17-19: Anticoagulants

Clinical Summary

Since the discovery of the cause of a hemorrhagic disorder in Wisconsin cattle in the early 20th century, warfarin and its analogs have been used as rodenticides and pharmacologic agents. Warfarin is actually named after the Wisconsin Alumni Research Foundation. Warfarin-like xenobiotics inhibit the activity of vitamin K 2,3-epoxide reductase, thus affecting the production of the vitamin K–dependent factors of II, VII, IX, and X. While the effect on the production of the vitamin K–dependent factors occurs soon after absorption of warfarin, the clinical effect is delayed until the available activated factors are depleted.

Long-acting anticoagulants, known as “superwarfarins,” were developed as rodenticides due to the development of warfarin-resistant rodents. Their mechanism of action is the same as warfarin, but they are more potent and exhibit a much longer duration of effect. Poisoned patients may present with any sequelae of an anticoagulated state spanning the spectrum from easy bruising to life-threatening hemorrhage. In 2018, there was an outbreak of poisoning by long-acting anticoagulants that were presumed adulterants in synthetic cannabinoids (“K2/Spice”). Deaths occurred as a result of major bleeding events.

Management and Disposition

Patients who have a supratherapeutic international normalized ratio without bleeding may require reversal with the administration of vitamin K. Life-threatening hemorrhage may require immediate reversal with administration of 4-factor prothrombin complex concentrate (PCC) or fresh frozen plasma. Guidelines for correction of vitamin K antagonists are published by the American College of Chest Physicians. Patients with intentional poisonings from the long-acting anticoagulants (“superwarfarins”) may require high-dose vitamin K therapy for several weeks to months due to the prolonged anticoagulant effects.

Pearls

1. Warfarin is a racemic mixture of R and S enantiomers, which are metabolized by different CYP P450 pathways. The S enantiomer is more potent that the R enantiomer. Genetic polymorphisms influence the dose needed to achieve a therapeutic level.

2. Single unintentional ingestions of the “superwarfarins” by children under 6 years of age rarely result in an ingestion with clinically significant anticoagulant effect. Repetitive ingestions can result in coagulopathy. If a toddler has a vitamin K–dependent coagulopathy and the history indicates the child ate a box of rat poison, one must have an index of suspicion for Munchausen by proxy.

3. If a patient is on chronic warfarin therapy, be wary of the many xenobiotic interactions that can potentiate or antagonize the anticoagulant effect.