Hemostatic Dysfunction
Johanna L. Watson • Debra Deem Morris
Basic Physiology of Normal Hemostasis
The basis for understanding the pathogenesis and manifestations of hemostatic disorders is a thorough understanding of the normal physiologic mechanism of hemostasis.
Hemostasis can be viewed as two interrelated components—coagulation and fibrinolysis (both with their respective inhibitors)—which function to arrest bleeding from a damaged blood vessel and maintain nutrient blood flow.Coagulation is mediated by blood vessels, platelets, and blood procoagulant proteins. When a blood vessel is damaged, vasoconstriction occurs, followed by rapid adherence of platelets to subendothelial collagen. Platelet adhesion causes membrane conformational changes that trigger aggregation, contraction, and granule secretion (the basic platelet reaction). Platelet phospholipoprotein (platelet factor 3) provides the necessary surface to catalyze interactions among the activated coagulation proteins that result in thrombin formation. Coagulant proteins are localized to this hemostatic plug because the platelet surface protects them from plasma anticoagulants. Through an incompletely understood mechanism, platelets also prevent spontaneous hemorrhage into the skin and mucous membranes by maintaining vascular integrity.
Procoagulant proteins circulate in the blood as precursor forms (zymogens) that must be altered during coagulation to become active. Numerous communications exist between the traditional extrinsic and intrinsic pathways, although initiating mechanisms remain distinct.26 The extrinsic system is initiated when lipoprotein tissue factor (TF) gains access to the bloodstream. TF is widely distributed in most tissues, including endothelial cells and monocytes, and it may be increased or secreted in response to numerous pathologic stimuli like bacterial endotoxin.
Intrinsic coagulation is initiated when blood is exposed to a negatively charged surface (e.g., activated platelets). Because of reciprocal activation between factor XII and prekallikrein, the intrinsic coagulation pathway stimulates formation of numerous inflammatory mediators such as kinins and complement. Both coagulation pathways culminate in the formation of activated factor X (Xa) by which thrombin is generated. In addition to catalyzing the conversion of fibrinogen to fibrin, thrombin promotes platelet aggregation, enhances cofactor activities of factors V and VIII, and activates factor XIII and protein C.27 Mechanisms to localize coagulation to the site of vascular injury are critical to protect against generalized thrombosis.28 Plasma anticoagulant proteins include the serpins, which inhibit activated coagulation factors, and the protein C system, which is directed against cofactors V and VIII.29 Antithrombin III (AT III), the main physiologic inhibitor of thrombin and Xa, normally provides 70% of the anticoagulant activity of plasma. Although not absolutely necessary, heparin accelerates AT III action by 2000-fold.30 Activated protein C destroys factors V and VIII, ultimately limiting its own activation, which depends on thrombin and endothelial cofactor, thrombomodulin. Protein S enhances the anticoagulant ability of protein C.The fibrinolytic system is activated at the same time as coagulation and functions to prevent tissue ischemia by limiting the extent of fibrin clot formation. Plasmin, primarily responsible for degradation of fibrin, exists in the plasma as the zymogen plasminogen. Plasminogen has a high affinity for fibrin, as does tissue plasminogen activator (tPA); because clots contain the necessary components to allow lysis from within, systemic plasmin formation is avoided. α2-Antiplasmin (α2-AP), the main physiologic inhibitor of plasmin, competes with the binding of plasminogen to fibrin, and the clot contains equal amounts of both glycoproteins.
Because of this molar balance between α2-AP and plasminogen, a normal blood clot does not lyse spontaneously, despite fixation of tPA. Physiologic plasminogen activator inhibitors (PAIs) are found in plasma, platelets, and endothelial cells; platelet-derived PAI protects a blood clot against premature lysis. Clot lysis is initiated if additional tPA is taken up from the surrounding tissues, and stasis upstream from the occluded vessel is a potent stimulus for release of endothelial tPA. Conversion of plasminogen to plasmin allows partial digestion of fibrin and exposure of additional plasminogen binding sites. When this additional plasminogen is converted to plasmin, the inhibitory effect of α2-AP is overcome and clot lysis is accelerated. Plasmin hydrolyzes fibrinogen and fibrin with equal affinity, as well as numerous other procoagulants, and it can activate complement and kininogen. The physiologic actions of plasmin are limited to the fibrin clot by the affinity between the latter and plasminogen and the presence of α2-AP in blood. Because of multiple interactions between the coagulation and fibrinolytic systems, the most important factor that determines the rate of fibrinolysis is the rate of fibrin formation.31