In differentiated tissues, activation and aggregation of platelets on the endothelial surface is abrogated by endothelial antithrombotic mediators such as nitric oxide (NO) and prostacyclin (PGI). The small amount of continuously expressed adhesion molecules on the endothelial surface does not sufficiently provoke platelet-endothelial interactions.
As a result of disruption of the endothelial surface and exposure of subendothelial matrix as well as in response to inflammatory cytokines (TNF, IL-1, IFN) and angiogenic growth factors (VEGF), platelet-endothelial interactions are mediated by endothelial and platelet-specific adhesion molecules. Platelet interaction with the endothelial surface and subendothelial matrix occurs in a sequence of initial short-timed contact (rolling) followed by adhesion and aggregation of activated platelets. Initiation of platelet rolling appears to be independent of platelet activation.
Platelet rolling on stimulated endothelium is mediated by endothelial P- and E-selectin. P-selectin and von Willebrand factor are released from Weibel-Palade bodies of endothelial cells and are presented on the endothelial surface within minutes following stimulation . Expression of E-selectin and a second phase of P-selectin expression depend on de novo protein synthesis and occur hours after the primary stimulus. The main ligand for endothelial P-selectin on platelets has been identified to be P-selectin binding ligand-1. Binding of endothelial P-selectin by glycoprotein (GP) Ib/IX/V as a second ligand depends on previous platelet activation. Platelets store P-selectin along with adhesion proteins fibronectin, fibrinogen, and von Willebrand factor (vWF) in their a-granules and release these factors within minutes following stimulation. P-selectin expression on activated platelets may also facilitate platelet rolling. The endothelial ligand for platelet P-selectin has not been identified.
Slowing down platelet trafficking along the endothelial surface ensures stable platelet adhesion by a fibrin-dependent bridging mechanism between GPIIb/IIIa on platelets and endothelial ICAM-1 or avß3-integrin on activated and proliferating endothelial cells. Adhesion proteins vWF, fibrin, and fibronectin are required for further platelet aggregation by GPIIb/IIIa binding. Receptors involved in platelet interaction with intact endothelial surface are depicted in Figure 1.
At sites of endothelial damage and exposure of sub-endothelial matrix platelet rolling and aggregation depend mainly on vWF . Plasmatic and endothelial vWF become immobilized on subendothelial matrix. Platelet rolling and adhesion are initiated by the binding of GPIb/IX/V to immobilized vWF that goes along with platelet activation. ATP and serotonin released from dense granules of activated platelets stimulate the aggregation of further platelets. This is accompanied by secretion of vWF, P-selectin, fibrinogen, and fibronectin from a-granules of platelets and transformation of GPIIb/IIIa into its active configuration. Thus, platelet adhesion to the subendothelial matrix is enhanced by fibrinmediated GPIIb/IIIa binding to immobilized vWF. Furthermore, different types of collagen receptors on platelets can cause a fast platelet activation on contact to the subendothe-lial matrix. Depending on the type of vessel wall, collagen receptors contribute differently to platelet-vessel wall interactions. Receptors involved in platelet rolling, adhesion, and aggregation on the subendothelial matrix are summarized in Figure 2.
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This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.