Dicumarol and other natural anticoagulants are found in sweet clover. Coumarin derivatives are used both therapeutically and as rodenticides. Warfarin is used widely as a therapeutic anticoagulant but is no longer popular as a rodenticide because of rodent resistance. The most common anticoagulant rodenticides available today contain long-acting “superwarfarins” such as brodifacoum, diphacinone, bromadiolone, chlorophacinone, difenacoum, pindone, and valone, which have profound and prolonged anticoagulant effects. Other non-anticoagulant rodenticides are described elsewhere (see rodenticides, miscellaneous).

1. All these compounds inhibit vitamin K 2,3-epoxide reductase and vitamin K quinone reductase, two enzymes responsible for the conversion of vitamin K to its active form, vitamin K quinol, the necessary cofactor in the hepatic synthesis of coagulation factors II, VII, IX, and X (as well as anticoagulant proteins C and S). Only the synthesis of new factors is affected, and the anticoagulant effect is delayed until currently circulating factors have been degraded.
2. Overdose during pregnancy has caused fetal hemorrhage, spontaneous miscarriage, and still birth. Major congenital malformations, fetal warfarin syndrome, and spontaneous miscarriage may occur with chronic use during pregnancy.
3. Pharmacokinetics
   1. Warfarin. The mean half-life of oral warfarin is approximately 35 hours. The onset of the anticoagulant effect may be apparent within 15-20 hours. Peak effects usually are not observed for 2-3 days because of the long half-lives of factors IX and X (24-60 hours).The duration of anticoagulant effect after a single dose of warfarin is normally about 5 days.
   2. Superwarfarins. The onset of anticoagulation after a superwarfarin ingestion may not be evident for up to 2 days after ingestion and may continue to produce significant anticoagulation for weeks to months after a single ingestion.

The toxic dose is highly variable.

1. Generally, a single small ingestion of warfarin (eg, 10-20 mg) will not cause serious intoxication (most warfarin-based rodenticides contain 0.05% warfarin). In contrast, chronic or repeated ingestion of even small amounts (eg, 2 mg/d) can produce significant anticoagulation. Patients with hepatic dysfunction, malnutrition, or a bleeding diathesis are at greater risk.
2. Superwarfarins are more potent and have significantly longer half-lives compared to warfarin. The minimum toxic dose is unclear. Single, intentional adult poisonings have resulted in life-threatening and prolonged anticoagulation. In contrast, single, accidental pediatric ingestions are unlikely to result in clinical anticoagulation, although minor elevation in coagulation studies and rare cases of anticoagulation have been reported. In contrast, repeated small superwarfarin ingestions have resulted in prolonged anticoagulation in both children and adults.
3. Multiple drug interactions are known to alter the anticoagulant effect of warfarin (see Table II-62 for selected examples of drug-drug interactions with warfarin).

Excessive anticoagulation may cause ecchymoses, subconjunctival hemorrhage, bleeding gums, or evidence of internal hemorrhage (eg, hematemesis, melena, hematochezia, menorrhagia, or hematuria). The most immediately life-threatening complications are massive GI bleeding and intracranial hemorrhage. With superwarfarin ingestions prolonged INR and risk of bleeding may persist for several weeks to months.

Is based on the history and evidence of anticoagulant effects. It is important to identify the exact product ingested to ascertain whether a superwarfarin is involved.

1. Specific levels. Brodifacoum levels are available through some commercial laboratories and may be useful in making the diagnosis and determining the end point for vitamin K therapy. Levels of less than 4-10 ng/mL are not expected to interfere with coagulation.
   1. Anticoagulant effect is best quantified by baseline and daily repeated measurement of the prothrombin time (PT/INR), which may not be elevated for 1 day (warfarin) or 2 days (superwarfarins) after ingestion. A normal PT/INR at 24 hours (warfarin) or 48 hours (superwarfarin) rules out significant ingestion.
   2. Blood levels of clotting factors II, VII, IX, and X will be decreased.
2. Other useful laboratory studies include CBC and blood type and crossmatch. The partial thromboplastin time, thrombin time, fibrinogen, and platelet count may be useful in ruling out other causes of bleeding.

The approach to treatment depends on several variables including the measured PT/INR, presence and severity of bleeding, any underlying medical condition requiring anticoagulation, the type of anticoagulant involved (warfarin or superwarfarin), and fluid status of the patient.

1. Emergency and supportive measures. If significant bleeding occurs, be prepared to treat shock with blood transfusions, a prothrombin complex concentrate (PCC), and/or fresh-frozen plasma (FFP) and obtain immediate neurosurgical consultation if intracranial bleeding is suspected.
   1. Take care not to precipitate hemorrhage in severely anticoagulated patients; prevent falls and other trauma. If possible, avoid the use of nasogastric or endotracheal tubes or central IV lines.
   2. Hold further anticoagulant doses.
   3. Avoid drugs that may enhance bleeding or decrease metabolism of the anticoagulant (see Table II-62 for selected examples. For a more complete list of drug interactions, consult a drug information reference).
2. Specific drugs and antidotes.
   1. Prothrombin complex concentrates. Four-factor prothrombin complex concentrate (4F-PCC, containing II, VII, IX, X, see clotting) is the preferred agent in conjunction with Vitamin K₁ for cases of life-threatening bleeding). Three-factor prothrombin complex concentrate (3F-PCC, containing II, IX, X) may be used in conjunction with recombinant factor VIIa (rFVIIa) and vitamin K₁ if 4F-PCC is not available.
   2. Fresh-frozen plasma (FFP) is preferred over whole blood because it contains higher concentrations of clotting factors. FFP and whole blood should be used cautiously in patients with volume overload.
   3. Vitamin K₁ (phytonadione) but not vitamin K₃ (menadione) effectively restores the production of clotting factors. It should be given if there is evidence of significant anticoagulation. Note: If vitamin K₁ is given prophylactically after an acute ingestion, the 48-hour PT/INR cannot be used to determine the severity of the overdose, and it is suggested that the patient be monitored for a minimum of 5 days after the last vitamin K₁ dose. Caution: Vitamin K-mediated reversal of anticoagulation may be dangerous for patients who require constant anticoagulation (eg, those with prosthetic heart valves). However, when vitamin K is indicated in these patients, heparin may be used for maintenance anticoagulation.
      1. Oral vitamin K₁. Doses of up to 800 mg daily have been required to maintain a satisfactory INR. Vitamin K can also be administered subcutaneously or IV, but the IV route is not recommended because of the risk for anaphylaxis, and the subcutaneous route is considered only when the oral route is not feasible.
      2. Because vitamin K will not begin to restore clotting factors for 6 or more hours (peak effect, 24 hours), patients with active hemorrhage may require immediate replacement of active clotting factors, such as 4F-PCC, fresh-frozen plasma, or fresh whole blood.
      3. Prolonged dosing of vitamin K may be required for several weeks to months in patients who have ingested a long-acting superwarfarin product. Blood levels of clotting factors (II, VII, IX, and X) may be useful in evaluating when vitamin K may be safely tapered.
3. Decontamination . Administer activated charcoal orally if conditions are appropriate (see Table I-37,). Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly and should be avoided in a person with prior anticoagulation.
4. Enhanced elimination. There is no role for enhanced elimination procedures.