Saturday, June 22, 2013

All about Vitamin K


THE ROLE OF VITAMIN K
Green plants are a nutritional source of vitamin K, an essential cofactor in the g-carboxylation of multiple Glu residues of several clotting factors and anticoagulant proteins. The vitamin K–dependent formation of g-carboxy-glutamate (Gla) residues permits the appropriate interactions of clotting factors, Ca2+, and membrane phospholipids and modulator proteins (Figures 54–1, 54–2, and 54–3). Oral anticoagulant drugs (e.g., coumadin, Figure 54–5) block Gla formation and thereby inhibit clotting; excess vitamin K1 can reverse these effects.
CHEMISTRY AND OCCURRENCE
Vitamin K activity is associated with at least two distinct natural substances, designated as vitamin K1 and vitamin K2. Vitamin K1, or phylloquinone (phytonadione), is 2-methyl-3-phytyl-1, 4-naphthoquinone; it is found in plants and is the only natural vitamin K available for therapeutic use. Vitamin K2 is actually a series of compounds (the menaquinones) in which the phytyl side chain of phylloquinone has been replaced by a side chain built up of 2–13 prenyl units. Considerable synthesis of menaquinones occurs in gram-positive bacteria; indeed, intestinal flora synthesize the large amounts of vitamin K contained in human and animal feces. In animals, menaquinone-4 can be synthesized from the vitamin precursor menadione (2-methyl-1,4- naphthoquinone), or vitamin K3. Depending on the bioassay system used, menadione is at least as active on a molar basis as phylloquinone.
PHYSIOLOGICAL FUNCTIONS AND PHARMACOLOGICALACTIONS
Phylloquinone and menaquinones are virtually devoid of pharmacodynamic activity. However, in subjects deficient in vitamin K, the vitamin performs its normal physiological function: to promote the biosynthesis of the g-carboxy-glutamate (Gla) forms of factors II (prothrombin), VII, IX, and X, anticoagulant proteins C and S, protein Z (a cofactor to the inhibitor of Xa), the bone Gla protein osteocalcin, matrix Gla protein, and growth arrest–specific protein 6 (Gas6). Figure 54–6 summarizes the coupling of the vitamin K cycle with glutamate carboxylation. Vitamin K, as KH2, the reduced hydroquinone, is an essential cofactor for g-glutamyl carboxylase. Using KH2, O2, CO2, and the glutamate-containing substrate, the enzyme forms a g-carboxy-glutamatyl protein (Gla protein) and concomitantly, the 2,3-epoxide of vitamin K. A coumarin-sensitive 2,3-epoxide reductase regenerates KH2. The g-glutamyl carboxylase and epoxide reductase are integral membrane proteins of the endoplasmic reticulum and function as a multicomponent complex. Two natural mutations in g-glutamyl carboxylase lead to bleeding disorders. With respect to proteins affecting blood coagulation, these reactions occur in the liver, but g-carboxylation of Glu also occurs in lung, bone, and other cell types.
HUMAN REQUIREMENTS
In patients made vitamin K–deficient by a starvation diet and antibiotic therapy for 3–4 weeks, the minimum daily requirement is estimated to be 0.03 mg/kg of body weight and possibly as high as 1 mg/kg, which is approximately the recommended intake for adults (70 mg/day).
SYMPTOMS OF DEFICIENCY
The chief manifestation of vitamin K deficiency is an increased bleeding tendency (see discussion of hypoprothrombinemia in section on oral anticoagulants, above). Ecchymoses, epistaxis, hematuria, GI bleeding, and postoperative hemorrhage are common; intracranial hemorrhage may occur. Hemoptysis is uncommon. The discovery of a vitamin K–dependent protein in bone suggests that the fetal bone abnormalities associated with the administration of oral anticoagulants during the first trimester of pregnancy (“fetal warfarin syndrome”) may be related to a deficiency of the vitamin. Evidence indicates a role for vitamin K in adult skeletal maintenance and osteoporosis. Low concentrations of the vitamin are associated with deficits in bone mineral density and fractures; vitamin K supplementation increases the carboxylation state of osteocalcin and also improves bone mineral density, but the relationship of these two effects is unclear. Bone mineral density in adults is not changed by therapeutic use of oral anticoagulants, but new bone formation may be impaired.
ABSORPTION, FATE, AND EXCRETION
The mechanism of intestinal absorption of compounds with vitamin K activity varies with their solubility. In the presence of bile salts, phylloquinone and the menaquinones are adequately absorbed from the intestine, almost entirely by way of the lymph. Phylloquinone is absorbed by an energy-dependent, saturable process in proximal portions of the small intestine; menaquinones are absorbed by diffusion in the distal portions of the small intestine and in the colon. Following absorption, phylloquinone is incorporated into chylomicrons in close association with triglycerides and lipoproteins. The extremely low phylloquinone levels in newborns may be partly related to very low plasma lipoprotein concentrations at birth and may lead to an underestimation of vitamin K tissue stores. Absorbed phylloquinone and menaquinones are concentrated in the liver, but the concentration of phylloquinone declines rapidly. Menaquinones, produced in the lower bowel, are less biologically active than phylloquinone due to their long side chain. Very little vitamin K accumulates in other tissues. Apparently, there is only modest storage of vitamin K in the body. Under circumstances in which lack of bile interferes with absorption of vitamin K, hypoprothrombinemia develops slowly over a period of several weeks.
THERAPEUTIC USES
Vitamin K is used therapeutically to correct the bleeding tendency or hemorrhage associated with its deficiency. Vitamin K deficiency can result from inadequate intake, absorption, or utilization of the vitamin, or as a consequence of the action of a vitamin K antagonist. Phylloquinone (AQUAMEPHYTON, KONAKION, MEPHYTON) is available as tablets and in a dispersion with buffered polysorbate and propylene glycol (KONAKION) or polyoxyethylated fatty acid derivatives and dextrose (AQUAMEPHYTON). KONAKION is administered only intramuscularly. AQUAMEPHYTON should be given by subcutaneous or intramuscular injection because severe reactions resembling anaphylaxis have followed its intravenous administration.
Inadequate Intake
After infancy, coagulopathy due to dietary deficiency of vitamin K is extremely rare: Vitamin K is present in many foods and also is synthesized by intestinal bacteria. Occasionally, the use of a broad-spectrum antibiotic may produce a hypoprothrombinemia that responds readily to small doses of vitamin K and reestablishment of normal bowel flora. Hypoprothrombinemia can occur in patients receiving prolonged intravenous alimentation. Patients on total parenteral nutrition should receive phylloquinone (1 mg/week, the equivalent of ~150 mg/day).
Hypoprothrombinemia of the Newborn
Healthy newborn infants show decreased plasma concentrations of vitamin K–dependent clotting factors for a few days after birth, the time required to obtain an adequate dietary intake of the vitamin and to establish a normal intestinal flora. In premature infants and in infants with hemorrhagic disease of the newborn, the concentrations of clotting factors are particularly depressed, possibly reflecting vitamin K deficiency. Measurements of non-g-carboxylated prothrombin suggest that true vitamin K deficiency occurs in ~3% of live births. Hemorrhagic disease of the newborn has been associated with breast-feeding; human milk has low concentrations of vitamin K. In addition, the intestinal flora of breast-fed infants may lack microorganisms that synthesize the vitamin. Commercial infant formulas are supplemented with vitamin K. In the neonate with hemorrhagic disease of the newborn, the administration of vitamin K raises the concentration of these clotting factors to the level normal for the newborn infant and controls the bleeding tendency within ~6 hours. The routine administration of 1 mg phylloquinone intramuscularly at birth is required by law in the U.S.. This dose may have to be increased or repeated if the mother has received anticoagulant or anticonvulsant drug therapy or if the infant develops bleeding tendencies. Alternatively, some clinicians treat mothers who are receiving anticonvulsants with oral vitamin K prior to delivery (10–20 mg/day for 2 weeks).
Inadequate Absorption
Vitamin K is poorly absorbed in the absence of bile. Thus, hypoprothrombinemia may be associated with either intrahepatic or extrahepatic biliary obstruction or a severe defect in the intestinal absorption of fat from other causes.
Biliary Obstruction or Fistula
Bleeding that accompanies obstructive jaundice or biliary fistula responds promptly to the administration of vitamin K. Oral phylloquinone administered with bile salts is both safe and effective and should be used in the care of the jaundiced patient, both preoperatively and postoperatively. In the absence of significant hepatocellular disease, the prothrombin activity of the blood rapidly returns to normal. If oral administration is not feasible, a parenteral preparation of vitamin K should be used; the usual dose is 10 mg/day.
Malabsorption Syndromes
Among the disorders that result in inadequate absorption of vitamin K from the GI tract are: cystic fibrosis, sprue, inflammatory bowel disease, dysentery, and extensive bowel resection. Since drugs that greatly reduce the bacterial population of the bowel are used frequently in these disorders, the availability of the vitamin may be further reduced. Moreover, dietary restrictions also may limit the availability of the vitamin. For immediate correction of the deficiency, parenteral therapy should be used.
Drug-Induced Hypoprothrombinemia
Anticoagulant drugs such as warfarin act as competitive antagonists of vitamin K and interfere with the hepatic biosynthesis of Gla-containing clotting factors. The treatment of bleeding caused by oral anticoagulants is discussed above. Vitamin K may be of help in combating the bleeding and hypoprothrombinemia that follow the bite of the tropical American pit viper or other species whose venom destroys or inactivates prothrombin.

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