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Anticoagulant Rodenticide Toxicity (view source)

Revision as of 15:07, 23 August 2010

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→‎Mechanism of Toxicity
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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.
 
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.
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Two simultaneous cascades are activated to achieve coagulation: the intrinsic and extrinsic pathways. The intrinsic pathway is activated by contact with collagen and involves the clotting factors XII, XI, IX and VIII. The extrinsic pathway is triggered by trauma and contact with "tissue factor", 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.  
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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.  
    
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 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.
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Anticoagulant rodenticides competitively inhibit vitamin K epoxide reductase<sup>4</sup>, preventing the recyling 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>.  
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Anticoagulant rodenticides competitively inhibit vitamin K epoxide reductase<sup>4</sup>, preventing the recyling 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>.
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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.
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Since factor VII has a half-life of only 6 hours, the extrinsic pathway is the first to be affected. This causes slight impatirement 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.
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Warfarin and similar compounds interfere with the regeneration of vitamin K from an intermediate formed during the action
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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
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inhibition of the enzyme involved in the regenerative process and leads to a reduction in available vitamin K, thereby resulting
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in defective blood clotting. Vitamin K dependent clotting factors are VII, IX, 11 and X so the intrinsic pathway (activated by blood
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vessel injury), the extrinsic pathway (activated by tissue injury) and the final common pathway (with conversion of prothrombin
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to thrombin, formation of fibrin and stabilisation of the platelets) is affected. However, the primary haemostatic response (formation
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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
 
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.
 
not subject to external trauma.
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species may become poisoned by eating rodents that have ingested bait. Contamination of foodstuffs by careless
 
species may become poisoned by eating rodents that have ingested bait. Contamination of foodstuffs by careless
 
use has also caused poisoning in all species.
 
use has also caused poisoning in all species.
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Fungi growing on poorly prepared hay or silage containing sweet vernal grass or sweet clover may break down
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natural coumarins in the plants to form dicoumarol and cause poisoning in herbivores. Coumarin rodenticides were
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originally developed from spoiled sweet clover hay when its anticoagulative effects were noticed.
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Barn owls have been shown to be affected by the 'second generation' anticoagulative rodenticides which were
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developed to counter increasing resistance to warfarin in rodents. These compounds are more persistent in the rodent
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and are toxic to owls when the rodent is eaten as prey. Farmers should be encouraged not to use second generation
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rodenticides if they have barn owls on their property. The barn owls are probably just as effective as the rodenticide
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anyway!
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Their effects are frequently
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delayed, and this often results in the late presentation
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of affected animals to veterinary practices once
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clinical signs have appeared. The management of such
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cases is detailed in an earlier article (Mayer 1990), as is
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that for alphachloralose poisoning (Foster 1995).
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===Similar Conditions===
 
The vitamin K-dependent clotting factors (II, VII, IX, X) arereduced in rodenticide toxicity
 
The vitamin K-dependent clotting factors (II, VII, IX, X) arereduced in rodenticide toxicity
 
(accidentally ingested or from therapeutic overdosage), in malabsorption syndromes, and in
 
(accidentally ingested or from therapeutic overdosage), in malabsorption syndromes, and in
 
sterilization of the gut by prolonged use of antibiotics. wsava
 
sterilization of the gut by prolonged use of antibiotics. wsava
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Fungi growing on poorly prepared hay or silage containing sweet vernal grass or sweet clover may break down
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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.
    
==Signalment==
 
==Signalment==
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