Vitamin K

A. Nutrition & Biochemistry

Source :
Understanding Nutrition 14
Harper’s Biochemistry 30

❯ LEARN IT Identify the main roles, defiiency symptoms, and sources for vitamin K.
Vitamin K appropriately gets its name from the Danish word koagulation (“coagulation” or
“clotting”). Its primary action is blood clotting, where its presence can make the difference between
life and death. Blood has a remarkable ability to remain liquid, but it can clot within seconds when the
integrity of that system is disturbed.

A. roles in the Body

1) Clotting
More than a dozen different proteins and the mineral calcium are involved in making a blood clot.
Vitamin K is essential for the activation of several of these proteins, among them prothrombin, made
by the liver as a precursor of the protein thrombin (see Figure 11-11). When any of the blood-clotting
factors is lacking, hemorrhagic disease results. If an artery or vein is cut or broken, bleeding goes
unchecked. Of course, this is not to say that hemorrhaging is always caused by vitamin K defiiency.
Another cause is the genetic disorder hemophilia, which is neither caused nor cured by vitamin K.

VITAMIN K IS REQUIRED FOR SYNTHESIS OF BLOOD-

CLOTTING PROTEINS
Vitamin K was discovered as a result of investigations into the cause of a bleeding disorder,
hemorrhagic (sweet clover) disease of cattle and of chickens fed on a fat-free diet. The missing
factor in the diet of the chickens was vitamin K, while the cattle feed contained dicumarol, an
antagonist of the vitamin.
Antagonists of vitamin K are used to reduce blood coagulation in patients at risk of thrombosis;
the most widely used is warfarin.

2) Metabolism of Bone
Vitamin K also participates in the metabolism of bone proteins, most notably osteocalcin. Without
vitamin K, osteocalcin cannot bind to the minerals that normally form bones, resulting in low bone
density.* An adequate intake of vitamin K helps to decrease bone turnover and protect against
fractures. The effectiveness of vitamin K supplements on bone health is inconclusive.40

3) Others
Vitamin K is historically known for its role in blood clotting, and more recently for its participation in
bone building, but researchers continue to discover proteins needing vitamin K’s assistance. These
proteins have been identified in the plaques of atherosclerosis, the kidneys, and the nervous system.

B. Chemistry & Structure

Three compounds have the biological activity of vitamin K (Figure 44–7): phylloquinone, the
normal dietary source, found in green vegetables; menaquinones, synthesized by intestinal
bacteria, with differing lengths of side chain; and menadione and menadiol diacetate, synthetic
compounds that can be metabolized to phylloquinone. Menaquinones are absorbed to some
extent, but it is not clear to what extent they are biologically active as it is possible to induce
signs of vitamin K deficiency simply by feeding a phylloquinonedeficient diet, without inhibiting
intestinal bacterial action.

Vitamin K Is the Coenzyme for Carboxylation of Glutamate in postsynthetic Modification of

Calcium-Binding proteins
Vitamin K is the cofactor for the carboxylation of glutamate residues in the postsynthetic
modification of proteins to form the unusual amino acid -carboxyglutamate (Gla) (Figure 44–
8).
Initially, vitamin K hydroquinone is oxidized to the epoxide, which activates a glutamate residue
in the protein substrate to a carbanion, which reacts nonenzymically with carbon dioxide to
form carboxyglutamate. Vitamin K epoxide is reduced to the quinone by a warfarin-sensitive
reductase, and the quinone is reduced to the active hydroquinone by either the same warfarin-
sensitive reductase or a warfarin-insensitive quinone reductase. In the presence of warfarin,
vitamin K epoxide cannot be reduced, but accumulates and is excreted. If enough vitamin K (as
the quinone) is provided in the diet, it can be reduced to the active hydroquinone by the
warfarin-insensitive enzyme, and carboxylation can continue, with stoichiometric utilization of
vitamin K and excretion of the epoxide. A high dose of vitamin K is the antidote to an overdose
of warfarin. Prothrombin and several other proteins of the blood-clotting system (Factors VII,
IX, and X, and proteins C and S, Chapter 52) each contain 4 to 6 -carboxyglutamate residues. -
Carboxyglutamate chelates calcium ions, and so permits the binding of the blood-clotting
proteins to membranes. In vitamin K deficiency, or in the presence of warfarin, an abnormal
precursor of prothrombin (preprothrombin) containing little or no -carboxyglutamate, and
incapable of chelating calcium, is released into the circulation.
Vitamin K Is Also Important in Synthesis of Bone & Other Calcium-Binding proteins
A number of other proteins undergo the same vitamin K-dependent carboxylation of glutamate to
 carboxyglutamate, including osteocalcin and the matrix Gla protein in bone, nephrocalcin in kidney and
the product of the growth arrest specific gene Gas6, which is involved in both the regulation of
differentiation and development in the nervous system, and control of apoptosis in other tissues. All of
these -carboxyglutamate containing proteins bind calcium, which causes a conformational change so that
they interact with membrane phospholipids. The release into the circulation of osteocalcin provides an
index of vitamin D status.

Vitamin K Deficiency Chapter 1 explains that a primary deficiency

develops in response to an inadequate dietary intake whereas a secondary deficiency occurs for other reasons. A
primary deficiency of vitamin K is rare, but a secondary deficiency may occur in two circumstances.
First, whenever fat absorption falters, as occurs when bile production fails, vitamin K absorption diminishes.
Second, some drugs disrupt vitamin K’s synthesis and action in the body: antibiotics kill the vitamin K–
producing bacteria in the intestine, and anticoagulant drugs interfere with vitamin K metabolism and activity.
Excessive bleeding due to a vitamin K deficiency can be fatal.
Newborn infants present a unique case of vitamin K nutrition because they are born with a sterile intestinal
tract, and the vitamin K–producing bacteria take weeks to establish themselves. Furthermore, vitamin
K is minimally transported across the placenta and its concentration in breast milk is low. At the same time,
plasma prothrombin concentrations are low, which reduces the likelihood of fatal blood clotting during the
stress of birth. To prevent hemorrhagic disease in the newborn, a single dose of vitamin K is given at birth by
intramuscular injection.41 Concerns that vitamin K given at birth raises the risks of childhood cancer are
unfounded.
Vitamin K Toxicity
Toxicity is not common, and no adverse effects have been reported with high intakes of vitamin K. Therefore, a
UL has not been established. High doses of vitamin K can, however, reduce the effectiveness of anticoagulant
drugs used to prevent blood clotting. People taking these drugs can continue eating their usual diets. Their blood
clotting times should be monitored closely and drug dosages adjusted accordingly.

Vitamin K recommendations and Sources

Like vitamin D, vitamin K can be obtained both from foods and from a nonfood source. Bacteria in the GI tract
synthesize vitamin K, although the amount is insufficient to meet the body’s needs and its bioavailability is
limited. Therefore the diet must also supply vitamin K, which is found primarily in leafy green vegetables such
as spinach and kale, fruits such as avocado and kiwi, and some vegetable oils such as soybean oil. Naturally
occurring vitamin K in foods is phylloquinone (sometimes called vitamin K1), whereas vitamin K produced by
GI bacteria is menaquinone (sometimes called vitamin K2).
B. Pharmacology
Source :
1) Katzung
2) Goodman & Gillman
3) Rang n Dale
4) Lipincott
VITAMIN K
Vitamin K is a fat-soluble substance found primarily in leafy green vegetables. The dietary requirement
is low because the vitamin is additionally synthesized by bacteria that colonize the human intestine. Two natural
forms exist: vitamins K1 andK2. Vitamin K1 (phytonadione; Figure 34–5) is found in food. Vitamin K2
(menaquinone) is found in human tissues and is synthesized by intestinal bacteria. Vitamins K 1 and K2 require
bile salts for absorption from the intestinal tract. Vitamin K1 is available clinically in oral and parenteral forms.
Onset of effect is delayed for 6 hours but the effect is complete by 24 hours when treating depression of
prothrombin activity caused by excess warfarin or vitamin K deficiency. Intravenous administration of vitamin
K1 should be slow, as rapid infusion can produce dyspnea, chest and back pain, and even death. Vitamin K
repletion is best achieved with intravenous or oral administration because its bioavailability after subcutaneous
administration is erratic. Vitamin K1 is currently administered to all newborns to prevent the hemorrhagic
disease of vitamin K deficiency, which is especially common in premature infants.
The water-soluble salt of vitamin K3 (menadione) should never be used in therapeutics. It is particularly
ineffective in the treatment of warfarin overdosage. Vitamin K deficiency frequently occurs in hospitalized
patients in intensive care units because of poor diet, parenteral nutrition, recent surgery, multiple antibiotic
therapy, and uremia. Severe hepatic failure results in diminished protein synthesis and a hemorrhagic diathesis
that is unresponsive to vitamin K.[1]

The Role of Vitamin K

Vitamin K confers biologic activity upon prothrombin and factors VII, IX, and X by participating in
their postribosomal modification.[1] Green plants are a nutritional source of vitamin K for humans, in whom
vitamin K is an essential cofactor in the γ-carboxylation of multiple glutamate residues of several clotting factors and
anticoagulant proteins. The vitamin K–dependent formation of Gla residues permits the appropriate interactions of
clotting factors, Ca2+, and membrane phospholipids and modulator proteins (see Figures 32–1, 32–2, and 32–3).
Vitamin K antagonists (coumarin derivatives) block Gla formation and thereby inhibit clotting; excess vitamin K1 can
reverse the effects.
Vitamin K activity is associated with at least two distinct natural substances, designated as vitamin K1 and vitamin K2.
Vitamin K1, or phytonadione (also referred to as phylloquinone), 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 actually is a series of
compounds (the menaquinones) in which the phytyl side chain of phytonadione 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 synthesizes the large amounts of vitamin K contained in human and animal feces. Menadione is at
least as active on a molar basis as phytonadione.[2]

Physiological Functions and Pharmacological Actions

Phytonadione and menaquinones promote the biosynthesis of the clotting factors II (prothrombin), VII, IX, and X as
well as the anticoagulant proteins C and S and protein Z (a cofactor to the inhibitor of Xa).
Figure 32–6 summarizes the coupling of the vitamin K cycle with glutamate carboxylation. The γ-glutamyl
carboxylase and epoxide reductase are integral membrane proteins of the endoplasmic reticulum and function as a
multicomponent complex. With respect to proteins affecting blood coagulation, these reactions occur in the liver, but
γ-carboxylation of glutamate also occurs in lung, bone, and other cell types. Mutations in γ-glutamyl carboxylase lead
to bleeding disorders.

Human Requirements
In patients rendered vitamin K deficient by a starvation diet and antibiotic therapy for 3–4 weeks, the minimum daily
requirement is estimated to be 0.03 μg/kg of body weight and possibly as high as 1 μg/kg, which is approximately the
recommended intake for adults (70 μg/d).

Symptoms of Deficiency
The major clinical manifestation of vitamin K deficiency is bleeding. Ecchymoses, epistaxis, hematuria, GI bleeding,
and postoperative hemorrhage are common; intracranial hemorrhage may occur. Hemoptysis is uncommon. The
presence of vitamin K–dependent proteins in bone such as osteocalcin and matrix Gla protein may explain why fetal
bone abnormalities can occur with maternal warfarin administration in the first trimester of pregnancy. Vitamin K
plays a role in adult skeletal maintenance and the prevention of osteoporosis. Low concentrations of the vitamin are
associated with decreased bone mineral density and subsequent fractures; vitamin K supplementation increases the
carboxylation state of osteocalcin and improves bone mineral density, but the relationship between these effects is
unclear. Bone mineral density in adults does not
appear to be changed with long-term warfarin therapy, but new bone formation may be affected.

Toxicity
Phytonadione and the menaquinones are nontoxic. Menadione and its derivatives (synthetic forms of vitamin K) may
produce hemolytic anemia and kernicterus in neonates and should not be used as therapeutic forms of vitamin K.

ADME
The mechanism of intestinal absorption of compounds with vitamin K activity varies depending on their solubility. In
the presence of bile salts, phytonadione and the menaquinones are adequately absorbed from the intestine,
phytonadione by an energy-dependent, saturable process in proximal portions of the small intestine and
menaquinones by diffusion in
the distal small intestine and the colon. After absorption, phytonadione is incorporated into chylomicrons in close
association with triglycerides and lipoproteins. The low phytonadione levels in newborns may partly reflect the low
plasma lipoprotein concentrations at birth and may lead to an underestimation of vitamin K tissue stores. After
absorption, phytonadione and menaquinones are concentrated in the liver, but the concentration of phytonadione
declines rapidly. Menaquinones, produced in the distal bowel, are less biologically active because of their long side
chain. Very little vitamin K accumulates in other tissues. There is only modest storage of vitamin K in the body.
Consequently, when lack of bile interferes with absorption of vitamin K, there is progressive reduction in the levels of
the vitamin K–dependent clotting factors over the course 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 warfarin.
Phytonadione is available in tablet form and in a dispersion with buffered polysorbate and propylene glycol or
polyoxyethylated fatty acid derivatives and dextrose. Phytonadione may be given by any route; however, the
subcutaneous route should be avoided in patients with a coagulopathy because of the risk of bleeding. The oral route
is preferred, but if
more rapid reversal is required, phytonadione can be given by slow intravenous infusion; it should not be given
rapidly because severe reactions resembling anaphylaxis can occur.

Inadequate Intake
After infancy, hypoprothrombinemia due to dietary deficiency of vitamin K is extremely rare. The vitamin is present
in many foods and is synthesized by intestinal bacteria. Occasionally, the use of a broad-spectrum antibiotic may itself
produce 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; to prevent
this, it is recommended that such patients receive 1 mg of phytonadione per week (the equivalent of about 150
μg/day).

Hypoprothrombinemia of the Newborn

Healthy newborn infants have decreased plasma concentrations of vitamin K–dependent clotting factors for a few
days after birth, the time required for adequate dietary intake of the vitamin and for establishment of normal
intestinal flora. Measurements of non-γ -carboxylated prothrombin suggest that vitamin K deficiency occurs in about
3% of live births.
Hemorrhagic disease of the newborn has been associated with breastfeeding; human milk has low concentrations of
vitamin K. In addition, the microbiome 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, administration of vitamin K raises the concentration of these clotting factors to levels normal for newborns
and controls the bleeding tendency within about 6 h. Routine administration of 1 mg phytonadione intramuscularly
at birth is required by law in the U.S. The dose may have to be increased or repeated if the mother has received
warfarin or anticonvulsant drug therapy or
if the infant develops a bleeding diathesis. Alternatively, some clinicians treat mothers who are receiving
anticonvulsants with oral vitamin K prior to delivery (20 mg/d for 2 weeks).

Inadequate Absorption
Vitamin K is poorly absorbed in the absence of bile. Thus, hypoprothrombinemia may be associated with intrahepatic
or extrahepatic biliary obstruction or with defective intestinal absorption of fat from other causes.

Biliary Obstruction or Fistula

Bleeding that accompanies obstructive jaundice or a biliary fistula responds promptly to the administration of
vitamin K. Oral phytonadione 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 level rapidly returns to normal. If oral administration is not feasible, a parenteral preparation
should be used. The usual daily dose of vitamin K is 10 mg.

Malabsorption Syndromes
Among the disorders that result in inadequate absorption of vitamin K from the intestinal tract are cystic fibrosis,
celiac disease, Crohn disease, ulcerative colitis, dysentery, and extensive resection of bowel. Because drugs that
reduce the bacterial population of the bowel are used frequently in many of these disorders, the availability of the
vitamin may be further
reduced. For immediate correction of the deficiency, parenteral vitamin K should be given.

Inadequate Utilization
Hepatocellular disease or long-standing biliary obstruction may be accompanied or followed by
hypoprothrombinemia. If inadequate secretion of bile salts is contributing to the syndrome, some benefit may be
obtained from the parenteral administration of 10 mg of phytonadione daily. Paradoxically, administration of large
doses of vitamin K or its analogues in
an attempt to correct the hypoprothrombinemia can be associated with severe hepatitis or cirrhosis, which may
contribute to a further reduction in the level of prothrombin.

Drug- and Venom-Induced Hypoprothrombinemia

Warfarin and its congeners 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 was described previously.
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 degrades or inactivates prothrombin.

VITAMIN K
Vitamin K (for Koagulation in German) is a fat-soluble vitamin (Fig. 24.3) occurring naturally in plants
(vitamin K1) and as a series of bacterial menaquinones (vitamin K 2) formed in the gut (see Shearer & Newman,
2008, for a review).
It is essential for the formation of clotting factors II, VII, IX and X, which are glycoproteins with
γ-carboxyglutamic acid (Gla) residues. The interaction of factors Xa and prothrombin (factor II) with Ca2 + and
phospholipid is shown in Figure 24.4. γ-Carboxylation occurs after the synthesis of the amino acid chain, and
the carboxylase enzyme requires reduced vitamin K as a co-factor (Fig. 24.5).

Binding does not occur in the absence of γ-carboxylation. Similar considerations apply to the proteolytic
activation of factor X by IXa and by VIIa (see Fig. 24.2). There are several other vitamin K-dependent Gla
proteins, including proteins C and S and osteocalcin in bone.

Administration and pharmacokinetic aspects

Natural vitamin K1 (phytomenadione) may be given orally or by injection. If given by mouth, it requires bile
salts for absorption, and this occurs by a saturable energy requiring process in the proximal small intestine. A
synthetic preparation, menadiol sodium phosphate, is also available. It is water-soluble and does not require
bile salts for its absorption. This synthetic compound takes longer to act than phytomenadione. There is very
little storage of vitamin K in the body. It is metabolized to more polar substances that are excreted in the urine
and the bile. Clinical uses of vitamin K are summarised in the clinical box
Vitamin K1 (phytonadione) administration can stop bleeding problems due to warfarin by increasing the
supply of active vitamin K1, thereby inhibiting the effect of warfarin. Vitamin K1 may be administered via
the oral, subcutaneous, or intravenous route. [Note: Intravenous vitamin K should be administered by
slow IV infusion to minimize the risk of hypersensitivity or anaphylactoid reactions.] For the treatment
of bleeding, the subcutaneous route of vitamin K1 is not preferred, as it is not as effective as oral or IV
administration. The response to vitamin K1 is slow, requiring about 24 hours to reduce INR (time to
synthesize new coagulation factors). Thus, if immediate hemostasis is required, fresh frozen plasma
should be infused.