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Vitamin K

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Vitamin K

Vitamin K is a fat-soluble vitamin. The "K" is derived from the German
word "koagulation." Coagulation refers to the process of blood clot
formation. Vitamin K is essential for the functioning of several
proteins involved in blood clotting (1). There are two naturally
occurring forms of vitamin K. Plants synthesize phylloquinone, which
is also known as vitamin K1. Bacteria synthesize a range of vitamin K
forms using repeating 5-carbon units in the side chain of the
molecule. These forms of vitamin K are designated menaquinone-n
(MK-n), where n stands for the number of 5-carbon units. MK-n are
collectively referred to as vitamin K2 (2). MK-4 is not produced in
significant amounts by bacteria; instead, it appears to be synthesized
by animals (including humans) from phylloquinone. MK-4 is also formed
from menadione, a synthetic form of vitamin K present in animal feed.
MK-4 is found in a number of organs other than the liver at higher
concentrations than phylloquinone (3). This fact, along with the
existence of a unique pathway for its synthesis, suggests that MK-4
has a unique biological function that has not yet been identified (4).

Function

The only known biological role of vitamin K is as a cofactor for an
enzyme that catalyzes the carboxylation of the amino acid, glutamic
acid, resulting in its conversion to gamma-carboxyglutamic acid (Gla)
(5). Although vitamin K-dependent gamma-carboxylation occurs only on
specific glutamic acid residues in a small number of vitamin
K-dependent proteins, it is critical to the calcium-binding function
of those proteins (6, 7).

Coagulation (clotting)

The ability to bind calcium ions (Ca2+) is required for the activation
of the seven vitamin K-dependent clotting factors, or proteins, in the
coagulation cascade. The term, coagulation cascade, refers to a series
of events, each dependent on the other, that stop bleeding through
clot formation. Vitamin K-dependent gamma-carboxylation of specific
glutamic acid residues in those proteins makes it possible for them to
bind calcium. Factors II (prothrombin), VII, IX, and X make up the
core of the coagulation cascade. Protein Z appears to enhance the
action of thrombin (the activated form of prothrombin) by promoting
its association with phospholipids in cell membranes. Protein C and
protein S are anticoagulant proteins that provide control and balance
in the coagulation cascade; protein Z also has an anticoagulatory
function. Control mechanisms for the coagulation cascade exist,
because uncontrolled clotting may be as life threatening as
uncontrolled bleeding. Vitamin K-dependent coagulation factors are
synthesized in the liver. Consequently, severe liver disease results
in lower blood levels of vitamin K-dependent clotting factors and an
increased risk of uncontrolled bleeding (hemorrhage) (8).

Some people are at risk of forming clots, which could block the flow
of blood in arteries of the heart, brain, or lungs, resulting in heart
attack, stroke, or pulmonary embolism, respectively. Some oral
anticoagulants, such as warfarin (Coumadin), inhibit coagulation
through antagonism of the action of vitamin K. Although vitamin K is a
fat-soluble vitamin, the body stores very little of it, and its stores
are rapidly depleted without regular dietary intake. Perhaps, because
of its limited ability to store vitamin K, the body recycles it
through a process called the vitamin K cycle. The vitamin K cycle
allows a small amount of vitamin K to function in the
gamma-carboxylation of proteins many times, decreasing the dietary
requirement. Warfarin prevents the recycling of vitamin K by
inhibiting two important reactions and creating a functional vitamin K
deficiency (see diagram). Inadequate gamma-carboxylation of vitamin
K-dependent coagulation proteins interferes with the coagulation
cascade, which inhibits blood clot formation. Large quantities of
dietary or supplemental vitamin K can overcome the anticoagulant
effect of vitamin K antagonists, so patients taking these drugs are
cautioned against consuming very large or highly variable quantities
of vitamin K in their diets (see Drug interactions). Experts now
advise a reasonably constant dietary intake of vitamin K that meets
current dietary recommendations (90-120 mcg/day) for patients on
vitamin K antagonists like warfarin (9).

Bone mineralization

Three vitamin-K dependent proteins have been isolated in bone:
osteocalcin, matrix Gla protein (MGP), and protein S. Osteocalcin
(also called bone Gla protein) is a protein synthesized by osteoblasts
(bone-forming cells). The synthesis of osteocalcin by osteoblasts is
regulated by the active form of vitamin D, 1,25(OH)2D3 or calcitriol.
The mineral-binding capacity of osteocalcin requires vitamin
K-dependent gamma-carboxylation of three glutamic acid residues. The
function of osteocalcin is unclear but is thought to be related to
bone mineralization. MGP has been found in bone, cartilage, and soft
tissue, including blood vessels. The results of animal studies suggest
MGP prevents the calcification of soft tissue and cartilage, while
facilitating normal bone growth and development. The vitamin
K-dependent anticoagulant protein S is also synthesized by
osteoblasts, but its role in bone metabolism is unclear. Children with
inherited protein S deficiency suffer complications related to
increased blood clotting as well as decreased bone density (7, 10, 11).

Cell growth

Gas6 is a vitamin K-dependent protein that was identified in 1993. It
has been found throughout the nervous system, as well in the heart,
lungs, stomach, kidneys, and cartilage. Although the exact mechanism
of its action has not been determined, Gas6 appears to be a cellular
growth regulation factor with cell-signaling activities. Gas6 appears
to be important in diverse cellular functions, including cell
adhesion, cell proliferation, and protection against apoptosis (6). It
may also play important roles in the developing and aging nervous
system (12, 13). Further, Gas6 appears to regulate platelet signaling
and vascular homeostasis (14).

Deficiency

Overt vitamin K deficiency results in impaired blood clotting, usually
demonstrated by laboratory tests that measure clotting time. Symptoms
include easy bruising and bleeding that may be manifested as
nosebleeds, bleeding gums, blood in the urine, blood in the stool,
tarry black stools, or extremely heavy menstrual bleeding. In infants,
vitamin K deficiency may result in life-threatening bleeding within
the skull (intracranial hemorrhage) (8). 

Adults

Vitamin K deficiency is uncommon in healthy adults for a number of
reasons: 1) vitamin K is widespread in foods (see Food sources); 2)
the vitamin K cycle conserves vitamin K; and 3) bacteria that normally
inhabit the large intestine synthesize menaquinones (vitamin K2),
although it is unclear whether significant amounts are absorbed and
utilized. Adults at risk of vitamin K deficiency include those taking
vitamin K antagonist anticoagulant drugs and individuals with
significant liver damage or disease (8). Additionally, individuals
with disorders of fat malabsorption may be at increased risk of
vitamin K deficiency (6). 

Infants

Newborn babies who are exclusively breast-fed are at increased risk of
vitamin K deficiency, because human milk is relatively low in vitamin
K compared to formula. Newborn infants, in general, have low vitamin K
status for the following reasons: 1) vitamin K is not easily
transported across the placental barrier; 2) the newborn's intestines
are not yet colonized with bacteria that synthesize menaquinones; and
3) the vitamin K cycle may not be fully functional in newborns,
especially premature infants (6). Infants whose mothers are on
anticonvulsant medication to prevent seizures are also at risk of
vitamin K deficiency. Vitamin K deficiency in newborns may result in a
bleeding disorder called vitamin K deficiency bleeding (VKDB) of the
newborn. Because VKDB is life-threatening and easily prevented, the
American Academy of Pediatrics and a number of similar international
organizations recommend that an injection of phylloquinone (vitamin K1)
be administered to all newborns (15).

Controversies around vitamin K administration and the newborn

Vitamin K and childhood leukemia: In the early 1990s, two
retrospective studies were published suggesting a possible association
between vitamin K injections in newborns and the development of
childhood leukemia and other forms of childhood cancer. However, two
large retrospective studies in the U.S. and Sweden that reviewed the
medical records of 54,000 and 1.3 million children, respectively,
found no evidence of a relationship between childhood cancers and
vitamin K injections at birth (16, 17). Moreover, a pooled analysis of
six case-control studies, including 2,431 children diagnosed with
childhood cancer and 6,338 cancer-free children, found no evidence
that vitamin K injections for newborns increased the risk of childhood
leukemia (18). In a policy statement, the American Academy of
Pediatrics recommended that routine vitamin K prophylaxis for newborns
be continued because VKDB is life-threatening and the risks of cancer
are unproven and unlikely (19). See the full text of the AAP policy
statement on vitamin K and the newborn.

Lower doses of vitamin K1 for premature infants: The results of two
studies of vitamin K levels in premature infants suggest that the
standard initial dose of vitamin K1 for full term infants (1.0 mg) may
be too high for premature infants (20, 21). These findings have led
some experts to suggest the use of an initial vitamin K1 dose of 0.3
mg/kg for infants with birth weights less than 1,000 g (2 lbs, 3 oz),
and an initial dose of 0.5 mg would probably prevent hemorrhagic
disease in newborns (20).

The Adequate Intake (AI)

In January 2001, the Food and Nutrition Board (FNB) of the Institute
of Medicine established the adequate intake (AI) level for vitamin K
in the U.S. based on consumption levels of healthy individuals. The AI
for infants was based on estimated intake of vitamin K from breast
milk (22).

Adequate Intake (AI) for Vitamin K

Life Stage 

Age 

Males (mcg/day)

Females (mcg/day)

Infants 

0-6 months 

2.0 

2.0 

Infants 

7-12 months 

2.5 

2.5 

Children 

1-3 years 

30 

30 

Children

4-8 years 

55 

55 

Children 

9-13 years 

60 

60 

Adolescents 

14-18 years 

75 

75 

Adults 

19 years and older

120 

90 

Pregnancy 

18 years and younger 

75 

Pregnancy

19 years and older

90 

Breast-feeding 

18 years and younger 

75 

Breast-feeding

19 years and older

90 

Disease Prevention

Osteoporosis

The discovery of vitamin K-dependent proteins in bone has led to
research on the role of vitamin K in maintaining bone health. 

Dietary vitamin K and osteoporotic fracture

Epidemiological studies have demonstrated a relationship between
vitamin K and age-related bone loss (osteoporosis). The Nurses' Health
Study followed more than 72,000 women for ten years. In an analysis of
this cohort, women whose vitamin K intakes were in the lowest quintile
(1/5) had a 30% higher risk of hip fracture than women with vitamin K
intakes in the highest four quintiles (23). A study in over 800
elderly men and women, followed in the Framingham Heart Study for
seven years, found that men and women with dietary vitamin K intakes
in the highest quartile (1/4) had a 65% lower risk of hip fracture
than those with dietary vitamin K intakes in the lowest quartile
(approximately 250 mcg/day vs. 50 mcg/day of vitamin K). However, the
investigators found no association between dietary vitamin K intake
and bone mineral density (BMD) in the Framingham subjects (24). Other
studies have not observed a relationship between dietary vitamin K
intake and measures of bone strength, BMD, or fracture incidence (25,
26). Because the primary dietary source of vitamin K is generally
green leafy vegetables, high vitamin K intake could just be a marker
for a healthy diet that is high in vegetables (27). 

Vitamin K-dependent carboxylation of osteocalcin and osteoporotic
fracture

Osteocalcin, a bone-related protein that circulates in the blood, has
been shown to be a sensitive marker of bone formation. Vitamin K is
required for the gamma-carboxylation of osteocalcin.
Undercarboxylation of osteocalcin adversely affects its capacity to
bind to bone mineral, and the degree of osteocalcin
gamma-carboxylation has been found to be a sensitive indicator of
vitamin K nutritional status (4). Circulating levels of
undercarboxylated osteocalcin (ucOC) were found to be higher in
postmenopausal women than premenopausal women and markedly higher in
women over the age of 70. In a study of 195 institutionalized elderly
women, the relative risk of hip fracture was six times higher in those
who had elevated ucOC levels at the beginning of the study (28). In a
much larger sample of 7,500 elderly women living independently,
circulating ucOC was also predictive of fracture risk (29). Although
vitamin K deficiency would seem the most likely cause of elevated
blood ucOC, investigators have also documented an inverse relationship
between measures of vitamin D nutritional status and ucOC levels, as
well as a significant lowering of ucOC by vitamin D supplementation
(7). It is also possible that an increased ucOC level is a marker for
poor overall nutritional status, including vitamin D or protein.

Vitamin K antagonists and osteoporotic fracture

Certain oral anticoagulants, such as warfarin, are known to be
antagonists of vitamin K. At least two studies have examined the
chronic use of warfarin and risk of fracture in older women. One study
reported no association between long-term warfarin treatment and
fracture risk (30), while the other found a significantly higher risk
of rib and vertebral fractures in warfarin users compared to nonusers
(31). Additionally, a study in elderly patients with atrial
fibrillation reported that long-term warfarin treatment was associated
with a significantly higher risk of osteoporotic fracture in men but
not in women (32). A meta-analysis of the results of 11 published
studies found that oral anticoagulation therapy was associated with a
very modest reduction in bone density at the wrist and no change in
bone density at the hip or spine (33). 

Vitamin K supplementation studies and osteoporosis

Vitamin K supplementation of 1,000 mcg/day of phylloquinone (Vitamin K1)
for two weeks (more than ten times the AI for vitamin K) resulted in a
decrease of ucOC levels in postmenopausal women, as well as increases
in several biochemical markers of bone formation. In Japan,
intervention trials in hemodialysis patients and osteoporotic women
using very high pharmacologic doses (45 mg/day) of menatetrenone
(MK-4) have reported significant reductions in the rate of bone loss
(34, 35). MK-4 is not found in significant amounts in the diet, but it
can be synthesized in small amounts by humans from phylloquinone. A
recent meta-analysis of seven Japanese randomized controlled trials
associated menatetrenone-4 supplementation with increased BMD and
reduced fracture incidence (36), but this meta-analysis did not
include data from an unpublished study that reported no effect on
fracture risk (37). Nevertheless, the meta-analysis reported that MK-4
supplementation lowered risk for vertebral fractures by 60%, hip
fractures by 77%, and nonvertebral fractures by 81%; all associations
were statistically significant. Six of the individual trials employed
45 mg of menatetrenone daily, while one trial used 15 mg of
menatetrenone daily (36). The 45 mg/day dose of menatetrenone was also
used in a more recent 3-year placebo-controlled intervention trial in
325 postmenopausal women. This study found that supplemental
menatetrenone improved measures of bone strength compared to placebo
(38). The doses used in most of the cited studies are about 500 times
higher than the AI for vitamin K. Some experts are not sure whether
the effects of such high doses of MK-4 represent a true vitamin K
effect.

Long-term clinical trials of phylloquinone supplementation at doses
attainable by dietary intake (200-1,000 mcg/day) have reported mixed
results with respect to effects on bone mineral density (39-41).
Phylloquinone supplementation at these levels does not appear to
benefit older individuals who are also taking vitamin D and calcium
supplements (41). Thus, evidence of a relationship between vitamin K
nutritional status and bone health in adults is considered weak.
Further investigation is required to determine the physiological
function of vitamin K-dependent proteins in bone and the mechanisms by
which vitamin K affects bone health and osteoporotic fracture risk (7).

Vascular calcification and cardiovascular disease

One of the hallmarks of cardiovascular disease is the formation of
atherosclerotic plaques in arterial walls. Calcification of
atherosclerotic plaques occurs as the condition progresses, resulting
in decreased elasticity of the affected vessels and increased risk of
clot formation, the usual cause of a heart attack or stroke. A
prospective cohort study in 807 men and women, aged 39 to 45 years,
did not find a correlation between dietary vitamin K1 intake and
coronary artery calcification, as measured by electron-beam computed
tomography (42). Additionally, vitamin K1 intake was not associated
with calcification of breast arteries in a cross-sectional study of
1,689 women, aged 49 to 70 years (43). A population-based study of
postmenopausal women, aged 60-79 years, found that women aged 60-69
with aortic calcifications had lower vitamin K intakes than those
without aortic calcifications, but this was not true for older women
(44). The mechanism by which vitamin K may promote mineralization of
bone, while inhibiting mineralization (calcification) of vessels, is
not entirely clear. One hypothesis is based on the function of matrix
Gla protein (MGP). MGP has been found to inhibit the calcification of
cartilage and bone during early embryonic development. Some
investigators have hypothesized that high levels of MGP found in
calcified vessels may represent a defense against vessel
calcification, but that inadequate vitamin K nutritional status
results in inadequate carboxylation and, presumably, inactive MGP.
Thus, insufficient dietary vitamin K may increase the risk of vascular
calcification (45). Support for this hypothesis comes from a small
human study that employed conformation-specific antibodies against MGP
to examine whether impaired carboxylation of this protein possibly
contributes to arterial calcification. In healthy subjects,
undercarboxylated MGP (ucMGP) was not detected in the innermost lining
of the carotid artery; in contrast, the majority of MGP in the carotid
arterial lining of patients with atherosclerosis was undercarboxylated
(46). Serum ucMGP may be decreased in those at risk of cardiovascular
calcification due to deposition of ucMGP in local areas of vascular
calcification (47). Further investigations are necessary to establish
the nature of the role of bone proteins like MGP in human
atherosclerotic plaque calcification.

Sources

Food sources

Phylloquinone (vitamin K1) is the major dietary form of vitamin K.
Green leafy vegetables and some vegetable oils (soybean, cottonseed,
canola, and olive) are major contributors of dietary vitamin K.
Hydrogenation of vegetable oils may decrease the absorption and
biological effect of dietary vitamin K (48). If you wish to check
foods for their nutrient content, including vitamin K, search the USDA
food composition database or view a list of foods containing a
specific nutrient. A number of good sources of vitamin K are listed in
the table below along with their vitamin K content in micrograms
(mcg).

Food

Serving

Vitamin K (mcg)

Olive oil

1. Tablespoon

8.1

Soybean oil

1. Tablespoon

25.0

Canola oil

1. Tablespoon

16.6

Mayonnaise

1. Tablespoon

3.7

Broccoli, cooked

1. cup (chopped)

220

Kale, raw

1. cup (chopped)

547

Spinach, raw

1. cup

145

Leaf lettuce (green), raw

1. cup (shredded)

62.5

Swiss chard, raw

1. cup

299

Watercress, raw

1. cup (chopped)

85

Parsley, raw

1/4 cup

246

Intestinal bacteria

Bacteria that normally colonize the large intestine synthesize
menaquinones (vitamin K2), which are an active form of vitamin K.
Until recently it was thought that up to 50% of the human vitamin K
requirement might be met by bacterial synthesis. However, research
indicates that the contribution of bacterial synthesis is much less
than previously thought, although the exact contribution remains
unclear (49).

Supplements

In the U.S., vitamin K1 is available without a prescription in
multivitamin and other supplements in doses that generally range from
10-120 mcg per supplement (50). A form of vitamin K2, menatetrenone
(MK-4), has been used to treat osteoporosis in Japan and is currently
under study in the United States (51).

Safety

Toxicity

Although allergic reaction is possible, there is no known toxicity
associated with high doses of the phylloquinone (vitamin K1) or
menaquinone (vitamin K2) forms of vitamin K (22). The same is not true
for synthetic menadione (vitamin K3) and its derivatives. Menadione
can interfere with the function of glutathione, one of the body's
natural antioxidants, resulting in oxidative damage to cell membranes.
Menadione given by injection has induced liver toxicity, jaundice, and
hemolytic anemia (due to the rupture of red blood cells) in infants;
therefore, menadione is no longer used for treatment of vitamin K
deficiency (6, 8). No tolerable upper level (UL) of intake has been
established for vitamin K (22).

Nutrient interactions

Large doses of vitamin A and vitamin E have been found to antagonize
vitamin K (8). Excess vitamin A appears to interfere with vitamin K
absorption, whereas a form of vitamin E (tocopherol quinone) may
inhibit vitamin K-dependent carboxylase enzymes. One study in adults
with normal coagulation status found that supplementation with 1,000
IU of vitamin E for 12 weeks decreased gamma-carboxylation of
prothrombin, a vitamin K-dependent protein (52). A vitamin E-vitamin K
interaction has also been reported in patients taking anticoagulatory
drugs like warfarin. Hemorrhage (excessive bleeding) was reported in a
man taking 5 mg of warfarin and 1,200 IU of vitamin E daily (53).

Drug interactions

The anticoagulant effect of vitamin K antagonists (e.g., warfarin) may
be inhibited by very high dietary or supplemental vitamin K intake. It
is generally recommended that individuals using warfarin try to
consume the AI for vitamin K (90-120 mcg), while avoiding large
fluctuations in vitamin K intake that might interfere with the
adjustment of their anticoagulant dose (9). When given to pregnant
women, warfarin, anticonvulsants, rifampin, and isoniazid can
interfere with fetal vitamin K synthesis and place the newborn at
increased risk of vitamin K deficiency (15). Other drugs can interfere
with endogenous synthesis of vitamin K or with vitamin K recycling.
Prolonged use of broad spectrum antibiotics may decrease vitamin K
synthesis by intestinal bacteria. Cephalosporins and salicylates may
decrease vitamin K recycling by inhibiting vitamin K epoxide reductase
(diagram). Further, cholestyramine, cholestipol, orlistat, mineral
oil, and the fat substitute, olestra, may decrease vitamin K
absorption (50).

Linus Pauling Institute Recommendation

Although the AI for vitamin K was recently increased, it is not clear
if it will be enough to optimize the gamma-carboxylation of vitamin
K-dependent proteins in bone (see Osteoporosis). Multivitamins
generally contain 10 to 25 mcg of vitamin K, while vitamin K or "bone"
supplements may contain 100 to 120 mcg of vitamin K. To consume the
amount of vitamin K associated with a decreased risk of hip fracture
in the Framingham Heart Study (about 250 mcg/day), an individual would
need to eat a little more than 1/2 cup of chopped broccoli or a large
salad of mixed greens every day. Though the dietary intake of vitamin
K required for optimal function of all vitamin K dependent proteins is
not yet known, the Linus Pauling Institute recommends taking a
multivitamin-mineral supplement and eating at least 1 cup of dark
green leafy vegetables daily. Replacing dietary saturated fats like
butter and cheese with monounsaturated fats found in olive oil and
canola oil will also increase dietary vitamin K intake and may also
decrease the risk of cardiovascular diseases.

Older adults (65 years and older)

Because older adults are at increased risk of osteoporosis and hip
fracture, the above recommendation for a multivitamin-mineral
supplement and at least 1 cup of dark green leafy vegetables/day is
especially relevant.

References

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Written in May 2004 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in May 2008 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in May 2008 by:
Sarah L. Booth, Ph.D.
Director, Vitamin K Research Program
Jean Mayer USDA Human Nutrition Research Center on Aging
Tufts University

Vitamin K and the Newborn Reviewed by
Dennis T. Costakos, M.D. F.A.A.P.
Franciscan Skemp Healthcare-Mayo Health System
Mayo Medical School

Copyright 2000-2010  Linus Pauling Institute

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