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Anticoagulant Rodenticide Toxicity (view source)
Revision as of 13:20, 23 August 2010
, 13:20, 23 August 2010→Mechanism of Toxicity
===Mechanism of Toxicity===
===Mechanism of Toxicity===
The circulatory system is a very dynamic tissue, which is in a continual state of repair and regeneration. The hemorrhage that occurs as a result of either normal activities or from various insults (trauma, infectious processes, shock, stress, malignancy, etc.) is arrested through an ordered interaction involving 3 major events.
The first phase is comprised of the platelet adhesion reaction in which activated platelets become sticky, attach to exposed endothelial connective tissue elements and build by aggregation to form a platelet plug. In the second phase, the so-called platelet release reaction, vasoactive and coagulation-triggering substances are released. The damaged vessel retracts, and the third phase, the coagulation mechanism by which soluble fibrinogen is converted to insoluble polymerized fibrin, is triggered.
This discussion addresses only those components of the coagulation mechanism (active in the second to third phases) whose concentration in plasma is influenced by vitamin K and only those compounds which act as vitamin K antagonists.
When the coagulation mechanism is set into motion, 2 separate "pathways" are simultaneously set into operation to effect hemostasis. The "intrinsic route" refers to a relatively slow process (lasting 5 - 15 minutes, in vitro), while the "extrinsic route" is a relatively rapid one (lasting 10 - 12 seconds), following contact between blood and damaged tissue. Following activation, both routes operate independently and eventually converge at the "common pathway." At this convergence, a single route (common coagulation pathway) is followed which eventually causes the soluble plasma protein, fibrinogen, to be converted into the insoluble fibrin (see Circulation diagram below).
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.
The vitamin K-dependent clotting factors include factor VII (in the extrinsic pathway), factor IX (in the intrinsic pathway), and factors X and II (prothrombin) (in the common pathway). These clotting factors are synthesized in the liver and vitamin K is an essential cofactor allowing the carboxylation of the acarboxy coagulation proteins to their functional form. Vitamin K metabolism is tightly conserved in the liver.
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).
The coumarin derivatives exert interaction of
The coumarin derivatives exert interaction of
their anticoagulant eftect by inhibiting the enzyme, vitamin K epoxide reductase (see box on page 63). This enizymiie is a component of
their anticoagulant eftect by inhibiting the enzyme, vitamin K epoxide reductase (see box on page 63). This enizymiie is a component of