Endothelial cells maintain a nonthrombogenic lining in blood vessels. This results from several phenomena, in-cluding (1) the maintenance of a transmural negative electrical charge, which is important in preventing ad-hesion of circulating platelets; (2) the release of plas-minogen activators, which activate the fibrinolytic path-way; (3) the activation of protein C, which degrades coagulation factors, a process involving thrombin and its endothelial cofactor (thrombomodulin); (4) the pro-duction of heparinlike proteoglycans, which inhibit co-agulation; and (5) the release of prostacyclin (PGI2), a potent inhibitor of platelet aggregation.
In normal individuals, injury severe enough to cause hemorrhage initiates coagulation. Vasoconstriction, combined with increased tissue pressure caused by ex-travasated blood, results in a reduction, or stasis, of blood flow. Stasis favors the restriction of thrombus formation to the site of injury. The extravasation of blood exposes platelets and the plasma clotting factors to subendothelial collagen and endothelial basement membranes, which result in activation of the clotting sequence. Several substances that participate in coagu-lation are released or become exposed to blood at the site of injury. These include adenosine diphosphate (ADP), a potent stimulus to platelet aggregation, and tissue factor, a membrane glycoprotein cofactor of fac-tor VII.
Platelet aggregation is the most important defense mechanism against leakage of blood from the circula-tion. Ordinarily, unstimulated platelets do not adhere to the endothelial cell surface. Following disruption of the endothelial lining and exposure of blood to the suben-dothelial vessel wall, platelets come into contact with and adhere within seconds to factor VIII:vWF polymers and fibronectin. The platelets change shape and then undergo a complex secretory process termed the release reaction. This results in the release of ADP from platelet granules and activation of platelet phospholi-pase A2. This enzyme, cyclooxygenase, and thrombox- ane synthetase sequentially convert arachidonic acid into cyclic endoperoxides and thromboxane A2 (TxA2). In contrast to endothelial cells, platelets lack PGI2 syn-thetase. Upon platelet activation with mediators of ag-gregation (ADP, serotonin, TxA2, epinephrine, throm-bin, collagen, platelet activating factor), the integrin platelet receptor for plasma fibrinogen, glycoprotein IIb/IIa (GPIIb/IIa), is expressed. The arginine– glycine–aspartic acid (RDG) tripeptide in the β-chain of fibrinogen mediates binding of fibrinogen to the GPIIb/IIIa complex. Fibrinogen, forming a bridge be-tween platelets, and the binding of fibrinogen and Von Willebrand’s factor to activated platelets via GPIIb/IIIa are key events in platelet–platelet interactions and play a major role in thrombus formation. Aggregation of cir-culating platelets to those already adherent amplifies the release reaction.
Other substances liberated from platelets during the release reaction include serotonin (which may promote vasospasm in coronary vessels), platelet factor 4 (a ba-sic glycoprotein that can neutralize the anticoagulant action of circulating heparin), platelet-derived growth factor (a mitogen that initiates smooth muscle cell pro-liferation and may be involved in atherogenesis), and factors that are also found in the plasma (factor V, fac-tor VIII:vWF, and fibrinogen). During aggregation, the rearrangement of the platelet membrane makes avail-able a phospholipid surface (platelet factor 3) that along with Ca++ is required for the activation of several clot-ting factors. The platelet aggregate becomes a hemostatic plug and is the structural foundation for the assembly of the fibrin network.
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