Changes

Normally, haemostastis is maintained by three key events⁴. 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 events⁴. 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 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.

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.  

Within each independent (intrinsic, extrinsic) pathway and in the common pathway, at least one coagulation (clotting) factor that depends on the action of vitamin K for its synthesis is involved. When vitamin K is deficient or inhibited, the flow of the cascade is interrupted, preventing eventual formation of the insoluble fibrin polymer.

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 is an essential cofactor and acts by facilitating the proteins' carboxylation to their fuctional forms.  

A very important enzyme, vitamin K epoxide reductase, is essential for the continued synthesis of new factors VII, IX, X and prothrombin. The action of dicumarol and the anticoagulant warfarin (as well as all other anticoagulant rodenticides) is to tie up this enzyme, preventing recycling of the vitamin K and depleting the liver of the active, reduced form of vitamin K (see Hepatocyte diagram below). When this occurs, final carboxylation (activation of) factors VII, IX, X, or prothrombin ceases. However, factors VII, IX, X, or prothrombin already in the bloodstream (synthesized previous to the anticoagulant insult) are not affected and can participate in the normal clotting mechanism. It is when these still-viable, vitamin K-dependent clotting factors reach the end of their life span that unchecked hemorrhage begins to take place. This is the reason for the usual 5-day "lag" time between ingestion of a toxic dose of an anticoagulant and appearance of clinical signs. Factor VII has the shortest half-life (6.2 hours), and thus it and the extrinsic pathway are the first to shut down. When this occurs, hemostasis is impaired slightly, and a mild degree of hemorrhage may occur, but clinical signs are usually not apparent, because the other pathway (intrinsic) is still operational and serves as a sort of "back-up." During this period of time, laboratory evaluation of the blood will reveal an abnormality in the now defunct (extrinsic) pathway. This abnormality is in the form of an elevated prothrombin time (PT).

A very important enzyme, vitamin K epoxide reductase, is essential for the continued synthesis of new factors VII, IX, X and prothrombin. The action of dicumarol and the anticoagulant warfarin (as well as all other anticoagulant rodenticides) is to tie up this enzyme, preventing recycling of the vitamin K and depleting the liver of the active, reduced form of vitamin K (see Hepatocyte diagram below). When this occurs, final carboxylation (activation of) factors VII, IX, X, or prothrombin ceases. However, factors VII, IX, X, or prothrombin already in the bloodstream (synthesized previous to the anticoagulant insult) are not affected and can participate in the normal clotting mechanism. It is when these still-viable, vitamin K-dependent clotting factors reach the end of their life span that unchecked hemorrhage begins to take place. This is the reason for the usual 5-day "lag" time between ingestion of a toxic dose of an anticoagulant and appearance of clinical signs. Factor VII has the shortest half-life (6.2 hours), and thus it and the extrinsic pathway are the first to shut down. When this occurs, hemostasis is impaired slightly, and a mild degree of hemorrhage may occur, but clinical signs are usually not apparent, because the other pathway (intrinsic) is still operational and serves as a sort of "back-up." During this period of time, laboratory evaluation of the blood will reveal an abnormality in the now defunct (extrinsic) pathway. This abnormality is in the form of an elevated prothrombin time (PT).