Toxicity from coumarins was first noted in animals. Livestock were difficult to feed on North American prairies until the introduction of melilots, or sweet clovers (ie, Melilotus alba, Melilotus officinalis), from Europe in the early 1900s.
In 1924, Schofield noted cattle in Alberta that were fed moldy spoiled sweet clover hay were dying from a previously undescribed hemorrhagic disorder; properly cured hay appeared harmless. Bishydroxycoumarin, the active ingredient responsible for this hemorrhagic disorder, was discovered in 1939 by Campbell and Link.
Bishydroxycoumarin is formed when fungi in moldy sweet clover oxidize coumarin to 4-hydroxycoumarin, an anticoagulant. In 1940, bishydroxycoumarin was synthesized and used clinically 1 year later as an oral anticoagulant under the American trade name dicumarol.
Coumarin-derivatives possessing a 4-hydroxy group with a carbon at the 3 position of the coumarin-base structure possess anticoagulant activity and are referred to as hydroxycoumarins, which are not present in coumarin itself.
Warfarin (name derived from Wisconsin Alumni Research Foundation and Coumarin) was synthesized and used as a rodenticide for nearly a decade prior to its 1954 introduction into clinical medicine.
Today, the 4-hydroxy coumarins are primarily used as anticoagulants and rodenticides. Second-generation rodenticides (long-acting anticoagulants, such as brodifacoum) are characterized by their clinical effects and very long half-lives.
Coumarin-derived products may be synthesized or obtained from tonka seeds (Dipteryx odorata, Dipteryx oppositifolia). Oral anticoagulants are divided into two groups, hydroxycoumarins (including warfarin) and indanediones.
This article focuses on hydroxycoumarins and their anticoagulant effects.
Warfarin binds and inhibits Vitamin K reductase which reduces the amount of Vitamin KH2 that is needed to perform gamma-carboxylation of the clotting factors II, VII, IX, X, and the anticoagulants protein C and S. Synthesis of these factors involves the carboxylation of specific glutamic acid residues in the liver, a step dependent on reduced vitamin K (vitamin K quinol). In this carboxylation reaction, vitamin K is oxidized to vitamin K 2, 3-epoxide. The 4-hydroxycoumarins block vitamin K 2, 3-epoxide reductase, which is needed for the reduction of vitamin K epoxide back to its active form. Dysfunctional coagulation factors are produced in the absence of reduced vitamin K. Half-lives of clotting factors are as follows:
Factor II - 60 hours
Factor VII - 4-6 hours
Factor IX - 24 hours
Factor X - 48 -72 hours
The bioavailability of warfarin is nearly complete when administered orally, intramuscularly, intravenously, or rectally. Therefore, orally ingested warfarin is completely absorbed and peak plasma concentrations occur about 3 hours postadministration. Ninety-nine percent is bound to plasma proteins, principally albumin, and distributes into a volume equivalent to the albumin space. Depletion of circulating coagulation factors must occur before any effects are evident. Factor VII has the shortest half-life; factor II has the longest. Clinical effects of a single massive dose of warfarin may begin to be apparent by 24 hours and are maximal by 36-48 hours. The patient may be hypercoagulable for a period of several hours after warfarin ingestion, prior to inhibition of factor production. Duration of action may be as long as 5 days.
Warfarin is metabolized extensively by hepatic microsomal enzymes and undergoes enterohepatic recirculation. Warfarin and its metabolites are excreted in urine and feces.
Long-acting anticoagulants, rodenticides, or superwarfarins (eg, difenacoum, brodifacoum) are 4-hydroxycoumarin derivatives; they are highly lipid-soluble and concentrate in the liver. Superwarfarins have a much longer duration of action than traditional warfarins. After intentional overingestion of superwarfarins, patients may be anticoagulated for weeks to months.
Numerous drug interactions with warfarin exist, both accelerating and inhibiting its metabolism. Lack of attention to possible interactions is a common cause of iatrogenic toxicity.
Drugs that potentiate anticoagulation are allopurinol, amiodarone, anabolic steroids, cephalosporins, cimetidine, cyclic antidepressants, erythromycin, ethanol, fluconazole, ketoconazole, metronidazole, nonsteroidal anti-inflammatory drugs (NSAIDs), omeprazole, sulfonylureas, thyroxine, and trimethoprim-sulfamethoxazole.
Drugs that antagonize anticoagulation are antacids, antihistamines, barbiturates, carbamazepine, corticosteroids, griseofulvin, oral contraceptives, phenytoin, and rifampin.
Genetic factors may increase a patient’s sensitivity to on warfarin (Coumadin). Specifically, genetic variations in the proteins CYP2C9 and VKORC1, which are responsible for warfarin’s primary metabolism and pharmacodynamic activity, respectively, have been identified as predisposing factors associated with decreased dose requirement and increased bleeding risk. Genotyping tests area available and may provide important guidance on the initiation of anticoagulant therapy.
Intentional ingestion of warfarin-containing products is rare; however, excessive anticoagulation and bleeding are not uncommon in patients taking warfarin therapeutically. In 2008, 2422 single exposures to warfarin were reported to the American Association of Poison Control Centers (AAPCC).[1] These centers cover approximately 95% of the US population, although reports to the AAPCC underestimate true incidence of exposures and poisonings. Of these exposures, 180 were intentional. Of all warfarin exposures, 21 major outcomes (life-threatening event or resultant disability) and 0 deaths were reported. In the same report, 11,201 single exposures to anticoagulant rodenticides (long-acting and warfarin type) were documented; 324 were intentional. A total of 17 major outcomes and no deaths were reported.
Mortality/Morbidity
Bleeding indicates major toxicity of 4-hydroxycoumarins.
Mucocutaneous, genitourinary, and GI are the most frequent sites of bleeding.
Serious bleeding includes massive hemorrhage with shock, intracranial bleeding, stroke, and pericardial tamponade.
Upper airway compromise due to an expanding hematoma also may occur.
Age
See the list below:
Intentional and chronic ingestions are more common in adolescents and adults than children. Munchausen syndrome or Munchausen syndrome by proxy may present as surreptitious ingestion or administration of one of these compounds by a caretaker.
Single accidental ingestions are the most common exposures in children younger than 6 years. Such exposures to warfarin or brodifacoum rarely result in clinical toxicity.
Elicit a history of exposure to medicinal hydroxycoumarins or rodenticides.
History may be difficult to obtain from patients who have ingested hydroxycoumarin products surreptitiously or with suicidal intent.
Ask the following questions to ascertain specific history:
Was ingestion a pharmaceutical or a long-acting rodenticide preparation?
Was ingestion intentional or unintentional? (Single unintentional ingestions of warfarin and warfarin-containing rodenticides usually are harmless; however, intentional and large unintentional ingestions of pharmaceutical-grade anticoagulants or rodenticides can produce life-threatening bleeding.)
How much was ingested?
When did the ingestion occur?
Was the ingestion a single acute ingestion or a chronic ingestion?
Obtain complete blood count, prothrombin time (PT) (expected to be normal if obtained shortly after ingestion), and International Normalized Ratio (INR).
Serial PTs at 24 and 48 hours postingestion should identify patients at risk of coagulopathy
The World Health Organization introduced INR in an effort to standardize the results of the PT test. Values of INR are independent of the reagents and methods and, therefore, are comparable between laboratories across the country and abroad. The INR is defined as the normal PT ratio that would result if the World Health Organization's primary international thromboplastin were used to test the patient's sample. INR = (Patient PT/ normal PT) ISIISI is the International Sensitivity Index of the thromboplastin used in the local laboratory.
A high performance liquid chromatographic method can be used to detect and quantify serum levels of the following 5 anticoagulant rodenticides: brodifacoum, bromadiolone, coumatetralyl, difenacoum, and warfarin. Warfarin and superwarfarin levels may be obtained; however, these specialized tests generally are not helpful in the ED setting.
In cases of surreptitious hydroxycoumarin use, vitamin K-2, -3 epoxide and vitamin K can be measured. Elevated levels of vitamin K-2, -3 epoxide suggest block of reductive step by a hydroxycoumarin.
Fresh frozen plasma provides active anticoagulation factors in patients with significant active bleeding.
Type and crossmatch packed red cells in patients with hemodynamic compromise or significant blood loss.
Implement supportive measures for severe or continuous bleeding.
The evaluation of patient with hydroxycoumarin ingestion varies, depending on clinical situation.
Single, small, acute ingestions of warfarin in children are unlikely to result in significant toxicity. Treatment may include only PTs at 24 and 48 hours. Utility of baseline coagulation studies soon after ingestion is probably small. Likewise, single small ingestions of rodenticide anticoagulants are unlikely to result in toxicity.
Patients requiring chronic anticoagulation may be merely observed if their coagulation studies are only moderately elevated and no evidence exists of bleeding or risk of significant trauma that may precipitate bleeding (eg, frequent falls in the nursing home).
Massive ingestions, particularly if intentional and repeated, require more aggressive interventions on initial visit.
GI decontamination
Consider activated charcoal in all large acute ingestions.
Consider gastric lavage in massive acute ingestion presenting within 1 hour of ingestion. Carefully consider risks of bleeding from this procedure.
Bleeding
Reverse life-threatening hemorrhage with fresh-frozen plasma (FFP) followed by vitamin K-1.
Use packed red blood cells for life-threatening hemorrhage.
Enhanced elimination
Warfarin undergoes enterohepatic recirculation. Multiple dose activated charcoal or cholestyramine may accelerate elimination.
Oral phenobarbital (30-60 mg/d) or rifampin (60 mg q12h) enhance hepatic P-450 metabolism of warfarin, decreasing its half-life. Consider only in cases of chronic brodifacoum ingestion refractory to vitamin K replacement.
For severe or continued bleeding, only vitamin K-1 (phytonadione) (not any other vitamin K derivatives) can be used as an effective antidote. Usual dose is 5-10 mg administered PO/SC. Intravenous injections, even in emergencies, carry substantial risk of anaphylaxis (fatalities have been reported) — Black Box warnings. Intravenous vitamin K should be used very cautiously in emergent conditions, should be diluted, and should be infused very slowly. If immediate hemostatic effect is necessary, adequate concentrations of vitamin K-dependent coagulation factors can be restored by transfusion of fresh frozen plasma (10-20 mL/kg). Since reversal of anticoagulant by vitamin K-1 requires synthesis of fully carboxylated coagulation proteins, significant improvement in homeostasis does not occur for several hours; more than 24 hours may be needed for maximal effect.
Small ingestions of plant material (equivalent to 10-20 mg warfarin) do not cause serious intoxication in adults, yet repeated or long-term ingestion of even smaller amounts (equivalent to 2 mg/d warfarin) can produce significant anticoagulation.
Recommendations from the Seventh ACCP Conference on antithrombotic and thrombolytic therapy:[2]
In patients with mild to moderately elevated INRs without major bleeding, vitamin K, when given, should be administered orally rather that subcutaneously (Grade 1 A).
For the management of patients with a low risk of thromboembolism, warfarin therapy should be stopped approximately 4 days prior to surgery (Grade 2C).
For patients with a high risk of thromboembolism, warfarin therapy should be stopped approximately 4 days before surgery, to allow the INR to return to normal, and therapy with full-dose unfractionated heparin or full dose low-molecular-weight heparin should begin as the INR falls (Grade 2C).
In patients undergoing dental procedures, tranexamic acid mouthwash (Grade 2B) or epsilon amino caproic acid mouthwash should be used without interrupting anticoagulant therapy (Grade 2B) if there is concern for local bleeding.
Grading: Grade 1 recommendations are strong, and indicate that the benefits do, or do not, outweigh the risks, burdens, and costs. Grade 2 suggest that individual patient's values may lead to different choices.
Clinical Context:
Emergency treatment in poisoning caused by drugs and chemicals. Network of pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of charcoal. Does not dissolve in water.
For maximum effect, administer within 30 min after ingesting poison.
Preferred GI decontamination method when decontamination is desired. Generally mixed and given with a cathartic (eg, 70% sorbitol) except in young pediatric patients in whom electrolyte disturbances may be of concern.
Cholestyramine forms a nonabsorbable complex with bile acids in the intestine that inhibits enterohepatic reuptake of intestinal bile salts. Rifampin is used to speed up metabolism of warfarin by induction of hepatic cytochrome P-450 mixed function oxidases.
Clinical Context:
Overcomes block produced by hydroxycoumarin in production of vitamin K dependent clotting factors; vitamin K-3 (menadione) is not effective for this purpose.
Dose needed varies with clinical situation, including amount of anticoagulant ingested and whether it is a short- or long-acting anticoagulant. Daily doses of 50-200 mg have been required.
Use extreme caution if considering IV administration. Complications of IV use include flushing, diaphoresis, hypotension, dyspnea, and anaphylactoid reactions. SC is preferable to IV administration, which carries a strong box warning against IV administration by the manufacturer. In the patient on chronic anticoagulation for medical reasons, reversal should be performed only very carefully if clinically indicated. Re-anticoagulation can be very difficult in this situation.
Hemodynamically stable adults who take warfarin therapeutically and who have an excessively elevated PT can be monitored closely as outpatients, provided they are in a safe environment and follow-up is arranged.
Young children who have accidentally ingested a small number of warfarin tablets or rodenticide pellets can be monitored on an outpatient basis. If concern exists regarding the dose, check PT at 24 and 48 hours.
Inadvertent exposures in adults without complications can be managed likewise.
Admit all patients with active bleeding or who have intentionally ingested these drugs. Avoid procedures that can precipitate hemorrhage (eg, nasogastric or endotracheal tubes, arterial punctures/line, central lines) unless necessary.
Certain medications and/or foods interfere with warfarin levels in patients who are taking it for therapeutic purposes:
Ketoconazole: Due to the inhibition of warfarin metabolism by ketoconazole, patients taking high-dose ketoconazole concomitantly with warfarin may need their warfarin dosage reduced by more than is currently recommended, as well as receive more frequent INR monitoring.[3]
Levofloxacin: An increase in INR seems to occur when levofloxacin and warfarin are concomitantly administered; therefore, close monitoring of INR is advised.[4]
Cranberry, ginkgo biloba, glucosamine: Consumption of these led to an increase in INR values in a patient receiving warfarin.[5]
Antiretroviral therapy: INR should be monitored in patients receiving warfarin with concomitant highly active antiretroviral therapy (HAART) that includes either a protease inhibitor or an NNRTI.[6]
Coenzyme Q, ginseng, St. John’s wort: These have led to decreased warfarin levels and effects.
Patients should contact their doctor for a list of food and medications to avoid. They should notify their doctor if they are consuming any food or medications that are on the doctor’s list that might alter warfarin levels. The doctor might need to conduct dose adjustments for appropriate anticoagulation.
For patient education resources, see the Poisoning Center and Poisoning - First Aid and Emergency Center, as well as Poisoning, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.
Arasi Thangavelu, MD, FACEP, FAAEM, Consulting Staff, Department of Emergency Medicine, Archbold Memorial Hospital
Disclosure: Nothing to disclose.
Coauthor(s)
Lisandro Irizarry, MD, MPH, FACEP, Chair, Department of Emergency Medicine, Wyckoff Heights Medical Center
Disclosure: Nothing to disclose.
Specialty Editors
John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals
Disclosure: Nothing to disclose.
Chief Editor
Asim Tarabar, MD, Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Disclosure: Nothing to disclose.
Additional Contributors
B Zane Horowitz, MD, FACMT, Professor, Department of Emergency Medicine, Oregon Health and Sciences University School of Medicine; Medical Director, Oregon Poison Center; Medical Director, Alaska Poison Control System
Disclosure: Nothing to disclose.
Acknowledgements
Michael Hodgman, MD Assistant Clinical Professor of Medicine, Department of Emergency Medicine, Bassett Healthcare
Michael Hodgman, MD is a member of the following medical societies: American College of Medical Toxicology, American College of Physicians, Medical Society of the State of New York, and Wilderness Medical Society
Martin EW, et al. Remington's Pharmaceutical Sciences. 13th ed. Mack Publishing Co; 1965.
Ministry of Agriculture, Fisheries and Food (MAFF). Food Surveillance Information Sheets. Survey of biologically active principles in mint products and herbal teas. November 1996. Available at http://archive.food.gov.uk/maff/archive/food/infsheet/1996/no99/99bap.htm. Accessed: December 10, 2004.
