Figure 222

The fibrinolytic system in blood vessels showing the physiological mechanisms of activation of plasminogen on fibrin to cause fibrinolysis and the pathophysiological mechanism in the blood to cause fibrinogenolysis. The release of t-PA from vascular endothelium and the inhibitory effect of a2-antiplasmin on plasmin activity are depicted. PAI-1, plasminogen activator inhibitor-1; FDP fibrin degradation products; factor, coagulation factor. (Modified with permission from Wiman B and Hamsten A. The fibrinolytic enzyme system and its role in the etiology of thromboembolic disease. Semin Thromb Hemost 1990;16:207.)

coagulation factors, a process involving thrombin and its endothelial cofactor (thrombomodulin); (4) the production of heparinlike proteoglycans, which inhibit coagulation; 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 coagulation 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 factor VII.

Platelet aggregation is the most important defense mechanism against leakage of blood from the circulation. 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 synthetase. Upon platelet activation with mediators of aggregation (ADP, serotonin, TxA2, epinephrine, thrombin, collagen, platelet activating factor), the integrin platelet receptor for plasma fibrinogen, glycoprotein Ilb/IIa (GPIIb/IIa), is expressed. The arginine-glycine-aspartic acid (RDG) tripeptide in the a-chain of fibrinogen mediates binding of fibrinogen to the GPIIb/IIIa complex. Fibrinogen, forming a bridge between 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 circulating 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 basic glycoprotein that can neutralize the anticoagulant action of circulating heparin), platelet-derived growth factor (a mitogen that initiates smooth muscle cell proliferation and may be involved in atherogenesis), and factors that are also found in the plasma (factor V, factor VIII:vWF, and fibrinogen). During aggregation, the rearrangement of the platelet membrane makes available a phospholipid surface (platelet factor 3) that along with Ca++ is required for the activation of several clotting factors. The platelet aggregate becomes a hemostatic plug and is the structural foundation for the assembly of the fibrin network.

Peripheral Neuropathy Natural Treatment Options

Peripheral Neuropathy Natural Treatment Options

This guide will help millions of people understand this condition so that they can take control of their lives and make informed decisions. The ebook covers information on a vast number of different types of neuropathy. In addition, it will be a useful resource for their families, caregivers, and health care providers.

Get My Free Ebook


Post a comment