Vitamin K
1. Identity: Chemical Names, Structure, and Forms
Vitamin K is the generic name for a family of compounds with a common chemical structure of 2-methyl-1,4-naphthoquinone, and is a fat-soluble vitamin that is naturally present in some foods and is available as a dietary supplement. The letter "K" derives from the German word Koagulation, reflecting its critical role in coagulation processes.
Vitamin K is the collective term for lipid-soluble compounds with vitamin K activity and having the common 2-methyl-1,4-naphtoquinone ring structure. It occurs naturally in two principal forms: phylloquinone, or vitamin K1 (2-methyl-3-phytyl-1,4-naphtoquinone) and menaquinones, or collectively referred to as vitamin K2 (multi-isoprenylquinones, several species).
1.1 Vitamin K1 (Phylloquinone)
Vitamin K1 is also called phylloquinone, phytomenadione, or phytonadione, and is synthesized in plants — particularly green leafy vegetables — because it is involved in photosynthesis. Vitamin K1 contains the functional naphthoquinone ring, an aliphatic side chain, and a phytyl side chain.
1.2 Vitamin K2 (Menaquinones)
The menaquinone series (vitamin K2) have unsaturated isoprenyl side chains and are designated as MK-4 through MK-13, based on the length of their side chain. MK-4, MK-7, and MK-9 are the most well-studied menaquinones. Vitamin K2, which is the main form stored in animals, has a number of subtypes referred to as menaquinones — homologues characterized by the different lengths of their isoprenoid side chains.
1.3 Vitamin K3 (Menadione) — Synthetic Form
A synthetic variant known as menadione (vitamin K3) also exists and has a basic 2-methyl-1,4-naphthoquinone structure — common to both K1 and K2 — but without any side chains. Menadione, which is sometimes called vitamin K3, is another synthetic form of vitamin K. It was shown to damage hepatic cells in laboratory studies conducted during the 1980s and 1990s, so it is no longer used in dietary supplements or fortified foods. Menadione can interfere with the function of glutathione, one of the body's natural antioxidants, resulting in oxidative damage to cell membranes. Menadione given by injection has induced liver toxicity, jaundice, and hemolytic anemia (due to the rupture of red blood cells) in infants; therefore, menadione is no longer used for treatment of vitamin K deficiency.
1.4 Supplement Forms and Bioavailability
Several forms of vitamin K are used in dietary supplements, including vitamin K1 as phylloquinone or phytonadione (a synthetic form of vitamin K1) and vitamin K2 as MK-4 or MK-7. One study found that both phytonadione and MK-7 supplements are well absorbed, but MK-7 has a longer half-life. MK-7, characterized by a longer isoprenoid side chain, displays superior pharmacokinetics, including a markedly extended half-life and higher bioavailability, with 2.5-fold greater availability over 24 hours and up to six-fold higher availability over 96 hours compared to phylloquinone.
2. Natural Sources and Dietary Distribution
Food sources of phylloquinone include vegetables, especially green leafy vegetables, vegetable oils, and some fruits. Meat, dairy foods, and eggs contain low levels of phylloquinone but modest amounts of menaquinones. The phylloquinone content of green vegetables depends on their content in chlorophyll (the green pigment), so that outer leaves have more phylloquinone than inner leaves. The efficiency of phylloquinone intestinal absorption varies among plant sources and is increased with the addition of a fat source to a meal.
The absorption efficiency of phylloquinone from plant sources is relatively low, with estimates of bioavailability ranging between 10 and 15%.
Natto — a traditional Japanese food made from fermented soybeans — has high amounts of menaquinones. Other fermented foods, such as cheese, also contain menaquinones. Among all dietary sources of MK-7, natto — a traditional Japanese fermented soybean product produced by inoculating cooked soybeans with Bacillus subtilis — stands out as the most concentrated natural source. Each 50-gram serving of natto typically provides approximately 380 µg of MK-7, a level shown in clinical studies to elevate serum MK-7 concentrations and promote osteocalcin carboxylation.
Menaquinones, which are predominantly of bacterial origin, are present in modest amounts in various animal-based and fermented foods. Almost all menaquinones, in particular the long-chain menaquinones, are also produced by bacteria in the human gut. MK-4 is found in some animal-based foods, and phylloquinone is converted to MK-4 in certain tissues. Menaquinones 5 to 13 are synthesized by some bacteria and are present in some fermented dairy products, meat, and vegetables.
The distribution of molecular forms of vitamin K in the liver is quite different from that in plasma in that the major transport form, phylloquinone, represents only about 10% of total stores; the remainder comprises bacterial menaquinones, mainly MKs 7–13.
3. History of Discovery
Danish biochemist Carl Peter Henrik Dam was awarded the 1943 Nobel Prize in medicine or physiology for his discovery of vitamin K, the blood coagulating factor. He shared the prize with American biochemist Edward A. Doisy (1893–1986), who, working independently in St. Louis, Missouri, elucidated the chemical nature of the vitamin.
Sometime during the late 1920s, Dam began his study of the formation and metabolism of cholesterol. During these studies, he found that chickens that had been fed a certain synthetic diet showed signs of defective blood clotting. In 1934, after much experimentation with the addition of vitamin C and other known vitamins, he concluded that a hitherto unknown factor was essential for the coagulation of blood. He called this substance "vitamin K" — from the first letter of the Danish and German word for coagulation — thus symbolizing its ability to coagulate blood and to prevent hemorrhage.
The new vitamin received the letter K because the initial discoveries were reported in a German journal, in which it was designated as Koagulationsvitamin.
In 1939, Edward Doisy succeeded in producing two variants of vitamin K in pure form, allowing him to determine its structure and to produce it by artificial means. This became especially important in treating bleeding among small children. Building upon Dam's research, Doisy and his research team discovered that Dam's vitamin K was actually two vitamins. The SLU team was soon able to identify the two substances' chemical structures, and Doisy and his team then developed a way to produce these vitamins synthetically, leading to a patent for the methods for producing vitamin K. Vitamin K was soon being used to prevent hemorrhaging in various situations and was considered a significant medical breakthrough.
Vitamin K was first described as a key factor implicated in blood coagulation nearly a century ago; however, accumulating evidence now indicates pleiotropic actions of vitamin K extending well beyond the coagulation cascade.
4. Traditional and Historical Use
While the biochemical identity of vitamin K was not elucidated until the 1930s, populations in East Asia had a long tradition of consuming foods now known to be exceptionally rich in menaquinones. The fermentation of soybeans has a long history in East Asia, and natto became an important part of Japanese cuisine during the Heian Period (794–1185) and has remained popular ever since. Natto is rich in vitamin K, which is vital for producing blood coagulation factors, and the food has long been considered an important source of protein in the Japanese diet.
Natto has been consumed in Japan for at least a thousand years, traditionally made by wrapping boiled soybeans in rice straw containing naturally occurring Bacillus subtilis and allowing them to ferment in a warm environment. The commercialization of natto production in the early 20th century, during the Taisho Period, led to more consistent and widely available natto, further cementing its place in Japanese food culture.
The formal clinical application of vitamin K began shortly after its isolation. Dam's discovery was of great importance because it advanced the understanding of blood coagulation and produced a new lifesaving therapy for bleeding diseases. Today, newborns and infants are among those who routinely receive vitamin K to guard against a rare but deadly bleeding disorder. This neonatal prophylaxis practice, now standard worldwide, was among the earliest and most consequential medical applications of the vitamin.
5. Key Constituents and Active Compounds
The biologically active forms of vitamin K are phylloquinone (K1) and the menaquinone series (K2). Vitamin K is essential for the activation of vitamin K-dependent proteins, which are involved in blood clotting, bone metabolism, and calcification.
Among the Gla protein family, 17 different members have been recognized: prothrombin, factor VII, factor IX, factor X, protein C, protein S, and protein Z — belonging to the coagulative cascade; matrix Gla protein (MGP), osteocalcin (OC), growth arrest-specific protein 6 (Gas6), and Gla-rich protein (GRP), playing a role in modulating bone and vascular mineralization; and several additional proline-rich and transmembrane Gla proteins.
As far as is currently known, 20 human proteins are found to be γ-carboxylated.
6. Mechanisms of Action
6.1 Gamma-Glutamyl Carboxylation — The Central Mechanism
Vitamin K-dependent (VKD) carboxylation is a post-translational modification that converts specific glutamate residues (Glu) to gamma-carboxyglutamate residues (Gla) in VKD proteins. It is essential for the biological function of proteins that control blood coagulation, vascular calcification, and other physiological processes.
Two enzymes are involved in γ-carboxylation: γ-glutamyl carboxylase (GGCX) and vitamin K oxidoreductase (VKORC1). γ-carboxylase requires reduced vitamin K (KH₂) as an essential cofactor; upon carboxylation, the KH₂ is oxidized to vitamin K epoxide (KO). This KO is then reconverted to KH₂ by VKORC1 — a cycle that perpetuates continued carboxylation activity.
Among the already identified vitamin K-dependent proteins, the coagulation cascade proteins — including factors VII, IX, X, and prothrombin, together with the regulatory proteins C and S — are the most well-acknowledged. Activities of coagulation factors II, VII, IX, and X are shown to be regulated by the γ-carboxylation of glutamate residues, explaining the anti-coagulative function of warfarin.
6.2 Bone Metabolism: Osteocalcin and Matrix Gla Protein
The spectrum of vitamin K-dependent proteins also encompasses several proteins involved in the regulation of bone metabolism and vascular remodeling, such as matrix Gla protein (MGP), osteocalcin, and Gla-rich protein (GRP).
The most relevant vitamin K-dependent proteins in bone metabolism are osteocalcin and matrix Gla-protein (MGP). When carboxylated, these proteins appear to have the ability to chelate and import calcium from the blood to the bone, thereby reducing the risk of osteoporosis. Carboxylated osteocalcin appears to contribute directly to bone quality and strength. An adequate vitamin K status is required for the carboxylation of MGP and osteocalcin.
6.3 The Steroid and Xenobiotic Receptor (SXR) Pathway
In addition, vitamin K acts on bone metabolism by other mechanisms, such as menaquinone-4 acting as a ligand for the nuclear steroid and xenobiotic receptor (SXR). Other modes of vitamin K action include the regulation of transcription by activating the steroid and xenobiotic receptor (SXR), physical association to 17β-Hydroxysteroid dehydrogenase type 4 (17β-HSD4), covalent modification of Bcl-2 antagonist killer 1 (Bak), and the modulation of protein kinase A (PKA) activity.
6.4 Osteoclast Inhibition
Specifically, vitamin K2 has been shown to inhibit the expression of the osteoclast differentiation factor (ODF)/RANK ligand, tartrate-resistant acid phosphatase activity, and mononuclear cell formation, and to induce apoptosis in osteoclastic cells, thereby reducing the lifespan of osteoclasts and their ensuing lytic activity.
6.5 Vascular Calcification Inhibition via MGP
High levels of uncarboxylated, dephosphorylated MGP have been associated with vascular calcification and are responsive to vitamin K treatment. Undercarboxylated osteocalcin (ucOC) and matrix Gla protein (ucMGP) are converted to carboxylated forms (cOC and cMGP respectively) by vitamin K acting as a cofactor, thus facilitating the deposition of calcium in bones and preventing vascular calcification.
7. Body Systems and Health Areas
- Hematological / Coagulation System: Essential cofactor for synthesis of coagulation factors II (prothrombin), VII, IX, and X, and anticoagulant proteins C and S.
- Skeletal System: Activates osteocalcin and MGP; influences osteoblast–osteoclast balance and bone mineral density.
- Cardiovascular System: Activates MGP to inhibit arterial calcification; involved in arterial stiffness and valve calcification.
- Renal System: Vitamin K deficiency is prevalent in chronic kidney disease patients, where vascular calcification is a major mortality factor.
- Metabolic / Endocrine: Undercarboxylated osteocalcin influences glucose homeostasis and insulin sensitivity.
- Neonatal Health: Critical to prevent vitamin K deficiency bleeding (VKDB) in newborns.
Vitamin K is a fat-soluble vitamin essential for the synthesis of vitamin K-dependent proteins that are involved in hemostasis, bone metabolism, and cardiovascular health. Deficiency can cause bleeding complications, with severity ranging from subtle laboratory abnormalities to life-threatening hemorrhages, as well as contribute to poor bone development, osteoporosis, and increased cardiovascular disease.
8. Scientific Evidence by Area of Use
8.1 Coagulation and Hemorrhage Prevention
The role of vitamin K in coagulation is the most firmly established application, underpinned by decades of biochemical, pharmacological, and clinical data. Vitamin K plays a large role in synthesizing coagulation factors in the blood, and vitamin K deficiency has been associated with uncontrolled bleeding.
Neonatal vitamin K deficiency bleeding (VKDB): Preterm as well as term babies are born with extremely low hepatic stores of vitamin K. To prevent this disastrous disease, a single vitamin K shot can almost entirely reduce the risk of vitamin K deficiency bleeding. A 0.5 mg or 1 mg (varying with birth weight) vitamin K shot is given intramuscularly to all babies at birth. The Canadian Paediatric Society has recommended that a 2.0 mg dose of oral vitamin K be given to newborns — first within 6 hours of birth, then at 2–4 weeks, and then at 6–8 weeks of age.
Evidence strength: Very strong. The efficacy of neonatal vitamin K prophylaxis is supported by extensive clinical data and has been incorporated into standard-of-care protocols worldwide.
8.2 Bone Health and Fracture Risk
Recent studies have proposed that adequate intake of vitamin K is associated with a low risk of fracture and high bone mineral density (BMD) to improve skeletal health in adults.
A 2022 systematic review and meta-analysis published in Biomedicines analyzed RCT data: a sum of 3,950 subjects from different RCTs in which patients took either placebo or vitamin K alone or in combination, with follow-up varying from 6 to 36 months, were included. The quantitative analysis showed that the odds ratios of any fracture were lower for vitamin K as compared to control — OR 0.42 (95% CI 0.27 to 0.66) for vertebral fractures and OR 0.44 (95% CI 0.23 to 0.88) for clinical fracture. For BMD, a meta-analysis of pooled interventional studies suggested a non-significant association between the use of vitamin K and improvement in femoral BMD (CI 95%, p = 0.08 [−0.03 to 0.20]). The authors concluded that vitamin K decreases general fracture risk and can be an option to counter bone loss disorders; however, insufficient evidence is available regarding a significant impact on femoral neck BMD.
The few studies that measured plasma phylloquinone generally found that higher circulating levels were associated with lower fracture risk. For example, the incidence of vertebral fractures was inversely correlated with lumbar BMD and plasma phylloquinone in a four-year prospective study that included 379 Japanese women aged 30–88 years. Yet, observational studies are not designed to make causal inferences, and only randomized controlled trials can evaluate whether phylloquinone may have beneficial effects on bone health.
Studies have indicated that vitamin K deficiency has a more pronounced effect on bone than on blood coagulation.
Evidence strength: Moderate for fracture risk reduction (primarily in postmenopausal women and populations at risk). Evidence for improvement in BMD is weaker and not consistent across all skeletal sites.
8.3 Cardiovascular Disease and Vascular Calcification
In an observational study conducted in the Netherlands in 564 postmenopausal women, dietary menaquinone (but not phylloquinone) intake was inversely associated with coronary calcification.
A 2023 systematic review and meta-analysis of RCTs on vitamin K and vascular calcification identified 14 trials comprising 1,533 patients. Analysis revealed that vitamin K supplementation had a significant effect on coronary artery calcification (CAC) scores, slowing down the progression of CAC [I² = 34%, MD = −17.37, 95% CI (−34.18, −0.56), p = 0.04].
However, a separate systematic review identified nine RCTs evaluating surrogate cardiovascular outcomes: the findings indicated that vitamin K does not consistently prevent progression of calcification, atherosclerosis, or arterial stiffness. There may be some benefit in people with calcification at study entry. Studies were heterogeneous, with relatively short follow-up and varied outcome measures. While vitamin K supplementation clearly improves the carboxylation of dephosphorylated MGP, its role in mitigating vascular calcification is uncertain based on current evidence.
A 2023 RCT (Trevasc-HDK) in hemodialysis patients examined the effect of vitamin K2 (MK-7) supplementation: researchers conducted a single-center RCT on maintenance hemodialysis patients to examine if vitamin K2 supplementation could reduce progression of coronary artery calcification over an 18-month study period. Patients were randomized to a vitamin K2 group receiving menaquinone-7 360 µg three times per week or a control group. That study did not demonstrate a beneficial effect of vitamin K2 in reducing progression of vascular calcification in this population at the studied dose and duration.
Evidence strength: Mixed to moderate. Meta-analytic data suggest some slowing of CAC progression, but individual large RCTs have shown null effects, especially in advanced chronic kidney disease populations. The evidence is not sufficient to support a definitive cardiovascular indication.
8.4 Chronic Kidney Disease (CKD)
There is a growing body of evidence suggesting that dialysis patients have a primary, functional deficiency of vitamin K2, as evidenced by reduced levels of circulating biomarkers including carboxylated forms of Matrix Gla Protein (MGP), osteocalcin, and fetuin-A, which are important inhibitors of vascular calcification. Decreased levels of vitamin K2 are known to lead to microvascular calcification and are associated with conditions such as calciphylaxis and peripheral arterial disease.
Vascular calcification, characterized by calcium deposition in the intimal and medial layers of the arterial wall, is frequently encountered in patients with chronic kidney disease and leads to an enhanced risk of adverse cardiovascular outcomes. While animal studies have shown promising effects of vitamin K supplementation in reducing aortic calcium content in uremic models, translation to human RCTs has been inconsistent (see Section 8.3 above).
Evidence strength: Preliminary to moderate for biomarker improvement (reduced ucMGP); clinical outcome benefit (morbidity/mortality) has not yet been definitively demonstrated in large RCTs.
8.5 Glucose Metabolism and Type 2 Diabetes
In type 2 diabetes mellitus, insulin sensitivity may be improved by vitamin K2 through involvement of osteocalcin (a vitamin K-dependent protein), anti-inflammatory properties, and lipid-lowering effects. Vitamin K2 may improve sensitivity to insulin in diabetic patients via metabolism of osteocalcin, which has a role in increasing adiponectin expression.
However, a clinical RCT found limitations: Rahimi Sakak et al. conducted an RCT on 68 patients with type 2 diabetes on oral glucose-lowering therapy. Patients were either administered 360 µg of MK-7 or placebo daily for 12 weeks. No significant difference in the atherogenic status between the MK-7 or placebo group was observed, and it was concluded that 360 µg of MK-7 supplementation for 12 weeks cannot improve insulin resistance-related indexes of cardiovascular risk.
Evidence strength: Weak to preliminary for metabolic outcomes. Mechanistic data are intriguing but few RCTs show significant clinical benefit in glucose regulation.
8.6 Energy Metabolism and Osteocalcin
Recent studies have revealed that the bone-specific, vitamin K-dependent protein osteocalcin has a close relationship with energy metabolism through insulin sensitivity. Research has examined the impact of vitamin K on bone health through influencing energy metabolism, in the light of a recent breakthrough in the understanding of the biological role of osteocalcin, which is the most abundant vitamin K-dependent, bone-specific protein. This is an active area of investigation but human clinical evidence remains limited.
Evidence strength: Preliminary; largely mechanistic and observational, with limited human interventional data.
9. Dosage Forms and Reported Dosages
9.1 Adequate Intake (AI) — Dietary Reference Values
Insufficient data were available to establish an Estimated Average Requirement (EAR) for vitamin K, so the Food and Nutrition Board (FNB) established Adequate Intakes (AIs) for all ages, based on vitamin K intakes in healthy population groups. No Tolerable Upper Intake Level (UL) has been set.
According to the National Academy of Sciences Food and Nutrition Board, the recommended adequate dietary intake for healthy adults is 120 µg/day for men and 90 µg/day for women. For children, the recommended range varies from 2 to 75 µg/day, depending on age.
9.2 Clinical Trial Dosages
- A dose of 0.5 mg or 1 mg (varying with birth weight) vitamin K is given intramuscularly to all babies at birth for VKDB prophylaxis.
- The Canadian Paediatric Society has recommended 2.0 mg oral vitamin K given to newborns within 6 hours of birth, then at 2–4 weeks, and at 6–8 weeks of age.
- In an RCT of type 2 diabetes patients, 360 µg of MK-7 daily was administered for 12 weeks.
- In the Trevasc-HDK hemodialysis RCT, patients received menaquinone-7 at 360 µg three times per week for 18 months.
- A review of literature found there were no adverse effects related to blood coagulation for people taking MK-7 at doses up to 6 µg/kg/day in adults.
9.3 Supplement Preparations
Forms used in dietary supplements include vitamin K1 as phylloquinone or phytonadione (a synthetic form of vitamin K1), and vitamin K2 as MK-4 or MK-7. Oral capsules, tablets, and liquid drops are available commercially. Parenteral forms (intravenous and intramuscular phytonadione) are used clinically for reversal of anticoagulation and neonatal prophylaxis.
10. Safety Considerations and Drug Interactions
10.1 General Safety Profile
No known toxicity is associated with high oral doses of the vitamin K1 or vitamin K2 forms of vitamin K, so regulatory agencies from the US, Japan, and the European Union concur that no tolerable upper intake levels need to be set. Clinically evident vitamin K deficiency states are rare in adults, and no adverse effects associated with vitamin K consumption have been reported in adults other than those related to anticoagulation treatment.
10.2 Intravenous Administration Risk
Vitamin K1 has been associated with severe adverse reactions such as bronchospasm and cardiac arrest when given intravenously. The reaction is described as a nonimmune-mediated anaphylactoid reaction, with an incidence of 3 per 10,000 treatments. The majority of reactions occurred when polyoxyethylated castor oil was used as the solubilizing agent.
10.3 Menadione (Vitamin K3) Toxicity
The US Food and Drug Administration has banned this form from sale as a human dietary supplement because overdoses have been shown to cause allergic reactions, hemolytic anemia, and cytotoxicity in liver cells.
10.4 Warfarin and Vitamin K Antagonists
The anticoagulant warfarin inhibits the enzyme vitamin K epoxide reductase (VKOR), preventing the recycling of vitamin K needed for blood clotting. Vitamin K supplementation or large dietary fluctuations in vitamin K intake can therefore undermine the therapeutic effect of warfarin. Newer blood thinners known as Direct Oral Anticoagulants (DOACs), such as apixaban (Eliquis) or rivaroxaban (Xarelto), do not interact with vitamin K — a primary difference from older anticoagulants like warfarin.
10.5 Bile Acid Sequestrants
Bile acid sequestrants, such as cholestyramine (Questran) and colestipol (Colestid), used to reduce cholesterol levels by preventing reabsorption of bile acids, can also reduce the absorption of vitamin K and other fat-soluble vitamins, although the clinical significance of this effect is not clear. Vitamin K status should be monitored in people taking these medications, especially when the drugs are used for many years.
10.6 Orlistat
The weight-loss drug orlistat reduces the absorption of dietary fat and, consequently, fat-soluble vitamins like vitamin K.
10.7 Antibiotics
Prolonged use of broad-spectrum antibiotics can kill the intestinal bacteria that naturally produce vitamin K2, potentially leading to a deficiency, especially in those with poor dietary intake.
10.8 Anticonvulsants
Certain anticonvulsant drugs such as phenytoin and phenobarbital can interfere with vitamin K metabolism, affecting key proteins in the body.
10.9 High-Dose Vitamin E
Excessively high amounts of vitamin E can antagonize the function of vitamin K, increasing the risk of bleeding.
10.10 Deficiency Risk Groups
Vitamin K deficiency is an often-overlooked condition that affects both adults and newborns and can lead to significant morbidity, primarily due to impaired coagulation. Individuals at elevated risk include newborns (particularly breastfed infants), patients with fat-malabsorption syndromes, those on prolonged antibiotic therapy, and those with chronic kidney disease.
References
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