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DESCRIPTION
Coumadin and warfarin are oral anticoagulant medications.
FORMS AND USES
- Coumadin and the short-acting coumarin-type anticoagulants are pharmaceutical preparations of warfarin.
- Coumadin is used in the prophylaxis and treatment of venous thrombosis, pulmonary embolism, and valvular thrombi; for prophylaxis of thrombus formation in atrial fibrillation; and as an adjunct in the treatment of coronary occlusion.
- Dose is titrated to maintain a prothrombin time (PT) of 1.5 to 2.5 times control, or international normalized ratio (INR) of 2.0 to 4.5, typically requiring 2.5 to 7.5 mg/day.
- Warfarin is still used occasionally as a rodenticide in lacing baits for mouse and rat control.
TOXIC DOSE
- Repeated ingestion over 2 to 3 days is needed to produce anticoagulation.
- A single ingestion does not produce anticoagulation unless a massive amount is ingested.
PATHOPHYSIOLOGY
- Warfarin induces vitamin K deficiency by inhibiting the regeneration of active vitamin K and thereby the activation of clotting factors II, VII, IX, and X.
- Anticoagulation is delayed until coagulation factors are depleted.
- Due to its relatively short half-life, a single ingestion of coumadin or warfarin cannot inhibit synthesis of clotting factors long enough to produce anticoagulation.
EPIDEMIOLOGY
- Poisoning is uncommon.
- Toxic effects following exposure are typically mild to moderate.
- Death occurs in chronic ingestion leading to hemorrhage.
CAUSES
- Toxic ingestion is usually accidental, by a child.
- Child neglect or abuse should be considered if the patient is less than 1 year of age, suicide attempt if the patient is over 6 years of age.
RISK FACTORS
Health-care workers have been reported to use coumadin to induce factitious coagulopathy.
DRUG AND DISEASE INTERACTIONS
- Drugs potentiate anticoagulant effect of coumadin and warfarin include: allopurinol, anabolic steroids, cephalosporin, chloral hydrate, cimetidine, clofibrate, cyclic antidepressants, erythromycin, ethanol, nonsteroidal antiinflammatory drugs, sulfonylureas, thyroxine, and many others.
- Coumadin and warfarin may produce bleeding at lower levels in patients with preexisting coagulation abnormality.
PREGNANCY AND LACTATION
- US FDA Pregnancy Category D. Positive evidence of human fetal risk exists, but benefits in certain situations (e.g., life-threatening situations or serious diseases) make use of the drug acceptable despite its risks.
- Warfarin is a known teratogen.
- Breastfeeding is acceptable during coumadin therapy.
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DIFFERENTIAL DIAGNOSIS
- Toxicologic causes of anticoagulation include ingestion of brodifacoum, parenteral heparin overdose, crotalid snake bite, thrombolytic administration, or any poison that produces hepatic failure.
- Nontoxicologic causes include hemophilia, sepsis, and other causes of disseminated intravascular coagulation, and vitamin K deficiency.
SIGNS AND SYMPTOMS
Unexpected bleeding or bruising is the hallmark of warfarin toxicity.
Vital Signs
Hypotension and tachycardia may occur as a result of hemorrhage.
HEENT
Epistaxis and gingival bleeding may occur.
Dermatologic
- Bruising and petechiae may develop.
- Purple toe syndrome (discoloration of feet and toes) occurs rarely during therapeutic use.
- Idiopathic skin necrosis is another complication of therapeutic use.
Pulmonary
- Upper airway bleeding may occur.
- Alveolar hemorrhage occurs rarely.
Gastrointestinal
Abdominal pain, hematemesis, and hematochezia may occur.
Renal
Hematuria may occur.
Musculoskeletal
Compartment syndrome, carpal tunnel syndrome, and hemarthrosis occur rarely.
Neurologic
- Intracranial hemorrhage is rare but catastrophic.
- Spontaneous epidural hemorrhage has been reported; symptoms include paresis, back pain, and urinary incontinence.
Reproductive
Menorrhagia may be a sign of anticoagulation.
PROCEDURES AND LABORATORY TESTS
Essential Tests
No tests are usually needed following a single accidental ingestion.
Recommended Tests
If the patient is symptomatic or chronic ingestion is suspected:
- INR or PT should be measured 12 to 24 hours postingestion to assess coagulation effect; if normal, no further evaluation is needed for warfarin ingestion.
- Partial thromboplastin time, fibrinogen, fibrin degradation products, complete blood count, platelets, stool test for blood, and blood type and crossmatch should be performed in patients with clinically significant prolongation of INR/PT or bleeding.
- Thrombocytopenia or depressed fibrinogen suggests coagulopathy from another etiology.
- Anemia or guaiac-positive stools suggest significant warfarin toxicity.
- Head CT followed by lumbar puncture should be performed in patients with altered mental status; coagulopathy may need to be reversed before lumbar puncture.
- Endoscopy may be useful if clinical evidence of gastrointestinal bleeding is present.
Not Recommended Tests
Serum levels of warfarin are not clinically helpful.
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- Treatment should focus on assessment and treatment of coagulopathy and control of bleeding.
- 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:
- Hemorrhage is present.
- Toxic effects are not consistent with warfarin.
- Coingestant, drug interaction, or underlying disease presents an unusual problem.
The patient should be referred to a health-care facility when:
- Repeated ingestion of warfarin or coumadin is possible.
- 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 if patient exhibits frank bleeding, severe coagulopathy, or marked anemia.
DECONTAMINATION
Out of Hospital
Decontamination is not needed for ingestion of a few tablets of coumadin or a handful of rodent bait.
In Hospital
- Decontamination is not needed for ingestion of a few tablets of coumadin or a handful of rodent bait.
- If the amount potentially ingested was large, gastric lavage should be considered in pediatric (tube size 24-32 French) or adult patients (tube size 36-42 French) presenting within 1 hour of ingestion; not recommended if bleeding is already present.
- 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
- Indication. Marked prolongation of PT or INR without bleeding.
- Method of administration. Vitamin K1 should be administered orally.
- Adult dose is 50 to 100 mg/day initially in single or divided doses.
- Pediatric dose is 0.6 mg/kg/day initially in single or divided doses.
- INR or PT should be repeated daily, and dose increased as needed to normalize INR or PT.
- Dosage may reach more than 200 mg/day in severe cases.
- Caution: Complete reversal may not be desired in patients with medical need for therapeutic anticoagulation.
- Indication. Severe prolongation of PT or INR and frank bleeding (the patient should first receive fresh frozen plasma as described below in ADJUNCTIVE THERAPY).
- Method of administration. Vitamin K1 should be administered intravenously.
- Vitamin K1 (25-50 mg) should be diluted with D5W or 0.9% saline and infused slowly at a rate not to exceed 1 mg/min. Dose is not well established in children; initial dose of 0.6 mg/kg or 5 to 10 mg, titrated to response, is a reasonable starting dose.
- Dose should be repeated two to four times daily; clinician should be prepared to treat anaphylactoid reactions.
- Parenteral vitamin K1 in doses as high as 400 mg per day have been used.
- Adverse effects and precautions
- Anaphylactoid reactions and even death have occurred during intravenous use of vitamin K1.
- In a patient who is anticoagulated for prosthetic valve, vitamin K1 should not be given unless anticoagulation is life-threatening.
- No other form of vitamin K should be used (e.g., K2, K3, menadione, K4, or menadiol).
ADJUNCTIVE TREATMENT
- Marked coagulopathy and active bleeding
- Fresh-frozen plasma should be administered intravenously; the pediatric dose is 15 to 25 ml/kg, and the adult dose is 2 to 4 units.
- On the basis of serial INR and PT determinations, further fresh-frozen plasma may be needed.
- Bleeding with anemia. Packed red blood cells should be administered as indicated.
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PATIENT MONITORING
Serial INR or PT monitoring is used to guide therapy of patients with coagulopathy.
EXPECTED COURSE AND PROGNOSIS
- Complications of hypotension from hemorrhage or intracranial bleeding occur rarely.
- If vitamin K therapy is instituted before bleeding complications cause injury, a complete recovery is expected.
DISCHARGE CRITERIA/INSTRUCTIONS
- From the emergency department. Asymptomatic patients with acute single ingestion that is not massive may be discharged after gastrointestinal decontamination and psychiatric evaluation, if needed.
- From the hospital.
- Patients may be discharged when hemodynamically stable without active bleeding and when INR or PT is normalizing.
- Effective oral vitamin K1 dose must be established and regular follow-up assured; psychiatric evaluation should be obtained as indicated.
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DIAGNOSIS
Measuring PT/INR too soon following ingestion may result in a false sense of security. At least 12 to 24 hours should elapse prior to measuring INR or PT.
TREATMENT
- Large doses of vitamin K may be required; undertreatment is common.
- Severe warfarin overdose in patients requiring therapeutic anticoagulation, e.g., patients with prosthetic heart valves, may require slow partial reversal of anticoagulation; PT should be monitored several times daily to assist in determining quantity and times of fresh-frozen plasma therapy.
Section Outline:
ICD-9-CM 964.2Poisoning by agents primarily affecting blood constituents: anticoagulants.
See Also: SECTION III, Vitamin K chapter.
RECOMMENDED READING
Hirsh J. Oral anticoagulant drugs. N Engl J Med 1991;324:1865-1875.
Author: Luke Yip
Reviewer: Katherine M. Hurlbut