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Anticoagulants have numerous clinical applications, including in the treatment of coronary artery disease, cerebrovascular events, deep venous thrombosis, and pulmonary embolism. The anticoagulants are a diverse group of xenobiotics that are widely studied and constantly in the process of therapeutic evolution. Bleeding is a major complication of these xenobiotics. Knowledge of anticoagulants will be of ever-increasing utility for clinicians as their use increases.

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The origins and discovery of anticoagulants are extraordinary.2,16,73,131 The discovery of modern-day oral anticoagulants originated following investigations of a hemorrhagic disorder in Wisconsin cattle in the early 20th century that resulted from the ingestion of spoiled sweet clover silage. The hemorrhagic agent, eventually identified as bishydroxycoumarin, would be the precursor to its synthetic congener warfarin (named after the Wisconsin Alumni Research Foundation). This knowledge also led to the use of warfarin as a rodenticide. "Superwarfarins" were subsequently developed as selective pressure caused rats to develop genetic resistance to warfarin. These potent anticoagulants permitted either small, repetitive ingestions or single, larger ingestions to successfully function as rodenticides.

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As in the case of warfarin, the origins of the anticoagulant heparin are equally fascinating. A medical student initially attempting to study ether-soluble procoagulants derived from porcine intestines serendipitously found that, over time, these apparent "procoagulants" actually prevented normal blood coagulation. The phospholipid anticoagulant responsible for this effect would later be identified as an early form of heparin. Shortly thereafter, the water-soluble mucopolysaccharide termed heparin (because of its abundance in the liver) was then discovered. Unfractionated heparin is a mixture of polysaccharide chains with varying molecular weights. Following the identification of the active pentasaccharide segment of heparin in the 1970s, multiple low-molecular-weight heparins were isolated and synthetic forms created.

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In the late 19th century, human urine was noted to have proteolytic activity with a specificity for fibrin. A substance found to be an activator of endogenous plasminogen leading to the consumption of fibrin, fibrinogen, and other coagulation proteins was isolated and purified and given the name urokinase. Streptokinase, a protein produced by β-hemolytic streptococci, tissue plasminogen activator (t-PA), and other synthetic thrombolytics were later discovered. Although known to exist for many years, ancrod (a purified derivative of snake venom) and hirudin (a product of leeches) only recently gained attention as naturally occurring antithrombotic therapeutic agents.

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The diversity of these anticoagulants and fibrinolytics has led to ever-increasing use in many fields of medicine. Warfarin is the most common oral anticoagulant in use today because of its utility in patients with cerebrovascular disease, cardiac dysrhythmias, and thromboembolic disease. During the period of 2005 to 2007, the total number of cases of reported warfarin exposures to the American Association of Poison Control Centers was 10,508 with eight deaths (Chap. 135). Throughout this time, there was a general trend toward an increasing number of reports. Additionally, because the common problem of excessive warfarin effects leading to hemorrhage is poorly quantitated ...

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