||This article possibly contains original research. (June 2014)|
|Use||Vitamin K deficiency, Warfarin overdose|
|Biological target||Gamma-glutamyl carboxylase|
Vitamin K refers to a group of structurally similar, fat-soluble vitamins the human body needs for complete synthesis of certain proteins that are required for blood coagulation, and also certain proteins that the body uses to control binding of calcium in bone and other tissues. The vitamin K-related modification of the proteins allows them to bind calcium ions, which they cannot do otherwise. Without vitamin K, blood coagulation is seriously impaired, and uncontrolled bleeding occurs. Low levels of vitamin K also weaken bones and promote calcification of arteries and other soft tissues.
Chemically, the vitamin K family comprises 2-methyl-1,4-naphthoquinone (3-) derivatives. Vitamin K includes two natural vitamers: vitamin K1 and vitamin K2. Vitamin K2, in turn, consists of a number of related chemical subtypes, with differing lengths of carbon side chains made of isoprenoid groups of atoms.
Vitamin K1, also known as phylloquinone, phytomenadione, or phytonadione, is synthesized by plants, and is found in highest amounts in green leafy vegetables because it is directly involved in photosynthesis. It may be thought of as the "plant" form of vitamin K. It is active as a vitamin in animals and performs the classic functions of vitamin K, including its activity in the production of blood-clotting proteins. Animals may also convert it to vitamin K2.
Vitamin K2, the main storage form in animals, has several subtypes, which differ in isoprenoid chain length. These vitamin K2 homologues are called menaquinones, and are characterized by the number of isoprenoid residues in their side chains. Menaquinones are abbreviated MK-n, where M stands for menaquinone, the K stands for vitamin K, and the n represents the number of isoprenoid side chain residues. For example, menaquinone-4 (abbreviated MK-4) has four isoprene residues in its side chain. Menaquinone-4 (also known as menatetrenone from its four isoprene residues) is the most common type of vitamin K2 in animal products since MK-4 is normally synthesized from vitamin K1 in certain animal tissues (arterial walls, pancreas, and testes) by replacement of the phytyl tail with an unsaturated geranylgeranyl tail containing four isoprene units, thus yielding menaquinone-4. This homolog of vitamin K2 may have enzyme functions distinct from those of vitamin K1.
Bacteria in the colon (large intestine) can also convert K1 into vitamin K2. In addition, bacteria typically lengthen the isoprenoid side chain of vitamin K2 to produce a range of vitamin K2 forms, most notably the MK-7 to MK-11 homologues of vitamin K2. All forms of K2 other than MK-4 can only be produced by bacteria, which use these forms in anaerobic respiration. The MK-7 and other bacterially derived forms of vitamin K2 exhibit vitamin K activity in animals, but MK-7's extra utility over MK-4, if any, is unclear and is a matter of investigation.
Three synthetic types of vitamin K are known: vitamins K3, K4, and K5. Although the natural K1 and all K2 homologues and synthetic K4 and K5 have proven nontoxic, the synthetic form K3 (menadione) has shown toxicity.
- 1 Discovery of vitamin K1
- 2 Conversion of vitamin K1 to vitamin K2 in animals
- 3 Subtypes of vitamin K2
- 4 Chemical structure
- 5 Physiology
- 6 Absorption and dietary need
- 7 Recommended amounts
- 8 Anticoagulant drug interactions
- 9 Food sources
- 10 Deficiency
- 11 Toxicity
- 12 Biochemistry
- 13 Injection in newborns
- 14 Health effects
- 15 History of discovery
- 16 References
- 17 Bibliography
- 18 External links
Discovery of vitamin K1
Vitamin K1 was identified in 1929 by Danish scientist Henrik Dam when he investigated the role of cholesterol by feeding chickens a cholesterol-depleted diet. After several weeks, the animals developed haemorrhages and started bleeding. These defects could not be restored by adding purified cholesterol to the diet. A second compound—together with the cholesterol—apparently 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.
Conversion of vitamin K1 to vitamin K2 in animals
The MK-4 form of vitamin K2 is produced by conversion of vitamin K1 in the testes, pancreas, and arterial walls. While major questions still surround the biochemical pathway for this transformation, the conversion is not dependent on gut bacteria, as it occurs in germ-free rats and in parenterally-administered K1 in rats. In fact, tissues that accumulate high amounts of MK-4 have a remarkable capacity to convert up to 90% of the available K1 into MK-4. There is evidence that the conversion proceeds by removal of the phytyl tail of K1 to produce menadione as an intermediate, which is then condensed with an activated geranylgeranyl moiety (see also prenylation) to produce vitamin K2 in the MK-4 (menatetrione) form.
Subtypes of vitamin K2
Vitamin K2 (menaquinone) includes several subtypes. The two subtypes most studied are menaquinone-4 (menatetrenone, MK-4) and menaquinone-7 (MK-7).
Menaquinone-7 is different from MK-4 in that it is not produced by human tissue. MK-7 may be converted from phylloquinone (K1) in the colon by E. coli bacteria. However, bacterially derived menaquinones (MK-7) appear to contribute minimally to overall vitamin K status. MK-4 and MK-7 are both found in the United States in dietary supplements for bone health.
The U.S. Food and Drug Administration (FDA) has not approved any form of vitamin K for the prevention or treatment of osteoporosis; however, MK-4 has been shown to decrease the incidence of fractures up to 87%. MK-4 (45 mg daily) has been approved by the Ministry of Health in Japan since 1995 for the prevention and treatment of osteoporosis.
Vitamin K2 as MK-4, but not as MK-7 (and also not vitamin K1) has also been shown to prevent bone loss and/or fractures in these circumstances:
- caused by corticosteroids (e.g., prednisone, dexamethasone, prednisolone),
- anorexia nervosa,
- cirrhosis of the liver,
- postmenopausal osteoporosis,
- disuse from stroke,
- Alzheimer's disease,
- Parkinson disease,
- primary biliary cirrhosis
The three synthetic forms of vitamin K are 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).
Vitamin K1, the precursor of most vitamin K in nature, is a steroisomer of phylloquinone, an important chemical in green plants, where it functions as an electron acceptor in photosystem I during photosynthesis. For this reason, vitamin K1 is found in large quantities in the photosynthetic tissues of plants (green leaves, and dark green leafy vegetables such as romaine lettuce, kale and spinach), but it occurs in far smaller quantities in other plant tissues (roots, fruits, etc.). Iceberg lettuce contains relatively little. The function of phylloquinone in plants appears to have no resemblance to its later metabolic and biochemical function (as "vitamin K") in animals, where it performs a completely different biochemical reaction.
Vitamin K (in animals) is involved in the carboxylation of certain glutamate residues in proteins to form gamma-carboxyglutamate (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, and are essential for the biological activity of all known Gla proteins.
At this time[update], 16 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, and X, and proteins C, S, and Z
- Bone metabolism: osteocalcin, also called bone Gla protein (BGP), matrix Gla protein (MGP), periostin, and the recently discovered Gla-rich protein (GRP).
- Vascular biology: growth arrest-specific protein 6 (Gas6)
- Unknown function: proline-rich g-carboxy glutamyl proteins (PRGPs) 1 and 2, and transmembrane g-carboxy glutamyl proteins (TMGs) 3 and 4.
Like other lipid-soluble vitamins (A, D, E), vitamin K is stored in the fat tissue of the human body.
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. Another at-risk group for deficiency were those subject to decreased production of K2 by normal intestinal microbiota, as seen in broad spectrum antibiotic use. Taking broad-spectrum antibiotics can reduce vitamin K production in the gut by nearly 74% in people compared with those not taking these antibiotics. Diets low in vitamin K also decrease the body's vitamin K concentration. Those with chronic kidney disease are at risk for vitamin K deficiency, as well as vitamin D deficiency, and particularly those with the apoE4 genotype. Additionally, in the elderly there is a reduction in vitamin K2 production.
Recent research results also demonstrate that the small intestine and large intestine (colon) seem to be inefficient at absorbing vitamin K supplements in rat populations low in Vitamin K. These results are reinforced by human cohort studies, where a majority of the subjects showed inadequate vitamin 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 vitamin K deficiency. And in an animal model MK-4 was shown to prevent arterial calcifications, pointing to its potential role in prevention of such calcification. In this study vitamin K1 was also tested, in an attempt to make connections between vitamin K1 intake and calcification reduction. Only vitamin K2 (as MK-4) was found to influence warfarin-induced calcification in this study.
The U.S. Dietary Reference Intake (DRI) for an Adequate Intake (AI) of vitamin K for a 25-year-old male is 120 micrograms (μg) per day. The AI for adult women is 90 μg/day, for infants is 10–20 μg/day, and for children and adolescents 15–100 μg/day. To get maximum carboxylation of osteocalcin, one may have to take up to 1000 μg of vitamin K1.
Anticoagulant drug interactions
Phylloquinone (K1) or menaquinone (K2) are capable of reversing the anticoagulant activity of the anticoagulant warfarin (tradename Coumadin). Warfarin works by blocking recycling of vitamin K, so that the body and tissues have lower levels of active vitamin K, and thus a deficiency of vitamin K.
Supplemental vitamin K (for which oral dosing is often more active than injectable dosing in human adults) reverses the vitamin K deficiency caused by warfarin, and therefore reduces the intended anticoagulant action of warfarin and related drugs. Sometimes small amounts of vitamin K (one milligram per day) are given orally to patients taking Coumadin so that the action of the drug is more predictable. The proper anticoagulant action of the drug is a function of vitamin K intake and drug dose, and due to differing absorption must be individualized for each patient. The action of warfarin and vitamin K both require two to five days after dosing to have maximum effect, and neither Coumadin or vitamin K shows much effect in the first 24 hours after they are given.
In two separate studies in the rat model, after long term administration of Coumadin to induce calcification of arteries in the rodents, supplemental vitamin K was found to reverse or prevent some of the arterial calcification attendant on the long-term blockade of vitamin K. A second study found that only vitamin K2 as MK-4, and not vitamin K1 was effective at preventing warfarin-induced arterial calcification in rats, suggesting differing roles for the two forms of the vitamin in some calcium-dependent processes.
|Food||Serving size||Vitamin K1 micrograms (μg)||Food||Serving size||Vitamin K1 micrograms (μg)|
|Kale, cooked||1/2 cup||531||Parsley, raw||1/4 cup||246|
|Spinach, cooked||1/2 cup||444||Spinach, raw||1 cup||145|
|Collards, cooked||1/2 cup||418||Collards, raw||1 cup||184|
|Swiss chard, cooked||1/2 cup||287||Swiss chard, raw||1 cup||299|
|Mustard greens, cooked||1/2 cup||210||Mustard greens, raw||1 cup||279|
|Turnip greens, cooked||1/2 cup||265||Turnip greens, raw||1 cup||138|
|Broccoli, cooked||1 cup||220||Broccoli, raw||1 cup||89|
|Brussels sprouts, cooked||1 cup||219||Endive, raw||1 cup||116|
|Cabbage, cooked||1/2 cup||82||Green leaf lettuce||1 cup||71|
|Asparagus||4 spears||48||Romaine lettuce, raw||1 cup||57|
|Table from "Important information to know when you are taking: Warfarin (Coumadin) and Vitamin K", Clinical Center, National Institutes of Health Drug Nutrient Interaction Task Force.|
Vitamin K1 is found chiefly in leafy green vegetables such as dandelion greens (which contain 778.4 μg per 100 g, or 741% of the recommended daily amount), spinach, swiss chard, lettuce and Brassica (e.g. cabbage, kale, cauliflower, broccoli, and brussels sprouts) and often the absorption is greater when accompanied by fats such as butter or oils; 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. Some vegetable oils, notably soybean, contain vitamin K, but at levels that would require relatively large calorific consumption to meet the USDA-recommended levels. Colonic bacteria synthesize a significant portion of humans' vitamin K needs; newborns often receive a vitamin K shot at birth to tide them over until their colons become colonized at five to seven days of age from the consumption of their mother's milk.
Phylloquinone's tight binding to thylakoid membranes in chloroplasts makes it less bioavailable. For example, cooked spinach has a 5% bioavailability of phylloquinone, however, fat added to it increases bioavailability to 13% due to the increased solubility of vitamin K in fat.
Food sources of vitamin K2 include fermented or aged cheeses, eggs, meats such as chicken and beef and their fat, livers, and organs, and in fermented vegetables, especially natto, as well as sauerkraut and kefir.
|Food 100 grams (3.5 oz) portion||Microgram (μg)||Proportion of vitamin K2||Food 100 grams (3.5 oz) portion||Microgram (μg)||Proportion of vitamin K2|
|Natto, cooked||1,103.4||(90% MK-7, 10% other MK)||Chicken Leg||8.5||(100% MK-4)|
|Goose liver pâté||369.0||(100% MK-4)||Ground beef (medium fat)||8.1||(100% MK-4)|
|Hard cheeses (Dutch Gouda style), raw||76.3||(6% MK-4, 94% other MK)||Chicken liver (braised)||6.7||(100% MK-4)|
|Soft cheeses (French Brie style)||56.5||(6.5% MK-4, 93.5% other MK)||Hot dog||5.7||(100% MK-4)|
|Egg yolk, (Netherlands)||32.1||(98% MK-4, 2% other MK)||Bacon||5.6||(100% MK-4)|
|Goose leg||31.0||(100% MK-4)||Calf’s liver (pan-fried)||6.0||(100% MK-4)|
|Egg yolk (U.S.)||15.5||(100% MK-4)||Sauerkraut||4.8||(100% MK-4)|
|Butter||15.0||(100% MK-4)||Whole milk||1.0||(100% MK-4)|
|Chicken liver (raw)||14.1||(100% MK-4)||Salmon (Alaska, Coho, Sockeye, Chum, and King wild (raw))||0.5||(100% MK-4)|
|Chicken liver (pan-fried)||12.6||(100% MK-4)||Cow’s liver (pan-fried)||0.4||(100% MK-4)|
|Cheddar cheese (U.S.)||10.2||(6% MK-4, 94% other MK)||Egg white||0.4||(100% MK-4)|
|Meat franks||9.8||(100% MK-4)||Skim milk||0.0|
|Chicken breast||8.9||(100% MK-4)|
|Table from Rhéaume-Bleue, pp. 66–67.|
Vitamin K2 (menaquinone-4) is synthesized by animal tissues and is found in meat, eggs, and dairy products. Menaquinone-7 is synthesized by bacteria during fermentation and is found in fermented soybeans (natto), and in most fermented cheeses. In natto, none of the vitamin K is from menaquinone-4, and in cheese only 2–7% is.
Average diets are usually not lacking in vitamin K, and primary 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 those who suffer from liver damage or disease (e.g., alcoholics), cystic fibrosis, or inflammatory bowel diseases, or have recently had abdominal surgeries. Secondary vitamin K deficiency can occur in bulimics, those on stringent diets, and those taking anticoagulants. Other drugs associated with vitamin K deficiency include salicylates, barbiturates, and cefamandole, although the mechanisms are still unknown. Vitamin K1 deficiency can result in coagulopathy, a bleeding disorder. Symptoms of K1 deficiency include anemia, bruising, and bleeding of the gums or nose in both sexes, and heavy menstrual bleeding in women.
Osteoporosis and coronary heart disease are strongly associated with lower levels of K2 (menaquinone). Vitamin K2 (MK-7) deficiency is also related to severe aortic calcification and all-cause mortality. 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.
Although allergic reaction from supplementation is possible, no known toxicity is associated with high doses of the phylloquinone (vitamin K1) or menaquinone (vitamin K2) forms of vitamin K, so no tolerable upper intake level (UL) has been set.
Blood clotting (coagulation) studies in humans using 45 mg per day of vitamin K2 (as MK-4) and even up to 135 mg/day (45 mg three times daily) of K2 (as MK-4), 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.
Unlike the safe natural forms of vitamin K1 and vitamin K2 and their various isomers, a synthetic form of vitamin K, vitamin K3 (menadione), is demonstrably toxic. The U.S. FDA has banned this form from over-the-counter sale in the United States because large doses have been shown to cause allergic reactions, hemolytic anemia, and cytotoxicity in liver cells.
Function in animals
The function of vitamin K2 in the animal cell is to add a carboxylic acid functional group to a glutamate amino acid residue in a protein, to form a gamma-carboxyglutamate (Gla) residue. This is a somewhat uncommon posttranslational modification of the protein, which is then known as a "Gla protein." The presence of two -COOH (carboxylate) groups on the same carbon in the gamma-carboxyglutamate residue allows it to chelate calcium ion. The binding of calcium ion in this way very often triggers the function or binding of Gla-protein enzymes, such as the so-called vitamin K dependent clotting factors discussed below.
Within the cell, vitamin K undergoes electron reduction to a reduced form called vitamin K hydroquinone by the enzyme vitamin K epoxide reductase (VKOR). Another enzyme then oxidizes vitamin K hydroquinone to allow carboxylation of Glu to Gla; this enzyme is called the gamma-glutamyl carboxylase or the vitamin K-dependent carboxylase. The carboxylation reaction only proceeds 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. Vitamin K epoxide is then reconverted to vitamin K by VKOR. The reduction and subsequent reoxidation of vitamin K coupled with carboxylation of Glu is called the vitamin K cycle. Humans are rarely deficient in vitamin K1 because, in part, vitamin K 1 is continuously recycled in cells.
Warfarin and other 4-hydroxycoumarins block the action of the VKOR. 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 clotting suppression, warfarin treatment must be carefully monitored to avoid overdose.
The following human Gla-containing proteins ("gla 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 to activate the Axl receptor tyrosine kinase and stimulate cell proliferation or prevent 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. 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. These snails produce a venom containing hundreds of neuroactive peptides, or conotoxins, which is sufficiently toxic to kill an adult human. Several of the conotoxins contain two to five Gla residues.
Methods of assessment
Vitamin K status can be assessed by:
- The prothrombin time (PT) test measures the time required for blood to clot. A blood sample is mixed with citric acid and put in a fibrometer; delayed clot formation indicates a deficiency. This test is insensitive to mild deficiency, as the values do not change until the concentration of prothrombin in the blood has declined by at least 50%.
- Undercarboxylated prothrombin (PIVKA-II), in a study of 53 newborns, found "PT (prothrombin time) is a less sensitive marker than PIVKA II", and as indicated above, PT is unable to detect subclinical deficiencies that can be detected with PIVKA-II testing.
- Plasma phylloquinone was found to be positively correlated with phylloquinone intake in elderly British women, but not men,
- Urinary γ-carboxyglutamic acid 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 and 417 μg for five days did not induce a significant change. Response may be age-specific.
- Undercarboxylated osteocalcin (UcOc) levels have been inversely correlated with stores of vitamin K and bone strength in developing rat tibiae. Another study following 78 postmenopausal Korean women found a supplement regimen of vitamins K and D, and calcium, but not a regimen of vitamin D and calcium, was inversely correlated with reduced UcOc levels.
Function in bacteria
Many bacteria, such as Escherichia coli found in the large intestine, can synthesize vitamin K2 (menaquinone-7 or MK-7, up to MK-11), but not vitamin K1 (phylloquinone). In these bacteria, menaquinone transfers two electrons between two different small molecules, during oxygen-independent metabolic energy production processes (anaerobic respiration). 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, passes two electrons to a menaquinone. The menaquinone, with the help of another enzyme, then transfers these two electrons to a suitable oxidant, such fumarate or nitrate (also called an electron acceptor). Adding two electrons to fumarate or nitrate converts 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 the final electron acceptor is not molecular oxygen, but 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. E. coli, as facultative anaerobes, can carry out both aerobic respiration and menaquinone-mediated anaerobic respiration.
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 1–4 μg/L of vitamin K1, while formula-derived milk can contain up to 100 μg/L in supplemented formulas. Vitamin K2 concentrations in human milk appear to be much lower than those of vitamin K1. Occurrence of vitamin K deficiency bleeding in the first week of the infant's life is estimated at 0.25 to 1.7%, with a prevalence of two to 10 cases per 100,000 births. Premature babies have even lower levels of the vitamin, so they are at a higher risk from this deficiency.
Bleeding in infants due to vitamin K deficiency can be severe, leading to hospitalization, blood transfusions, brain damage, and death. Supplementation can prevent most cases of vitamin K deficiency bleeding in the newborn. Intramuscular administration is more effective in preventing late vitamin K deficiency bleeding than oral administration.
As a result of the occurrences of vitamin K deficiency bleeding, the Committee on Nutrition of the American Academy of Pediatrics has recommended 0.5 to 1.0 mg vitamin K1 be administered to all newborns shortly after birth.
In the UK vitamin K supplementation is recommended for all newborns within the first 24 hours. This is usually given as a single intramuscular injection of 1 mg shortly after birth but as a second-line option can be given by three oral doses over the first month.
Controversy arose in the early 1990s regarding this practice, when two studies suggested a relationship between parenteral administration of vitamin K and childhood cancer, 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. Doctors reported emerging concerns in 2013, after treating children for serious bleeding problems. They cited lack-of newborn Vitamin K administration, as the reason that the problems occurred, and recommended that breast-fed babies could have an increased risk unless they receive a preventative dose.
There is no good evidence that vitamin K supplementation helps prevent osteoporosis or fractures in postmenopausal women.
45 mg daily MK-4 has been approved by the Ministry of Health in Japan since 1995 for the prevention and treatment of osteoporosis.
MK-4 (but not MK-7 or vitamin K1) prevented bone loss and/or fractures in the following circumstances:
- caused by corticosteroids (e.g., prednisone, dexamethasone, prednisolone)
- anorexia nervosa
- cirrhosis of the liver
- postmenopausal osteoporosis
- disuse from stroke
- Alzheimer's disease
- Parkinson disease
- primary biliary cirrhosis
- leuprolide treatment (for prostate cancer).
Menaquinone-7 (MK-7), which is abundant in fermented soybeans (natto), has been demonstrated to stimulate osteoblastic bone formation and to inhibit osteoclastic bone resorption. 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. On 19 February 2011, HSA (Singapore) approved a health supplement that contains vitamin K2 (MK-7) and vitamin D3 for increasing bone mineral density.
||This section may be too long and excessively detailed. (October 2015)|
The potential benefit of vitamin K in reducing cardiovascular disease (CVD) risk is due to its function as a cofactor in the post-translational modification of matrix gla protein (MGP) in vascular smooth muscle cells (VSMC). Increased calcification of blood vessels is a risk factor for CVD as it lends to the hardening of arteries and/or to the development of hard atherosclerotic plaque. MGP may play a role in preventing ectopic calcification in the arteries. Although the mechanism of MGP on arterial calcification is not fully understood, it is known that MGP must be in its active form to have a beneficial effect in the blood vessel. MGP becomes activated by carboxylation, which requires vitamin k as a cofactor. Because it is thought that phylloquinones exerts its actions mainly in the liver, it is speculated that menaquinones may have a more significant influence in the extra-hepatic regions of the body, such as VSMCs, where they are known to travel to by LDL. In addition, menaquinones have been demonstrated to have a longer half-life in circulation compared to phylloquinone. Menaquinones may therefore be important for preventing vascular calcification (VC) and thus reducing risk for CVD.
Previous research conducted on MGP knockout mice demonstrated the importance of MGP on inhibiting VC. Luo, Ducy, McKee, Pinero, Loyer, Behringer, and Karsenty (1997) found that the aorta of MGP knockout mice became severely calcified within the first two months of life, leading to rupture of the artery and finally death of the mice due to internal hemorrhaging. This study became a basis for many future studies to further explore the influence of MGP on VC since it was hypothesized that if a human had low levels of MGP they could develop VC more quickly than those with optimal levels of MGP. It became a question as to whether MGP could help to reduce the risk of CVD development. However, because MGP undergoes different post-translational modifications, several forms of MGP can exist in the human body, so which form of MGP is most effective at preventing VC? Schurgers, Spronk, Soute, Schiffers, DeMay, andVermeer (2007) found that the carboxylated form of MGP was responsible for reducing VC in rats. In the study, rats were subjected to a dose of warfarin to induce VC. Warfarin is a commonly prescribed drug given to humans to help prevent heart disease and stroke by reducing the development of blood clots in the blood vessels. Warfarin acts to inhibit the vitamin k cycle; thereby preventing activation of essential blood clotting factors. In the aforementioned study, VC was significantly decreased in the rats inflicted with VC via warfarin, when supplemented for 6 weeks with a high dose of either menaquinone or phylloquinone. Both menaquinone and phylloquinone supplementation in concentrations of 100 μg/g (supplied in the rat food), were able to inflict a significant reduction in VC in the rats. When examining the different MGP forms in the rats, it was found that the high menaquinone and phylloquinone supplement groups had greater levels of carboxylated MGP compared to the control, rats receiving warfarin, and rats receiving a normal phylloquinone dose. Furthermore, levels of uncarboxylated MGP were higher in the rats receiving warfarin and in the rats receiving a normal phylloquinone dose. This study demonstrated a benefit of both menaquinone and phylloquinone on VC but did not determine the mechanism by which carboxylated MGP was able to reduce VC. In 2008, Wallin, Schurgers, and Wajih set out to help establish this mechanism. The researchers evaluated uncarboxylated MGP and carboxylated MGP by experimenting with the glutamic acid and gamma-carboxyglutamic acid residues of MGP. It was found that the gamma-carboxyglutamic acid residues were capable of inhibiting a protein called bone morphogenic protein-2 (BMP-2), that may play a role in differentiation of vascular smooth muscle cells (VSMCs) into bone-like cells. On the other hand, the glutamic acid residues were unable to inhibit BMP-2, which confirmed that MGP must be carboxylated to be active in VC inhibition.
Intervention studies with menaquinones in humans have become more frequently published in recent years. In a randomized, double blind, placebo controlled human trial, menaquinone-7 supplementation was studied in healthy adults for its influence on circulating forms of MGP. In the twelve-week study, sixty adults were divided into three supplement groups: placebo, 180 μg menaquinone-7/day, and 360 μg menaquinone-7/day and circulating forms of MGP were analyzed from blood and urine samples that were collected at weeks 1, 4, and 12. The researchers found that after only 4 weeks of menaquinone-7 supplementation, the total level of dephosphorylated-uncarboxylated MGP was decreased compared to baseline and that the effect was dose dependent with 360 μg menaquinone-7/day having a greater effect than 180 μg menaquinone-7/day. Furthermore, no change in dephosphorylated-uncarboxylated MGP was evident in the placebo group. In another study examining the relationship between menaquinone-7 supplementation and circulating dephosphorylated-uncarboxylated MGP levels, 165 patients undergoing chronic hemodialysis were divided into three menaquinone-7 supplementation groups: 360 μg/day, 720 μg/day, or 1080 μg/day for a total of 8 weeks. At baseline, it was determined through 3-day food diaries that there was a significant inverse relationship between menaquinone intake and dephosphorylated-uncarboxylated MGP levels, whereas phylloquinone intake had no association. After 8 weeks of menaquinone-7 supplementation, the researchers found that circulating dephosphorylated-uncarboxylated MGP levels had significantly decreased, and that the effect was dose dependent. Unfortunately, other forms of MGP were not measured. In both of these aforementioned studies, neither examined the relationship of dephosphorylated-uncarboxylated MGP levels to VC or CVD. However, a recent cohort study investigating vitamin k insufficiency and CVD found that high circulating dephosphorylated-uncarboxylated MGP levels (greater than 400 pmol/L) were significantly associated with increased risk of fatal and non-fatal CVD in 577 healthy men and women aged 55 – 65 years.
If VC can be prevented or reduced by menaquinones then the risk for CVD may also be reduced. Future strategies to reduce the risk of CVD may one day encourage increasing one’s intake of dietary menaquinone.
Coronary heart disease
A study by Gast et al. (2009), reports "an inverse association between vitamin K2 and risk of CHD with a Hazard Ratio (HR) of 0.91 [95% CI 0.85–1.00] per 10 μg/d vitamin K2 intake. This association was mainly due to vitamin K2 subtypes MK-7, MK-8 and MK-9. Vitamin K1 intake was not significantly related to CHD. The authors conclude that "a high intake of menoquinones, especially MK-7, MK-8 and MK-9, could protect against CHD. However, more research is necessary to define optimal intake levels of vitamin K for the prevention of CHD."
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.
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 that involved 21 women with viral liver cirrhosis found that women in the supplement group were 90% less likely to develop liver cancer. A prospective (i.e., longitudinal) study performed in healthy men reported a significant inverse association between vitamin K2 consumption and the risk of advanced prostate cancer.
In 2006, a clinical trial showed that K2 as the menaquinone-4 (MK-4) (called menatetrenone in the study) might be able to reduce recurrence of liver cancer after surgery. It should be noted that this was a small pilot study and other similar studies did not show much effect. MK-4 is now being tested along with other drugs to reduce liver cancer and has shown promising early results.
Diabetes in the elderly
A research shows that total diabetes risk of individuals who have highest circulating levels of vitamin K1 were 51% lower than those with the lowest levels. The researchers conclude that dietary phylloquinone intake is associated with reduced risk of type 2 diabetes.
A research shows that the risk of developing non-Hodgkin lymphoma was decreased by 45 percent for the study participants who had the highest vitamin K levels compared to participants with the lowest levels of the vitamin.
As antidote for poisoning by 4-hydroxycoumarin
Vitamin K antagonists are substances that reduce blood clotting by reducing the active form of vitamin K. They are used as rat poisons and as medications to prevent thrombosis. Examples include 4-hydroxycoumarins such as 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 recycling of vitamin K and thus cause simple deficiency of active vitamin K. This deficiency results in decreased vitamin K-dependent synthesis of some clotting factors by the liver. Death is usually a result of internal hemorrhage. Treatment for rodenticide poisoning 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, after poisoning (this is necessary for the more potent 4-hydoxycoumarins used as rodenticides, which act by being fat-soluble and thus having a longer residence time in the body). If caught early, prognosis is good even when great amounts of the drug or poison are ingested, as these drugs are not true vitamin K antagonists, so the same amount of fresh vitamin K administered each day is sufficient for any dose of poison (although as noted, this must be continued for a longer time with more potent poisons). No matter how large the dose of these agents, they can do no more than prevent vitamin K from being recycled, and this metabolic problem may always be simply reversed by giving sufficient vitamin K (often 5 mg per day) to ensure that enough fresh vitamin K resides in the tissues to carry out its normal functions, even when efficient use of it by the body is prevented by the poison.[medical citation needed]
A recent study has shown that rats who are fed excess amounts of vitamin K had greater amounts of brain sulfatide concentrations. This study indicates that vitamin K has more uses than originally thought, thus furthering the importance of daily vitamin K intake. The same study showed that a diet with insufficient vitamin K levels decreased the brain sulfatide concentrations in rats at the (p < 0.01) significance level. Another study involving rats has indicated that different species, strains and genders of rats required different amounts of vitamin K intake, depending on how much was stored in their livers. This may indicate that different humans should have different needs for their vitamin K intake. A third study looked at the way rats and chicks are able to recycle parts of vitamin K. The study found that chicks are about 10% less efficient in recycling the vitamin K than their rat counterparts. This evidence also helps to confirm that vitamin K levels are unique to each species, and the previous study shows that required vitamin K intake also varies within species.
Vitamin K may be applied topically, typically as a 5% cream, to diminish postoperative bruising from cosmetic surgery and injections, to treat broken capillaries (spider veins), to treat rosacea, and to aid in the fading of hyperpigmentation and dark under-eye circles.
History of discovery
In 1929, Danish scientist Henrik Dam investigated the role of cholesterol by feeding chickens a cholesterol-depleted diet. 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. 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.
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).
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.
The precise function of vitamin K was not discovered until 1974, when three laboratories (Stenflo et al., Nelsestuen et al., and Magnusson et al.) 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.
- "Vitamin K Overview". University of Maryland Medical Center.
- Higdon (February 2008). "Vitamin K". Linus Pauling Institute, Oregon State University. Retrieved 12 April 2008.
- Dam, H. (1935). "The Antihæmorrhagic Vitamin of the Chick.: Occurrence And Chemical Nature". Nature 135 (3417): 652–653. doi:10.1038/135652b0.
- Newman P., Shearer MJ; Newman, Paul (2008). "Metabolism and cell biology of vitamin K". Thrombosis and Haemostasis: 530–547. doi:10.1160/TH08-03-0147.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Al Rajabi, Ala (2011) The Enzymatic Conversion of Phylloquinone to Menaquinone-4. Ph.D. thesis, Tufts University, Friedman School of Nutrition Science and Policy.
- 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.
- 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.
- Weber, P (2001). "Vitamin K and bone health". Nutrition 17 (10): 880–887. doi:10.1016/S0899-9007(01)00709-2. PMID 11684396.
- 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.
- 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.
- 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.
- 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.
- 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. doi:10.1053/j.ajkd.2003.09.013. PMID 14712427.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- McGee, W (1 February 2007). "Vitamin K". MedlinePlus. Retrieved 2 April 2009.
- Furie B, Bouchard BA, Furie BC (15 March 1999). "Vitamin K-dependent biosynthesis of gamma-carboxyglutamic acid". Blood 93 (6): 1798–808. PMID 10068650.
- Mann KG (1999). "Biochemistry and physiology of blood coagulation". Thromb. Haemost. 82 (2): 165–74. PMID 10605701.
- 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.
- 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.
- Viegas, C. S. B.; Simes, D. C.; Laizé, V.; Williamson, M. K.; Price, P. A.; Cancela, M. L. (2008). "Gla-rich Protein (GRP), A New Vitamin K-dependent Protein Identified from Sturgeon Cartilage and Highly Conserved in Vertebrates". Journal of Biological Chemistry 283 (52): 36655–36664. doi:10.1074/jbc.M802761200. PMC 2605998. PMID 18836183.
- Viegas, C. S. B.; Cavaco, S.; Neves, P. L.; Ferreira, A.; João, A.; Williamson, M. K.; Price, P. A.; Cancela, M. L.; Simes, D. C. (2009). "Gla-Rich Protein is a Novel Vitamin K-Dependent Protein Present in Serum That Accumulates at Sites of Pathological Calcifications". The American Journal of Pathology 175 (6): 2288–2298. doi:10.2353/ajpath.2009.090474. PMC 2789615. PMID 19893032.
- 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.
- 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.
- "Vitamin K". National Institute of Health. Retrieved 26 May 2009.
- 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.
- Ferland G, Sadowski JA, O'Brien ME (1993). "Dietary induced subclinical vitamin K deficiency in normal human subjects". The Journal of Clinical Investigation 91 (4): 1761–8. doi:10.1172/JCI116386. PMC 288156. PMID 8473516.
- Holden, RM; Morton, AR; Garland, JS; Pavlov, A; Day, AG; Booth, SL (April 2010). "Vitamins K and D status in stages 3–5 chronic kidney disease". Clinical journal of the American Society of Nephrology : CJASN 5 (4): 590–7. doi:10.2215/CJN.06420909. PMC 2849681. PMID 20167683.
- Hodges SJ, Pilkington MJ, Shearer MJ, Bitensky L, Chayen J (1990). "Age-related changes in the circulating levels of congeners of vitamin K2, menaquinone-7 and menaquinone-8". Clinical Science 78 (1): 63–6. PMID 2153497.
- Groenen-van Dooren MM, Ronden JE, Soute BA, Vermeer C (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.
- Komai M, Shirakawa H (2007). "[Vitamin K metabolism. Menaquinone-4 (MK-4) formation from ingested VK analogues and its potent relation to bone function]". Clin Calcium (in Japanese) 17 (11): 1663–72. PMID 17982185.
- Geleijnse JM; Vermeer C; Grobbee DE; Schurgers, LJ; Knapen, MH; Van Der Meer, IM; Hofman, A; Witteman, JC (2004). "Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study" (PDF). J. Nutr. 134 (11): 3100–5. PMID 15514282.
- Beulens JW, Bots ML, Atsma F, Bartelink ML, Prokop M, Geleijnse JM, Witteman JC, Grobbee DE, van der Schouw YT (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.
- Nimptsch K, Rohrmann S, Kaaks R, Linseisen J (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)" (PDF). Am. J. Clin. Nutr. 91 (5): 1348–58. doi:10.3945/ajcn.2009.28691. PMID 20335553.
- 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.
- Binkley NC, Krueger DC, Kawahara TN, angelke JA, Chappell RJ, Suttie JW (2002). "A high phylloquinone intake is required to achieve maximal osteocalcin gamma-carboxylation" (PDF). Am. J. Clin. Nutr. 76 (5): 1055–60. PMID 12399278.
- 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.
- Crowther MA; Douketis JD; Schnurr T; Steidl, L; Mera, V; Ultori, C; Venco, A; Ageno, W (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". Ann. Intern. Med. 137 (4): 251–4. doi:10.7326/0003-4819-137-4-200208200-00009. PMID 12186515.
- "Important Information to Know When You Are Taking: Warfarin (Coumadin) and Vitamin K" (PDF). The National Institute of Health. National Institute of Health Clinical Center Drug-Nutrient Interaction Task Force. Retrieved 17 April 2015.
- "Guidelines For Warfarin Reversal With Vitamin K" (PDF). American Society of Health-System Pharmacists. American Society of Health-System Pharmacists. Retrieved 17 April 2015.
- Schurgers, L. J.; Spronk, H. M. H.; Soute, B. A. M.; Schiffers, P. M.; Demey, J. G.; Vermeer, C. (2006). "Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats". Blood 109 (7): 2823–2831. doi:10.1182/blood-2006-07-035345. PMID 17138823.
- Spronk, H. M. H.; Soute, B. A. M.; Schurgers, L. J.; Thijssen, H. H. W.; De Mey, J. G. R.; 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.
- Pradaxa Drug Interactions. Pradaxapro.com (19 March 2012). Retrieved on 21 April 2013.
- Bauersachs, R; The EINSTEIN Investigators (2010). "Oral Rivaroxaban for Symptomatic Venous Thromboembolism". New England Journal of Medicine 363 (26): 2499–2510. doi:10.1056/NEJMoa1007903. PMID 21128814.
- Rhéaume-Bleue, p. 42
- Important information to know when you are taking: Warfarin (Coumadin) and Vitamin K. National Institutes of Health Clinical Center. cc.nih.gov
- Nutrition Facts and Information for Parsley, raw. Nutritiondata.com. Retrieved on 21 April 2013.
- Nutrition facts, calories in food, labels, nutritional information and analysis. Nutritiondata.com (13 February 2008). Retrieved on 21 April 2013.
- Vitamin K. Vivo.colostate.edu (2 July 1999). Retrieved on 21 April 2013.
- food sources for vitamin K2. Livestrong.com. Retrieved on 21 April 2013.
- Elder SJ, Haytowitz DB, Howe J, Peterson JW, Booth SL (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.
- 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.
- "On the Trail of the Elusive X-Factor: Vitamin K2 Revealed".[verification needed]
- "Micronutrient Data Centre: Vitamin K".
- 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.
- 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.
- 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.
- Gast, G. C. M.; De Roos, N. M.; Sluijs, I.; Bots, M. L.; Beulens, J. W. J.; Geleijnse, J. M.; Witteman, J. C.; Grobbee, D. E.; Peeters, P. H. M.; Van Der Schouw, Y. T. (2009). "A high menaquinone intake reduces the incidence of coronary heart disease". Nutrition, Metabolism and Cardiovascular Diseases 19 (7): 504–510. doi:10.1016/j.numecd.2008.10.004. PMID 19179058.
- Geleijnse; Vermeer, C; Grobbee, DE; Schurgers, LJ; Knapen, MH; van der Meer, IM; Hofman, A; Witteman, JC (2004). "Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: The Rotterdam Study". The Journal of nutrition 134 (11): 3100–5. PMID 15514282.
- Rasmussen, S. E.; Andersen, N. L.; Dragsted, L. O.; Larsen, J. C. (2005). "A safe strategy for addition of vitamins and minerals to foods". European Journal of Nutrition 45 (3): 123–135. doi:10.1007/s00394-005-0580-9. PMID 16200467.
- 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.
- 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.
- 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.
- Suttie JW (1985). "Vitamin K-dependent carboxylase". Annu. Rev. Biochem. 54: 459–77. doi:10.1146/annurev.bi.54.070185.002331. PMID 3896125.
- Presnell SR, Stafford DW (2002). "The vitamin K-dependent carboxylase". Thromb. Haemost. 87 (6): 937–46. PMID 12083499.
- Stafford DW (2005). "The vitamin K cycle". J. Thromb. Haemost. 3 (8): 1873–8. doi:10.1111/j.1538-7836.2005.01419.x. PMID 16102054.
- Rhéaume-Bleue, p. 79.
- Whitlon DS, Sadowski JA, Suttie JW (1978). "Mechanism of coumarin action: significance of vitamin K epoxide reductase inhibition". Biochemistry 17 (8): 1371–7. doi:10.1021/bi00601a003. PMID 646989.
- Terlau H, Olivera BM (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.
- Buczek O, Bulaj G, Olivera BM (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.
- Prothrombin Time. webmd.com
- Dituri, F.; Buonocore, G.; Pietravalle, A.; Naddeo, F.; Cortesi, M.; Pasqualetti, P.; Tataranno, M. L.; Agostino, R. (2012). "PIVKA-II plasma levels as markers of subclinical vitamin K deficiency in term infants". Journal of Maternal-Fetal and Neonatal Medicine 25 (9): 1660–1663. doi:10.3109/14767058.2012.657273. PMID 22280352.
- Thane CW; Bates CJ; Shearer MJ; Unadkat, N.; Harrington, D.J.; Paul, A.A.; Prentice, A.; Bolton-Smith, C. (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.
- McKeown NM; Jacques PF; Gundberg CM; Peterson, JW; Tucker, KL; Kiel, DP; Wilson, PW; Booth, SL (2002). "Dietary and nondietary determinants of vitamin K biochemical measures in men and women" (PDF). J. Nutr. 132 (6): 1329–34. PMID 12042454.
- Yamano M, Yamanaka Y, Yasunaga K, Uchida K (1989). "Effect of vitamin K deficiency on urinary gamma-carboxyglutamic acid excretion in rats". Nippon Ketsueki Gakkai Zasshi 52 (6): 1078–86. PMID 2588957.
- Matsumoto, T.; Miyakawa, T.; Yamamoto, D. (2012). "Effects of vitamin K on the morphometric and material properties of bone in the tibiae of growing rats". Metabolism 61 (3): 407–414. doi:10.1016/j.metabol.2011.07.018. PMID 21944271.
- Je SH, Joo NS, Choi BH, Kim KM, Kim BT, Park SB, Cho DY, Kim KN, Lee DJ, S. H. (2011). "Vitamin K Supplement Along with Vitamin D and Calcium Reduced Serum Concentration of Undercarboxylated Osteocalcin While Increasing Bone Mineral Density in Korean Postmenopausal Women over Sixty-Years-Old". Journal of Korean Medical Science 26 (8): 1093–1098. doi:10.3346/jkms.2011.26.8.1093. PMC 3154347. PMID 21860562.
- Bentley R, Meganathan R (1982). "Biosynthesis of vitamin K (menaquinone) in bacteria" (PDF). Microbiol. Rev. 46 (3): 241–80. PMC 281544. PMID 6127606.
- Haddock BA, Jones CW (1977). "Bacterial respiration" (PDF). Bacteriol Rev 41 (1): 47–99. PMC 413996. PMID 140652.
- Shearer MJ (1995). "Vitamin K". Lancet 345 (8944): 229–34. doi:10.1016/S0140-6736(95)90227-9. PMID 7823718.
- 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.
- American Academy of Pediatrics Committee on Fetus and Newborn (2003). "Controversies concerning vitamin K and the newborn. American Academy of Pediatrics Committee on Fetus and Newborn" (PDF). Pediatrics 112 (1 Pt 1): 191–2. doi:10.1542/peds.112.1.191. PMID 12837888.
- Logan, S; Gilbert, R (1998). "VITAMIN K FOR NEWBORN BABIES" (PDF). Department of Health. Retrieved 12 October 2014.
- "Postnatal care: Routine postnatal care of women and their babies [CG37]". www.nice.org.uk. NICE. July 2006. Retrieved 12 October 2014.
- "Neonatal vitamin K administration and childhood cancer in the north of England: retrospective case-control study".
- McMillan DD (1997). "Routine administration of vitamin K to newborns". Paediatr Child Health 2 (6): 429–31.
- "Newborns get rare disorder after parents refused shots".
Having four cases since February just at Vanderbilt was a little bit concerning to me
- Hamidi MS, Gajic-Veljanoski O, Cheung AM (2013). "Vitamin K and bone health". J Clin Densitom (Review) 16 (4): 409–13. doi:10.1016/j.jocd.2013.08.017. PMID 24090644.
- 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.
- Yamaguchi M (2006). "Regulatory mechanism of food factors in bone metabolism and prevention of osteoporosis". Yakugaku Zasshi 126 (11): 1117–37. doi:10.1248/yakushi.126.1117. PMID 17077614.
- 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.
- Schurgers, L., J., and Vermeer, C. (2008). "Differential lipoprotein transport pathways of k-vitamins in healthy subjects". Biochemica et Biophysica Acta 1570: 27–32.
- Luo, G., Ducy, P., McKee, M. D., Pinero, G. J., Loyer, E., Behringer, R. R., & Karsenty, G. (1997). "Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein". Nature 386: 78–81. doi:10.1038/386078a0.
- Schurgers, L. J., Spronk, H. M. H., Soute, B. A. M., Schiffers, P. M., DeMay, J. G. R., and Vermeer, C. (2007). "Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin k in rats.". Blood Journal 107: 2823–2831. doi:10.1182/blood-2006-07-035345.
- Wallin, R., Schurgers, L., and Wajih, N. (2008). "Effects of the blood coagulation vitamin k as an inhibitor of arterial calcification.". Thrombosis Research 122: 411–417. doi:10.1016/j.thromres.2007.12.005. PMC 2529147. PMID 18234293.
- Dalmeijer, G. W., van der Schouw, Y. T., Magdeleyns, E., Ahmed, N., Vermeer, C., and Beulens, J. W. J. (2012). "The effect of menaquinone-7 supplementation on circulating species of matrix gla protein.". Atherosclerosis, 225: 397–402. doi:10.1016/j.atherosclerosis.2012.09.019.
- Caluwe, R., Vandercasteele, S., Van Vlem, B., Vermeer, C., and De Vriese, A. S. (2014). "Vitamin k2 supplementation in haemodialysis patients: A randomized dose-finding study.". Nephrology Dialysis Transplantation 29: 1385–1390. doi:10.1093/ndt/gft.464.
- van den Heuvel, E. G. H . M, van Scoor, N. M., Lips. P., Magdeleyns, E. J. P., Deeg, D. J. H., Vermeer, C., and den Heijer, M. (2014). "Circulating uncarboxylated matrix gla protein, a marker of vitamin k status, as a risk factor of cardiovascular disease.". Maturitas 77: 137–141. doi:10.1016/j.maturitas.2013.10.008.
- Allison AC (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.
- "Vitamin K Found to Protect Against Liver Cancer". utraingredients.com (21 July 2004)
- 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.
- Nimptsch K, Rohrmann S, Linseisen J (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)" (PDF). Am. J. Clin. Nutr. 87 (4): 985–92. PMID 18400723.
- American Cancer Society: Vitamin K. Cancer.org. Retrieved on 21 April 2013.
- Ibarrola-Jurado, N.; Salas-Salvado, J.; Martinez-Gonzalez, M. A.; Bullo, M. (2012). "Dietary phylloquinone intake and risk of type 2 diabetes in elderly subjects at high risk of cardiovascular disease". American Journal of Clinical Nutrition 96 (5): 1113–1118. doi:10.3945/ajcn.111.033498. PMID 23034962.
- Cerhan J. 101st Annual Meeting of the American Association for Cancer Research (AACR). 2012
- Lung D. Tarabar A, ed. "Rodenticide Toxicity Treatment & Management". Retrieved March 2014.
- Sundaram, K. S.; Fan, J. H.; Engelke, J. A.; Foley, A. L.; Suttie, J. W.; Lev, M. (1996). "Vitamin K status influences brain sulfatide metabolism in young mice and rats". The Journal of nutrition 126 (11): 2746–2751. PMID 8914944.
- Preusch, P. C.; Suttie, J. W. (1981). "Vitamin K-dependent reactions in rat liver: Role of flavoproteins". The Journal of nutrition 111 (12): 2087–2097. PMID 7310534.
- Will, B. H.; Usui, Y.; Suttie, J. W. (1992). "Comparative metabolism and requirement of vitamin K in chicks and rats". The Journal of nutrition 122 (12): 2354–2360. PMID 1453219.
- Cohen, JL; Bhatia, AC (November 2009). "The role of topical vitamin K oxide gel in the resolution of postprocedural purpura". Journal of drugs in dermatology : JDD 8 (11): 1020–4. PMID 19894369.
- Leu, S; Havey, J; White, LE; Martin, N; Yoo, SS; Rademaker, AW; Alam, M (September 2010). "Accelerated resolution of laser-induced bruising with topical 20% arnica: a rater-blinded randomized controlled trial". The British journal of dermatology 163 (3): 557–63. doi:10.1111/j.1365-2133.2010.09813.x. PMID 20412090.
- 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.
- Fieser, L. F. (1939). "Synthesis of Vitamin K1". Journal of the American Chemical Society 61 (12): 3467–3475. doi:10.1021/ja01267a072.
- Dam, Henrik (12 December 1946). The discovery of vitamin K, its biological functions and therapeutical application. Nobel Prize lecture
- Warner, E. D.; Brinkhous, K. M.; Smith, H. P. (1938). "Bleeding Tendency of Obstructive Jaundice". Proceedings of the Society of Experimental Biology and Medicine 37: 628–630. doi:10.3181/00379727-37-9668P.
- Stenflo J, Fernlund P, Egan W, Roepstorff P (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.
- Nelsestuen GL, Zytkovicz TH, Howard JB (1974). "The mode of action of vitamin K. Identification of gamma-carboxyglutamic acid as a component of prothrombin" (PDF). J. Biol. Chem. 249 (19): 6347–50. PMID 4214105.
- Magnusson S, Sottrup-Jensen L, Petersen TE, Morris HR, Dell A (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.
- Rhéaume-Bleue, Kate (2012). Vitamin K2 and the Calcium Paradox. John Wiley & Sons, Canada. ISBN 1118065727.
- 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
- Vitamin K: the effect on health beyond coagulation – an overview, Cees Vermeer, "