Hemostasis, the physiologic process that maintains vascular integrity and minimizes bleeding in the face of injury, requires a complex and coordinated interplay of cellular elements (platelets) and humoral (clotting) factors working in concert. Platelets are exposed to collagen, fibronectin, and other molecules in the subendothelial matrix at the site of vascular injury, which leads to platelet adherence, activation, and aggregation to form an initial platelet plug, a process that can be viewed as primary hemostasis. von Willebrand factor (vWF) facilitates platelet adherence to subendothelial collagen at the site of endothelial injury, especially in high-shear areas such as arterioles. While vWF also helps cross-link platelets, soluble fibrinogen is the primary molecule that links platelets together to form the platelet plug.
The serial, cascading activation of clotting factors at the site of endothelial injury leads to the formation of a fibrin clot, which constitutes secondary hemostasis. Platelets present at the site of a vascular injury facilitate clot formation by providing a phospholipid surface on which coagulation factor complexes assemble in space. The tissue injury (extrinsic) pathway of coagulation involves the conversion of factor X to factor Xa by activated factor VII in the presence of TF. Factor Xa binds factor Va in the presence of phospholipid and calcium to form the prothrombinase complex. The common pathway involves the cleavage of factor II (prothrombin) by the prothrombinase complex to yield factor IIa (thrombin), and thrombin then cleaves fibrinogen to form fibrin, which is stabilized through cross-linking performed by factor XIIIa. The contact (intrinsic) pathway of coagulation begins with the activation of contact factors (kallikrein, XII, others), leading sequentially to the formation of factors XIa and IXa; the intrinsic pathway tenase complex (factors IXa, VIIIa), converts factor X to factor Xa, which binds factor Va in the presence of phospholipid and calcium, forming prothrombinase complex, which leads to formation of thrombin and fibrin mesh via the common pathway as outlined above.
In vivo, the tissue injury (extrinsic) pathway usually provides the initial activation of coagulation, which then activates the contact pathway coagulation cascade through thrombin-mediated activation of factor XI. Excessive activation of coagulation is controlled by the activity of endogenous proteins such as proteins C and S (which inactivate factor Va and factor VIIIa), thrombomodulin (via a negative feedback mechanism), and the plasminogen/plasmin system, which leads to fibrinolysis.
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To evaluate patients for defects of hemostasis, the clinical context must be considered carefully (Table 14–1). Heritable defects are suggested by bleeding that begins in infancy or childhood, is recurrent, and occurs at multiple anatomic sites, although other patterns of presentation are possible. Acquired disorders of hemostasis typically are associated with bleeding that begins later in life and ...