Chapter 58: Antithrombotics

HISTORY AND EPIDEMIOLOGY

Antithrombotics have numerous clinical applications, including in the treatment of coronary artery disease, cerebrovascular events, hypercoagulable states, deep vein thrombosis (DVT), and pulmonary embolism (PE). The antithrombotics are a diverse group of xenobiotics that are widely studied and constantly in the process of therapeutic evolution.

The origins and discovery of antithrombotics are extraordinary.^6,29,156,259 The discovery of modern-day oral anticoagulants originated after 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). Warfarin was rapidly marketed as both a medicine and a rodenticide. “Superwarfarins” were subsequently developed for the rat population that had developed increasing genetic resistance to 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 a variant form of heparin. Shortly thereafter, the water-soluble mucopolysaccharide termed heparin (because of its abundance in the liver) was ­discovered. Unfractionated heparin (UFH) is a mixture of polysaccharide chains with varying molecular weights. After the identification of the active pentasaccharide segment of heparin in the 1970s, multiple low-molecular-weight heparins (LMWHs) were isolated, and synthetic forms were created.

Hirudin, a 65–amino acid polypeptide, was produced by the salivary glands of the medicinal leech (Hirudo medicinalis).²⁵⁶ Antistasin and antistasinlike proteins are naturally secreted by the Mexican leech, Haementeria officinalis, and the earthworm.^106,370 These xenobiotics have not been used therapeutically; however, they inspired the development of the synthetic factor inhibitors, such as direct thrombin inhibitors (DTIs) and factor Xa inhibitors.

In the late 19th century, human urine was noted to have proteolytic activity with 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 Malayan pit viper, only recently gained therapeutic attention as a naturally occurring antithrombotic.

In the early 20th century, the antithrombotic properties of aspirin were noted in anecdotal reports of patients having a predisposition to bleeding while taking aspirin. Clinicians also noted lower rates of myocardial infarction (MI), and studies to elucidate the effects of aspirin on coagulation soon followed with further research exposing the role of platelet aggregation in thrombosis.²⁵¹ These discoveries led to the development of the ...