The blood coagulation system, like a powerful idling engine, is always active and generating thrombin at very low levels, poised for explosive thrombin generation. Positive feedback activation of factors V, VII, VIII, and XI imparts special threshold properties to blood coagulation, making the coagulant response nonlinearly responsive to stimuli. Overt blood coagulation represents a threshold system with apparent all-or-none responses to various levels of stimuli, and an ensemble of opposing reactions determines the ultimate upregulation and downregulation of thrombin generation both locally and systemically. Cellular and humoral anticoagulant mechanisms synergize with plasma coagulation inhibitors to prevent massive thrombin generation in the absence of a substantial procoagulant stimulus. This chapter highlights mechanisms that inhibit blood coagulation, with an emphasis on defects of plasma proteins that cause hereditary thrombophilias. Major thrombophilic defects involve the anticoagulant protein C pathway, comprising multiple cofactors or effectors that additionally include thrombomodulin, endothelial protein C receptor, protein S, high-density lipoprotein, and factor V. Activated protein C exerts multiple protective homeostatic actions, including proteolytic inactivation of factors Va and VIIIa, as well as direct cell-signaling activities involving protease activated receptors 1 and 3, endothelial cell protein C receptor, integrin CD11b/CD18, and apolipoprotein E receptor 2. The factor V Leiden variant causes hereditary activated protein C resistance by impairing the ability of the protein C pathway to inhibit coagulation because it cannot properly cleave factor Va Leiden. Plasma protease inhibitors are also key to block coagulation. Antithrombin inhibits thrombin and factors Xa, IXa, XIa, and XIIa, in reactions stimulated by physiologic heparan sulfate or pharmacologic heparins. Tissue factor pathway inhibitor neutralizes the extrinsic coagulation pathway factors VIIa and Xa. Other plasma protease inhibitors can also neutralize various coagulation proteases.
Control of coagulation reactions is essential for normal hemostasis. As part of the tangled web of host defense systems that respond to vascular injury, the blood coagulation factors (Chap. 113) act in concert with the endothelium and blood cells, especially platelets, to generate a protective fibrin-platelet clot, forming a hemostatic plug. Pathologic thrombosis occurs when the protective clot is extended beyond its beneficial size, when a clot occurs inappropriately at sites of vascular disease, or when a clot embolizes to other sites in the circulatory bed. For normal hemostasis, both procoagulant and anticoagulant factors must interact with the vascular components and cell surfaces, including the vessel wall (Chap. 115) and platelets (Chap. 112). Moreover, the action of the fibrinolytic system must be integrated with coagulation reactions for timely formation and dissolution of blood clots (Chap. 135). This chapter on control of coagulation highlights the major physiologic mechanisms for downregulation of blood coagulation reactions and the plasma proteins that inhibit blood coagulation, with an emphasis on those mechanisms whose defects are clinically significant based on insights gleaned from consideration of the hereditary thrombophilias (Chap. 130). Chapter 113 provides a complete description of blood coagulation factors and hemostatic pathways.
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