Porth's Essentials of Pathophysiology, 4e

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Disorders of Hemostasis

C h a p t e r 1 2

Vessel Spasm Vessel spasm is initiated by endothelial injury and caused by local and humoral mechanisms. It is a transient event, usually lasting less than one minute, that results from neural reflexes and humoral factors released from plate- lets and traumatized tissue. 1 For smaller vessels, release of the vasoconstrictor TXA 2 is responsible for much of the vessel spasm. Platelet Plug Formation The platelet plug, the second line of defense, is initi- ated as platelets come in contact with the vessel wall. Small breaks in the vessel wall are often sealed with the platelet plug rather than with a blood clot. Platelet plug formation involves adhesion, granule release, and aggregation of platelets. 3 Platelets are attracted to a damaged vessel wall, become activated, and change from smooth disks to spiny spheres, exposing glyco- protein receptors on their surfaces. Platelet adhesion requires a protein molecule called von Willebrand factor (vWF). This factor is produced by both mega- karyocytes and endothelial cells and circulates in the blood as a carrier protein for coagulation factor VIII. Adhesion to the vessel subendothelial layer occurs when the platelet membrane receptor binds to vWF at the injury site, linking the platelet to exposed collagen fibers. Degranulation and release of the contents of both the α - and δ -granules occur soon after platelet adhe- sion. The δ -granule contents’, including calcium, is required for the coagulation component of hemostasis. 3 The binding of ADP to the platelet membrane induces a conformation change of the gpIIb/IIIa receptors, allowing them to bind fibrinogen and form aggregates. Besides ADP, platelets secrete the prostaglandin TXA 2 , which is an important stimulus for platelet aggrega- tion. The combined actions of ADP and TXA 2 lead to the expansion of the enlarging platelet aggregate, which is called the primary hemostatic platelet plug . Conversion of the primary platelet plug into a definitive clot (known as a secondary hemostatic plug ) occurs as the coagulation pathway is activated on the surface of the aggregated platelets and fibrinogen is converted to fibrin (factor Ia), thereby creating a fibrin meshwork that cements the platelets and other blood components together. Platelet aggregation inhibitors, including aspirin, clopidogrel (Plavix), and ticlopidine (Ticlid), can be used to prevent platelet aggregation and clot forma- tion in persons who are at risk for myocardial infarc- tion, stroke, or peripheral artery disease. 6,7 Low-dose aspirin therapy inhibits prostaglandin synthesis, including TXA 2 . Clopidogrel and ticlopidine achieve their antiplatelet effects by inhibiting the ADP path- way in platelets. Unlike aspirin, these drugs have no effect on prostaglandin synthesis. Drugs that act as gpIIb/IIIa receptor inhibitors (abciximab, eptifibatide, tirofiban) have been developed for use in the treat- ment of persons with acute coronary syndromes (see Chapter 19). 7 ( text continues on page 266 )

Blood coagulation is regulated by several natural antico- agulants, such as antithrombin III and proteins C and S, which work by inactivating some of the clotting factors. The plasma also contains a plasma protein called plas- minogen that gets activated and converted to plasmin, an enzyme capable of digesting the fibrin strands of the clot. In addition to removing clots that are no longer needed, plasmin scavenges continually to prevent clots from forming inappropriately. Endothelium The blood vessels themselves play an important role in preventing and controlling the formation of blood clots. Blood vessels are lined with endothelial cells that modulate several, frequently opposing stages of normal hemostasis. Under most circumstances endothelial cells maintain an environment that promotes blood flow by blocking platelet adhesion and activation, inhibiting the coagulation process, and lysing blood clots. It should be noted, however, that the endothelium can be activated by infectious agents, hemodynamic factors, plasma mediators, and cytokines that are liberated during an inflammatory reaction. An intact endothelial surface prevents platelets and plasma coagulation factors from interacting with the underlying thrombogenic subendothelial extracellular matrix. Moreover, if platelets are activated, they are inhibited from adhering to the surrounding uninjured endothelium by endothelial prostacyclin (prostaglan- din I 2 [PGI 2 ]) and nitric oxide (see Chapter 18). Both of these mediators are potent vasodilators and inhibitors of platelet aggregation. Endothelial cells also elaborate an enzyme called adenosine diphosphatase (ADP) that degrades and further inhibits platelet aggregation. The anticoagulant effects of endothelial cells are mediated by membrane-bound heparin and thrombomodulin, both of which inactivate thrombin (factor IIa). In addition, endothelial cells synthesize tissue plasminogen activator, promoting fibrinolytic activity that clears fibrin deposits from endothelial cell surfaces. Although endothelial cells exhibit properties that inhibit blood clotting, they are also capable of exhibit- ing numerous procoagulant properties in response to injury and activation. An important function of activated endothelial cells is the synthesis of von Willebrand factor, which participates in platelet adhesion and blood clotting. Clot Formation and Dissolution Hemostasis is divided into five stages: (1) vessel spasm, (2) formation of the platelet plug, (3) blood coagula- tion or development of an insoluble fibrin clot, (4) clot retraction, and (5) clot dissolution. 1 During the process of hemostasis, hairlike fibrin strands glue the aggregated platelets together and intertwine to form the structural basis of the blood clot. In the presence of fibrin, plasma becomes gel-like and traps red blood cells and other formed elements in the blood (see Fig. 12-1). Hemostasis is complete when fibrous tissue grows into the clot and seals the hole in the vessel.