Anticoagulant Rodenticide Toxicity

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

Description

Anticoagulant rodenticides were first discovered during ingvestigations into mouldy sweet clover poisoning in cattle¹. In this condition, naturally occuring coumarin in clover is converted by fungi to a toxic agent, dicumarol, which causes a haemorrhagic syndrome when ingested. Initially, warfarin was synthesised and used in this way for rodent control, but as rodents have developed a resistance to the substance new, second generation anticoagulant rodenticides have been developed. These include coumarin (bromadiolone and brodifacoum) and indandione (pindone and diaphacinone) rodenticides, which along with warfarin may cause toxicity following accidental ingestion in animals.

Anticoagulant rodenticide toxiticy is one of the most common causes of acquired coagulopathy in small animals. Warfarin itself has a short half-life and a fairly low toxicity in non-rodent species, so unless large or repeated doses are consumed clinical bleeding is rare. However, the second generation anticoagulant rodenticides are far more potent, with tendency to accumulate in the liver and a long half life (4-6 days) owing to high levels of plasma protein binding². This means it is possible for a domestic animal to acquire secondary poisoning by ingesting a killed rodent.

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. Widely available to the general public as rodenticides. Dogs in particular seem to find them palatable. Cats and other species may become poisoned by eating rodents that have ingested bait. Contamination of foodstuffs by careless use has also caused poisoning in all species. Fungi growing on poorly prepared hay or silage containing sweet vernal grass or sweet clover may break down natural coumarins in the plants to form dicoumarol and cause poisoning in herbivores. Coumarin rodenticides were originally developed from spoiled sweet clover hay when its anticoagulative effects were noticed. Barn owls have been shown to be affected by the 'second generation' anticoagulative rodenticides which were developed to counter increasing resistance to warfarin in rodents. These compounds are more persistent in the rodent and are toxic to owls when the rodent is eaten as prey. Farmers should be encouraged not to use second generation rodenticides if they have barn owls on their property. The barn owls are probably just as effective as the rodenticide anyway!

Another group of agents frequently involved in poisoning events are the anticoagulant rodenticides. They are frequently scavenged by dogs and, although few animals display clinical signs, there are nevertheless the occasional cases where prolonged vitamin K, therapy and sometimes even blood transfusions are required. Poisonings have also occurred as a result of ingestion of rodents killed with these baits. The 'second generation' rodenticides such as difenacoum, bromadiolone, coumatetralyl and chlorophacinone appear to be more commonly implicated, although they now have a larger share of the market than the older warfarin-based and alphachloralose-type rodenticides. Their effects are frequently delayed, and this often results in the late presentation of affected animals to veterinary practices once clinical signs have appeared. The management of such cases is detailed in an earlier article (Mayer 1990), as is that for alphachloralose poisoning (Foster 1995).

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.

If ingestion was recent (in past three hours) induce vomiting. Stomach lavage may also be indicated if dogs fail to vomit. Coumarin rodenticide preparations are often in the form of blue or green granules.

• Give the specific antidote - vitamin K. Phytomenadione, a vitamin K1 analogue available as tablets or injection

(Konakion; Roche), is the drug of choice and reverses low prothrombin levels in 30 minutes. Menadiol (Synkavit; Roche) is a synthetic K3 and is not as effective. Dose. 2 - 5 to 10 mg three times daily orally for five days because most coumarins are metabolised and excreted slowly over two to four days, and longer in some instances. If clinical signs are severe can give 5 mg intravenously over six to eight hours. However, as anaphalactic reactions to intravenous administration have been reported in the dog intramuscular route is preferable.

• Give a whole blood transfusion - this replaces the clotting factors as well as replacing blood loss through haemorrhage.

References

1. Murphy, M J and Talcott, P A (2005) Anticoagulant Rodenticides. In Small Animal Toxicology (Second Edition), Saunders.
2. Campbell, A (1999) Common causes of poisoning in small animals. In Practice, 21(5), 244-249.
3. Beasley, V (1999) Toxicants that Interfere with the Function of Vitamin K. In Veterinary Toxicology, International Veterinary Information Service.
4. DeWilde, L (2007) Why is Fluffy Bleeding? Secondary Hemostatic Disorders. In Proceedings of the North American Veterinary Conference 2007, NAVC.
5. Dodds, W J (2005) Bleeding Disorders in Animals. In Proceedings of the World Small Animal Veterinary Association 2005, IVIS.
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.