Warfarin and Superwarfarin Toxicity 

Overdose of or drug interactions with the oral anticoagulant warfarin (Coumadin) can lead to toxicity, as can exposure to superwarfarins, long-acting anticoagulants used in rodenticides. (See Etiology and Prognosis.)^{[1, 2]}

In the early 20th century, bis -hydroxycoumarin was discovered after livestock had eaten spoiled sweet clover and died of a hemorrhagic disease. Today, coumarin derivatives are used therapeutically as anticoagulants and commercially as rodenticides.

Warfarin is the most common oral anticoagulant in current use. Broad-ranging applications, such as in the treatment of mechanical valves, chronic atrial fibrillation, deep venous thrombosis, pulmonary embolism, and dilated cardiomyopathy, have led to widespread exposure to this drug. (See Etiology and Epidemiology.)^[3]

Additionally, although warfarin is no longer used primarily as a rodenticide, several long-acting coumarin derivatives (the so-called superwarfarin anticoagulants, such as brodifacoum, diphenadione, chlorophacinone, and bromadiolone) are used for this purpose and can produce profound and prolonged anticoagulation. Common commercial products containing superwarfarins include D-con Mouse Prufe I and II, Ramik, and Talon-G. (See Prognosis.)

Coumarins inhibit hepatic synthesis of the vitamin K ̶ dependent coagulation factors II, VII, IX, and X and the anticoagulant proteins C and S. Vitamin K is a cofactor in the synthesis of these clotting factors. The vitamin K ̶ dependent step involves carboxylation of glutamic acid residues and requires regeneration of the used vitamin K back to its reduced form.

Coumarins and related compounds inhibit vitamin K₁ -2,3 epoxide reductase, preventing vitamin K from being reduced to its active form. The degree of effect on the vitamin K ̶ dependent proteins depends on the dose and duration of treatment with warfarin.

Since warfarin does not affect the activity of previously synthesized and circulating coagulation factors, depletion of these mature factors through normal catabolism must occur before the anticoagulant effects of warfarin are observed. Each factor differs in its degradation half-life; factor II requires 60 hours, factor VII requires 4-6 hours, factor IX requires 24 hours, and factor X requires 48-72 hours. The half-lives of proteins C and S are approximately 8 and 30 hours, respectively. As a result, 3-4 days of therapy may be needed before complete clinical response to any 1 dosage is observed.

Because warfarin also reduces the activity of anticoagulant proteins C and S, a transient hypercoagulable state may occur shortly after treatment with warfarin is started. Rapid loss of protein C temporarily shifts the balance in favor of clotting until sufficient time has passed for warfarin to decrease the activity of coagulant factors.

The oral bioavailability of warfarin and the superwarfarins is nearly 100%. Warfarin is highly bound (approximately 97%) to plasma protein, mainly albumin. The high degree of protein binding is one of several mechanisms whereby other drugs interact with warfarin. Warfarin is distributed to the liver, lungs, spleen, and kidneys. It does not appear to be distributed to breast milk in significant amounts. It crosses the placenta and is a known teratogen.

The duration of anticoagulant effect after a single dose of warfarin is usually 5-7 days. However, superwarfarin products may continue to produce significant anticoagulation for weeks to months after a single ingestion. In one reported overdose case with measured serum levels, the half-life of brodifacoum was 56 days.^[4]

Warfarin is metabolized by hepatic cytochrome P-450 (CYP) isoenzymes predominantly to inactive hydroxylated metabolites, which are excreted in the bile. It also is metabolized by reductases to reduced metabolites (warfarin alcohols), which are excreted in the kidneys. Warfarin metabolism may be altered in the presence of hepatic dysfunction or advanced age but is not affected by renal impairment. Drug interactions are extensive and many known examples are enumerated below. Excessive anticoagulation may also occur because of unintentional or intentional overdose.

Lack of familiarity with the interactions between warfarin and other drugs may lead to clinically relevant and avoidable increases or decreases in prothrombin time (PT).

Drugs that prolong PT

Note that the S-isomer is more potent than the R-isomer; thus, drugs that inhibit S-isomer metabolism have a greater effect on PT.

Drugs that inhibit warfarin metabolism include the following:

• Allopurinol
• Amiodarone
• Azole antifungals
• Capecitabine
• Cephalosporin antibiotics
• Chloramphenicol
• Chlorpropamide
• Cimetidine
• Cotrimoxazole
• Disulfiram
• Ethanol (acute ingestion)
• Flutamide
• Isoniazid (INH)
• Macrolide antibiotics
• Metronidazole
• Omeprazole
• Penicillin antibiotics
• Phenytoin
• Propafenone
• Propoxyphene
• Quinidine
• Quinolone antibiotics
• Statins (particularly lovastatin and pravastatin)
• Sulfinpyrazone
• Sulfonamides
• Tamoxifen
• Tolbutamide
• Zafirlukast
• Zileuton

Many oral antibiotics, especially parenteral cephalosporins, can inhibit vitamin K activity. A high penicillin dose also can inhibit the activity of vitamin K, possibly due to decreased gastrointestinal (GI) flora synthesis of vitamin K. A recent nested case-control study of continuous warfarin users using Medicare data found that exposure to an antibiotic (azole, cephalosporins, cotrimoxazole, macrolides, penicillin, quinolones), within a period of 60 days, was associated with a two-fold increased risk of bleeding requiring hospitalization.^[5]

An additive anticoagulant effect is produced by the following drugs:

• Aspirin
• Clopidogrel
• Heparin
• Low ̶ molecular weight heparin
• Direct thrombin inhibitors (eg, argatroban, lepirudin)

Drugs that interfere with protein binding

Drugs that interfere with protein binding include the following:

• Chloral hydrate
• Clofibrate
• Diazoxide
• Ethacrynic acid
• Miconazole (including intravaginal use)
• Nalidixic acid (displaces protein binding)
• Salicylates
• Sulfonamides
• Sulfonylureas

Drugs that can reduce PT by decreasing the warfarin effect

The following drugs cause inhibition of warfarin absorption:

• Cholestyramine
• Sucralfate
• Aluminum hydroxide
• Colestipol

The following drugs cause enhanced warfarin metabolism:

• Barbiturates
• Carbamazepine
• Ethanol
• Glutethimide
• Griseofulvin
• Phenytoin
• Rifampin

The following foods have a very high vitamin K content (>200 mcg):

• Brussel sprouts
• Chick peas
• Collard greens
• Coriander
• Endive
• Kale
• Liver
• Parsley
• Red leaf lettuce
• Spinach
• Swiss chard
• Black/green teas
• Turnip greens
• Watercress

The following foods have a high vitamin K content (100-200 mcg):

• Basil
• Broccoli
• Butterhead lettuce
• Canola oil
• Chives
• Coleslaw
• Cucumbers (with peel)
• Green onions
• Mustard greens
• Soybean oil

The following foods have a medium vitamin K content (50-100 mcg):

• Apples (green)
• Asparagus
• Cabbage
• Cauliflower
• Mayonnaise
• Nuts (pistachios)
• Summer squash

The following foods have a low vitamin K content (< 50 mcg):

• Apples (red)
• Avocados
• Beans
• Breads/grains
• Carrots
• Celery
• Cereal
• Coffee
• Corn
• Cucumbers (without the peel)
• Dairy products
• Eggs
• Fruits
• Iceberg lettuce
• Meats/fish/poultry
• Pastas
• Peanuts
• Peas
• Potatoes
• Rice
• Tomatoes

Occurrence in the United States

According to American Association of Poison Control Centers (AAPCC) data, 10,822 superwarfarin exposures and 2838 warfarin exposures were reported to US poison control centers in 2009.^[6] More than 79% (10,847) of these exposures occurred in children younger than 6 years. More than 94% (12,875) of all warfarin or superwarfarin exposures involved unintentional exposure to rodenticide. This provides the reason for the rare incidence of major outcomes (29 cases) or deaths (1 case) within this category of rodenticides.

Age-related demographics

Complications from incorrect dosing of warfarin occur most often in adults. Unintentional ingestions of superwarfarins are far more common in children, with approximately 89% of reported exposures occurring in children younger than age 6 years. Pediatric exposures usually involve a single small ingestion and result in no symptoms or alteration in the PT.^[7] Adults who intentionally ingest superwarfarin agents are more likely to ingest a toxic dose and to experience the anticoagulant effects of these products.

Hemorrhage

Bleeding is the primary adverse effect of warfarin and superwarfarin toxicity and is related to the intensity of anticoagulation, length of therapy, the patient's underlying clinical state, and use of other drugs that may affect hemostasis or interfere with warfarin metabolism.^[8] Fatal or nonfatal hemorrhage may occur from any tissue or organ.

Children rarely ingest enough product to develop clinical evidence of anticoagulation. A study of 595 children younger than age 6 years who had ingested superwarfarin rodenticides found only 2 with elevated PTs (international normalized ratio [INR] 1.5 and 1.8), and neither had symptoms.^[7]

Over the 20-year period from 1985-2004, the AAPCC’s Toxic Exposure Surveillance System (TESS) database reported no deaths in children younger than age 6 years after ingestion of superwarfarins and only 1 adult death due to unintentional ingestion.^[9] Virtually all cases of severe hemorrhage occurred after intentional self-poisoning.

Minor bleeding from mucous membranes, subconjunctival hemorrhage, hematuria, epistaxis, and ecchymoses may occur.

Major bleeding complications include GI hemorrhage, intracranial bleeding, and retroperitoneal bleeding. Massive hemorrhage usually involves the GI tract but may involve the spinal cord or cerebral, pericardial, pulmonary, adrenal, or hepatic sites. Although rare, massive intraocular hemorrhage has been reported in patients with preexisting disciform macular degeneration.

Skin necrosis

Skin necrosis, usually observed between the third and eighth days of therapy, is a relatively uncommon, adverse reaction to warfarin. When skin necrosis occurs, it can be extremely severe and disfiguring and may require treatment through debridement or amputation of the affected tissue, limb, breast, or penis.

It occurs more frequently in women and in patients with preexisting protein C deficiency and is found, less commonly, in men and in patients with protein S deficiency. Patients initially become hypercoagulable because warfarin depresses levels of the anticoagulant proteins C and S more quickly than it does coagulant proteins II, VII, IX, and X.

Extensive thrombosis of the venules and capillaries occurs within the subcutaneous fat. Women note an intense, painful burning in areas such as the thigh, buttocks, waist, and/or breast several days after beginning warfarin; skin necrosis and permanent scarring may follow.

Immediate withdrawal of warfarin therapy is indicated. Heparin can be substituted safely for warfarin; however, treatment of patients who require long-term anticoagulant therapy remains problematic.

Restarting warfarin therapy at a low dose (eg, 2 mg) while continuing heparin treatment for 2-3 days may be reasonable. The dosage of warfarin can be increased gradually over several weeks.

Warfarin and pregnancy

Warfarin crosses the placenta during pregnancy and has the potential to cause teratogenesis and bleeding in the fetus. Warfarin and other coumarin derivatives cause an embryopathy commonly termed fetal warfarin syndrome (FWS). No data are available on whether superwarfarin compounds cross the placenta or are excreted in breast milk.^[6]

During the first trimester, particularly during weeks 6-12 of gestation, embryopathy caused by exposure and characterized by nasal hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) may occur.

Central nervous system (CNS) abnormalities, including dorsal midline dysplasia characterized by agenesis of the corpus callosum, Dandy-Walker malformation, and midline cerebellar atrophy have been reported.

Ventral midline dysplasia, characterized by optic atrophy and eye abnormalities, has been observed. Seizures, deafness, blindness, and mental retardation can occur in any trimester. Spontaneous fetal abortion and stillbirth are known to occur, and an increased risk of fetal mortality is associated with warfarin use.

Although rare, other teratogenic occurrences reported after in utero exposure to warfarin include the following:

• Urinary tract abnormalities (eg, single kidney)
• Asplenia
• Anencephaly
• Spina bifida
• Cranial nerve palsy
• Hydrocephalus
• Cardiac defects and congenital heart disease
• Polydactyly
• Deformities of toes
• Diaphragmatic hernia
• Corneal leukoma
• Cleft palate
• Cleft lip
• Schizencephaly
• Microcephaly

The effects of anticoagulation on the fetus are a particular concern during labor, when the combination of the trauma of delivery and anticoagulation may lead to bleeding in the neonate.

A few small studies have looked at the use warfarin in pregnancy after the 12th week of gestation, but these studies are insufficient to recommend the use of warfarin in the pregnant patient. Thus, do not administer warfarin during pregnancy.

Additional complications

Other adverse reactions that occur infrequently with chronic warfarin therapy include the following:

• Agranulocytosis
• Alopecia
• Anaphylactoid reactions
• Anorexia
• Cold intolerance
• Diarrhea
• Dizziness
• Elevated hepatic enzyme levels
• Exfoliative dermatitis
• Headache
• Hepatitis
• Jaundice
• Leukopenia
• Nausea and/or vomiting
• Pruritus
• Urticaria

Rare events of tracheal or tracheobronchial calcification have been reported in association with long-term warfarin therapy. The clinical significance is not known. Priapism is associated with anticoagulant administration; however, a causal relationship with warfarin is not established.

Instruct regular users of warfarin in the proper use of their medication and in methods of avoiding accidental overdose (eg, employment of daily pillboxes). Generally, the primary care provider handles this.

After acute ingestions by children, instruct parents to remove possible sources of intoxication (eg, poisons on the floor, under the sink, in the garage).

For patient education information, see the First Aid and Injuries Center, as well as Poisoning, Activated Charcoal, and Poison Proofing Your Home.