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Toxicity, Warfarin and Superwarfarins

Author: Kent R Olson, MD, FACEP, Clinical Professor of Medicine and Pharmacy, University of California San Francisco; Medical Director, San Francisco Division, California Poison Control System
Coauthor(s): David N Trickey, MD, Staff Physician, Department of Emergency Medicine, Carl R Darnall Army Medical Center; Michael A Miller, MD, Assistant Chief, Department of Emergency Medicine, Tripler Army Medical Center Hawaii; Medical Toxicologist, Tripler Army Medical Center and Central Texas Poison Center, Scott and White Memorial Hospital; Lisa M Yungmann Hile, MD, Consulting Staff, Medical Director of Emergency Medicine Physician Assistant Fellowship Program, Department of Emergency Medicine, Darnall Army Medical Center
Contributor Information and Disclosures

Updated: Sep 22, 2009

Introduction

Background

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 (Coumadin) is the most common oral anticoagulant used today. Broad ranging uses such as treatment for mechanical valves, chronic atrial fibrillation, deep venous thrombosis (treatment and prevention), pulmonary embolism, and dilated cardiomyopathy have led to widespread exposure to this drug.

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, 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.

Pathophysiology

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 K ₁ -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.

Because 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 one 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.¹

Warfarin is metabolized by hepatic cytochrome P-450 (CYP) isoenzymes predominately 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 numerous and include agents from a variety of pharmaceutical classes, such as antibacterials, antimycobacterials, antifungals, antiarrhythmics, anticonvulsants, antihyperlipidemics, antineoplastics, nonsteroidal anti-inflammatory agents, H2-receptor antagonists, immunosuppressive agents, and many others. Excessive anticoagulation may also occur because of accidental or intentional overdose.

Lack of familiarity with these interactions may lead to clinically relevant and avoidable increases or decreases of prothrombin time (PT).

Drugs that can prolong the prothrombin time: (Note that the S-isomer is more potent than the R-isomer; thus, drugs that inhibit S-isomer metabolism have a greater effect on the PT.)

• Inhibition of warfarin metabolism
  • Allopurinol
  • Amiodarone
  • Azole antifungals
  • Capecitabine
  • Chloramphenicol
  • Chlorpropamide
  • Cimetidine
  • Ciprofloxacin
  • Cotrimoxazole
  • Disulfiram
  • Ethanol (acute ingestion)
  • Flutamide
  • Isoniazid (INH)
  • Metronidazole
  • Norfloxacin
  • Ofloxacin
  • Omeprazole
  • Phenytoin
  • Propafenone
  • Propoxyphene
  • Quinidine
  • Statins (particularly lovastatin and pravastatin)
  • Sulfinpyrazone
  • Sulfonamides
  • Tamoxifen
  • Tolbutamide
  • Zafirlukast
  • Zileuton
• Inhibition of vitamin K activity
  • Oral antibiotics, especially parenteral cephalosporins (Oral cefaclor, cefixime, cefpodoxime, cefuroxime, cephalexin, and cephradine have not been shown to interact with warfarin.)
  • High dose of penicillins (possibly due to decreased GI flora synthesis of vitamin K)
• Additive anticoagulant effect
  • Aspirin
  • Heparin

Drugs that interfere with protein binding

• 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

• Inhibition of warfarin absorption
  • Cholestyramine
  • Sucralfate
  • Aluminum hydroxide
  • Colestipol
• Enhanced warfarin metabolism
  • Barbiturates
  • Carbamazepine
  • Ethanol
  • Glutethimide
  • Griseofulvin
  • Phenytoin
  • Rifampin
• Promote vitamin K activity
  • Foods with very high vitamin K content (>200 mcg) include the following:
    • Brussel sprouts
    • Chick peas
    • Collard greens
    • Coriander
    • Endive
    • Kale
    • Liver
    • Parsley
    • Red leaf lettuce
    • Spinach
    • Swiss chard
    • Black/green teas
    • Turnip greens
    • Watercress
  • Foods with high vitamin K content (100-200 mcg) include the following:
    • Basil
    • Broccoli
    • Butterhead lettuce
    • Canola oil
    • Chives
    • Coleslaw
    • Cucumbers (with peel)
    • Green onions
    • Mustard greens
    • Soybean oil
  • Foods with medium vitamin K content (50-100 mcg) include the following:
    • Apples (green)
    • Asparagus
    • Cabbage
    • Cauliflower
    • Mayonnaise
    • Nuts (pistachios)
    • Summer squash
  • Foods with low vitamin K content (<50 mcg) include the following:
    • 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

Frequency

United States

According to the American Association of Poison Control Centers data, 11,683 superwarfarin exposures and 380 warfarin exposures were reported to US poison control centers in 2007.² More than 87% (10,514) of these exposures occurred in children younger than 6 years. More than 95% (11,522) of all warfarin or superwarfarin exposures involved unintentional exposure to the rodenticide. This provides the reason for the rare incidence of major outcomes (10 cases) or deaths (1 case) within this category of rodenticides. 

International

Data are not available.

Mortality/Morbidity

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. 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 6 years who had ingested "superwarfarin" rodenticides found only two with elevated prothrombin times (INR 1.5 and 1.8) and neither had symptoms.³ Over the 20-year period from 1985-2004, The American Association of Poison Control Centers’ Toxic Exposure Surveillance System (TESS) database reported no deaths in children younger than 6 years after ingestion of superwarfarins and only 1 adult death due to unintentional ingestion.⁴ 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 gastrointestinal 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.
• Hypercoagulable presentations are theoretically possible.

Race

Racial predilection does not appear to exist for this type of toxicity.

Sex

No significant difference between the sexes is apparent for this toxicity.

Age

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 6 years. Pediatric exposures usually involve a single small ingestion and result in no symptoms or alteration in the prothrombin time.³ Adults who intentionally ingest superwarfarin agents are more likely to ingest a toxic dose and to experience anticoagulant effects of these products.

Clinical

History

• Obtain an accurate history of the amount of warfarin or superwarfarin ingested, when it was ingested, and over what period it was ingested. Additionally, inquire about the circumstances of the ingestion to determine the patient's disposition.
  • If the ingestion was suicidal or surreptitious in nature, the history may be difficult to obtain or the patient or caregiver may give misleading information.
  • An accurate medication list is important because many other drugs increase or decrease the metabolism of warfarin (see Examples of drug interactions with warfarin).
• The toxic dose is highly variable.
  • Generally, a single ingestion of warfarin (10-20 mg) does not cause serious intoxication.
  • In contrast, chronic or repeated ingestion of even small amounts (2-5 mg/d) eventually can lead to significant anticoagulation, especially in the presence of interacting drugs.
  • Patients with hepatic dysfunction, malnutrition, or a bleeding diathesis are at greatest risk.
  • Superwarfarins are extremely potent and can produce prolonged effects even after a small ingestion; as little as 1 mg in an adult can cause coagulopathy.
• Bleeding is the only expected symptom of significance in the history. Internal bleeding may present a vast array of symptoms or be occult.

Physical

Do not expect to see physical evidence of bleeding after an acute ingestion for at least 24 hours.

• Life-threatening complications include massive GI bleeding and intracranial hemorrhage.
• More common findings of excessive anticoagulation are ecchymoses, subconjunctival hemorrhage, epistaxis, vaginal bleeding, bleeding gums, or hematuria.
• In all patients, if prolongation of the PT is observed after an acute ingestion, it may appear in as early as 8-12 hours; however, peak effects commonly are delayed until at least 1-2 days postingestion.

Causes

Warfarin toxicity can occur as a result of ingestion of pharmaceutical Coumadin or after exposure to the rodenticide superwarfarins. It may be from intentional or unintentional overdose or as a consequence of drug interactions.

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