Vitamin K

"Vitamin K" has also been used as a slang term for ketamine, an unrelated anaesthetic.

Vitamin K₁ (phylloquinone). Both forms of the vitamin contain a functional naphthoquinone ring and an aliphatic side chain. Phylloquinone has a phytyl side chain.

Vitamin K₂ (menaquinone). In menaquinone the side chain is composed of a varying number of isoprenoid residues.

Vitamin K is a group of structurally similar, fat soluble vitamins that are needed for the posttranslational modification of certain proteins, mostly required for blood coagulation, but also involved in metabolic pathways in bone and other tissue. They are 2-methyl-1,4-naphthoquinone (3-)derivatives. This group of vitamins includes two natural vitamers: vitamin K₁ and vitamin K₂.

Vitamin K₁ is also known as vitamin K_j, phylloquinone or phytomenadione (also called phytonadione). Vitamin K₁ is synthesized by plants and is found in green leafy vegetables and can be found in soybean oil.

Vitamin K₂ homologs (menaquinones) are characterized by the number of isoprenoid residues comprising the side chain. Menaquinones are abbreviated MK-n, where n represents the number of isoprenoid side chains. Thus, menaquinone-4 abbreviated MK-4, has 4 isoprene residues in the side chain. Bacteria can produce a range of vitamin K₂ forms, including the conversion of K₁ to K₂ by bacteria in the small intestines. No known toxicity exists for vitamins K₁ and K₂.

Three synthetic types of vitamin K are known: vitamins K₃, K₄, and K₅. Although the natural K₁ and K₂ forms are nontoxic, the synthetic form K₃ (menadione) has shown toxicity.^[1]

Vitamin K was identified in 1929 by Danish scientist Henrik Dam when he investigated the role of cholesterol by feeding chickens a cholesterol-depleted diet.^[2] After several weeks, the animals developed hemorrhages and started bleeding. These defects could not be restored by adding purified cholesterol to the diet. It appeared that—together with the cholesterol—a second compound had been extracted from the food, and this compound was called the coagulation vitamin. The new vitamin received the letter K because the initial discoveries were reported in a German journal, in which it was designated as Koagulationsvitamin.

Subtypes of vitamin K₂

Vitamin K₂ (menaquinone), is itself a category of vitamin K that includes many types of vitamin K₂. The two subtypes of vitamin K₂ that have been most studied are menaquinone-4 (menatetrenone, MK4) and menaquinone-7 (MK7).

MK4 is produced via conversion of vitamin K₁ in the body, in the testes, pancreas and arterial walls.^[3] While major questions still surround the biochemical pathway for the transformation of vitamin K₁ to MK4, studies demonstrate that the conversion is not dependent on gut bacteria, occurring in germ-free rats^[4][5] and in parenterally-administered K₁ in rats.^[6][7] In fact, tissues that accumulate high amounts of MK4 have a remarkable capacity to convert up to 90% of the available K₁ into MK4.^[8][9]

In contrast to MK4, menaquinone-7 (MK7) is not produced by humans but is converted from phylloquinone in the intestines by gut bacteria.^[10] However, bacteria-derived menaquinones (MK7) appear to contribute minimally to overall vitamin K status.^[11][12] MK4 and MK7 are both found in the United States in dietary supplements for bone health.

The US FDA has not approved any form of vitamin K for the prevention or treatment of osteoporosis; however, MK4 has been shown to decrease fractures up to 87%.^[13] In the amount of 45 mg daily MK4 has been approved by the Ministry of Health in Japan since 1995 for the prevention and treatment of osteoporosis.^[14]

Vitamin K₂ (MK4, but not MK7 or vitamin K₁) has also been shown to prevent bone loss and/or fractures in the following circumstances:

• caused by corticosteroids (e.g., prednisone, dexamethasone, prednisolone),^{[15][16][17][18]}
• anorexia nervosa,^[19]
• cirrhosis of the liver,^[20]
• postmenopausal osteoporosis,^{[21][22][23][24][25][26]}
• disuse from stroke,^[27]
• Alzheimer’s disease,^[28]
• Parkinson disease,^[29]
• primary biliary cirrhosis^[30]
• and leuprolide treatment (for prostate cancer).^[31]

Vitamin K absorption and dietary need

Previous theory held that dietary deficiency is extremely rare unless the intestine (small bowel) was heavily damaged, resulting in malabsorption of the molecule. The other at-risk group for deficiency were those subject to decreased production of K₂ by normal flora, as seen in broad spectrum antibiotic use.^[32] Taking broad-spectrum antibiotics can reduce vitamin K production in the gut by nearly 74% in people compared to those not taking these antibiotics.^[33] Diets low in vitamin K also decrease the body's vitamin K concentration.^[34] Additionally, in the elderly there is a reduction in vitamin K₂ production.^[35]

Recent research results also demonstrate that the small intestine and large intestine (colon) seem to be inefficient at absorbing vitamins K.^[36][37] These results are reinforced by human cohort studies, where a majority of the subjects showed inadequate vitamins K amounts in the body. This was revealed by the presence of large amounts of incomplete gamma-carboxylated proteins in the blood, an indirect test for vitamins K deficiency.^[38][39][40] And in an animal model MK4 was shown to prevent arterial calcifications, pointing to its potential role in cardiovascular disease prevention.^[41] In this study vitamin K₁ was also tested and shown to not prevent arterial calfications.

Chemical structure

All members of the vitamin K group of vitamins share a methylated naphthoquinone ring structure (menadione), and vary in the aliphatic side chain attached at the 3-position (see figure 1). Phylloquinone (also known as vitamin K₁) invariably contains in its side chain four isoprenoid residues, one of which is unsaturated.

Menaquinones have side chains composed of a variable number of unsaturated isoprenoid residues; generally they are designated as MK-n, where n specifies the number of isoprenoids.

It is generally accepted that the naphthoquinone is the functional group, so that the mechanism of action is similar for all K-vitamins. Substantial differences may be expected, however, with respect to intestinal absorption, transport, tissue distribution, and bio-availability. These differences are caused by the different lipophilicity of the various side chains, and by the different food matrices in which they occur.

There are three synthetic forms of vitamin K, vitamins K₃, K₄, and K₅, which are used in many areas including the pet food industry (vitamin K₃) and to inhibit fungal growth (vitamin K₅).^[42]

Physiology

Vitamin K is involved in the carboxylation of certain glutamate residues in proteins to form gamma-carboxyglutamate residues (abbreviated Gla residues). The modified residues are often (but not always) situated within specific protein domains called Gla domains. Gla residues are usually involved in binding calcium. The Gla residues are essential for the biological activity of all known Gla-proteins.^[43]

At this time^[update] 15 human proteins with Gla domains have been discovered, and they play key roles in the regulation of three physiological processes:

• Blood coagulation: (prothrombin (factor II), factors VII, IX, X, protein C, protein S, and protein Z).^[44]
• Bone metabolism: osteocalcin, also called bone Gla-protein (BGP), matrix Gla protein (MGP),^[45] and periostin.^[46]
• Vascular biology: growth arrest-specific protein 6 (Gas6)^[47]
• unknown function: proline-rich g-carboxy glutamyl proteins (PRGPs) 1 and 2, and transmembrane g-carboxy glutamyl proteins (TMGs) 3 and 4.^[48]

Like other liposoluble vitamins (A, D, E), vitamin K is stored in the fat tissue of the human body.

Recommended amounts

The U.S. Dietary Reference Intake (DRI) for an Adequate Intake (AI) of vitamin K for a 25-year old male is 120 micrograms/day. The Adequate Intake (AI) for adult women is 90 micrograms/day, for infants is 10–20 micrograms/day, for children and adolescents 15–100 micrograms/day. In 2002 it was found that to get maximum carboxylation of osteocalcin, one may have to take up to 1000 μg of vitamin K₁.^[49]

Toxicity

Although allergic reaction from supplementation is possible, there is no known toxicity associated with high doses of the phylloquinone (vitamin K₁) or menaquinone (vitamin K₂) forms of vitamin K and therefore no tolerable upper intake level (UL) has been set.^{[citation needed]}

Blood clotting (coagulation) studies in humans using 45 mg per day of vitamin K₂ (as MK4)^[26] and even up to 135 mg/day (45 mg three times daily) of K2 (as MK4),^[50] showed no increase in blood clot risk. Even doses in rats as high as 250 mg/kg body weight did not alter the tendency for blood-clot formation to occur.^[51]

However, a synthetic form of vitamin K, vitamin K₃ (menadione), is demonstrably toxic. In fact, the FDA has banned this synthetic form of the vitamin from over-the-counter supplements because large doses have been shown to cause allergic reactions, hemolytic anemia, and cytotoxicity in liver cells.^[1]

Drug interactions

Phylloquinone (K₁)^[52][53] or menaquinone (K₂) are capable of blocking the blood thinning action of anticoagulants like warfarin, which work by interfering with the action of vitamin K. They also reverse the tendency of these drugs to cause arterial calcification in the long term.

Sources

Vitamin K₁ is found chiefly in leafy green vegetables such as spinach, swiss chard, and Brassica (e.g. cabbage, kale, cauliflower, broccoli, and brussels sprouts); some fruits such as avocado, kiwifruit and grapes are also high in vitamin K. By way of reference, two tablespoons of parsley contain 153% of the recommended daily amount of vitamin K.^[54] Some vegetable oils, notably soybean, contain vitamin K, but at levels that would require relatively large calorific consumption to meet the USDA recommended levels.^[55] Colonic bacteria synthesize a significant portion of humans' vitamin K needs; this is one of the reasons why newborns often receive a vitamin K shot at birth - in order to tide them over until day 5-7 when their colon becomes colonized.

It is believed that phylloquinone's tight binding to the thylakoid membranes in the chloroplasts is the reason behind the poor bioavailability of vitamin K in green plants. For example, cooked spinach has a 5% bioavailability of phylloquinone. However when one adds fat to the spinach, the bioavailability increases to 13% due to the increased solubility of vitamin K in fat.^[56]

Vitamin K₂ (Menaquinone-4) is synthesized by animal tissues and is found in meat, eggs, and dairy products.^[57] Menaquinone-7 is synthesized by bacteria during fermentation and is found in fermented soybeans (natto).^[58] In natto 0% of vitamin K is from MK-4 and in cheese 2–7%.^[59]

Deficiency

Main article: Vitamin K deficiency

Average diets are usually not lacking in vitamin K and primary vitamin K deficiency is rare in healthy adults. Newborn infants are at an increased risk of deficiency. Other populations with an increased prevalence of vitamin K deficiency include individuals who suffer from liver damage or disease (e.g. alcoholics), people with cystic fibrosis, inflammatory bowel diseases or those who have recently had abdominal surgeries. Groups that may suffer from secondary vitamin K deficiency include bulimics, those on stringent diets, and those taking anticoagulants. Other drugs that have been associated with vitamin K deficiency include salicylates, barbiturates, and cefamandole, although the mechanism is still unknown. There is no difference between the sexes as both males and females are affected equally. Symptoms of deficiency include heavy menstrual bleeding in women, anemia, bruising, and bleeding of the gums or nose. They could also have disorders such as coagulopathy.^[59]

Osteoporosis^[60][61] and coronary heart disease^[62][63] are strongly associated with lower levels of K₂ (menaquinone). Menaquinone is not inhibited by salicylates as happens with K₁, so menaquinone supplementation can alleviate the chronic vitamin K deficiency caused by long term aspirin use.^{[citation needed]}

Biochemistry

Function

The function of vitamin K in the cell is to convert glutamate in proteins to gamma-carboxyglutamate (Gla).

Within the cell, vitamin K undergoes electron reduction to a reduced form of vitamin K (called vitamin K hydroquinone) by the enzyme vitamin K epoxide reductase (or VKOR).^[64] Another enzyme then oxidizes vitamin K hydroquinone to allow carboxylation of Glu to Gla; this enzyme is called the gamma-glutamyl carboxylase^[65][66] or the vitamin K-dependent carboxylase. The carboxylation reaction will only proceed if the carboxylase enzyme is able to oxidize vitamin K hydroquinone to vitamin K epoxide at the same time; the carboxylation and epoxidation reactions are said to be coupled reactions. Vitamin K epoxide is then re-converted to vitamin K by vitamin K epoxide reductase. The reduction and subsequent re-oxidation of vitamin K coupled with carboxylation of Glu is called the vitamin K cycle.^[67] One of the reasons humans are rarely deficient in vitamin K is that vitamin K is continually recycled in our cells.

Warfarin and other coumarin drugs block the action of the vitamin K epoxide reductase.^[68] This results in decreased concentrations of vitamin K and vitamin K hydroquinone in the tissues, such that the carboxylation reaction catalyzed by the glutamyl carboxylase is inefficient. This results in the production of clotting factors with inadequate Gla. Without Gla on the amino termini of these factors, they no longer bind stably to the blood vessel endothelium and cannot activate clotting to allow formation of a clot during tissue injury. As it is impossible to predict what dose of warfarin will give the desired degree of suppression of the clotting, warfarin treatment must be carefully monitored to avoid over-dosing. (See the warfarin article.)

Gamma-carboxyglutamate proteins, or Gla-proteins

At present, the following human Gla-containing proteins have been characterized to the level of primary structure: the blood coagulation factors II (prothrombin), VII, IX, and X, the anticoagulant proteins C and S, and the Factor X-targeting protein Z. The bone Gla-protein osteocalcin, the calcification inhibiting matrix Gla protein (MGP), the cell growth regulating growth arrest specific gene 6 protein (Gas6), and the four transmembrane Gla proteins (TMGPs) the function of which is at present unknown. Gas6 can function as a growth factor that activates the Axl receptor tyrosine kinase and stimulates cell proliferation or prevents apoptosis in some cells. In all cases in which their function was known, the presence of the Gla residues in these proteins turned out to be essential for functional activity.

Gla-proteins are known to occur in a wide variety of vertebrates: mammals, birds, reptiles, and fish. The venom of a number of Australian snakes acts by activating the human blood clotting system. Remarkably, in some cases activation is accomplished by snake Gla-containing enzymes that bind to the endothelium of human blood vessels and catalyze the conversion of procoagulant clotting factors into activated ones, leading to unwanted and potentially deadly clotting.

Another interesting class of invertebrate Gla-containing proteins is synthesized by the fish-hunting snail Conus geographus.^[69] These snails produce a venom containing hundreds of neuro-active peptides, or conotoxins, which is sufficiently toxic to kill an adult human. Several of the conotoxins contain 2–5 Gla residues.^[70]

Methods of assessment

Prothrombin time test:

Measures the time required for blood to clot

Blood sample mixed with citric acid and put in a fibrometer.

Delayed clot formation indicates a deficiency.

Unfortunately insensitive to mild deficiency as the values do not change until the concentration of prothrombin in the blood has declined by at least 50% ^[71]

Plasma Phylloquinone:

Was found to be positively correlated with phylloquinone intake in elderly British women, but not men ^[72]

However an article by Schurges et al. reported no correlation between FFQ and plasma phylloquinone ^[73]

Urinary γ-carboxyglutamic acid:

Urinary Gla responds to changes in dietary vitamin K intake.

Several days are required before any change can be observed.

In a study by Booth et al. increases of phylloquinone intakes from 100 μg to between 377–417 μg for 5 days did not induce a significant change Response may be age-specific ^[74]

Function in bacteria

Many bacteria, such as Escherichia coli found in the large intestine, can synthesize vitamin K₂ (menaquinone-7),^[75] but not vitamin K₁ (phylloquinone). In these bacteria, menaquinone will transfer two electrons between two different small molecules, in a process called anaerobic respiration.^[76] For example, a small molecule with an excess of electrons (also called an electron donor) such as lactate, formate, or NADH, with the help of an enzyme, will pass two electrons to a menaquinone. The menaquinone, with the help of another enzyme, will in turn transfer these 2 electrons to a suitable oxidant, such fumarate or nitrate (also called an electron acceptor). Adding two electrons to fumarate or nitrate will convert the molecule to succinate or nitrite + water, respectively. Some of these reactions generate a cellular energy source, ATP, in a manner similar to eukaryotic cell aerobic respiration, except that the final electron acceptor is not molecular oxygen, but say fumarate or nitrate (In aerobic respiration, the final oxidant is molecular oxygen (O₂) , which accepts four electrons from an electron donor such as NADH to be converted to water.) Escherichia coli can carry out aerobic respiration and menaquinone-mediated anaerobic respiration.

Vitamin K injection in newborns

The blood clotting factors of newborn babies are roughly 30 to 60% that of adult values; this may be due to the reduced synthesis of precursor proteins and the sterility of their guts. Human milk contains between 1 and 4 micrograms/litre of vitamin K₁, while formula derived milk can contain up to 100 micrograms/litre in supplemented formulas. Vitamin K₂ concentrations in human milk appear to be much lower than those of vitamin K₁. It is estimated that there is a 0.25 to 1.7% occurrence of vitamin K deficiency bleeding in the first week of the infant's life with a prevalence of 2-10 cases per 100,000 births.^[77] Premature babies have even lower levels of the vitamin and are at a higher risk from this deficiency.

Bleeding in infants due to vitamin K deficiency can be severe, leading to hospitalizations, blood transfusions, brain damage and death. Supplementation with vitamin K can prevent most cases of vitamin K deficiency bleeding in the newborn. Intramuscular administration of vitamin K is more effective in preventing late vitamin K deficiency bleeding than oral administration.^[78][79]

USA

As a result of the occurrences of vitamin K deficiency bleeding, the Committee on Nutrition of the American Academy of Pediatrics has recommended that 0.5 to 1.0 mg vitamin K₁ be administered to all newborns shortly after birth.^[79]

UK

In the UK, vitamin K is administered to newborns as either a single injection at birth or three orally administered doses given at birth and then over the baby's first month.

Controversy

Controversy arose in the early 1990s regarding this practice when two studies were shown suggesting a relationship between parenteral administration of vitamin K and childhood cancer (14)^{[verification needed][citation needed]}. However, poor methods and small sample sizes led to the discrediting of these studies and a review of the evidence published in 2000 by Ross and Davies found no link between the two.^{[80][verification needed]}

Vitamin K and bone health

There is physiological and observational evidence that vitamin K plays a role in bone growth and the maintenance of bone density, but efforts to delay the onset of osteoporosis by vitamin K supplementation have proven ineffective.

Vitamin K takes part in the post translational modification as a cofactor in γ-carboxylation of vitamin K dependant proteins (VKDPs). VKDPs have glutamate residues (Glu). Biophysical studies have suggested that supplemental vitamin K promotes osteotrophic processes and slows osteoclastic processes via calcium bonding. Study of Atkins et al.^[81] revealed that phylloquinone, menatetrenone (MK4) and menadione promote in vitro mineralisaton by human primary osteoblasts. Other studies have shown that vitamin K antagonists (usually a class of anticoagulants) lead to early calcification of the epiphysis and epiphysial line in mice and other animals, causing seriously decreased bone growth. This is due to defects in osteocalcin and matrix Gla protein. Their primary function is to prevent overcalcification of the bone and cartilage. Vitamin K is important in the process of carboxylating glutamic acid (Glu) in these proteins to gamma-carboxyglutamic acid (Gla), which is necessary for their function.^[82][83] Vitamin D is reported to regulate the OC transcription by osteoblast thereby showing that vitamin K and vitamin D work in tandem for the bone metabolism and development. Lian and his group discovered two nucleotide substitution regions which they named "osteocalcin box" in the rat and human osteocalcin genes.^[84] They found a region 600 nucleotides immediately upstream from the transcription start site that support a 10-fold stimulated transcription of the gene by 1,25-dihydroxy vitamin D.

Vitamin K₁ and bone health

Data from the 1998 Nurses Health Study, an observational study, indicated an inverse relationship between dietary vitamin K₁ and the risk of hip fracture. After being given 110 micrograms/day of vitamin K, women who consumed lettuce one or more times per day had a significantly lower risk of hip fracture than women who consumed lettuce one or fewer times per week. In addition to this, high intakes of vitamin D but low intakes of vitamin K were suggested to pose an increased risk of hip fracture.^[83][85] The Framingham Heart Study^[86] is another study that showed the similar result. Subjects in the highest quartile of vitamin K₁ intake (median K₁ intake of 254 μg/ day) has 35% lower risk of hip fracture than those in the lowest quartile. Comparing with the daily recommended intake (DRI) of 90 and 120 μg/ day, both the above intakes are higher than existing DRI.

In the face of this evidence, a large multicentre randomized placebo-controlled trial was performed to test the supplementation of vitamin K in post-menopausal women with osteopenia. Despite heavy doses of vitamin K₁, no differences were found in bone density between the supplemented and placebo groups.^[87]

Vitamin K₂ (MK4) and bone health

In contrast, MK4 has been shown in numerous studies to reduce fracture risk, stop and reverse bone loss. In Japan, MK4 in the dose of 45 mg daily is recognized as a treatment for osteoporosis.^[85][88] MK4 has been shown to decrease fractures up to 87%.^[13] In the amount of 45 mg daily MK4 has been approved by the Ministry of Health in Japan since 1995 for the prevention and treatment of osteoporosis.^[14]

MK4 (but not MK7 or vitamin K₁) prevented bone loss and/or fractures in the following circumstances:

• caused by corticosteroids (e.g., prednisone, dexamethasone, prednisolone),^{[15][16][17][18]}
• anorexia nervosa,^[19]
• cirrhosis of the liver,^[20]
• postmenopausal osteoporosis,^{[21][22][23][24][25][26]}
• disuse from stroke,^[27]
• Alzheimer’s disease,^[28]
• Parkinson disease,^[29]
• primary biliary cirrhosis^[30] and
• leuprolide treatment (for prostate cancer).^[31]

Vitamin K₂ (MK7) and bone health

Menaquinone-7 (MK7), which is abundant in fermented soybeans (natto), has been demonstrated to stimulate osteoblastic bone formation and to inhibit osteoclastic bone resorption.^[89] In another study, use of MK-7 caused significant elevations of serum Y-carboxylated osteocalcin concentration, a biomarker of bone formation. MK-7 also completely inhibited a decrease in the calcium content of bone tissue by inhibiting the bone-resorbing factors parathyroid hormone and prostaglandin E₂.^[90] On 19 February 2011, HSA (Singapore) approved a health supplement which contains vitamin K₂ (MK7) and vitamin D₃ for increasing bone mineral density.^[91]

Vitamin K and Alzheimer's disease

Research into the antioxidant properties of vitamin K indicates that the concentration of vitamin K is lower in the circulation of carriers of the APOE4 gene, and recent studies have shown its ability to inhibit nerve cell death due to oxidative stress. It has been hypothesized that vitamin K may reduce neuronal damage and that supplementation may hold benefits to treating Alzheimer's disease, although more research is necessary in this area.^[92]

Vitamin K used topically

Vitamin K may be applied topically, typically as a 5% cream, to diminish postoperative bruising from cosmetic surgery and injections, broken capillaries (spider veins), to treat rosacea and to aid in the fading of hyperpigmentation and dark under-eye circles.^{[citation needed]}

Vitamin K and cancer

While researchers in Japan were studying the role of vitamin K₂ as the menaquinone-4 (MK-4) form in the prevention of bone loss in females with liver disease, they discovered another possible effect. This two year study which involved 21 women with viral liver cirrhosis found that women in the supplement group were 90% less likely to develop liver cancer.^[93][94] A German study performed on men with prostate cancer found a significant inverse relationship between vitamin K₂ consumption and advanced prostate cancer.^[95]

Vitamin K as antidote for poisoning by 4-hydroxcoumarin drugs

Vitamin K is a true antidote for poisoning by 4-hydroxycoumarin anticoagulant drugs (sometimes loosely referred to as coumarins). These include the pharmaceutical warfarin, and also anticoagulant-mechanism poisons such as bromadiolone, which are commonly found in rodenticides. 4-Hydroxycoumarin drugs possess anticoagulatory and rodenticidal properties because they inhibit vitamin K-dependent synthesis of some clotting factors by the liver. Death is usually a result of internal hemorrhage. Treatment usually consists of repeated intravenous doses of vitamin K, followed by doses in pill form for a period of at least two weeks, though possibly up to 2 months, afterwards (in the case of the more potent 4-hydoxycoumarins used as rodenticides). If caught early, prognosis is good, even when great amounts of the drug or poison are ingested.

History of discovery

In 1929, Danish scientist Henrik Dam investigated the role of cholesterol by feeding chickens a cholesterol-depleted diet.^[2] After several weeks, the animals developed hemorrhages and started bleeding. These defects could not be restored by adding purified cholesterol to the diet. It appeared that—together with the cholesterol—a second compound had been extracted from the food, and this compound was called the coagulation vitamin. The new vitamin received the letter K because the initial discoveries were reported in a German journal, in which it was designated as Koagulationsvitamin. Edward Adelbert Doisy of Saint Louis University did much of the research that led to the discovery of the structure and chemical nature of vitamin K.^[96] Dam and Doisy shared the 1943 Nobel Prize for medicine for their work on vitamin K (K₁ and K₂) published in 1939. Several laboratories synthesized the compound(s) in 1939.^[97]

For several decades the vitamin K-deficient chick model was the only method of quantifying vitamin K in various foods: the chicks were made vitamin K-deficient and subsequently fed with known amounts of vitamin K-containing food. The extent to which blood coagulation was restored by the diet was taken as a measure for its vitamin K content. Three groups of physicians independently found this: Biochemical Institute, University of Copenhagen (Dam and Johannes Glavind), University of Iowa Department of Pathology (Emory Warner, Kenneth Brinkhous, and Harry Pratt Smith), and the Mayo Clinic (Hugh Butt, Albert Snell, and Arnold Osterberg).^[98]

The first published report of successful treatment with vitamin K of life-threatening hemorrhage in a jaundiced patient with prothrombin deficiency was made in 1938 by Smith, Warner, and Brinkhous.^[99]

The precise function of vitamin K was not discovered until 1974, when three laboratories (Stenflo et al.,^[100] Nelsestuen et al.,^[101] and Magnusson et al.^[102]) isolated the vitamin K-dependent coagulation factor prothrombin (Factor II) from cows that received a high dose of a vitamin K antagonist, warfarin. It was shown that while warfarin-treated cows had a form of prothrombin that contained 10 glutamate amino acid residues near the amino terminus of this protein, the normal (untreated) cows contained 10 unusual residues that were chemically identified as gamma-carboxyglutamate, or Gla. The extra carboxyl group in Gla made clear that vitamin K plays a role in a carboxylation reaction during which Glu is converted into Gla.

The biochemistry of how vitamin K is used to convert Glu to Gla has been elucidated over the past thirty years in academic laboratories throughout the world.

References

1. ^ ^{a b} Higdon (February 2008). "Vitamin K". Linus Pauling Institute, Oregon State University. http://lpi.oregonstate.edu/infocenter/vitamins/vitaminK/. Retrieved 2008-04-12. 
2. ^ ^{a b} Dam, H. (1935). "The Antihæmorrhagic Vitamin of the Chick.: Occurrence And Chemical Nature". Nature 135 (3417): 652–653. doi:10.1038/135652b0. 
3. ^ Sell, DR; Monnier VM (1990). "End-stage renal disease and diabetes catalyze the formation of a pentose-derived crosslink from aging human collagen". Journal of Clinical Investigation 85 (2): 380–384. doi:10.1172/JCI114449. PMC 296435. PMID 2298912. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=296435. 
4. ^ Davidson, RT; Foley AL, Engelke JA, Suttie JW (1998). "Conversion of Dietary Phylloquinone to Tissue Menaquinone-4 in Rats is Not Dependent on Gut Bacteria1". Journal of Nutrition 128 (2): 220–223. PMID 9446847. 
5. ^ Ronden, JE; Drittij-Reijnders M-J, Vermeer C, Thijssen HHW. (1998). "Intestinal flora is not an intermediate in the phylloquinone-menaquinone-4 conversion in the rat". Biochimica et Biophysica Acta (BBA) - General Subjects 1379 (1): 69–75. doi:10.1016/S0304-4165(97)00089-5. PMID 9468334. 
6. ^ Thijssen, HHW; Drittij-Reijnders MJ (1994). "Vitamin K distribution in rat tissues: dietary phylloquinone is a source of tissue menaquinone-4". British Journal of Nutrition 72 (3): 415–425. doi:10.1079/BJN19940043. PMID 7947656. 
7. ^ Will, BH; Usui Y, Suttie JW (1992). "Comparative Metabolism and Requirement of Vitamin K in Chicks and Rats". Journal of Nutrition 122 (12): 2354–2360. PMID 1453219. 
8. ^ Davidson, RT; Foley AL, Engelke JA, Suttie JW (1998). "Conversion of Dietary Phylloquinone to Tissue Menaquinone-4 in Rats is Not Dependent on Gut Bacteria". Journal of Nutrition 128 (2): 220–223. PMID 9446847. 
9. ^ Ronden, JE; Drittij-Reijnders M-J, Vermeer C, Thijssen HHW (1998). "Intestinal flora is not an intermediate in the phylloquinone-menaquinone-4 conversion in the rat". Biochimica et Biophysica Acta (BBA) - General Subjects 1379 (1): 69–75. doi:10.1016/S0304-4165(97)00089-5. PMID 9468334. 
10. ^ Vermeer, C; Braam L (2001). "Role of K vitamins in the regulation of tissue calcification". Journal of bone and mineral metabolism 19 (4): 201–206. doi:10.1007/s007740170021. PMID 11448011. 
11. ^ Suttie, JW (1995). "The importance of menaquinones in human nutrition". Annual Review of Nutrition 15: 399–417. doi:10.1146/annurev.nu.15.070195.002151. PMID 8527227. 
12. ^ Weber, P (2001). "Vitamin K and bone health". Nutrition 17 (10): 880–887. doi:10.1016/S0899-9007(01)00709-2. PMID 11684396. 
13. ^ ^{a b} Sato, Y; Kanoko T, Satoh K, Iwamoto J (2005). "Menatetrenone and vitamin D2 with calcium supplements prevent nonvertebral fracture in elderly women with Alzheimer's disease". Bone 36 (1): 61–8. doi:10.1016/j.bone.2004.09.018. PMID 15664003. 
14. ^ ^{a b} Iwamoto, I; Kosha S, Noguchi S-i (1999). "A longitudinal study of the effect of vitamin K2 on bone mineral density in postmenopausal women a comparative study with vitamin D3 and estrogen-progestin therapy". Maturitas 31 (2): 161–164. doi:10.1016/S0378-5122(98)00114-5. PMID 10227010. 
15. ^ ^{a b} Inoue, T; Sugiyama T, Matsubara T, Kawai S, Furukawa S (2001). "Inverse correlation between the changes of lumbar bone mineral density and serum undercarboxylated osteocalcin after vitamin K2 (menatetrenone) treatment in children treated with glucocorticoid and alfacalcidol". Endocrine Journal 48 (1): 11–18. doi:10.1507/endocrj.48.11. PMID 11403096. 
16. ^ ^{a b} Sasaki, N, Kusano E, Takahashi H, Ando Y, Yano K, Tsuda E, Asano Y; Kusano E, Takahashi H, Ando Y, Yano K, Tsuda E, Asano Y (2005). "Vitamin K2 inhibits glucocorticoid-induced bone loss partly by preventing the reduction of osteoprotegerin (OPG)". Journal of bone and mineral metabolism 23 (1): 41–47. doi:10.1007/s00774-004-0539-6. PMID 15616893. 
17. ^ ^{a b} Yonemura, K; Fukasawa H, Fujigaki Y, Hishida A. (2004). "Protective effect of vitamins K2 and D3 on prednisolone-induced loss of bone mineral density in the lumbar spine". American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation 43 (1): 53–60. PMID 14712427. 
18. ^ ^{a b} Yonemura, K; Kimura M, Miyaji T, Hishida A (2000). "Short-term effect of vitamin K administration on prednisolone-induced loss of bone mineral density in patients with chronic glomerulonephritis". Calcified Tissue International 66 (2): 123–128. doi:10.1007/PL00005832. PMID 10652960. 
19. ^ ^{a b} Iketani, T; Kiriike N, B. Stein M (2003). "Effect of menatetrenone (vitamin K2) treatment on bone loss in patients with anorexia nervosa". Psychiatry Research 117 (3): 259–269. doi:10.1016/S0165-1781(03)00024-6. PMID 12686368. 
20. ^ ^{a b} Shiomi, S; Nishiguchi S, Kubo S (2002). "Vitamin K2 (menatetrenone) for bone loss in patients with cirrhosis of the liver". The American Journal of Gastroenterology 97 (4): 978–981. doi:10.1111/j.1572-0241.2002.05618.x. PMID 12003435. 
21. ^ ^{a b} Cockayne, S; Adamson J, Lanham-New S, Shearer MJ, Gilbody S, Torgerson DJ (2006). "Vitamin K and the Prevention of Fractures: Systematic Review and Meta-analysis of Randomized Controlled Trials". Archives of Internal Medicine 166 (12): 1256–1261. doi:10.1001/archinte.166.12.1256. PMID 16801507. 
22. ^ ^{a b} Iwamoto, I; Kosha S, Noguchi S-i (1999). "A longitudinal study of the effect of vitamin K2 on bone mineral density in postmenopausal women a comparative study with vitamin D3 and estrogen-progestin therapy". Maturitas 31 (2): 161–164. doi:10.1016/S0378-5122(98)00114-5. PMID 10227010. 
23. ^ ^{a b} Iwamoto, J; Takeda T, Ichimura S (2000). "Effect of combined administration of vitamin D3 and vitamin K2 on bone mineral density of the lumbar spine in postmenopausal women with osteoporosis". Journal of Orthopaedic Science 5 (6): 546–551. doi:10.1007/s007760070003. PMID 11180916. 
24. ^ ^{a b} Purwosunu, Y; Muharram, Rachman IA, Reksoprodjo S, Sekizawa A (2006). "Vitamin K2 treatment for postmenopausal osteoporosis in Indonesia". The journal of obstetrics and gynaecology research 32 (2): 230–234. doi:10.1111/j.1447-0756.2006.00386.x. PMID 16594930. 
25. ^ ^{a b} Shiraki, M; Shiraki Y, Aoki C, Miura M (2000). "Vitamin K2 (Menatetrenone) Effectively Prevents Fractures and Sustains Lumbar Bone Mineral Density in Osteoporosis". Journal of Bone and Mineral Research 15 (3): 515–522. doi:10.1359/jbmr.2000.15.3.515. PMID 10750566. 
26. ^ ^{a b c} Ushiroyama, T; Ikeda A, Ueki M (2002). "Effect of continuous combined therapy with vitamin K2 and vitamin D3 on bone mineral density and coagulofibrinolysis function in postmenopausal women". Maturitas 41 (3): 211–221. doi:10.1016/S0378-5122(01)00275-4. PMID 11886767. 
27. ^ ^{a b} Sato, Y; Honda Y, Kuno H, Oizumi K (1998). "Menatetrenone ameliorates osteopenia in disuse-affected limbs of vitamin D- and K-deficient stroke patients". Bone 23 (3): 291–296. doi:10.1016/S8756-3282(98)00108-2. PMID 9737352. 
28. ^ ^{a b} Sato, Y; Kanoko T, Satoh K, Iwamoto J (2005). "Menatetrenone and vitamin D2 with calcium supplements prevent nonvertebral fracture in elderly women with Alzheimer's disease". Bone 36 (1): 61–68. doi:10.1016/j.bone.2004.09.018. PMID 15664003. 
29. ^ ^{a b} Sato, Y; Honda Y, Kaji M (2002). "Amelioration of osteoporosis by menatetrenone in elderly female Parkinson's disease patients with vitamin D deficiency". Bone 31 (1): 114–118. doi:10.1016/S8756-3282(02)00783-4. PMID 12110423. 
30. ^ ^{a b} Nishiguchi, S; Shimoi S, Kurooka H (2001). "Randomized pilot trial of vitamin K2 for bone loss in patients with primary biliary cirrhosis". Journal of Hepatology 35 (4): 543–545. doi:10.1016/S0168-8278(01)00133-7. PMID 11682046. 
31. ^ ^{a b} Somekawa, Y; Chigughi M, Harada M, Ishibashi T (1999). "Use of vitamin K2 (menatetrenone) and 1,25-dihydroxyvitamin D3 in the prevention of bone loss induced by leuprolide". The Journal of clinical endocrinology and metabolism 84 (8): 2700–2704. doi:10.1210/jc.84.8.2700. PMID 10443663. 
32. ^ "Vitamin K". http://www.nlm.nih.gov/medlineplus/druginfo/natural/patient-vitamink.html. Retrieved 2009-05-26. 
33. ^ Conly, J; Stein K (1994). "Reduction of vitamin K2 concentrations in human liver associated with the use of broad spectrum antimicrobials". Clinical and investigative medicine. Médecine clinique et experimentale 17 (6): 531–539. PMID 7895417. 
34. ^ Ferland G, Sadowski JA, O'Brien ME (April 1993). "Dietary induced subclinical vitamin K deficiency in normal human subjects". J. Clin. Invest. 91 (4): 1761–8. doi:10.1172/JCI116386. PMC 288156. PMID 8473516. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=288156. 
35. ^ Hodges SJ, Pilkington MJ, Shearer MJ, Bitensky L, Chayen J (January 1990). "Age-related changes in the circulating levels of congeners of vitamin K2, menaquinone-7 and menaquinone-8". Clin. Sci. 78 (1): 63–6. PMID 2153497. 
36. ^ Groenen-van Dooren MM, Ronden JE, Soute BA, Vermeer C (September 1995). "Bioavailability of phylloquinone and menaquinones after oral and colorectal administration in vitamin K-deficient rats". Biochem. Pharmacol. 50 (6): 797–801. doi:10.1016/0006-2952(95)00202-B. PMID 7575640. http://linkinghub.elsevier.com/retrieve/pii/0006-2952(95)00202-B. 
37. ^ Komai M, Shirakawa H (November 2007). "[Vitamin K metabolism. Menaquinone-4 (MK-4) formation from ingested VK analogues and its potent relation to bone function]" (in Japanese). Clin Calcium 17 (11): 1663–72. doi:CliCa071116631672. PMID 17982185. 
38. ^ Geleijnse JM, Vermeer C, Grobbee DE, et al. (November 2004). "Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study". J. Nutr. 134 (11): 3100–5. PMID 15514282. http://jn.nutrition.org/cgi/pmidlookup?view=long&pmid=15514282. 
39. ^ Beulens JW, Bots ML, Atsma F, et al. (April 2009). "High dietary menaquinone intake is associated with reduced coronary calcification". Atherosclerosis 203 (2): 489–93. doi:10.1016/j.atherosclerosis.2008.07.010. PMID 18722618. http://linkinghub.elsevier.com/retrieve/pii/S0021-9150(08)00507-8. 
40. ^ Nimptsch K, Rohrmann S, Kaaks R, Linseisen J (May 2010). "Dietary vitamin K intake in relation to cancer incidence and mortality: results from the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg)". Am. J. Clin. Nutr. 91 (5): 1348–58. doi:10.3945/ajcn.2009.28691. PMID 20335553. http://www.ajcn.org/cgi/pmidlookup?view=long&pmid=20335553. 
41. ^ Spronk, HMH; Soute BAM, Schurgers LJ, Thijssen HHW, De Mey JGR, Vermeer C (2003). "Tissue-Specific Utilization of Menaquinone-4 Results in the Prevention of Arterial Calcification in Warfarin-Treated Rats". Journal of vascular research 40 (6): 531–537. doi:10.1159/000075344. PMID 14654717. 
42. ^ McGee, W (2007-02-01). "Vitamin K". MedlinePlus. http://www.nlm.nih.gov/medlineplus/ency/article/002407.htm. Retrieved 2009-04-02. 
43. ^ Furie B, Bouchard BA, Furie BC (15 March 1999). "Vitamin K-dependent biosynthesis of gamma-carboxyglutamic acid". Blood 93 (6): 1798–808. PMID 10068650. http://bloodjournal.hematologylibrary.org/cgi/content/full/93/6/1798. 
44. ^ Mann KG (1999). "Biochemistry and physiology of blood coagulation". Thromb. Haemost. 82 (2): 165–74. PMID 10605701. http://www.schattauer.de/index.php?id=1268&pii=th99080165&no_cache=1. 
45. ^ Price PA (1988). "Role of vitamin-K-dependent proteins in bone metabolism". Annu. Rev. Nutr. 8: 565–83. doi:10.1146/annurev.nu.08.070188.003025. PMID 3060178. 
46. ^ Coutu DL, Wu JH, Monette A, Rivard GE, Blostein MD, Galipeau J (2008). "Periostin, a member of a novel family of vitamin K-dependent proteins, is expressed by mesenchymal stromal cells". J. Biol. Chem. 283 (26): 17991–18001. doi:10.1074/jbc.M708029200. PMID 18450759. 
47. ^ Hafizi S, Dahlbäck B (2006). "Gas6 and protein S. Vitamin K-dependent ligands for the Axl receptor tyrosine kinase subfamily". FEBS J. 273 (23): 5231–44. doi:10.1111/j.1742-4658.2006.05529.x. PMID 17064312. 
48. ^ Kulman JD, Harris JE, Xie L, Davie EW (2007). "Proline-rich Gla protein 2 is a cell-surface vitamin K-dependent protein that binds to the transcriptional coactivator Yes-associated protein". Proc. Natl. Acad. Sci. U.S.A. 104 (21): 8767–72. doi:10.1073/pnas.0703195104. PMC 1885577. PMID 17502622. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1885577. 
49. ^ Binkley NC, Krueger DC, Kawahara TN, Engelke JA, Chappell RJ, Suttie JW (November 2002). "A high phylloquinone intake is required to achieve maximal osteocalcin gamma-carboxylation". Am. J. Clin. Nutr. 76 (5): 1055–60. PMID 12399278. http://www.ajcn.org/cgi/pmidlookup?view=long&pmid=12399278. 
50. ^ Asakura, H; Myou S, Ontachi Y, Mizutani T, Kato M, Saito M, Morishita E, Yamazaki M, Nakao S (2001). "Vitamin K administration to elderly patients with osteoporosis induces no hemostatic activation, even in those with suspected vitamin K deficiency". Osteoporosis International 12 (12): 996–1000. doi:10.1007/s001980170007. PMID 11846334. 
51. ^ Ronden, JE; Groenen-van Dooren MMCL, Hornstra G, Vermeer C (1997). "Modulation of arterial thrombosis tendency in rats by vitamin K and its side chains". Atherosclerosis 132 (1): 61–67. doi:10.1016/S0021-9150(97)00087-7. PMID 9247360. 
52. ^ Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E (2004). "The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy". Chest 126 (3 Suppl): 204S–233S. doi:10.1378/chest.126.3_suppl.204S. PMID 15383473. http://www.chestjournal.org/cgi/content/full/126/3_suppl/204S.  (summary)
53. ^ Crowther MA, Douketis JD, Schnurr T, et al. (2002). "Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of warfarin-associated coagulopathy. A randomized, controlled trial" (PDF). Ann. Intern. Med. 137 (4): 251–4. PMID 12186515. http://www.annals.org/cgi/reprint/137/4/251. 
54. ^ Nutrition Facts and Information for Parsley, raw
55. ^ Nutrition facts, calories in food, labels, nutritional information and analysis – NutritionData.com
56. ^ NutritionData.com
57. ^ Elder SJ, Haytowitz DB, Howe J, Peterson JW, Booth SL (January 2006). "Vitamin k contents of meat, dairy, and fast food in the U.S. Diet". J. Agric. Food Chem. 54 (2): 463–7. doi:10.1021/jf052400h. PMID 16417305. 
58. ^ Tsukamoto Y, Ichise H, Kakuda H, Yamaguchi M (2000). "Intake of fermented soybean (natto) increases circulating vitamin K₂ (menaquinone-7) and gamma-carboxylated osteocalcin concentration in normal individuals". J. Bone Miner. Metab. 18 (4): 216–22. doi:10.1007/s007740070023. PMID 10874601. http://link.springer.de/link/service/journals/00774/bibs/0018004/00180216.htm. 
59. ^ ^{a b} "On the Trail of the Elusive X-Factor: Vitamin K2 Revealed". http://www.westonaprice.org/abcs-of-nutrition/175#fig4. 
60. ^ Ikeda; Iki, M; Morita, A; Kajita, E; Kagamimori, S; Kagawa, Y; Yoneshima, H (2006). "Intake of fermented soybeans, natto, is associated with reduced bone loss in postmenopausal women: Japanese Population-Based Osteoporosis (JPOS) Study". The Journal of nutrition 136 (5): 1323–8. PMID 16614424. 
61. ^ Katsuyama; Ideguchi, S; Fukunaga, M; Saijoh, K; Sunami, S (2002). "Usual dietary intake of fermented soybeans (Natto) is associated with bone mineral density in premenopausal women". Journal of nutritional science and vitaminology 48 (3): 207–15. doi:10.3177/jnsv.48.207. PMID 12350079. 
62. ^ Sano; Fujita, H; Morita, I; Uematsu, H; Murota, S (1999). "Vitamin K2 (menatetrenone) induces iNOS in bovine vascular smooth muscle cells: no relationship between nitric oxide production and gamma-carboxylation". Journal of nutritional science and vitaminology 45 (6): 711–23. doi:10.3177/jnsv.45.711. PMID 10737225. 
63. ^ http://www.npicenter.com/anm/templates/newsATemp.aspx?articleid=23259
64. ^ Oldenburg J, Bevans CG, Müller CR, Watzka M (2006). "Vitamin K epoxide reductase complex subunit 1 (VKORC1): the key protein of the vitamin K cycle". Antioxid. Redox Signal. 8 (3–4): 347–53. doi:10.1089/ars.2006.8.347. PMID 16677080. 
65. ^ Suttie JW (1985). "Vitamin K-dependent carboxylase". Annu. Rev. Biochem. 54: 459–77. doi:10.1146/annurev.bi.54.070185.002331. PMID 3896125. 
66. ^ Presnell SR, Stafford DW (June 2002). "The vitamin K-dependent carboxylase". Thromb. Haemost. 87 (6): 937–46. PMID 12083499. 
67. ^ Stafford DW (August 2005). "The vitamin K cycle". J. Thromb. Haemost. 3 (8): 1873–8. doi:10.1111/j.1538-7836.2005.01419.x. PMID 16102054. 
68. ^ Whitlon DS, Sadowski JA, Suttie JW (April 1978). "Mechanism of coumarin action: significance of vitamin K epoxide reductase inhibition". Biochemistry 17 (8): 1371–7. doi:10.1021/bi00601a003. PMID 646989. 
69. ^ Terlau H, Olivera BM (January 2004). "Conus venoms: a rich source of novel ion channel-targeted peptides". Physiol. Rev. 84 (1): 41–68. doi:10.1152/physrev.00020.2003. PMID 14715910. 
70. ^ Buczek O, Bulaj G, Olivera BM (December 2005). "Conotoxins and the posttranslational modification of secreted gene products". Cell. Mol. Life Sci. 62 (24): 3067–79. doi:10.1007/s00018-005-5283-0. PMID 16314929. 
71. ^ No Author. http://www.webmd.com/a-to-z-guides/prothrombin-time
72. ^ Thane CW, Bates CJ, Shearer MJ, et al (June 2002). "Plasma phylloquinone (vitamin K1) concentration and its relationship to intake in a national sample of British elderly people". Br. J. Nutr. 87 (6): 615–22. doi:10.1079/BJNBJN2002582. PMID 12067432. 
73. ^ McKeown NM, Jacques PF, Gundberg CM, et al (June 2002). "Dietary and nondietary determinants of vitamin K biochemical measures in men and women". J. Nutr. 132 (6): 1329–34. PMID 12042454. http://jn.nutrition.org/cgi/pmidlookup?view=long&pmid=12042454. 
74. ^ Yamano M, Yamanaka Y, Yasunaga K, Uchida K (September 1989). "Effect of vitamin K deficiency on urinary gamma-carboxyglutamic acid excretion in rats". Nippon Ketsueki Gakkai Zasshi 52 (6): 1078–86. PMID 2588957. 
75. ^ Bentley R, Meganathan R (September 1982). "Biosynthesis of vitamin K (menaquinone) in bacteria". Microbiol. Rev. 46 (3): 241–80. PMC 281544. PMID 6127606. http://mmbr.asm.org/cgi/pmidlookup?view=long&pmid=6127606. 
76. ^ Haddock BA, Jones CW (March 1977). "Bacterial respiration". Bacteriol Rev 41 (1): 47–99. PMC 413996. PMID 140652. http://mmbr.asm.org/cgi/pmidlookup?view=long&pmid=140652. 
77. ^ Shearer MJ (January 1995). "Vitamin K". Lancet 345 (8944): 229–34. doi:10.1016/S0140-6736(95)90227-9. PMID 7823718. 
78. ^ Wintrobe's Clinical Hematology, 11th Edition. J.P. Greer, Foerster J., Lukens, J.N., Rodgers, G.M., Paraskevas, F., and Glader, B., editor. Philadelphia, PA, USA: Lippincott Williams and Wilkens.
79. ^ ^{a b} American Academy of Pediatrics Committee on Fetus and Newborn (July 2003). "Controversies concerning vitamin K and the newborn. American Academy of Pediatrics Committee on Fetus and Newborn". Pediatrics 112 (1 Pt 1): 191–2. PMID 12837888. http://pediatrics.aappublications.org/cgi/pmidlookup?view=long&pmid=12837888. 
80. ^ McMillan DD (1997). "Routine administration of vitamin K to newborns". Paediatr Child Health 2 (6): 429–31. http://www.pulsus.com/journals/abstract.jsp?sCurrPg=abstract&jnlKy=5&atlKy=105&isuKy=378&isArt=t&fromfold=. 
81. ^ Gerald JA, Katie JW, Asiri R W, et al. (2009). "Vitamin K promotes mineralization, osteoblast‐to‐osteocyte transition, and an anticatabolic phenotype by γ‐carboxylation‐dependent and independent mechanisms". Am J Physiol Cell Physiol 297 (6): C1358–C1367. doi:10.1152/ajpcell.00216.2009. PMID 19675304. 
82. ^ Drenckhahn, D. & Kugler, P (2003), "Knochengewebe". In Benninhoff & D. Drenhahn, Anatomie Band 1:147. Munich, Germany: Urban & Fisher
83. ^ ^{a b} Dr. Susan E. Brown, PhD. "Key vitamins for bone health — vitamins K1 and K2". womentowomen.com. http://www.womentowomen.com/bonehealth/keynutrients-vitamink.aspx. Retrieved 11 August 2010. 
84. ^ Lian J, Stewart C, Puchacz E, Mackowiak S, Shalhoub V, Collart D, Zambetti G & Stein G (1989). "Structure of the rat osteocalcin gene and regulation of vitamin D-dependent expression". Proc Natl Acad Sci 86 (4): 1143–1147. doi:10.1073/pnas.86.4.1143. PMC 286642. PMID 2784002. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=286642. 
85. ^ ^{a b} Kanai, T (1997). "Serum vitamin K level and bone mineral density in post-menopausal women". International Journal of Gynecology & Obstetrics 56: 25. doi:10.1016/S0020-7292(96)02790-7. 
86. ^ Booth SL, Tucker K, Chen H, et al. (2000). "Dietary vitamin K intakes are associated with hip fracture but not with bone mineral density in elderly men and women". Am J Clin Nutr 71 (5): 1201–1208. PMID 10799384. 
87. ^ Cheung, AM; Weber, P; Willett, WC; Rockett, H; Booth, SL; Colditz, GA; Hu, H; Vieth, R et al. (2008). Torgerson, David. ed. "Vitamin K Supplementation in Postmenopausal Women with Osteopenia (ECKO Trial): A Randomized Controlled Trial". PLoS Med. 5 (10): e196. doi:10.1371/journal.pmed.0050196. PMC 2566998. PMID 18922041. http://www.ncbi.nlm.nih.gov/pubmed/18922041?dopt=Abstract. 
88. ^ Feskanich, Diane; Weber, P; Willett, W; Rockett, H; Booth, S; Colditz, G (1999). "Vitamin K intake and hip fractures in women: a prospective study". American Journal of Clinical Nutrition 69 (1): 74–9. PMID 9925126. http://www.ajcn.org/cgi/pmidlookup?view=long&pmid=9925126. 
89. ^ Yamaguchi M (November 2006). "Regulatory mechanism of food factors in bone metabolism and prevention of osteoporosis". Yakugaku Zasshi 126 (11): 1117–37. PMID 17077614. http://www.jstage.jst.go.jp/article/yakushi/126/11/126_1117/_article. 
90. ^ Tsukamoto Y (2004). "Studies on action of menaquinone-7 in regulation of bone metabolism and its preventive role of osteoporosis". BioFactors 22 (1-4): 5–19. doi:10.1002/biof.5520220102. PMID 15630245. http://onlinelibrary.wiley.com/doi/10.1002/biof.5520220102/abstract. 
91. ^ http://iabpi.com/fitness-natto-essence Ref. no. HPRG (HSU) 2011-02-0016
92. ^ Allison (2001). "The possible role of vitamin K deficiency in the pathogenesis of Alzheimer's disease and in augmenting brain damage associated with cardiovascular disease". Medical hypotheses 57 (2): 151–5. doi:10.1054/mehy.2001.1307. PMID 11461163. 
93. ^ "Vitamin K Found to Protect Against Liver Cancer"
94. ^ Saxena SP, Israels ED, Israels LG (2001). "Novel vitamin K-dependent pathways regulating cell survival". Apoptosis 6 (1–2): 57–68. doi:10.1023/A:1009624111275. PMID 11321042. 
95. ^ Nimptsch K, Rohrmann S, Linseisen J (April 2008). "Dietary intake of vitamin K and risk of prostate cancer in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition. (EPIC-Heidelberg)". Am. J. Clin. Nutr. 87 (4): 985–92. PMID 18400723. http://www.ajcn.org/cgi/pmidlookup?view=long&pmid=18400723. 
96. ^ MacCorquodale, D. W.; Binkley, S. B.; Thayer, S. A.; Doisy, E. A. (1939). "On the constitution of Vitamin K1". Journal of the American Chemical Society 61 (7): 1928–1929. doi:10.1021/ja01876a510. 
97. ^ Fieser, L. F. (1939). "Synthesis of Vitamin K1". Journal of the American Chemical Society 61 (12): 3467–3475. doi:10.1021/ja01267a072. 
98. ^ Dam, Henrik (December 12, 1946). The discovery of vitamin K, its biological functions and therapeutical application. Nobel Prize lecture
99. ^ Warner, E. D.; Brinkhous, K. M.; Smith, H. P. (1938). Proceedings of the Society of Experimental Biology and Medicine 37: 628. 
100. ^ Stenflo J, Fernlund P, Egan W, Roepstorff P (July 1974). "Vitamin K Dependent Modifications of Glutamic Acid Residues in Prothrombin". Proc. Natl. Acad. Sci. U.S.A. 71 (7): 2730–3. doi:10.1073/pnas.71.7.2730. PMC 388542. PMID 4528109. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=388542. 
101. ^ Nelsestuen GL, Zytkovicz TH, Howard JB (October 1974). "The mode of action of vitamin K. Identification of gamma-carboxyglutamic acid as a component of prothrombin". J. Biol. Chem. 249 (19): 6347–50. PMID 4214105. http://www.jbc.org/cgi/pmidlookup?view=long&pmid=4214105. 
102. ^ Magnusson S, Sottrup-Jensen L, Petersen TE, Morris HR, Dell A (August 1974). "Primary structure of the vitamin K-dependent part of prothrombin". FEBS Lett. 44 (2): 189–93. doi:10.1016/0014-5793(74)80723-4. PMID 4472513. 

External links

• Jane Higdon, "Vitamin K", Micronutrient Information Center, Linus Pauling Institute, Oregon State University
• Vitamin K: Another Reason to Eat Your Greens
• Vitamin K: Signs of Deficiency
• Vitamin K: Vitamin Deficiency, Dependency, and Toxicity: Merck Manual Professional
• An Alternative Perspective on Vitamin K Prophylaxis
• Health Benefits of Vitamin K₂
• Vitamin K content: USDA National Nutrient Database for Standard Reference, Release 19