Hemostasis and Thrombosis

Hemostasis The rapid cessation of bleeding after vessel injury is a vital function of the organism. To reach this goal, a variety of chemical factors have been developed that form together the functional unit of the clotting cascade. This system becomes activated within seconds after tissue injury to avoid life-threatening blood loss. In physiological conditions, hemostasis is well controlled and carefully balanced by a variety ofprocoagulant and anticoagulant factors. In arteries, clotting starts with the targeted adhesion of platelets to the subendothe-lium in an area of endothelial injury. There is activation of the arachidonic acid cascade with subsequent thromboxane formation, platelet aggregation, and secretion of vasoconstrictor, inflammatory, and mitogenic factors. The activation of the coagulation cascade, culminating in thrombin formation, occurs at the surface of activated platelets that not only provide clotting factors but also act as a matrix to localize thrombin formation to the side where it is needed. The result is an occluding thrombus that stops bleeding mechanically by "plugging" the site of vessel injury while local vasoconstriction prevents the thrombus washout. Generation of thromboxane A2 by activated platelets acts as amplifying factor for platelet aggregation and vessel constriction (Figure 2.24).

At about the same time, platelet inhibitory, an-tithrombotic mechanisms (prostacyclin, NO, and endothelial nucleotidases) become activated in the noninjured endothelium in the vicinity of the thrombus. These anticoagulatory factors are also activated by thrombus formation and limit thrombus growth to the site of vessel injury. Activation of the fibrinolytic system (tissue plasminogen activator (tPA)) and subsequent clot lysis allow recanali-zation of the thrombus and restitution ofblood flow and initiate the healing phase of vessel wall injury.

Aspirin can principally modify all three components of the hemostatic system, that is, platelet function, plasmatic coagulation, and fibrinolysis,

Figure 2.24 Platelet adhesion, activation, aggregation, and formation of a platelet-fibrin thrombus. Thrombin generation occurs at the surface of activated platelets that also synthesize thromboxane A2 (TXA2). Both compounds are released from the thrombus and stimulate thrombus growth and stability. Aspirin not only inhibits thromboxane formation but may also reduce thrombin generation.

Vessel wall

Figure 2.24 Platelet adhesion, activation, aggregation, and formation of a platelet-fibrin thrombus. Thrombin generation occurs at the surface of activated platelets that also synthesize thromboxane A2 (TXA2). Both compounds are released from the thrombus and stimulate thrombus growth and stability. Aspirin not only inhibits thromboxane formation but may also reduce thrombin generation.

though inhibition ofplatelet function is clearly the most significant - and most intensively studied -component. Platelet activation is also a trigger event with at least two components sensitive to aspirin: thromboxane biosynthesis and thrombin generation. The actions of aspirin on platelets, plasmatic coagulation, and fibrinolysis are discussed separately for formal reasons. However, in vivo they form a functional unit and a separate alteration of only one component without changing the others does not usually occur.

Thrombosis This well-balanced dynamic equilibrium between hemostatic factors derived from the vessel wall, circulating in plasma or generated by blood cells, is disturbed in atherosclerosis, the most frequent cause of atherothrombosis. Atherosclerosis is a chronic inflammatory disease that is associated with "endothelial dysfunction," that is, loss of the antithrombotic properties of the endothelium and its conversion into a prothrombotic surface that expresses adhesion molecules and becomes a target for inflammatory cytokines and growth factors [236]. Platelet adhesion and activation, the initial processes of arterial thrombosis, occur and are facilitated by platelet hyperreactivity. Acute thrombotic events in atherosclerotic vessels, clinically appearing as acute coronary syndromes, transient ischemic attacks, or atherothrombotic stroke are initiated by erosions or rupture of an atherosclerotic plaque [237]. This exposes thrombogenic material from inside the plaque to the flowing blood. Plaque material contains procoagulant tissue factor, generated by macrophages and smooth muscle cells [238]. The availability of TF starts the extrinsic pathway ofcoagulation, eventually resulting in thrombin formation at the surface of activated platelets. Inhibition of platelet function by aspirin will, therefore, block not only thromboxane formation but also thrombin generation at the platelet surface [239, 240].

Arteries Versus Veins The mechanisms causing thrombus formation in the arterial and venous circulations are basically the same, that is, local disturbances of hemostasis caused by a pathological interaction between blood constituents and the vessel wall. However, the pathomechanisms of thrombus formation differ: in arterial thrombosis, the platelets and their adhesion to the vessel wall under high shear stress conditions initiate thrombus formation in endothelium-denuded or dys-functioning areas. In the low-pressure venous system, it is stasis and fibrin formation facilitated by the accumulation of nondegraded activated clotting factors that cause thrombosis. This is the reason for different pharmacological approaches in the treatment of arterial and venous thrombosis and the different efficacy of aspirin in the prevention of arterial (Sections 4.1.1, 4.1.2 and 4.1.3) but much less if any in venous (Section 4.1.4) thrombotic events.

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