The anticoagulants

Because the coumarins are effective orally and are relatively inexpensive, they have proved practical for long-term usc. The synthetiC compounds now available had their origin in veterinary medicine. In the 1920s a new malady of cattle involving fatal bleeding appeared. The disorder was traced to stacks af decomposing sweet clover hay. Roderick in 1931 emphaSized that the decreased coaguability of the blood was due to a deficit of prothrombin (factor II). More recently, the coumarin derivatives have been shown to have more than a hypoprothrombinemic effect.' They also depress factors VII, IX, and X. Link and his co-workers isolated the substance from the hay and identified it chemically as bishydroxycoumarin (Fig. 1). Bishydroxycoumarin (Dicumarol) was released for clinical use in. 1940. Since then, a variety of related agents have been proved effective (Table I). They all act in essentially the same way to prevent manufacture of coagulation proteins. Vitamin K, (Mephyton) counteracts those effects. An informative article comparing coumarin derivatives points out that there is no striking difference in onset of effect or smoothness of contro}.12 The agent of choice is the established drug with which the doctor is most familiar. The coumarins are usually given orally. Warfarin, however, can be given parenterally. The drugs are absorbed from the gastrointestinal tract, but absorption is slow, limited, and erratic and varies with the patient and the dose administered. The duration of action and patient sensitivity vary greatly from patient to patient, and cumulative action may be a complication. Furthermore, the mild hypoprothrombinemic effects of aspirin may complicate the expected response as may other agents such as bowel-sterilizing antibiotics. With most of these agents in common doses now used, maximal effects are seen usually only after 24 to 48 hours, although the drug can be demonstrated to be present prior to the maximal effect on the blood-clotting scheme. There is no difference in the speed of action after intravenous or oral dose. The size of the dose determines the maximal decrease in the clotting proteins and the duration of effect. The aim of therapy is to decrease the prothrombin activity as determined by the one stage QUick test to between 15 and 25 per cent of normal. The fate of these compounds is relatively unknown. They are almost completely metabolized by a slow degradation process. With clinically effective doses of bishydroxycoumarin and phenprocoumon, the prothrombin activity usually does not return to normal for 1 to 2 weeks after stopping the drug. The coumarins cause bleeding in patients who have some predisposing cause such as a duodenal ulcer. If the Quick prothrombin test result drops below 10 per cent of normal, clotting time is altered and patients are very likely to bleed from minor injuries. The coumarins cause no liver damage. In the doses used in