COAGULATION AND THROMBI
Haemostasis, the physiological response to vascular injury, results in the formation of a haemostatic plug that prevents blood loss. Under normal conditions, factors that promote blood coagulation are balanced by those that inhibit it. Pathologic thrombosis occurs when procoagulant stimuli overwhelm natural anticoagulant and fibrinolytic systems. Venous thrombi, which form under low shear conditions, are predominantly composed of fibrin and red cells. Thrombi may develop anywhere within the venous system but most commonly arise in the deep veins of the leg through an interplay among 3 factors that include vessel wall damage, venous stasis, and hypercoagulability. Direct damage to the veins helps explain the propensity to deep vein thrombosis (DVT) after major orthopedic surgery. Thrombi often originate in the calf, either in the muscular sinuses or valve cusps of deep veins. Immobility delays emptying of muscular veins and retards clearance of activated clotting factors. With stasis, endothelial cells lining the avascular valve cusps are activated by hypoxemia, a process exacerbated by inflammatory cytokines generated postoperatively or in medical illness. Leukocytes tethered to activated endothelial cells express tissue factor, whereas platelets become activated and aggregate. Congenital or acquired disorders associated with hypercoagulability promote coagulation at these sites, thereby increasing the risk of thrombosis. Signs and symptoms develop when there is obstruction to venous outflow and inflammation of the vessel wall and perivascular tissue. Symptoms of pulmonary embolism arise when segments of thrombus detach and embolize to the pulmonary circulation. Arterial thrombi form under high shear conditions and are composed primarily of platelet aggregates held together by fibrin strands. Obstruction of anterograde arterial flow leads to ischemia, which manifests as unstable angina or myocardial infarction in the case of coronary arteries or stroke if cerebral vessels are involved. Most arterial thrombi are superimposed on disrupted atherosclerotic plaques. After damage to the endothelial lining of veins or arteries, platelets adhere to newly exposed subendothelial matrix components, particularly collagen and von Willebrand factor, via constitutively expressed receptors. Adherent platelets become activated and recruit additional platelets by synthesizing thromboxane A2 and releasing adenosine diphosphate (ADP). Platelet activation induces conformational changes in glycoprotein (GP) IIb/IIIa, one of the most abundant receptors on the platelet surface. By binding fibrinogen or under high shear conditions, von Willebrand factor, conformationally activated GPIIb/IIIa cross-links adjacent platelets, resulting in platelet aggregation. Damage to the vascular wall and the resultant exposure of tissue factor (TF)-expressing cells to blood initiates coagulation in both the arteries and veins. In the presence of calcium, TF binds activated factor VII (factor VIIa), which is found in small amounts in plasma, thereby forming factor VIIa/TF complex. This complex, also known as extrinsic tenase, activates factors IX and X, although factor X activation is more efficient. Factor Xa then converts small amounts of prothrombin to thrombin. This thrombin activates factors V and VIII, key cofactors in coagulation, and activates platelets, a process that induces expression of anionic phospholipid on their surface. These thrombin-mediated events are critical for propagation of coagulation. Propagation is effected when factor IXa binds to factor VIIIa on the surface of activated platelets to form intrinsic tenase, a complex that efficiently activates factor X. Factor Xa binds to factor Va on the activated platelet surface to form the prothrombinase complex that converts prothrombin to thrombin. In the final step of coagulation, thrombin converts fibrinogen to fibrin and activates factor XIII, which stabilizes the...
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