Dicumarol and other natural anticoagulants are found in sweet clover. Coumarin derivatives are used both therapeutically and as rodenticides. Warfarin (Coumadin) is used widely as a therapeutic anticoagulant but is no longer popular as a rodenticide because rats and mice have become resistant. 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.

1. 
   

   Mechanism of toxicity. 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, a necessary cofactor in the hepatic synthesis of coagulation factors II, VII, IX, and X. Only the synthesis of new factors is affected, and the anticoagulant effect is delayed until currently circulating factors have been degraded. Peak effects usually are not observed for 2–3 days because of the long half-lives of factors IX and X (24–60 hours).

   
   
   
   
   1. 
      

      The duration of anticoagulant effect after a single dose of warfarin is usually 2–7 days. (See also Table II–61.)

      
      
   2. 
      

      Superwarfarin products may continue to produce significant anticoagulation for weeks to months after a single ingestion.

   
   
   
   
2. 
   

   Toxic dose. 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 extremely potent and can have prolonged effects even after a single small ingestion. However, in a large study of accidental superwarfarin ingestions in children, no serious cases of anticoagulation occurred.

      
      
   3. 
      

      Multiple drug interactions are known to alter the anticoagulant effect of warfarin (see Table II–60 for examples of drug-drug interactions with warfarin).

      
      
      
      
      
      

      
      

      Table II-60 Warfarin Interactions (Selected Examples) 
      

      
      

      Table II-60 Warfarin Interactions (Selected Examples)
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      

      Increased Anticoagulant Effect	Decreased Anticoagulant Effect
      Acetaminophen	Azathioprine
      Allopurinol	Barbiturates
      Amiodarone	Carbamazepine
      Anabolic/androgenic steroids	Cholestyramine
      Anticoagulant/antiplatelet drugs	Glutethimide
      Chloral hydrate	Nafcillin
      Cimetidine	Oral contraceptives
      Disulfiram	Phenytoin
      Ginkgo biloba	Rifampin
      Nonsteroidal anti-inflammatory agents
      Quinidine
      Salicylates
      Selective serotonin reuptake inhibitors
      Sulfonamides

      
      
      
      
      
      

   
   
   
   
3. 
   

   Clinical presentation. 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.

   
   
   
   
   1. 
      

      Anticoagulant effects from warfarin may be apparent within 15 hours, but with superwarfarins, peak effects commonly are delayed for up to 2 days after ingestion.

      
      
   2. 
      

      Evidence of continuing anticoagulant effects from warfarin may persist for 5 days, whereas anticoagulation from superwarfarins may persist for several weeks, or even months.

   
   
   
   
4. 
   

   Diagnosis 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 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. 
         

         An anticoagulant effect is best quantified by baseline and daily repeated measurement of the prothrombin time (PT/INR), which may not be elevated until 1–2 days after ingestion. A normal PT/INR 48 hours after exposure 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 cross-match. The partial thromboplastin time, thrombin time, fibrinogen, and platelet count may be useful in ruling out other causes of bleeding.

   
   
   
   
5. 
   

   Treatment

   
   
   
   
   1. 
      

      Emergency and supportive measures. If significant bleeding occurs, be prepared to treat shock with transfusions of whole blood and 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. 
         

         Avoid drugs that may enhance bleeding or decrease metabolism of the anticoagulant (see Table II–60 for examples, and for a more complete list of drug interactions, consult a drug information reference).

      
      
      
      
   2. 
      

      Specific drugs and antidotes. Vitamin K1 (phytonadione [See 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.

      
      
      
      
      1. 
         

         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 with fresh frozen plasma or fresh whole blood. (FFP is preferred because it contains higher concentrations of clotting factors.)

         
         
         
         
         1. 
            

            Factor IX complex (factors II, VII, IX, and X) may be used as an alternative or adjunct therapy along with vitamin K1 and FFP. Suggested dosing (BebulinVH) is 25–35 units/kg for minor, 40–55 units/kg for moderate, and 60–70 units/kg for major symptoms of bleeding.

            
            
         2. 
            

            Recombinant activated factor VIIa (Novoseven) may also be used as an alternative or adjunct to FFP and vitamin K1. The optimal dose is unknown, but doses of 35–120 mcg/kg have been used successfully to reverse warfarin and superwarfarin anticoagulation.

         
         
         
         
      2. 
         

         Administer oral vitamin K1 (See Vitamin K1 (Phytonadione)). 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 used only when the oral route is not feasible. 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.

         
         
      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 following superwarfarin poisonings.

      
      
      
      
   3. 
      

      Decontamination (See Decontamination). Administer activated charcoal orally if conditions are appropriate (see Table I–38). 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.