Porth's Essentials of Pathophysiology, 4e

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Disorders of Hemostasis

C h a p t e r 1 2

amounts by mast cells in connective tissue surrounding capillaries. Heparin binds to antithrombin III, causing a conformational change that increases the ability of antithrombin III to inactivate thrombin (IIa), factor Xa, and other clotting factors. By promoting the inactiva- tion of clotting factors, heparin ultimately suppresses the formation of fibrin and therefore inhibits coagulation. Pharmacologic preparations of heparin are extracted from animal tissues. Heparin is unable to cross the membranes of the gastrointestinal tract and must be given by injec- tion, usually by intravenous infusion. Low–molecular- weight heparins have been developed that inhibit activa- tion of factor X, but have little effect on thrombin and other coagulation factors. The low–molecular-weight heparins are given by subcutaneous injection and require less-frequent administration and monitoring compared with the standard (unfractionated) heparin. Clot Retraction Clot retraction normally occurs within 20 to 60 min- utes after a clot has formed, contributing to hemostasis by squeezing serum from the clot and joining the edges of the broken vessel. Platelets, through the action of their actin and myosin filaments, also contribute to clot retraction. Clot retraction therefore requires large num- bers of platelets, and failure of clot retraction is indica- tive of a low platelet count. Clot Dissolution The dissolution of a blood clot begins shortly after its formation; this allows blood flow to be reestablished and permanent tissue repair to take place. 1 The process in which the strands of the clot are dissolved is called fibrinolysis. As with clot formation, clot dissolution requires a sequence of steps controlled by activators and inhibitors. Plasminogen, the proenzyme for the fibri- nolytic process, normally is present in the blood in its inactive form. It is converted to its active form, plasmin, by plasminogen activators (PAs) formed in the vascular endothelium, liver, and kidneys. The plasmin formed from plasminogen digests the fibrin strands of the clot and certain clotting factors, such as fibrinogen (I), fac- tor V, factor VIII, prothrombin (II), and factor XII. The most important of the plasminogen activators is tissue- type plasminogen activator (tPA), which is synthesized principally by endothelial cells and is most active when attached to fibrin. The affinity of tPA for fibrin makes it a useful therapeutic agent, since it largely confines its activity to sites of recent thrombosis. 3 Another plas- minogen activator called urokinase-type plasminogen activator (uPA) is present in the tissues and can activate plasminogen in the fluid phase. As with other potent physiologic systems, the activity of plasmin is tightly controlled. Excess circulating plas- min is rapidly inactivated by α 2 -antiplasmin, which lim- its the fibrinolytic process to the local clot rather than allowing it to spread throughout the entire circulation. 3 Endothelial cells further modulate the coagulation/anti- coagulation process by releasing PA inhibitors, which block fibrinolysis and confer an overall procoagulation

effect. The PA inhibitors are increased by certain cyto- kines and probably play a role in the intravascular thrombosis accompanying severe inflammation.

SUMMARY CONCEPTS

■■ Hemostasis is an orderly multistep physiological process that preserves vascular integrity by balancing the processes that maintain blood in a fluid state and prevent excessive bleeding following injury. ■■ Hemostasis involves platelets, plasma clotting factors, naturally occurring anticoagulants, and the endothelial cells that line blood vessels, in order to transform blood into a semisolid clot with erythrocytes trapped in its fibrin meshwork. ■■ The process of hemostasis begins when a loss of endothelial integrity causes platelet activation. Upon activation, platelets undergo adhesion, granule release, and aggregation to form a primary platelet plug. ■■ The formation of the secondary hemostatic plug cements the platelet plug, forming an insoluble hemostatic clot.To occur, the formation of the definitive clot requires activation of the coagulation

cascade, which terminates with thrombin converting fibrinogen into insoluble fibrin.

■■ The final step of the process involves fibrinolysis or clot dissolution, which involves the action of plasmin to dissolve the clot and allow blood flow to be reestablished and tissue healing to take place.

Hypercoagulability States Hypercoagulability represents an exaggerated form of hemostasis that predisposes to thrombosis and blood vessel occlusion. There are two general forms of hyperco- agulability states: conditions that create increased plate- let function and conditions that cause accelerated activity of the coagulation system. Chart 12-1 summarizes con- ditions commonly associated with hypercoagulability states. Arterial thrombi are usually due to turbulence and composed largely of platelet aggregates, whereas venous thrombi are usually due to stasis of flow and composed largely of platelet aggregates and fibrin complexes that result from activation of the coagulation cascade. Increased Platelet Function Increased platelet function predisposes to platelet adhe- sion, formation of platelet clots, and the disruption of blood flow. The causes of increased platelet function