Anticoagulant rodenticides poisoning

In 1940 a small pharmaceutical company in England suggested that dicoumarol could kill rodents. In the following years studies confirmed this hypothesis and immediately after the Second World War the first anticoagulant rodenticide, warfarin, was put on the market and widely used in many countries. Accidental or deliberately encouraged ingestion of rodenticides is the cause of a significant number of cases of intoxication and poisoning and these products are a potential danger to both mammals and birds.

The products on the market are available in various formulations: traps, bait incorporated in cereals, powders of various concentrations for household or professional use, filter paper sachets containing pressed cereals, sugars and aromas, paste balls in filter paper sachets, and paraffin blocks. The products are often brightly coloured to discourage accidental ingestion. The concentration of the active principle varies from 0.005-0.05% in bait and from 0.25-1% in the concentrated formulations.

CLASSIFICATION

The anticoagulant rodenticides can be divided, on the basis of their chemical structure, into hydroxycoumarins and indandione derivatives. The former are by far and away more common and are, therefore, responsible for most of the cases of poisoning of humans and animals. The first commercially available anticoagulant rodenticide was warfarin. Subsequently other compounds of similar potency were introduced and came to be defined as first-generation anticoagulant rodenticides. These compounds are characterized by moderate toxicity, with an LD₅₀ between 10 and 50 mg/kg p.c., and by the fact that repeated exposure is necessary for them to have their toxic effect.

Some rodent species have developed resistance to warfarin, probably following repeated exposure and the widespread use of this poison. For this reason second-generation anticoagulant rodenticides have been developed and marketed. These are often called “superwarfarin” or long-acting rodenticides, and are characterized by greater toxicity than warfarin, with LD₅₀ values between 0.2-3.9 mg/kg p.c. A single dose of these products is toxic (Table 1).

SOURCES OF INTOXICATION

The leading cause of poisoning of both domestic and wild animals is the ingestion of bait: the fact that bait containing anticoagulant rodenticides does not have an unpleasant smell or taste makes it attractive to animals. Secondary poisoning (ingestion of animals – still alive or dead – poisoned by anticoagulant rodenticides) is another important cause of intoxication, not only of domestic animals, but also of wild ones. The risk of poisoning through skin contact or by drinking contaminated water is low. Ruminants are at a lower risk of poisoning following ingestion of anticoagulants because these compounds are partially broken down in the rumen.

It is important to determine what substance has caused the poisoning, even though this is not always possible, in order to optimise the duration and the dose of the treatment. The most practical way is to check the contents of the package of the product suspected of having caused the poisoning, although it should be noted that this approach is not always successful since it was shown that in 25% of dogs poisoned, the anticoagulant in the circulation was not the one thought to be the cause by the animal’s owner.

MECHANISM OF ACTION

The mechanism of action of the two classes of anticoagulant rodenticides is essentially identical, although the severity and duration of the signs depend on the specific type of anticoagulant ingested. Anticoagulants interfere with the enzyme (vitamin K epoxide reductase) necessary for the  reduction of vitamin K from it inactive form (vitamin K epoxide) to its active one (quinone form). Interference with this reductase enzyme decreases the production of active vitamin K, which is an essential co-factor for the activation of some clotting factors (factor II [prothrombin], factor VII [proconvertin], factor IX [Christmas factor or antihaemophilic factor B] and factor X [Stuart factor]). The decrease in clotting factors is proportional to their half-lives which, in the dog, for example, can range from 6 to about 41 hours. The concentration of clotting factors, therefore, decreases only after a period of latency which varies from 12-24 hours to 5-7 days after ingestion of the anticoagulant. Furthermore, the duration of the effect of the anticoagulant varies as a function of the half-life of the toxic substance: for example, warfarin reduces the amount of clotting factors for about 7-10 days, while difacinone (a second-generation product) does so for 3-4 weeks.

Animals that may be particularly susceptible to the toxic effects of anticoagulants are young subjects with hypoprothrombinaemia and patients with reduced production of clotting factors as a result of hepatic impairment or gastrointestinal malabsorption syndrome. Concomitant administration of other drugs with high serum-protein binding (e.g., non-steroidal anti-inflammatory drugs) or the presence of other pathological conditions (e.g., chronic kidney disease) can also predispose an animal to the toxic effects of anticoagulants.

SIGNS

Animals exposed to anticoagulant poisons are asymptomatic until the reserves of clotting factors decrease and, therefore, often for 1-2 days after exposure. Initially, the animal has non-specific signs: drowsiness, weakness, ataxia, mucosal pallor, decrease or loss of appetite, polyuria, and polydipsia. Hypothermia may be present in the initial phase, while hyperthermia occurs later (2-3 days). Tachycardia and tachypnoea with episodes of dyspnoea are always present. Bleeding is the most common sign and occurs in the form of petechiae and ecchymoses of the skin and mucosae, melaena, hyphaema (haemorrhage in the anterior chamber of the eye, between the cornea and iris) and petechial haemorrhages of the eye, vomiting and haematemesis, epistaxis, otorrhagia, vaginal bleeding, dysuria and haematuria, haemothorax, and haemoperitoneum. In addition to these signs, the animals can manifest pain, fever, and limping as a result of bleeding into joints.

In the late stages of intoxication (after 1 week) there is often bilateral and symmetrical swelling of the abdomen, frequently accompanied by prolapse of the ventral abdominal wall and lordosis of the vertebral column, caused by a bloody effusion (ascites). The animal frequently adopts the posture of a sitting dog. The formation of a massive haematoma at the site of an injection or venous puncture is equally characteristic. Occasionally the poisoning can be acute and the animal is found dead without any premonitory signs. Sudden death occurs following bleeding into the pericardium, thorax, abdomen, mediastinum or cranium.

DIAGNOSIS

The diagnosis of intoxication by anticoagulant rodenticides is essentially based on the history (exposure to the poison), clinical signs, presence of a bleeding diathesis and on the response to treatment with vitamin K₁.

Exposure to anticoagulant rodenticides is usually accidental, although there are numerous cases of intentional poisoning. It may, therefore, not be known that the animal has been exposed to anticoagulants and in this case the diagnosis must be based only on the signs.

The presence of a bleeding disorder is fundamental to the diagnosis. Prolonged bleeding, the formation of haematomas at injection sites, decreased haematocrit, a delay in the whole blood clotting time (WBCT) or an increase in the activated clotting time (ACT) are often indicators of poisoning by anticoagulant rodenticides. The results of the coagulation tests also include increases in the prothrombin time (PT), thrombin time (TT), and partial thromboplastin time (PTT), decreases in clotting factors and positivity for markers of vitamin K deficiency (PIVKA: protein induced by vitamin K absence or by vitamin K antagonists, the only test specific for this type of intoxication) (Table 2). Given that clotting factor VII has the shortest half-life (6.2 hours), the PT test is the most sensitive method for making a diagnosis of anticoagulant poisoning in the early phases and is the test used for monitoring the trend in the clotting disorder and the outcome of treatment.

Other possible laboratory findings include:

• haematological changes: hypochromic anaemia, decreased haematocrit, leukocytosis with neutrophilia, thrombocytopenia, increased erythrocyte sedimentation rate, decreased mean corpuscular volume;
• biochemical changes: hypoproteinaemia, hypoalbuminaemia, hyperglycaemia, bilirubinaemia, increased activity of alanine aminotransferase, alkaline phosphatase and gamma glutamyltransferase;
• urinary changes: proteinuria, haematuria and the presence of numerous erythrocytes in the sediment.

Finally, a positive response to treatment with vitamin K₁ in the 24 hours after starting therapy can provide further confirmation of the diagnosis of poisoning by an anticoagulant rodenticide.

The search for anticoagulants and their metabolites in the blood is not a widely used test.

At post-mortem examination, a common finding is haemothorax together with haemopericardium or haemoperitoneum, and widespread haemorrhages in various districts with blood that does not clot.

DIFFERENTIAL DIAGNOSIS

In the case of massive haemorrhage the differential diagnosis includes disseminated intravascular coagulation, congenital clotting factor deficiencies, platelet deficiencies, von Willebrand’s disease and canine ehrlichiosis. Prolonged prothrombin time, partial thromboplastin time, or thrombin time in the presence of normal concentrations of fibrinogen and fibrin degradation products and platelet counts, as well as a positive therapeutic response to vitamin K₁, are strongly indicative of intoxication by anticoagulant rodenticides.

TREATMENT

The treatment of poisoning by anticoagulant rodenticides is based on the administration of vitamin K₁ (phytomenadione) which is immediately available for the synthesis of new clotting factors, a process which requires from 6 to 12 hours. The daily dose of vitamin K₁ necessary ranges from 0.25 to 2.5 mg/kg for 1 week in the case of exposure to a short-acting (first-generation) anticoagulant, and from 2.5 to 5 mg/kg for 3-4 weeks following exposure to a long-acting anticoagulant or when the product that has caused the poisoning is unknown. The first dose can be given subcutaneously through small calibre needles to minimise the risk of haematoma development. The injections can be made at more than one point to facilitate rapid absorption. Intravenous or intramuscular administration is contraindicated because of the risk of anaphylaxis (i.v.) and the formation of haematomas (i.m.). The route of choice for subsequent doses is oral, with the same dose divided into two daily administrations. The bioavailability of vitamin K is considerably higher if it is administered with food, in particular fatty foods.

Treatment can be withdrawn gradually once the PT value is normal. The duration of the treatment varies depending on the type of anticoagulant that has caused the intoxication. The PT must be checked about 48-72 hours after therapy has been stopped. If the result is within the normal range, the test should be repeated once again after another 48-72 hours as further monitoring. If the PT is found to be increased in these controls, vitamin K₁–based treatment must be continued for at least 1 week.

Emergency treatment

• if the subject has severe, acute signs, it is essential to protect the patency of the airways and supply oxygen;
• ensure a venous access and take blood samples for laboratory investigations;
• administer fresh blood or plasma, depending on the severity of the bleeding;
• administer electrolyte solutions with care, in order to avoid overhydration or excessive dilution of the blood;
• start treatment with vitamin K₁ when the patient is stable;
• keep the animal in a peaceful, confined space to prevent excessive physical activity.

Induction of vomiting may only be useful if the animal is still asymptomatic and the exposure has been very recent (with the preceding few hours); the same holds true for gastric lavage, treatment with absorbent substances or cathartics. Given that the bleeding diathesis can be manifested clinically from 2-5 days after exposure to the poison, the administration of emetics and purges is not advised. Nevertheless, treatment with activated charcoal can be useful in the case of poisoning by substances that undergo entero-hepatic recirculation. The administration of vitamin K₃ (menadione) is not effective in the treatment of intoxication by anticoagulant rodenticides.

Practical approach to the bleeding patient

PROGNOSIS

The prognosis depends on the phase of the intoxication at the time of starting treatment. If the animal is in the asymptomatic phase, the prognosis is good to excellent; otherwise the prognosis is unfavourable and depends on the type and severity of the bleeding disorder. If the animal survives the acute phase of the clotting disorder, from the second day onwards the prognosis improves. It should be noted that after the disappearance of the signs of intoxication, most dogs have a greater predisposition to recurrent and periodic ascites, as a result of anticoagulant-induced liver damage.

THERAPEUTIC USE OF ANTICOAGULANTS

Warfarin (coumadin) is used in human medicine as an anticoagulant in the prophylaxis and treatment of pulmonary embolism, deep vein thrombosis, and arterial thromboembolism in patients with chronic atrial fibrillation, mechanical or biological prosthetic heart valves, intracardiac mural thromboses or acute myocardial infarction, and in the prophylaxis of re-infarction. 

In veterinary medicine warfarin is used mainly for long-term oral treatment or prophylaxis of recurrent thrombotic conditions in the dog, cat and horse. Its use is, however, controversial, because of the lack of proven benefits in reducing mortality, the cost of monitoring the clinical state (prothrombin time) and its potential severe adverse effects (haemorrhages).

Suggested readings

1. Avvelenamento da rodenticidi. In: Il Manuale Merck Veterinario 8^th edn. Merck & Co., Inc. Whitehouse Station, NJ, USA; pp. 2138-9.
2. DormanDC. Anticoagulant, cholecalciferol and bromethalin-based rodenticides. Vet Clin North Am Small Anim Pract 1990;20:339-52.
3. Gfeller RW, Messonnier SP. Rodenticidi antagonisti della vitamina K. In: Tossicologia ed Avvelenamenti nei Piccoli Animali. 2005 Poletto Editore.
4. http://www.vet.uga.edu/VPP/clerk/Harrell/index.php[9]
5. Murphy MJ. Anticoagulant rodenticides. In: Veterinary Toxicology. Basic and Clinical Principles. Gupta RG. 1_^stedn. 2007 Academic Press, Elsevier, USA
6. PlumbDC. Plumb’s Veterinary Drug Handbook. 6_^th ed. 2008 Blackwell Publishing Professional, Ames, Iowa, USA.
7. Valchev I, Binev R, Yordanova V, Nikolov Y. Anticoagulant rodenticide intoxication in animals: a review. Turk J Vet Anim Sci 2008;32:237-43.