Platelet adhesion

Following vessel wall injury, platelets rapidly adhere to exposed elements in the subendothelial matrix; initiating the first step in the haemostatic response leading to the formation of a platelet plug. This primary adhesion is mediated by the synergistic function of several receptors on the platelet surface. Collagen is the main component of the subendothelium matrix and is also considered to play the principal role in the adhesion process. Nine types of collagen have been identified in the vessel wall but the main constituents have been determined as collagen type I and type III [7].The local flow conditions are also important in determining the platelet behaviour. Blood is always moving inside the vessels, but the conditions can vary from almost stagnant to extremely high flow rates. The velocity of blood, in relation to the stationary vessel wall, gives rise to shear forces in the moving blood that can be described by a velocity gradient. Shear forces will lead to a higher concentration of erythrocytes and other large blood cells in the middle of the high-velocity flow, and the platelet concentration will be highest closer to the vessel wall where the fluid velocity is lower [8, 9]. The highest shear rate, or velocity gradient, is always found closest to the vessel wall [8]. Under high shear conditions, the initial tethering and arrest of platelets from the flowing blood to collagen is facilitated by the glycoprotein (GP) Ib-IX-V receptor, a heterotrimer composed of two disulfide linked GPIba-GPIbß in complex with two GPIX and one GPV [10, 11]. The binding is mediated by von Willebrand factor (VWF), a multimeric plasma protein that rapidly binds to exposed collagen. Long multimers of VWF can contain several binding sites for the GPIb-IX-V adhesion receptors and upon binding GPIb-IX-V is capable of outside-in signaling leading to platelet activation [12, 13]. The GPVI receptor binds directly to collagen via the specific Gly-Pro-Hyp peptide repeat sequence and has an important role in platelet activation by outside-in signaling [14, 15]. The GPVI activation has been found to be mediated by the Fc receptor γ-chain, also involved in platelet interaction with immunoglobulins [16, 17]. The integrin α2β1 adhesion receptor (also known as GPIa/IIa) can bind to collagen directly. Although it has been indicated that the α2β1 integrin is not involved in the initial tethering of platelets to collagen under high shear, it is still considered important for firm adhesion and securing the platelets [18]. α2β1 has also been proposed to be involved in platelet spreading on the collagen surface [19]. The integrin α2β1 receptor must be activated by inside-out signaling to attain a state of high affinity for its ligand [20]. The two collagen receptors GPVI and α2β1 are both essential for platelet adhesion and aggregation on collagen in flow conditions, blockade of either receptor will abolish the platelet plug forming capabilities [21].