Platelets are part of the cardiovascular system and normally circulate in blood in a quiescent form. In response to tissue injury, platelets become activated and form a thrombus (blood clot) to block further loss of blood and begin the process of tissue repair. Under certain conditions of inflammation or disease, platelets can aberrantly be activated to form a thrombus. This type of unrestricted thrombus formation can lead to blockage of cerebral vessels (stroke) or coronary vessels (heart attack). In thrombosis, platelet adhesion and aggregation are initiated by engagement of specific membrane receptors that lead to platelet activation and integrin-dependent aggregation. At high shear stress, platelet adhesion is mediated primarily by binding of the platelet membrane glycoprotein (GP) Ib-IX-V complex to its ligand, von Willebrand Factor (VWF), and binding of GPVI to collagen. The binding of VWF to GPIb-IX-V is a critical event in initiating thrombosis. Distinct sites in the vWF A1 domain bind GPIb-IX-V, and leucine-rich repeats two through four of GPIb are involved in the binding of VWF. Signalling through GPIb-IX-V is dependent upon 14-3-3 zeta and the p85 subunit of PI 3-kinase, which bind to the alpha chain of GPIb. The cytosolic regulatory protein, calmodulin, also interacts directly with the cytoplasmic domains of both GPIb-IX-V and GPVI, associations that regulate the adhesive function and/or signal transduction mediated by these receptors. Activation of platelet signalling pathways leads to metalloproteinase-dependent shedding of platelet receptors, and is a key mechanism for regulation of platelet receptor levels and thus platelet function.
Posted on: Mon, 08 Jul 2013 03:37:27 +0000
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