Anticoagulation: Antithrombin Therapy

Hemostasis and the Coagulation Cascade

Hemostasis refers to the formation of a platelet-fibrin clot at the site of vascular endothelial injury and involves the activation of platelets as well as the coagulation cascade. Fibrinolysis refers to the dissolution of a platelet-fibrin clot by separate protease reactions. A delicate balance between the carefully regulated systems of coagulation and fibrinolysis is required to keep blood fluid and vessels patent within the circulation; disturbances in either system will cause a tendency toward thrombosis or bleeding. Coagulation, as shown in Fig. 35.1 , has often been represented as two independent pathways that converge to a common pathway with thrombin generation as the endpoint of the cascade. This model provides a basic representation of the processes observed in clinical coagulation laboratory testing. The prothrombin time (PT) measures the factors of the extrinsic pathway and activated partial thromboplastin time (aPTT) measures factors of the intrinsic pathway. However, this model is a simplification of a complex physiologic process and has certain inadequacies when applied to the multifaceted in vivo hemostatic processes that involve interactions between cellular-based (e.g., vascular- and platelet-mediated) and soluble coagulation processes. Others have demonstrated that, under normal circumstances, in vivo hemostasis is initiated by tissue factor (TF), a transmembrane glycoprotein that is a member of the class II cytokine receptor superfamily and functions both as the receptor and the essential cofactor for factors (F) VII and VIIa. Assembly of the TF/FVIIa complex on cellular surfaces leads to the activation of FX and initiates coagulation. TF is constitutively expressed in cells surrounding blood vessels and large organs to form a hemostatic barrier. In addition to its role in hemostasis, the TF/FVIIa complex has been shown to elicit intracellular signaling, resulting in the induction of various genes, thus explaining its role in various biologic functions, such as embryonic development, cell migration, inflammation, apoptosis, and angiogenesis.

Cell-Based Model of Coagulation

In the cell-based model, coagulation occurs in three overlapping phases: initiation, priming, and propagation. A disruption in vascular endothelium brings plasma into contact with TF-bearing cells; FVII binds to the exposed TF and is rapidly activated by coagulation proteases and by noncoagulation proteases. The FVIIa/TF complex then activates FX and FIX. The activated forms of these two proteins (FIXa and FXa) play very different roles in subsequent coagulation reactions. FXa can activate plasma FV on the TF cell. If FXa diffuses from the protected environment of the cell surface from which it was activated, it can be rapidly inhibited by the TF pathway inhibitor (TFPI) or antithrombin (AT). However, the FXa that remains on the TF cell surface can combine with FVa to produce small amounts of thrombin (the enzyme responsible for clot formation). This thrombin, although not sufficient to cleave fibrinogen throughout a site of injury, nonetheless plays a critical role in amplifying the initial thrombin signal. The initial FVIIa/TF complex is subsequently inhibited by the action of the TFPI in complex with FXa. In contrast to FXa, FIXa is not inhibited by TFPI, and is only slowly inhibited by AT. FIXa moves in the fluid phase from TF-bearing cells to nearby platelets at the injury site.

In the priming (or amplification) phase, low concentrations of thrombin activate platelets adhering to the injury site to release FV from their α-granules. Thrombin cleaves the partially activated FV to yield a fully active form. Thrombin also cleaves FVIII, releasing it from von Willebrand factor. These activated factors bind to platelet surfaces and provide the backbone for thrombin generation that occurs during the propagation phase.

In the propagation phase, the phospholipid surface of activated platelets acts as a cofactor for the activation of the FVIIIa/FIXa complex and the FVa/FXa complex, which accelerates the generation of FXa and thrombin, respectively. The burst of thrombin leads to the bulk cleavage of fibrinogen to fibrin. Soluble fibrin is stabilized by FXIIIa and activated by thrombin to form a fibrin network (i.e., a thrombus).

Arterial Thrombosis

Although arterial thrombosis can result from different mechanisms, the most clinically relevant in the context of cardiovascular medicine and PCI are endothelial erosion and plaque rupture. Plaque rupture results in the exposure of thrombogenic substances (e.g., collagen and TF) to the circulation, with the resulting activation of platelets and coagulation cascade that can lead to partial or complete obstruction of the vessel. This sequence of events, coupled with the simultaneous release of vasoactive substances, can result in thrombus formation and vasoconstriction. When this occurs in the coronary circulation, the result is myocardial ischemia and ACS.

Antithrombins: Mechanism of Action

Anticoagulant agents specifically target the soluble coagulation cascade proteins required to form fibrin clots. Fig. 35.2 displays the mechanisms of action of the different thrombin inhibitors described here. The heparin derivatives in current clinical use include unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), and the synthetic pentasaccharide derivative fondaparinux. These are all parenteral agents that must be administered by intravenous (IV) or subcutaneous (SC) injection. They are classified as indirect anticoagulants because they require a plasma cofactor, AT, to exert their anticoagulant activity. By contrast, the direct thrombin inhibitors (DTIs), such as bivalirudin, bind thrombin at its active site and/or its fibrin recognition site (exosite 1), essentially displacing it from fibrin, to provide a direct anticoagulant effect.

Unfractionated Heparin