The generic term vitamin K is now used to describe not a single chemical entity, but a group of quinone compounds that have characteristic anti-hemorrhagic effects and are fat soluble. The basic molecule is a naphthoquinone, and the various isomers differ in the nature and length of the side chain. Vitamin K extracted from plant material was named phylloquinone or vitamin K1 (Illus. 5-1). Vitamin K-active compounds from material that had undergone bacterial fermentation were named menaquinones or vitamin K2. The simplest form of vitamin K is the synthetic menadione (K3), which has no side chain. Menaquinone-4 is synthesized in the liver from ingested menadione or changed to a biologically active menaquinone by intestinal microorganisms. Rumen microorganisms synthesize large quantities of vitamin K2, and the vitamin K content of cow’s milk is reportedly 10 times higher than that of monogastric species.
Vitamin K1 is a golden yellow, viscous oil. Naturally occurring sources of vitamin K are fat soluble; stable to heat; and labile to oxidation, alkali, strong acids, light and irradiation. Vitamin K1 is slowly degraded by atmospheric oxygen, but fairly rapidly destroyed by light. In contrast to naturally occurring sources of vitamin K, vitamin K3salts of menadione are water soluble.Vitamin K antagonists increase the need for this vitamin. Deficiency of this vitamin is produced by ingestion of the antagonist, dicumarol, or by feeding of sulfonamides (in monogastric species) at levels sufficient to inhibit intestinal synthesis of vitamin K. Supplementation of vitamin K will overcome the anticoagulation effect of dicumarol. Mycotoxins are also antagonists that may cause vitamin K deficiency.
Like all fat-soluble vitamins, vitamin K is absorbed in association with dietary fats and requires the presence of bile salts and pancreatic juice for adequate uptake from the alimentary tract. Absorption of vitamin K depends on its incorporation into mixed micelles, and optimal formation of these micellar structures requires the presence of both bile and pancreatic juice. Thus, any malfunction of the fat absorption mechanism (e.g., biliary obstruction) reduces availability of vitamin K (Ferland, 2006). Unlike phylloquinone and the menaquinones, menadione salts are relatively water soluble, and, therefore, are absorbed satisfactorily from low-fat diets. Male animals are more susceptible to dietary vitamin K deprivation than females, apparently as a result of a stimulation of phylloquinone absorption by estrogens. The administration of estrogens increases absorption in both male and female animals (Jolly et al., 1977).
The lymphatic system is the major route of transport of absorbed phylloquinone from the intestine. Shearer et al.(1970) demonstrated the association of phylloquinone with serum lipoproteins, but little is known of the existence of specific carrier proteins. Ingested phylloquinone is absorbed by an energy-dependent process from the proximal portion of the small intestine (Hollander, 1973). In contrast to the active transport of phylloquinone, menaquinone is absorbed from the small intestine by a passive noncarrier-mediated process.
The measured efficiency of vitamin K absorption ranges from 10% to 70%, depending on the form of the vitamin administered. Some reports have indicated that menadione is completely absorbed, but phylloquinone is absorbed only at a rate of 50%. The complete absorption of menadione may be due to aqueous solubility of the menadione salts. Rats were found to excrete about 60% of ingested phylloquinone in the feces within 24 hours of ingestion, but only 11% of ingested menadione (Griminger and Donis, 1960; Griminger, 1984). However, 38% of ingested menadione, but only a small amount of phylloquinone, was excreted via the kidneys during the same period. The conclusion was that although menadione is well absorbed, it is poorly retained, while the opposite is true for phylloquinone. Normal human subjects were found to excrete less than 20% of a large (1 mg) dose of phylloquinone in feces, but as much as 70%-80% of the ingested phylloquinone was excreted unaltered in the feces of patients with impaired fat absorption caused by obstructive jaundice, pancreatic insufficiency, or adult celiac disease (Suttie, 2007).
Griminger and Brubacher (1966) showed that a major portion of the phylloquinone fed to chicks was absorbed and deposited in the liver intact and, as such, had equally as good biological activity upon prothrombin synthesis as menaquinone found in the chick’s liver following feeding of menadione. Therefore, menaquinone is most likely produced if menadione is fed or if the intestinal microorganisms degrade the dietary K1 or K2 to menadione. Formation of menaquinone is not required for metabolic activity of vitamin K, since phylloquinone is equally active in synthesis of the vitamin K-dependent, blood-clotting proteins (Scott et al., 1982).
A number of studies have shown that phylloquinone is specifically concentrated and retained but menadione is poorly retained in the liver. Menadione is found to be widely distributed in all tissues and to be very rapidly excreted. Although phylloquinone is rapidly concentrated in the liver, it does not have a long retention time in this organ (Thierry et al.,1970). The inability to rapidly develop a vitamin K deficiency in most species results, therefore, from the difficulty in preventing absorption of the vitamin from the diet or from intestinal synthesis rather than from a significant storage of the vitamin. Some breakdown products of vitamin K are excreted in the urine. One of the principal excretory products is a chain-shortened and oxidized derivative of vitamin K, which forms gamma-lactone and is probably excreted as a glucuronide.
Vitamin K dependent proteins can be identified by γ-carboxyglutamic acid residues (Gla); this amino acid is common to all vitamin K proteins. Discovery of the new amino acid clarified the role of vitamin K in blood coagulation and led to the discovery of additional vitamin K-dependent proteins (e.g., bone proteins) (Ferland, 2006; Suttie, 2007). Coagulation time of blood is increased when vitamin K is deficient because the vitamin is required for the synthesis of prothrombin (factor II). Plasma clotting factors VII (proconvertin), IX (Christmas factor) and X (Stuart-Prower factor) also depend on vitamin K for their synthesis. These four blood-clotting proteins are synthesized in the liver in inactive precursor forms and then converted to biologically active proteins by the action of vitamin K (Suttie and Jackson, 1977). In deficiency, administration of vitamin K brings about a prompt response in four to six hours. In the absence of the liver, this response does not occur.
Bleeding disorders result from an inability of a liver microsomal enzyme, currently called the vitamin K-dependent carboxylase (Esmon et al., 1975), to carry out the normal post-translational conversion of specific glutamyl residues in the vitamin K-dependent plasma proteins to gamma-carboxyglutamyl residues (Nelsestuen et al., 1974). The result of insufficient vitamin K to serve as a cofactor for this enzyme is, therefore, a decrease in the rate of thrombin generation.
The action of converting inactive precursor proteins to biologically active forms involves the carboxylation of glutamic acid residues in the inactive molecules. Carboxylation allows prothrombin and the other procoagulant proteins to participate in a specific protein-calcium phospholipid interaction that is a necessity for their biological role (Suttie and Jackson, 1977). Four other vitamin K-dependent proteins have also been identified in plasma (i.e., proteins C, S, Z and M). Protein C and protein S play an anticoagulant rather than a procoagulant role in normal hemostasis (Suttie and Olson, 1990). Protein C inhibits coagulation, and, stimulated by protein S, it promotes fibrinolysis. Also, a protein C-S complex can partially hydrolyze the activated factors V and VIII and thus inactivate them. Protein S also has the potential to be involved in the regulation of bone turnover (Binkley and Suttie, 1995). Function for proteins M and Z is unclear. Protein Z has been shown to have an anticoagulant function under some conditions (Suttie, 2007).
The blood clotting mechanism can apparently be stimulated by either an intrinsic system, in which all the factors are in the plasma, or an extrinsic system. In the extrinsic system of coagulation, injury to the skin or other tissue frees tissue thromboplastin that in the presence of various factors and calcium changes prothrombin in the blood to thrombin. The enzyme thrombin facilitates the conversion of the soluble fibrinogen into insoluble fibrin. Fibrin polymerizes into strands and enmeshes the formed elements of the blood, especially the red blood cells, to form the blood clot (Griminger, 1984). The final active component in both the intrinsic and extrinsic systems appears to activate the Stuart factor, which in turn leads to activation of prothrombin. The various steps involved in blood clotting are presented in Figure 5-1. The action of vitamin K is required at four different sites in these reactions.
Figure 5-1: The Mechanism of Blood Clotting
The vitamin K-dependent clotting factors (synthesis of each is inhibited by dicumarol) include factor IX, plasma thromboplastin components (PTC); factor X, Stuart-Prower factors; factor VII, proconvertin; and factor II, prothrombin.
Adapted from Scott et al., (1982) and McDowell (1989)
Continuing research has revealed that vitamin K-dependent reactions are present in most tissues and not just blood, and that a reasonably large number of proteins are subjected to this post-translational carboxylation of specific glutamate residues to gamma-carboxyglutamate residues (Vermeer, 1986). Atherocalcin is a vitamin K-dependent protein in atherosclerotic tissue. A vitamin K-dependent carboxylase system has been identified in skin, which may be related to calcium metabolism in skin (de Boer-van den Berg et al., 1986). Two of the best characterized vitamin K-dependent proteins not involved in hemostasis are osteocalcin or bone Gla protein (BGP) and matrix Gla protein, which were initially discovered in bone. Osteocalcin is a protein containing three Gla residues that give the protein its mineral-binding properties. Osteocalcin appears in embryonic chick bone and rat bone matrix at the beginning of mineralization of the bone (Gallop et al., 1980). It accounts for 15% to 20% of the non-collagen protein in the bone of most vertebrates and is one of the most abundant proteins in the body. Osteocalcin is produced by osteoblasts, with synthesis controlled by 1,25-dihydroxy vitamin D. About 20 percent of the newly synthesized protein is released in the circulation and can be used as a measure of bone formation. Matrix Gla protein-deficient mice have abnormal calcification leading to osteopenia, fractures and premature death owing to arterial calcification (Booth and Mayer, 1997).
As is true for other non-blood vitamin K-dependent proteins, the physiological role of osteocalcin remains largely unknown. However, reduced osteocalcin content of cortical bone (Vanderschueren et al., 1990) and alteration of osteocalcin distribution within osteons (Ingram et al., 1994) are associated with aging. It remains unknown whether any of these findings are related to the age-related increased risk of fracture. Osteocalcin may play a role in the control of bone remodeling because it has been reported to be a chemoattractant for monocytes, the precursors of osteoclasts. Serum osteocalcin has been shown to be a good predictor of bone turnover in pigs (Carter et al., 1996). This suggests a possible role for osteocalcin in bone resorption (Binkley and Suttie, 1995).
Several reports have indicated that warfarin treatment alters the functional properties of bone particles prepared from rats. However, vitamin K-deficient chick embryos were able to mobilize sufficient quantities of calcium for normal skeletal development, although they exhibited severe reduction in blood clotting and bone osteocalcin concentration (Lavelle et al., 1994).
Observations that vitamin K could be involved in the pathogenesis of bone mineral loss have been summarized (Binkley and Suttie, 1995; Cashman and O’Connor, 2008): (1) low blood vitamin K in patients with bone fractures; (2) concentration of circulating under gamma-carboxylated osteocalcin associated with age, low bone mineral density and hip fracture risk; (3) anticoagulant therapy associated with decreased bone density; and (4) decreased bone loss and calcium excretion with Vitamin K supplementation.
Both in vitro and in vivo studies to date suggest a role of vitamin K in the regulation of multiple enzymes involved in sphingolipid metabolism within the myelin-rich regions in the brain (Denisava and Booth, 2005). The brain is enriched with sphingolipids, which are important membrane constituents and major lipid signaling molecules that have a role in motor and cognitive behavior.
Vitamin K requirement of mammals is met by a combination of dietary intake and microbial biosynthesis in the gut, which may involve intestinal microorganisms (such as Escherichia coli). Animals that practice some degree of coprophagy, such as the dog, can utilize much of the vitamin K that is eliminated in the feces. In rats, the majority of menaquinone absorbed resulted from fecal ingestion compared to dietary sources or from direct synthesis and absorption from the intestine (Kindberg et al., 1987). Duello and Matschiner (1971a, b) isolated 19 vitamin K analogs in dog liver and suggested that most were absorbed from the intestine, all of which were presumably derived from bacterial synthesis in the intestine. Animal feces contain substantial amounts of vitamin K even when none is present in feed. Despite the intestinal synthesis, animals can be rendered deficient when fed vitamin K-free diets, and coprophagy is prevented if animals are maintained germ-free or if a vitamin K antagonist is given. Difficulties in demonstrating dietary requirement in many species include the varying degrees to which they utilize vitamin K synthesized by intestinal bacteria and the degree to which different species practice coprophagy.
Vitamin K requirements can be altered by age, sex, breed, antivitamin K factors, disease conditions and any condition influencing lipid absorption or altering intestinal flora. Rapid rate of food passage through the digestive tract may also influence vitamin K synthesis in poultry. Swine are able to obtain more benefit from vitamin K intestinal synthesis than are poultry. First defecation in pigs, for a specific portion of diet, may occur about 15 hours after feeding, but most of the given meal will be retained in the tract appreciably longer. A comparable time period for chickens would be approximately three hours (Griminger, 1984) and consequently, less vitamin K synthesis and absorption occur. For dogs and cats, a slower rate of food passage, more similar to the pig vs. the chicken, would be expected.
Excess vitamin A and calcium has been shown to influence vitamin K requirements. Rats fed excess retinol had two- to three-fold higher carboxylase activities of endogenous, prothrombin precursors, which is an indicator of vitamin K deficiency. Hall et al. (1991) reported a hemorrhagic condition in pigs fed 2.7% dietary calcium. The condition was cured with vitamin K supplementation and was not produced in treatments receiving less dietary calcium.
Neither vitamin K absorption, function nor requirement has been studied in cats. Requirements for vitamin K for both dogs and cats are low compared to other species. Although no evidence of vitamin K deficiency was observed in dogs or cats fed a diet containing 60 µg of vitamin K activity per kg (27.3 µg per lb), 75% of rats fed this diet died of hemorrhage (Reber and Malhotra, 1961).
Because of the wide species variation in vitamin K intakes and the variable capacity of gut microflora for synthesis, the actual requirements for vitamin K have been difficult to determine. Dietary vitamin K requirements for dogs are low compared to other species. Requirements range from as low as 1 µg per kg (0.45 µg per lb) of body weight per day for dogs to a range of 100 to 300 µg per kg (45.5 to 136 µg per lb) per day for chicken and turkey poults. These values are equivalent to 50 µg per kg (22.7 µg per lb) diet in dogs and approximately 0.5 to 2.0 mg per kg (0.23 to 0.91 mg per lb) diet for poultry. During studies with bile diversion in adult dogs, 0.5 µg of vitamin K per kg (0.23 µg per lb) of body weight given intravenously supported adequate prothrombin formation, whereas growing puppies required 10 to 15 µg per kg (4.5 to 6.8 µg per lb) of body weight which declined to 5 µg or less per kg (2.3 µg per lb) body weight as the dogs approached mature weight (Quick et al., 1954; 1962). It is doubtful that supplemental vitamin K is necessary for the normal dog. The NRC (2006) recommendation for vitamin K for the various dog life stages range from 1.60 to 1.64 mg per kg (0.73 to 0.75 mg per lb) of diet. The AAFCO (2007) has no recommended vitamin K requirement for dogs.
The NRC (2006) recommended vitamin K concentrations for all cats in the various life stages is 1.0 mg per kg (0.45 mg per lb) of diet. The Association of American Feed Control Officials (AAFCO, 2007) recommends 100 µg per kg (45.5 µg per lb) for cats in growth, reproduction, and maintenance, with the notation that vitamin K does not need to be added unless diets contain greater than 25% fish on a dry matter basis. The recommendation is warranted because vitamin K deficiency has been observed in cats fed certain commercial foods containing high levels of salmon or tuna (Hand et al., 2010).
There are two major natural sources of vitamin K, phylloquinones (vitamin K1) in plant sources and menaquinones (vitamin K2) produced by bacterial flora. Vitamin K derived from bacterial flora would be considered the most important source for ruminants since adequate vitamin K is available even when animals are fed vitamin K-free diets.
Vitamin K is present in fresh dark-green plants. It is abundant in pasture and green roughages, thus providing high quantities of vitamin K to grazing livestock. Swine, poultry and feedlot animals would, however, receive little vitamin K from diets based on grains and oilseed meals.
Green leaves are the richest natural sources of vitamin K1. Light is important for its formation, and parts of plants that do not normally form chlorophyll contain little vitamin K. However, natural loss of chlorophyll as in the yellowing of leaves during autumn does not bring about a corresponding change in vitamin K. Alfalfa meal is a good plant source of vitamin K, while liver and fish meal are good animal sources of the vitamin. All by-product feedstuffs of animal origin, including fish meal and fish liver oils, are much higher in vitamin K after they have undergone extensive bacterial putrefaction. Cereals and oil cakes contain only small amounts of vitamin K.
The menaquinones (vitamin K2) are produced by the bacterial flora in animals and are especially important in providing the vitamin K requirements of most mammals. However, the chick does not receive sufficient vitamin K from intestinal microbial synthesis (Scott et al., 1982). The type of diet, independent of vitamin K concentration, will influence total menaquinone synthesis. Rats fed a diet based on boiled white rice had less menaquinone production and more severe vitamin K deficiency than animals consuming diets based on autoclaved black-eyed beans (Mathers et al., 1990).
Vitamin K production in the rumen of ruminants and subsequent passage along the small intestine, a region of active absorption, make such synthesized vitamin K highly available to the host. In nonruminants, the site of synthesis is in the lower gut, an area of poor absorption. Thus, availability to the host is limited unless the animal practices coprophagy, in which case the synthesized vitamin K is highly available.
Vitamin K1 is not utilized by the feed industry, due to cost and lack of a stabilized form. Instead, water-soluble menadione (vitamin K3) salts are used to provide vitamin K activity in feeds. Because of poor stability, menadione is not used as the pure vitamin, but is produced as water-soluble salts (Table 5-1). Water-soluble derivatives of menadione, including menadione sodium bisulfite (MSB), menadione sodium bisulfite complex (MSBC), and menadione dimethylpyrimidinol bisulfite (MPB), are the principal forms of vitamin K included in pet food because of their stability during manufacturing and storage. The menadione concentration is 50% for MSB, 45.4% of MPB, and 33% for MSBC (Table 5-1) (Schneider, 1986).
The major clinical sign of vitamin K deficiency in all species is impairment of blood coagulation (Griminger, 1984). Other clinical signs include low prothrombin levels, increased clotting time and hemorrhaging. Prolonged clotting times and excessive bleeding have been reported in vitamin K deficiency in cats and dogs under various conditions (Hand et al., 2010). Vitamin K deficiency usually occurs secondary to other conditions such as malabsorptive diseases (inflammatory bowel disease), ingestion of coagulant antagonists (coumarin, indanedione), destruction of gut microflora by antibiotic therapy (sulfonamides and broad-sprectrum antibiotics) and congenital defects. An example of a congenital defect is a γ-glutamyl carboxylase defect found in the Devon rex breed of cats (Hand et al., 2010). In its most severe form, a lack of vitamin K will cause subcutaneous and internal hemorrhages, which can be fatal. Vitamin K deficiency can result from dietary deficiency, lack of microbial synthesis within the gut, inadequate intestinal absorption or inability of the liver to use the available vitamin K. Accidental dicumarol (warfarin) poisoning should be considered in dogs or cats observed with hemorrhagic syndromes (Kohn et al., 2003; Petterino et al., 2004; Douketis and Spyropoulos, 2010).
Measurement of clotting time or prothrombin has been used to evaluate the body status of vitamin K 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. The currently available method for measuring the inadequacy of vitamin K intake is to measure the plasma concentration of one of the vitamin K-dependent clotting factors, prothrombin (factor II), factor VII, factor IX, or factor X (Suttie, 1984). 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 greater than 40 to 60 seconds; with severe deficiency, prothrombin time can be as long as 5 to 6 minutes.
Vitamin K deficiency signs are only occasionally described for dogs; however, accidental intake of dicumarol types of rat poison such as warfarin and diphenadione (vitamin K antagonist) will result in a hemorrhagic condition in dogs (Kerr, 1986; Mount and Kass, 1989; Petterino et al., 2004; Douketis and Spyropoulos, 2010). Clinical signs in dogs include paleness and evidence of slow but persistent bleeding from a number of sites including gums, bowel, and several injection punctures (Kerr, 1986). Prothrombin time in untreated animals was 7.5 minutes compared to 10 seconds after six injections with vitamin K. Dicumarol also induces liver parenchymal cell ultrastructural changes (Barnhart et al., 1964), such as collapse of membranous elements of the endoplasmic reticulum around the mitochondria and reduced cytoplasmic ribosome concentration.Vitamin K deficiency characterized by excessive bleeding was reported in a Boston terrier with bile and cystic duct obstructions (Neer and Hedlund, 1989). The deficiency has also been induced experimentally by biliary diversion; dogs developed depressed levels of plasma prothrombin and exhibited massive hemorrhage (Quick et al., 1962). Vitamin K absorption from both diet and intestinal bacterial synthesis was apparently reduced. Some reports indicate that newborn pups suspected of vitamin K deficiency sometimes respond to vitamin K therapy.
Vitamin K deficiency is rare in cats. However, vitamin K antagonism attributable to ingestion of rodenticides containing warfarin or related compounds is a cause of hemorrhaging in cats. Clinical signs of vitamin K deficiency could include hematomas in the elbows, hemorrhage in the conjunctiva, extensive hemorrhage in and around the stifle joint, with necropsy revealing extensive hemorrhage in the bladder, sublumbar area, pelvic canal and perineum (Maddison et al., 1990). Kohn et al. (2003) reported hemorrhage in seven cats with suspected anticoagulant rodenticide intoxication. With vitamin K therapy, plasma coagulation times improved in all cats and returned to normal in 1 to 5 days.Vitamin K is fat soluble, and fat malabsorption may result in a deficiency in cats (Green 1983; Prentice, 1985). Vitamin K deficiency associated with fat malabsorption attributable to exocrine pancreatic insufficiency has been reported in a cat (Perry et al., 1989).
Apparent genetic abnormalities may bring about vitamin K deficiencies in cats. A complex coagulation failure, which includes factor X deficiency, has been observed in Devon rex cats in the United Kingdom (Evans, 1985; Littlewood et al., 1995), and a possibly similar abnormality has been described in a family of boxers (Dodds, 1981). Maddison et al. (1990) suggested that vitamin K-dependent hemorrhaging in Devon rex cats in Australia could be due to malabsorption of vitamin K or possibly to a defective epoxide reductase activity. In this condition there are marked reductions in factors II, VII, IX and X, the vitamin-K dependent coagulation factors. This genetic effect appears to be inherited as an autosomal trait.
As long as bacterial synthesis in the intestinal tract remains functional and dog and cat foods contain animal by-products rich in vitamin K (e.g., liver and fish meal), supplementary dietary vitamin K is not necessary. Supplementary vitamin K has not been proven to be beneficial to dogs and cats unless they have consumed a source of anticoagulants such as dicumarol.When dogs and cats accidentally consume a dicumarol-based rat poison (e.g., warfarin), vitamin K should be administered subcutaneously or orally. When vitamin K1 is given it takes six to 12 hours for clinically significant synthesis of clotting factors to occur after vitamin therapy (Squires, 1993). Warfarin intoxication can usually be adequately treated with 1 mg/kg/day vitamin K1 orally or subcutaneously for a week. Second-generation, long-acting anticoagulants may require 2.5 to 5.0 mg/kg/day vitamin K1 orally or subcutaneously for up to six weeks. Two days after cessation of vitamin K1 administration for both short- and long-acting anticoagulant rodenticide intoxication, coagulation function should be checked (ideally, by measurement of prothrombin time). In dogs receiving warfarin, vitamin K1administered orally or parenterally reduced prothrombin time, but vitamin K3 (menadione) was less effective. In treating warfarin poisoning in dogs, menadione compared to vitamin K1 is not as prompt, not as potent and not as prolonged in action (Kerr, 1986). However, on a weight basis, menadione is about as effective as vitamin K1 in preventing prolongation of clotting time, whereas it may take several times as much menadione as K1 to cure an existing deficiency (NRC, 1985). Marks (1975) observed that the most common cause of vitamin K deficiency in veterinary practice is the accidental poisoning of animals with warfarin.
Antagonists other than dicumarol promote vitamin K deficiency. Mycotoxins are toxic substances produced by molds. Vitamin K supplementation may be helpful in correcting vitamin K deficiency induced by mycotoxins. Use of sulfa drugs, antibiotics and other medications will likely reduce intestinal synthesis of the vitamin. Sulfonamides and broad-spectrum antibiotic drugs can virtually sterilize the lumen of the intestine (McDowell, 2000). Various diseases or conditions affecting the gastrointestinal tract that require oral administration of certain antimicrobial drugs will decrease synthesized vitamin K.
To assure proper vitamin K nutrition, supplementation of pet foods with vitamin K is advisable. For dogs it may be prudent to provide 22 µg menadione (or vitamin K equivalent) per kg (10 µg per lb) of body weight daily for adult maintenance and 44 µg per kg (20 µg per lb) of body weight during growth (NRC, 1985). This would be more than supplied by a dry diet concentration of 1.0 mg menadione per kg (0.45 mg per lb).
For cats, a supplemental level of 100 µg per kg (45.5 µg per lb) is suggested by NRC (1986) and at least 1 mg per kg (0.45 mg per lb) by Ralston Purina (1987). AAFCO (1992) recommends a minimum of 0.1 mg per kg (0.045 mg per lb) vitamin K for cat foods. This recommendation relates to added vitamin K activity required for cat diets containing more than 25% fish on a dry-matter basis, since fish oil contains antivitamin K activity (Corbin, 1996).
For prevention or treatment of a vitamin K deficiency, both dietary and injectable sources are used. Stability of the naturally occurring sources of vitamin K is poor. However, stability of the water-soluble menadione salts is satisfactory in multivitamin premixes unless trace minerals are present (Frye, 1978). Basic pH conditions also accelerate the destruction of menadione salts; thus, soluble or slightly soluble basic mineral substances should not be included in multivitamin premixes containing menadione. Gadient (1986) concludes that vitamin K in the form of menadione sodium bisulfite (MSB) or menadione sodium bisulfite complex (MSBC) is very sensitive to moisture and trace minerals, sensitive to light and basic pH, and moderately sensitive to reduction and acid pH. Choline chloride is particularly destructive to vitamin K with an average monthly loss of 34% to 38% for MSBC and menadione dimethylpyrimidinol bisulfite (MPB) when stored in a vitamin premix with choline (Gadient, 1986). Less water-soluble forms or coated K3forms exhibit superior stability as compared to uncoated MSB. At higher temperatures, uncoated MSB preparations lost about 60% activity (Gropp and Mehringer, 1990). Heat, moisture and trace minerals increase the rate of destruction of menadione salts in both pressure-pelleted and extruded feeds (Hoffmann-La Roche, 1981). For these reasons, greater quantities of vitamin K3 are recommended in premixes that contain large quantities of choline chloride and certain trace minerals, especially when premixes are exported or stored for an extended period of time (Schneider, 1986).
Toxic effects of the vitamin K family are manifested mainly as hematological and circulatory derangements. In dogs, Heinz body hemolytic anemia (denatured globin chains within red blood cells) was reported at dosages of 26 mg menadione per kg (11.8 mg per lb) (Fernandez et al., 1984). Not only is species variation encountered, but profound differences are observed in the ability of the various vitamin K compounds to evoke a toxic response (Barash, 1978). Vitamin K administered to cats has resulted in hypersensiticity reactions (e.g., angioedema) (Iraguen et al., 2011). The naturally occurring forms of vitamin K, phylloquinone and menaquinone, are nontoxic at very high dosage levels. The synthetic menadione compounds, however, have shown toxic effects when fed to humans, rabbits, dogs and mice in excessive amounts. The toxic dietary level of menadione is at least 1,000 times the dietary requirement (NRC, 1987). Menadione compounds can safely be used at low levels to prevent the development of a deficiency but should not be used to treat a hemorrhagic condition. The LD50 for a single parenteral dose of menadione or its water-soluble derivative is in the range of 75 to 200 mg per kg (34 to 91 mg per lb) of body weight for chicks, mice, rats, rabbits and dogs, and the LD50 for a single oral dose is 600 to 800 mg per kg (273 to 364 mg per lb) of body weight, at least for chicks and mice. Specifically for dogs, the LD50 was 100 to 150 mg per kg (45.5 to 68.2 mg per lb) body weight (Richards and Shapiro, 1945). Vitamin K toxicity data for cats is not available (NRC, 1987).
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