Platelets normally circulate in an unstimulated disk-shaped form. During hemostasis or thrombosis, platelets become activated and help form hemostatic plugs or thrombi (Figure 1). Three major steps are involved: (1) adhesion to exposed collagen in blood vessels; (2) release (exocytosis) of the contents of their storage granules; and (3) aggregation.

Fig1. (A) Diagrammatic representation of platelet activation by collagen, thrombin, thromboxane A2 and ADP, and inhibition by prostacyclin. The external environment (Out), the plasma membrane, and the inside of a platelet (In) are depicted from top to bottom. Platelet responses include, depending on the agonist, change of platelet shape, release of the contents of the storage granules, and aggregation. (AC, adenylyl cyclase; cAMP, cyclic AMP; COX-1, cyclooxgenase-1; cPLA2 , cytosolic phospholipase A2 ; DAG, 1,2-diacylglycerol; GP, glycoprotein; IP, prostacyclin receptor; IP3 , inositol 1,4,5-trisphosphate; P2Y1 , P2Y12 , purinoceptors; PAR, protease activated receptor; PIP2 , phosphatidylinositol 4,5-bisphosphate; PKC, protein kinase C; PL, phospholipid; PLCβ, phospholipase Cβ; PLCγ, phospholipase Cγ; TP, thromboxane A2 receptor; TxA2 , thromboxane A2 ; VWF, von Willebrand factor.) The G-proteins that are involved are not shown. (B) Diagrammatic representation of platelet aggregation mediated by fibrinogen binding to activated GPIIb-IIIa molecules on adjacent platelets. Signaling events initiated by all aggregating agents transform GPIIb-IIIa from its resting state to an activated form that can bind divalent fibrinogen or, at the high shear that occurs in small vessels, multivalent von Willebrand factor.

Platelets adhere to collagen via specific receptors on the platelet surface, including the glycoprotein complexes GPIa-IIa (α2β1 integrin) and GPIb-IX-V, and GPVI. The binding of GPIb-IX-V to collagen is mediated via von Willebrand factor; this interaction is especially important in platelet adherence to the subendothelium under conditions of high shear stress that occur in small vessels and partially stenosed arteries.

Platelets that are bound to collagen change shape and spread out on the subendothelium. These adherent platelets release the contents of their storage granules (the dense gran ules and the alpha granules); some of the molecules released amplify the responses to vessel wall injury. Granule release is also stimulated by thrombin.

Thrombin, formed from the coagulation cascade (described later), is the most potent activator of platelets and initiates activation by interacting with its receptors protease-activated receptor-1 (PAR-1), PAR-4, and GPIb-IX-V on the platelet plasma membrane (see Figure 1A). The further events leading to platelet activation on binding to PAR-1 and PAR-4 are examples of outside-in transmembrane signaling, in which a chemical messenger outside the cell generates effector molecules inside the cell . In this instance, thrombin acts as the external chemical messenger (stimulus or agonist). The interaction of thrombin with its G-protein–coupled receptors PAR-1 and PAR-4 stimulates the activity of an intracellular phospholipase Cβ (PLCβ). This enzyme hydrolyzes the mem brane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2 , a polyphosphoinositide) to form the two internal effector molecules (1,2-diacylglycerol [DAG] and 1,4,5-inositol trisphosphate [IP3 ]).

Hydrolysis of PIP2 is also involved in the action of many hormones and drugs. DAG stimulates protein kinase C (PKC), which phosphorylates the protein pleckstrin (47 kDa). This results in aggregation and release of the contents of the storage granules. ADP released from dense granules can also activate platelets via its specific G-protein–coupled receptors (see Figure 1A; P2Y1 , P2Y12 ), resulting in aggregation of additional platelets. IP3 causes release of Ca2+ into the cytosol mainly from the dense tubular system (or residual smooth endo plasmic reticulum from the megakaryocyte), which then inter acts with calmodulin and myosin light-chain kinase, leading to phosphorylation of the light chains of myosin. These chains then interact with actin, causing changes of platelet shape.

Collagen-induced activation of a platelet cytosolic phospholipase A2 (cPLA2 ) by increased levels of intracellular Ca2+ results in liberation of arachidonic acid from platelet mem brane phospholipids, leading to the formation of thromboxane A2 (TxA2). TxA2 , in turn, by binding to its specific G-protein–coupled receptor (TP), can further activate PLCβ, promoting platelet aggregation (see Figure 1A).

All of the aggregating agents, including thrombin, collagen, ADP, TxA2 , and others such as platelet-activating factor, via an inside-out signaling pathway, modify the platelet surface glycoprotein complex GPIIb-IIIa(αIIbβ3 integrin) so that the receptor has a higher affinity for fibrinogen or von Willebrand factor (see Figure 1B). Molecules of divalent fibrinogen or multivalent von Willebrand factor then link adjacent activated platelets to each other, forming a platelet aggregate. von Willebrand factor–mediated platelet aggregation occurs under conditions of high shear stress. Agents such as epinephrine, serotonin, and vasopressin, exert synergistic effects with other aggregating agents.

Activated platelets, besides forming a platelet aggregate, accelerate the activation of the coagulation factor X and pro thrombin by exposing the procoagulant anionic phospholipid phosphatidylserine on their membrane surface (see following section for more detail). Polyphosphate, released from the dense granules, accelerates factor V activation and also accelerates factor XI activation by thrombin.

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مواضيع ذات صلة

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The Biochemical Basis of The ABO System

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