An Important Role In Homeostasis Biology Essay

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Platelets are small, irregularly shaped cells that circulate in the blood of mammals. They play an important role in homeostasis in which they have the ability to adhere to a damaged vessel wall and cause aggregation in response to the agonists such as thrombin, collagen or adenosine diphosphate (ADP). These properties are known to be mediated by cell surface glycoproteins such as Fibrinogen (Fg) and the abundant glycoprotein V (GPV) which is found at the surface of blood platelets. (Moog et al 2001). It is a subunit of the platelet GPIb-V-IX receptor von Willebrand factor and thrombin. This has shown to promote platelet adhesion to the subendothelium which becomes activated and triggers the recruitment of more platelets forming a platelet plug in which follows the arrest of bleeding. To perform this function, subendothelial - bound vWF binds to its platelet receptor glycoprotein (GP) Ib, establishing a transient bond that can slow down the platelets and lead to activation of platelet αIIbβ3 (integrin GPIIb//IIIa). After that first adhesion step, different receptor-ligand interactions synergistically promote stable platelet adhesion ( Ni et al - 2000) .Key roles for the leucine-rich von Wille-brand factor (VWF) receptor glycoprotein (GP) Ib -IX-V and the integrin αIIbβ3 in platelet tethering and aggregate formation are established (Moog et al 2001). Recent evidence indicates that collagen is the connective tissue component to which platelets adhere. Butler and Cunningham showed that soluble collagen contained only galactose and galactosyl-glucose units o-glycosidically linked to the hydroxyl group of hydroxylysine. It has led to propose that the collagen carbohydrate side chain represents the "recognition site" and that the binding involves an enzyme substrate (or inhibitor) type interaction e.g. platelet - glycosyltransferase complexes with collagen - gal (Puett et al 1973). It has been considered that collagen is the vascular substrate in haemostasis. There is evidence that a major component of the material underlying the endothial cell of large vessel is non- collagenous in nature. Platelets adhere to a vessel wall where it is denuded of endothelium via a specific platelet collagen receptor made up of glycoproteins. This interaction is mediated by the von Willebrand factor glycoprotein which allows platelets to remain attached to the vessel wall despite the high sheer force within the vascular lumen. Platelet aggregation is mediated by fibrinogen. This simply links adjacent platelets on the platelet glycoprotein IIb/IIa complex. Substances released by these cells further cause platelet activation and aggregation such as the release of agonists adenosine diphosphate, serotonin, thromboxane TxA (2), which act in the autocrine and paracrine mode to cause additional platelets to circulate and adhere to the original deposition. These are known as aggregating platelets which undergo dramatic morphological changes which is important in further aggregation and coagulation. Platelet aggregation is the first step in haemostasis, the second step is the formation of fibrin initiated only after this has occurred. The secreted agonists interact with their G-protein coupled receptors and generate inside- out signalling leading to activation of integrins such as alpha(IIb)beta(3) to their ligands such as fibrinogen, thus increasing their ligand affinity and supports processes such as clot formation and platelet aggregation, (Bristol-Myers Squibb aus dm Jahr 2002.

From recent studies it has shown that the integrin α2β1 glycoprotein supports platelet adhesion to collagen, it has been led to believe that the integrin α2β1 (GP1a-IIa) is the platelet collagen receptor. "The first evidence for this came from studies on a patient with a severe bleeding problem who was found to have platelets that were unresponsive to collagen, and an 80% reduction in expression of the integrin α2 (GP1a) subunit. Subsequently, the α2 subunit was identified through affinity chromatography as a major collagen-binding protein. Immunoprecipitation with a monoclonal antibody (mAb) that prevents platelet activation by collagen, and affinity chromatography later identified the α2β1 heterodimer as a collagen receptor on the platelet" (Watson & Gibbins)

Patients with reduced levels of expression of α2β1 glycoprotein or in the presence of autoantibodies to the integrin are found to exhibit impaired platelet activation by collagen but not by other agonists. This group of patients can be subdivided into those whose platelets are unresponsive to collagen and those whose platelets respond only to high concentrations of collagen. The former group may have other defects that account for the more severe phenotype. For example, platelets from the patient used in the original study on the α2 subunit exhibit impaired adhesion to several extracellular matrix proteins that do not bind to α2β1. .

Binding to α2β1 is now recognized to be the major interaction supporting platelet adhesion to most forms of collagen under flow conditions. The rapid adhesion of platelets to collagen fibres under these conditions is dramatically reduced by removal of Mg2+ ions, which are required for binding of collagen to α2β1, or antibodies to the integrin. By contrast, other surface proteins play significant roles in adhesion to collagen fibres under static conditions or after longer incubation times, partly owing to platelet activation".

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