eMedicine Specialties > Emergency Medicine > Toxicology

Toxicity, Warfarin and Superwarfarins

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
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

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.

Differential Diagnoses

Other Problems to Be Considered

Liver failure
Factor X deficiency
Factor V deficiency
Afibrinogenemia
Dysfibrinogenemia
Vitamin K deficiency
Malabsorptive states
Domestic violence
Retroperitoneal hemorrhage

Workup

Laboratory Studies

• Blood levels of warfarin are neither readily available nor helpful. Specific levels of superwarfarin rodenticides (eg, brodifacoum) may be useful in cases where the ingestion is denied or for purposes of estimating the necessary duration of vitamin K₁ therapy. However, most reference laboratories do not perform this analysis. (National Medical Laboratory [NMS] in Willow Grove, Pennsylvania, offers a qualitative screen for anticoagulant rodenticides and a quantitative analysis for brodifacoum.) 
• The anticoagulant effect is best quantified by baseline and daily repeated measurement of the prothrombin time (PT) and the international normalized ratio (INR), which may not be elevated until 1-2 days postingestion.
  • A normal PT 48-72 hours after ingestion rules out significant ingestion.
  • Blood levels of vitamin K–dependent clotting factors (II, VII, IX, and X) are decreased if measured, but these are rarely available in a timely fashion and usually do not aid in clinical management. However, depressed levels may provide supporting evidence for suspected poisoning by warfarin or superwarfarins.⁴
  • Note: A "mixing study" using an aliquot of normal serum mixed with the patient's serum will restore an abnormal prothrombin time to normal. This may be useful when trying to distinguish anticoagulation caused by warfarin or a superwarfarin from that caused by a factor inhibitor (eg, lupus anticoagulant) or anti-factor antibodies.⁵
• Other laboratory tests that may be indicated include a blood count for baseline hemoglobin and/or hematocrit or to assess for anemia if the ingestion is more remote.
• A blood type and crossmatch or antibody screening is indicated if substantial blood loss is suggested.
• In addition, other laboratory tests (eg, acetaminophen level) or toxicology screening may be indicated to rule out co-ingestions.

Imaging Studies

• If intracranial bleeding is suggested, obtain a noncontrast CT scan of the head.

Treatment

Prehospital Care

Initiate usual supportive measures, including intravenous access if any suggestion of remote or active bleeding is evident. After an acute intentional ingestion, administer activated charcoal per local protocols. Infuse crystalloid solution if signs of significant blood loss are present.

Emergency Department Care

Initiate usual advanced supportive measures. Evaluate for current or remote bleeding with a thorough physical examination, including a rectal examination as indicated to check for occult GI bleeding. If significant bleeding has occurred and the patient is unstable, be prepared to treat the patient with transfusions of packed cells and fresh frozen plasma as first-line therapy. Further evaluation varies, depending on the situation.

• Warfarin and superwarfarin ingestions generally are acute or chronic. In either situation, determine whether the ingestion was accidental or intentional and whether the patient requires long-term anticoagulation (eg, mechanical heart valve, chronic atrial fibrillation).
• For acute ingestions, generally no evidence of bleeding is present on the initial clinical examination, unless the ingestion occurred more than 12-24 hours before ED presentation.
  • Obtain a baseline PT/INR and make arrangements for a repeat measurement in 24-48 hours.
  • Administer activated charcoal if it was not already given in the field.
  • Gastric lavage is unnecessary if rapid administration of activated charcoal is feasible. Do not induce emesis.
  • Treat any co-ingestions, evaluate the patient for suicidal intention, and refer appropriately.
  • Avoid drugs that may enhance bleeding or decrease metabolism of the anticoagulant.
  • Do not administer vitamin K prophylactically because (1) it is not needed in most patients, and (2) its presence masks the onset of anticoagulant effects in the few patients who do require prolonged treatment and follow-up care.
  • If the prothrombin time is elevated, treatment with vitamin K is appropriate (see Medication). Because vitamin K does not immediately restore therapeutic levels of clotting factors, treat patients who are experiencing acute hemorrhage with fresh frozen plasma (FFP). Recombinant activated factor VII, while costly, may have an advantage over FFP in that it does not carry a risk of transmission of viral disease, allergic reaction, or volume overload.⁶
• Chronic intoxication resulting from therapeutic use of warfarin can be evaluated with a careful physical examination and a measurement of the PT and INR.
  • If INR is higher than therapeutic levels but less than 6 and the patient is not bleeding, withhold warfarin for 2-3 days and restart when the INR approaches the therapeutic range.
  • If INR is higher than 6 but less than 10 and the patient is not actively bleeding, or the INR is less than 6 but the patient requires more rapid reversal (eg, for elective surgery), administer 5-10 mg of vitamin K-1 orally with the expectation that the INR will begin to fall within 8 hours with a maximal effect in about 24 hours.
  • If the INR is higher than 10 and the patient is not bleeding, a higher daily dose of oral vitamin K-1 may be administered. In the setting of superwarfarin-induced coagulopathies, 50-200 mg is recommended.
  • If very rapid reversal of anticoagulant effect is essential because of serious bleeding, administer fresh frozen plasma (FFP). Successful reversal of severe coagulopathy and life-threatening hemorrhage has also been reported using recombinant activated factor VII^7,8 or activated prothrombin complex concentrate (APCC).⁹ While costly, these newer therapies may have an advantage over FFP in that they do not carry the same risk of transmission of viral disease, allergic reaction, or volume overload.
  • Note: If the patient has a critical need for ongoing anticoagulation (eg, mechanical heart valve), heparin should be given as a temporary measure while fully reversing the effects of warfarin.
• Chronic ingestions of rodenticide superwarfarin may be intentional (eg, Munchhausen syndrome) and can occur in the setting of child abuse (Munchhausen by proxy). These patients should be admitted for psychiatric or protective services evaluation.

Consultations

Since most warfarin and superwarfarin exposures result in minor or no significant effects, the regional poison control center can aid in decreasing the referral of patients to health care facilities as well as decreasing the performance of unnecessary laboratory tests in minor, accidental exposures. The poison centers and clinical toxicologists may be helpful in evaluating a large anticoagulant overdose and can assist with long-term follow-up care after ingestion of a superwarfarin.

• Obtaining a psychiatric referral is appropriate for intentional ingestions. Contact child welfare or protective services if child abuse is suspected.
• The patient's primary care provider or the local coagulation clinic is an appropriate referral if an accidental overdose occurs and the patient is considered to be at low risk for bleeding complications.
• Consulting a neurosurgeon is appropriate for intracranial hemorrhage.
• Consulting a gastroenterologist is appropriate for most GI bleeds.
  

Medication

Packed red cells and fresh frozen plasma may be required for immediate management of life-threatening hemorrhagic complications. Alternative treatments to FFP include prothrombin complex concentrate (APCC)⁹ or recombinant factor VIIa. Data are limited on the use of recombinant factor VIIa for the reversal of warfarin-induced coagulopathy. In a small study, 13 patients who required rapid reversal of warfarin-induced coagulopathy were treated with recombinant factor VIIa with success.⁸ Successful treatment of severe bleeding in 4 patients with superwarfarin toxicity has also been reported.⁷ On the basis of such limited data, the role of recombinant factor VIIa or APCC in the treatment of warfarin and superwarfarin is unclear.

Vitamin K is the only effective antidote for long-term management, but reversal of anticoagulation takes several hours. Administering vitamin K IV has no advantage, and reports have documented acute cardiovascular collapse after administration by this route, presumably caused by an anaphylactoid reaction. IM or SC administration may cause hematoma. In the authors' opinion, oral administration, when possible, is preferred.

GI decontaminants

Empirically used to minimize systemic absorption of the toxin.

Activated charcoal (Liqui-Char)

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.
Administer to patients who present 1-2 h postingestion or in patients in whom co-ingestants may delay gastric emptying or gut motility; minimal benefit is expected if more than 4 h have passed since the ingestion.

Dosing

Adult

1 g/kg PO or 10 times the amount of drug ingested; for each gram of drug ingested, administer 10 g activated charcoal

Pediatric

1 g/kg PO; not to exceed 10 times the amount of drug ingested

Interactions

May inactivate ipecac syrup if used concomitantly; effectiveness of other medications decreases with coadministration; do not mix with sherbet, milk, or ice cream (decreases adsorptive properties)

Contraindications

Documented hypersensitivity; poisoning or overdose of mineral acids and alkalies; unprotected airway with absent gag reflex; bowel infarction or ileus

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Adverse effects include nausea, vomiting, and aspiration if the airway is not secure; monitor for bowel sounds to minimize risk of charcoal ileus; not very effective in poisonings of ethanol, methanol, and iron salts; induce emesis before giving activated charcoal; after emesis with ipecac syrup, patient may not tolerate activated charcoal for 1-2 h; can administer in early stages of gastric lavage; without sorbitol, gastric lavage returns are black

Antidotes

Used in the management of poisoning and overdose, prevention of toxic effects, or metabolic disorders where toxic substances accrue. Mechanisms of action are variable (eg, antagonists, toxin transformation, altered metabolism, chelation, directed antibodies).

Vitamin K (Phytonadione, AquaMEPHYTON)

Can overcome competitive block produced by warfarin and other related anticoagulants. (Note: Vitamin K-3 (menadione) is not effective for this purpose.) Clinical effect is delayed several hours while liver synthesis of clotting factors is initiated and plasma levels of clotting factors II, VII, IX, and X are gradually restored.
Not to be administered prophylactically. Use only if evidence of anticoagulation exists. Required dose varies with clinical situation, including amount of anticoagulant ingested and whether it is a short-acting or long-acting anticoagulant.

Dosing

Adult

50-800 mg PO divided tid/qid after ingestion of superwarfarins; treatment may be required for >8 wk; initial dose for superwarfarin is 50-150 mg PO divided tid/qid; increase dosing prn (Much smaller doses are needed [2-20 mg] for warfarin.)

Pediatric

1-5 mg PO initial; increase prn based on daily PT; higher doses necessary for superwarfarin-induced coagulopathies

Interactions

Effects of warfarin sodium and dicumarol are antagonized by phytonadione; sucralfate may decrease PO vitamin K absorption

Contraindications

Documented hypersensitivity (usually only reported in patients who previously received vitamin K IV and experienced a sudden cardiovascular reaction [eg, hypotension, bradycardia])

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Do not administer IV; complications of IV use include flushing, diaphoresis, hypotension, dyspnea, and anaphylactoid reactions (PO is preferable to IV; product insert carries a warning against IV administration by the manufacturer); in patients on long-term anticoagulation for medical reasons, perform reversal only very cautiously and if clinically indicated

Follow-up

Further Inpatient Care

• All patients with signs of active bleeding or who are at significant risk of life-threatening hemorrhage require admission to the hospital.
• In addition, suicidal ingestions require psychiatric evaluation and observation for 36-48 hours to monitor for anticoagulation.

Further Outpatient Care

• Patients who are already on warfarin, who have had an accidental overdose, and who are hemodynamically stable with no evidence of active bleeding can follow up with their regular source of anticoagulation care. Recommendations from a recent article are listed in Treatment.
• Children with acute accidental ingestions can be discharged home with follow-up care by their pediatrician in the office or by telephone at 48 hours. Most authorities no longer recommend routine follow-up PT measurement because the incidence of significant anticoagulation in children after accidental exposure is extremely low.

Transfer

• If the patient has any type of hemorrhage that the current facility is not capable of managing appropriately, transfer to a higher level of care is indicated.

Deterrence/Prevention

• Instruct regular users of warfarin in proper use of their medication and in problem-solving methods to avoid accidental overdose (eg, 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 sink, in garage).
  

Complications

• Hemorrhagic complications, as described above, are the major concern.
• Skin necrosis, usually observed between the third and eighth days of therapy, is a relatively uncommon adverse reaction to warfarin.
  • When it 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, 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 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 crosses the placenta during pregnancy and has the potential to cause teratogenesis and bleeding in the fetus. Warfarin and other Coumadin 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.²
  • 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.
  • 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 reports following in utero exposure to warfarin include 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, and 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 used 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.
• Other adverse reactions that occur infrequently with chronic warfarin therapy include agranulocytosis, alopecia, anaphylactoid reactions, anorexia, cold intolerance, diarrhea, dizziness, elevated hepatic enzyme levels, exfoliative dermatitis, headache, hepatitis, jaundice, leukopenia, nausea and/or vomiting, pruritus, and urticaria.
• Rare events of tracheal or tracheobronchial calcification are 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.

Patient Education

• For excellent patient education resources, visit eMedicine's Drug Overdose Center and Poisoning - First Aid and Emergency Center. Also, see eMedicine's patient education articles Poisoning, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.

Miscellaneous

Medicolegal Pitfalls

• Using IV vitamin K is associated with acute cardiovascular collapse (probably an anaphylactoid response) in a small group of patients; furthermore, it is not medically necessary because the effects of vitamin K take several hours. For immediate reversal of anticoagulation, use fresh frozen plasma.
• Failure to recognize a co-ingestion with another substance that can cause morbidity or mortality is a pitfall.

Special Concerns

• See Complications for discussion of complications associated with pregnancy.

References

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Keywords

superwarfarin toxicity, warfarin, Coumadin, brodifacoum, diphenadione, chlorophacinone, bromadiolone, coumarin, vitamin K, vitamin K-1, bis -hydroxycoumarin, superwarfarin anticoagulants, S isomer metabolism, warfarin effect, superwarfarin rodenticides, brodifacoum, ingestion of superwarfarin

Contributor Information and Disclosures

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
Kent R Olson, MD, FACEP is a member of the following medical societies: American Academy of Clinical Toxicology and American College of Medical Toxicology
Disclosure: Nothing to disclose.

Coauthor(s)

David N Trickey, MD, Staff Physician, Department of Emergency Medicine, Carl R Darnall Army Medical Center
David N Trickey, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, and Emergency Medicine Residents Association
Disclosure: Nothing to disclose.

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
Michael A Miller, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, and American College of Medical Toxicology
Disclosure: None None None

Lisa M Yungmann Hile, MD, Consulting Staff, Medical Director of Emergency Medicine Physician Assistant Fellowship Program, Department of Emergency Medicine, Darnall Army Medical Center
Disclosure: Nothing to disclose.

Medical Editor

David A Peak, MD, Assistant Residency Director of Harvard Affiliated Emergency Medicine Residency, Attending Physician, Massachusetts General Hospital; Consulting Staff, Department of Hyperbaric Medicine, Massachusetts Eye and Ear Infirmary
David A Peak, MD is a member of the following medical societies: American College of Emergency Physicians, American Medical Association, Society for Academic Emergency Medicine, and Undersea and Hyperbaric Medical Society
Disclosure: Nothing to disclose.

Pharmacy Editor

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart & St. Joseph's Hospitals
John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists
Disclosure: Nothing to disclose.

Managing Editor

John G Benitez, MD, MPH, FACMT, FACPM, FAAEM, Associate Professor, Department of Medicine, Clinical Pharmacology Division, Vanderbilt University; Managing Director, Tennessee Poison Center
John G Benitez, MD, MPH, FACMT, FACPM, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine, American College of Medical Toxicology, American College of Preventive Medicine, Society for Academic Emergency Medicine, Undersea and Hyperbaric Medical Society, and Wilderness Medical Society
Disclosure: Nothing to disclose.

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
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.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, John C Stein Jr, MD, to the development and writing of this article.

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