The major clinical sign of vitamin K deficiency in all species is impaired blood coagulation (Griminger, 1984b). Other clinical signs include low plasma prothrombin levels, increased clotting time and hemorrhaging. In its most severe form, a lack of vitamin K will cause subcutaneous and internal hemorrhages, which can be fatal.
Microorganisms in the rumen synthesize large amounts of vitamin K, and a deficiency is seen only in the presence of a metabolic antagonist, such as dicumarol from moldy sweet clover (Melilotus officinalis; M. alba). Dicumarol is a fungal metabolite produced from substrates in sweet clover hay, which is common in the Northern Plains of the United States and in Canada. The coumarins in fresh sweet clover are not active because they are bound to glycosides. They are activated when sweet clover is improperly cured (Vermeer, 1984). This condition, referred to as "sweet clover poisoning" or "hemorrhagic sweet clover disease," has been responsible for a large number of animal deaths. Affected animals can die from hemorrhage following a minor injury, or even from apparently spontaneous bleeding. Dicumarol passes through the placenta in pregnant animals, and newborn animals may become affected immediately after birth. All species of animals studied have been shown to be susceptible, but cases of poisoning have involved mainly cattle and, to a very limited extent, sheep. Anti-vitamin K toxicity has been observed in sheep fed Ferula communis brevifolia powder (Tligui et al., 1994), and in cattle fed sweet vernal (Anthoxanthum odoratum) hay (Pritchard et al., 1983). A low-coumarin variety of sweet clover (Melilotus dentata) is available for use as forage.
Clinical signs of dicumarol poisoning relate to the hemorrhages caused by failure of blood coagulation. First appearance of clinical disease varies greatly and depends to a large extent on dicumarol content of the particular sweet clover fed and animal age. If dietary dicumarol is low or variable, animals may consume the forage for months before signs of disease appear. In an experiment with calves, dicumarol poisoning was produced by feeding naturally spoiled sweet clover hay that contained a minimum of 90 mg per kg dicumarol (Alstad et al., 1985). The minimum time required to develop clinical signs of vitamin K deficiency in these calves was three weeks. A case of sweet clover poisoning in dairy cattle in California (Puschner et al., 1998) was caused by feeding of sweet clover silage that contained dicumarol produced by mold infestation. Symptoms included subcutaneous hemorrhage, bleeding from the reproductive tract, weakness and death. Other reported symptoms are subcutaneous hemorrhage and clotting in the brisket, neck and hips; stiffness and lameness; dull, listless behavior and pale mucous membranes. Dicumarol has been reported to cause reproductive failure when fed at sub-clinically toxic levels.
Dicumarol poisoning can be reversed by administration of vitamin K. Parenteral vitamin K1 was an effective treatment for calves at rates of 1.1, 2.2 and 3.3 mg per kg body weight. Other researchers have reported that vitamin K1 injections were effective in treating sweet clover poisoning in cattle, but that vitamin K3 (menadione) were not (Casper et al., 1989). Pritchard et al. (1983) reported that large oral doses of vitamin K1 were effective in treatment of sweet vernal poisoning of cattle, but that vitamin K3 gave less consistent results in terms of prothrombin time. This may reflect a greater antagonism of dicumoral against menadione.
Another common cause of induced vitamin K deficiency in veterinary practice is the accidental poisoning of animals with warfarin (a synthetic coumarin used as a rodent poison). Initial clinical signs may be stiffness and lameness caused by bleeding into the muscles and joints. Hematomas, epistaxis or gastrointestinal bleeding may be observed. Death may occur suddenly with little preliminary evidence of disease and is caused by spontaneous massive hemorrhage or bleeding after injury, surgery or parturition. DeHoogh (1989) reported that two possible early embryonic deaths occurred and one cow aborted from sweet clover poisoning.
Measurement of clotting time or prothrombin time has been used to evaluate vitamin K status and is considered a fairly good measure of vitamin K deficiency. Prolongation of the clotting time in the absence of liver disease indicates vitamin K deficiency. Further clarification of a deficiency can be provided by assays for specific vitamin K-dependent factors, or by the rapid response to administration of vitamin K. Currently vitamin K status is assessed by measurement of the plasma concentration of one or more of the vitamin K-dependent clotting factors, prothrombin (factor II), factor VII, factor IX or factor X (Suttie, 1991). More recently, plasma osteocalcin has been proposed as the most sensitive index of vitamin K status in animals and humans (Vermeer et al., 1995).
In experimentally induced dicumarol poisoning, "hemorrhagic sweet clover disease," Alstad et al. (1985) reported that normal prothrombin time is equal to or less than 20 seconds. Deficiency of vitamin K was characterized by prothrombin times of greater than 40 to 60 seconds, and with severe deficiency, prothrombin time can be as long as 5 to 6 minutes.
