Anticoagulant Rodenticide Toxicity

Also known as: Warfarin Toxicity, Anticoagulant Rodenticide Toxicity/ Poisoning.

Description

One of the most common causes of an acquired coagulopathy in dogs is the accidental ingestion of an anticoagulant rodenticide. The first generatlion coumarin-derivative anticoagulant, warfarin. has a short half-life of about 12 hours and a relatively low toxicity in non-target species. Therefore, repeated or massive exposure would generally be required to produce clinical bleeding in a dog. The second generation coumarin derivatives (bromadiolone and brodifacoum) and indandione rodenticides (pindone and diaphacinone), developed in response to wartarin resistance in target species, are tar more potent than warfarin. They have much longer lasting etfects (half-lives of four to six days) as they are more completely bound to plasmla proteins and, compared to warfarin, have an enhanced tendency to accumulate in hepatic tissue. Secondary poisoning through ingestion ol killed target species is more likely to occur with these latter agents. The coumarin derivatives exert interaction of their anticoagulant eftect by inhibiting the enzyme, vitamin K epoxide reductase (see box on page 63). This enizymiie is a component of the vitamin K epoxide cycle required tf)r hepatic synthesis of the functional clotting factors F-II, F-VII, F-IX and F-X. Inhibition of the enzyme causes the accumulation of the inactive vitamin K epoxide and prevents the carboxylation of vitamin K-dependent coagulation proteins. The acarboxy precursor proteins are incapable of being activated during the coagulation process and thus cannot actively participate in fibrin formation.

Warfarin and similar compounds interfere with the regeneration of vitamin K from an intermediate formed during the action of vitamin K as an essential co-factor in the production of several of the factors involved in the clotting cascade. This is by competitive inhibition of the enzyme involved in the regenerative process and leads to a reduction in available vitamin K, thereby resulting in defective blood clotting. Vitamin K dependent clotting factors are VII, IX, 11 and X so the intrinsic pathway (activated by blood vessel injury), the extrinsic pathway (activated by tissue injury) and the final common pathway (with conversion of prothrombin to thrombin, formation of fibrin and stabilisation of the platelets) is affected. However, the primary haemostatic response (formation of platelet plug) is unaffected. Increased blood vessel fragility also appears to be a result of coumarin toxicity and may account for bleeding at sites that are not subject to external trauma. Following absorption, coumarins are carried bound to plasma albumin. Therefore, effects are potentiated by drugs that are also bound to albumin such as phenylbutazone, or conditions that result in low plasma albumin levels such as renal insufficiency.

Signalment

• Most commonly seen in the dog and pig, after eating bait for rodents.
  • Warfarin poisoning is therefore relatively common in farm dogs.

Diagnosis

Differentials (7)

• Other causes of blood loss and anaemia: Trauma and clotting defects such

as inherited conditions, autoimmune disorders, chronic liver disease and disseminated intravascular coagulation (DIC).

• Other causes of dyspnoea: Thoracic fluid, heart disease, lung disease and

respiratory obstruction.

• Other causes of acute collapse: Trauma, endotoxaemia and causes of shock

Clinical Signs

The diagnosis of anticoagulant rodenticide toxicosis is dependent on a thorough patient history and physical examination, and appropriate haemostatic testing. The likelihood of exposure to a specific rodenticide may be difficult to reliably determine. The onset of clinical signs is delayed for several days post-exposure while the plasma concentrations of the vitamin K-dependent clotting factors become depleted. Symptoms may be non-specific if there is internal bleeding, and might include depression, weakness, pallor, dyspnoea, abdominal swelling, or even sudden death. Other possible signs include anaemia, external haematomas, bruising, excessive bleeding from venepuncture sites or other sites of injury, epistaxis, haematemesis, haematochezia, melaena, haematuria and/or lameness.

Laboratory Tests

Coagulation screening tests are unlikely to reveal abnormalities until at least 36 to 72 hours post-exposure. The prothrombin time (PT) generally becomes prolonged first (by 36 to 48 hours), since F-VII, a component of the tissue factor-mediated coagulation pathway, has the shortest half-life (about six hours) and is therefore the first factor to become depleted. The partial thromboplastin time (PTT) and activated clotting time (ACT) are usually prolonged by 48 to 72 hours post-exposure. The thrombin clotting time (TCT), platelet count and buccal mucosal bleeding time (BMBT) (an assessment of platelet function) are usually normal (see table below). The so-called 'proteins induced by vitamin K antagonism' (PIVKA) are acarboxylated proteins formed as a result of anticoagulant rodenticide toxicity. While not normally detected in the circulation, these increase in the plasma of poisoned animals and can be detected using the PIVKA test which is available through some veterinary diagnostic laboratories. PIVKA are usually cleared within 12 hours of administration of vitamin K. Samples for coagulation testing should be collected before initiating vitamin K therapy. Other possible confirmatory tests include quantitation of vitamin K epoxide concentrations and determination of the specific anticoagulant in the blood, liver and/or stomach contents.

Pathology

• Gastric haemorrhage
• Haemorrhage elsewhere in body, particularly mediastinum

Treatment

Treatment of anticoagulant rodenticide poisoning must be supportive in nature and is directed at correcting the hypovolaemia and coagulopathy. Fresh blood or plasma will help to correct the hypovolaemia and enhance haemostasis by restoring depleted clotting factors. Vitamin K1 (5 mg/kg) should be given as a loading dose subcutaneously at multiple sites, followed by subcutaneous or oral doses (1.25 to 2.5 mg/kg) at eight to 12 hour intervals for as long as necessary (until the toxin is metabolised or excreted). The duration of treatment will depend on the anticoagulant involved. A one-week treatment may be undertaken initially. The PT and PTT must be checked 48 to 72 hours after cessation of vitamin K1 therapy. With the more persistent anticoagulants, these clotting tests may become prolonged again, indicating a residual toxic effect and the need for continued vitamin K1 therapy. In some patients, treatment for a month or more may be required. Although less expensive, vitamin K3 is relatively ineffective and is not recommended as a treatment for anticoagulant rodenticide toxicity. Hypocoagulable patients are at great risk of internal haemorrhage. Physical activity must therefore be minimised and their condition monitored closely. Other forms of supportive therapy may be indicated to reduce discomfort and to protect the animal from injury. The administration of drugs with known antiplatelet effects is contraindicated, as is the administration of agents by intramuscular injection.

References

1. Beasley, V (1999) Toxicants that Interfere with the Function of Vitamin K. In Veterinary Toxicology, International Veterinary Information Service.
2. DeWilde, L (2007) Why is Fluffy Bleeding? Secondary Hemostatic Disorders. In Proceedings of the North American Veterinary Conference 2007, NAVC.
3. Dodds, W J (2005) Bleeding Disorders in Animals. In Proceedings of the World Small Animal Veterinary Association 2005, IVIS.
4. Murphy, M J and Talcott, P A (2005) Anticoagulant Rodenticides. In Small Animal Toxicology (Second Edition), Saunders.
5. Campbell, A (1999) Common causes of poisoning in small animals. In Practice, 21(5), 244-249.
6. Keen, P and Livingston, A (1983) Adverse reactions to drugs. In Practice, 5(5), 174-180.
7. Mayer, S (1990) Coumarin Derivatives. In Practice, 12(4), 174-175.
8. Johnstone, I (2002) Bleeding disorders in dogs 2. Acquired disorders. In Practice, 24(2), 62-68.