Changes

==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.  

==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 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 binding^{2, 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.  

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^{2, 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.  

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.

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 involves the 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.  

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 include 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 in the process itself becomes oxidised. 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.

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 recyling of vitamin K and depriving the liver of the active, reduced form of the vitamin^1-6. 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.

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 vitamin^1-6. 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 impairement of haemostasis is impaired slightly 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 indandosides txicity may also increase the fragility of blood vessels, exacerbating the problem by causing bleeding at sites that are not subject to trauma⁶.

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===

===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.

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. in herbivores.

==Signalment==

==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.

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 also been reported in the pig, and also in barn owls who have consumed rodents poisoned with second generation anticoagulant rodenticides⁶.

==Diagnosis==

==Diagnosis==

Ideally, a diagnosis of anticoagulant rodenticide toxicosis should be made based on a history of ingestion of the substance. is usually diagnosed based on history of ingestion of the substance. Differential diagnoses when massive hemorrhage is encountered include disseminated intravascular coagulation, congenital factor deficiencies, von Willebrand’s disease, platelet deficiencies, and canine ehrlichiosis. A prolonged prothrombin, partial thromboplastin, or thrombin time in the presence of normal fibrinogen, fibrin degradation products, and platelet counts is strongly suggestive of anticoagulant rodenticide toxicosis, as is a positive therapeutic response to vitamin K1.  

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^1-8. 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.  

The diagnosis of anticoagulant rodenticide toxicosis is

#Other causes of blood loss and anaemia, such as inherited clotting defects, trauma, autoimmune diseases, chronic liver disease and disseminated intravascular coagulation.

dependent on a thorough patient history and physical

#Conditions causing dyspnoea, including pleural effusions, congestive heart failure, primary pulmonary disease and respiratory obstruction.

examination, and appropriate haemostatic testing. The

#Causes of acute collapse, such as trauma, endotoxaemia and causes of shock⁶.

concentrations of the vitamin K-dependent clotting

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.

Clinical signs generally reflect some manifestation of hemorrhage, including anemia, hematomas, melena, hemothorax, hyphema, epistaxis, hemoptysis, and hematuria. Signs dependent on hemorrhage, such as weakness, ataxia, colic, and polypnea, may be seen. Depression and anorexia occur in all species even before bleeding occurs.

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.

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

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

for coagulation testing should be collected before initiating

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 cavity⁷. 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==

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^1-9. 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 absorption^{7, 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.

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

be checked 48 to 72 hours after cessation of vitamin K1

therapy. With the more persistent anticoagulants, these

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

contraindicated, as is the administration of agents by

intramuscular injection.

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.

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.

over two to four days, and longer in some instances.

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.

Vitamin K1 is antidotal. Recommended dosages vary from 0.25-2.5 mg/kg in warfarin (coumarin) exposure, to 2.5-5 mg/kg in the case of long-acting rodenticide intoxication (diphacinone, brodifacoum, bromadiolone). Vitamin K1 is administered SC (with the smallest possible needle to minimize hemorrhage) in several locations to speed absorption. IV administration of vitamin K1 is contraindicated, as anaphylaxis may occasionally result. The oral form of K1 may be used daily after the first day, commonly at the same level as the loading dose (divided bid). Fresh or frozen plasma (9 mL/kg) or whole blood (20 mL/kg) IV is required to replace needed clotting factors and RBC if bleeding is severe. One week of vitamin K1 treatment is usually sufficient for first-generation anticoagulants. For intermediate and second-generation anticoagulants or if anticoagulant type is unknown, treatment should continue for 2-4 wk to control longterm effects. Administration of oral vitamin K1 with a fat-containing ration, such as canned dog food, increases its bioavailability 4-5 times as compared with vitamin K1 given PO alone. 

Coagulation should be monitored weekly until values remain normal for 5-6 days after cessation of therapy. Vitamin K3 given as a feed supplement is ineffective in the treatment of anticoagulant rodenticide toxicosis. Additional supportive therapy may be indicated, including thoracocentesis (to relieve dyspnea due to hemothorax) and supplemental oxygen if needed.

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

==Prognosis==

|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==

==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.

#Johnstone, I (2002) Bleeding disorders in dogs 2. Acquired disorders. ''In Practice'', '''24(2)''', 62-68.

#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''.

#Merck & Co (2008) '''The Merck Veterinary Manual (Eighth Edition)''', ''Merial''.

#Dodds, W J (2005) Bleeding Disorders in Animals. In '''Proceedings of the World Small Animal Veterinary Association 2005''', ''IVIS''.

#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''.

[[Category:Stomach_and_Abomasum_-_Pathology]] [[Category:WikiClinical Canine]] [[Category:WikiClinical Feline]]

[[Category:Stomach_and_Abomasum_-_Pathology]] [[Category:Gastric Diseases - Dog]] [[Category:Gastric Diseases - Cat]][[Category:Coagulation Defects|Z]]

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