Platelet physiology

Physiological agonists cannot penetrate the plasma membrane barrier and therefore, they must first couple to specific interactive domains on the platelet surface membrane in order to trigger the sequence of activation signals (21 -29, reviewed by Ryningen and Holmsen in this book). The physiological agonists that are known to activate platelets include adenosine diphosphate (ADP), epinephrine (adrenaline), thromboxane A2 (Txj\ ), thrombin, and platelet activation factor (PAF). In addition, cell matrix components such as laminin, fibronectin, collagen and von Willebrand factor also trigger platelet activation. Platelet adherence to surfaces and resulting activation leads to the development of stickiness, change in shape, formation of pseudopods, adhesion, followed by aggregation and secretion of granule contents. (Fig. 4).

Receptors for ADP, epinephrine, thromboxane, thrombin and PAF have been well characterized (27, 31, reviewed in other chapters). Membrane spanning receptors of epinephrine, thrombin and thromboxane are coupled to the ubiquitous GTP-binding proteins. Platelets contain monomelic, low molecular weight G proteins as well as heterotrimeric membrane associated G-proteins. GTP binding to the a-subunit of G-proteins facilitates the interaction with effector enzymes, resulting in the hydrolysis of GTP to GDP, which terminates its stimulatory role (29).

Figure 4. Scanning electronmicrograph of activated platelets Platelet activation resulting in shape change and formation of pseudopods (PS) (Courtesy: James G. White, MD).

Agonist-mediated activation of platelets stimulates phospholipase C (PLC) and it then triggers the hydrolysis of phosphatidyl inositol 4,5-bisphosphate (PIP2), the formation of second messengers such as 1,2-diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) (30-38, also reviewed in this book). Diacylglycerol (DAG) is a substrate for protein kinase C (PKC), which is recognized as a multifunctional enzyme (25). This lipid intermediate is also a substrate for phosphatide acid. Diacylglycerol (DAG) induces translocation of cytosolic PKC to membranes, which acts as a trigger mechanism for its activation. On the other hand, IP, is known to mobilize ionized calcium from internal membrane stores. However, thrombin and PAF can also mobilize calcium from the external milieu. Ionized calcium plays a central role in all platelet functional responses and it is therefore considered as an important bioregulator in platelet pathophysiology (3136, also reviewed elsewhere in this book). Elevated cytosolic calcium is essential for the assembly of filamentous actin. Furthermore, it is also considered essential for the activation of phospholipase A2, a key enzyme to mobilize arachidonic acid (AA) from membrane phospholipids for farther metabolism (reviewed elsewhere in this book). It is well documented that free AA then is converted to cyclic endoperoxides such as PGGj and PGHj in the presence of cyclooxygenase (27, 11, 23). These transient metabolites are further transformed into novel thromboxanes by thromboxane synthetase. Thromboxane A2 is the major metabolite of AA metabolism in platelets (31). It is a vasoconstrictor and potent platelet agonist, hi endothelial cells, AA is converted to cyclic endoperoxides by cyclooxygenase, and these metabolites are further transformed to prostacylcin (PGI2) by prostacyclin synthetase. Prostacyclin is a vasodilator and a potent platelet antagonist (31). Thus both phosphoinositol pathway and AA metabolism, contribute significantly to the activation of platelets by soluble agonists (27,2, 10, 11, 14). These events promote the expression of an activation dependent epitope on the platelet glycoprotein GP1 lb/111a receptor (39-46). Activation of this receptor promotes fibrinogen binding and facilitates platelet adhesion, aggregation and growth of the thrombus. However, activation of this receptor is not essential for its interaction with surface bound fibrinogen. Apart from the agonists mentioned above, shear force also can induce platelet activation (discussed elsewhere in this book). It is believed that fibrinogen plays a role in the adhesion and aggregation of platelets under low shear rates. Furthermore, at high shear forces von Willebrand factor interaction with GPlb/lX seems to be important (31, also discussed in other chapters of this book). Circulating adhesive proteins such as fibrinogen, cell matrix components, bacterial membrane proteins, certain tumor cells and biomaterial surfaces also interact with the platelet plasma membrane at discrete domains. Binding of ligands to integrin and non-integrin receptors induce activation signaling mechanisms (27, 31,62, also discussed in other chapters of this book). Binding results in the activation and stimulation of various effector enzymes and formation of second messengers, leading to aggregation and secretion of granule contents. Specific mechanisms involved in the process of centralization of granules and release of their contents are poorly understood(26,27, 31).

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