The formation of lipid rafts is required for out-inside signaling in contrast with the activation of receptor itself by ligand only. On the other hand, lipid rafts may serve as a platform to concentrate activated GPIb-IX-V and GPIIb/IIIa in their respective local membrane when vWF self-association occurs. Another possible pathway from GPIb-IX-V to GPIIb/IIIa is shown in the right platelet. This leads to the formation of an “activation complex” consisting of RapI, RIAM and talin, which finally cooperates with kindlin3 to activate GPIIb/IIIa. The elevated Ca2+ and DAG together increase CalDAG-GEFI activity that in turn activates RapIb. The activated GPIb-IX-V subsequently increases the level of intracellular calcium, which is regulated by PLCγ2 derived second messengers inositol 1,4,5 trisphosphate (IP3) and diacylglycerol (DAG). Here we have depicted the events subsequent to the interaction between vWF and GPIb-IX-V. The generally known signaling pathway from GPIb-IX-V to GPIIb/IIIa is shown in the left platelet which depends on the out-inside and inside-out signaling. After the conformation alteration, activated GPIIb/IIIa binds to the C domain (in red) of associated vWF by RGDS within C domain. Associated vWF binds to GPIb-IX-V through A1 domain (in yellow), leading to a shift of GPIIb/IIIa conformation from a low-affinity to high affinity. Lateral associated vWF are formed by different multi-vWF through disulfide bond. Proposed mechanism of associated vWF activating GPIIb/IIIα. The elongated vWF multimers tend to be oriented to each other in laminar flow. The laminae close to the vessel wall have less velocity than those near the center (depicted schematically by arrows of different length). Timerik and assoc series#Laminar flow in a cylindrical vessel can be visualized as a series of fluid layers with different velocity. vWF multimers undergo conformational change from a loosely coiled ball to an elongated structure in turbulent flow. Turbulent flow is always highly irregular, in which the blood proteins tend to move in different directions at different speeds. B: The turbulence and laminar flow are two of the complex and diverse forms of flow in blood. It is speculated that the paralleled vWF multimers are more prone to self-associate to form vWF fibers. Increasing vWF multimer size: In laminar flow, the elongated vWF multimers that tend to flow in parallel are undesirable substrates of TSP-1 and ADAMTS13, because some corresponding sites of vWF are buried in vWF fibers. Reducing vWF multimer size: In turbulent flow, the elongated vWF multimers are reduced by TSP-1 and ADAMTS13 due to the elevated activities of TSP-1 and ADAMTS13 (cleavage and reduction activity) in response to turbulent flow and can’t self-associate. Model for regulation of the balance of vWF self-association and two forms of flows in blood vessel.A: The regulation of vWF multimer size equilibrates between reducing vWF multimer size and increasing vWF multimer size. Developments in these areas will refine our understanding of the role played by vWF self-association in physiological hemostasis and pathological thrombosis. Along with the classical signaling pathways in activated platelets, evidence is emerging that lipid rafts also play important roles in various phases of hemostasis and thrombosis and facilitate the interaction between the key signaling molecules. Moreover, in addition to proteolysis and reduction of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), the regulation of vWF multimer size and self-association may depend on a disulfide bond reductase activity ascribed to thrombospondin-1 (TSP-1). The self-association of vWF is also supported by a rapidly expanding reservoir of novel evidences that the thiol/disulfide exchange regulates vWF multimer size in the blood circulation. Through multiple functional domains, vWF mediates the attachment of platelets to exposed tissues, where immobilized vWF is able to support a homotypic and/or heterotypic self-association. The crucial role of vWF in platelet function is particularly apparent when hemodynamic conditions create blood flow with high shear stress. Von Willebrand factor (vWF) is a multimeric glycoprotein essential for hemostasis after vascular injury, which modulates platelet-surface and platelet-platelet interactions by linking platelet receptors to the extracellular matrix and to each other.
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