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INTRODUCTION

SUMMARY

Under normal circumstances the blood coagulation system is always active and generating thrombin at very low levels, primed for explosive thrombin generation when needed. 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. 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 those mechanisms whose defects are clinically significant based on insights gleaned from consideration of the hereditary thrombophilia’s—such as the activated protein C pathway—antithrombin and tissue factor pathway inhibitor. These pathways are responsible for downregulation of blood coagulation reactions and contain the plasma proteins that inhibit blood coagulation. 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. 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 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 and platelets. Moreover, the action of the fibrinolytic system must be integrated with coagulation reactions for timely formation and dissolution of blood clots.

PHYSIOLOGIC ANTICOAGULANT PATHWAYS

Although the cascade model1,2 for blood coagulation was described 70 years ago, the basic outline of sequential conversions of protease zymogens to active serine proteases is still useful, albeit with important modifications to represent blood coagulation reactions (Chap. 112). The major conceptual advances for procoagulant pathways in the past two decades emphasize both positive and negative feedback reactions modulating thrombin generation as depicted in Figure 113–1.

Figure 113–1.

Blood coagulation pathways and protein C anticoagulant pathway. Thrombin can be either a procoagulant (left) or an anticoagulant (right), depending on cofactors and surfaces. Coagulant thrombin clots fibrinogen and activates platelets and factors V, VIII, XI, and XIII. Conversion of zymogen protein C to the active protease, APC, by thrombomodulin-bound thrombin is enhanced by ...

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