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Vitamin K


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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, vitamin K1 and vitamin K2. Vitamin K1, also known as phylloquinone, is synthesized by plants and is the predominant form in the diet. Vitamin K2 comes from animal sources and synthesis by intestinal bacteria. Vitamin K2 includes a range of vitamin K forms, collectively referred to as menaquinones, with 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 (2).

Function

Vitamin K functions 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) (3). 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 (4, 5).

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) (6).

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 (7).

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 (5, 8, 9).

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 (4). It may also play important roles in the developing and aging nervous system (10, 11). Further, Gas6 appears to regulate platelet signaling and vascular homeostasis (12).

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) (6)

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 (6). Additionally, individuals with disorders of fat malabsorption may be at increased risk of vitamin K deficiency (4)

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 (4). 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 (13).

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 (14, 15). 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 (16). 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 (17).

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 (18, 19). 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 (18).

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 (20).

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 (21). 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 (22). Other studies have not observed a relationship between dietary vitamin K intake and measures of bone strength, BMD, or fracture incidence (23, 24). 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 (25)

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 (26). 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 (27). In a much larger sample of 7,500 elderly women living independently, circulating ucOC was also predictive of fracture risk (28). 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 (5). 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 (29), while the other found a significantly higher risk of rib and vertebral fractures in warfarin users compared to nonusers (30). 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 (31). 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 (32)

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 (33, 34). 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 (35), but this meta-analysis did not include data from an unpublished study that reported no effect on fracture risk (36). 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 (35). 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 (37). 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 (38-40). Phylloquinone supplementation at these levels does not appear to benefit older individuals who are also taking vitamin D and calcium supplements (40). 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 (5).

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 (41). 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 (42). 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 (43). 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 (44). 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 (45). Serum ucMGP may be decreased in those at risk of cardiovascular calcification due to deposition of ucMGP in local areas of vascular calcification (46). 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 (47). If you wish to check foods for their nutrient content, including vitamin K, search the USDA food composition database. 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 (48).

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 (49). 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 (50).

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 (20). 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 (4, 6). No tolerable upper level (UL) of intake has been established for vitamin K (20).

Nutrient interactions

Large doses of vitamin A and vitamin E have been found to antagonize vitamin K (6). 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 (51). 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 (52).

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 (7). 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 (13). 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 (49).

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 (> 50 years)

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


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

Last updated 12/19/11  Copyright 2000-2014  Linus Pauling Institute


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The Linus Pauling Institute Micronutrient Information Center provides scientific information on the health aspects of dietary factors and supplements, foods, and beverages for the general public. The information is made available with the understanding that the author and publisher are not providing medical, psychological, or nutritional counseling services on this site. The information should not be used in place of a consultation with a competent health care or nutrition professional.

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