Platelets play a central role in hemostasis
During vascular injury, platelets play a central role in hemostasis. The first step involves adhesion of the platelets to the exposed sub-endothelium. This is mediated by the engagement of platelet surface glycoproteins (GPIb / V / IX complex, GPVI, αIIb β3, α2 β1, α5/β1 and α6/β1 integrins) which allow the binding of platelets to exposed ligands (subendothelial-bound von Willebrand factor (vWF) , collagen, fibronectin and laminin). It is a complex process that depends on shear stress. Under low shear conditions, platelets mostly adhere to collagen, fibronectin and laminin, via β1 integrins, whereas under high shear conditions, platelets adhere to subendothelial-bound vWF through GPIb. In the latter situation, binding of vWF to GPIb initiates platelet activation by increasing calcium flux across the platelet membrane. This then promotes dense granule secretion of ADP which induces the activation of αIIbβ3 integrin (inside-out signaling). Subsequently, platelet-platelet interaction or aggregation is initiated by the binding of fibrinogen or RGD-containing ligands to the activated αIIbβ3 integrin, which then generates signals (outside-in signaling), culminating in irreversible formation of aggregates with subsequent cessation of hemorrhage. The key factor for successful platelet function is the ultimate activation of the αIIbβ3 integrin.
The physiological agonists thrombin (from activation of blood coagulation), thromboxane A2 (TXA2) and ADP (the latter two released from the platelets themselves) participate in the activation of platelet αIIbβ3 integrin. ADP utilizes two major purinergic receptors, P2RY1 and P2RY12 ; TXA2 activates platelets by binding to G-protein coupled receptor family proteins, while thrombin cleaves multiple cell receptors including GPIb and the protease-activated receptors (PARs) . Furthermore, platelets adhere to collagen and, although many candidates have been proposed as platelet collagen receptors, α2β1 integrin and GPVI play a pivotal role in this activity.