CD62P) in the membranes of platelet of α granules and Weibel- Paled bodies of endothelial cells. CD62P can only be expressed on the surface of activated platelets and endothelial cells.
Once platelets are activated the cofactors Va and VIIIa are rapidly localised to the platelet membrane surface. The FIXa formed by the FVIIa/TF complex binds to the surface of activated platelets. Specific sites on the activated platelets bind FIXa and promote formation of active FIXa/VIIIa complexes. Once the platelet complex is assembled FX is recruited from the plasma and is activated to FXa on the platelet surface. FXa then associates with factor FVa and generates thrombin sufficient to clot fibrinogen and form haemostatic plug. FXIII, activated by thrombin, cross links fibrin and stabilises the haemostatic plug rendering it impermeable.
Once a fibrin platelet clot is formed over an area of injury the clotting process must be terminated to avoid thrombotic occlusion in adjacent normal areas of the vasculature. If the coagulation mechanism were not controlled, clotting could occur throughout the entire vascular tree. Endothelial cells play a major role in confining the coagulation reactions to a site of injury and preventing clot extension to areas where an intact endothelium is present. Endothelial cells have anticoagulant and antitrombotic activities. Activated coagulation factors that move to an endothelial cells surface are rapidly inhibited by antithrombin (ATIII) associated with glycosaminoglycans (GAG) on the endothelial surface. Moreover thrombin that reaches the endothelial cell surface binds to thrombomodulin (TM). Once bound thrombin can no longer cleave fibrinogen, instead thrombin/TM complex activates protein C, then binds to its cofactor protein S and inactivates factor Va or VIIIa. This prevents the generation of additional thrombin in the vasculature.
The endothelial cell posses other anticoagulant feature, such as, the protease inhibitors ATIII and TFPI are always present bound to heparan sulphates expressed on the endothelial surface, where they can inactivate proteases near an intact endothelium. Endothelial cells also inhibit platelate activation by releasing the inhibitors prostacyclin and nitric oxide, as well as digesting ADP by their membrane ecto-ADPase CD39.The Role of plasma protease inhibitor is critical in localising the coagulation reactions to specific cell surfaces by directly inhibiting protease that escape into the fluid phase. Protease inhibitors impose a threshold effect on the coagulation process. Thus in the presence of inhibitors coagulation does not proceed unless procoagulant factors are generated in sufficient amounts to overcome the effects of inhibitors. If the triggering event is not sufficiently strong the system returns to base line rather than continuing through the coagulation process.
TFPI and its activity- TFPI consists of a single chain polypeptide structure with a molecular weight of 34,000- 40,000. It consist of 3 kunitz protease inhibitor domains. The 2nd domain binds and inhibits FXa, as a result the 1st kunitz bind and inhibit the FVIIa/TF complex. However, the 3rd kunitz function is not clear. Mainly TF bound to heparian sulphates on the surface of endothelial cells. Administration of heparian releases endothelial cells bound TFPI and raises plasma level several fold. Antithrombin is a member of large family of serine protease inhibitors (serpins). Thrombin inhibition by antithrombin in the presence of heparin molecules on the endothelial surface. The binding of antithrombin to the heparin results in rapid inactivation of thrombin. Once a haemostatic clot has been formed, some provision must be made for its eventual removal as wound healing takes place. Finally dissociation of clots accomplished by the fibrinolytic system.
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