DESCRIPTION

Long-acting anticoagulants (super-warfarins) are warfarin derivatives used as rodenticides.

FORMS AND USES

This chapter discusses brodifacoum (Bromione, d-Con Mouse Prufe II, Havoc, Talon, Talon-G), difenacoum (Ratak), bromadiolone (Super-caid, Maki), chlorophacinone (Caid, Liphadione), diphacinone (Diphacin, Promar, Ramik), flocoumafen, pindone (Pival, Pivacin, Pivalyn, Tri-Ban), valone, and coumatetralyl.

TOXIC DOSE

• Mouthful amounts of rat bait have produced mild prothrombin time (PT) prolongation in children.
• Doses of 1 to 2 mg of brodifacoum may cause anticoagulation in adults.

PATHOPHYSIOLOGY

• Super-warfarins produce vitamin K deficiency by inhibiting the regeneration of active vitamin K, thereby inhibiting the formation of clotting factors II, VII, IX, and X.
• Anticoagulation is delayed until existing vitamin K stores are depleted.
• Half-lives of super-warfarins are long; a single ingestion may cause coagulopathy, which can last weeks to months.

EPIDEMIOLOGY

• Poisoning is common.
• Toxic effects following exposure occur rarely and are typically mild.
• Death is rare, usually due to hemorrhagic complications (especially intracranial) in adults with deliberate ingestion.

CAUSES

• Most cases involve accidental ingestion by children.
• Child neglect or abuse should be considered if the patient is less than 1 year of age, a suicide attempt if the patient is over 6 years of age.

DRUG AND DISEASE INTERACTIONS

Allopurinol, anabolic steroids, cephalosporins, chloral hydrate, cimetidine, clofibrate, cyclic antidepressants, erythromycin, ethanol, nonsteroidal antiinflammatory drugs, sulfonylureas, and thyroxine may potentiate anticoagulant effect.

PREGNANCY AND LACTATION

• Fetal intraventricular hemorrhage has been reported.
• Teratogenicity has been reported with other oral anticoagulants, such as coumadin.

Section Outline:

• DESCRIPTION
• FORMS AND USES
• TOXIC DOSE
• PATHOPHYSIOLOGY
• EPIDEMIOLOGY
• CAUSES
• DRUG AND DISEASE INTERACTIONS
• PREGNANCY AND LACTATION

DIFFERENTIAL DIAGNOSIS

• Toxicologic causes of anticoagulation include heparin, coumadin, and crotalid snake envenomation as well as hepatic failure from any cause (e.g., acetaminophen, Amanita species mushrooms).
• Nontoxicologic causes include hemophilia, vitamin K deficiency, or any cause of disseminated intravascular coagulation (sepsis or shock).

SIGNS AND SYMPTOMS

Accidental pediatric exposures usually cause minimal or no anticoagulation. However, intentional overdose may cause severe coagulopathy that may last weeks to months, often with bleeding (most common sites are gastrointestinal and genitourinary tracts).

Vital Signs

Hypotension and tachycardia may occur as a result of hemorrhage.

HEENT

Epistaxis or gingival bleeding may develop.

Dermatologic

Ecchymosis, hematoma, and occasionally necrosis (purple toe syndrome) may develop.

Cardiovascular

Pericardial tamponade may develop rarely.

Pulmonary

Hemothorax, hemoptysis, and alveolar hemorrhage are rare effects.

Gastrointestinal

• Hematemesis, hematochezia, or melena may occur.
• Gastroinestinal or retroperitoneal bleeding have been reported in adults with severe coagulopathy.

Renal

Hematuria may develop.

Hematologic

• PT, partial thromboplastin time (PTT), and international normalized ratio (INR) become prolonged.
• Platelet count and fibrinogen level remain unaffected, but fibrin split products may be elevated.

Musculoskeletal

Muscle hematoma, compartment syndrome, or hemarthroma develop rarely.

Neurologic

Intracranial hemorrhage is uncommon but is the most common cause of death.

Endocrine

Adrenal hemorrhage and insufficiency may occur rarely.

Genitourinary

Excessive vaginal bleeding and hematuria have been reported.

PROCEDURES AND LABORATORY TESTS

Essential Tests

• After accidental overdose, INR or PT should be measured in 24 to 48 hours.
• After deliberate ingestion, INR or PT levels should be obtained immediately and followed every 24 hours for 48 hours.
• Elevated INR or PT suggests significant exposure.

Recommended Tests

• PTT, fibrinogen, fibrin degradation products, complete blood count, platelets, guaic of stool, and type and crossmatch blood are ordered for patients with clinically significant prolongation of INR/PT.
  • Thrombocytopenia or depressed fibrinogen suggests coagulopathy from another etiology.
  • Anemia or guaiac-positive stool suggests significant toxicity.
• Levels of specific clotting factors are used to distinguish between an anticoagulant ingestion with liver dysfunction and a primary hematologic disorder.
• Serum levels of long-acting anticoagulants (from reference laboratories) are not useful in an acute setting, but they may confirm occult ingestion in child abuse or factitious disorder.
• Head CT followed by lumbar puncture is used in patients with altered mental status.
• Endoscopy may be useful if clinical evidence of gastrointestinal bleeding is present.

Section Outline:

• DIFFERENTIAL DIAGNOSIS
• SIGNS AND SYMPTOMS
  • Vital Signs
  • HEENT
  • Dermatologic
  • Cardiovascular
  • Pulmonary
  • Gastrointestinal
  • Renal
  • Hematologic
  • Musculoskeletal
  • Neurologic
  • Endocrine
  • Genitourinary
• PROCEDURES AND LABORATORY TESTS
  • Essential Tests
  • Recommended Tests

• Treatment focuses on assessment and treatment of coagulopathy and control of bleeding.
• The dose and time of exposure should be determined for all substances involved.

DIRECTING PATIENT COURSE

The health-care professional should call the poison control center when:

• A history of anticoagulant ingestion is obtained.
• Toxic effects are not consistent with brodifacoum.
• Coingestant, drug interaction, or underlying disease presents an unusual problem.

The patient should be referred to a health-care facility when:

• Attempted suicide or homicide is possible.
• Patient or caregiver seems unreliable.
• Any toxic effects develop.
• Coingestant, drug interaction, or underlying disease presents an unusual problem.

Admission Considerations

Inpatient management is warranted for patients with frank bleeding or severe coagulopathy.

DECONTAMINATION

Out of Hospital

Ipecac should be administered to induce emesis within 1 hour of an acute single ingestion for an alert pediatric patient if health-care evaluation will be delayed.

In Hospital

• Ipecac should be administered to induce emesis within 1 hour of ingestion for the pediatric patient who is too small to have effective gastric lavage.
• Ipecac is not recommended in adults.
• Gastric lavage should be performed in pediatric (tube size 24-32 French) or adult (tube size 36-42 French) patients for large ingestion presenting within 1 hour of ingestion.
• One dose of activated charcoal (1-2 g/kg) should be administered without a cathartic if a substantial ingestion has occurred within the previous few hours.

ANTIDOTES

Vitamin K1 reverses the effect of brodifacoum on vitamin K regeneration.

Indications

• Marked prolongation of PT or INR without bleeding
• Severe prolongation of PT or INR and frank bleeding (may be used in conjunction with fresh or frozen plasma)

Method of Administration

• Marked prolongation of PT or INR without bleeding
  • Vitamin K1 can be administered orally; adult initial dose is 50 to 100 mg/day initially in single or divided doses. Pediatric dose is not established; initial dose of 0.6 mg/kg or 10 to 15 mg is appropriate and will be titrated to effect in any case.
  • INR and PT are repeated daily and dose is increased as needed to normalize INR or PT.
  • Dosage may reach more than 200 mg/day.
  • Daily dosing will be needed due to extremely long half-life.
• Severe prolongation of PT/INR and frank bleeding
  • The initial dose of vitamin K1 for adults is 25 to 50 mg in D5W or 0.9% saline and infused intravenously at a rate not to exceed 1 mg/min. Pediatric dose is not established; initial dose of 0.6 mg/kg or 5 to 10 mg titrated to effect is reasonable starting dose.
  • Dose is repeated two to four times daily until PT or INR normalize.
  • Anaphylactoid reactions occur occasionally.
  • Parenteral vitamin K1 doses as high as 400 mg have been used.
  • Daily dosing will be needed due to extremely long half-life.
• Patients with prosthetic heart valves should not receive a high dose of vitamin K1 intravenously unless life-threatening bleeding is present.

Not Recommended Therapies

• No other form of vitamin K should be used (e.g., K2, menaquione, K3, menadione, K4, or menadiol).
• Phenobarbital may shorten the half-life of long-acting anticoagulants, but an improved outcome has not been demonstrated.

ADJUNCTIVE TREATMENT

• Patients with coagulopathy and active bleeding
  • Fresh frozen plasma is administered; pediatric dose is 10 to 25 ml/kg; adult dose is 2 to 4 units intravenously.
  • Based on serial INR and PT determinations, fresh frozen plasma is further administered as needed to return values toward normal.
• Bleeding and anemia. Packed red blood cells are administered as indicated.
• Both multiple-dose activated charcoal and cholestyramine have theoretical value because brodifacoum undergoes enterohepatic recirculation; however, they have not been demonstrated to alter outcome and are not routinely recommended.

Section Outline:

• DIRECTING PATIENT COURSE
  • Admission Considerations
• DECONTAMINATION
  • Out of Hospital
  • In Hospital
• ANTIDOTES
  • Indications
  • Method of Administration
  • Not Recommended Therapies
• ADJUNCTIVE TREATMENT

PATIENT MONITORING

• Children with accidental ingestion should have PT and INR levels tested at 24 to 48 hours.
• In patients treated with vitamin K1, serial PT/INR will be needed until vitamin K therapy is no longer needed.

EXPECTED COURSE AND PROGNOSIS

• PT or INR becomes prolonged within 24 to 48 hours; peaks around 72 hours, and may persist for weeks or months in serious poisonings.
• Most patients will have no significant complications. Neurologic injury from intracranial bleeding or hypotension may occur in severe cases.

DISCHARGE CRITERIA/INSTRUCTIONS

• From the emergency department
  • Asymptomatic children may be discharged after decontamination with follow-up PT or INR at 48 hours.
  • Adults may be discharged if INR or PT is normal, after adequate decontamination and psychiatric evaluation, provided repeat PT or INR can be obtained 24 hours and 48 hours after ingestion.
• From the hospital
  • Patient may be discharged when hemodynamically stable without active bleeding and normalizing INR/PT.
  • Effective oral vitamin K1 dose must be established and regular follow-up ensured.
• A psychiatric evaluation should be obtained as indicated.

Section Outline:

• PATIENT MONITORING
• EXPECTED COURSE AND PROGNOSIS
• DISCHARGE CRITERIA/INSTRUCTIONS

Diagnosis can be elusive in adults with surreptitious ingestion.

TREATMENT

• Large oral or intravenous doses (greater than 200 mg) of vitamin K1 may be required for initial reversal of coagulopathy after intentional ingestion.
• Premature administration of vitamin K when coagulation is still normal is not recommended because it may instill a false sense of security by delaying the development of coagulopathy.

Poisoning by agents primarily affecting blood constituents: anticoagulants.

See Also: SECTION III, Vitamin K chapter; and SECTION IV,Coumadin chapter.

RECOMMENDED READING

Smolinske SC, Scherger DS, Kearns PS, et al. Superwarfarin poisoning in children: a prospective study. Pediatrics 1989;84:490-494.

Author: Luke Yip

Reviewer: Katherine M. Hurlbut