Changes

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 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 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.

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 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 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===