Friday, September 29, 2023
This activity is intended for cardiologists, internists, primary care physicians, and other healthcare providers involved in the management of patients at risk for thromboembolism.
The goal of this activity is to help physicians better understand the mechanism of coagulation and the rationale for developing new anticoagulants for long-term management of venous thromboembolism.
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CME Released: 7/29/2010
Valid for credit through: 7/29/2011, 11:59 PM EST
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Thrombosis is a major cause of morbidity and mortality worldwide. Traditional anticoagulant therapies (heparin and warfarin), although efficacious, are associated with limitations in their utility for long-term administration. Consequently, there is an ongoing search for new anticoagulant agents. A better understanding of the biochemical pathways involved in coagulation has led to the identification of new targets for anticoagulant agents. This article reviews the key events in the cell-based model of coagulation, the rationale for current and new targets for anticoagulant agents, and the efficacy and safety of new oral anticoagulant agents in late-stage clinical development.
Coagulation is the process through which blood clots are formed at sites of injury to blood vessels. Such clots must form rapidly to arrest hemorrhage from the wound, but once formed, the clotting process must be quickly regulated to prevent the clot from expanding to the point where it obstructs blood flow. Once bleeding is controlled, the fibrinolytic system degrades the blood clot so that blood flow is restored and healing can occur.
Coagulation involves a regulated sequence of events in which a series of inactive enzyme precursors, or zymogens, become activated. The end result of this process is the timely generation of thrombin, which is also known as factor IIa (FIIa), the enzyme that not only converts fibrinogen to fibrin but also amplifies its own generation and serves as a potent platelet agonist. The original "cascade" or "waterfall" models of coagulation proposed 2 independent pathways by which coagulation could be initiated in a platelet-free environment.[1,2] Although the concept of distinct extrinsic and intrinsic pathways is useful for understanding in vitro tests of coagulation, we now know that these pathways are intricately linked. We also know that platelets and other cellular components of the blood are integral parts of the coagulation system. Building on this information, a cell-based model of coagulation has evolved in an attempt to better understand the complex reactions that occur on the surface of cells and the integration of processes that result in the formation of a platelet-fibrin thrombus.[3-5]
According to the cell-based model of coagulation, the initiating or triggering event occurs on the surface of intact tissue factor (TF)-bearing cells or cell fragments, known as microparticles, which are exposed or generated at sites of vascular injury.[4,5] Such cells include monocytes, macrophages, and smooth muscle cells among others. As a transmembrane protein, TF on the surface of these cells binds circulating FVIIa and the resultant TF:FVIIa complex initiates the generation of a small amount of thrombin (the spark). This thrombin then amplifies its own generation, which results in a burst of thrombin (the flame) that converts fibrinogen to fibrin, stabilizes the fibrin network, and activates platelets.[4,5] The precisely synchronized sequence of events is counterbalanced by a system of anticoagulant and fibrinolytic mechanisms, which serve to ensure that the hemostatic effect is regulated and does not extend inappropriately. In pathological states, these events can escape normal control mechanisms due to either inherited or acquired defects, resulting in thrombosis, which is the generation of an occlusive thrombus that obstructs or limits blood flow in an artery or vein.
Based on current knowledge of the main triggers and a better understanding of the structure and function of the key coagulation enzymes, anticoagulant therapy is moving towards targeted therapy. This article reviews our current understanding of the coagulation system, identifies the major enzymes in this pathway, and provides a rationale for the selection of targets for novel anticoagulants.
