Anticoagulants

The development of oral anticoagulants can be linked directly to a widespread cattle epidemic in the United States and Canada during the mid-1920s. A scientist traced the cause of this outbreak to the cattle feed, a fodder containing spoiled sweet clover, which caused the cattle to bleed to death internally. Mixing alfalfa, a food rich in vitamin K, into the fodder seemed to prevent the disease. In 1941, research showed that the decaying sweet clover contained a substance that produced an anti-vitamin-K effect. The substance was isolated from the sweet clover, and called it dicumarol. During the 1940s, the agent was synthesized and widely used in the United States to treat postoperative thrombosis. In 1948, a more powerful synthetic compound was derived for use, initially as a rodentcide. This substance, known as warfarin, is now one of the most widely prescribed oral anticoagulants. There are numerous other agents in clinical use. Acenocoumarol, ethyl biscoumacetate, and phenprocoumon, which are seldom used in the United States, are widely prescribed elsewhere in the world.

Most oral anticoagulants work by suppressing the action of vitamin K in the coagulation process. These agents are extremely similar in chemical structure to vitamin K and effectively displace it from the enzymatic process, which is necessary for the synthesis of prothrombin and other clotting factors. Indeed, one of the ways to treat irregular bleeding, the most common side effect of oral anticoagulants, is vitamin K therapy.

In addition to bleeding, another side effect of oral anticoagulant use is negative interaction with numerous other drugs and substances. Even unaided, oral anticoagulants can have serious effects. For example, use of warfarin during pregnancy can cause birth defects, fetal hemorrhages, and miscarriage. Dicumarol, the original oral anticoagulant, is seldom used today because it causes painful intestinal problems and is clinically inferior to warfarin.

Over the past two decades, the search for new, less toxic anticoagulants has led to the development and use of a number of synthetic agents, including fibrinlysin, thrombolytin, and urokinase. The enzyme streptokinase, developed in the early 1980s, is routinely injected into the coronary artery to stop a heart attack. Another new agent, tissue plasminogen activator, a blood protein, is being generated in large quantities using recombinant-DNA techniques. The search is on for a natural anticlotting factor that can be produced in mass quantities.