Summary of Vitamin K
Primary Information, Benefits, Effects, and Important Facts
Vitamin K is an essential vitamin. It is one of the four fat-soluble vitamins, along with vitamin A, vitamin D, and vitamin E. It was named vitamin K after the German word koagulation, because vitamin K’s role in blood coagulation was first discovered in Germany. Vitamin K can be found in dark green vegetables, matcha tea and natto (fermented soybeans). Vitamin K2 can also be found in animal products, since it is a result of bacterial fermentation.
The Recommended Daily Intake (RDI) of vitamin K is sufficient to support healthy blood coagulation. Higher levels of vitamin K, however, provide benefits for cardiovascular and bone health. Unfortunately, it is difficult to obtain high levels of vitamin K from food alone. Most people don’t like natto enough to eat 50g a day, so supplementation of vitamin K is a popular option.
Optimal levels of vitamin K are associated with improved bone circumference and diameter. Vitamin K can also protect cardiovascular health. It reduces the calcification and stiffening of arteries, which reduces the risk of cardiovascular-related mortality. Vitamin K may have a role to play in cancer therapy and anti-aging treatments. It may also help with regulating insulin sensitivity and reducing skin reddening, but more research is needed to determine if vitamin K has an active role to play in these areas.
Vitamin K’s main mechanism is through the vitamin K cycle, which is a cyclical metabolic pathway that uses vitamin K to target specific proteins. When a protein expresses glutamate, it is targetted by vitamin K, which causes it to collect more calcium ions. Calcium ions are removed from the blood stream, which prevents buildup in the arteries.
Vitamin K is often supplemented alongside vitamin D, since vitamin D also supports bone health. In fact, taking both together will improve the effects of each, since they are known to work synergistically. Excessive vitamin D can lead to arterial calcification, but vitamin K reduces this buildup.
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Things To Know & Note
Also Known As
Phylloquinone, Menaquinone, MK-4, MK-7, Menatetrenone, Phytonadione
Do Not Confuse With
Pyrroloquinoline quinone (sounds similar to phylloquinone, totally different molecule)
Caution NoticeExamine.com Medical Disclaimer
Vitamin K is fat soluble (and the longer chain a menaquinone gets, the more fat soluble it becomes) and needs to be ingested either with a fat-containing meal or with a capsule containing fatty acids
Menadione (Vitamin K3) tends to actually have a toxicity associated with it rather than the pretty safe menaquinones and phylloquinone
How to Take Vitamin K
Recommended dosage, active amounts, other details
Vitamin K comes in a variety of different forms, known as vitamers. Forms of vitamin K are either phylloquinones (vitamin K1) or menaquinones (vitamin K2). There are different vitamers within the vitamin K2 class, abbreviated as MK-x.
The minimum effective dose for phylloquinone (vitamin K1) is 50mcg, which is enough to satisfy the Recommended Daily Intake (RDI) for vitamin K. The maximum dose for vitamin K1 is 1,000mcg.
The minimum effective dose for short chain menaquinones (MK-4) is 1,500mcg. Doses of up to 45mg (45,000mcg) have been safely used in a superloading dosing protocol.
The minimum effective dose for longer chain menaquinones (MK-7, MK-8, and MK-9) is between 90-360mcg. Further research is needed to determine the maximum effective dose for MK-7.
A topical application of vitamin K should contain at least 5% phylloquinone.
Vitamin K should be supplemented alongside fatty acids, even if the vitamin is coming from a plant-based source, so consider taking vitamin K at meal time. Microwaving plant-based sources of vitamin K will increase the absorption rate of the vitamin.
Frequently Asked Questions about Vitamin K
Human Effect Matrix
The Human Effect Matrix looks at human studies (it excludes animal and in vitro studies) to tell you what effects vitamin k has on your body, and how strong these effects are.
|Grade||Level of Evidence [show legend]|
|Robust research conducted with repeated double-blind clinical trials|
|Multiple studies where at least two are double-blind and placebo controlled|
|Single double-blind study or multiple cohort studies|
|Uncontrolled or observational studies only|
Level of Evidence
? The amount of high quality evidence. The more evidence, the more we can trust the results.
Magnitude of effect
? The direction and size of the supplement's impact on each outcome. Some supplements can have an increasing effect, others have a decreasing effect, and others have no effect.
Consistency of research results
? Scientific research does not always agree. HIGH or VERY HIGH means that most of the scientific research agrees.
|Notable||Moderate See all 15 studies|
|-||High See all 3 studies|
|-||Very High See all 3 studies|
|Notable||Very High See 2 studies|
|Notable||Very High See 2 studies|
|Notable||Very High See 2 studies|
|Minor||- See study|
|Minor||Very High See 2 studies|
|-||- See study|
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|-||Very High See 2 studies|
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|-||Very High See 2 studies|
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|Minor||Moderate See 2 studies|
Studies Excluded from Consideration
Confounded with an assortment of other vitamins
Scientific Research on Vitamin K
Click on any below to expand the corresponding section. Click on to collapse it.
The term 'Vitamin K' refers to quinone structures and can be subdivided into vitamin K1 (the plant derived phylloquinone), vitamin K2 (the series of structures known as menaquinones, abbreviated with MK-x), or vitamin K3 (the not commonly supplemented menadione). Phylloquinone, menadione, and all the menaquinone structures are known as vitamers of vitamin K, and can all contribute to the vitamin-like effects of vitamin K.
Vitamin K was discovered in 1929 in studies on sterol metabolism, and was named after its coagulation properties (as it was discovered in Germany, Vitamin K was named after Koagulation rather than Coagulation) by Henrik Dam. Vitamin K has clinical usage in preventing hemhorrage while vitamin K antagonists (dicoumarol or warfarin) prevent excessive blood clotting or induce hemhorrage.
Vitamin K is a term used to refer to a collection of molecules with structural similarity that are important in blood clotting. They are divided into plant based (phylloquinone) or bacterial based (menaquinone) sources mostly
The main dietary form of Vitamin K is K1 (known as phylloquinone or Phytonadione), which derives its name from the sidechain being the same phytyl sidechain as chlorophyll and being a quinone structure (hence, phylloquinone). The main dietary sources of phylloquinone in the (American) diet include dark green vegetables and added fats (such as cooking oils). Vegetables also appear to be the main source of phylloquinone in the Japanese diet.
Menaquinones are either synthesized in animals (short chain menaquinones) or synthesized by bacteria (longer chain quinones). It is not certain how much dietary MK-4 contributes to overall vitamin K status, as although low (420mcg) dosages of MK-4 do not affect circulating concentrations of MK-4 significantly, dietary MK-4 is still inversely correlated with reduced risk of cardiovascular disease. MK-4 is found mostly in animal products, and MK-7 (the most common longer chain menaquinone) is found in fermented foods with the most common source being natto.
It should be noted that dietary values may not necessarily reflect serum values (weak correlation and sometimes no correlation), which is thought to be due to unreliability with absorption, since phylloquinone (the main dietary source of vitamin K) from plants is poorly absorbed,. Unreliability is still seen with isolated phylloquinone,, which may be related to serum triglycerides (positively related); plasma vitamin K doesn't, however, appear to be related to heredity or genetics but instead related to biological and environmental factors.
Although dietary intake is the main predictor of vitamin K status, it is surprisingly a poor predictor. There appears to be a lot of variability between vitamin K intake and vitamin K status in the body and the reasons for these variations, while many mechanisms are speculated, are currently unknown
The foods that contain the highest levels of vitamin K (phylloquinone unless otherwise specified) include:
Legumes and Nuts
Raw kidney beans (57+/-14µg/100g)
Raw sugar peas (49+/-3µg/100g)
Runner beans (26µg/100g)
French beans (39µg/100g)
Broad beans (19µg/100g)
Chick peas (21µg/100g)
Deep-fried bean curd (62+/-40µg/100g)
Fermented soybean products such as Natto (796-939µg/100g; vitamin K as MK-7)
Melon (yellow at 0.1µg/100g, water at 0.3µg/100g)
Grapes (8.0-9.0µg/100g) and raisins (4µg/100g)
Vegetables and other Herbs
Green powdered tea (Matcha; 3,049+/-145µg/100g) or the green tea leaves themselves (1,876+/-118µg/100g for green and 1,036+/-91µg/100g for black), tea itself has none since phylloquinone is fat soluble and not leeched out from the tea leaves into the steeped water (although this issue is circumvented with Matcha tea)
Raw perilla (1,007+/-123µg/100g)
Seaweeds including dried Wakame (1,293+/-231µg/100g), dried Hijiki (175+/-38µg/100g), and dried Laver (413+/-78µg/100g)
Cabbage (Raw is 127+/-20µg/100g; boiled is 180+/-20µg/100g)
Komatsuna (Raw is 319+/-64µg/100g; boiled is 425+/-107µg/100g)
Garland chrysthanthemum (Raw is 230+/-39µg/100g; boiled is 627+/-86µg/100g)
Kale (618µg/100g or 17.5µg/100g) although aojira (drink derived from kale) has a highly variable 90-3,100µg/100g. The reason for such a low reading in one study is not known, but usually kale is seen as a good source of phylloquinone (no menaquinones present)
Cauliflower at 31µg/100g
Brussel sprouts (147µg/100g)
Spinach (Raw is 498+/-155µg/100g; boiled is 525+/-72µg/100g)
Oils and Condiments
Mayonnaise (197+/-17µg/100g for whole egg type; 189+/-19µg/100g for egg yolk type) although eggs themselves are not good sources for vitamin K (0.6-7µg/100g phylloquinone, 7-64µg/100g MK-4 concentrated in the yolk)
Soybean oil (234+/-48µg/100g)
Mixed vegetable oils (164+/-97µg/100g)
Rapeseed oil (92+/-25µg/100g)
Margarine (67+/-68µg/100g phylloquinone)
Hen egg yolk (64+/-31µg/100g)
Beef chuck (15+/-7µg/100g
Chicken thigh (27+/-15µg/100g)
Vitamin K does not appear to be significantly damaged with gamma-irradiation, and perhaps due to weakening the cell walls broccoli that is microwaved has been noted to have approximately double the bioavailability of raw broccoli. Damaging the bacteria in natto (Bacillus subtilis) appears to be able to reduce MK-7 concentrations in natto, and methods that are successful in doing this include boiling whereas washing is not destructive and single or double heating (Steamed at 100°C for 15 minutes) are less destructive than boiling.
For the most part, phylloquinone is found in dark green or otherwise leafy vegetables with particularly high levels in some vegetables common to the Japanese diet (green tea, although Matcha is likely the only type that is bioactive, and seaweeds). MK-4 is found in animal products (although there is not much MK-4 and it is not sure how relevant this is to the human diet) and while MK-7 is found in a variety of fermented foods, it is only appreciably found in natto.
Cooking does not seem to damage phylloquinone (microwaving actually enhances absorption), while boiling natto appears to destroy the bacteria and reduce serum MK-7 from the food
Vitamin K is a quinone structure similar to Coenzyme Q10, and in particular have a 2-methyl-1,4-naphtoquinone ring structure (due to this, vitamin K vitamers are sometimes called 'napthaquinones'); differences between forms of Vitamin K occur at the third carbon from the ring structure, where they differ based upon the sidechains that consist of isoprene units, and a lack of any sidechain is referred to as menadione (rarely referred to as Vitamin K3). Phylloquinone has a saturated isoprene side chain connected to the third carbon of the side chain, whereas menaquinones have unsaturated isoprene side chains (and menadione does not have a sidechain), and although it is infrequent and not well investigated some intestinal bacteria can create partially saturated menaquinones. These partially saturated menaquinones have the designation of MK-x(H2) or MK-x(H4) with the brackets referring to the amount of hydrogens.
While phylloquinone only refers to a single structure, the term menaquinone refers to many structures that vary in side-chain length. The shortest menaquinone that is supplemented is MK-4 (four isoprene groups) and while menaquinones can be found up to MK-13, the most common long chain menaquinone is MK-7 (since it is found in natto and a popular supplement).
All of the above quinones are known to be fat soluble (lipophilic), and as the chain length increases into the MK-7 to MK-10 range the lipophilicity further increases relative to shorter quinones (such as MK-4).
Phylloquinones (K1) and Menaquinones (K2) form the basic structural classes of Vitamin K vitamers (with the n referring to an undetermined amount of repeating units within the brackets), while the menadione ring (K3) and the menaquinone with three additional isoprenoid groups (MK-4) or six additional groups (MK-7) are also notable 'Vitamin K structures'
The synthesis of γ-carboxyglutamate (from glutamate) is considered the central mechanism of action for Vitamin K in the human body, and this occurs from something called the Vitamin K cycle. Specifically, it appears that vitamin K1 (phylloquinone) is reduced into hydroquinone (KH2) via either the quinone reductase enzyme (an NADPH dependent conversion) or via Vitamin K oxidoreductase (the target of warfarin), with subsequent oxidation of hydroquinone into a Vitamin K1 2,3-epoxide being the cofactor in the enzymatic transformation of glutamate into γ-carboxyglutamate (alongside carbon dioxide and oxygen). The epoxide is then converted back into phylloquinone again via Vitamin K oxidoreductase for reentry into what is known as the Vitamin K cycle.
γ-carboxyglutamate is important since, relative to glutamate, it can bind to calcium ions, which alters biological activity of the protein that has become carboxylated. This reaction is delocalized in the body and while the liver appears to be the prime location for carboxylation, it has also been detected in the lungs, spleen, testes, bone, and kidneys.
Vitamin K is required to synthesize γ-carboxyglutamate from glutamate via the Vitamin K cycle (a cycle where phylloquinone is converted into hydroquinone and then a vitamin K epoxide, to return to phylloquinone). The production of γ-carboxyglutamate from glutamate on some specific enzymes is able to alter their function, and these enzymes are known to be 'Vitamin K dependent' and mediate the effects of dietary or supplement vitamin K
The proteins that are 'Vitamin K dependent' tend to be clustered around blood clotting (where they positively regulate blood clotting) and bone metabolism. Although the actions of vitamin K are not exclusive to these areas of the body, these two are commonly thought to be the main areas of action. A list of known vitamin K dependent enzymes include:
Osteocalcin, a protein with three carboxyglutamic acid residues, which is a negative regulator of bone growth and soft tissue calcification, positive regulator of bone maturation and angiogenesis. May also reduce blood glucose and improve pancreatic β-cell proliferation and have antiobese effects and appears to be maximally carboxylated at around 1,000mcg phylloquinone or around 320-500mcg MK-7
Prothrombin (also known as factor IIor FII), which is sufficiently stimulated with 200mcg phylloquinone
Protein C (involved in blood coagulation with protein S as its cofactor)
Growth Arrest Specific Gene-6 protein (Gas6), a 75kDa protein with 11-12 carboxyglutamic acid resides, with 44% homology to protein S that works via Tyro3, Axl, and Mer (TAM) family receptors as a ligand and is involved in cell cycle regulation and neurology (chemotaxis, mitogenesis, cell growth, and myelination).
Periostin (osteoblast specific factor-2 at 90kDa) expressed mostly in collagen and bone tissue with roles in wound repair, allergies/inflammation (pro-asthmatic and exacerbates ectopic dermatitis), and bone tissue
Various enzymes require vitamin K, and their activities are reduced when vitamin K is insufficient. Their activities may be increased with increasing dietary vitamin K until they reach their rate limit
Although carboxylation of the above proteins is by far the most prominent role of vitamin K, there are some other mechanisms that are not associated with the vitamin K cycle. These include inhibitory effects on osteoclasts, which may be unique to menaquinones (phylloquinones failed to have direct actions in this one study that MK-4 was active), induction of osteoclast apoptosis, inhibition of vitamin D induced osteocalcin mRNA induction but accumulation in the extracellular matrix, and inhibitory effects on prostaglandin synthesis (particular PGE2).
Vitamin K also has a role in sphingolipid metabolism (elaborated on in the neurology section), antioxidative stress (neurology section), and has been noted to bind to the SXR/PXR receptor (bone and skeleton section) and a large protein (40,000kDa) in osteoblasts that is homologous to GADPH (glyceraldehyde-3-phosphate dehydrogenase) of which both phylloquinone and menaquinone bind to. These aforementioned mechanisms are not blocked by warfarin treatment, and are thought to be independent of the vitamin K cycle because of that.
Although the vitamin K cycle and its target proteins consist of the largest system, which vitamin K influences, there are some direct effects of vitamin K vitamers that do not require the vitamin K cycle
The RDI of vitamin K for adults (US) appears to be 65-80mcg (143-176nmol) daily, which is roughly based upon a required intake of around 0.75-1mcg per kilogram bodyweight and somewhat similar to other recommendations including european (75mcg; 165mcg), the WHO (55-65mcg; 121-143nmol), Belgium (50-70mcg; 110-154nmol), New Zealand and Japan (60-70mcg; 132-154nmol), Germany (60-80mcg; 132-176nmol), and Canada/US/Albania (90-120mcg; 198-264nmol)(most values from here with data from EURRECA)
For studies that assess overall dietary intake assuming an RDI of 65-80mcg, it has been found that some age groups (25-30yrs for both genders) have subpar dietary intake of vitamin K, while most have sufficient intake.
Despite the above RDI, it appears that osteocalcin (a protein involved in bone metabolism, see appropriate section) is maximally activated at a dietary intake of 1,000mcg of phylloquinone daily (specifically, 1,000mcg was greater than 500mcg but 2,000mcg was not significantly better than 1,000mcg). This maximal activation (as assessed by percent ucOC) is not common even among sufficient dietary intakes and appears to be correlated with lower bone mass and increased hip fractures rates (relative to lower ucOC in serum via higher vitamin K intake). 500mcg appears to be more than sufficient for normalizing osteocalcin concentrations following dietary restriction.
The RDI of vitamin K is fairly reasonable at 1mcg/kg or so (a lack of consensus from one country to another) and usually a mixed diet is sufficient to reach the RDI. The 'optimal' intake of vitamin K is not currently known, but there are benefits associated with consuming more than the RDI in some cases
As vitamin K is an essential vitamin, it does have deficiency states and the body attempts to regulate its levels (urinary excretion of vitamin K metabolite are reduced during dietary restriction and increased during repletion).
Severe deficiencies of Vitamin K are known to lead to muscular and subcutaneous hemhorrhages and is known to cause bleeding disorders in infancy (called either 'Vitamin K Deficiency Bleeding' or simply VKDB) that are treatable with Vitamin K supplementation. Vitamin K deficiencies are also associated with reduced locomotion in rats (lethargy).
True deficiencies of Vitamin K manifest themselves as excessive bleeding disorders mostly
A subclinical deficiency of Vitamin K (not a true deficiency that results in hemhorraging, but below optimal levels) is known as 'undercarboxylation' of vitamin K dependent proteins. Two of the three proteins involved in soft tissue calcification (Ostecalcin and MGP) appear to be generally undercarboxylated in non-supplementing populations (10-40% of the proteins not being activate) and osteocalcin is known to be maximally stimulated at 1,000mcg dietary intake or so, which is more than 10-fold higher than the RDA. At the RDA, proteins involved in clotting appear to be maximally carboxylated despite those involved in calcification being slightly less active.
Populations at higher risk of deficiency are persons on hemodialysis (including specific deficiencies of MK4 and MK7), Celiac and Crohn's disease (due to lipid malabsorption) but not so much ulcerative colitis, and although according to the RDI it does not seem that vitamin K is deficient in the elderly it is thought that they require more than currently recommended. Elderly persons with Alzheimer's disease appear to have further reduced vitamin K intake, which is thought to be due to less intake of vegetables.
Either reduced vitamin K dietary intake or demonstrated undercarboxylation is associated with increased frequency of incident knee osteoarthritis, osteoporosis, vertebral and hip fractures, vascular calcification, increased risk for cardiovascular incidents (related to vascular calficiation), soft tissue calcification,.
A vitamin K deficiency is not necessarily associated with lower bone mineral density; with some sources suggesting a relationship in women only and others finding no correlation. Furthermore, antagonists of vitamin K (Warfarin usually) are further noted to be associated with modest increased fracture rates (some data suggest no relation) and also not associated with bone mineral density.
Subclinical deficiencies of Vitamin K (a reduced level of carboxylated vitamin K dependent proteins, but not low enough to cause symptoms of a true deficiency state) appear to be somewhat common in society despite meeting the RDI of vitamin K intake, and survey research suggests this increases the risk of cardiovascular disease (via tissue calcification) and fracture rate
It appears that there is a molecule known as PIVKA-II (protein induced by vitamin K absence II or alternatively known as des-γ-carboxy prothrombin) that has its production suppressed by Vitamin K and is normally below 2ng/mL in healthy persons but is increased in deficiency states induced by either dietary restriction or drug treatment.
Other possible biomarkers of a vitamin K deficiency include the percentage of osteocalcin that is not γ-carboxylated in serum (% ucOC), as variances in the percentage of osteocalcin that is carboxylated is due to variations in dietary vitamin K intake in humans (and ingestion of vitamin K antagonsists such as warfarin). Percent ucOC appears to be the most sensitive biomarker for vitamin K status in humans, is responsive to supplemental phylloquinone, and it is consistently decreased (improved) up until a dietary intake of around 1,000mcg daily.
When vitamin K is lower than optimal, the carboxylation rate of proteins is also reduced. Uncarboxylated proteins can be measured in the blood and the percentage of some of these proteins (usually osteocalcin) that remain uncarboxylated can indicative vitamin K status
Vitamin K tends to be supplemented in one of three forms; Vitamin K1 (phylloquinone) or one of two possible Vitamin K2s (menaquinones), MK-4 or MK-7. Phylloquinone tends to have the standard vitamin-like action of supporting vitamin K dependent proteins, while MK-4 and MK-7 have alternate mechanisms of action.
Vitamin K1 (phylloquinone) or one of the two vitamin K2 variants (MK-4 or MK-7) are the most common vitamin K supplements to be used. Vitamin K3 (menadione) is not commonly used
MK-4 is the most popular menaquinone to supplement, synonymous with the name menatetrenone. 100mcg of MK-4 is equivalent to 225nmol (molar mass of 444.65). Supplementation of MK-4 increases bodily levels of MK-4, but either has no influence or lowers bodily concentrations of phylloquinone.
MK-4 is a supplement that appears to have benefits at a dose of around 1,500mcg but is usually used in pharmacological doses of 45mg. At least one study using dosages of MK-4 found in food (420mcg) failed to find any increases in blood concentrations of MK-4, suggesting that 1,500mcg is the bare minimum and that food sources of MK-4 may not contribute to bodily menaquinone storages easily. Supplementation of MK-4 does not appear to reliably increase circulating concentrations of phylloquinone (a spike observed at week two was no longer present at week four) despite increasing serum concentrations of MK-4 and improving carboxylation of proteins (osteocalcin and MGP), thus MK-4 can act as a vitamin.
For its unique properties, MK-4 appears to induce differentiation of leukemic cells (a property useful in differentiation therapy) potently at 1µM, which is not observed with phylloquinone. It has been speculated that MK-4 has a direct action independent of the vitamin K cycle either through proteins (direct binding rather than carboxylation) or acting upon a receptor. There are also differences in transportation and distribution between menaquinones and phylloquinone (elaborated on in the pharmacology section), which can be summed up with menaquinones being better partitioned to the periphery and not the liver, and MK-4 appears to have a unique role on osteoclasts that is not seen with phylloquinone or MK-7 (and perhaps underlies why superloading of MK-4 is used rather than other menaquinone sources).
MK-4 (Menatetrenone) does not appear to increase the amount of active vitamin K in the body, although still appears to be active in carboxylating proteins. It requires higher dosages than phylloquinone, and although 45mg (a very high pharmacological dose) is used it is possible that 1,500mcg is also effective. MK-4 may have a unique role on inducing bone growth that is not seen with phylloquinone or MK-7
MK-7 is another popular supplemental menaquinone, and is known to be pretty much unique to fermented soy products (also found in other fermented products, but to a much lower level). It has a molar mass of 649.0 and 100mcg of MK-7 is equivalent to 154nmol. MK-7 is not the only long-chain menaquinone (fermented foods also possess MK-8 and MK-9) but it is the most popular supplemental form of a long-chain menaquinone. Phylloquinone and MK-4 are thought to be more similar than MK-4 and MK-7 as the prolongation of the chain increases lipophilicity (fat solubility).
Supplemental MK-7 (90-360mcg) has been noted to increase plasma MK-7 concentrations without increasing phylloquinone concentrations, but is able to dose-dependently reduce levels of uncarboxylated proteins (ucOC and dephoshorylated ucMGP) with the reduction in dp-ucMGP being quantified at 31% (180μg) and 46% (360μg) and ucOC being reduced by 60% (180μg) and 74% (360μg), although not all MGP species are affected. MK-7 has also been noted to not affect thrombin status.
When comparing MK-7 against MK-4, the efficacy of long chain menaquinones such as MK-7 on blood clotting seem to exceed that of phylloquinone and MK-4, which is thought to be due to the prolonged half-life relative to other forms of Vitamin K.
MK-7 is similar to MK-4 in the sense that it does not increase phylloquinone concentrations, but can support the Vitamin K cycle and improve vitamin status in the body. Unlike MK-4, you can modify the diet to get sufficient MK-7 (albeit only natto, really) and for most instances MK-7 is more bioactive than MK-4 on a weight basis
Menadione (Vitamin K3) is the isolated backbone to other vitamin K vitamers. It is also an intermediate in the conversion of phylloquinone into MK-4, and due to this is able to increase bodily MK-4 without affecting phylloquinone concentrations. The MK-4 increase implicates oral menadione as conferring vitamin-like properties although the menadione molecule itself cannot function as a cofactor of the vitamin K cycle.
Menadione is not a commonly supplemented form of vitamin K in part due to it not naturally occurring to significant levels in food (a requirement for supplements being sold in the USA) and due to increased risk of toxicity relative to the menaquinones and phylloquinone (elaborated on in the safety section).
Menadione does have some unique properties when it comes to cancer therapy, but this is currently experimental and this isn't to say that other forms of vitamin K are inactive.
Menadione appears to be a prodrug for MK-4, and can support vitamin K status in the body without influencing phylloquinone concentrations. That being said, Menadione is not a common supplement due to a less than desirable toxicity profile (relative to the other vitamin K vitamers)
Intestinal absorption of vitamin K (phylloquinone used most in studies, the following also applies to menaquinones) occurs via the enterocytes, where packaging of fatty acids into micelles enters the enterocyte and is repackaged into a chylomicron for transport via the lymphatic system. This method of absorption is similar to dietary fatty acids and the other fat-soluble essential vitamins (A, D, and E), and this requires dietary lipids to be coingested (Review of fat absorption), which is evidenced by vitamin K deficiencies in scenarios associated with fat malabsorption.
Vitamin K is absorbed via formation of micelles, standard fat absorption that occurs with fat soluble vitamins. This means that absorption of dietary fat alongside the vitamin K is fairly important (and consuming fatty acids alongside plant based sources of vitamin K appears to be a prudent idea to enhance absorption)
Phylloquinone has been determined to have a bioavailability of 5-10% when consumed from plant based foods, and this bioavailability is enhanced when consumed alongside fatty acids (3-fold) or when the phylloquinone is taken out of the food matrix (supplemental form). When comparing the 10-hour AUC of phylloquinone food-bound sources have been noted to have 4% the AUC of supplements, although later studies pinpointed this value at either 9-28%; studies comparing oils against plants have noted that either the oil has 60% the AUC or is not significantly different. Supplementation tends to have bioavailability of 80% or more.
The reduced bioavailability of plant-sourced vitamin K appears to be due to a tight binding of phylloquinone to the thylakoid membrane of plant chloroplasts. This binding slows down absorption rates relative to free phylloquinone and appears to reduce total absorption rates as well as evidenced by the reduced AUC values. Although they are also food products, phylloquinone found in oil products do not appear to be hindered (oil having greater phylloquinone absorption relative to vegetables and food with phylloquinone from oil having a better effect than foods with phylloquinone bound to vegetables). The cooking process does not seem to significantly modify absorption of phylloquinone from plants (suggesting that it does not potently 'free' phylloquinone).
MK-4 has been implicated in having more complete intestinal absorption yet a lower AUC (20%) relative to phylloquinone, which is thought to be due to enhanced absorption but rapid metabolism after absorption.
Longer chain menaquinones are sort of the opposite, as MK-9 has also been found to have less absorption than MK-4 and phylloquinone but a very long half-life; MK-7 has been noted to support vitamin K status better than MK-4 due to this.
MK-4 appears to be moderately well absorbed, but MK-7 is better absorbed. In regards to phylloquinone, it appears to inherently be well absorbed but when it is consumed via plants it may have reduced bioavailability
In accordance with fat absorption, vitamin K gets initially distributed to the body via chylomicrons that leave the lymphatic duct prior to being taken up by the liver as chylomicron fragments and repackaged into lipoproteins (see the distribution section). This is assumed due to other fat soluble vitamins following the same motif and vitamin K being transported in chylomicrons (although apparently no direct proof exists). The excretion into bile acids following parental administration supports hepatic uptake of vitamin K.
Following a single pass around the body in the form of chylomicrons (directly absorbed from the intestines), vitamin K is then thought to be taken up by the liver and repackaged into lipoproteins for constant transportation that is elaborated on in the distribution section
Phylloquinone appears to be transported in the blood mostly in the triacylglycerol-rich lipoprotein fraction (75-90% total phylloquinone in the blood when measured at Cmax) of serum lipoproteins (comparably less in LDL and HDL), and this high percentage applies to both moderate dietary intakes from plant based food (70-400mcg) and pharacological dosing of phylloquinone supplements. Phylloquinone still tends to highly associate with the triglyceride rich fragment even in a fasted state (70%).
Long chain menaquinones (this study used MK-9) appear to be transported more by LDL and are not at all present in HDL; MK-4 is transported somewhat evenly in both the aforementioned. The differences in transportation are thought to be due to differences in lipophilicity (fat solubility) which is known to differ depending on chain length.
In accordance with vitamin K being absorbed via chylomicrons, it is also distributed via lipoproteins. The higher length menaquinones appear to be partitioned into LDL whereas others including phylloquinone are in the triglyceride rich fraction
Unlike other fat soluble vitamins, although vitamin K can bioaccumulate in tissue it appears to have a shorter duration; phylloquinone (45-1000μg) has been noted to be 60-70% excreted within 5 days.
MK-4 has been confirmed to bioaccumulate in the rat testes (525% increase to 995.9pmol/g) and concomitantly lower concentrations of vitamin K1 (20% of baseline).
Vitamin K does appear to bioaccumulate in various tissues following oral ingestion, and among the fat soluble vitamins it appears to have a relatively short time in the body prior to being excreted
When comparing the different forms of vitamin K against one another, it seems that phylloquinone has preferential uptake towards the liver (relative to extrahepatic tissue such as bone) whereas menaquinone uptake is somewhat more balanced.
Without supplementation or intentional food intake, the basal fasting levels of vitamin K (phylloquinone) in otherwise normal adults appears to be 1.3+/-0.64ng/mL.
Orally ingested phylloquinone at dietary intake levels (70-400mcg) appears to peak in serum (Tmax) at a time around 6-10 hours after oral ingestion, with slower absorption for plant-bound sources relative to supplemental phylloquinone. Despite this prolonged absorption, phylloquinone is no longer detectable in serum (to a level greater than fasting levels) 72 hours after a mixed meal or one day following supplementation (2µmol; 909mcg).
Supplemental MK-9 (2µmol; 1,298mcg) has been found to be detectable in plasma 48 hours following oral ingestion, whereas it reached its peak after 4 hours and remained at 25% of this peak value when measured at 24 hours, and this prolonged half-life extends to MK-7. Daily supplementation of MK-7 has been found to plateau at day 20 at an oral dose of 0.22µmol (143mcg) reaching 7-8 fold higher levels than an equimolar dose of phylloquinone and being more biologically active (assessed by γ-carboxylation of osteocalcin).
Phylloquinone is the basic form of vitamin K in serum, and relative to that MK-4 appears to have a relative quick half-life whereas MK-7 and other long chain menaquinones have a very prolonged half-life and greater bioactivity
Bone cells (osteoblasts) appear to be able to uptake phylloquinone from lipoproteins, with the efficiency of the triglyceride fraction in donating its phylloquinone being less than LDL but greater than HDL and mediated via the LDL receptor which are expressed on these bone cells (LRP1 and, to a lesser degree, VLDLR); this uptake is dependent on both heparan sulfate proteoglycans and ApoE. Due to this dependence on ApoE, it is thought that genetic variations in ApoE can influence vitamin K status. ApoE4 (15-20% of the population) is known to have a faster excretion and thus less AUC for the molecule relative to ApoE3 (60-70%) with ApoE2 (5–10%) being slowest, and studies on vitamin K note a correlation with ApoE2 (better vitamin K status) and ApoE4 (worse vitamin K status) although it is not 100% consensus. In vitro, ApoE4 appears to best accumulate vitamin K into bone cells and it doesn't necessarily predict serum pylloquinone concentrations (ApoE4 being associated with high and low concentrations).
Interestingly, the chylomicrons may also deposit vitamin K into bone tissue (prior to reaching the liver) via perisinusoidal macrophages and this appears to account to about 20-50% of the liver's vitamin K uptake and can occur within 4 hours after an injection of chylomicrons containing vitamin K. Vitamin K delivery to bone tends to be less than the liver, as in instances where biomarker proteins (Gla) are fully γ-carboxylated in the liver they are not in bone.
Phylloquinone is taken up into bone cells either from lipoproteins (via the LDL receptors) or directly from chylomicrons (via macrophages). Uptake via the LDL receptors appears to be associated with apolipoproteins and may have a genetic component to it (ApoE4 having better uptake than ApoE2)
Due to being taken up by LDL, it is thought that the menaquinones have more bone uptake as MK-4 is concentrated more in the LDL fraction than is phylloquinone and longer chain menaquinones even more localized to LDL. An equimolar dose of MK-7 relative to phylloquinone does appear to have more of an ability to γ-carboxylate osteocalcin, which only occurs in bone marrow cells and is thought to be reflective of enhanced uptake.
Due to vitamin K being taken up in part by the LDL receptor, the forms of vitamin K that are localized to the LDL portion of lipoproteins are thought to (and have some evidence) for better cellular uptake. This implicates longer chain menaquinones in being better than phylloquinone
Vitamin K (as menaquinones) are bacterial fermentation byproducts and as such, they can be produced by human intestinal microflora. Specific microbial species that can produce menaquinones include Bacteroides (MK-10 and MK-11), Enterobacteria (MK-8), Veillonella (MK-7), and Eubacteiium lentum (MK-6).
However, colonic absorption of vitamin K (phylloquinone and menaquinones) appears to be somewhat poor, possibly since vitamin K absorption across the intestinal wall requires bile acids to solubilize fat (to make micelles) and there are much less of these in the large intestines although the smaller absorptive area may also play a role. This poor absorption, and the fact that dietary restriction is enough to cause insufficiency symptoms (should not occur readily if the colon was able to support vitamin K status) suggests that colonic menaquinone production does not significantly contribute to systemic vitamin K status (although there does appear to be some absorption thought to occur, since MK-10 and MK-13 are detectable in rat and human liver).
Colonic microflora can ferment phylloquinone into menaquinones of various chain lengths, but due to the poor absorption from the colon into circulation this is not thought to contribute too much to bodily vitamin K status
Phylloquinone is able to convert into MK-4 in the body, and this appears to be indepedent of colonic microflora since it has been noted to occur in germ free rats. It is currently thought that the human gene UBIAD1 (a prenylase) mediates this conversion, and it is thought to comprise about 5-25% of total ingested phylloquinone.
Phylloquinone may be converted into MK-4 in the body after absorption, not associated with colonic microflora
Phylloquinone and menaquinones are metabolized via having their polyisoprenoid side chains shortened to two carboxylic groups, which are then glucuronidated and excreted in both the bile and urine. This side chain shortening does not have its metabolic pathway fully elucidated at this time, but CYP4F2 appears to play a role via ω-hydroxylation which is followed up by β-oxidation until the chain is shortened enough.
When phylloquinone, MK-4, or MK-7 are orally ingested urinary levels of menadione (vitamin K3) which are normally around 5μg are increased suggesting it is a metabolite.
Vitamin K appears to be metabolized via the CYP4F2 enzyme, and after its side chain is shortened it is glucuronidated and excreted. Alternatively, menadione appears to be a metabolite (possibly another pathway)
Vitamin K (as phylloquinone) does appear to be absorbed through the skin as evidenced by studies using 2-5% phylloquinone cream that note topical benefits, and it appears to be absorbed into the skin during in vitro testing at 2.5% concentration in a manner that is augmented with monoolein, (monoolein being an absorption enhancer that seems to work on a variety of compounds) and being more effective with nanodispersion than with a vaseline base.
Vitamin K has been noted to, upon single administration in vitro, accumulate for up to 12 hours with the highest rate of absorption in the 2-6 hour range becoming fairly linear afterwards.
Vitamin K can be absorbed through the skin when topically applied in creams, although it is better absorbed either as nanodispersion capsules or with monoolein (fatty acid based delivery system). Phylloquinone has been tested, but although theoretically menaquinones should be better absorbed (due to enhanced fat solubility) they have not yet been tested
It has been noted that, relative to phylloquinone, MK-9 seems to be partitioned to the mitochondria more whereas phylloquinone is found in the cytoplasm and menaquinones has been detected in human and rat mitochondrial fractions (MK-4 through MK-13) where they may serve a bioenergetic role. It has been suggested that menaquinones are electron carriers (as they work downstream of the ETC) and when irradiation impairs mitochondrial efficiency it can be rescued with vitamin K.
Furthermore, application of vitamin K antagonists (2-chloro-3-phytyl-1,4-naphthoquinone) or the mitochondria derived from vitamin K deficiency chicks seem to have impaired ATP production. Addition of MK-4 to mitochondria that do not have any functional impairment has failed to improve ATP production.
Vitamin K (particularly the menaquinones) appears to preserve mitochondrial ATP production when the mitochondria is influenced by stimuli that reduce ATP production, with no apparent effect on normal mitochondria. The mechanisms underlying this protective effect are not currently known
The enzymes that synthesize MK-4 from phylloquinone (MenA and UBIAD1) are structurally similar to one known as Heix, which is known to be protective against pink1 deficiencies when overexpressed (Pink1 is a protein involved in longevity and Parkinson's). Supplementation of MK-4 to pink1 defective drosophilia enhances energy production and locomotion and reverses the phenotype associated with pink1 defective drosophilia, with no apparent effect on otherwise normal controls.
Vitamin K appears to preserve the phenotype of a defect in drosophilia that suggests it could play a role in longevity and aging. Implications for oral supplementation not currently known
The carboxylase enzyme in the vitamin K cycle appears to be expressed in neural tissue during neonatal development and is thought to play a role in cognition as the vitamin K antagonist, warfarin, is able to induce neural complications in neonates (warfarin embryopathy which consists of optic atrophy, dilation of the cerebral ventricles, blindness, microencephaly, and mental retardation); in particular, it has been noted that the Gas6 protein (a vitamin K dependent protein) is highly involved in neurology.
Despite phylloquinone being the predominant circulating vitamin K vitamer, MK-4 seems to accumulate in the brain and comprises over 98% of total vitamin K and is present in all tested brain regions, with higher levels in the midbrain and pons medulla while it is lowest in cerebellum, olfactory bulb, thalamus, hippocampus, and striatum. Dietary restriction for 9 days (sufficient to reduce MK-4 in all other tissues) does not significantly affect brain concentrations but it appears that brain concentrations of MK-4 do reflect the diet, as an adequate diet (500mcg/kg of food intake in rats) is outperformed by an excessive (2000mcg/kg) diet.
Both phylloquinone and MK-4 are readily taken up by neurons (oligodendrocytes).
Vitamin K appears to have some roles in the brain as evidenced by expression of the vitamin K cycle in neonates and warfarin (vitamin K antagonist) being able to cause mental retardation when given to neonates. Dietary vitamin K (usually phylloquinone) increases brain concentrations of vitamin K, and the most relevant vitamer is MK-4
Vitamin K is involved in sphingolipid synthesis (Sphingolipids are a class of complex lipids that help form cell membranes with the main classes being ceramide, sphingomyelin, cerebroside, sulfatide, and ganglioside) and the lipid sulfatide (comprises 4-7% of myelin) appears particularly sensitive to vitamin K as it is known to be influenced by vitamin K status, readily rescued with oral vitamin K after depleted by warfarin, and unlike total sphingolipids the lipid sulfatides appear to linearly correlate with dietary intake of phylloquinone and brain concentrations of MK-4.
When looking at studies using the bacterial strain B. melaninogenicus, it appears that incubation with vitamin K promotes ceramide formation, its phosphorylation, and incorporation of ceramide (as ceramide phosphorylethanolamine or phosphorylglycerol) into cellular membranes, and this appears to be through inducing the activity of the 3-KDS synthase (serine palmitoyltransferase) enzyme. Ceramide can convert cerebroside (via galactosylceramide synthase) and then into sulfatide (galactosylceramide sulfotransferase), and these mechanisms are independent of the vitamin K cycle and more related to the menadione structure (not the side chains) somehow influencing phosphorylation of the enzyme. Treatment with warfarin is also known to reduce the levels of this enzyme (17%) coinciding with moderate reductions in cerebrosides and sphingomyelin (12-17%) with a more drastic drop in sulfatides (42%), and this sensitivity seems to only occur in the brain (spleen and kidney resistant).
In line with increasing dietary vitamin K increasing brain concentrations of MK-4, a dietary surplus (2000mcg/kg of food intake in rats; four-fold the adequate intake) is able to increase enzyme activity within 1-2 weeks (26-31%) and increase brain concentrations of sulfatides (15-18%). It has also been noted that the class of sphingolipids known as gangliosides appears to be negatively correlated with MK-4 in rats but over a lifetime of feeding the opposite persists (higher intakes being associated with lower sulfatide and cerebrosides concentrations than an adequate intake and lower gangliosides in some brain regions).
Vitamin K supports sphingolipid synthesis, and production of sulfatide in particular seems sensitive to changes in the diet (whereas total sphingolipid synthesis rates are more resistant). This is potentially a supplemental avenue due to higher than needed doses further stimulating the enzyme of production
In the CNS, vitamin K has been shown to reduce oxidative death to cells (over 75% preservation at 100nM) with the EC50 values for cytoprotection being 30nM (phylloquinone) or 2nM (MK-4), concentrations which seem to be similar to fasting levels of vitamin K sufficient adults (2.9 ± 1.4nM). It appears that vitamin K was able to prevent glutathione depletion (from BSO) but also protected cells that were depleted of glutathione prior to incubation with vitamin K. Since MK-4 was more potent than phylloquinone and menadione was ineffective, the sidechain of vitamin K appears to be of importance despite the reaction being independent of the vitamin K cycle, and it appears that removing MK-4 from the culture does not immediately abolish the protection and is more potent when incubated before the stressor (both suggestive of inducing antioxidant enzymes, although glutathione is not affected).
Vitamin K has also demonstrated potency in protecting neurons from glutamate-induced cell death with similar potency to the oxidative protection and mercury-induced cell death (which tends to deplete glutathione). Vitamin K, at concentrations between 0.01-200µM, has failed to prevent cellular death induced by hydrogen peroxide (H2O2), nitric oxide, kainate, and menadione.
Although the mechanisms for the antioxidative effects is not fully known, blocking activation of the 12-LOX enzyme is shown to play at least a partial role and the vitamin K epoxide reductase complex subunit 1-like 1 (VKORC1L1) mediates the antioxidative effects.
Vitamin K appears to protect against oxidative stress (Glutathione depletion) and glutamate. While it does not appear to protect against all forms of oxidative stress, it is remarkably potent at doing so with MK-4 being more potent than phylloquinone (thankfully, it bioaccumulates there on its own)
The vitamin K dependent protein Gas6 also appears to be anti-apoptotic in serum deprived cells, hippocampal cells, TNF-α cytotoxicity, phospholipase A2IIA induced apoptosis, and in response to β-amyloid toxin. This preservation is via MAPK and PI3K dependent means which are known to respond to the receptors Gas6 binds to (Tyro3 and Axl). Activation of MAPK from gas6 is known to recruit ERK and cREBP while activation of PI3K is known to activate Akt, all of which can explain the prosurvival effects.
Gas6 is known to decline with aging, and is thought to have a role in cognitive decline during aging (vitamin K deficiency throughout life has been shown once to be associated with cognitive impairment, but no causative factor has been identified).
Protein S also appears to be expressed in the brain, to a lesser extent than Gas6. It has been detected in the choroid plexus, hippocampal cells, and individual astrocytes and glio/neuroblastoma cells. Protein S appears to be a ligand for the same receptors that Gas6 is and its mRNA synthesis is upregulated in response to nerve injury, and similar to Gas6 it also appears to protect neurons from apoptosis.
It should be noted that not all pro-survial actions are due to these two proteins, as sometimes warfarin (inhibitor of the vitamin K cycle, and thus hinders protein functions) does not abolish the enhanced survival.
Gas6 and Protein S, two structurally related proteins that both act through the same class of receptors (the TAM family) appear to protect neurons and other brain cells from apoptosis
Gas6 also has growth inducing properties in isolated neurons, and was synergistic with cAMP activation (forskolin from coleus forskohlii) and in the presence of NGF both phylloquinone and MK-4 seem to promote neurite outgrowth in PC12D cells (albeit at a very high concentration of 50μg/mL) with MK-4 being slightly more potent.
There appear to be neuronal growth inducing properties for vitamin K, both through the proteins (Gas6 and Protein S) and possibly independent of them as well. It is not sure if the independent mechanisms are related to sphingolipid metabolism or not
In older persons with Alzheimer's relative to age-matched healthy controls, dietary phylloquinone intake was lower in persons with AD (63+/-90μg) relative to healthy controls (139+/-233μg) and this correlation appears to persist when looking at serum values of phylloquinone and percent ucOC which are less desirable in those with Alzhiemer's (lower phylloquinone and higher percent ucOC) and even in those with AD lower levels are associated with worse scores on the MMSE. and at least in rats a lifetime dietary restriction of vitamin K to low levels is associated with cognitive impairment upon aging.
Although there are currently no interventions, there appears to be an inverse correlation with vitamin K status and cognitive health in older individuals. Paired with the neuroprotective properties of vitamin K, this suggests that vitamin K could attenuate diseases of cognitive aging
Vitamin K appears to have a few interactions with myelin, including supporting the production of one of its components (sulfatide) and the vitamin K dependent protein Gas6 appears to be involved with myelination (mice lacking Gas6 have less myelin and are more sensitive to multiple sclerotic stressors and injections of Gas6 stimulate remyelination).
Somewhat similar in essence to Vitamin D, vitamin K is also implicated in supporting the myelin sheath of neurons
Vitamin K is thought to have a role in memory, particularly during the aging process, due to the protective actions of two vitamin K-dependent proteins (Gas6 and protein S) and animal evidence which noted that higher brain concentrations of MK-4 were associated with more myelin sulfitides in the hippocampus and cortex of aged yet not young rats; this is thought to be related to the aforementioned proteins since the aging process is associated with a loss of Gas6 and how lifetime dietary phylloquinone increases cognitive performance in aged rats (relative to a low phylloquinone diet) despite exerting no cognitive enhancing effect in young mice.
In elderly persons (aged 70-85) who were free of cognitive disease states serum phylloquinone appeared to be positively correlated with better memory performance including verbal episodic memory performance, 20-minute verbal recall, and both free and cued recall tasks; when assessing executive functions and processing speed there was no significant association with phylloquinone.
Vitamin K is known to accumulate in cardiac tissue of rats, and a sufficient diet has been reported to have a concentration of 23.3+/-4.7pmol/g (second only to the liver). In the heart, vitamin K may positively influence cell growth (secondary to carboxylating Gas6, which then acts via ERK).
Vitamin K is present in cardiac tissue, and the vitamin K dependent protein Gas6 also positively regulates cell division and growth in this tissue
Vitamin K has been noted to inhibit potassium channels in the heart (IC50 2.6+/-0.3µmol/L) and inhibits the influx of sodium (IC50 of around 10µmol/L); these effects are seen as antiarrythmic, and have occurred at 1.5µmol/L infusions. The authors remarked that these observations may explain instances of lethality with vitamin K injections (see case study section), and are though to occur at too high doses to be relevant to oral ingestion.
Although injections of vitamin K appear to have anti-arrythmic properties, this doesn't appear to be relevant to oral supplementation due to the high concentration of vitamin K required
The most important and popular role for vitamin K is that of promoting blood clotting, as the vitamin was named after this role and a deficiency of vitamin K causes hemhorraging. The RDI values for vitamin K (ranging between 60-120mcg daily) are in reference to the role for vitamin K in blood clotting.
Vitamin K promotes coagulation secondary to the vitamin K cycle as there are various proteins that can be γ-carboxylated by vitamin K (to become activated) which are involved in coagulation, and inhibiting the vitamin K cycle confers anti-coagulant effects (hence, the efficacy of Warfarin).
The first known mechanisms of action for vitamin K and the one it is best known for is promoting proper blood clotting (coagulation), since a collection of proteins that all positively mediate blood clotting are vitamin K dependent and malfunction during a vitamin K deficiency
The most well known target protein is prothrombin (also known as Factor II), which was the first protein to be discovered to be γ-carboxylated by vitamin K. Subsequently factors VII, IX, and X as well as proteins C, S, and Z were discovered to be vitamin K dependent which collectively is seven different vitamin K dependent proteins which all regulate clotting with most of them exclusively regulating this process (exception is likely protein S, which is similar to Gas6 in action and may mediate cellular proliferation)
Calcification of arteries is a process known to contribute to artherosclerosis and particularly arterial stiffness, and arteries that are heavily calcified can have parts that are histomorphologically indistinguishable from bone tissue. Levels of calcium in the coronary arteries appears to be an independent predictor of all cause mortality and cardiovascular disease mortality, and seems to apply to both diseased persons and those without an apparent disease state and is still predictive in youth (those under 45 years). Building off of this, it seems that vitamin K is negatively correlated with calcium progression over time (nonsignificant overall, but significant in hypertensive persons).
Incidence of new cases of coronary arterial calcification are said to increase by around 6% each year, with older individuals (80 or above) having greater risk than younger individuals (60 or below).
Arterial calcification is excessive deposition of calcium in the arteries, and aside from contributing to arterial stiffness it is an independent risk factor for all cause mortality
Matrix Gla protein (MGP) is a vitamin K dependent protein with 9 glutamate residues with at least five needing to be carboxylated to increase activity of MGP. It exists in a few 'species', like most vitamin K dependent proteins it can be carboxylated or uncarboxylated (MGP and ucMGP) but can also be phosphorylated or unphosphorylated (pMGP and p-ucMGP; dpMGP and dp-ucMGP).
MGP is known as a negative regulator of calcification since it sequesters calcium ions when it is carboxylated and abolishing MGP causes spontaneous calcification of arteries. Supplemental vitamin K is desired in this instance since uncarboxylated MGP (from a relative deficiency of vitamin K) accumulates at the side of calcification indicating inactivity (osteocalcin and sialoprotein also accumulating) and MGP at this site is inversely related to vitamin K availability; higher serum levels of uncarboxylated MGP (ucMGP) are also a biomarker of cardiovascular disease. Furthermore, warfarin can induce arterial calcification via reducing vitamin K levels which is treatable with supplemental vitamin K.
MGP is not the only negative regulator of calcification (as there is a network of proteins involved in calcification such as osteocalcin and sometimes benefit observed is not associated with MGP) but it is the most potent vitamin K dependent protein for removing calcium from arterial walls. Other proteins involved in calcification including osteonectin, osteopontin, and sialoprotein are not vitamin K dependent and thought to be independent of supplementation (whereas MGP and osteocalcin are implicated in supplementation).
MGP is the main protein of a small network of proteins that negatively regulates arterial calcification, and acts to remove calcium from the arterial wall (subsequently, reducing the risk for all cause mortality and arterial stiffness). It is the most relevant vitamin K depedent protein, with osteocalcin playing a role
A comparative study in rats between phylloquinone and MK-4 has found that both were equally effective in reducing calcification induced by the vitamin K antagonist Warfarin, an observation that has not always been seen (sometimes phylloquinone fails where MK-4 succeeds). Furthermore, the study that noted a therapeutic effect of vitamin K on calcification (removing preformed plaques) was the one finding no difference between forms.
Supplemental vitamin K appears to have unreliable effects on total MGP (decrease, no significant effect, or a strong trend to increase) but appears to reduce levels of uncarboxylated MGP (indicative of a better vitamin K status) with 500mcg phylloquinone or 180-360mcg MK-7. MK-7 has been noted to only reduce dephosphorylated ucMGP (dp-ucMGP) in the dosage range of 180-360mcg with no effect on phosphorylated.
When looking at survey research, there appears to be an inverse association between dietary MK-4 and cardiovascular disease/arterial calficiation although phylloquinone in the diet has twice failed to be associated with calcification. This lack of assocaition does not hold in interventions, where both phylloquinone (500mcg; in addition to vitamin D and calcium) is able to reduce arterial stifness and elsewhere has been noted at the same dose to reduce the progression of calcification when in a multivitamin format over three years.
Vitamin K appears to carboxylate MGP, and vitamin K appears to reduce coronary calcification and improve arterial elasticity based on the limited trials in existence right now. Oddly, the studies that try to find an association between MGP and the beneficial effect on calcium fail to find a relationship
While MK-4 and MK-7 are thought to be better, phylloquinone is not ineffective. Human evidence to support the usage of menaquinones over phylloquinone currently does not exist, but it is plausible that they are better suited to reduce arterial calcification
One study in healthy males noted that subjects (prior to treatment) with higher serum decarboxylated prothrombin (indicative of a worse vitamin K status) experienced higher spikes in insulin for 120 minutes after an oral glucose tolerance test (relative to better vitamin K status), and that supplemental MK-4 at 90mg for one week was able to normalize the elevated glucose in the worse off group. The groups with better vitamin K status at baseline did not experience significant alterations in postprandial insulin spikes.
May reduce postprandial insulin spikes in those who are relatively deficienct (and normalizing said deficiency), but the limited evidence suggests that this does not occur as a per se effect
Osteocalcin is a vitamin K dependent protein maximally carboxylated (activated) at a dietary intake of 1,000mcg phylloquinone, and aside from its role in bone maturation also appears to be involved in reducing arterial calcification (to a lesser degree than the other protein known as MGP) and improving insulin sensitivity.
Both total osteocalcin (regardless of carboxylation status) and total carboxylated osteocalcin appear to be associated with insulin sensitivity in overweight persons, older individuals of both sexes, and in lean otherwise physically active persons. Uncarboxylated osteocalcin is not associated with insulin sensitivity, which is somewhat odd as animal studies suggest the uncarboxylated form is the active form.
It has also been noted that this increased sensitivity may be selective for skeletal muscle rather than hepatic tissue (adipose not assessed) and the aforementioned correlation between higher osteocalcin carboxylation and improved insulin sensitivity is also seen with dietary phylloquinone and dietary phylloquinone is further associated with reduced diabetes risk (17% reduced risk per every additional 100mcg) and hyperglycemia (OR 0.18; 95% CI of 0.05-0.73).
Higher levels of total osteocalcin and a higher rate of carboxylation (indicative of a better vitamin K status) appear to be positively associated with a better sensitivity to insulin. That being said, currently there are no interventions assessing the effects of vitamin K supplementation
It is thought that the actions on insulin sensitivity are explained by either the pancreatic benefits or interactions with adiponectin. Vitamin K (via osteocalcin) can increase adiponectin content and secretion.
Osteocalcin has also been implicated in proliferating pancreatic β-cells (the cells that produce insulin) with a remarkable potency of doubling a pancreatic culture at 0.03ng/mL (6pM). Increased pancreatic β-cell count has also been noted with genetic overexpression of osteocalcin or incubations of cells with ostecalcin.
The aforementioned insulin sensitivity may be regulated through either enhancing adiponectin activity in the body, or from promoting pancreatic beta-cell proliferation
In regards to interventions, one study using 10mg thrice dail (30mg each day) MK-4 in otherwise healthy young men over the course of 4 weeks improved both insulin sensitivity and the deposition index. These changes occurred without apparent changes in fasting blood glucose or adiponectin, but improvements in insulin sensitivity were associated with the increase in carboxylated osteocalcin.
High dose MK-4 has been noted to, fairly acutely, increase insulin sensitivity associated with osteocalcin but not adiponectin
Osteocalcin secreted from bone and activated by Vitamin K appears to be an endocrine regulator of fat mass, as genetic alterations to mice to increase osteocalcin activity increases adiponectin expression (3-fold) and secretion (2-fold). Adiponectin is an insulin sensitizing hormone with anti-obese properties, and mice with higher osteocalcin activity either from genetic alterations or exogenous osteocalcin appear protected from obesity. It has also been noted (unpublished observations noted here) that osteocalcin deficient mice accumulate visceral body fat.
The role for vitamin K in the aforementioned mechanisms is not fully ascertained since uncarboxylated osteocalcin also appears active (and thus the above information would be more reflective of total osteocalcin rather than the percent carboxylated, and thus supplements that increase osteocalcin per se such as Vitamin D). Total osteocalcin levels in serum are positively associated with adiponectin and negatively associated with fat mass as well, and higher carboxylation rates of osteocalcin are also associated with reduced body mass (and it was suggested in cross-sectional analysis that supplemental MK-4 protected from the increase in body fat seen in control).
While not directly reflective of Vitamin K, osteocalcin (one of the major vitamin K dependent proteins) appears to have anti-obese properties via stimulating adiponectin secretion in fat cells. Osteocalcin appears to form a link between bone metabolism and fat metabolism
In regards to osteoblasts (promotes bone formation and mineral accrual), vitamin K appears to stimulate stromal cell and subsequent osteoblast formation ina concentration depedent manner in the range of 0.5-10µM with similar efficacy between phylloquinone and menaquinone. This may be related to being a ligand for the SXR/PXR receptor which after heterodimerization with the vitamin A receptor (RXR) induces the Msx2 osteoblast transcription factor independent of the vitamin K cycle.
MK-4 has also been found to accumulate carboxylated osteocalcin in the extrcellular matrix of bone cells, where it aids in mineral accumulation and while it had no inherent effect on total protein content of osteocalcin it was able to augment the increase in mRNA seen with vitamin D. Along these lines, MK-4 also promotes vitamin D induced bone cell mineralization but these mechanisms are dependent on osteocalcin (inhibited by warfarin) which may explain why some studies do note that Warfarin prevents bone mineralization induced by vitamin K in osteoblasts.
In regards to osteoblasts, both phylloquinone and menaquinones appear to promote osteoblast differentiation (independent of the vitamin K cycle) and increase bone mineralization rates, although the latter is partially dependent on ostecalcin and the vitamin K cycle
In regards to osteoclasts, MK-4 has been found to inhibit osteoclast-like multinucleated cell formation (where it antagonizes vitamin D) in a concentration dependent manner with phylloquinone not having any effect on osteoclastic function, although at least one study has suggested efficacy from phylloquinone. The sidechain appears to be important, and MK-4 may be the only menaquinone to do so (as the sidechain is a geranylgeraniol group, which appears important). Elsewhere, incubating an osteoclast with geranylgeraniol has been found to exert the same effects as MK-4 and it was thought that MK-4 is merely a prodrug for geranylgeraniol (its sidechain). Inhibition occurs at 10µM (not 1µM), which suggest that a pharmacological dose of MK-4 is required for interactions with osteoclasts.
In regards to osteoclasts, vitamin K appears to be able to antagonize the actions of vitamin D (ultimately, this would promote bone growth since osteoclasts are negative regulators of bone mass) but this may require pharmacological dosing of MK-4 to have effects
A protein known as osteocalcin (discovered by two groups and named both osteocalcin and bone Gla protein, although the former is now the universally accepted name) is a small protein that is carboxylated via a vitamin K dependent enzyme and produced in osteoblasts under the regulation of Vitamin D; after three of its glutamate residues are carboxylated, it can bind to hydroxyapatite in bone tissue. This protein is only one of the vitamin K dependent proteins in bone (the other two being matrix Gla protein and protein S), appears to be the most abundant, and the only one exclusively produced in bone tissue. Only when it is carboxylated can it bind to calcium ions.
Osteocalcin appears to be a negative regulator of bone growth, as in vitro it can reduce bone mineral deposition and abolishing it in younger rats can cause hyperostosis (excessive growth of bone) and small increases in mechanical strength from thicker bone tissue.
It also has a role in bone maturation, appearing to collect in the protein fragment of bone tissue during skeletal growth and tissue maturation and reducing osteocalcin activity in mature bone is associated with reduced remodelling. Osteocalcin deficiency in menopausal rats is associated with less bone remodelling.
Osteocalcin is a protein that is subject to carboxylation from Vitamin K dependent enzymes, and its activity is suppressed in Vitamin K deficiencies. While this protein's activity is suppressive of excessive bone growth in youth, it appears to support bone remodelling during aging
As mentioned previously in the deficiency section, the percentage of overall osteocalcin that remained uncarboxylated (% ucOC) is a biomarker of vitamin K status (more carboxylation indicates a better status, less carboxylation indicates a worse status) and osteocalcin continually gets carboxylated up until a daily intake of around 1,000mcg phylloquinone. MK-7 is better at carboxylating osteocalcin than an equal dose of MK-4, although the exact oral dose for maximal carboxylation for menaquinones is not ascertained, and it is thought to be the best biomarker to reflect bone health since osteocalcin can only be carboxylated from within bone cells (osteoblasts).
The percentage of uncarboxylated osteocalcin is indicative of vitamin K metabolism in bone tissue, and may be maximally stimulated (indicative of maximal benefits to bone) at an intake of 1,000mcg phylloquinone
Vitamin K is implicated in bone mineral density as deprivation of dietary vitamin K in research animals is able to accelerate bone loss during aging (ovarectomized rats) which is treatable with supplemental vitamin K and associations between vitamin K and bone mineral density in survey research (lowest quartiles of vitamin K dietary intake having less bone mass than the highest quartile).
Vitamin K supplementation for the purpose of preserving bone mineral density is a somewhat controversial topic, and according to some meta-analyses there is caution for bias. It should be noted that although bias is a possibility, many trials conducted note a large degree of intragroup variability suggesting that some persons respond better to treatment than others.
When looking at studies using pharmacological dosages of vitamin K (45mg of MK-4 daily), there has been benefit noted in postmenopausal women over a year, in women diagnosed with osteoporosis, in women with primary biliary cirrhosis (both groups had UDCA as well), xxx. When vitamin K succeeds in stalling bone mineral density losses, it still appears to be less potent than estrogen replacement therapy and its potency is somewhat comparable to vitamin D in isolation. Some studies assessing chemical-induced bone loss have noted that MK-4 confers protection against leuprolide (at 45mg MK-4) and against glucocorticoides (at 15mg) and at least one study has used a dosage as low as 1,500mcg (which is sufficient to increase protein carboxylation) and appeared to reduce the rate of bone loss over a year in postmenopausal women. Although there are less studies investigating the forms of vitamin K that are not MK4, 1,000mcg of phylloquinone daily has been noted to improve bone mineral density over time and MK-7 at 180μg daily for three years has resulted in increased bone mineral density of the lumbar spine and femoral neck (but not hip) yet all around improvements in bone strength.
In contrast to the above, there have been failures of vitamin K to preserve bone mass to a level greater than placebo. This includes studies using phylloquinone and assess bone loss in female athletes, 500-600mcg phylloquinone in postmenopausal women or both genders
It is currently not sure what can explain the differences observed. The form of supplementation does not appear to be an issue (assuming the correct dose is used) as there have been failures and successes with phylloquinone, MK-4, and MK-7.
MK-4 appears to have some limited evidence that practical dosages of 1,500mcg or so can preserve bone mineral density over time in older individuals, whereas there is more evidence to suggest that pharmacological superdoses of 45mg are effective
In persons who experienced surgery (which tends to be associated with increased risk of osteoporosis), the addition of supplemental MK-7 (180µg) was able to attenuate losses in lumbar bone mineral density. Elsewhere, MK-4 (15mg) is able to attenuate bone losses induced by corticosteroids.
Vitamin K, currently the menaquinones are researched for this, appear to potentially have benefit with post-surgery related bone losses
Lower vitamin K status appears to be correlated with a higher risk for fractures as assessed by serum phylloquinone, dietary intake, and percentage uncarboxylated osteocalcin. It has been noted in reviews that the inverse association (protective) of vitamin K on fractures seems to be more reliable than that for bone mineral density (BMD), despite BMD being the golden standard for predicting fracture risk in osteoporosis. One study in postmenopausal women given MK-4 at the standard pharmacological dose (45mg) noted that despite not improving BMD there was an improvement in biomarkers of bone strength (femoral neck width; FMW) and bone mineral content (BMC).
Despite there being somewhat unreliable benefits to bone mineral density, there do appear to be other benefits to bone width and overall mineral content that can occur independently of density changes and the reduced risk of fractures appears to be more reliable than changes in BMD
In older women with osteopenia, 5,000mcg of phylloquinone daily (with calcium and vitamin D) reduced the risk of fracture with a hazard ratio (HR) of 0.45 (less than half the risk) which was similar to the risk reduction seen with 45mg MK-4 daily for 2 years in women with osteoporosis (RR of 0.44). One trial using 15mg MK-4 noted that there was a reduced risk (RR 0.61) but only in persons with worse bone constitution (5 or more vetebral fractures reported).
Studies using high dose supplementation of vitamin K appear to report a halving of risk
Subclinical vitamin K deficiency appears to be associated with a greater risk for incident knee osteoarthritis (RR 1.56 with a 95% CI of 1.08-2.25) and is associated with an increased risk for developing knee osteoarthritis in one or both knees (RRs of 1.33 and 2.12, respectively), an observation previously noted when looking at cohorts with low vitamin K status or low phylloquinone intake in the diet.
Mechanistically, it has been noted that chondrocytes isolated from persons with osteoarthritis secrete less carboxylated MGP which is produced within chondrocytes (specifically the proliferative and late hypertrophic phases but not in the early hypertrophy) where it regulates mineralization. Cartilage is one of the few places MGP is known to accumulate, alongside bone and dentin (a type of bone teeth are composed of) and similar to what is observed with arterial calcification mice that are deficient in MGP also experience cartilage calcification; genetic faults in MGP in humans are also associated with cartilage calcification and polymorphisms associated with osteoarthritis.
Low vitamin K status is associated with a greater risk of developing osteoarthritis, although the relationships are not incredibly strong. This is possible related to MGP (a vitamin K dependent protein) having roles in cartilage maturation and calcification, and currently there are no interventions using vitamin K to treat osteoarthritis
Interleukin 6 (IL-6) appears to be negatively correlated with dietary phylloquinone intake (27.9% less in the top tertile of intake relative to lowest) and with plasma phylloquinone, IL-6 seems further correlated with uncarboxylated osteocalcin (suggesting that improving vitamin K status reduces IL-6). Other studies have noted a similar inverse correlation between vitamin K concentrations and C-Reactive Protein (CRP) although one study to then administer supplemental phylloquinone (500mcg) failed to find a reduction in CRP.
Elsewhere, it has been noted that LPS stimulation of cells (normally produces IL-6 via acting on TLR4) is inhibited by vitamin K (both phylloquinone and MK-4) which is thought to be independent of the vitamin K cycle. In a rat model using a control and both a deficient and surplus phylloquinone (75mg/kg), it was found that LPS-induced inflammation was greater in the deficient rats and lesser than control in the supplemented rats (which had less IL-6 expression).
It is possible that higher levels of vitamin K are able to actively suppress IL-6 secretion from inflammatory stressors, although the mechanisms underlying this are not currently known
Menadione (Vitamin K3) has been noted to inhibit NF-kB translocation induced by TNF-α at 50µM, which was not replicated with phylloquinone or MK-4.
Menadione has some other potential antiinflammatory properties, but they appear to be a moderate potency relative to some other supplements (in regards to NF-kB inhibition, Feverfew still outperforms)
SHBG is a negative regulator protein that binds to sex hormones (both testosterone and estrogen) and limits their bioactivity, a higher SHBG concentration is associated with less hormonal effects and a lower concentration associated with higher hormonal effects.
The vitamin K dependent protein known as Gas6 is known to interact with TAM family receptors but is also thought to do this primarily via its laminin G-like (some support from carboxylation) that looks structurally similar to the binding site of SHBG.
Gas6 has some structural similarities to SHBG, which is a protein that sequesters steroid hormones. The implications of this structural similarity are not currently known
Oral MK-4 at 75mg/kg in rats over 5 weeks is able to increase circulating testosterone levels from week two onward by approximately two-fold (data derived from graph).
This was independent of changes in luteinizing hormone, and in vitro analysis noted that the increase in testosterone was local to the testes in a dose dependent manner; the mechanism appears to be from an upregulation of CYP11A (via activatin PKA, this enzyme mediates conversion of cholesterol to pregnenolone) without influencing StAR, and vitamin K1 was ineffective.
MK-4 has been found to increase testosterone in rats (human equivalent dose of 12mg/kg) whereas phylloquinone was ineffective
It has been noted that testosterone acting upon its receptor is able to induce activity of Gas6, a vitamin K dependent protein, which is thought to mediate the interactions of testosterone on reducing arterial calcification.
Testosterone itself can induce activity of some vitamin K dependent proteins
Patients recieving glucocorticoids (medications that act similar to cortisol) appear to be at greater risk for fractures over time and 15mg of MK-4 for one year has been found to significantly reduce the losses in bone mineral density associated with glucocorticoid usage. This may be related to the increase in osteoprotegerin (OPG; a cytokine that interferes with RANKL acting upon RANK and thus osteoclastogenesis) which is suppressed by glucocorticoids yet preserved with MK-4. OPG has been found to not be significantly influenced when glucocorticoids are not used (500mcg phylloquinone), suggesting that this suppression is not unilateral.
Although not completely reflective of 'how vitamin K influences cortisol', the cortisol-induced bone losses seen with pharmaceutical glucocorticoid usage appear to be protected against with supplemental vitamin K
Vitamin K is known to accumulate in the liver, and appears to be the organ that accumulates most dietary vitamin K; a standard sufficient diet in rats has been noted to be related to a tissue concentration of 32.4+/-3.3pmol/g which is reduced to less than 2pmol/g during dietary restriction (absolute deprivation for 9 days). Supplementation of phylloquinone can increase hepatic concentrations of MK-4.
The pancreas is known to actually secrete MK-4 upon stimulation with cholecystokinin-8 or secretin alongside phospholipase and calveolin-1. Although the role of MK-4 in the pancreas is not fully known, it is thought to be independent of the vitamin K cycle as staining for glutamate residues on pancreatic proteins suggest they are not overly prominent.
MK-4 is present in the pancreas, its role there is currently unknown
Supplementation of Vitamin K (as MK-4) has been found to increase testicular concentrations of MK-4 to 525% of baseline (995.9pmol/g) following oral supplementation of 75mg/kg in rats for 5 weeks.
MK-4 is known to bioaccumulate in the testicles (and appears to be biologically active; see the testosterone section)
Menadione appears to have anti-cancer properties, which suggests a role for the backbone of the vitamin K molecules rather than the side-chain seen with the common forms of the vitamin
It is thought that the ability of some vitamin K dependent proteins to (once carboxylated) act upon receptors that interact with cell survival and regulation underlie their interactions with cancer cells and the Gas6 protein is implicated due to promoting cell survival under conditions that do not allow cell proliferation, possible suppression of inflammation (interfering with inflammatory cytokines), and aiding in phagocytosis of cells that express phosphatidylserine.
Gas6 (and by extension due to sharing the same receptors, Protein S) may play an antiproliferative role and confer some anticancer properties. The practical significance of this information towards vitamin K supplementation is not yet known
Hepatocellular carcinomas are tumors that commonly occur after infection of hepatitis B or C that has a fairly poor long-term prognosis. Vitamin K3 (menadione) appears to have potent anti-proliferative properties whereas MK-4 also has anti-proliferative effects, albeit somewhat weaker with vitamin K1 (phylloquinone) having the weakest anti-proliferative properties. MK-4 tends to be used since menadione has a less than desirable safety profile whereas MK-4 is comparatively safe.
Vitamin K appears to have antiproliferative effects in liver tumors, with MK-4 being more potent than phylloquinone
In persons who underwent surgery to remove a liver tumor (curative hepatectomy for primary hepatocellular carcinoma) given either 45mg of MK-4 daily or placebo, there appeared to be greater survival rates with MK-4 supplementation (58.1% and 31.0% at 36 and 60 months) than placebo (all patients passed away by month 36). A previous pilot study also noted a decrease in death rates (64% survival after 36 months improved to 87%), but failed to reach statistical significance (P=0.51).
For recurrence rates, a pilot study noted that the 83.2% and 91.6% recurrence rates seen in control (24 and 36 months) was reduced with supplementation of MK-4 at 45mg to 39% and 64.3%. while the placebo controlled trial noted a strong trend (28 with MK-4 and 33 with placebo) that failed to reach statistical significance.
Although the trials cannot be found online, four trials have been referred to in review articles where supplemental phylloquinone at a pharmacological dose (40mg) have also benefitted persons with hepatocellular carcinoma. Results from these trials appear to suggest beneficial responses in about 20% of participants and about half of the participant pool having disease stasis (other half of treatment not noting any particular benefit with phylloquinone).
Pharmacologically high doses of MK-4 supplementation (45mg) appear to reduce the risk of a liver tumor re-emerging (after it has been removed from surgery) and can prolong survival of this group of persons as well
Purpura is a condition usually seen after operations or laser treatment which causes medically benign reddish and purplish spots on the skin; purpura is thought to be due to alterations in cutaneous blood flow, and vitamin K is thought to help accelerate the clearing of blood from these regions when topically applied. Studies with vitamin K and purpura note that 1% phylloquinone is effective when paired with 0.3% retinol
5% phylloquinone has been found to be ineffective, while elsewhere 2% phylloquinone epoxide was effective in a pilot study. It is thought that topical phylloquinone epoxide, rather than phylloquinone itself, is more effective due to being less allergenic and susceptable to heat or light damage.
In regards to purpurea, it appears that vitamin K is able to reduce symptoms somewhat. However, the quality of studies at this point in time are pretty lacklustre
In persons with bags under their eyes, topical vitamin K (1% phylloquinone) paired with retinol and both vitamin C and vitamin E (all 0.1%) was able to reduce the darkening of these bags (which was due to hemostasis, or the accumulation of blood) and reduced wrinkles; no control was used.
Vitamin K has been implicated in reducing bags under the eyes and removing wrinkles, but the evidence for this is currently confounded with the inclusion of other vitamins. While vitamin K may have a role in clearing blood from the area, it is not known how it influences wrinkles
For studies on bruising, vitamin K pretreatment of 5% phylloquinone before laser therapy (to induce bruising) was able to reduce the severity of bruising without influencing how many subjects bruised. Elsewhere, 0.5% phylloquinone cream has failed to influence bruising from a physical stressor (suction).
Has some potential usage against bruising, but the evidence is mixed. The first study was promising but conditional in how bruises occurred, whereas the latter showed no effect
Despite the potential for fat soluble compounds on topical application, menaquinones have not yet been tested for topical application despite their increased fat solubility. It is not sure if they can replace phylloquinone since the mechanisms underlying the observed effects are not yet known
An absolute maternal deficiency of vitamin K (fairly rare) has been noted to cause chondrodysplasia punctata in the infants while a relative deficiency appears to be a risk factor for breast feeding mothers for their children to get vitamin K deficiency bleeding.
There does appear to be a placental barrier to vitamin K (20:1-40:1 higher levels in the mother rather than neonate) which suggests that the neonate is resistant to spikes in vitamin K from dietary supplements. The levels of vitamin K in the livers of infants at term are lower than an adult (2.2pmol/g relative to an adults 12pmol/g; another study noting 2-4pmol/g at gestation week 10), but due to not being 20-40 fold different there does seem to be controlled uptake of vitamin K on an as needed basis.
While there is no direct research into the topic, vitamin K appears to have a role in development of a children where it needs to be consumed in standard dietary amounts and supplementation of vitamin K might not influence the neonate due to the placental barrier (so supplementing vitamin K during this time may not influence the neonate in a beneficial nor negative manner)
The AI for vitamin K in infants, based off of a consumption of 0.78L milk daily, is a concentration of 2.5μg/L for the age period of 0-6 months (around 2μg daily); this appears to be within the range observed in breast milk for women who are not currently supplementing additional vitamin K (just consuming mixed diets) which have been noted at 0.86-1.17μg (daily totals) to 2.31-3.15μg.
Vitamin K is detectable in breast milk and also added to infant formulas. There is, however, a large disparity in which breast milk confers less phylloquinone to the infant (0.55-0.74μg or 8.3-9.3μg/kg bodyweight) than does a bottle formula, which usually have an added 50mcg phylloquinone.
Breast fed infants tend to have a circulating concentration in the range of 0.13–0.24μg/L (which is hypothesized to be increased by 80.0+/-37.7ng/mL with supplementation of 5,000mcg phylloquinone) while formula fed infants appear to have circulating levels of 4.4–6.0μg/L.
Vitamin K is actually at lower concentrations in breast milk than it is in formulas for infants. Supplemental vitamin K to the mother is able to increase concentrations of vitamin K in the breast milk. While this should logically reduce the risk of infant bleeding from vitamin K deficiency within the first 0-6 months of life (higher rates in breast feeding mothers) there are no trials currently investigating this
Vitamin K deficiencies occur in those with cystic fibrosis (CF) at a higher rate than in the normal population due to a higher frequency of fat malabsorption, and other fat soluble vitamins (Vitamin E, Vitamin D, and Vitamin A) are also sometimes deficient.)
According to recent meta-analyses on the topic, the body of evidence is fairly weak at the moment and has a possible risk of bias.
Pseudoxanthoma elasticum is a genetic disorder characterized by calcified elastic fibers in cutaneous, ocular and vascular tissues. PE is caused by loss of function mutations in ABCC6 gene which is hypothesized to impair vitamin K deliver to periphery and PE tends to have less activity of MGP, the vitamin K dependent protein that negatively regulates calcification that also reflects peripheral vitamin K status.
For interventions, in mice that are double deficient for the ABCC6 gene (mice with Pseudoxanthoma elasticum) supplemental phylloquinone or MK-4 at up to 100mg/kg have failed to influence calcification despite higher circulating phylloquinone and MK-4 in the blood (no changes noted in carboxylated status of MGP); this study is duplicated in medline.
Pseudoxanthoma elasticum (PE) is a disease state characterized by excessive calcification of peripheral tissue, which is something that vitamin K normally treats. The limited evidence in animals at this moment in time does not support a usage for vitamin K in treating PE
At least one study has noted that the chemotherapeutic effects of vitamin K3 (Menadione) are synergistic with vitamin C in vitro at a 1:100 ratio which has been replicated elsewhere. Although vitamin C is the most common supplement to be implicated in being synergistic with menadione, this appears to be more a property of menadione itself since it has also demonstrated synergism with 5-Fluorouracil, bleomycin, cisplatin, doxorubicin, vinblastine, and dacarbazine while being additive with other chemotherapeutics.
Vitamin C is one of the many compounds that is synergistic with menadione in cell cultures. The practical significance of this information towards oral supplementation of other forms of vitamin K is not clear
Vitamin D and Vitamin K are thought to be highly synergistic as they both interact with proteins involved in bone and tissue calcification (namely osteocalcin, where vitamin D creates the protein and vitamin K carboxylates/activates it). One study has noted that supplemental vitamin K was able to elevate parathyroid hormone (PTH) concentrations as well, which (due to PTH being inversely related to vitamin D) a suppression of vitamin D concentrations and a higher need to supplement if superloading (45mg) the variant of vitamin K known as MK-4.
The most important interaction between the two is in bone health, where the addition of vitamin K (usually MK-4) to bone cells is able to augment a vitamin D induced osteocalcin production and due to MK-4 localizing osteocalcin to the extracellular matrix to promote mineralization they appear synergistic in osteoblasts (dependent on the vitamin K cycle). In osteoclasts (negative regulators of bone mass), vitamin K (MK-4 only, phylloquinone inactive) suppresses the proliferative effects of vitamin D; this can also indirectly support bone mass and is independent of the vitamin K cycle, but may only apply to pharmacological doses of MK-4 (45mg or so).
Vitamin D and Vitamin K (vitamin A as well to a degree, but is not the topic here) are vitamins that appear to work together in the function of some vitamin K dependent enzymes. Additionally, vitamin K appears to promote the beneficial effects of vitamin D on osteoblasts while higher doses of MK-4 are able to suppress the negative effects of vitamin D on osteoclast formation
In studies that compare a vitamin K only group against a vitamin K group also given vitamin D, the combination therapy groups tend to experience greater benefits to bone health as assessed by bone mineral density.
Some trials on bone health either use vitamin D regardless (keeping the only difference between groups the vitamin K) or they compare vitamin K against combined therapy with vitamin D and vitamin K; it appears that combination therapy routinely outperforms vitamin K alone
Toxicity of Vitamin D is hypothesized to be related to an imbalance with Vitamin K, as the former vitamin can increase a protein known as matrix Gla protein (MGP) while Vitamin K activates it via carboxylation; if MGP is not carboxylated then it can independently promote arterial calcification. This hypothesis is supported by how Vitamin D toxicity and Vitamin K deficiency are phenotypically similar, and how Warfarin can augment the toxicity of Vitamin D while having a similar toxicity profile and both Vitamin D and Warfarin toxicity being protected against by a common drug (ibandronate).
Vitamin D toxicity is thought to be secondary to either vitamin K depletion (excessive levels of vitamin K dependent proteins depleting the bodily reserves) or secondary to an accumulation of unactivated proteins due to a relatively higher vitamin D intake to vitamin K
Supplementation of high dose vitamin E (1000 IU) daily for 12 weeks has been shown to increase circulating levels of PIVKA-II (suggesting less coagulant effects of vitamin K) although it was unable to influence plasma phylloquinone or the carboxylation state of osteocalcin.
May antagonize the coagulatory effects of vitamin K. Whether this is good or bad depends on context
Sesamin is a lignan compound from sesame seeds, most well known to inhibiting the metabolism of Vitamin E which indirectly causes a preservation of bodily levels of vitamin E. It appears that dietary inclusion of 0.2% sesamin to rats has this same effect on phylloquinone in rats and while 1-10% of sesame seeds also have a similar effect, that tissue concentrations of MK-4 require a higher intake of 20% sesame seeds.
Sesamin inhibits the metabolism of vitamin E, which indirectly preserves vitamin E concentrations in the body. It appears that sesamin may do this same thing to vitamin K but there is less overall evidence investigating this synergism
Anticoagulants are drugs or supplements that aim to prevent or reduce coagulation and blood clotting, and tend to be used in persons at immediate risk for a cardiovascular incident; the most popular anticoagulant currently is Warfarin, a potent vitamin K antagonist (inhibitor) and other vitamin K inhibitors that are sometimes used as anticoagulants include acenocoumarol.
It has been noted that in persons on stable anticoagulant therapy, the dose of phylloquinone that increases thrombin activity (100mcg) is lower than that which increases osteocalcin activity (300mcg) which limits the usage of vitamin K to support bone health, and supplemental MK-7 appears to also be implicated in adversely interacting with anticoagulants at doses as low as 50mcg. This antagonistic property can be adverse (if impairing the anticoagulatory effect) or beneficial (preventing excessive blood thinning) depending on context.
In instances where anticoagulant therapy is unstable, low dose vitamin K supplementation in persons with insufficient intake (100-150mcg phylloquinone supplementation) has been found to improve stability during therapy. It has been noted that the logic behind this combination therapy is that vitamin K antagonists and oral vitamin K need to be balanced, and while dietary fluctuations precede fluctuations in coagulation deprivation of all vitamin K is unpractical; supplementation of vitamin K (with an appropriate increase in anticoagulant to counter it) reduces possible variance from the diet.
While supplemental vitamin K is normally seen as antagonistic to anticoagulants that work via inhibiting vitamin K utilization (for obvious reasons), in a few instances where the patient is unstable and not reliably responding to anticoagulants then low doses of phylloquinone (with an appropriate increase in anticoagulant) can be useful. This is a nutrient interaction that needs to be mentioned to a medical doctor
Menadione (Vitamin K3) appears to be toxic when injected into rats at 25mg/kg or more, causing kidney and cardiovascular degeneration.
In the past, clinical injections of vitamin K have been used (for its procoagulant effects to minimize bleeding) and although they were potentially safely used there have been case studies where it caused facial flushing, altered sensations of taste, diaphoresis, chest pain, dyspnea, cyanosis, and respiratory and cardiac arrest which sometime led to death. These cases may be related to electrophysiological effects of vitamin K at high concentrations (micromolar range) and are not thought to be related to oral supplementation as the high concentrations are not reached; currently, no cases of cardiovascular complications from oral vitamin K supplements have been reported.
It is possible to induce toxicity and possibly death with injections of vitamin K, but this likely does not apply to oral supplementation in the standard dosage range
Menadione (Vitamin K3) is a particular vitamer of vitamin K that is known to actually have a detectable toxicity level, whereas the menaquinone and phylloquinone are considered relatively safe.
Injections of menadione at fairly low concentrations have been found to be lethal to research animals
Disruption of NQO2 gene expression (NQO2−/− mice) reduces menadione toxicity and cellular accumulation of NADPH and NAD whereas ablation of NQO1 has the oppposing effect and increases menadione toxicity. NQO1 is known to catalyze the metabolism of quinone structures including menadione, which is converted into menadiol and confers both antioxidant and prooxidant properties. Glutathione also appears to have a role, as glutathione acting upon menadione is able to create semiquinone metabolites (prooxidants) and the superoxide radical and can cause mitochondrial dysfunction via increasing calcium cycling to an excessive level.
Excessive menadione concentrations in a cellular system are converted (by enzymes that are normally antioxidative, particular glutathione) into free radicals, causing oxidative stress
- Mitsuishi T, et al. The effects of topical application of phytonadione, retinol and vitamins C and E on infraorbital dark circles and wrinkles of the lower eyelids. J Cosmet Dermatol. (2004)
- Ferland G. The discovery of vitamin K and its clinical applications. Ann Nutr Metab. (2012)
- The occurrence and chemical nature of vitamin K.
- Treatment of the hemorrhagic tendency in jaundice; with special reference to vitamin k.
- Vitamin K as a prophylactic in 13,000 infants.
- Hemorrhagic Sweet Clover Disease, Dicumarol, and Warfarin: the Work of Karl Paul Link.
- Trumbo P, et al. Dietary reference intakes: vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. J Am Diet Assoc. (2001)
- Shearer MJ, Bach A, Kohlmeier M. Chemistry, nutritional sources, tissue distribution and metabolism of vitamin K with special reference to bone health. J Nutr. (1996)
- Booth SL, Pennington JA, Sadowski JA. Food sources and dietary intakes of vitamin K-1 (phylloquinone) in the American diet: data from the FDA Total Diet Study. J Am Diet Assoc. (1996)
- Kamao M, et al. Vitamin K content of foods and dietary vitamin K intake in Japanese young women. J Nutr Sci Vitaminol (Tokyo). (2007)
- Thijssen HH, Drittij-Reijnders MJ. Vitamin K distribution in rat tissues: dietary phylloquinone is a source of tissue menaquinone-4. Br J Nutr. (1994)
- Sato T, Schurgers LJ, Uenishi K. Comparison of menaquinone-4 and menaquinone-7 bioavailability in healthy women. Nutr J. (2012)
- Geleijnse JM, et al. Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study. J Nutr. (2004)
- Thane CW, Wang LY, Coward WA. Plasma phylloquinone (vitamin K1) concentration and its relationship to intake in British adults aged 19-64 years. Br J Nutr. (2006)
- Mummah-Schendel LL, Suttie JW. Serum phylloquinone concentrations in a normal adult population. Am J Clin Nutr. (1986)
- Novotny JA, et al. Vitamin K absorption and kinetics in human subjects after consumption of 13C-labelled phylloquinone from kale. Br J Nutr. (2010)
- Garber AK, et al. Comparison of phylloquinone bioavailability from food sources or a supplement in human subjects. J Nutr. (1999)
- Jones KS, et al. The effect of different meals on the absorption of stable isotope-labelled phylloquinone. Br J Nutr. (2009)
- Booth SL, Lichtenstein AH, Dallal GE. Phylloquinone absorption from phylloquinone-fortified oil is greater than from a vegetable in younger and older men and women. J Nutr. (2002)
- Shea MK, et al. Genetic and non-genetic correlates of vitamins K and D. Eur J Clin Nutr. (2009)
- Booth SL, Al Rajabi A. Determinants of vitamin K status in humans. Vitam Horm. (2008)
- Dreher ML. Pistachio nuts: composition and potential health benefits. Nutr Rev. (2012)
- Bolling BW, McKay DL, Blumberg JB. The phytochemical composition and antioxidant actions of tree nuts. Asia Pac J Clin Nutr. (2010)
- Sakamaki N, et al. Determination of vitamin K in aojiru (green juice) products by HPLC. Shokuhin Eiseigaku Zasshi. (2006)
- Bolton-Smith C, et al. Compilation of a provisional UK database for the phylloquinone (vitamin K1) content of foods. Br J Nutr. (2000)
- Lester GE, Hallman GJ, Pérez JA. gamma-Irradiation dose: effects on baby-leaf spinach ascorbic acid, carotenoids, folate, alpha-tocopherol, and phylloquinone concentrations. J Agric Food Chem. (2010)
- Lippi G, et al. Comment on effects of microwave cooking conditions on bioactive compounds present in broccoli inflorescences. J Agric Food Chem. (2008)
- Homma K, et al. Treatment of natto, a fermented soybean preparation, to prevent excessive plasma vitamin K concentrations in patients taking warfarin. J Nutr Sci Vitaminol (Tokyo). (2006)
- Usui Y, et al. Measurement of vitamin K in human liver by gradient elution high-performance liquid chromatography using platinum-black catalyst reduction and fluorimetric detection. J Chromatogr. (1989)
- Shino M. Determination of endogenous vitamin K (phylloquinone and menaquinone-n) in plasma by high-performance liquid chromatography using platinum oxide catalyst reduction and fluorescence detection. Analyst. (1988)
- Schurgers LJ, Vermeer C. Determination of phylloquinone and menaquinones in food. Effect of food matrix on circulating vitamin K concentrations. Haemostasis. (2000)
- Suttie JW. Mechanism of action of vitamin K: synthesis of gamma-carboxyglutamic acid. CRC Crit Rev Biochem. (1980)
- Burnier JP, et al. Gamma-carboxyglutamic acid. Mol Cell Biochem. (1981)
- Dowd P, et al. Mechanism of action of vitamin K. Nat Prod Rep. (1994)
- Oldenburg J, et al. The vitamin K cycle. Vitam Horm. (2008)
- Esmon CT, Suttie JW, Jackson CM. The functional significance of vitamin K action. Difference in phospholipid binding between normal and abnormal prothrombin. J Biol Chem. (1975)
- Vitamin K-dependent carboxylase: evidence for a hydroperoxide intermediate in the reaction.
- Buchthal SD, Bell RG. Vitamin K dependent carboxylation of glutamate residues to gamma-carboxyglutamate in microsomes from spleen and testes: comparison with liver, lung, and kidney. Biochemistry. (1983)
- Gilbert KA, Rannels SR. Glucocorticoid effects on vitamin K-dependent carboxylase activity and matrix Gla protein expression in rat lung. Am J Physiol Lung Cell Mol Physiol. (2003)
- Lian JB, Friedman PA. The vitamin K-dependent synthesis of gamma-carboxyglutamic acid by bone microsomes. J Biol Chem. (1978)
- Traverso HP, Hauschka PV, Gallop PM. Vitamin K-dependent gamma-carboxyglutamic acid formation by mouse renal adenocarcinoma cells (RAG). Calcif Tissue Int. (1980)
- Nakao M, et al. Synthesis of human osteocalcins: gamma-carboxyglutamic acid at position 17 is essential for a calcium-dependent conformational transition. Pept Res. (1994)
- Cairns JR, Price PA. Direct demonstration that the vitamin K-dependent bone Gla protein is incompletely gamma-carboxylated in humans. J Bone Miner Res. (1994)
- Vitamin K nutrition and osteoporosis.
- Hauschka PV, et al. Osteocalcin and matrix Gla protein: vitamin K-dependent proteins in bone. Physiol Rev. (1989)
- Theuwissen E, Smit E, Vermeer C. The role of vitamin K in soft-tissue calcification. Adv Nutr. (2012)
- Neve A, Corrado A, Cantatore FP. Osteocalcin: skeletal and extra-skeletal effects. J Cell Physiol. (2013)
- Ferron M, et al. Osteocalcin differentially regulates beta cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice. Proc Natl Acad Sci U S A. (2008)
- Lee NK, et al. Endocrine regulation of energy metabolism by the skeleton. Cell. (2007)
- Binkley NC, et al. A high phylloquinone intake is required to achieve maximal osteocalcin gamma-carboxylation. Am J Clin Nutr. (2002)
- Dalmeijer GW, et al. The effect of menaquinone-7 supplementation on circulating species of matrix Gla protein. Atherosclerosis. (2012)
- Booth SL, et al. Dietary phylloquinone depletion and repletion in older women. J Nutr. (2003)
- van Dam-Mieras MC, Hemker HC. Half-life time and control frequency of vitamin K-dependent Coagulation factors. Theoretical considerations on the place of factor VII in the control of oral anticoagulation therapy. Haemostasis. (1983)
- Nemerson Y. Regulation of the initiation of coagulation by factor VII. Haemostasis. (1983)
- Schafer C, et al. The serum protein alpha 2-Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification. J Clin Invest. (2003)
- Viegas CS, et al. Gla-rich protein (GRP), a new vitamin K-dependent protein identified from sturgeon cartilage and highly conserved in vertebrates. J Biol Chem. (2008)
- Hepner M, Karlaftis V. Protein S. Methods Mol Biol. (2013)
- Li J, et al. Novel role of vitamin k in preventing oxidative injury to developing oligodendrocytes and neurons. J Neurosci. (2003)
- Hepner M, Karlaftis V. Protein C. Methods Mol Biol. (2013)
- Tanabe K, et al. Roles of gamma-carboxylation and a sex hormone-binding globulin-like domain in receptor-binding and in biological activities of Gas6. FEBS Lett. (1997)
- Nakano T, et al. Cell adhesion to phosphatidylserine mediated by a product of growth arrest-specific gene 6. J Biol Chem. (1997)
- Varnum BC, et al. Axl receptor tyrosine kinase stimulated by the vitamin K-dependent protein encoded by growth-arrest-specific gene 6. Nature. (1995)
- Manfioletti G, et al. The protein encoded by a growth arrest-specific gene (gas6) is a new member of the vitamin K-dependent proteins related to protein S, a negative coregulator in the blood coagulation cascade. Mol Cell Biol. (1993)
- Prieto AL, et al. Gas6, a ligand for the receptor protein-tyrosine kinase Tyro-3, is widely expressed in the central nervous system. Brain Res. (1999)
- Hamilton DW. Functional role of periostin in development and wound repair: implications for connective tissue disease. J Cell Commun Signal. (2008)
- Coutu DL, et al. Periostin, a member of a novel family of vitamin K-dependent proteins, is expressed by mesenchymal stromal cells. J Biol Chem. (2008)
- Shiraishi H, et al. Periostin contributes to the pathogenesis of atopic dermatitis by inducing TSLP production from keratinocytes. Allergol Int. (2012)
- Masuoka M, et al. Periostin promotes chronic allergic inflammation in response to Th2 cytokines. J Clin Invest. (2012)
- Romanos GE, et al. Periostin: Role in formation and maintenance of dental tissues. J Cell Physiol. (2013)
- Hoshi K, et al. Nuclear vitamin K2 binding protein in human osteoblasts: homologue to glyceraldehyde-3-phosphate dehydrogenase. Biochem Pharmacol. (1999)
- Hara K, et al. The inhibitory effect of vitamin K2 (menatetrenone) on bone resorption may be related to its side chain. Bone. (1995)
- Taira H, et al. Menatetrenone (vitamin K2) acts directly on circulating human osteoclast precursors. Calcif Tissue Int. (2003)
- Kameda T, et al. Vitamin K2 inhibits osteoclastic bone resorption by inducing osteoclast apoptosis. Biochem Biophys Res Commun. (1996)
- Koshihara Y, Hoshi K. Vitamin K2 enhances osteocalcin accumulation in the extracellular matrix of human osteoblasts in vitro. J Bone Miner Res. (1997)
- Koshihara Y, Hoshi K, Shiraki M. Vitamin K2 (menatetrenone) inhibits prostaglandin synthesis in cultured human osteoblast-like periosteal cells by inhibiting prostaglandin H synthase activity. Biochem Pharmacol. (1993)
- Denisova NA, Booth SL. Vitamin K and sphingolipid metabolism: evidence to date. Nutr Rev. (2005)
- Tabb MM, et al. Vitamin K2 regulation of bone homeostasis is mediated by the steroid and xenobiotic receptor SXR. J Biol Chem. (2003)
- Igarashi M, et al. Vitamin K induces osteoblast differentiation through pregnane X receptor-mediated transcriptional control of the Msx2 gene. Mol Cell Biol. (2007)
- Frick PG, Riedler G, Brögli H. Dose response and minimal daily requirement for vitamin K in man. J Appl Physiol. (1967)
- Suttie JW, et al. Vitamin K deficiency from dietary vitamin K restriction in humans. Am J Clin Nutr. (1988)
- Commission Directive 2008/100/EC.
- Dietary Intake and Adequacy of Vitamin K.
- Shearer MJ, Fu X, Booth SL. Vitamin K nutrition, metabolism, and requirements: current concepts and future research. Adv Nutr. (2012)
- Matthys C, et al. EURRECA: development of tools to improve the alignment of micronutrient recommendations. Eur J Clin Nutr. (2010)
- Binkley NC, et al. Vitamin K supplementation reduces serum concentrations of under-gamma-carboxylated osteocalcin in healthy young and elderly adults. Am J Clin Nutr. (2000)
- Knapen MH, et al. Vitamin K-induced changes in markers for osteoblast activity and urinary calcium loss. Calcif Tissue Int. (1993)
- Knapen MH, Hamulyák K, Vermeer C. The effect of vitamin K supplementation on circulating osteocalcin (bone Gla protein) and urinary calcium excretion. Ann Intern Med. (1989)
- Vergnaud P, et al. Undercarboxylated osteocalcin measured with a specific immunoassay predicts hip fracture in elderly women: the EPIDOS Study. J Clin Endocrinol Metab. (1997)
- Szulc P, et al. Serum undercarboxylated osteocalcin correlates with hip bone mineral density in elderly women. J Bone Miner Res. (1994)
- Szulc P, et al. Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture in elderly women. J Clin Invest. (1993)
- Szulc P, et al. Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture: a three year follow-up study. Bone. (1996)
- Harrington DJ, et al. Excretion of the urinary 5C- and 7C-aglycone metabolites of vitamin K by young adults responds to changes in dietary phylloquinone and dihydrophylloquinone intakes. J Nutr. (2007)
- Shearer MJ. Vitamin K deficiency bleeding (VKDB) in early infancy. Blood Rev. (2009)
- Puckett RM, Offringa M. Prophylactic vitamin K for vitamin K deficiency bleeding in neonates. Cochrane Database Syst Rev. (2000)
- Cocchetto DM, et al. Behavioral perturbations in the vitamin K-deficient rat. Physiol Behav. (1985)
- Vitamin K, an example of triage theory: is micronutrient inadequacy linked to diseases of aging?.
- Cranenburg EC, et al. Characterisation and potential diagnostic value of circulating matrix Gla protein (MGP) species. Thromb Haemost. (2010)
- Fusaro M, et al. Vitamin K, vertebral fractures, vascular calcifications, and mortality: VItamin K Italian (VIKI) dialysis study. J Bone Miner Res. (2012)
- Westenfeld R, et al. Effect of vitamin K2 supplementation on functional vitamin K deficiency in hemodialysis patients: a randomized trial. Am J Kidney Dis. (2012)
- Hussaini SH, Ahmed S, Heatley RV. Celiac disease and hypoprothrombinemia. Nutrition. (1999)
- Schoon EJ, et al. Low serum and bone vitamin K status in patients with longstanding Crohn's disease: another pathogenetic factor of osteoporosis in Crohn's disease. Gut. (2001)
- Kuwabara A, et al. High prevalence of vitamin K and D deficiency and decreased BMD in inflammatory bowel disease. Osteoporos Int. (2009)
- Iijima H, Shinzaki S, Takehara T. The importance of vitamins D and K for the bone health and immune function in inflammatory bowel disease. Curr Opin Clin Nutr Metab Care. (2012)
- Booth SL. Vitamin K status in the elderly. Curr Opin Clin Nutr Metab Care. (2007)
- Presse N, et al. Low vitamin K intakes in community-dwelling elders at an early stage of Alzheimer's disease. J Am Diet Assoc. (2008)
- Misra D, et al. Vitamin K deficiency is associated with incident knee osteoarthritis. Am J Med. (2013)
- Weber P. The role of vitamins in the prevention of osteoporosis--a brief status report. Int J Vitam Nutr Res. (1999)
- Booth SL, et al. Dietary vitamin K intakes are associated with hip fracture but not with bone mineral density in elderly men and women. Am J Clin Nutr. (2000)
- Feskanich D, et al. Vitamin K intake and hip fractures in women: a prospective study. Am J Clin Nutr. (1999)
- Ueland T, et al. Undercarboxylated matrix Gla protein is associated with indices of heart failure and mortality in symptomatic aortic stenosis. J Intern Med. (2010)
- Ueland T, et al. Circulating levels of non-phosphorylated undercarboxylated matrix Gla protein are associated with disease severity in patients with chronic heart failure. Clin Sci (Lond). (2011)
- Booth SL, et al. Vitamin K intake and bone mineral density in women and men. Am J Clin Nutr. (2003)
- Caraballo PJ, et al. Long-term use of oral anticoagulants and the risk of fracture. Arch Intern Med. (1999)
- Caraballo PJ, et al. Changes in bone density after exposure to oral anticoagulants: a meta-analysis. Osteoporos Int. (1999)
- Jamal SA, et al. Warfarin use and risk for osteoporosis in elderly women. Study of Osteoporotic Fractures Research Group. Ann Intern Med. (1998)
- Rosen HN, et al. Vitamin K and maintenance of skeletal integrity in adults. Am J Med. (1993)
- Naraki T, et al. gamma-Carboxyglutamic acid content of hepatocellular carcinoma-associated des-gamma-carboxy prothrombin. Biochim Biophys Acta. (2002)
- Bach AU, et al. Assessment of vitamin K status in human subjects administered "minidose" warfarin. Am J Clin Nutr. (1996)
- Gundberg CM, Lian JB, Booth SL. Vitamin K-dependent carboxylation of osteocalcin: friend or foe. Adv Nutr. (2012)
- Sokoll LJ, et al. Changes in serum osteocalcin, plasma phylloquinone, and urinary gamma-carboxyglutamic acid in response to altered intakes of dietary phylloquinone in human subjects. Am J Clin Nutr. (1997)
- Price PA, Williamson MK. Effects of warfarin on bone. Studies on the vitamin K-dependent protein of rat bone. J Biol Chem. (1981)
- Shiraki M, et al. Vitamin K2 (menatetrenone) effectively prevents fractures and sustains lumbar bone mineral density in osteoporosis. J Bone Miner Res. (2000)
- Thijssen HH, Drittij-Reijnders MJ, Fischer MA. Phylloquinone and menaquinone-4 distribution in rats: synthesis rather than uptake determines menaquinone-4 organ concentrations. J Nutr. (1996)
- Ito A, et al. Menaquinone-4 enhances testosterone production in rats and testis-derived tumor cells. Lipids Health Dis. (2011)
- Koitaya N, et al. Low-dose vitamin K2 (MK-4) supplementation for 12 months improves bone metabolism and prevents forearm bone loss in postmenopausal Japanese women. J Bone Miner Metab. (2013)
- Ozuru R, et al. Time-dependent effects of vitamin K2 (menatetrenone) on bone metabolism in postmenopausal women. Endocr J. (2002)
- Iwamoto I, et al. 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. (1999)
- Sell S. Stem cell origin of cancer and differentiation therapy. Crit Rev Oncol Hematol. (2004)
- Sakai I, et al. Novel role of vitamin K2: a potent inducer of differentiation of various human myeloid leukemia cell lines. Biochem Biophys Res Commun. (1994)
- Booth SL. Roles for vitamin K beyond coagulation. Annu Rev Nutr. (2009)
- Shearer MJ, Newman P. Metabolism and cell biology of vitamin K. Thromb Haemost. (2008)
- Schurgers LJ, et al. Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7. Blood. (2007)
- Theuwissen E, et al. Low-dose menaquinone-7 supplementation improved extra-hepatic vitamin K status, but had no effect on thrombin generation in healthy subjects. Br J Nutr. (2012)
- Brugè F, et al. Olive oil supplemented with menaquinone-7 significantly affects osteocalcin carboxylation. Br J Nutr. (2011)
- Groenen-van Dooren MM, et al. Bioavailability of phylloquinone and menaquinones after oral and colorectal administration in vitamin K-deficient rats. Biochem Pharmacol. (1995)
- Sato T, et al. Difference in the metabolism of vitamin K between liver and bone in vitamin K-deficient rats. Br J Nutr. (2002)
- Okano T, et al. Conversion of phylloquinone (Vitamin K1) into menaquinone-4 (Vitamin K2) in mice: two possible routes for menaquinone-4 accumulation in cerebra of mice. J Biol Chem. (2008)
- Thijssen HH, et al. Menadione is a metabolite of oral vitamin K. Br J Nutr. (2006)
- Chawla D, et al. Vitamin K1 versus vitamin K3 for prevention of subclinical vitamin deficiency: a randomized controlled trial. Indian Pediatr. (2007)
- Metabolism of vitamin K1 (phylloquinone) in man.
- Blomstrand R, Forsgren L. Vitamin K1-3H in man. Its intestinal absorption and transport in the thoracic duct lymph. Int Z Vitaminforsch. (1968)
- Shearer MJ, Barkhan P, Webster GR. Absorption and excretion of an oral dose of tritiated vitamin K1 in man. Br J Haematol. (1970)
- Intestinal Fatty acid Absorption.
- Koivu-Tikkanen TJ, et al. Intestinal, hepatic, and circulating vitamin K levels at low and high intakes of vitamin K in rats. Br J Nutr. (2000)
- Gijsbers BL, Jie KS, Vermeer C. Effect of food composition on vitamin K absorption in human volunteers. Br J Nutr. (1996)
- Booth SL, et al. Response of vitamin K status to different intakes and sources of phylloquinone-rich foods: comparison of younger and older adults. Am J Clin Nutr. (1999)
- Shearer MJ, McBurney A, Barkhan P. Studies on the absorption and metabolism of phylloquinone (vitamin K1) in man. Vitam Horm. (1974)
- Furt F, et al. A bimodular oxidoreductase mediates the specific reduction of phylloquinone (vitamin K₁) in chloroplasts. Plant J. (2010)
- Eugeni Piller L, et al. Plastid lipid droplets at the crossroads of prenylquinone metabolism. J Exp Bot. (2012)
- Schurgers LJ, Vermeer C. Differential lipoprotein transport pathways of K-vitamins in healthy subjects. Biochim Biophys Acta. (2002)
- Cooper AD. Hepatic uptake of chylomicron remnants. J Lipid Res. (1997)
- Shearer MJ, et al. Clearance from plasma and excretion in urine, faeces and bile of an intravenous dose of tritiated vitamin K 1 in man. Br J Haematol. (1972)
- Lamon-Fava S, et al. Plasma lipoproteins as carriers of phylloquinone (vitamin K1) in humans. Am J Clin Nutr. (1998)
- Erkkilä AT, et al. Plasma transport of vitamin K in men using deuterium-labeled collard greens. Metabolism. (2004)
- Spronk HM, et al. Tissue-specific utilization of menaquinone-4 results in the prevention of arterial calcification in warfarin-treated rats. J Vasc Res. (2003)
- Price PA, Faus SA, Williamson MK. Warfarin causes rapid calcification of the elastic lamellae in rat arteries and heart valves. Arterioscler Thromb Vasc Biol. (1998)
- Dolnikowski GG, et al. HPLC and GC/MS determination of deuterated vitamin K (phylloquinone) in human serum after ingestion of deuterium-labeled broccoli. J Nutr Biochem. (2002)
- Kurilich AC, et al. Isotopic labeling and LC-APCI-MS quantification for investigating absorption of carotenoids and phylloquinone from kale (Brassica oleracea). J Agric Food Chem. (2003)
- Fu X, et al. Measurement of deuterium-labeled phylloquinone in plasma by high-performance liquid chromatography/mass spectrometry. Anal Chem. (2009)
- Newman P, et al. The uptake of lipoprotein-borne phylloquinone (vitamin K1) by osteoblasts and osteoblast-like cells: role of heparan sulfate proteoglycans and apolipoprotein E. J Bone Miner Res. (2002)
- Niemeier A, et al. Expression of LRP1 by human osteoblasts: a mechanism for the delivery of lipoproteins and vitamin K1 to bone. J Bone Miner Res. (2005)
- Weintraub MS, Eisenberg S, Breslow JL. Dietary fat clearance in normal subjects is regulated by genetic variation in apolipoprotein E. J Clin Invest. (1987)
- Saupe J, Shearer MJ, Kohlmeier M. Phylloquinone transport and its influence on gamma-carboxyglutamate residues of osteocalcin in patients on maintenance hemodialysis. Am J Clin Nutr. (1993)
- Yan L, et al. Effect of apolipoprotein E genotype on vitamin K status in healthy older adults from China and the UK. Br J Nutr. (2005)
- Pilkey RM, et al. Subclinical vitamin K deficiency in hemodialysis patients. Am J Kidney Dis. (2007)
- Apolipoprotein E genotype is a determinant of serum vitamin K, but not BMD, in older men and women.
- Hussain MM, et al. Chylomicron-chylomicron remnant clearance by liver and bone marrow in rabbits. Factors that modify tissue-specific uptake. J Biol Chem. (1989)
- Hussain MM, et al. Uptake of chylomicrons by the liver, but not by the bone marrow, is modulated by lipoprotein lipase activity. Arterioscler Thromb Vasc Biol. (1997)
- Hussain MM, et al. Chylomicron metabolism. Chylomicron uptake by bone marrow in different animal species. J Biol Chem. (1989)
- Niemeier A, et al. Uptake of postprandial lipoproteins into bone in vivo: impact on osteoblast function. Bone. (2008)
- Kohlmeier M, et al. Transport of vitamin K to bone in humans. J Nutr. (1996)
- Conly JM, Stein K. The production of menaquinones (vitamin K2) by intestinal bacteria and their role in maintaining coagulation homeostasis. Prog Food Nutr Sci. (1992)
- Production of Menaquinones by Intestinal Anaerobes.
- Conly JM, Stein KE. The absorption and bioactivity of bacterially synthesized menaquinones. Clin Invest Med. (1993)
- Ichihashi T, et al. Colonic absorption of menaquinone-4 and menaquinone-9 in rats. J Nutr. (1992)
- Distribution of bile acids in rats.
- Suttie JW. The importance of menaquinones in human nutrition. Annu Rev Nutr. (1995)
- Ronden JE, et al. Intestinal flora is not an intermediate in the phylloquinone-menaquinone-4 conversion in the rat. Biochim Biophys Acta. (1998)
- Nakagawa K, et al. Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme. Nature. (2010)
- McBurney A, Shearer MJ, Barkhan P. Preparative isolation and characterization of the urinary aglycones of vitamin K1 (phylloquinone in man. Biochem Med. (1980)
- McDonald MG, et al. CYP4F2 is a vitamin K1 oxidase: An explanation for altered warfarin dose in carriers of the V433M variant. Mol Pharmacol. (2009)
- Cohen JL, Bhatia AC. The role of topical vitamin K oxide gel in the resolution of postprocedural purpura. J Drugs Dermatol. (2009)
- Shah NS, et al. The effects of topical vitamin K on bruising after laser treatment. J Am Acad Dermatol. (2002)
- Lopes LB, Speretta FF, Bentley MV. Enhancement of skin penetration of vitamin K using monoolein-based liquid crystalline systems. Eur J Pharm Sci. (2007)
- Lopes LB, et al. Reverse hexagonal phase nanodispersion of monoolein and oleic acid for topical delivery of peptides: in vitro and in vivo skin penetration of cyclosporin A. Pharm Res. (2006)
- Lopes LB, Collett JH, Bentley MV. Topical delivery of cyclosporin A: an in vitro study using monoolein as a penetration enhancer. Eur J Pharm Biopharm. (2005)
- Reedstrom CK, Suttie JW. Comparative distribution, metabolism, and utilization of phylloquinone and menaquinone-9 in rat liver. Proc Soc Exp Biol Med. (1995)
- Vos M, et al. Vitamin K2 is a mitochondrial electron carrier that rescues pink1 deficiency. Science. (2012)
- Bhalerao S, Clandinin TR. Cell biology. Vitamin K2 takes charge. Science. (2012)
- PARMAR SS, LOWENTHAL J. Oxidative phosphorylation in mitochondria from animals treated with 2-chloro-3-phytyl-1,4-naphthoquinone, an antagonist of vitamin K-1. Biochem Biophys Res Commun. (1962)
- Suvarna K, et al. Menaquinone (vitamin K2) biosynthesis: localization and characterization of the menA gene from Escherichia coli. J Bacteriol. (1998)
- Clark IE, et al. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature. (2006)
- Park J, et al. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature. (2006)
- Huber AM, et al. Tissue phylloquinone and menaquinones in rats are affected by age and gender. J Nutr. (1999)
- Carrié I, et al. Menaquinone-4 concentration is correlated with sphingolipid concentrations in rat brain. J Nutr. (2004)
- Carrié I, et al. Lifelong low-phylloquinone intake is associated with cognitive impairments in old rats. J Nutr. (2011)
- Novel growth factor Gas6, phosphatidylserine and their age-related changes in the rat brain.
- Romero EE, et al. Cloning of rat vitamin K-dependent gamma-glutamyl carboxylase and developmentally regulated gene expression in postimplantation embryos. Exp Cell Res. (1998)
- Pauli RM. Mechanism of bone and cartilage maldevelopment in the warfarin embryopathy. Pathol Immunopathol Res. (1988)
- Hall JG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med. (1980)
- Ferland G. Vitamin K and the nervous system: an overview of its actions. Adv Nutr. (2012)
- Bartke N, Hannun YA. Bioactive sphingolipids: metabolism and function. J Lipid Res. (2009)
- Norton WT, Poduslo SE. Myelination in rat brain: changes in myelin composition during brain maturation. J Neurochem. (1973)
- The Lipid Sulfatide Is a Novel Myelin-Associated Inhibitor of CNS Axon Outgrowth.
- Sundaram KS, et al. Vitamin K status influences brain sulfatide metabolism in young mice and rats. J Nutr. (1996)
- Sundaram KS, Lev M. Warfarin administration reduces synthesis of sulfatides and other sphingolipids in mouse brain. J Lipid Res. (1988)
- Crivello NA, et al. Age- and brain region-specific effects of dietary vitamin K on myelin sulfatides. J Nutr Biochem. (2010)
- Lev M. Vitamin K deficiency in Fusiformis nigrescens. I. Influence on whole cells and cell envelope characteristics. J Bacteriol. (1968)
- Lev M, Milford AF. Vitamin K stimulation of sphingolipid synthesis. Biochem Biophys Res Commun. (1971)
- Lev M, Milford AF. Effect of vitamin K depletion and restoration on sphingolipid metabolism in Bacteroides melaninogenicus. J Lipid Res. (1972)
- Lev M, Milford AF. The 3-ketodihydrosphingosine synthetase of Bacteroides melaninogenicus: induction by vitamin K. Arch Biochem Biophys. (1973)
- Lev M. Sphingolipid biosynthesis and vitamin K metabolism in Bacteroides melaninogenicus. Am J Clin Nutr. (1979)
- Sundaram KS, Lev M. Vitamin K and phosphate mediated enhancement of brain sulfotransferase activity. Biochem Biophys Res Commun. (1990)
- Sundaram KS, Lev M. Purification and activation of brain sulfotransferase. J Biol Chem. (1992)
- Sundaram KS, Lev M. Regulation of sulfotransferase activity by vitamin K in mouse brain. Arch Biochem Biophys. (1990)
- Sakaue M, et al. Vitamin K has the potential to protect neurons from methylmercury-induced cell death in vitro. J Neurosci Res. (2011)
- Li J, Wang H, Rosenberg PA. Vitamin K prevents oxidative cell death by inhibiting activation of 12-lipoxygenase in developing oligodendrocytes. J Neurosci Res. (2009)
- Westhofen P, et al. Human vitamin K 2,3-epoxide reductase complex subunit 1-like 1 (VKORC1L1) mediates vitamin K-dependent intracellular antioxidant function. J Biol Chem. (2011)
- Allen MP, et al. Growth arrest-specific gene 6 (Gas6)/adhesion related kinase (Ark) signaling promotes gonadotropin-releasing hormone neuronal survival via extracellular signal-regulated kinase (ERK) and Akt. Mol Endocrinol. (1999)
- Funakoshi H, et al. Identification of Gas6, a putative ligand for Sky and Axl receptor tyrosine kinases, as a novel neurotrophic factor for hippocampal neurons. J Neurosci Res. (2002)
- Shankar SL, et al. The growth arrest-specific gene product Gas6 promotes the survival of human oligodendrocytes via a phosphatidylinositol 3-kinase-dependent pathway. J Neurosci. (2003)
- Yagami T, et al. Effect of Gas6 on secretory phospholipase A(2)-IIA-induced apoptosis in cortical neurons. Brain Res. (2003)
- Yagami T, et al. Gas6 rescues cortical neurons from amyloid beta protein-induced apoptosis. Neuropharmacology. (2002)
- Prieto AL, et al. Localization and signaling of the receptor protein tyrosine kinase Tyro3 in cortical and hippocampal neurons. Neuroscience. (2007)
- He X, et al. The gene encoding vitamin K-dependent anticoagulant protein S is expressed in multiple rabbit organs as demonstrated by northern blotting, in situ hybridization, and immunohistochemistry. J Histochem Cytochem. (1995)
- Stitt TN, et al. The anticoagulation factor protein S and its relative, Gas6, are ligands for the Tyro 3/Axl family of receptor tyrosine kinases. Cell. (1995)
- Phillips DJ, et al. Protein S, an antithrombotic factor, is synthesized and released by neural tumor cells. J Neurochem. (1993)
- Liu D, et al. Protein S confers neuronal protection during ischemic/hypoxic injury in mice. Circulation. (2003)
- Zhong Z, et al. Protein S protects neurons from excitotoxic injury by activating the TAM receptor Tyro3-phosphatidylinositol 3-kinase-Akt pathway through its sex hormone-binding globulin-like region. J Neurosci. (2010)
- Nakajima M, et al. Age-dependent survival-promoting activity of vitamin K on cultured CNS neurons. Brain Res Dev Brain Res. (1993)
- Li R, et al. Identification of Gas6 as a growth factor for human Schwann cells. J Neurosci. (1996)
- Tsang CK, Kamei Y. Novel effect of vitamin K(1) (phylloquinone) and vitamin K(2) (menaquinone) on promoting nerve growth factor-mediated neurite outgrowth from PC12D cells. Neurosci Lett. (2002)
- Reddi K, et al. Interleukin 6 production by lipopolysaccharide-stimulated human fibroblasts is potently inhibited by naphthoquinone (vitamin K) compounds. Cytokine. (1995)
- Moriya M, et al. Vitamin K2 ameliorates experimental autoimmune encephalomyelitis in Lewis rats. J Neuroimmunol. (2005)
- Ohsaki Y, et al. Vitamin K suppresses lipopolysaccharide-induced inflammation in the rat. Biosci Biotechnol Biochem. (2006)
- Sato Y, et al. Thyroid hormone targets matrix Gla protein gene associated with vascular smooth muscle calcification. Circ Res. (2005)
- Binder MD, et al. Gas6 deficiency increases oligodendrocyte loss and microglial activation in response to cuprizone-induced demyelination. J Neurosci. (2008)
- Tsiperson V, et al. GAS6 enhances repair following cuprizone-induced demyelination. PLoS One. (2010)
- Presse N1, et al. Vitamin K status and cognitive function in healthy older adults. Neurobiol Aging. (2013)
- Stenhoff J, Dahlbäck B, Hafizi S. Vitamin K-dependent Gas6 activates ERK kinase and stimulates growth of cardiac fibroblasts. Biochem Biophys Res Commun. (2004)
- Drolet B, et al. Vitamin K modulates cardiac action potential by blocking sodium and potassium ion channels. J Cardiovasc Pharmacol Ther. (2000)
- Soedirman JR, et al. Pharmacokinetics and tolerance of intravenous and intramuscular phylloquinone (vitamin K1) mixed micelles formulation. Br J Clin Pharmacol. (1996)
- Stafford DW. The vitamin K cycle. J Thromb Haemost. (2005)
- Nelsestuen GL, Zytkovicz TH, Howard JB. The mode of action of vitamin K. Identification of gamma-carboxyglutamic acid as a component of prothrombin. J Biol Chem. (1974)
- Stenflo J, et al. Vitamin K dependent modifications of glutamic acid residues in prothrombin. Proc Natl Acad Sci U S A. (1974)
- Cranenburg EC, Schurgers LJ, Vermeer C. Vitamin K: the coagulation vitamin that became omnipotent. Thromb Haemost. (2007)
- Krueger T, et al. Coagulation meets calcification: the vitamin K system. Int J Artif Organs. (2009)
- Zieman SJ, Melenovsky V, Kass DA. Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler Thromb Vasc Biol. (2005)
- Calcification in atherosclerosis: Bone biology and chronic inflammation at the arterial crossroads.
- Detrano RC, et al. Predicting coronary events with coronary calcium: pathophysiologic and clinical problems. Curr Probl Cardiol. (2000)
- Jeziorska M, McCollum C, Wooley DE. Observations on bone formation and remodelling in advanced atherosclerotic lesions of human carotid arteries. Virchows Arch. (1998)
- Tota-Maharaj R, et al. Coronary artery calcium for the prediction of mortality in young adults 75 years old. Eur Heart J. (2012)
- Kramer CK, et al. Coronary artery calcium score prediction of all cause mortality and cardiovascular events in people with type 2 diabetes: systematic review and meta-analysis. BMJ. (2013)
- Detrano R, et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med. (2008)
- Thompson GR, Partridge J. Coronary calcification score: the coronary-risk impact factor. Lancet. (2004)
- Shea MK, et al. Association between circulating vitamin K1 and coronary calcium progression in community-dwelling adults: the Multi-Ethnic Study of Atherosclerosis. Am J Clin Nutr. (2013)
- Shea MK, et al. Vitamin K supplementation and progression of coronary artery calcium in older men and women. Am J Clin Nutr. (2009)
- Kuller LH, et al. Incident coronary artery calcium among postmenopausal women. Atherosclerosis. (2008)
- Kronmal RA, et al. Risk factors for the progression of coronary artery calcification in asymptomatic subjects: results from the Multi-Ethnic Study of Atherosclerosis (MESA). Circulation. (2007)
- Murshed M, et al. Extracellular matrix mineralization is regulated locally; different roles of two gla-containing proteins. J Cell Biol. (2004)
- Schurgers LJ, Cranenburg EC, Vermeer C. Matrix Gla-protein: the calcification inhibitor in need of vitamin K. Thromb Haemost. (2008)
- Luo G, et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature. (1997)
- Schurgers LJ, et al. Novel conformation-specific antibodies against matrix gamma-carboxyglutamic acid (Gla) protein: undercarboxylated matrix Gla protein as marker for vascular calcification. Arterioscler Thromb Vasc Biol. (2005)
- Dhore CR, et al. Differential expression of bone matrix regulatory proteins in human atherosclerotic plaques. Arterioscler Thromb Vasc Biol. (2001)
- Schurgers LJ, et al. The circulating inactive form of matrix gla protein is a surrogate marker for vascular calcification in chronic kidney disease: a preliminary report. Clin J Am Soc Nephrol. (2010)
- Cranenburg EC, et al. The circulating inactive form of matrix Gla Protein (ucMGP) as a biomarker for cardiovascular calcification. J Vasc Res. (2008)
- Schurgers LJ, et al. Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats. Blood. (2007)
- High expression of genes for calcification-regulating proteins in human atherosclerotic plaques.
- Schurgers LJ, et al. Novel effects of diets enriched with corn oil or with an olive oil/sunflower oil mixture on vitamin K metabolism and vitamin K-dependent proteins in young men. J Lipid Res. (2002)
- Shea MK, et al. Circulating uncarboxylated matrix gla protein is associated with vitamin K nutritional status, but not coronary artery calcium, in older adults. J Nutr. (2011)
- Villines TC, et al. Vitamin K1 intake and coronary calcification. Coron Artery Dis. (2005)
- Braam LA, et al. Beneficial effects of vitamins D and K on the elastic properties of the vessel wall in postmenopausal women: a follow-up study. Thromb Haemost. (2004)
- Sakamoto N, et al. Possible effects of one week vitamin K (menaquinone-4) tablets intake on glucose tolerance in healthy young male volunteers with different descarboxy prothrombin levels. Clin Nutr. (2000)
- Gower BA, et al. Associations of total and undercarboxylated osteocalcin with peripheral and hepatic insulin sensitivity and β-cell function in overweight adults. J Clin Endocrinol Metab. (2013)
- Shea MK, et al. Gamma-carboxylation of osteocalcin and insulin resistance in older men and women. Am J Clin Nutr. (2009)
- Pittas AG, et al. Association between serum osteocalcin and markers of metabolic phenotype. J Clin Endocrinol Metab. (2009)
- Kindblom JM, et al. Plasma osteocalcin is inversely related to fat mass and plasma glucose in elderly Swedish men. J Bone Miner Res. (2009)
- Im JA, et al. Relationship between osteocalcin and glucose metabolism in postmenopausal women. Clin Chim Acta. (2008)
- Fernández-Real JM, et al. The relationship of serum osteocalcin concentration to insulin secretion, sensitivity, and disposal with hypocaloric diet and resistance training. J Clin Endocrinol Metab. (2009)
- Yoshida M, et al. Phylloquinone intake, insulin sensitivity, and glycemic status in men and women. Am J Clin Nutr. (2008)
- Juanola-Falgarona M, et al. Association between dietary phylloquinone intake and peripheral metabolic risk markers related to insulin resistance and diabetes in elderly subjects at high cardiovascular risk. Cardiovasc Diabetol. (2013)
- Ibarrola-Jurado N, et al. Dietary phylloquinone intake and risk of type 2 diabetes in elderly subjects at high risk of cardiovascular disease. Am J Clin Nutr. (2012)
- Pan Y, Jackson RT. Dietary phylloquinone intakes and metabolic syndrome in US young adults. J Am Coll Nutr. (2009)
- Vitamin K2 Supplementation Improves Insulin Sensitivity via Osteocalcin Metabolism: A Placebo-Controlled Trial.
- Yamauchi T, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. (2001)
- Kubota N, et al. Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chem. (2002)
- Kadowaki T, et al. Adiponectin, adiponectin receptors, and epigenetic regulation of adipogenesis. Cold Spring Harb Symp Quant Biol. (2011)
- Knapen MH, et al. Association of vitamin K status with adiponectin and body composition in healthy subjects: uncarboxylated osteocalcin is not associated with fat mass and body weight. Br J Nutr. (2012)
- Koshihara Y, et al. Vitamin K stimulates osteoblastogenesis and inhibits osteoclastogenesis in human bone marrow cell culture. J Endocrinol. (2003)
- Mani S, et al. Activation of the steroid and xenobiotic receptor (human pregnane X receptor) by nontaxane microtubule-stabilizing agents. Clin Cancer Res. (2005)
- Kliewer SA, et al. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell. (1998)
- Koshihara Y, et al. Vitamin K2 promotes 1alpha,25(OH)2 vitamin D3-induced mineralization in human periosteal osteoblasts. Calcif Tissue Int. (1996)
- Akedo Y, et al. Vitamin K2 modulates proliferation and function of osteoblastic cells in vitro. Biochem Biophys Res Commun. (1992)
- Akiyama Y, et al. Effect of vitamin K2 (menatetrenone) on osteoclast-like cell formation in mouse bone marrow cultures. Eur J Pharmacol. (1994)
- Price PA, et al. Characterization of a gamma-carboxyglutamic acid-containing protein from bone. Proc Natl Acad Sci U S A. (1976)
- Hauschka PV, Lian JB, Gallop PM. Direct identification of the calcium-binding amino acid, gamma-carboxyglutamate, in mineralized tissue. Proc Natl Acad Sci U S A. (1975)
- Fusaro M, et al. Vitamin K, bone fractures, and vascular calcifications in chronic kidney disease: an important but poorly studied relationship. J Endocrinol Invest. (2011)
- Dowd TL, et al. The three-dimensional structure of bovine calcium ion-bound osteocalcin using 1H NMR spectroscopy. Biochemistry. (2003)
- Hoang QQ, et al. Bone recognition mechanism of porcine osteocalcin from crystal structure. Nature. (2003)
- Mizuguchi M, et al. Fourier-transform infrared spectroscopic study of Ca2+-binding to osteocalcin. Calcif Tissue Int. (2001)
- Ducy P, et al. Increased bone formation in osteocalcin-deficient mice. Nature. (1996)
- Hauschka PV, Reid ML. Timed appearance of a calcium-binding protein containing gamma-carboxyglutamic acid in developing chick bone. Dev Biol. (1978)
- Lian JB, et al. Concentrations of osteocalcin and phosphoprotein as a function of mineral content and age in cortical bone. Calcif Tissue Int. (1982)
- Ingram RT, et al. Age- and gender-related changes in the distribution of osteocalcin in the extracellular matrix of normal male and female bone. Possible involvement of osteocalcin in bone remodeling. J Clin Invest. (1994)
- Boskey AL, et al. Fourier transform infrared microspectroscopic analysis of bones of osteocalcin-deficient mice provides insight into the function of osteocalcin. Bone. (1998)
- Akiyama Y, et al. Inhibitory effect of vitamin K2 (menatetrenone) on bone resorption in ovariectomized rats: a histomorphometric and dual energy X-ray absorptiometric study. Jpn J Pharmacol. (1999)
- Mawatari T, et al. Effect of vitamin K2 on three-dimensional trabecular microarchitecture in ovariectomized rats. J Bone Miner Res. (2000)
- Fang Y, et al. Effect of vitamin K on bone mineral density: a meta-analysis of randomized controlled trials. J Bone Miner Metab. (2012)
- Braam LA, et al. Vitamin K1 supplementation retards bone loss in postmenopausal women between 50 and 60 years of age. Calcif Tissue Int. (2003)
- Purwosunu Y, et al. Vitamin K2 treatment for postmenopausal osteoporosis in Indonesia. J Obstet Gynaecol Res. (2006)
- Ushiroyama T, Ikeda A, Ueki M. Effect of continuous combined therapy with vitamin K(2) and vitamin D(3) on bone mineral density and coagulofibrinolysis function in postmenopausal women. Maturitas. (2002)
- Nishiguchi S, et al. Randomized pilot trial of vitamin K2 for bone loss in patients with primary biliary cirrhosis. J Hepatol. (2001)
- Somekawa Y, et al. Use of vitamin K2 (menatetrenone) and 1,25-dihydroxyvitamin D3 in the prevention of bone loss induced by leuprolide. J Clin Endocrinol Metab. (1999)
- Sasaki N, et al. Vitamin K2 inhibits glucocorticoid-induced bone loss partly by preventing the reduction of osteoprotegerin (OPG). J Bone Miner Metab. (2005)
- Knapen MH, et al. Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women. Osteoporos Int. (2013)
- Braam LA, et al. Factors affecting bone loss in female endurance athletes: a two-year follow-up study. Am J Sports Med. (2003)
- Volpe SL, Leung MM, Giordano H. Vitamin K supplementation does not significantly impact bone mineral density and biochemical markers of bone in pre- and perimenopausal women. Nutr Res. (2008)
- Booth SL, et al. Effect of vitamin K supplementation on bone loss in elderly men and women. J Clin Endocrinol Metab. (2008)
- Shea MK, et al. Vitamin K, circulating cytokines, and bone mineral density in older men and women. Am J Clin Nutr. (2008)
- Binkley N, et al. Vitamin K treatment reduces undercarboxylated osteocalcin but does not alter bone turnover, density, or geometry in healthy postmenopausal North American women. J Bone Miner Res. (2009)
- Forli L, et al. Dietary vitamin K2 supplement improves bone status after lung and heart transplantation. Transplantation. (2010)
- Emaus N, et al. Vitamin K2 supplementation does not influence bone loss in early menopausal women: a randomised double-blind placebo-controlled trial. Osteoporos Int. (2010)
- Hart JP, et al. Circulating vitamin K1 levels in fractured neck of femur. Lancet. (1984)
- Luukinen H, et al. Strong prediction of fractures among older adults by the ratio of carboxylated to total serum osteocalcin. J Bone Miner Res. (2000)
- Vermeer C. Vitamin K: the effect on health beyond coagulation - an overview. Food Nutr Res. (2012)
- Penington NJ, Kelly JS, Fox AP. A study of the mechanism of Ca2+ current inhibition produced by serotonin in rat dorsal raphe neurons. J Neurosci. (1991)
- Falcone TD, Kim SS, Cortazzo MH. Vitamin K: fracture prevention and beyond. PM R. (2011)
- Knapen MH, Schurgers LJ, Vermeer C. Vitamin K2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women. Osteoporos Int. (2007)
- Vitamin K Supplementation in Postmenopausal Women with Osteopenia (ECKO Trial): A Randomized Controlled Trial.
- Inoue T, et al. Randomized controlled study on the prevention of osteoporotic fractures (OF study): a phase IV clinical study of 15-mg menatetrenone capsules. J Bone Miner Metab. (2009)
- Neogi T, et al. Low vitamin K status is associated with osteoarthritis in the hand and knee. Arthritis Rheum. (2006)
- Oka H, et al. Association of low dietary vitamin K intake with radiographic knee osteoarthritis in the Japanese elderly population: dietary survey in a population-based cohort of the ROAD study. J Orthop Sci. (2009)
- Wallin R, Schurgers LJ, Loeser RF. Biosynthesis of the vitamin K-dependent matrix Gla protein (MGP) in chondrocytes: a fetuin-MGP protein complex is assembled in vesicles shed from normal but not from osteoarthritic chondrocytes. Osteoarthritis Cartilage. (2010)
- Newman B, et al. Coordinated expression of matrix Gla protein is required during endochondral ossification for chondrocyte survival. J Cell Biol. (2001)
- Luo G, et al. The matrix Gla protein gene is a marker of the chondrogenesis cell lineage during mouse development. J Bone Miner Res. (1995)
- Yagami K, et al. Matrix GLA protein is a developmental regulator of chondrocyte mineralization and, when constitutively expressed, blocks endochondral and intramembranous ossification in the limb. J Cell Biol. (1999)
- Hale JE, Fraser JD, Price PA. The identification of matrix Gla protein in cartilage. J Biol Chem. (1988)
- Munroe PB, et al. Mutations in the gene encoding the human matrix Gla protein cause Keutel syndrome. Nat Genet. (1999)
- Misra D, et al. Matrix Gla protein polymorphism, but not concentrations, is associated with radiographic hand osteoarthritis. J Rheumatol. (2011)
- Shea MK, et al. Vitamin K and vitamin D status: associations with inflammatory markers in the Framingham Offspring Study. Am J Epidemiol. (2008)
- Kopp E, Medzhitov R. Recognition of microbial infection by Toll-like receptors. Curr Opin Immunol. (2003)
- Tanaka S, et al. Vitamin K3 attenuates lipopolysaccharide-induced acute lung injury through inhibition of nuclear factor-kappaB activation. Clin Exp Immunol. (2010)
- Sasaki T, et al. Crystal structure of a C-terminal fragment of growth arrest-specific protein Gas6. Receptor tyrosine kinase activation by laminin G-like domains. J Biol Chem. (2002)
- Requirement of gamma-carboxyglutamic acid residues for the biological activity of Gas6: contribution of endogenous Gas6 to the proliferation of vascular smooth muscle cells.
- Roles of γ-carboxylation and a sex hormone-binding globulin-like domain in receptor-binding and in biological activities of Gas6.
- Grishkovskaya I, et al. Crystal structure of human sex hormone-binding globulin: steroid transport by a laminin G-like domain. EMBO J. (2000)
- Steroidogenic Enzymes in Leydig Cells.
- Son BK, et al. Androgen receptor-dependent transactivation of growth arrest-specific gene 6 mediates inhibitory effects of testosterone on vascular calcification. J Biol Chem. (2010)
- Lukert BP, Raisz LG. Glucocorticoid-induced osteoporosis: pathogenesis and management. Ann Intern Med. (1990)
- Reid IR. Glucocorticoid osteoporosis--mechanisms and management. Eur J Endocrinol. (1997)
- Isolation of a Novel Cytokine from Human Fibroblasts That Specifically Inhibits Osteoclastogenesis.
- Simonet WS, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. (1997)
- Lacey DL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. (1998)
- Sasaki N, et al. Glucocorticoid decreases circulating osteoprotegerin (OPG): possible mechanism for glucocorticoid induced osteoporosis. Nephrol Dial Transplant. (2001)
- Thomas DD, et al. Exocrine pancreatic secretion of phospholipid, menaquinone-4, and caveolin-1 in vivo. Biochem Biophys Res Commun. (2004)
- Stenberg LM, et al. Synthesis of gamma-carboxylated polypeptides by alpha-cells of the pancreatic islets. Biochem Biophys Res Commun. (2001)
- Prasad KN, Edwards-Prasad J, Sakamoto A. Vitamin K3 (menadione) inhibits the growth of mammalian tumor cells in culture. Life Sci. (1981)
- Wu FY, et al. Vitamin K3-induced cell cycle arrest and apoptotic cell death are accompanied by altered expression of c-fos and c-myc in nasopharyngeal carcinoma cells. Oncogene. (1993)
- Ngo EO, et al. Menadione-induced DNA damage in a human tumor cell line. Biochem Pharmacol. (1991)
- Su WC, Sun TP, Wu FY. The in vitro and in vivo cytotoxicity of menadione (vitamin K3) against rat transplantable hepatoma induced by 3'-methyl-4-dimethyl-aminoazobenzene. Gaoxiong Yi Xue Ke Xue Za Zhi. (1991)
- Lamson DW, Plaza SM. The anticancer effects of vitamin K. Altern Med Rev. (2003)
- Saxena SP, Israels ED, Israels LG. Novel vitamin K-dependent pathways regulating cell survival. Apoptosis. (2001)
- Bellosta P, et al. Signaling through the ARK tyrosine kinase receptor protects from apoptosis in the absence of growth stimulation. Oncogene. (1997)
- Avanzi GC, et al. GAS6 inhibits granulocyte adhesion to endothelial cells. Blood. (1998)
- Ishimoto Y, et al. Promotion of the uptake of PS liposomes and apoptotic cells by a product of growth arrest-specific gene, gas6. J Biochem. (2000)
- [No authors listed. Predictive factors for long term prognosis after partial hepatectomy for patients with hepatocellular carcinoma in Japan. The Liver Cancer Study Group of Japan. Cancer. (1994)
- Nishikawa Y, et al. Growth inhibition of hepatoma cells induced by vitamin K and its analogs. J Biol Chem. (1995)
- Chlebowski RT, et al. Vitamin K3 inhibition of malignant murine cell growth and human tumor colony formation. Cancer Treat Rep. (1985)
- Wang Z, et al. The growth inhibitory effects of vitamins K and their actions on gene expression. Hepatology. (1995)
- Wu FY, Liao WC, Chang HM. Comparison of antitumor activity of vitamins K1, K2 and K3 on human tumor cells by two (MTT and SRB) cell viability assays. Life Sci. (1993)
- Hassan GS. Menadione. Profiles Drug Subst Excip Relat Methodol. (2013)
- Ishizuka M, et al. Effect of menatetrenone, a vitamin k2 analog, on recurrence of hepatocellular carcinoma after surgical resection: a prospective randomized controlled trial. Anticancer Res. (2012)
- Mizuta T, et al. The effect of menatetrenone, a vitamin K2 analog, on disease recurrence and survival in patients with hepatocellular carcinoma after curative treatment: a pilot study. Cancer. (2006)
- Hepatocellular Carcinoma: Current Management and Future Trends.
- Lou WW, et al. Effects of topical vitamin K and retinol on laser-induced purpura on nonlesional skin. Dermatol Surg. (1999)
- Kovács RK, et al. Lack of the effect of topical vitamin K on bruising after mechanical injury. J Am Acad Dermatol. (2004)
- Howe AM, et al. Binder's syndrome due to prenatal vitamin K deficiency: a theory of pathogenesis. Aust Dent J. (1992)
- Irving MD, et al. Chondrodysplasia punctata: a clinical diagnostic and radiological review. Clin Dysmorphol. (2008)
- Shearer MJ. Vitamin K metabolism and nutriture. Blood Rev. (1992)
- Greer FR, et al. Vitamin K status of lactating mothers, human milk, and breast-feeding infants. Pediatrics. (1991)
- Canfield LM, et al. Quantitation of vitamin K in human milk. Lipids. (1990)
- Canfield LM, et al. Vitamin K in colostrum and mature human milk over the lactation period--a cross-sectional study. Am J Clin Nutr. (1991)
- Kojima T, et al. Vitamin K concentrations in the maternal milk of Japanese women. Acta Paediatr. (2004)
- Greer FR. Are breast-fed infants vitamin K deficient. Adv Exp Med Biol. (2001)
- Conway SP, et al. Vitamin K status among children with cystic fibrosis and its relationship to bone mineral density and bone turnover. Pediatrics. (2005)
- Sokol RJ, et al. Fat-soluble vitamins in infants identified by cystic fibrosis newborn screening. Pediatr Pulmonol Suppl. (1991)
- Jagannath VA, et al. Vitamin K supplementation for cystic fibrosis. Cochrane Database Syst Rev. (2013)
- Bergen AA, et al. Mutations in ABCC6 cause pseudoxanthoma elasticum. Nat Genet. (2000)
- Ringpfeil F, et al. Pseudoxanthoma elasticum: mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter. Proc Natl Acad Sci U S A. (2000)
- Borst P, van de Wetering K, Schlingemann R. Does the absence of ABCC6 (multidrug resistance protein 6) in patients with Pseudoxanthoma elasticum prevent the liver from providing sufficient vitamin K to the periphery. Cell Cycle. (2008)
- Li Q, et al. Pseudoxanthoma elasticum: reduced gamma-glutamyl carboxylation of matrix gla protein in a mouse model (Abcc6-/-). Biochem Biophys Res Commun. (2007)
- Brampton C, et al. Vitamin K does not prevent soft tissue mineralization in a mouse model of pseudoxanthoma elasticum. Cell Cycle. (2011)
- Noto V, et al. Effects of sodium ascorbate (vitamin C) and 2-methyl-1,4-naphthoquinone (vitamin K3) treatment on human tumor cell growth in vitro. I. Synergism of combined vitamin C and K3 action. Cancer. (1989)
- De Loecker W, et al. Effects of sodium ascorbate (vitamin C) and 2-methyl-1,4-naphthoquinone (vitamin K3) treatment on human tumor cell growth in vitro. II. Synergism with combined chemotherapy action. Anticancer Res. (1993)
- Zhang W, et al. Synergistic cytotoxic action of vitamin C and vitamin K3. Anticancer Res. (2001)
- von Gruenigen VE, et al. The in vitro antitumor activity of vitamins C and K3 against ovarian carcinoma. Anticancer Res. (2003)
- Waxman S, Bruckner H. The enhancement of 5-fluorouracil anti-metabolic activity by leucovorin, menadione and alpha-tocopherol. Eur J Cancer Clin Oncol. (1982)
- Liao WC, Wu FY, Wu CW. Binary/ternary combined effects of vitamin K3 with other antitumor agents in nasopharyngeal carcinoma CG1 cells. Int J Oncol. (2000)
- Nutter LM, et al. Menadione: spectrum of anticancer activity and effects on nucleotide metabolism in human neoplastic cell lines. Biochem Pharmacol. (1991)
- Masterjohn C. Vitamin D toxicity redefined: vitamin K and the molecular mechanism. Med Hypotheses. (2007)
- Steingrimsdottir L, et al. Relationship between serum parathyroid hormone levels, vitamin D sufficiency, and calcium intake. JAMA. (2005)
- Miyake N, et al. 1,25-Dihydroxyvitamin D3 promotes vitamin K2 metabolism in human osteoblasts. Osteoporos Int. (2001)
- Price PA, Faus SA, Williamson MK. Warfarin-induced artery calcification is accelerated by growth and vitamin D. Arterioscler Thromb Vasc Biol. (2000)
- Price PA, Buckley JR, Williamson MK. The amino bisphosphonate ibandronate prevents vitamin D toxicity and inhibits vitamin D-induced calcification of arteries, cartilage, lungs and kidneys in rats. J Nutr. (2001)
- Price PA, Faus SA, Williamson MK. Bisphosphonates alendronate and ibandronate inhibit artery calcification at doses comparable to those that inhibit bone resorption. Arterioscler Thromb Vasc Biol. (2001)
- Booth SL, et al. Effect of vitamin E supplementation on vitamin K status in adults with normal coagulation status. Am J Clin Nutr. (2004)
- Hanzawa F, et al. Dietary Sesame Seed and Its Lignan, Sesamin, Increase Tocopherol and Phylloquinone Concentrations in Male Rats. J Nutr. (2013)
- Schurgers LJ, et al. Effect of vitamin K intake on the stability of oral anticoagulant treatment: dose-response relationships in healthy subjects. Blood. (2004)
- Crowther MA, et al. Low-dose oral vitamin K reliably reverses over-anticoagulation due to warfarin. Thromb Haemost. (1998)
- Denas G, et al. Effectiveness and safety of a management protocol to correct over-anticoagulation with oral vitamin K: a retrospective study of 1,043 cases. J Thromb Thrombolysis. (2009)
- Rombouts EK, Rosendaal FR, Van Der Meer FJ. Daily vitamin K supplementation improves anticoagulant stability. J Thromb Haemost. (2007)
- Vitamin K1 supplementation to improve the stability of anticoagulation therapy with vitamin K antagonists: a dose-finding study.
- Sconce E, et al. Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin. Blood. (2007)
- Reese AM, et al. Low-dose vitamin K to augment anticoagulation control. Pharmacotherapy. (2005)
- Chiou TJ, et al. Cardiac and renal toxicity of menadione in rat. Toxicology. (1997)
- Songy KA Jr, Layon AJ. Vitamin K-induced cardiovascular collapse. J Clin Anesth. (1997)
- Barash P, Kitahata LM, Mandel S. Acute cardiovascular collapse after intravenous phytonadione. Anesth Analg. (1976)
- Lefrère JJ, Girot R. Acute cardiovascular collapse during intravenous vitamin K1 injection. Thromb Haemost. (1987)
- Rich EC, Drage CW. Severe complications of intravenous phytonadione therapy. Two cases, with one fatality. Postgrad Med. (1982)
- Havel M, et al. Tolerability of a new vitamin K1 preparation for parenteral administration to adults: one case of anaphylactoid reaction. Clin Ther. (1987)
- Anaphylactic Shock and Vitamin K1.
- Disruption of the DT Diaphorase (NQO1) Gene in Mice Leads to Increased Menadione Toxicity.
- In Vivo Role of NAD(P)H:Quinone Oxidoreductase 1 (NQO1) in the Regulation of Intracellular Redox State and Accumulation of Abdominal Adipose Tissue.
- Radjendirane V, et al. Disruption of the DT diaphorase (NQO1) gene in mice leads to increased menadione toxicity. J Biol Chem. (1998)
- The three-dimensional structure of NAD(P)H:quinone reductase, a flavoprotein involved in cancer chemoprotection and chemotherapy: mechanism of the two-electron reduction.
- Tampo Y, Yonaha M. Enzymatic and molecular aspects of the antioxidant effect of menadione in hepatic microsomes. Arch Biochem Biophys. (1996)
- Cadenas E. Antioxidant and prooxidant functions of DT-diaphorase in quinone metabolism. Biochem Pharmacol. (1995)
- Monks TJ, et al. Quinone chemistry and toxicity. Toxicol Appl Pharmacol. (1992)
- Takahashi N, et al. Formation of glutathione-conjugated semiquinones by the reaction of quinones with glutathione: an ESR study. Arch Biochem Biophys. (1987)
- Wilson I, et al. Reactivity of thiols towards derivatives of 2- and 6-methyl-1,4-naphthoquinone bioreductive alkylating agents. Chem Biol Interact. (1987)
- Grant TW, et al. Semiquinone anion radicals formed by the reaction of quinones with glutathione or amino acids. FEBS Lett. (1986)
- Gant TW, et al. Redox cycling and sulphydryl arylation; their relative importance in the mechanism of quinone cytotoxicity to isolated hepatocytes. Chem Biol Interact. (1988)
- Zadziński R, et al. Menadione toxicity in Saccharomyces cerevisiae cells: activation by conjugation with glutathione. Biochem Mol Biol Int. (1998)
- Menadione-(2-methyl-1,4-naphthoquinone) dependent enzymic redox cycling and calcium release by mitochondria.
- Bahadoran Z, et al. The Nitrate-Independent Blood Pressure-Lowering Effect of Beetroot Juice: A Systematic Review and Meta-Analysis. Adv Nutr. (2017)
- Lara J, et al. Effects of inorganic nitrate and beetroot supplementation on endothelial function: a systematic review and meta-analysis. Eur J Nutr. (2016)
- Aune D, et al. Fruit and vegetable intake and the risk of cardiovascular disease, total cancer and all-cause mortality-a systematic review and dose-response meta-analysis of prospective studies. Int J Epidemiol. (2017)
- Ried K. Garlic Lowers Blood Pressure in Hypertensive Individuals, Regulates Serum Cholesterol, and Stimulates Immunity: An Updated Meta-analysis and Review. J Nutr. (2016)
- Ried K, Toben C, Fakler P. Effect of garlic on serum lipids: an updated meta-analysis. Nutr Rev. (2013)
- El Asmar MS, Naoum JJ, Arbid EJ. Vitamin k dependent proteins and the role of vitamin k2 in the modulation of vascular calcification: a review. Oman Med J. (2014)
- Knapen MH, et al. Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women. A double-blind randomised clinical trial. Thromb Haemost. (2015)
- . Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. . ()
- Cockayne S, et al. Vitamin K and the prevention of fractures: systematic review and meta-analysis of randomized controlled trials. Arch Intern Med. (2006)
- Kodama S, et al. Fasting and post-challenge glucose as quantitative cardiovascular risk factors: a meta-analysis. J Atheroscler Thromb. (2012)
- Mannucci E, et al. Is glucose control important for prevention of cardiovascular disease in diabetes?. Diabetes Care. (2013)
- Lan J, et al. Meta-analysis of the effect and safety of berberine in the treatment of type 2 diabetes mellitus, hyperlipemia and hypertension. J Ethnopharmacol. (2015)
- Schaffer SW, et al. Physiological roles of taurine in heart and muscle. J Biomed Sci. (2010)
- Ahmadian M, Dabidi Roshan V, Ashourpore E. Taurine Supplementation Improves Functional Capacity, Myocardial Oxygen Consumption, and Electrical Activity in Heart Failure. J Diet Suppl. (2017)
- Ahmadian M, et al. Taurine supplementation has anti-atherogenic and anti-inflammatory effects before and after incremental exercise in heart failure. Ther Adv Cardiovasc Dis. (2017)
- Beyranvand MR, et al. Effect of taurine supplementation on exercise capacity of patients with heart failure. J Cardiol. (2011)
- Sun Q, et al. Taurine Supplementation Lowers Blood Pressure and Improves Vascular Function in Prehypertension: Randomized, Double-Blind, Placebo-Controlled Study. Hypertension. (2016)
- Militante JD, Lombardini JB. Treatment of hypertension with oral taurine: experimental and clinical studies. Amino Acids. (2002)
- Dam H. The antihaemorrhagic vitamin of the chick. Biochem J. (1935)
- Shearer MJ, Newman P. Recent trends in the metabolism and cell biology of vitamin K with special reference to vitamin K cycling and MK-4 biosynthesis. J Lipid Res. (2014)
- Ageno W, et al. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. (2012)
- Booth SL. Vitamin K: food composition and dietary intakes. Food Nutr Res. (2012)
- Kurosu M, Begari E. Vitamin K2 in electron transport system: are enzymes involved in vitamin K2 biosynthesis promising drug targets?. Molecules. (2010)
- Davidson RT, et al. Conversion of dietary phylloquinone to tissue menaquinone-4 in rats is not dependent on gut bacteria. J Nutr. (1998)
- Beulens JW, et al. The role of menaquinones (vitamin K₂) in human health. Br J Nutr. (2013)
- Miggiano GA, Robilotta L. Vitamin K-controlled diet: problems and prospects. Clin Ter. (2005)
- Holmes MV, Hunt BJ, Shearer MJ. The role of dietary vitamin K in the management of oral vitamin K antagonists. Blood Rev. (2012)
- Ikeda Y, et al. Intake of fermented soybeans, natto, is associated with reduced bone loss in postmenopausal women: Japanese Population-Based Osteoporosis (JPOS) Study. J Nutr. (2006)
- Katsuyama H, et al. Usual dietary intake of fermented soybeans (Natto) is associated with bone mineral density in premenopausal women. J Nutr Sci Vitaminol (Tokyo). (2002)
- Shearer MJ. Vitamin K. Lancet. (1995)
- American Academy of Pediatrics Committee on Fetus and Newborn. Controversies concerning vitamin K and the newborn. American Academy of Pediatrics Committee on Fetus and Newborn. Pediatrics. (2003)
- Groenen-van Dooren MM, et al. The relative effects of phylloquinone and menaquinone-4 on the blood coagulation factor synthesis in vitamin K-deficient rats. Biochem Pharmacol. (1993)
- Theuwissen E, et al. Effect of low-dose supplements of menaquinone-7 (vitamin K2 ) on the stability of oral anticoagulant treatment: dose-response relationship in healthy volunteers. J Thromb Haemost. (2013)
- Asakura H, et al. Vitamin K administration to elderly patients with osteoporosis induces no hemostatic activation, even in those with suspected vitamin K deficiency. Osteoporos Int. (2001)
- Mayer O Jr, et al. Desphospho-uncarboxylated matrix Gla-protein is associated with mortality risk in patients with chronic stable vascular disease. Atherosclerosis. (2014)
- Chatrou ML, et al. Vascular calcification: the price to pay for anticoagulation therapy with vitamin K-antagonists. Blood Rev. (2012)
- Gast GC, et al. A high menaquinone intake reduces the incidence of coronary heart disease. Nutr Metab Cardiovasc Dis. (2009)
- Beulens JW, et al. High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis. (2009)
- Kurnatowska I, et al. Effect of vitamin K2 on progression of atherosclerosis and vascular calcification in nondialyzed patients with chronic kidney disease stages 3-5. Pol Arch Med Wewn. (2015)
- Fulton RL, et al. Effect of Vitamin K on Vascular Health and Physical Function in Older People with Vascular Disease--A Randomised Controlled Trial. J Nutr Health Aging. (2016)
- Gage BF, et al. Risk of osteoporotic fracture in elderly patients taking warfarin: results from the National Registry of Atrial Fibrillation 2. Arch Intern Med. (2006)
- Hodges SJ, et al. Age-related changes in the circulating levels of congeners of vitamin K2, menaquinone-7 and menaquinone-8. Clin Sci (Lond). (1990)
- Pisani P, et al. Major osteoporotic fragility fractures: Risk factor updates and societal impact. World J Orthop. (2016)
- Dhanwal DK, et al. Epidemiology of hip fracture: Worldwide geographic variation. Indian J Orthop. (2011)
- Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int. (2006)
- Cheung AM, et al. Vitamin K supplementation in postmenopausal women with osteopenia (ECKO trial): a randomized controlled trial. PLoS Med. (2008)
- Nowak JK, et al. Prevalence and correlates of vitamin K deficiency in children with inflammatory bowel disease. Sci Rep. (2014)
- Nakajima S, et al. Association of vitamin K deficiency with bone metabolism and clinical disease activity in inflammatory bowel disease. Nutrition. (2011)
- Shiratori T, et al. Severe Dextran-Induced Anaphylactic Shock during Induction of Hypertension-Hypervolemia-Hemodilution Therapy following Subarachnoid Hemorrhage. Case Rep Crit Care. (2015)
- Riegert-Johnson DL, Volcheck GW. The incidence of anaphylaxis following intravenous phytonadione (vitamin K1): a 5-year retrospective review. Ann Allergy Asthma Immunol. (2002)
- Bullen AW, et al. Skin reactions caused by vitamin K in patients with liver disease. Br J Dermatol. (1978)
- Fu X, et al. Measurement of Multiple Vitamin K Forms in Processed and Fresh-Cut Pork Products in the U.S. Food Supply. J Agric Food Chem. (2016)
- Manoury E, et al. Quantitative measurement of vitamin K2 (menaquinones) in various fermented dairy products using a reliable high-performance liquid chromatography method. J Dairy Sci. (2013)
- Elder SJ, et al. Vitamin k contents of meat, dairy, and fast food in the u.s. Diet. J Agric Food Chem. (2006)
- Shimogawara K, Muto S. Purification of Chlamydomonas 28-kDa ubiquitinated protein and its identification as ubiquitinated histone H2B. Arch Biochem Biophys. (1992)
- Hirauchi K, et al. Measurement of K vitamins in animal tissues by high-performance liquid chromatography with fluorimetric detection. J Chromatogr. (1989)
- Chen GC, et al. Cheese consumption and risk of cardiovascular disease: a meta-analysis of prospective studies. Eur J Nutr. (2017)
- Hao G, et al. Vitamin K intake and the risk of fractures: A meta-analysis. Medicine (Baltimore). (2017)