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Warfarin

Clinical Effects:

WARFARIN AND RELATED AGENTS
  • USES: Therapeutic anticoagulation medication used for the treatment of deep venous thrombosis, pulmonary embolism, and other hypercoagulable states, and to prevent thromboembolic complications in patients with atrial fibrillation, prosthetic heart valves, or recent myocardial infarction. It may also be used to prevent thromboembolic complications in patients with stroke, impaired left ventricular function, or cancer. EPIDEMIOLOGY: Exposures are common. Inadvertent exposures rarely produce clinical effects. A single deliberate overdose generally does not result in coagulopathy, but a large ingestion by a patient who is chronically using warfarin may produce significant coagulopathy. Adverse events during therapeutic dosing are common. PHARMACOLOGY: Inhibits hepatic synthesis of Vitamin K dependent factors: II, VII, IX, and X, and also inhibits the activity of vitamin K 2,3-epoxide reductase. TOXICOLOGY: Excessive inhibition of factors II, VII, IX, and X can cause significant prolongation of INR and excessive bleeding after minor trauma. The risk of hemorrhage depends on patient comorbidities and severity of anticoagulation. ADVERSE EFFECTS: The primary adverse effect is bleeding, which can be more severe with comorbid conditions, such as advanced age and liver dysfunction. Warfarin can also cause skin necrosis. Warfarin is a human teratogen and increases the risk of fetal death. OVERDOSE: GENERAL: Excessive chronic doses, drug interactions, and less commonly acute overdose can cause profound anticoagulation. Effects can include bleeding at virtually any site: epistaxis, bleeding from gums, ecchymosis, hematochezia, hematuria, menorrhagia, hemarthrosis, and bleeding from minor skin or soft tissue trauma. SEVERE TOXICITY: More life-threatening complications include intracranial hemorrhage, retroperitoneal hemorrhage, or massive gastrointestinal bleed.

Range of Toxicity:

WARFARIN AND RELATED AGENTS
  • TOXICITY: A toxic dose is highly variable. ADULT: Small ingestions (10 to 20 mg) in adults will not cause serious intoxication. However, chronic or repeated supratherapeutic ingestions of small amounts, or drug interactions in patients on a stable warfarin dose, can cause significant anticoagulation. PEDIATRIC: Greater than 0.5 mg/kg may prolong PT/INR; usually without bleeding. A relationship between mg/kg ingested and amount of hypocoagulability has not yet been established. THERAPEUTIC DOSE: ADULT: INITIAL DOSE: 2 to 5 mg/day orally with dosage adjustments based on INR response. MAINTENANCE DOSE: Range 2 to 10 mg/day orally. PEDIATRIC: INFANTS and CHILDREN: Loading: 0.2 mg/kg/dose, daily for 2 days, followed by daily doses determined by the INR; Maximum: Up to 10 mg/dose.

Treatment:

WARFARIN AND RELATED AGENTS
  • Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: Monitor INR and hemoglobin, evaluate for clinical evidence of bleeding. Warfarin should be withheld until INR approaches therapeutic range. MANAGEMENT OF SEVERE TOXICITY: Supportive care, including intravenous crystalloids, oxygen, and mechanical ventilation may be required. With significant bleeding, hemorrhagic shock may result, and patients may require transfusions of packed red blood cells and fresh frozen plasma. Products such as cryoprecipitate, and other factor concentrates may be required for severe bleeding. Vitamin K1 (5 to 10 mg) every 6 hours should also be administered, higher doses for more significant ingestions. Surgical consultation may be required depending on the extent and location of hemorrhage.
  • Decontamination: PREHOSPITAL: Emesis should probably be avoided because of the risk of subsequent bleeding. Patients on chronic anticoagulation therapy should receive activated charcoal after an acute overdose unless contraindicated. HOSPITAL: Activated charcoal should be considered following a large, recent ingestion in a patient who does not have evidence of significant GI bleeding.
  • Antidote: PHYTONADIONE: Vitamin K1 (phytonadione): An oral formulation is preferred for patients who do not have severe hemorrhage. For acute ingestions, vitamin K1 is rarely indicated. Low dose vitamin K1 may be administered for patients with mildly elevated INRs who are clinically asymptomatic. For treatment of significantly elevated INR and/or bleeding, the following guidelines are recommended by the American College of Chest Physicians: INR LESS THAN 5.0, NO SIGNIFICANT BLEEDING: Lower warfarin dose or omit next dose of warfarin and monitor INR; INR BETWEEN 5.0 AND 9.0, NO SIGNIFICANT BLEEDING: Omit next 1 or 2 doses of warfarin OR omit next warfarin dose and administer oral Vitamin K1 (1 to 2.5 mg). If more rapid reversal is necessary, give oral Vitamin K1 (less than or equal to 5 mg) and repeat INR in 24 hours. Give additional vitamin K1 orally (1 to 2 mg) as needed. INR GREATER THAN 9.0, NO SIGNIFICANT BLEEDING: Hold warfarin therapy and give oral Vitamin K1 (2.5 to 5 mg). Repeat INR in 24 hours. Give additional Vitamin K1, if necessary. SERIOUS BLEEDING: Hold warfarin. Administer 10 mg Vitamin K1 by slow intravenous infusion along with fresh frozen plasma, prothrombin complex concentrates (PCC), or factor VII until bleeding is controlled. Follow INR. Vitamin K1 administration may need to be repeated every 12 hours.
  • Monitoring of patient: Asymptomatic children with an inadvertent ingestion do not require any testing. Monitor INR, vital signs, and perform a clinical exam for evidence of bleeding. If the INR is normal, no additional testing is required at the time of initial evaluation, but serial INR testing over several days may be needed as the INR may not increase for several days. Monitor serial hemoglobin and/or hematocrit in patients with prolonged INR or clinical evidence of bleeding.
  • Enhanced elimination procedure: There is no role for enhanced elimination.
  • Drug interaction: Many xenobiotics can interact with warfarin anticoagulation, both by potentiation and antagonism, either by affecting warfarin protein biding, or affecting metabolism by cytochrome P450 (CYP2C9 (primary isoenzyme), CYP2C19, CYP2C8, CYP2C18, CYP1A2, and CYP3A4).
  • Patient disposition: HOME CRITERIA: Children with inadvertent ingestions of 0.5 mg/kg or less of warfarin can be observed at home. While children with larger single ingestions may develop prolongation of INR/PT, clinically significant bleeding has not been reported in this setting; a PT or INR is probably NOT routinely necessary in these children unless bleeding develops. A medical evaluation may be necessary, if there is any suspicion of chronic ingestion, coingestants or in a child with a history of bleeding diathesis. OBSERVATION CRITERIA: Any patient with deliberate ingestions, a significant ingestion, or patients with comorbidities, should be referred to a health care facility for observation. Patients who are asymptomatic and who have a normal INR at baseline can be followed as an outpatient or on a psychiatric ward with twice daily INR. All symptomatic patients should be sent to a health care facility for observation. ADMISSION CRITERIA: Patients with bleeding should be admitted. Patients with significantly elevated INR, and significant comorbidities, may also require admission until the INR is improving. Patients with hypotension, or significant hemorrhage, should be admitted to an intensive care unit. CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity. A hematology consult should also be considered. If significant hemorrhage develops, surgical consultation may be warranted.
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