Changes

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.

 

Anticoagulant rodenticides inhibit vitamin K epoxide reductase, preventing the recyling of vitamin K and depriving the liver of the active, reduced form of the vitamin. Activation of factors II, VII, IX and 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).

Once the lifespan of factor IX (in the back-up intrinsic path) is at an end (half-life 13.9 hours), that pathway will be shut down and be defunct. It is at this point that hemorrhage begins to go unchecked and the most common time that the first signs of observable clinical abnormalities are noted. It is also at this point that laboratory evaluation of the blood will reveal an elevated partial thromboplastin time (PTT or APTT) as representative of a defect within that particular (intrinsic) pathway. PT is still elevated. From this point, deterioration of the patient due to hemorrhage may be quite rapid (assuming that no more active vitamin K is added to the system).

Once the lifespan of factor IX (in the back-up intrinsic path) is at an end (half-life 13.9 hours), that pathway will be shut down and be defunct. It is at this point that hemorrhage begins to go unchecked and the most common time that the first signs of observable clinical abnormalities are noted. It is also at this point that laboratory evaluation of the blood will reveal an elevated partial thromboplastin time (PTT or APTT) as representative of a defect within that particular (intrinsic) pathway. PT is still elevated. From this point, deterioration of the patient due to hemorrhage may be quite rapid (assuming that no more active vitamin K is added to the system).