Difference between revisions of "Anticoagulant Rodenticide Toxicity"

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Also known as: '''''warfarin toxicity/poisoning — anticoagulant rodenticide poisoning — vitamin K antagonist toxicity/poisoning
−
Also known as: Warfarin Toxicity, Anticoagulant Rodenticide Toxicity/ Poisoning.
 
  
−
==Description==
+
==Introduction==
 +
Anticoagulant rodenticides were first discovered during investigations into mouldy sweet clover poisoning in cattle<sup>1</sup>. 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 or malicious administration in animals.
  
−
Anticoagulant rodenticides were first discovered during ingvestigations into mouldy sweet clover poisoning in cattle<sup>1</sup>. 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 binding<sup>2, 3</sup>. These newer drugs are therefore more commonly implicated in cases of poisoning<sup>3</sup>, and it is possible for a domestic animal to acquire secondary poisoning by ingesting a killed rodent<sup>2</sup>. High plasma protein binding also means that the effects of anticoagulant rodenticides are potentiated by administration of other highly plasma protein bound drugs, and low plasma albumin levels.  
  
−
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 binding<sup>2</sup>. This means it is possible for a domestic animal to acquire secondary poisoning by ingesting a killed rodent.
+
===Mechanism of Toxicity===
 +
[[Image:Coagulation Cascade.jpg|thumb|right|300px|Coagulation cascade. Source: Wikimedia Commons; Author: Joe D (2007)]]
 +
Normally, haemostastis is maintained by three key events<sup>3</sup>. Firstly, platelets are activated, adhere to endothelial connective tissue and aggregate to form a platelet plug. Next, substances are released that trigger coagulation and vasoconstriction. Finally, fibrinogen is polymerised to fibrin which reinforces the platelet plug. Some components of the coagulation and fibrin formation stages are dependent on vitamin K, and it is these which are influenced by anticoagulant rodenticide activity.
  
 +
Two simultaneous cascades are activated to achieve coagulation: the intrinsic and extrinsic pathways. The intrinsic pathway is activated by contact with collagen due to blood vessel injury and involves the clotting factors XII, XI, IX and VIII. The extrinsic pathway is triggered by tissue injury and is effected via factor VII. These pathways progress independently before converging at the common pathway, which involves the factors X, V, II and I and ultimately results in the formation of fibrin from fibrinogen.
  
−
The coumarin derivatives exert interaction of
+
Within each of the three arms of the coagulation cascade, certain clotting factors are dependent on vitamin K for activity. These are factor VII, factor XI and factors II and X in the extrinsic, intrinsic and common pathways respectively. Vitamin K carboxylates these factors to their fuctional forms, and becomes oxidised itself in the process. Vitamin K is always required for the production of new II, VII, IX, and X in the liver and levels are tightly regulated. It is therefore essential that vitamin K is recycled after it is oxidised in the carboxylation reaction, and the enzyme vitamin K epoxide reductase is respsonsible for this.
−
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.
 
  
 +
Anticoagulant rodenticides competitively inhibit vitamin K epoxide reductase<sup>4</sup>, preventing the recycling of vitamin K and depriving the liver of the active, reduced form of the vitamin<sup>1-6</sup>. Activation of factors II, VII, IX and X ceases, but there is a quantity of these already in the circulation that are not affected. A time-lag therefore exists between ingestion of anticoagulant rodenticide and the clinical manifestation of toxicity (unchecked haemorrhage), while the supply of still-viable, vitamin K-dependent clotting factors reach the end of their life span. This delay is around 5 days in length<sup>3</sup>, and may mean that patients present late to veterinary practices after intoxication<sup>6</sup>.
  
−
Warfarin and similar compounds interfere with the regeneration of vitamin K from an intermediate formed during the action
+
Since factor VII has a half-life of only 6 hours, the extrinsic pathway is the first to be affected. This causes slight impairment of haemostasis giving a mild degree of haemorrhage, but the intrinsic pathway is still functional and is able to prevent the development of overt clinical signs. After around 14 hours, factor IX of the intrinsic pathway reaches the end of its life-span, and this pathway ceases to operate. Haemorrhage can then proceed unchecked, and clinical signs become obvious. Coumarin and indandione toxicity may also increase the fragility of blood vessels, exacerbating the problem by causing bleeding at sites that are not subject to trauma<sup>6</sup>.
−
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
+
===Similar Conditions===
−
events are the anticoagulant rodenticides. They are
+
Malabsorption syndromes and sterilisation of the gastrointestinal tract by prolonged antibiotic usage will also result in the depletion of vitamin K-dependent clotting factors<sup>7</sup>. In herbivores, 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.
−
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==
 
==Signalment==
−
* Most commonly seen in the dog and pig, after eating bait for rodents.
+
Anticoagulant rodenticide toxcity is most often seen in dogs, due to their scavenging behaviour and the fact they appear to find rodent bait especially palatable. Farm dogs are particularly at risk since rodenticides are frequently used in this environment and many dogs are allowed to roam freely outdoors. In the cat, toxicity usually occurs via the consumption of poisoned rodents. Anticoagulant rodenticide toxicity has been reported in the pig, and also in barn owls who have consumed rodents poisoned with second generation anticoagulant rodenticides<sup>6</sup>.
−
** Warfarin poisoning is therefore relatively common in farm dogs.
 
  
 
==Diagnosis==
 
==Diagnosis==
−
Differentials (7)
+
Ideally, a diagnosis of anticoagulant rodenticide toxicosis should be made based on a history of ingestion of the substance. Failing this, clinical signs, certain laboratory parameters and response to treatment will be suggestive of the condition.
−
* 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===
 
===Clinical Signs===
−
The diagnosis of anticoagulant rodenticide toxicosis is
+
As described above, the onset of clinical signs in anticoagulant rodenticide toxicosis is delayed for up to five days while vitamin K dependent factors become depleted, due to the gradual degradation of functional factors already in the circulation. When signs occur, they are related to defective haemostasis and unchecked haemorrhage although depression and anorexia may be seen before bleeding begins. Visible signs can include external haematomas, bruising, epistaxis, hyphaema, haematemesis, haemtotochezia, melaena, haematuria or excessive bleeding from sites of venupuncture or injury<sup>1-8</sup>. Lameness may also occur if there are haemorrhages into joints. Non-specific symptoms are also possible, related to internal bleeding. Such examples are weakness, ataxia, dyspnoea, abdominal swelling and pallor.  
−
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.
 
  
−
===Diagnostic Imaging===
+
Differential diagnoses include:
 +
#Other causes of blood loss and anaemia, such as inherited clotting defects, trauma, autoimmune diseases, chronic liver disease and disseminated intravascular coagulation.
 +
#Conditions causing dyspnoea, including pleural effusions, congestive heart failure, primary pulmonary disease and respiratory obstruction.
 +
#Causes of acute collapse, such as trauma, endotoxaemia and causes of shock<sup>6</sup>.
  
 
===Laboratory Tests===
 
===Laboratory Tests===
 +
Routine haematology reveals an anaemia due to loss of whole blood. Because time is required for regeneration to begin, the anaemia may initially appear non-regenerative. Haemorrhage is also likely to give a reduction in total protein and/or indications of dehydration (e.g. increased urea and creatinine) on biochemistry. Secondary complications such as pre-renal azotaemia are possible.
 +
 +
Laboratory tests are unlikely to show abnormalities until 36-72 hours after exposure, due to the delay in onset of haemorrhagic signs. Prothrombin time (PT) is a measure of functionality of the extrinsic (and common) pathway, and because factor VII has the shortest half life and thus becomes depleted most rapidly, this parameter is generally the first to become prolonged. Partial thromboplastin time (PTT) and activated clotting time (ACT) are related to the function of the intrinsic and common pathways, and usually become prolonged by 48-72 hours post-ingestion when levels of factor IX are reduced. Platelet count and buccal mucosal bleeding time assess platelet function, and since only secondary haemostasis is affected by vitamin K epoxide reductase antagonism, these measures are usually within normal limits.
 +
 +
The 'proteins induced by vitamin K antagonism'(PIVKAs) are acarboxylated proteins that form as a result of anticoagulant rodenticide toxicity. PIVKAs are not normally detected in the circulation and are increased in the plasma of intoxicated animals. However, PIVKAs are rapidly cleared following adminstration of vitamin K, and so samples should be obtained before therapy is initiated.
  
−
Coagulation screening tests are unlikely to reveal abnormalities
+
It may also be possible to assay vitamin K epoxide and specific anticoagulant in the blood, but these tests are not normally necessary.
−
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===
 
===Pathology===
−
 
+
Pathologic findings commonly include free blood in the thorax, lungs and abdominal cavity<sup>7</sup>. Haemorrhage into the gastrointestinal tract, cranial vault and urinary tract may also be seen, as well as intramuscular and subcutaneous bleeding.
−
* [[Gastritis, Haemorrhagic|Gastric haemorrhage]]
 
−
* Haemorrhage elsewhere in body, particularly mediastinum
 
  
 
==Treatment==
 
==Treatment==
 +
If ingestion of rodenticide occured in the past three hours, vomiting should be induced in an attempt to reduce absorption. If animals fail to vomit, stomach lavage may be indicated.
  
−
Treatment of anticoagulant rodenticide poisoning must
+
The treatment of anticoagulant rodenticide poisoning aims to correct the hypovolaemia and coagulopathy present. A whole blood or plasma tranfusion immediately provides vitamin K dependent clotting factors, helps to restore blood volume and, in the case of whole blood, supplements red blood cells<sup>1-9</sup>. This may need to be followed with larger volumes of crystalloids to compensate for large volumes of fluid loss. The specific treatment of anticoagulant rodenticide toxicosis is administration of vitamin K<sub>1</sub>. This is given as a subcutaneous loading dose at 5mg/kg, and is followed by oral or subcutaneous administration at 2.5-5mg/kg once daily, for 1-6 weeks. If given ''per os'', providing a small amount of fat such as canned dog food aids absorption<sup>7, 8</sup>. Intravenous administration of vitamin K<sub>1</sub> is contraindicated as anaphylactic reactions may occur. Treatment with the less expensive vitamin K<sub>3</sub> is also contraindicated as it is not efficacious in the face of anticoagulant rodenticide toxicity. The duration of treatment depends on the anticoagulant as well as patient factors, and coagulation parameters should be monitored to detmine the progress being made.
−
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
+
Hypocoagulable patients are at risk of internal haemorrhage, so physical activity should be kept to minimum. Unnecessary surgical procedures and venupuncture should be avoided, although thoracocentesis may be required in the event of haemothorax<sup>7</sup>.
−
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.
 
  
 
==Prognosis==
 
==Prognosis==
 +
The prognosis for anticoagulant rodenticide toxicity is guarded, but improves if the patient survives the first 48 hours of acute coagulopathy<sup>7</sup>.
 +
 +
{{Learning
 +
|Vetstream = [https://www.vetstream.com/canis/Content/Disease/dis02574.asp, Anticoagulant rodenticide toxicity]
 +
|literature search = [http://www.cabdirect.org/search.html?q=title:(Anticoagulant+)+AND+title:(Rodenticide)+AND+title:(Toxicity) Anticoagulant rodenticide toxicity publications]
 +
|flashcards = [[Small Animal Emergency and Critical Care Medicine Q&A 22]]
 +
}}
  
 
==Links==
 
==Links==
 +
*[http://www.merckvetmanual.com/mvm/index.jsp?cfile=htm/bc/213000.htm The Merck Veterinary Manual - Rodenticide Poisoning]
 +
*[http://www.vetstreamfelis.com/ACI/October/VMD2/dis02574.asp VetStream Felis - Anticoagulant rodenticide poisoning]
  
 
==References==
 
==References==
−
 
 
#Murphy, M J and Talcott, P A (2005) Anticoagulant Rodenticides. In '''Small Animal Toxicology (Second Edition)''', ''Saunders''.
 
#Murphy, M J and Talcott, P A (2005) Anticoagulant Rodenticides. In '''Small Animal Toxicology (Second Edition)''', ''Saunders''.
 
#Campbell, A (1999) Common causes of poisoning in small animals. ''In Practice'', '''21(5)''', 244-249.
 
#Campbell, A (1999) Common causes of poisoning in small animals. ''In Practice'', '''21(5)''', 244-249.
 
#Beasley, V (1999) Toxicants that Interfere with the Function of Vitamin K. In '''Veterinary Toxicology''', ''International Veterinary Information Service''.
 
#Beasley, V (1999) Toxicants that Interfere with the Function of Vitamin K. In '''Veterinary Toxicology''', ''International Veterinary Information Service''.
 +
#Mayer, S (1990) Coumarin Derivatives. ''In Practice'', '''12(4)''', 174-175.
 +
#Johnstone, I (2002) Bleeding disorders in dogs 2. Acquired disorders. ''In Practice'', '''24(2)''', 62-68.
 +
#Merck & Co (2008) '''The Merck Veterinary Manual (Eighth Edition)''', ''Merial''.
 +
#Tilley, L P and Smith, W K (2007) '''Blackwell's Five Minute Veterinary Consult: Canine and Feline (Fourth Edition)''', ''Blackwell''.
 +
#Dodds, W J (2005) Bleeding Disorders in Animals. In '''Proceedings of the World Small Animal Veterinary Association 2005''', ''IVIS''.
 
#DeWilde, L (2007) Why is Fluffy Bleeding? Secondary Hemostatic Disorders. In '''Proceedings of the North American Veterinary Conference 2007''', ''NAVC''.
 
#DeWilde, L (2007) Why is Fluffy Bleeding? Secondary Hemostatic Disorders. In '''Proceedings of the North American Veterinary Conference 2007''', ''NAVC''.
−
#Dodds, W J (2005) Bleeding Disorders in Animals. In '''Proceedings of the World Small Animal Veterinary Association 2005''', ''IVIS''.
 
 
#Keen, P and Livingston, A (1983) Adverse reactions to drugs. ''In Practice'', '''5(5)''', 174-180.
 
#Keen, P and Livingston, A (1983) Adverse reactions to drugs. ''In Practice'', '''5(5)''', 174-180.
−
#Mayer, S (1990) Coumarin Derivatives. ''In Practice'', '''12(4)''', 174-175.
+
 
−
#Johnstone, I (2002) Bleeding disorders in dogs 2. Acquired disorders. ''In Practice'', '''24(2)''', 62-68.
+
 
−
[[Category:Stomach_and_Abomasum_-_Pathology]]
+
[[Category:Stomach_and_Abomasum_-_Pathology]] [[Category:Gastric Diseases - Dog]] [[Category:Gastric Diseases - Cat]][[Category:Coagulation Defects|Z]]
−
[[Category:To_Do_-_Lizzie]]
+
[[Category:Lymphoreticular and Haematopoietic Diseases - Dog]][[Category:Lymphoreticular and Haematopoietic Diseases - Cat]]
 +
[[Category:Toxicology]]
 +
[[Category:Cardiology Section]]

Latest revision as of 13:59, 6 September 2015

Also known as: warfarin toxicity/poisoning — anticoagulant rodenticide poisoning — vitamin K antagonist toxicity/poisoning

Introduction

Anticoagulant rodenticides were first discovered during investigations 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 or malicious administration 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, 3. These newer drugs are therefore more commonly implicated in cases of poisoning3, and it is possible for a domestic animal to acquire secondary poisoning by ingesting a killed rodent2. High plasma protein binding also means that the effects of anticoagulant rodenticides are potentiated by administration of other highly plasma protein bound drugs, and low plasma albumin levels.

Mechanism of Toxicity

Coagulation cascade. Source: Wikimedia Commons; Author: Joe D (2007)

Normally, haemostastis is maintained by three key events3. Firstly, platelets are activated, adhere to endothelial connective tissue and aggregate to form a platelet plug. Next, substances are released that trigger coagulation and vasoconstriction. Finally, fibrinogen is polymerised to fibrin which reinforces the platelet plug. Some components of the coagulation and fibrin formation stages are dependent on vitamin K, and it is these which are influenced by anticoagulant rodenticide activity.

Two simultaneous cascades are activated to achieve coagulation: the intrinsic and extrinsic pathways. The intrinsic pathway is activated by contact with collagen due to blood vessel injury and involves the clotting factors XII, XI, IX and VIII. The extrinsic pathway is triggered by tissue injury and is effected via factor VII. These pathways progress independently before converging at the common pathway, which involves the factors X, V, II and I and ultimately results in the formation of fibrin from fibrinogen.

Within each of the three arms of the coagulation cascade, certain clotting factors are dependent on vitamin K for activity. These are factor VII, factor XI and factors II and X in the extrinsic, intrinsic and common pathways respectively. Vitamin K carboxylates these factors to their fuctional forms, and becomes oxidised itself in the process. Vitamin K is always required for the production of new II, VII, IX, and X in the liver and levels are tightly regulated. It is therefore essential that vitamin K is recycled after it is oxidised in the carboxylation reaction, and the enzyme vitamin K epoxide reductase is respsonsible for this.

Anticoagulant rodenticides competitively inhibit vitamin K epoxide reductase4, preventing the recycling of vitamin K and depriving the liver of the active, reduced form of the vitamin1-6. Activation of factors II, VII, IX and X ceases, but there is a quantity of these already in the circulation that are not affected. A time-lag therefore exists between ingestion of anticoagulant rodenticide and the clinical manifestation of toxicity (unchecked haemorrhage), while the supply of still-viable, vitamin K-dependent clotting factors reach the end of their life span. This delay is around 5 days in length3, and may mean that patients present late to veterinary practices after intoxication6.

Since factor VII has a half-life of only 6 hours, the extrinsic pathway is the first to be affected. This causes slight impairment of haemostasis giving a mild degree of haemorrhage, but the intrinsic pathway is still functional and is able to prevent the development of overt clinical signs. After around 14 hours, factor IX of the intrinsic pathway reaches the end of its life-span, and this pathway ceases to operate. Haemorrhage can then proceed unchecked, and clinical signs become obvious. Coumarin and indandione toxicity may also increase the fragility of blood vessels, exacerbating the problem by causing bleeding at sites that are not subject to trauma6.

Similar Conditions

Malabsorption syndromes and sterilisation of the gastrointestinal tract by prolonged antibiotic usage will also result in the depletion of vitamin K-dependent clotting factors7. In herbivores, 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.

Signalment

Anticoagulant rodenticide toxcity is most often seen in dogs, due to their scavenging behaviour and the fact they appear to find rodent bait especially palatable. Farm dogs are particularly at risk since rodenticides are frequently used in this environment and many dogs are allowed to roam freely outdoors. In the cat, toxicity usually occurs via the consumption of poisoned rodents. Anticoagulant rodenticide toxicity has been reported in the pig, and also in barn owls who have consumed rodents poisoned with second generation anticoagulant rodenticides6.

Diagnosis

Ideally, a diagnosis of anticoagulant rodenticide toxicosis should be made based on a history of ingestion of the substance. Failing this, clinical signs, certain laboratory parameters and response to treatment will be suggestive of the condition.

Clinical Signs

As described above, the onset of clinical signs in anticoagulant rodenticide toxicosis is delayed for up to five days while vitamin K dependent factors become depleted, due to the gradual degradation of functional factors already in the circulation. When signs occur, they are related to defective haemostasis and unchecked haemorrhage although depression and anorexia may be seen before bleeding begins. Visible signs can include external haematomas, bruising, epistaxis, hyphaema, haematemesis, haemtotochezia, melaena, haematuria or excessive bleeding from sites of venupuncture or injury1-8. Lameness may also occur if there are haemorrhages into joints. Non-specific symptoms are also possible, related to internal bleeding. Such examples are weakness, ataxia, dyspnoea, abdominal swelling and pallor.

Differential diagnoses include:

  1. Other causes of blood loss and anaemia, such as inherited clotting defects, trauma, autoimmune diseases, chronic liver disease and disseminated intravascular coagulation.
  2. Conditions causing dyspnoea, including pleural effusions, congestive heart failure, primary pulmonary disease and respiratory obstruction.
  3. Causes of acute collapse, such as trauma, endotoxaemia and causes of shock6.

Laboratory Tests

Routine haematology reveals an anaemia due to loss of whole blood. Because time is required for regeneration to begin, the anaemia may initially appear non-regenerative. Haemorrhage is also likely to give a reduction in total protein and/or indications of dehydration (e.g. increased urea and creatinine) on biochemistry. Secondary complications such as pre-renal azotaemia are possible.

Laboratory tests are unlikely to show abnormalities until 36-72 hours after exposure, due to the delay in onset of haemorrhagic signs. Prothrombin time (PT) is a measure of functionality of the extrinsic (and common) pathway, and because factor VII has the shortest half life and thus becomes depleted most rapidly, this parameter is generally the first to become prolonged. Partial thromboplastin time (PTT) and activated clotting time (ACT) are related to the function of the intrinsic and common pathways, and usually become prolonged by 48-72 hours post-ingestion when levels of factor IX are reduced. Platelet count and buccal mucosal bleeding time assess platelet function, and since only secondary haemostasis is affected by vitamin K epoxide reductase antagonism, these measures are usually within normal limits.

The 'proteins induced by vitamin K antagonism'(PIVKAs) are acarboxylated proteins that form as a result of anticoagulant rodenticide toxicity. PIVKAs are not normally detected in the circulation and are increased in the plasma of intoxicated animals. However, PIVKAs are rapidly cleared following adminstration of vitamin K, and so samples should be obtained before therapy is initiated.

It may also be possible to assay vitamin K epoxide and specific anticoagulant in the blood, but these tests are not normally necessary.

Pathology

Pathologic findings commonly include free blood in the thorax, lungs and abdominal cavity7. Haemorrhage into the gastrointestinal tract, cranial vault and urinary tract may also be seen, as well as intramuscular and subcutaneous bleeding.

Treatment

If ingestion of rodenticide occured in the past three hours, vomiting should be induced in an attempt to reduce absorption. If animals fail to vomit, stomach lavage may be indicated.

The treatment of anticoagulant rodenticide poisoning aims to correct the hypovolaemia and coagulopathy present. A whole blood or plasma tranfusion immediately provides vitamin K dependent clotting factors, helps to restore blood volume and, in the case of whole blood, supplements red blood cells1-9. This may need to be followed with larger volumes of crystalloids to compensate for large volumes of fluid loss. The specific treatment of anticoagulant rodenticide toxicosis is administration of vitamin K1. This is given as a subcutaneous loading dose at 5mg/kg, and is followed by oral or subcutaneous administration at 2.5-5mg/kg once daily, for 1-6 weeks. If given per os, providing a small amount of fat such as canned dog food aids absorption7, 8. Intravenous administration of vitamin K1 is contraindicated as anaphylactic reactions may occur. Treatment with the less expensive vitamin K3 is also contraindicated as it is not efficacious in the face of anticoagulant rodenticide toxicity. The duration of treatment depends on the anticoagulant as well as patient factors, and coagulation parameters should be monitored to detmine the progress being made.

Hypocoagulable patients are at risk of internal haemorrhage, so physical activity should be kept to minimum. Unnecessary surgical procedures and venupuncture should be avoided, although thoracocentesis may be required in the event of haemothorax7.

Prognosis

The prognosis for anticoagulant rodenticide toxicity is guarded, but improves if the patient survives the first 48 hours of acute coagulopathy7.


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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. Mayer, S (1990) Coumarin Derivatives. In Practice, 12(4), 174-175.
  5. Johnstone, I (2002) Bleeding disorders in dogs 2. Acquired disorders. In Practice, 24(2), 62-68.
  6. Merck & Co (2008) The Merck Veterinary Manual (Eighth Edition), Merial.
  7. Tilley, L P and Smith, W K (2007) Blackwell's Five Minute Veterinary Consult: Canine and Feline (Fourth Edition), Blackwell.
  8. Dodds, W J (2005) Bleeding Disorders in Animals. In Proceedings of the World Small Animal Veterinary Association 2005, IVIS.
  9. DeWilde, L (2007) Why is Fluffy Bleeding? Secondary Hemostatic Disorders. In Proceedings of the North American Veterinary Conference 2007, NAVC.
  10. Keen, P and Livingston, A (1983) Adverse reactions to drugs. In Practice, 5(5), 174-180.
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