Anticoagulant Rodenticide Toxicosis in the Dog and Cat

Todd W. Harrell, DVM; Kenneth S. Latimer, DVM, PhD; Perry J. Bain, DVM, PhD; Paula M. Krimer, DVM, DVSc

Class of 2003 (Harrell) and Department of Pathology (Latimer, Bain, Krimer), College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7388

Introduction

Anticoagulant rodenticides are probably the most commonly used rodenticides in the United States today (Table 1). It has been estimated that approximately 95% of all rodenticides used are anticoagulant baits.⁴ Not only are these baits easy to use and readily accessible over the counter, they are extremely effective in killing rodents and other pests. However, they also are lethal to non-target species, including domestic dogs and cats. The most common route of rodenticide toxicosis is by direct ingestion of the baits. Capture and ingestion of poisoned rodents also can lead to toxicosis, especially with newer second-generation anticoagulant rodenticides.^1,4 Physicians commonly prescribe oral anticoagulants to human patients with various thrombotic disorders,³ but there have been no case reports of coagulopathy in companion animals due to the ingestion of these oral medications.

Anticoagulant rodenticides exert their effect by inducing a secondary vitamin K-dependent coagulopathy leading to uncontrollable hemorrhage and death. Reports of natural anticoagulant rodenticide toxicosis are relatively common in dogs but have not been published concerning cats. One possible reason that more dogs than cats are poisoned by rodenticides is that lethal doses of many common anticoagulant rodenticides is much lower in the dog versus the cat.¹

Veterinarians should consider anticoagulant rodenticide toxicosis in the differential diagnosis whenever any bleeding disorder is encountered, especially in dogs. Newer second-generation rodenticide compounds may be more lethal and have prologed effects on hemostasis after ingestion. Anticoagulant rodenticide toxicosis is a potentially fatal condition, but it may be treated successfully if the diagnosis is made quickly and appropriate therapy is instituted.

Pathophysiology of Anticoagulant Rodenticide Toxicity

Anticoagulant rodenticides exert their effect by interfering with the recycling of vitamin K₁. Vitamin K is an essential cofactor in the post-ribosomal carboxylation of clotting factors II, VII, IX, and X by a vitamin K-dependent carboxylase that is synthesized in the liver (Fig. 1).^1-4

Figure 1. Vitamin K is responsible for the carboxylation or activation of clotting factors II, VII, IX, and X in the liver. Vitamin K reductase enzymes keep the vitamin in an active (reduced) state.

Factors II, VII, IX, and X are proteins that serve as enzymatic factors (serine proteases) in the intrinsic, extrinsic, and common pathways of coagulation (Fig. 2).

Figure 2. Schematic diagram of the intrinsic, extrinsic, and common pathways of coagulation. The vitamin K-dependent clotting factors (II, VII, IX, and X) are shown in red. Factor IX is in the intrinsic pathway, factor VII is in the extrinsic pathway, and factors X and II are in the common pathway. These four clotting factors are not activated if the function of vitamin K1 is inhibited.

Each of these coagulation proteins is synthesized by the liver. Carboxylation of these clotting factors is necessary to bind phospholipid membrane surfaces in a Ca²⁺-dependent manner. The vitamin K-dependent carboxylase concomitantly converts the active vitamin K to an inactive epoxide, which is then recycled back to vitamin K by another enzyme, called vitamin K epoxide reductase. The vitamin K epoxide reductase is the enzyme that is inhibited by anticoagulant rodenticides (Fig. 3), blocking the turnover of vitamin K and rapidly depleting the liver of its active vitamin K stores. With the depletion of liver vitamin K stores, coagulopathy occurs because factors II, VII, IX, and X are not carboxylated and remain nonfunctional. Because anticoagulant rodenticides do not block activated (functional or carboxylated) circulating clotting factors, there is a lag of approximately 12-24 hours between ingestion of the offending compound and the onset of clinical signs of bleeding.⁵

Figure 3. Anticoagulant rodenticides inhibit the activity of vitamin K epoxide reductase (red arrow). If vitamin K1 is not maintained in a reduced state by vitamin K epoxide reductase, then clotting factors II, VII, IX, and X will not be activated via carboxylation. Clinical signs, including internal bleeding and respiratory distress, will occur if these four clotting factors are nonfunctional.

Currently, there are two families of anticoagulant rodenticides: the hydroxycoumarins and the indandiones.¹ The hydroxycoumarins are further subdivided into first-generation and second-generation rodenticide compounds. The indandiones usually are grouped with the second-generation compounds because their properties are very similar to second-generation hydroxycoumarins. The most common first-generation anticoagulant rodenticides encountered in the United States are warfarin and coumafuryl. These compounds rarely are encountered today; they gradually are being phased out because of the emergence of rodents that are resistant to these first-generation compounds.^1,4

The newer second-generation compounds were developed to kill rodent populations that had become resistant to the first-generation rodenticides. Today, these second-generation compounds are largely implicated in rodenticide toxicosis. The most common second-generation compounds that will be encountered in veterinary practice are brodifacoum and bromadiolone (hydroxycoumarins), as well as diphacinone and chlorophacinone (indandiones).⁶

Although first- and second-generation rodenticides share the same mechanism of secondary vitamin K-dependent coagulapathy, they differ significantly in their duration of action and response to therapy. The first generation compounds are considered "short-acting" compounds and often require multiple doses to exert their toxic effects.^1,4,7 Warfarin, for example has a half life of 14.5 hours in the dog. Its clinical effects last only 1 week, even at a high concentration.⁴ Second-generation compounds, on the other hand, have a much longer half-life (4-6 days) and their clinical effects can last anywhere from 12 to 30 days, depending on the amount of rodenticide ingested.^4,7 They also differ from first-generation compounds in that only a single dose is needed to cause clinical signs of hemorrhage.^1,4 Inandiones, in addition to their effects on vitamin K recycling, also interfere with pancreatic exocrine function, potentially altering the uptake of oral, lipid-soluble vitamin K.⁷ However, the significance of altered pancreatic exocrine function has not been determined. Secondary anticoagulant rodenticide toxicosis also can occur if poisoned rodents are captured and consumed. In such cases, a second-generation compound is most likely involved.⁴ Certain drugs such as fluconazole, cimetidine, phenylbutazone, and sulfonamides may prolong or exacerbate the effects of anticoagulant rodenticides, as can anti-platelet drugs such as aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs).^1,3,12

It is extremely important that veterinarians familiarize themselves with the common anticoagulant rodenticides, particularly the long-acting, second-generation compounds. Treating a case of second-generation rodenticide toxicosis with a treatment regimen indicated for first- generation rodenticide toxicosis often will be ineffective and may lead to fatal hemorrhage that may have been avoided.

Clinical Signs and Diagnosis of Anticoagulant Rodenticide Toxicosis

Animals poisoned with anticoagulant rodenticides often may be initially asymptomatic. Because anticoagulant rodenticides do not have a direct effect on activated vitamin K or active clotting factors II, VII, IX, and X circulating in the blood, there is often a delay of about 12-24 hours post ingestion before clinical signs develop.⁴ Initial clinical signs are rather nonspecific and include lethargy, weakness, and pallor.⁴ Signs of external hemorrhage such as melena, petechial to ecchymotic hemorrhage of mucosal surfaces, hyphema, hematamesis, epistaxis, and hematuria may or may not be apparent. With second-generation anticoagulant rodenticide toxicosis, internal hemorrhage is common and may include hemothorax, hemoperitoneum, hemomediastinum, hemorrhage into fascial planes, and ventral hematomas.^4,9 Hemorrhage into the cranial vault also may occur, but is uncommon.^4,12

Lethargy and respiratory distress of rapid onset are the two most common clinical signs reported in second-generation rodenticide toxicosis.^5,6,9,10 Thoracic radiographs of these animals often reveal pleural effusion and pulmonary edema.^4,5 Pericardial effusion with cardiac tamponade also may occur.⁹ Formation of large hematomas, persistent bleeding at venipuncture sites, and / or persistent bleeding during surgery strongly suggest anticoagulant rodenticide toxicosis.^4,5

Because these clinical signs are not pathognomonic for anticoagulant rodenticide poisoning, a thorough medical history and appropriate laboratory testing are necessary to exclude other hemostatic abnormalities such as disseminated intravascular coagulation (DIC), autoimmune thrombocytopenia, and hereditary coagulopathy. While specific toxicologic (rodenticide analysis) and diagnostic laboratory tests (PIVKA, proteins induced by vitamin K absence) are available to diagnose anticoagulant rodenticide toxicosis, they are costly and, more importantly, too time-consuming to be of any benefit to the veterinarian, owner, or patient when faced with acute respiratory distress or hemorrhage.^4,6,11 Thus, the veterinarian must rely on the clinical signs, medical history, physical examination, and response to vitamin K₁ therapy to make a presumptive diagnosis of rodenticide toxicosis.

Laboratory findings in animals poisoned with anticoagulant rodenticides are rather nonspecific, but can provide critical information to guide treatment. The complete blood count will often reveal a normocytic, normochromic anemia that is either regenerative or nonregenerative, depending on the acuteness and severity of blood loss.^4,5 Leukocytosis is commonly present,⁴ but thrombocytopenia may or may not be present.^4,5 The routine biochemical profile shows no consistent pattern related to anticoagulant rodenticide toxicosis, although a hypoproteinemia commonly is observed 24 to 48 hours after acute blood loss.

Coagulation screening tests (one-stage prothrombin time [OSPT or PT], activated partial thromboplastin time [APTT or PTT], thrombin time [TT], and activated clotting time [ACT]) are necessary for the presumptive diagnosis of anticoagulant rodenticide toxicosis.^4,5,7,8,12 The OSPT is the first test to be prolonged in anticoagulant rodenticide toxicosis.^5,7,8 The OSPT detects deficiencies in both the extrinsic and common coagulation pathways (see Fig. 2). It is the most sensitive of the assays because factor VII, a component of the extrinsic pathway, has the shortest half-life of all the vitamin K-dependent clotting factors.^4,7 The ACT and APTT assays both detect deficiencies in the intrinsic as well as the common coagulation pathways (see Fig. 2). The ACT is the least sensitive assay, as prolonged clotting times may not be evident until 3 days after rodenticide ingestion.⁸ The ACT is not prolonged until the activities of factors IX, X, and/or II are <5% of normal. The thrombin time is normal (within the reference interval) in anticoagulant rodenticide toxicosis. To diagnose anticoagulant rodenticide poisoning, the OSPT should be checked every 6 to 8 hours after the first 1-2 days of vitamin K₁ therapy.⁴ If anticoagulant rodenticide poisoning is involved, the OSPT should begin to normalize.

Treatment and Follow-up

Note: Treatment of animals should only be performed by a licensed veterinarian. Veterinarians should consult the current literature and current pharmacological formularies before initiating any treatment protocol. These treatment guidelines are adapated from references 4 and 12, listed below.

The treatment of choice for anticoagulant rodenticide toxicosis is vitamin K₁,^4,12 which can be administered subcutaneously or orally. If given orally, vitamin K₁ should be given with canned food to enhance its absorption.¹² Vitamin K₁ should never be given intravenously because anaphylactic reactions have been reported.¹² Vitamin K₃ is not efficacious in the treatment of anticoagulant rodenticide toxicosis and, therefore, should not be used. ^4,12 In emergency situations (discussed later), Vitamin K₁ should be given subcutaneously after the patient is stabilized; however, its effects will be delayed for several hours. Therefore, whole blood or plasma must be transfused to immediately restore activated vitamin K-dependent clotting factors.^4,5

Some dogs or cats will be presented soon after consuming an anticoagulant rodenticide bait and initially will appear asymptomatic. In these cases, vomiting should be induced immediately, followed by administration of activated charcoal.⁴ The animal should be placed on oral vitamin K₁ at a dose of 2.5-5.0 mg / kg every 24 hours for at least 5-7 days. The OSPT should be checked 2-3 days after the cessation of therapy.⁴

However, most cases of anticoagulant rodenticide poisoning encountered in clinical veterinary practice will be due to second-generation compounds and will be presented with acute, severe signs of putative toxicosis. In these situations, a patent airway should be established and oxygen should be administered. Thoracic auscultation should be performed to detect the presence of pleural and / or pulmonary fluid, followed by chest radiographs if the patient is stable. Thoracocentesis may have to be performed, but should be considered on a case-by-case basis. While the benefit of thoracocentesis is improved ventilation, the risk is reinitiating hemmorhage.⁷ If life-threatening cardiac tamponade is present secondary to pericardial effusion, then pericardiocentesis is indicated, but only after clotting function is restored.^5,10

Depending upon the severity of bleeding, fresh whole blood or plasma may transfusions may be necessary to restore blood volume and replace essential vitamin-K dependent clotting factors.^4,5 Isotonic fluids should be administered to help restore blood volume. Once the patient is stabilized, vitamin K₁ should be administered subcutaneously at multiple sites with a loading dose of 5 mg / kg.⁴ Only small gauge needles should be used to collect blood samples or to give injections. All unnecessary surgical procedures also should be avoided. Oral vitamin K₁ therapy should begin12 hours after the initial subcutaneous loading dose is given; however, parenteral vitamin K therapy should continue if the patient has anorexia, maldigestion, or malabsorption.⁴ After stabilization and initial treatment, the patient should be maintained on an oral regimen of vitamin K₁ (2.5-5.0 mg / kg every 24 hours) for 3-6 weeks. Physical activity should be minimized during the course of treatment.^4,12 If the patient survives the first 48 hours of an acute coagulopathy, the clinical prognosis improves.¹² Patient follow-up, including rechecking the OSPT, should occur 2-3 days after the last dose of vitamin K₁. If the OSPT is significantly prolonged (>15 seconds), vitamin K₁ therapy should be continued for two more weeks and then the OSPT should be rechecked. If the OSPT prolongation is mild, then a 1- week additional course of vitamin K₁ is sufficient.⁴

Summary

Anticoagulant rodenticide toxicosis can present with a variety of acute and chronic clinical signs. However, with the introduction of second-generation anticoagulants, the presenting clinical signs will often be acute and severe. The most common clinical signs include lethargy, respiratory distress, and persistent bleeding post-venipuncture; external bleeding may or may not be apparent. Because the clinical signs are nonspecific and rapid diagnostic tests often are not available, the veterinarian must obtain a thorough history from the owner, including the identification of the offending anticoagulant rodenticide, if known. The best coagulation screening test to assist in clinical diagnosis and monitor treatment of anticoagulant rodenticide toxicosis is the OSPT. The treatment of choice is vitamin K₁, although whole blood or plasma may have to be transfused in more severe cases of toxicosis. Oral vitamin K₁ therapy should continue for up to 6 weeks (second-generation compounds) after the patient is stabilized, and a follow-up OSPT is recommended 2-3 days after cessation of therapy.

References

1. Petterino C, Paolo B: Toxicology of various anticoagulant rodenticides in animals. Vet Human Toxicol 43:353-360, 2001.

2. Furie B, Bouchard A, Furie B: Vitamin K-dependent biosynthesis of ?-carboxyglutamic acid. Blood 93:1798-1808, 1999.

3. Hirsh J: Oral anticoagulant drugs. New Engl J Med 324:1865-1875, 1991.

4. Mount M: Diagnosis and therapy of anticoagulant rodenticide intoxicants. Vet Clin N Am Small Anim Pract 18:115-129, 1988.

5. Schulman A, Lusk R, Lippincott C, Ettinger S: Diphacinone-induced coagulopathy in the dog. J Am Vet Med Assoc 188:402-405, 1986.

6. DuVall M, Murphy M, Ray A, Reagor J: Case studies on second-generation anticoagulant rodenticide toxicities in nontarget species. J Vet Diagn Invest 1:66-68, 1989.

7. Mount M, Feldman B: Mechanism of diphacinone rodenticide toxicosis in the dog and its therapeutic implications. Am J Vet Res 44:2009-2017, 1983.

8. Woody B, Murphy M, Ray A, Green R: Coagulopathic effects and therapy of brodifacoum toxicosis in dogs. J Vet Int Med 6:23-28, 1992.

9. Peterson J, Streeter V: Laryngeal obstruction secondary to brodifacoum toxicosis in a dog. J Am Vet Med Assoc 208:352-353, 1996.

10. Petrus D, Henik R: Pericardial effusion and cardiac tamponade secondary to brodifacoum toxicosis in a dog. J Am Vet Med Assoc 215:647-648, 1999.

11. Mount M, Kass P: Diagnostic importance of vitamin K₁ and its epoxide measured in serum of dogs exposed to an anticoagulant rodenticide. Am J Vet Res 50:1704-1709, 1989.

12. Murphy MJ: Rodenticide anticoagulant poisoning. In: Tilley L, Smith F (eds.): The 5-minute Veterinary Consult. Lippincott Williams and Wilkins, Baltimore, 2000, pp. 1176-1177.

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