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side chain of phylloquinone has been replaced
by a side chain built up of 2–13 prenyl units.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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