Anticoagulant Rodenticides (Warfarin and Congeners)
Anticoagulant rodenticides inhibit the enzyme vitamin K epoxide reductase, which normally reactivates vitamin K, a crucial component in a number of normal clotting factors, after those factors are consumed in normal maintenance. Potentially dangerous to all mammals and birds, anticoagulant rodenticides are a common cause of poisoning in pets and wildlife. Intoxications in domestic animals have resulted from contamination of feed with anticoagulant concentrate, malicious use of these chemicals, and feed mixed in equipment used to prepare rodent bait.
All anticoagulants have the basic coumarin or indanedione nucleus. The “first-generation” anticoagulants (warfarin, pindone, coumafuryl, coumachlor, isovaleryl indanedione, and others less frequently used) require multiple feedings to result in toxicity. The “intermediate” anticoagulants (chlorophacinone and in particular diphacinone) require fewer feedings than “first-generation” chemicals, and thus are more toxic to nontarget species. The “second-generation” anticoagulants (brodifacoum, bromadiolone, difethiolone) are highly toxic to nontarget species (dogs, cats, livestock, or wildlife) after a single feeding. Secondary poisoning in nontarget animal species from anticoagulants has also been documented. The concentration of brodifacoum and bromadiolone in the bait available as pellets or blocks is usually 0.005% and that of difethiolone 0.0025%.
Anticoagulants antagonize vitamin K, which interferes with the normal synthesis of coagulation proteins (factors I, II, VII, IX, and X) in the liver; thus, adequate amounts are not available to convert prothrombin into thrombin. A latent period, dependent on species, dose, and activity, is required, during which clotting factors already present are used up. New products have a longer biologic half-life and therefore prolonged effects (which require prolonged treatment). For example, the half-life in canine plasma of warfarin is 15 hr, diphacinone is 5 days, and bromadiolone is 6 days, with maximum effects estimated at 12–15 days. Brodifacoum may continue to be detectable in serum for up to 24 days. All of these may be detected in liver even after serum levels drop.
Clinical signs generally reflect some manifestation of hemorrhage, including anemia, hematomas, melena, hemothorax, hyphema, epistaxis, hemoptysis, and hematuria, any of which may lead to weakness, ataxia, colic, polypnea, etc. Petechiae rarely develop until after repeated small bleeds have consumed too many platelets. Depression and anorexia may be seen in all species even before bleeding occurs. Typically, the onset of clinical signs is delayed (due to consumption of vitamin K–dependent clotting factors) for 3-7 days after exposure (can be a little earlier with a fairly large dose). Dogs can also show nonspecific clinical signs, such as limping or swollen joints (due to hemorrhage in the joints), coughing or wheezing (bleeding in the lungs), bulging of eyes (retrobulbar hemorrhages), and pale mucous membrane color. Sudden death with no obvious clinical signs is also possible.
Anticoagulant rodenticide toxicosis may be diagnosed based on history of availability of the bait in the animal’s environment and evidence of exposure (missing or chewed up package/bait, passing of greenish blue feces [color of the bait]) but cannot be discounted if there is no known history of exposure. Differential diagnoses when hemorrhage is encountered include disseminated intravascular coagulation, congenital factor deficiencies, von Willebrand disease, platelet deficiencies, and canine ehrlichiosis. A prolonged prothrombin time (PT), activated partial thromboplastin time (APTT), or thrombin time in the presence of normal fibrinogen, fibrin degradation products, and platelet counts is strongly suggestive of anticoagulant rodenticide toxicosis, as is a positive therapeutic response to vitamin K1. Stomach contents, serum, or plasma can be analyzed for the presence of anticoagulant to confirm a diagnosis. Most veterinary diagnostic laboratories have an “anticoagulant screen” to detect most of the anticoagulants available in the market in the serum, plasma, liver, or kidney.
Vitamin K1 is antidotal. Because the vast majority of exposures are to the second-generation agents, recommended dosages are generally 3–5 mg/kg/day, PO, for 3–4 wk. Treating for an extra week will not be harmful, whereas discontinuing treatment too soon can be lethal. The best way to know when to stop vitamin K1 treatment is by checking the PT time 72 hr after the last dose of vitamin K1 has been given. If PT at that point is normal, treatment with vitamin K1 can be stopped; if it is still prolonged, treatment with vitamin K1 for 1 more week is warranted. The doses should be administered with small amounts of fatty food (milk, meat, or cheese), because fat will enhance vitamin K1 absorption. Administering half of the daily dose every 12 hr will provide more constant levels of vitamin K1. In animals exhibiting clinical signs when coagulation factors are abnormal, it is probably safer to avoid injections (unless the animal is unable to take vitamin K1 orally) because of the risk of bleeding and hematoma formation at the injection site. Also, the possibility of anaphylactoid reaction cannot be excluded when vitamin K1 injection is administered parentally.
Fresh or frozen plasma (9 mL/kg) or whole blood (20 mL/kg) IV may be indicated to replace needed clotting factors and RBCs immediately if bleeding is present. Administration of oxygen may be very useful. Activity should be limited as much as possible during the first week of therapy to minimize bleeds due to trauma to tissues. Oral vitamin K1 alone (3–5 mg/kg, PO) can be used to prevent coagulopathy after a known exposure to an anticoagulant.
If a coagulopathy has developed, rechecking the PT and APTT every 24 hr until normalized should be considered. At the end of a course of vitamin K1 supplementation, a coagulation profile is needed ~48–72 hr after the last dose to confirm that no indication of coagulopathy remains.
Vitamin K3 given as a feed supplement is ineffective in treatment of anticoagulant rodenticide toxicosis. Administration of vitamin K3 by injection in horses has been associated with acute renal failure and is never an appropriate treatment.
To increase protection to nontarget animal species and children, the US EPA has promulgated new rules on packaging and availability of anticoagulants. Some of the highlights of these new rules include the following: 1) Consumer products available in retail, hardware, grocery, or convenient stores with under a pound of bait can no longer contain second-generation anticoagulants (brodifacoum, difethialone, bromadiolone, or difenacoum). 2) Only first-generation anticoagulants (warfarin, diphacinone, chlorophacinone) or rodenticides other than anticoagulants (bromethalin, cholecalciferol) are allowed for sale in retail stores for use by consumers. 3) All outdoor, above-ground use must be in a bait station intended to be resistant to children and pets. 4) Loose poison baits (pellets, meals) are prohibited. 5) All outdoor products are to be placed within 50 feet of a building. 6) Professional use products are available in quantities of at least 8 or 16 pounds (second-generation anticoagulants) or at least 4 pounds (first-generation anticoagulants); they are to be placed in bait stations. 7) Professional class anticoagulants (second-generation) are not to be marketed in “consumer” stores (grocery, hardware, or club stores).
The possible unintended end result of these new EPA regulations is likely to be a higher incidence of exposure to rodent baits that contain either bromethalin or cholecalciferol (vitamin D3).