Vitamin K
Overview
 
Vitamin K is a group of structurally similar, fat soluble vitamins that are needed for the posttranslational modification
Posttranslational modification
Posttranslational modification is the chemical modification of a protein after its translation. It is one of the later steps in protein biosynthesis, and thus gene expression, for many proteins....

 of certain proteins required for blood coagulation and in metabolic pathways in bone and other tissue. They are 2-methyl-1,4-naphthoquinone (3-)derivatives. This group of vitamins includes two natural vitamer
Vitamer
A vitamer of a particular vitamin is any of a number of chemical substances, each of which shows vitamin activity. Very commonly each "vitamin" is not a single chemical, but rather multiple chemical substances called vitamers, each of which is defined by its different biological activity.For...

s: vitamin K1 and vitamin K2.

Vitamin K1 is also known as vitamin Kj, phylloquinone
Phylloquinone
Phylloquinone is a polycyclic aromatic ketone, based on 2-methyl-1,4-naphthoquinone, with a 3-phytyl substituent.It is a fat-soluble vitamin that is stable to air and moisture but decomposes in sunlight. It is found naturally in a wide variety of green plants.-Terminology:It is often called...

 or phytomenadione (also called phytonadione).
Vitamin K1 is required for blood coagulation
Coagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...

 and is synthesized by plants, is found in green leafy vegetables, and can be found in soybean oil.

Vitamin K2 is involved in bone metabolism.
Encyclopedia
Vitamin K is a group of structurally similar, fat soluble vitamins that are needed for the posttranslational modification
Posttranslational modification
Posttranslational modification is the chemical modification of a protein after its translation. It is one of the later steps in protein biosynthesis, and thus gene expression, for many proteins....

 of certain proteins required for blood coagulation and in metabolic pathways in bone and other tissue. They are 2-methyl-1,4-naphthoquinone (3-)derivatives. This group of vitamins includes two natural vitamer
Vitamer
A vitamer of a particular vitamin is any of a number of chemical substances, each of which shows vitamin activity. Very commonly each "vitamin" is not a single chemical, but rather multiple chemical substances called vitamers, each of which is defined by its different biological activity.For...

s: vitamin K1 and vitamin K2.

Vitamin K1 is also known as vitamin Kj, phylloquinone
Phylloquinone
Phylloquinone is a polycyclic aromatic ketone, based on 2-methyl-1,4-naphthoquinone, with a 3-phytyl substituent.It is a fat-soluble vitamin that is stable to air and moisture but decomposes in sunlight. It is found naturally in a wide variety of green plants.-Terminology:It is often called...

 or phytomenadione (also called phytonadione).
Vitamin K1 is required for blood coagulation
Coagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...

 and is synthesized by plants, is found in green leafy vegetables, and can be found in soybean oil.

Vitamin K2 is involved in bone metabolism. Vitamin K2 homologs (menaquinones) are characterized by the number of isoprenoid residues comprising the side chain. Menaquinones are abbreviated MK-n, where n represents the number of isoprenoid side chains. Thus, menaquinone-4
Menatetrenone
Menatetrenone , also known as MK4, is a menaquinone compound used as a hemostatic agent and as adjunctive therapy for the pain of osteoporosis. It is marketed for the latter indication in Japan by Eisai Co., under the trade name Glakay....

 abbreviated MK-4, has 4 isoprene residues in the side chain. Bacteria can produce a range of vitamin K2 forms, including the conversion of K1 to K2 (MK-7) by bacteria in the small intestines. No known toxicity exists for vitamins K1 and K2.

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

Vitamin K was identified in 1929 by Danish
Denmark
Denmark is a Scandinavian country in Northern Europe. The countries of Denmark and Greenland, as well as the Faroe Islands, constitute the Kingdom of Denmark . It is the southernmost of the Nordic countries, southwest of Sweden and south of Norway, and bordered to the south by Germany. Denmark...

 scientist Henrik Dam
Henrik Dam
Henrik Dam was a Danish biochemist and physiologist.He was awarded the Nobel Prize in Medicine in 1943 for joint work with Edward Doisy work in discovering vitamin K and its role in human physiology. Dam's key experiment involved feeding a cholesterol-free diet to chickens...

 when he investigated the role of cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...

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

Subtypes of vitamin K2

Vitamin K2 (menaquinone), is itself a category of vitamin K that includes many types of vitamin K2. The two subtypes of vitamin K2 that have been most studied are menaquinone-4 (menatetrenone
Menatetrenone
Menatetrenone , also known as MK4, is a menaquinone compound used as a hemostatic agent and as adjunctive therapy for the pain of osteoporosis. It is marketed for the latter indication in Japan by Eisai Co., under the trade name Glakay....

, MK4) and menaquinone-7 (MK7).

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

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

The US FDA has not approved any form of vitamin K for the prevention or treatment of osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...

; however, MK4 has been shown to decrease fractures up to 87%. In the amount of 45 mg daily MK4 has been approved by the Ministry of Health in Japan since 1995 for the prevention and treatment of osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...

.

Vitamin K2 (MK4, but not MK7 or vitamin K1) has also been shown to prevent bone loss and/or fractures in the following circumstances:
  • caused by corticosteroids (e.g., prednisone, dexamethasone, prednisolone),
  • anorexia nervosa,
  • cirrhosis of the liver,
  • postmenopausal osteoporosis,
  • disuse from stroke,
  • Alzheimer's disease
    Alzheimer's disease
    Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...

    ,
  • Parkinson disease,
  • primary biliary cirrhosis
    Primary biliary cirrhosis
    Primary biliary cirrhosis, often abbreviated PBC, is an autoimmune disease of the liver marked by the slow progressive destruction of the small bile ducts within the liver. When these ducts are damaged, bile builds up in the liver and over time damages the tissue. This can lead to scarring,...

  • and leuprolide treatment (for prostate cancer).

Vitamin K absorption and dietary need

Previous theory held that dietary deficiency is extremely rare unless the intestine (small bowel) was heavily damaged, resulting in malabsorption
Malabsorption
Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal tract.Impairment can be of single or multiple nutrients depending on the abnormality...

 of the molecule. The other at-risk group for deficiency were those subject to decreased production of K2 by normal flora, as seen in broad spectrum antibiotic use. Taking broad-spectrum antibiotics can reduce vitamin K production in the gut by nearly 74% in people compared with those not taking these antibiotics. Diets low in vitamin K also decrease the body's vitamin K concentration. Additionally, in the elderly there is a reduction in vitamin K2 production.

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

Chemical structure

All members of the vitamin K group of vitamins share a methylated
Methylation
In the chemical sciences, methylation denotes the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. Methylation is a form of alkylation with, to be specific, a methyl group, rather than a larger carbon chain, replacing a hydrogen atom...

 naphthoquinone
Naphthoquinone
Naphthoquinone is a class of natural phenols based on the C6-C4 skeleton.1,4-Naphthoquinone can be viewed as derivatives of naphthalene through the replacement of two hydrogen atoms by two ketone groups....

 ring structure (menadione
Menadione
Menadione is a synthetic chemical compound sometimes used as a nutritional supplement because of its vitamin K activity. It is an analog of 1,4-naphthoquinone with a methyl group in the 2-position.-Terminology:...

), and vary in the aliphatic side chain
Side chain
In organic chemistry and biochemistry, a side chain is a chemical group that is attached to a core part of the molecule called "main chain" or backbone. The placeholder R is often used as a generic placeholder for alkyl group side chains in chemical structure diagrams. To indicate other non-carbon...

 attached at the 3-position (see figure 1). Phylloquinone
Phylloquinone
Phylloquinone is a polycyclic aromatic ketone, based on 2-methyl-1,4-naphthoquinone, with a 3-phytyl substituent.It is a fat-soluble vitamin that is stable to air and moisture but decomposes in sunlight. It is found naturally in a wide variety of green plants.-Terminology:It is often called...

 (also known as vitamin K1) invariably contains in its side chain four isoprenoid
Isoprene
Isoprene , or 2-methyl-1,3-butadiene, is a common organic compound with the formula CH2=CCH=CH2. Under standard conditions it is a colorless liquid...

 residues, one of which is unsaturated.

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

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

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

Physiology

Vitamin K is involved in the carboxylation
Carboxylation
Carboxylation in chemistry is a chemical reaction in which a carboxylic acid group is introduced in a substrate. The opposite reaction is decarboxylation.-Carboxylation in organic chemistry:In organic chemistry many different protocols exist for carboxylation...

 of certain glutamate residues in proteins to form gamma-carboxyglutamate residues (abbreviated Gla residues). The modified residues are often (but not always) situated within specific protein domains called Gla domain
Gla domain
Vitamin K-dependent carboxylation/gamma-carboxyglutamic domain is a protein domain that contains post-translational modifications ofmany glutamate residues by vitamin K-dependent carboxylation to form gamma-carboxyglutamate . The Gla residues are responsible for the high-affinity binding of...

s. Gla residues are usually involved in binding calcium
Calcium in biology
Calcium plays a pivotal role in the physiology and biochemistry of organisms and the cell. It plays an important role in signal transduction pathways, where it acts as a second messenger, in neurotransmitter release from neurons, contraction of all muscle cell types, and fertilization...

. The Gla residues are essential for the biological activity of all known Gla-proteins.

15 human proteins with Gla domain
Gla domain
Vitamin K-dependent carboxylation/gamma-carboxyglutamic domain is a protein domain that contains post-translational modifications ofmany glutamate residues by vitamin K-dependent carboxylation to form gamma-carboxyglutamate . The Gla residues are responsible for the high-affinity binding of...

s have been discovered, and they play key roles in the regulation of three physiological processes:
  • Blood coagulation
    Coagulation
    Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...

    : (prothrombin (factor II), factors VII
    Factor VII
    Factor VII is one of the proteins that causes blood to clot in the coagulation cascade. It is an enzyme of the serine protease class. A recombinant form of human factor VIIa has U.S. Food and Drug Administration approval for uncontrolled bleeding in hemophilia patients...

    , IX
    Factor IX
    Factor IX is one of the serine proteases of the coagulation system; it belongs to peptidase family S1. Deficiency of this protein causes hemophilia B. It was discovered in 1952 after a young boy named Stephen Christmas was found to be lacking this exact factor, leading to...

    , X
    Factor X
    Factor X, also known by the eponym Stuart-Prower factor or as prothrombinase, is an enzyme of the coagulation cascade. It is a serine endopeptidase .-Physiology:...

    , protein C
    Protein C
    Protein C, also known as autoprothrombin IIA and blood coagulation factor XIV, is a zymogenic protein, the activated form of which plays an important role in regulating blood clotting, inflammation, cell death and maintaining the permeability of blood vessel walls in humans and other animals...

    , protein S
    Protein S
    Protein S is a vitamin K-dependent plasma glycoprotein synthesized in the endothelium. In the circulation, Protein S exists in two forms: a free form and a complex form bound to complement protein C4b. In humans, protein S is encoded by the PROS1 gene...

    , and protein Z
    Protein Z
    Protein Z also known as PROZ is a protein which in humans is encoded by the PROZ gene.Protein Z is a member of the coagulation cascade, the group of blood proteins that leads to the formation of blood clots. It is vitamin K-dependent, and its functionality is therefore impaired in warfarin therapy...

    ).
  • Bone
    Bone
    Bones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...

     metabolism: osteocalcin
    Osteocalcin
    Osteocalcin, also known as bone gamma-carboxyglutamic acid-containing protein , is a noncollagenous protein found in bone and dentin. In humans, the osteocalcin is encoded by the BGLAP gene.- Function :...

    , also called bone Gla-protein (BGP), matrix Gla protein
    Matrix gla protein
    Matrix gla protein is a protein found in numerous body tissues that requires vitamin K for its optimum function. It is present in bone , as well as in heart, kidney and lung...

     (MGP), and periostin.
  • Vascular biology: growth arrest-specific protein 6 (Gas6)
  • unknown function: proline-rich g-carboxy glutamyl proteins (PRGPs) 1 and 2, and transmembrane g-carboxy glutamyl proteins (TMGs) 3 and 4.


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

Recommended amounts

The U.S. Dietary Reference Intake
Dietary Reference Intake
The Dietary Reference Intake is a system of nutrition recommendations from the Institute of Medicine of the U.S. National Academy of Sciences. The DRI system is used by both the United States and Canada and is intended for the general public and health professionals...

 (DRI) for an Adequate Intake (AI) of vitamin K for a 25-year old male
Male
Male refers to the biological sex of an organism, or part of an organism, which produces small mobile gametes, called spermatozoa. Each spermatozoon can fuse with a larger female gamete or ovum, in the process of fertilization...

 is 120 micrograms/day. The Adequate Intake (AI) for adult women is 90 micrograms/day, for infants is 10–20 micrograms/day, for children and adolescents 15–100 micrograms/day. In 2002 it was found that to get maximum carboxylation
Carboxylation
Carboxylation in chemistry is a chemical reaction in which a carboxylic acid group is introduced in a substrate. The opposite reaction is decarboxylation.-Carboxylation in organic chemistry:In organic chemistry many different protocols exist for carboxylation...

 of osteocalcin
Osteocalcin
Osteocalcin, also known as bone gamma-carboxyglutamic acid-containing protein , is a noncollagenous protein found in bone and dentin. In humans, the osteocalcin is encoded by the BGLAP gene.- Function :...

, one may have to take up to 1000 μg of vitamin K1.

Toxicity

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

Blood clotting (coagulation
Coagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...

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

However, a synthetic form of vitamin K, vitamin K3 (menadione), is demonstrably toxic. In fact, the FDA has banned this synthetic form of the vitamin from over-the-counter supplements because large doses have been shown to cause allergic reactions, hemolytic anemia
Hemolytic anemia
Hemolytic anemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells , either in the blood vessels or elsewhere in the human body . It has numerous possible causes, ranging from relatively harmless to life-threatening...

, and cytotoxicity in liver cells.

Drug interactions

Phylloquinone (K1) or menaquinone (K2) are capable of blocking the blood thinning action of anticoagulants like warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...

, which work by interfering with the action of vitamin K. They also reverse the tendency of these drugs to cause arterial calcification in the long term.

Sources

Food Serving Size Vitamin K (mcg) Food Serving Size Vitamin K (mcg)
Kale, cooked 1/2 cup 531 Parsley, raw 1/4 cup 246
Spinach, cooked 1/2 cup 444 Spinach, raw 1 cup 145
Collards, cooked 1/2 cup 418 Collards, raw 1 cup 184
Swiss chard, cooked 1/2 cup 287 Swiss chard, raw 1 cup 299
Mustard greens, cooked 1/2 cup 210 Mustard greens, raw 1 cup 279
Turnip greens, cooked 1/2 cup 265 Turnip greens, raw 1 cup 138
Broccoli, cooked 1 cup 220 Broccoli, raw 1 cup 89
Brussels sprouts, cooked 1 cup 219 Endive, raw 1 cup 116
Cabbage, cooked 1/2 cup 82 Green leaf lettuce 1 cup 71
Asparagus 4 spears 48 Romaine lettuce, raw 1 cup 57
Table from "Important information to know when you are taking: Warfarin (Coumadin) and Vitamin K", Clinical Center, National Institutes of Health Drug Nutrient Interaction Task Force.http://www.cc.nih.gov/ccc/patient_education/drug_nutrient/coumadin1.pdf

Vitamin K1 is found chiefly in leafy green vegetables such as spinach
Spinach
Spinach is an edible flowering plant in the family of Amaranthaceae. It is native to central and southwestern Asia. It is an annual plant , which grows to a height of up to 30 cm. Spinach may survive over winter in temperate regions...

, swiss chard, and Brassica
Brassica
Brassica is a genus of plants in the mustard family . The members of the genus may be collectively known either as cabbages, or as mustards...

 (e.g. cabbage
Cabbage
Cabbage is a popular cultivar of the species Brassica oleracea Linne of the Family Brassicaceae and is a leafy green vegetable...

, kale
Kale
Kale is very high in beta carotene, vitamin K, vitamin C, lutein, zeaxanthin, and reasonably rich in calcium. Kale, as with broccoli and other brassicas, contains sulforaphane , a chemical with potent anti-cancer properties. Boiling decreases the level of sulforaphane; however, steaming,...

, cauliflower
Cauliflower
Cauliflower is one of several vegetables in the species Brassica oleracea, in the family Brassicaceae. It is an annual plant that reproduces by seed...

, broccoli
Broccoli
Broccoli is a plant in the cabbage family, whose large flower head is used as a vegetable.-General:The word broccoli, from the Italian plural of , refers to "the flowering top of a cabbage"....

, and brussels sprout
Brussels sprout
The Brussels sprout is a cultivar of wild cabbage grown for its edible buds. The leafy green vegetables are typically 2.5–4 cm in diameter and look like miniature cabbages. The sprout is Brassica oleracea, in the "gemmifera" group of the family Brassicaceae...

s); some fruit
Fruit
In broad terms, a fruit is a structure of a plant that contains its seeds.The term has different meanings dependent on context. In non-technical usage, such as food preparation, fruit normally means the fleshy seed-associated structures of certain plants that are sweet and edible in the raw state,...

s such as avocado
Avocado
The avocado is a tree native to Central Mexico, classified in the flowering plant family Lauraceae along with cinnamon, camphor and bay laurel...

, kiwifruit
Kiwifruit
The kiwifruit, often shortened to kiwi in many parts of the world, is the edible berry of a cultivar group of the woody vine Actinidia deliciosa and hybrids between this and other species in the genus Actinidia....

 and grapes are also high in vitamin K. By way of reference, two tablespoons of parsley
Parsley
Parsley is a species of Petroselinum in the family Apiaceae, native to the central Mediterranean region , naturalized elsewhere in Europe, and widely cultivated as an herb, a spice and a vegetable.- Description :Garden parsley is a bright green hairless biennial herbaceous plant in temperate...

 contain 153% of the recommended daily amount of vitamin K. Some vegetable oils, notably soybean, contain vitamin K, but at levels that would require relatively large calorific consumption to meet the USDA recommended levels.
Colonic bacteria synthesize a significant portion of humans' vitamin K needs; this is one of the reasons why newborns often receive a vitamin K shot at birth - in order to tide them over until day 5-7 when their colon becomes colonized.

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

Vitamin K2 (Menaquinone-4) is synthesized by animal tissues and is found in meat, eggs, and dairy products. Menaquinone-7 is synthesized by bacteria during fermentation and is found in fermented soybeans (natto
Natto
is a traditional Japanese food made from soybeans fermented with Bacillus subtilis. It is popular especially as a breakfast food. As a rich source of protein and probiotics, nattō and the soybean paste miso formed a vital source of nutrition in feudal Japan. Nattō can be an acquired taste because...

). In natto 0% of vitamin K is from MK-4 and in cheese 2–7%.

Deficiency

Average diets are usually not lacking in vitamin K and primary vitamin K deficiency is rare in healthy adults. Newborn infants are at an increased risk of deficiency. Other populations with an increased prevalence of vitamin K deficiency include individuals who suffer from liver damage or disease (e.g. alcoholics), people with cystic fibrosis, inflammatory bowel diseases or those who have recently had abdominal surgeries. Groups that may suffer from secondary vitamin K deficiency include bulimics, those on stringent diets, and those taking anticoagulants. Other drugs that have been associated with vitamin K deficiency include salicylates, barbiturates, and cefamandole, although the mechanism is still unknown. There is no difference between the sexes as both males and females are affected equally. Symptoms of deficiency include heavy menstrual bleeding in women, anemia, bruising, and bleeding of the gums or nose. They could also have disorders such as coagulopathy
Coagulopathy
Coagulopathy is a condition in which the blood’s ability to clot is impaired. This condition can cause prolonged or excessive bleeding, which may occur spontaneously or following an injury or medical and dental procedures.The normal clotting process depends on the interplay of various proteins in...

.

Osteoporosis and coronary heart disease are strongly associated with lower levels of K2 (menaquinone). Menaquinone is not inhibited by salicylates as happens with K1, so menaquinone supplementation can alleviate the chronic vitamin K deficiency caused by long term aspirin use.

Function

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

Within the cell, vitamin K undergoes electron reduction
Redox
Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....

 to a reduced form of vitamin K (called vitamin K hydroquinone) by the enzyme vitamin K epoxide reductase
Vitamin K epoxide reductase
Vitamin K epoxide reductase is an enzyme that reduces vitamin K after it has been oxidised in the carboxylation of glutamic acid. Its C1 subunit is the target of anticoagulant warfarin.- See also :* Oxidoreductase...

 (or VKOR). Another enzyme then oxidizes vitamin K hydroquinone to allow carboxylation of Glu to Gla; this enzyme is called the gamma-glutamyl carboxylase
Gamma-glutamyl carboxylase
Gamma-glutamyl carboxylase is an enzyme that in humans is encoded by the GGCX gene, located on chromosome 2 at 2p12.-Function:Gamma-glutamyl carboxylase is an enzyme that catalyzes the posttranslational modification of vitamin K-dependent proteins...

 or the vitamin K-dependent carboxylase. The carboxylation reaction will only proceed if the carboxylase enzyme is able to oxidize vitamin K hydroquinone to vitamin K epoxide at the same time; the carboxylation and epoxidation reactions are said to be coupled reactions. Vitamin K epoxide is then re-converted to vitamin K by vitamin K epoxide reductase
Vitamin K epoxide reductase
Vitamin K epoxide reductase is an enzyme that reduces vitamin K after it has been oxidised in the carboxylation of glutamic acid. Its C1 subunit is the target of anticoagulant warfarin.- See also :* Oxidoreductase...

. The reduction and subsequent re-oxidation of vitamin K coupled with carboxylation of Glu is called the vitamin K cycle. One of the reasons humans are rarely deficient in vitamin K is that vitamin K is continually recycled in cells.

Warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...

 and other coumarin
Coumarin
Coumarin is a fragrant chemical compound in the benzopyrone chemical class, found in many plants, notably in high concentration in the tonka bean , vanilla grass , sweet woodruff , mullein , sweet grass , cassia cinnamon and sweet clover...

 drugs block the action of the vitamin K epoxide reductase
Vitamin K epoxide reductase
Vitamin K epoxide reductase is an enzyme that reduces vitamin K after it has been oxidised in the carboxylation of glutamic acid. Its C1 subunit is the target of anticoagulant warfarin.- See also :* Oxidoreductase...

. This results in decreased concentrations of vitamin K and vitamin K hydroquinone in the tissues, such that the carboxylation reaction catalyzed by the glutamyl carboxylase is inefficient. This results in the production of clotting factors with inadequate Gla. Without Gla on the amino termini of these factors, they no longer bind stably to the blood vessel endothelium
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...

 and cannot activate clotting to allow formation of a clot during tissue injury. As it is impossible to predict what dose of warfarin will give the desired degree of suppression of the clotting, warfarin treatment must be carefully monitored to avoid over-dosing. (See the warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...

 article.)

Gamma-carboxyglutamate proteins, or Gla-proteins

At present, the following human Gla-containing proteins have been characterized to the level of primary structure: the blood coagulation factors II (prothrombin), VII, IX, and X, the anticoagulant proteins C and S, and the Factor X-targeting protein Z
Protein Z
Protein Z also known as PROZ is a protein which in humans is encoded by the PROZ gene.Protein Z is a member of the coagulation cascade, the group of blood proteins that leads to the formation of blood clots. It is vitamin K-dependent, and its functionality is therefore impaired in warfarin therapy...

. The bone Gla-protein osteocalcin
Osteocalcin
Osteocalcin, also known as bone gamma-carboxyglutamic acid-containing protein , is a noncollagenous protein found in bone and dentin. In humans, the osteocalcin is encoded by the BGLAP gene.- Function :...

, the calcification inhibiting matrix Gla protein
Matrix gla protein
Matrix gla protein is a protein found in numerous body tissues that requires vitamin K for its optimum function. It is present in bone , as well as in heart, kidney and lung...

 (MGP), the cell growth
Cell growth
The term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...

 regulating growth arrest specific gene 6 protein (Gas6), and the four transmembrane Gla proteins (TMGPs) the function of which is at present unknown. Gas6 can function as a growth factor
Growth factor
A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes....

 that activates the Axl receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...

 tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....

 and stimulates cell proliferation or prevents apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

 in some cells. In all cases in which their function was known, the presence of the Gla residues in these proteins turned out to be essential for functional activity.

Gla-proteins are known to occur in a wide variety of vertebrates: mammals, birds, reptiles, and fish. The venom
Venom
Venom is the general term referring to any variety of toxins used by certain types of animals that inject it into their victims by the means of a bite or a sting...

 of a number of Australian snakes acts by activating the human blood clotting system. Remarkably, in some cases activation is accomplished by snake Gla-containing enzymes that bind to the endothelium of human blood vessels and catalyze the conversion of procoagulant clotting factors into activated ones, leading to unwanted and potentially deadly clotting.

Another interesting class of invertebrate Gla-containing proteins is synthesized by the fish-hunting snail Conus geographus
Conus geographus
Cnous geographus, common name the geography cone, is a species of predatory sea snail, a marine gastropod mollusk in the family Conidae, the cone snails, cone shells or cones. Although all cone snails hunt and kill prey using venom, the venom of this species is known to be especially potent...

. These snails produce a venom containing hundreds of neuro-active peptides, or conotoxins, which is sufficiently toxic to kill an adult human. Several of the conotoxins contain 2–5 Gla residues.

Methods of assessment

Prothrombin time test:
Measures the time required for blood to clot
Blood sample mixed with citric acid and put in a fibrometer.
Delayed clot formation indicates a deficiency.

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

Plasma Phylloquinone:
Was found to be positively correlated with phylloquinone intake in elderly British women, but not men

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

Urinary γ-carboxyglutamic acid:
Urinary Gla responds to changes in dietary vitamin K intake.
Several days are required before any change can be observed.

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

Function in bacteria

Many bacteria, such as Escherichia coli
Escherichia coli
Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans, and are occasionally responsible for product recalls...

 found in the large intestine
Large intestine
The large intestine is the third-to-last part of the digestive system — — in vertebrate animals. Its function is to absorb water from the remaining indigestible food matter, and then to pass useless waste material from the body...

, can synthesize vitamin K2 (menaquinone-7), but not vitamin K1 (phylloquinone). In these bacteria, menaquinone will transfer two electrons between two different small molecules, in a process called anaerobic respiration
Anaerobic respiration
Anaerobic respiration is a form of respiration using electron acceptors other than oxygen. Although oxygen is not used as the final electron acceptor, the process still uses a respiratory electron transport chain; it is respiration without oxygen...

. For example, a small molecule with an excess of electrons (also called an electron donor) such as lactate
Lactic acid
Lactic acid, also known as milk acid, is a chemical compound that plays a role in various biochemical processes and was first isolated in 1780 by the Swedish chemist Carl Wilhelm Scheele. Lactic acid is a carboxylic acid with the chemical formula C3H6O3...

, formate
Formate
Formate or methanoate is the ion CHOO− or HCOO− . It is the simplest carboxylate anion. It is produced in large amounts in the hepatic mitochondria of embryonic cells and in cancer cells by the folate cycle Formate or methanoate is the ion CHOO− or HCOO− (formic acid minus one hydrogen ion). It...

, or NADH, with the help of an enzyme, will pass two electrons to a menaquinone. The menaquinone, with the help of another enzyme, will in turn transfer these 2 electrons to a suitable oxidant, such fumarate or nitrate
Nitrate
The nitrate ion is a polyatomic ion with the molecular formula NO and a molecular mass of 62.0049 g/mol. It is the conjugate base of nitric acid, consisting of one central nitrogen atom surrounded by three identically-bonded oxygen atoms in a trigonal planar arrangement. The nitrate ion carries a...

 (also called an electron acceptor). Adding two electrons to fumarate or nitrate
Nitrate
The nitrate ion is a polyatomic ion with the molecular formula NO and a molecular mass of 62.0049 g/mol. It is the conjugate base of nitric acid, consisting of one central nitrogen atom surrounded by three identically-bonded oxygen atoms in a trigonal planar arrangement. The nitrate ion carries a...

 will convert the molecule to succinate or nitrite
Nitrite
The nitrite ion has the chemical formula NO2−. The anion is symmetric with equal N-O bond lengths and a O-N-O bond angle of ca. 120°. On protonation the unstable weak acid nitrous acid is produced. Nitrite can be oxidised or reduced, with product somewhat dependent on the oxidizing/reducing agent...

 + water
Water
Water is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a...

, respectively. Some of these reactions generate a cellular energy source, ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...

, in a manner similar to eukaryotic cell aerobic respiration, except that the final electron acceptor is not molecular oxygen, but say fumarate or nitrate
Nitrate
The nitrate ion is a polyatomic ion with the molecular formula NO and a molecular mass of 62.0049 g/mol. It is the conjugate base of nitric acid, consisting of one central nitrogen atom surrounded by three identically-bonded oxygen atoms in a trigonal planar arrangement. The nitrate ion carries a...

 (In aerobic respiration, the final oxidant is molecular oxygen (O2) , which accepts four electrons from an electron donor such as NADH to be converted to water
Water
Water is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a...

.) Escherichia coli
Escherichia coli
Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans, and are occasionally responsible for product recalls...

 can carry out aerobic respiration and menaquinone-mediated anaerobic respiration
Anaerobic respiration
Anaerobic respiration is a form of respiration using electron acceptors other than oxygen. Although oxygen is not used as the final electron acceptor, the process still uses a respiratory electron transport chain; it is respiration without oxygen...

.

Vitamin K injection in newborns

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

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

USA

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

UK

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

Controversy

Controversy arose in the early 1990s regarding this practice when two studies were shown suggesting a relationship between parenteral
Parenteral
Parenteral is a route of administration that involves piercing the skin or mucous membrane. Parenteral nutrition refers to providing nutrition via the veins.-Etymology:...

 administration of vitamin K and childhood cancer (14). However, poor methods and small sample sizes led to the discrediting of these studies and a review of the evidence published in 2000 by Ross and Davies found no link between the two.

Vitamin K and bone health

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

Vitamin K takes part in the post translational modification as a cofactor in γ-carboxylation of vitamin K dependant proteins (VKDPs). VKDPs have glutamate residues (Glu). Biophysical studies have suggested that supplemental vitamin K promotes osteotrophic
Osteoblast
Osteoblasts are mononucleate cells that are responsible for bone formation; in essence, osteoblasts are specialized fibroblasts that in addition to fibroblastic products, express bone sialoprotein and osteocalcin.Osteoblasts produce a matrix of osteoid, which is composed mainly of Type I collagen...

 processes and slows osteoclast
Osteoclast
An osteoclast is a type of bone cell that removes bone tissue by removing its mineralized matrix and breaking up the organic bone . This process is known as bone resorption. Osteoclasts were discovered by Kolliker in 1873...

ic processes via calcium bonding. Study of Atkins et al. revealed that phylloquinone
Phylloquinone
Phylloquinone is a polycyclic aromatic ketone, based on 2-methyl-1,4-naphthoquinone, with a 3-phytyl substituent.It is a fat-soluble vitamin that is stable to air and moisture but decomposes in sunlight. It is found naturally in a wide variety of green plants.-Terminology:It is often called...

, menatetrenone
Menatetrenone
Menatetrenone , also known as MK4, is a menaquinone compound used as a hemostatic agent and as adjunctive therapy for the pain of osteoporosis. It is marketed for the latter indication in Japan by Eisai Co., under the trade name Glakay....

 (MK4) and menadione
Menadione
Menadione is a synthetic chemical compound sometimes used as a nutritional supplement because of its vitamin K activity. It is an analog of 1,4-naphthoquinone with a methyl group in the 2-position.-Terminology:...

 promote in vitro mineralisaton by human primary osteoblasts. Other studies have shown that vitamin K antagonists (usually a class of anticoagulants) lead to early calcification of the epiphysis
Epiphysis
The epiphysis is the rounded end of a long bone, at its joint with adjacent bone. Between the epiphysis and diaphysis lies the metaphysis, including the epiphyseal plate...

 and epiphysial line in mice and other animals, causing seriously decreased bone growth. This is due to defects in osteocalcin
Osteocalcin
Osteocalcin, also known as bone gamma-carboxyglutamic acid-containing protein , is a noncollagenous protein found in bone and dentin. In humans, the osteocalcin is encoded by the BGLAP gene.- Function :...

 and matrix Gla protein
Matrix gla protein
Matrix gla protein is a protein found in numerous body tissues that requires vitamin K for its optimum function. It is present in bone , as well as in heart, kidney and lung...

. Their primary function is to prevent overcalcification of the bone and cartilage. Vitamin K is important in the process of carboxylating glutamic acid (Glu) in these proteins to gamma-carboxyglutamic acid (Gla), which is necessary for their function. Vitamin D is reported to regulate the OC transcription by osteoblast thereby showing that vitamin K and vitamin D work in tandem for the bone metabolism and development. Lian and his group discovered two nucleotide substitution regions which they named "osteocalcin box" in the rat and human osteocalcin genes. They found a region 600 nucleotides immediately upstream from the transcription start site that support a 10-fold stimulated transcription of the gene by 1,25-dihydroxy vitamin D.

Vitamin K1 and bone health

Data from the 1998 Nurses Health Study, an observational study
Observational study
In epidemiology and statistics, an observational study draws inferences about the possible effect of a treatment on subjects, where the assignment of subjects into a treated group versus a control group is outside the control of the investigator...

, indicated an inverse relationship between dietary vitamin K1 and the risk of hip fracture
Hip fracture
A hip fracture is a femoral fracture that occurs in the proximal end of the femur , near the hip.The term "hip fracture" is commonly used to refer to four different fracture patterns and is often due to osteoporosis; in the vast majority of cases, a hip fracture is a fragility fracture due to a...

. After being given 110 micrograms/day of vitamin K, women who consumed lettuce
Lettuce
Lettuce is a temperate annual or biennial plant of the daisy family Asteraceae. It is most often grown as a leaf vegetable. It is eaten either raw, notably in salads, sandwiches, hamburgers, tacos, and many other dishes, or cooked, as in Chinese cuisine in which the stem becomes just as important...

 one or more times per day had a significantly lower risk of hip fracture than women who consumed lettuce one or fewer times per week. In addition to this, high intakes of vitamin D
Vitamin D
Vitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate ....

 but low intakes of vitamin K were suggested to pose an increased risk of hip fracture. The Framingham Heart Study is another study that showed the similar result. Subjects in the highest quartile of vitamin K1 intake (median K1 intake of 254 μg/ day) has 35% lower risk of hip fracture than those in the lowest quartile. Comparing with the daily recommended intake (DRI) of 90 and 120 μg/ day, both the above intakes are higher than existing DRI.

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

Vitamin K2 (MK4) and bone health

In contrast, MK4 has been shown in numerous studies to reduce fracture risk, stop and reverse bone loss. In Japan, MK4 in the dose of 45 mg daily is recognized as a treatment for osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...

. MK4 has been shown to decrease fractures up to 87%. In the amount of 45 mg daily MK4 has been approved by the Ministry of Health in Japan since 1995 for the prevention and treatment of osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...

.

MK4 (but not MK7 or vitamin K1) prevented bone loss and/or fractures in the following circumstances:
  • caused by corticosteroids (e.g., prednisone
    Prednisone
    Prednisone is a synthetic corticosteroid drug that is particularly effective as an immunosuppressant drug. It is used to treat certain inflammatory diseases and some types of cancer, but has significant adverse effects...

    , dexamethasone
    Dexamethasone
    Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant...

    , prednisolone
    Prednisolone
    Prednisolone is the active metabolite of prednisone, which is also used as a drug.-Uses:Prednisolone is a corticosteroid drug with predominant glucocorticoid and low mineralocorticoid activity, making it useful for the treatment of a wide range of inflammatory and auto-immune conditions such as...

    ),
  • anorexia nervosa,
  • cirrhosis of the liver,
  • postmenopausal osteoporosis,
  • disuse from stroke,
  • Alzheimer's disease
    Alzheimer's disease
    Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...

    ,
  • Parkinson disease,
  • primary biliary cirrhosis
    Primary biliary cirrhosis
    Primary biliary cirrhosis, often abbreviated PBC, is an autoimmune disease of the liver marked by the slow progressive destruction of the small bile ducts within the liver. When these ducts are damaged, bile builds up in the liver and over time damages the tissue. This can lead to scarring,...

     and
  • leuprolide treatment (for prostate cancer).

Vitamin K2 (MK7) and bone health

Menaquinone-7 (MK7), which is abundant in fermented soybeans (natto), has been demonstrated to stimulate osteoblastic bone formation and to inhibit osteoclastic bone resorption. In another study, use of MK-7 caused significant elevations of serum Y-carboxylated osteocalcin
Osteocalcin
Osteocalcin, also known as bone gamma-carboxyglutamic acid-containing protein , is a noncollagenous protein found in bone and dentin. In humans, the osteocalcin is encoded by the BGLAP gene.- Function :...

 concentration, a biomarker of bone formation. MK-7 also completely inhibited a decrease in the calcium content of bone tissue by inhibiting the bone-resorbing factors parathyroid hormone
Parathyroid hormone
Parathyroid hormone , parathormone or parathyrin, is secreted by the chief cells of the parathyroid glands as a polypeptide containing 84 amino acids...

 and prostaglandin E2.
On 19 February 2011, HSA (Singapore) approved a health supplement which contains vitamin K2 (MK7) and vitamin D3 for increasing bone mineral density.

Vitamin K and Alzheimer's disease

Research into the antioxidant properties of vitamin K indicates that the concentration of vitamin K is lower in the circulation of carriers of the APOE4
Apolipoprotein E
Apolipoprotein E is a class of apolipoprotein found in the chylomicron and IDLs that binds to a specific receptor on liver cells and peripheral cells. It is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.-Function:...

 gene, and recent studies have shown its ability to inhibit nerve cell
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...

 death due to oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...

. It has been hypothesized that vitamin K may reduce neuronal damage and that supplementation may hold benefits to treating Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...

, although more research is necessary in this area.

Vitamin K used topically

Vitamin K may be applied topically, typically as a 5% cream, to diminish postoperative bruising from cosmetic surgery and injections, broken capillaries (spider veins), to treat rosacea
Rosacea
Rosacea is a chronic condition characterized by facial erythema . Pimples are sometimes included as part of the definition. Unless it affects the eyes, it is typically a harmless cosmetic condition...

 and to aid in the fading of hyperpigmentation
Hyperpigmentation
In dermatology, hyperpigmentation is the darkening of an area of skin or nails caused by increased melanin.-Causes:Hyperpigmentation may be caused by sun damage, inflammation, or other skin injuries, including those related to acne vulgaris...

 and dark under-eye circles.

Vitamin K and cancer

While researchers in Japan were studying the role of vitamin K2 as the menaquinone-4 (MK-4) form in the prevention of bone loss in females with liver disease, they discovered another possible effect. This two year study which involved 21 women with viral liver cirrhosis found that women in the supplement group were 90% less likely to develop liver cancer
Liver cancer
Liver tumors or hepatic tumors are tumors or growths on or in the liver . Several distinct types of tumors can develop in the liver because the liver is made up of various cell types. These growths can be benign or malignant...

. A German study performed on men with prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...

 found a significant inverse relationship between vitamin K2 consumption and advanced prostate cancer.

Vitamin K as antidote for poisoning by 4-hydroxcoumarin drugs

Vitamin K is a true antidote
Antidote
An antidote is a substance which can counteract a form of poisoning. The term ultimately derives from the Greek αντιδιδοναι antididonai, "given against"....

 for poisoning by 4-hydroxycoumarin anticoagulant drugs (sometimes loosely referred to as coumarin
Coumarin
Coumarin is a fragrant chemical compound in the benzopyrone chemical class, found in many plants, notably in high concentration in the tonka bean , vanilla grass , sweet woodruff , mullein , sweet grass , cassia cinnamon and sweet clover...

s). These include the pharmaceutical warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...

, and also anticoagulant-mechanism poisons such as bromadiolone
Bromadiolone
Bromadiolone is a potent rodenticide. It is a second-generation 4-hydroxycoumarin derivative, often called a "super-warfarin" for its added potency and tendency to accumulate in the liver of the poisoned organism...

, which are commonly found in rodenticides. 4-Hydroxycoumarin drugs possess anticoagulatory
Anticoagulant
An anticoagulant is a substance that prevents coagulation of blood. A group of pharmaceuticals called anticoagulants can be used in vivo as a medication for thrombotic disorders. Some anticoagulants are used in medical equipment, such as test tubes, blood transfusion bags, and renal dialysis...

 and rodenticidal properties because they inhibit vitamin K-dependent synthesis of some clotting factors by the liver. Death is usually a result of internal hemorrhage. Treatment usually consists of repeated intravenous doses of vitamin K, followed by doses in pill form for a period of at least two weeks, though possibly up to 2 months, afterwards (in the case of the more potent 4-hydoxycoumarins used as rodenticides). If caught early, prognosis is good, even when great amounts of the drug or poison are ingested.

History of discovery

In 1929, Danish
Denmark
Denmark is a Scandinavian country in Northern Europe. The countries of Denmark and Greenland, as well as the Faroe Islands, constitute the Kingdom of Denmark . It is the southernmost of the Nordic countries, southwest of Sweden and south of Norway, and bordered to the south by Germany. Denmark...

 scientist Henrik Dam investigated the role of cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...

 by feeding chickens a cholesterol-depleted diet. After several weeks, the animals developed hemorrhages and started bleeding. These defects could not be restored by adding purified cholesterol to the diet. It appeared that—together with the cholesterol—a second compound had been extracted from the food, and this compound was called the coagulation vitamin. The new vitamin received the letter K because the initial discoveries were reported in a German journal, in which it was designated as Koagulationsvitamin. Edward Adelbert Doisy
Edward Adelbert Doisy
Edward Adelbert Doisy was an American biochemist. He received the Nobel Prize in Physiology or Medicine in 1943 with Henrik Dam for their discovery of vitamin K and its chemical structure.Doisy was born in Hume, Illinois, on November 3, 1893. He completed his A.B. degree in 1914 and his M.S...

 of Saint Louis University
Saint Louis University
Saint Louis University is a private, co-educational Jesuit university located in St. Louis, Missouri, United States. Founded in 1818 by the Most Reverend Louis Guillaume Valentin Dubourg SLU is the oldest university west of the Mississippi River. It is one of 28 member institutions of the...

 did much of the research that led to the discovery of the structure and chemical nature of vitamin K. Dam and Doisy shared the 1943 Nobel Prize
Nobel Prize
The Nobel Prizes are annual international awards bestowed by Scandinavian committees in recognition of cultural and scientific advances. The will of the Swedish chemist Alfred Nobel, the inventor of dynamite, established the prizes in 1895...

 for medicine for their work on vitamin K (K1 and K2) published in 1939. Several laboratories synthesized the compound(s) in 1939.

For several decades the vitamin K-deficient chick model was the only method of quantifying vitamin K in various foods: the chicks were made vitamin K-deficient and subsequently fed with known amounts of vitamin K-containing food. The extent to which blood coagulation was restored by the diet was taken as a measure for its vitamin K content. Three groups of physicians independently found this: Biochemical Institute, University of Copenhagen (Dam and Johannes Glavind), University of Iowa
University of Iowa
The University of Iowa is a public state-supported research university located in Iowa City, Iowa, United States. It is the oldest public university in the state. The university is organized into eleven colleges granting undergraduate, graduate, and professional degrees...

 Department of Pathology (Emory Warner, Kenneth Brinkhous
Kenneth Brinkhous
Kenneth Merle Brinkhous was a professor and chairperson in the Department of Pathology and Laboratory Medicine at the University of North Carolina at Chapel Hill. Brinkhous remained active in research until shortly before his death.-Education:...

, and Harry Pratt Smith), and the Mayo Clinic
Mayo Clinic
Mayo Clinic is a not-for-profit medical practice and medical research group specializing in treating difficult patients . Patients are referred to Mayo Clinic from across the U.S. and the world, and it is known for innovative and effective treatments. Mayo Clinic is known for being at the top of...

 (Hugh Butt
Hugh Butt
Hugh Roland Butt was an American physician who developed methods to treat hemorrhaging patients with vitamin K.Butt was born in Belhaven, North Carolina. He earned his M.D...

, Albert Snell
Albert Snell
Albert Snell was an English former professional footballer. Following the end of his football career, Albert Snell entered teaching and then later became known as a photographer.- Playing career :...

, and Arnold Osterberg).

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

The precise function of vitamin K was not discovered until 1974, when three laboratories (Stenflo et al., Nelsestuen et al., and Magnusson et al.) isolated the vitamin K-dependent coagulation factor prothrombin (Factor II) from cows that received a high dose of a vitamin K antagonist, warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...

. It was shown that while warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...

-treated cows had a form of prothrombin that contained 10 glutamate amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

residues near the amino terminus of this protein, the normal (untreated) cows contained 10 unusual residues that were chemically identified as gamma-carboxyglutamate, or Gla. The extra carboxyl group in Gla made clear that vitamin K plays a role in a carboxylation reaction during which Glu is converted into Gla.

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

External links

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