Vitamin K deficiency

Contents

Vitamin K Deficiency

Vitamin K Deficiency

Vitamin K deficiency is very rare. People who do not regularly eat a lettuce salad or green leafy vegetables are likely to be vitamin K deficient; national data suggests that only about one in four Americans meets the goal for vitamin K intake from food ¹. The current US dietary guidelines for intakes of vitamin K is set at 90 micrograms (mcg)/day for women and 120 mcg/day for men ², ³. Inadequate intake of vitamin K is unlikely to cause symptoms. Vitamin K deficiency results from extremely inadequate intake, fat malabsorption (eg, due to biliary obstruction, malabsorption disorders, cystic fibrosis, or resection of the small intestine) or use of coumarin anticoagulants. Vitamin K deficiency is particularly common among breastfed infants ⁴. Vitamin K deficiency is only considered clinically relevant when prothrombin time (PT) increases significantly due to a decrease in the prothrombin activity of blood ³, ⁵. Therefore, easy bruising and bleeding problems that may be manifested as nosebleed (epistaxis), hematoma (abnormal collection of blood outside of a blood vessel), gastrointestinal bleeding with blood in the stool or tarry black stools (melena), extremely heavy menstrual bleeding (menorrhagia), blood in the urine (hematuria), bleeding gums, and oozing from venipuncture sites are the classic signs of vitamin K deficiency, although these effects occur only in severe cases. Easy bruisability also is observed ⁶. In infants, vitamin K deficiency may result in life-threatening bleeding within the skull (intracranial hemorrhage) ⁷. Because vitamin K is required for the carboxylation of osteocalcin in bone, vitamin K deficiency could also reduce bone mineralization and reduce bone strength and increase the risk of getting osteoporosis because the body needs vitamin K for healthy bones ⁸.

Several studies suggest that low vitamin K levels are related to osteoporosis, pathological fractures and vascular calcifications ⁹. Supplementing menaquinone-7 (MK-7) at the dose of at least 200 mcg per day might help protecting from vascular calcification, osteoporosis and cancer ¹⁰. Moreover, supplementation of 5 mg daily phylloquinone (vitamin K1) in 440 postmenopausal women with osteopenia for 2 years in a randomized, placebo-controlled, double-blind trial caused a > 50% reduction in clinical fractures vs. placebo, although no protection against the age-related decline in bone mineral density was observed ¹¹.

A meta-analysis has shown that in seven Japanese trials reporting fractures, vitamin K2 (menaquinones) administration significantly reduced the risk of hip (77% reduction), vertebral (60% reduction) and all non-vertebral fractures (81% reduction) ¹². Vitamin K administration also significantly delayed the progression of coronary artery calcifications and the deterioration of arterial elasticity ¹³. A lower risk of coronary heart disease and severe aortic calcifications was observed with higher menaquinones intake, but not with phylloquinone intake. This finding suggests that the dietary phylloquinone intake, without menaquinones, may not be sufficient to suppress arterial calcifications ¹⁴.

Vitamin K2 (menaquinones) have been shown to play an important role also in cancer. In a small (40 patients) randomized study the administration of menaquinones 45 mg/day reduced the development of hepatocellular carcinoma in patients with liver cirrhosis: the risk ratio for the development of hepatocellular carcinoma in patients given menaquinones was 0.13 ¹⁵.

Vitamin K2 (menaquinones) have additional properties in certain cell and tissue types, particularly in bone tissue and in the immune system. Much of the available evidence relates specifically to menaquinone-4 (MK-4), which was found to have a role in bone health since the 1990s. Low circulating levels of vitamin K2 (menaquinones) are associated with osteoporotic fractures in the elderly ¹⁶ and vitamin K2 (menaquinones) improved bone mineral density in Japanese women ¹⁷. In an experimental setting, MK-4 reduced bone losses caused by either estrogen withdrawal or corticosteroid treatment in experimental model on rats ¹⁸, ¹⁹. Moreover, other in vitro studies showed that menaquinone-4 (MK-4) inhibits the synthesis of prostaglandin E2 (PGE2), a bone reabsorption-inducing agent, in cultured osteoblasts ²⁰ and inhibits the formation of osteoclast-like cells in bone marrow-derived cultures ²¹. Finally, experimental data suggests a possible role of MK-4 on pancreatic exocrine cells metabolism. Stimulation of pancreatic acinar cells with secretagogues cholecystokinin-8 and secretin induces secretion of MK-4, along with phospholipase and the membrane trafficking protein caveolin-1 ²², although a well-defined function of MK-4 in this setting remains unclear.

In the Vitamin K Italian (VIKI) study ²³, a comprehensive assessment of vitamin K status was carried out in a cohort of hemodialysis patients and in healthy controls, including most vitamin K subtypes (in particular phylloquinone [vitamin K1], MK-4, MK-5, MK-6, and MK-7), adjusted for triglycerides levels. Vitamin K deficiency was found in 35.4% of hemodialysis patients for MK-7, 23.5% for PK and 14.5% for MK-4. With the limitations of its observational nature, this is the first study to relate vitamin K1 (phylloquinone) and vitamin K2 (menaquinones) deficiency directly both to vertebral fractures and vascular calcification in the dialysis population ²³. In particular, vitamin K1 (phylloquinone) deficiency was the strongest predictor of vertebral fractures, while lower MK-4 and MK-7 levels were associated with vascular calcification. The results in hemodialysis patients may point out a possible role of vitamin K deficiency as a cause of bone and vascular disease also in the general population. It can be hypothesized that a diet rich in vitamin K and/or vitamin K supplements might be of help in preventing bone disease and avoiding vascular calcifications, opening interesting perspectives for research in human health.

The frequent use of warfarin enhances the problem of vitamin K deficiency and its role on bone and vascular disease ²⁴. Warfarin may predispose to bone fractures and vascular calcification by different mechanisms: directly, by inhibition of gamma-carboxylation of osteocalcin and other bone matrix proteins; indirectly, because patients treated with warfarin may limit their dietary intake of foods rich in vitamin K. New oral anticoagulant seems to have less influence on bone metabolism, but their long-term effects need more studies ²⁵, ²⁶.

Finally, vitamin K status was found to be inversely and significantly related to individual inflammatory markers and to the inflammatory process in a human population study based on the Framingham Offspring Study cohort ²⁷. This finding is supported by studies on rats demonstrating that animals with vitamin K-deficient diets had an enhanced expression of genes involved in acute inflammatory response compared to those with normal or phylloquinone-supplemented diets and that a supplemented diet suppressed the inflammatory response ²⁸.

Most people in the United States get enough vitamin K from the foods they eat. Also, bacteria in the colon make some vitamin K that the body can absorb. However, certain groups of people may have trouble getting enough vitamin K:

Newborns who don’t receive an injection of vitamin K at birth
People with conditions (such as cystic fibrosis, celiac disease, ulcerative colitis, and short bowel syndrome) that decrease the amount of vitamin K their body absorbs
People who have had bariatric (weight loss) surgery

Certain antibiotics (particularly some cephalosporins and other broad-spectrum antibiotics), salicylates, megadoses of vitamin E, and individuals with significant liver damage or disease increase risk of bleeding in patients with vitamin K deficiency ⁷. Additionally, individuals with fat malabsorption disorders, including inflammatory bowel disease and cystic fibrosis, may be at increased risk of vitamin K deficiency ⁸, ²⁹, ³⁰, ³¹.

Vitamin K deficiency can occur during the first few weeks of infancy due to low placental transfer of phylloquinone, low clotting factor levels, and low vitamin K content of breast milk ⁵. Clinically significant vitamin K deficiency in adults is very rare and is usually limited to people with malabsorption disorders or those taking drugs that interfere with vitamin K metabolism ³², ⁵, ⁹, ³³, ³⁴. In healthy people consuming a varied diet, achieving a vitamin K intake low enough to alter standard clinical measures of blood coagulation is almost impossible ³.

Neonates are prone to vitamin K deficiency because of the following:

The placenta transmits lipids and vitamin K relatively poorly.
The neonatal liver is immature with respect to prothrombin synthesis.
Breast milk is low in vitamin K, containing about 2.5 mcg/L (cow’s milk contains 5000 mcg/L).
The neonatal gut is sterile during the first few days of life.

Treatment consists of vitamin K given orally or, when fat malabsorption is the cause or when risk of bleeding is high, parenterally.

Currently, there is not a consensus on a plasma vitamin K level indicating deficiency or insufficiency. Similarly, it is not clear which vitamer should be considered as reference for determining the vitamin K status ⁹. Data obtained in healthy subjects and osteoporotic patients supplemented with menaquinone-4 (MK-4) showed a large variability of vitamin K levels. In healthy subjects, levels of MK-4, vitamin K1 (phylloquinone) and MK-7 (reported as ng/mL and mean ± SD) were 0.15 ± 0.17, 1.81 ± 1.10 and 16.27 ± 20.58, respectively, while in osteoporotic patients receiving MK-4, these levels were 46.83 ± 46.41, 0.62 ± 0.25 and 4.18 ± 6.28, respectively ³⁵. The influence of supplementation on menaquinone-4 (MK-4) levels was also observed in another study involving postmenopausal Japanese women ³⁶, in contrast with the low MK-4 bioavailability reported in humans by Sato ³⁷. Other authors measured vitamin K1 (phylloquinone) levels, demonstrating that vitamin K deficiency affects 24% of the general population and 29% of hemodialysis patients ³⁸, ³⁹. Vitamin K deficiency impairs blood coagulation process leading to issues with bleeding. Recent research has linked vitamin K deficiency to issues with osteoporosis and cystic fibrosis ⁴⁰, ⁴¹, ⁴².

Protein induced by vitamin K absence (PIVKA-II) also known as des-gamma-carboxy prothrombin (DCP), is currently the best test commonly available to determine vitamin K status ⁴³, ³¹. PIVKA-II or des-gamma-carboxy prothrombin (DCP) is an abnormal form of prothrombin, a clotting factor produced by the liver. In the absence of vitamin K, there is a production of PIVKA-II and is a sensitive marker for vitamin K deficiency status ³¹. PIVKA-II levels reflect the functional marker of coagulation. PIVKA-II has minimal variability based on other factors such as age that influence vitamin K plasma and serum concentration ⁴⁴. Increased PIVKA-II levels start to become apparent in individuals consuming less than 60 mcg of vitamin K per day ⁴⁵. At birth, elevated PIVKA-II levels exist in 10-50% of newborns and 70% of non-supplemented healthy infants on day of life 4 or 5 ⁴⁶.

The monitoring of vitamin K administration or levels is usually through prothrombin time (PT) and INR (international normalized ratio). These values measure the presence of vitamin K-dependent factors, which is especially important to utilize in patients who have warfarin toxicity or vitamin K-related bleeding disorders (coagulopathies).

What is Vitamin K?

Vitamin K is a fat-soluble vitamin that is naturally present in some foods and is available as a dietary supplement that is important for blood clotting and healthy bones and other diverse physiological functions ⁴⁷. Vitamin K has thus been clinically applied for the treatment and prevention of bleeding and osteoporosis ⁴⁸. Vitamin K is present in the diet in the forms of phylloquinone (vitamin K1) and menaquinones (vitamin K2) ⁴⁹. Vitamin K1 (phylloquinone), which is the major dietary source, is concentrated in leafy vegetables (e.g., green vegetables) because it is directly involved in photosynthesis and is the vitamin K form best characterized in terms of food composition and dietary intakes. Vitamin K1 (phylloquinone) is active in animals and is responsible for the production of coagulation factors. Vitamin K1 (phylloquinone) is also can be converted into vitamin K2 (menaquinones) in animals ⁴⁹. Vitamin K2 or menaquinones are the product of bacterial production or intestinal bacteria conversion from dietary vitamin K1 (phylloquinone) and are also found in fermented foods (e.g., cheeses and the Japanese soybean product natto [fermented soybeans]) (Figure 1) ⁵⁰, ⁵¹. Vitamin K2 (menaquinones) have unsaturated isoprenyl side chains and are designated as MK-4 through MK-13, based on the length of their side chain ⁴⁹, ⁵². MK-4, MK-7, and MK-9 are the most well-studied menaquinones. Food composition databases are limited for vitamin K2 (menaquinones) and their presence in foods varies by region. Dietary intakes of all forms of vitamin K vary widely among age groups and population subgroups. Similarly, the utilization of vitamin K from different forms and food sources appear to vary, although our understanding of vitamin K is still rudimentary in light of new developments regarding the vitamin K2 (menaquinones) ⁵³.

Phylloquinone, also referred to as vitamin K1, is a compound present in all photosynthetic plants (e.g., green vegetables) and is the major dietary form of vitamin K in most diets ⁵⁴. Vitamin K1 (phylloquinone) is the primary dietary source of vitamin K. Green leafy vegetables and some plant oils (soybean, canola, olive, and cottonseed) are major contributors of dietary vitamin K ⁵⁵. Mixed dishes have also been found to significantly contribute to vitamin K intake in the US ⁵⁶. However, vitamin K1 (phylloquinone) bioavailability from green vegetables is lower than from oil or supplements ⁵⁵. Also, the phylloquinone content of green vegetables depends on their content in chlorophyll (green pigment), so that outer leaves have more phylloquinone than inner leaves ⁵⁵. The efficiency of phylloquinone intestinal absorption varies among plant sources and is increased with the addition of a fat source to a meal. Finally, the hydrogenation of vegetable oils may decrease the absorption and biological effect of dietary phylloquinone ⁴², ⁵⁷. A number of phylloquinone-rich foods are listed in Table 5, with their content in phylloquinone expressed in micrograms (μg). In general, green, leafy vegetables contain the highest known phylloquinone concentrations and contribute approximately 60% of total phylloquinone intake ⁵¹, ⁵⁸. As indicated, spinach and collards, which have concomitant high concentrations of chlorophyll associated with the photosynthetic process, hence, dark leaf color have substantially higher concentrations of phylloquinone compared to the more commonly consumed iceberg lettuce, which is substantially paler, hence, lower chlorophyll concentrations. The other plant sources of phylloquinone are certain plant oils including soybean, canola (also known as rapeseed), cottonseed, and olive. Margarine, spreads, and salad dressings derived from these plant oils are important dietary sources of phylloquinone ⁵⁹, ⁶⁰. Plant oils are used for preparation of multiple mixed dishes, hence many commercially prepared foods including baked goods also contain small amounts of phylloquinone.

Menaquinones also known as vitamin K2, are the other category of vitamin K present in the food supply are primarily of bacterial origin and they are present in modest amounts in various animal-based and fermented foods (e.g., cheeses, curds, and the Japanese soybean product natto [fermented soybeans]) ⁴², ⁶¹. Almost all vitamin K2 (menaquinones), in particular the long-chain menaquinones (MK-n), are also produced by bacteria in the human gut ⁴⁷, ⁶². Gut flora converts vitamin K1 (phylloquinone) into vitamin K2 (menaquinone). A range of vitamin K2 forms can be created. This transformation takes place via the gut bacteria lengthening the isoprenoid side chain. Bacteria are the primary producers of vitamin K2 (menaquinones), which they use during anaerobic respiration. They differ in structure from vitamin K1 (phylloquinone) due to the 3-substituted lipophilic side chain. The most important forms of vitamin K2 (menaquinones) contain 4 to 10 repeating isoprenoid units. These are indicated by MK-4 to MK-10. The most notable forms include MK-7 to MK-11. The MK-7 and other bacterially derived forms of vitamin K2 exhibit vitamin K activity in animals. Pharmacological doses of menaquinone-4 (MK-4; brand name, menatetrenone) are currently used in Japan in the treatment of osteoporosis ⁶³. Accordingly, most intervention trials investigating the effect of high-dose MK-4 on bone loss have been conducted in Japanese postmenopausal women. In a three-year placebo-controlled trial among postmenopausal women with osteopenia, adding a MK-7 supplement (375 mcg/day) to combined calcium-vitamin D supplementation did not affect bone mineral density (BMD) or other bone health parameters despite reductions in serum undercarboxylated osteocalcin (ucOC) ⁶⁴. At present, the potential role for supplemental menaquinones on bone health still needs to be established in large, randomized, and well-controlled trials.

The dominant dietary form of vitamin K in the United States and Europe is vitamin K1 (phylloquinone) (90% of daily intake), whereas the major form in Japan is vitamin K2 (menaquinones) (10%), especially menaquinone-7 (MK-7) ⁹. Vitamin K1 (phylloquinone) has a phythyl side chain, whereas vitamin K2 (menaquinones) comprises homologs that vary in the number (n) of isoprenyl groups of the side chain (from n = 1 to n = 14) ⁶⁵. Among the vitamin K homologs, menaquinone-4 (MK-4) (n = 4) shows the greatest variety of physiological activities ⁶⁶. Although vitamin K1 (phylloquinone) and menaquinone-4 (MK-4) have the same number of carbon atoms in the side chain, they differ in the degree of unsaturation. In Japan, vitamin K1 (phylloquinone) is applied as an antihemorrhagic agent and menaquinone-4 (MK-4) as a therapeutic agent for osteoporosis ⁴⁸.

The review of five randomized clinical trials that assessed the effect of phylloquinone (vitamin K1) supplementation on hip bone mineral density (BMD) using doses ranging from 200 mcg/day to 5,000 mcg/day for durations of 12 to 36 months found little promising benefit for bone health ⁶⁷. Although supplementation with phylloquinone decreased uncarboxylated osteocalcin (ucOC) levels in all five studies, only one study reported an effect of supplemental phylloquinone on bone mineral density (BMD) ⁶³. In this study, 150 postmenopausal women were randomized to receive a placebo, minerals (500 mg/day of calcium, 150 mg/day of magnesium, and 10 mg/day of zinc) plus vitamin D (320 IU/day), or minerals, vitamin D, and phylloquinone (1,000 mcg/day) ⁶³. The rate of BMD loss at the femoral neck, but not at the lumbar spine, was significantly lower in subjects with supplemental phylloquinone compared to the other two groups ⁶³. Therefore, evidence of a putative benefit of phylloquinone on bone health in older adults is considered weak. None of the studies were designed to assess the effect of phylloquinone on osteoporotic-related fractures. Further investigation may seek to evaluate whether phylloquinone supplementation could improve skeletal health in subjects at high-risk for vitamin K inadequacy (e.g., individuals with malabsorption syndromes or cystic fibrosis).

Menadione, which is sometimes called “vitamin K3,” is another synthetic form of vitamin K. The synthetic vitamin K3 or menadione is very toxic, and as a result, has been banned from over-the-counter sales in the United States because ingestion could result in allergic reactions, hemolytic anemia, and cytotoxicity in liver cells ⁴². Vitamin K3 or menadione was shown to damage liver cells in laboratory studies conducted during the 1980s and 1990s, so it is no longer used in dietary supplements or fortified foods ³, ⁶⁸. Vitamin K3 (menadione) can interfere with the function of glutathione, one of the body’s natural antioxidants, resulting in oxidative damage to cell membranes. Menadione (vitamin K3) given by injection has induced liver toxicity, jaundice, hyperbilirubinemia, and hemolytic anemia (due to the rupture of red blood cells) in infants and kernicterus in infants; therefore, menadione (vitamin K3) is no longer used for treatment of vitamin K deficiency ⁴², ⁶⁹, ⁷⁰, ⁶¹.

In the United States, vitamin K3 (menadione) is used in poultry feed and some swine feeds as a source of vitamin K ⁴⁹. As such, menaquinone-4 (MK-4) formed from vitamin K3 (menadione) is present in poultry and pork products in the U.S. food supply and is the primary dietary source of MK-4 ⁶¹. Menaquinone-4 (MK-4) is present at high concentrations in human, poultry and pork tissues ⁷¹. Although humans generally obtain vitamin K1 (phylloquinone) and menaquinone-7 (MK-7) from the diet, intake of menaquinone-4 (MK-4) in animal foods is extremely low. Vitamin K3 (menadione), a synthetic vitamin K analog (Figure 1), is the primary source of vitamin K in poultry feed and some swine feeds, along with small amounts of phylloquinone (vitamin K1) ⁴⁹. As such, MK-4 formed from vitamin K3 (menadione) is present in poultry and pork products in the U.S. food supply and is the primary dietary source of MK-4 ⁶¹. Although menaquinone-4 (MK-4) is also formed from tissue-specific conversion of phylloquinone (vitamin K1) ⁷², the impact on dietary intake from this conversion is likely negligible as animal organs containing high MK-4 concentrations including kidney, brain, and pancreas, are not commonly consumed in most regions of the world. Menaquinone-4 (MK-4) is also found in modest amounts in milk, butter, and cheeses, which may make a small contribution to total vitamin K intake. The high consumption of poultry, pork, and dairy products in the United States ⁷³, however, suggests that MK-4 may make a relevant contribution to total vitamin K intake. In regions where food systems do not use vitamin K3 (menadione) in animal feed or consumption of dairy products is low, MK-4 is most likely not an important dietary source of vitamin K. For example, MK-4 has been estimated to account for ∼3% of total vitamin K intake in the Netherlands ⁷⁴ and is found in animal products in relatively lower amounts compared with the United States and Japan ⁷¹.

Menaquinone-4 (MK-4) is unique among the vitamin K2 (menaquinones) in that it is produced by the body from vitamin K1 (phylloquinone) via a conversion process that does not involve bacterial action. Instead, menaquinone-4 (MK-4) is formed by a realkylation step from vitamin K3 (menadione) present in animal feeds or is the product of tissue-specific conversion directly from dietary vitamin K1 (phylloquinone) ⁵, ⁷⁵, ⁷⁶. In the United States, vitamin K3 (menadione) is the synthetic form of vitamin K used in poultry feed. As such, MK-4 formed from vitamin K3 (menadione) is present in poultry products in the US food supply ⁷⁷. However, MK-4 formed from vitamin K1 (phylloquinone) is limited to organs not commonly consumed in the diet including kidney. The exceptions are dairy products with menaquinone-4 (MK-4) found in milk, butter, and cheese, albeit in modest amounts. Therefore it is unlikely that menaquinone-4 (MK-4) is an important dietary source of vitamin K in food supplies that do not use vitamin K3 (menadione) for poultry feed nor are rich in dairy products.

There is growing interest in the health benefits of longer-chain menaquinones (vitamin K2), which are limited to certain foods in the food supply. Menaquinone-7 (MK-7) is primarily the product of fermentation using bacillus subtilis natto and is present in a traditional Japanese soybean-based product called natto ⁴². Natto contains approximately 2.5 times more MK-7 compared to the vitamin K1 (phylloquinone) content of spinach. Natto also contains MK-8 and phylloquinone (84 and 35 µg/100g, respectively), although both are modest in concentration compared to MK-7 ⁷⁸. Some cheeses also contain MK-8 and MK-9 ⁷⁸, but these are dependent on cheese production practices, hence the food composition databases are limited in their ability to characterize vitamin K2 (menaquinone) intake across different food supplies.

Data on the bioavailability of different forms of vitamin K from food are very limited ⁴⁹. The absorption rate of vitamin K1 (phylloquinone) in its free form is approximately 80%, but its absorption rate from foods is significantly lower ⁵². Vitamin K1 (phylloquinone) in plant foods is tightly bound to chloroplasts, so it is less bioavailable than that from oils or dietary supplements ⁴⁹. For example, the body absorbs only 4% to 17% as much phylloquinone from spinach as from a tablet ⁵². Consuming vegetables at the same time as some fat improves vitamin K1 (phylloquinone) absorption from the vegetables, but the amount absorbed is still lower than that from oils. Limited research suggests that long-chain menaquinones (vtamin K2) may have higher absorption rates than phylloquinone from green vegetables ⁵.

Like dietary fats and other fat-soluble vitamins, ingested vitamin K is incorporated into mixed micelles via the action of bile and pancreatic enzymes, and it is absorbed by enterocytes of the small intestine ⁷⁹. From there, vitamin K is incorporated into chylomicrons, secreted into the lymphatic capillaries, transported to the liver, and repackaged into very low-density lipoproteins ⁵². Vitamin K is present in the liver and other body tissues, including the brain, heart, pancreas, and bone ⁷⁹.

In the circulation, vitamin K is carried mainly in lipoproteins ⁵². Compared to the other fat-soluble vitamins, very small amounts of vitamin K circulate in the blood. Vitamin K is rapidly metabolized and excreted. Based on phylloquinone measurements, the body retains only about 30% to 40% of an oral physiological dose, while about 20% is excreted in the urine and 40% to 50% in the feces via bile ⁸⁰. This rapid metabolism accounts for vitamin K’s relatively low blood levels and tissue stores compared to those of the other fat-soluble vitamins ⁸⁰.

Little is known about the absorption and transport of vitamin K produced by gut bacteria, but research indicates that substantial quantities of long-chain menaquinones (vitamin K2) are present in the large bowel ⁵. Although the amount of vitamin K that the body obtains in this manner is unclear, experts believe that these vitamin K2 (menaquinones) satisfy at least some of the body’s requirement for vitamin K ⁵.

Total circulating levels of the bone protein, osteocalcin (OC), have been shown to be sensitive markers of bone formation ⁵⁵. Several hormones and growth factors, including vitamin D but not vitamin K, regulate osteocalcin synthesis by osteoblasts ⁵⁵. However, vitamin K is an essential cofactor for the gamma-carboxylation of three glutamic acid residues in osteocalcin ⁵⁵. Undercarboxylation of osteocalcin (uncarboxylated osteocalcin [ucOC]) in human bone and serum has been linked to poor vitamin K status ⁵⁵. The degree of osteocalcin gamma-carboxylation is responsive to vitamin K nutritional interventions, and thus is used as a relative indicator of vitamin K status ⁸¹.

Circulating levels of uncarboxylated osteocalcin (ucOC) were found to be higher in postmenopausal women than premenopausal women and markedly higher in women over the age of 70. Also, high ratios of uncarboxylated osteocalcin (ucOC) to total osteocalcin (OC) (ucOC/OC) appear to be predictive of hip fracture risk in elderly women ⁸², ⁸³. Although vitamin K deficiency would seem the most likely cause of elevated blood uncarboxylated osteocalcin (ucOC) to total osteocalcin (OC) (ucOC/OC) ratio, some investigators have documented an inverse relationship between biochemical measures of vitamin D nutritional status and uncarboxylated osteocalcin (ucOC) levels, as well as a significant lowering of ucOC/OC ratio by vitamin D supplementation ⁸⁴. It has been suggested that increased circulating ucOC/OC ratio could reflect a poor overall nutritional status that would include vitamin D deficiency, which would explain the above-mentioned observations ⁸⁵. However, in several randomized, placebo-controlled intervention studies conducted in young girls ⁸⁵, ⁸⁶ or menaquinone-7 (vitamin K (2)): the Postmenopausal Health Study II. Calcif Tissue Int. 2012 Apr;90(4):251-62. doi: 10.1007/s00223-012-9571-z)) and postmenopausal women ⁸⁷, vitamin D supplementation failed to decrease ucOC/OC ratios or show any additive effect on ucOC/OC lowering by supplemental vitamin K.

Figure 1. Vitamin K chemical structure

Footnote: Forms of vitamin K. (A) Menadione (vitamin K3) represents the basic structure common to vitamin K1 and vitamin K2; (B) phylloquinone (vitamin K1), which is the primary dietary source; (C) menaquinone-4 (MK-4), which is a conversion product from menadione (vitamin K3) or phylloquinone (vitamin K1); and (D) menaquinones (vitamin K2), which can vary in length from MK-4 to MK-13.

[Source ⁴⁹ ]

Figure 2. Vitamin K1 chemical structure

Figure 3. Vitamin K2 chemical structure

Are all forms of vitamin K the same?

There are surprisingly little data on the relative biological availability of different forms of vitamin K among different food sources. Furthermore, there is a growing body of literature to suggest that our understanding of vitamin K is still rudimentary in light of new developments regarding different forms ⁴⁹.

As previously stated, vitamin K1 (phylloquinone) is of plant origin, with absolute intakes being predominantly from green leafy vegetables. Vitamin K1 (phylloquinone) is tightly bound to the membranes of plant chloroplasts, and is less bioavailable compared to phylloquinone obtained from plant oils and/or dietary supplements ⁸⁸. Some estimates place the absorption of vitamin K1 (phylloquinone) to be 10% from plants compared to supplements ⁸⁹. However there appear to be differences in absorption compared to the plant species, with vitamin K1 (phylloquinone) obtained from broccoli and collards having greater absorption compared to spinach ⁹⁰. Similarly, and not unexpected because vitamin K is a fat-soluble vitamin, addition of a fat source to the meal results in higher absorption ⁸⁰.

The commercial hydrogenation of phylloquinone-rich oils results in a transformation of phylloquinone into a hydrogenated form, 2′,3′-dihydrophylloquinone ⁹¹. Vitamin K1 (phylloquinone) differs from 2′,3′-dihydrophylloquinone by a saturation of a single bond at the 2′,3′ position of the side chain ⁹¹. Surprisingly this single substitution results in a lower absorption of dihydophylloquinone compared to an equimolar amount of phylloquinone ⁹². There is also indirect evidence of lower activity of dihydrophylloquinone as an enzyme cofactor, which currently is the only known function of vitamin K. The implications of this poor bioavailability and activity are currently unknown, although at least one study suggests a detrimental effect on bone mineral density among older adults in a community-based cohort ⁹³. The potential impact of poor utilization of dihydrophylloquinone on bone health will be of little importance in the future should hydrogenated oils be removed from the food supply. It is anticipated that the decrease in hydrogenation of plant oils will also reduce the presence of dihydrophylloquinone in the US food supply ⁴⁹.

Vitamin K2 (menaquinones) are poorly understood in terms of vitamin K absorption and utilization. MK-7, when administered in the form of natto in equimolar amounts to vitamin K1 (phylloquinone) administered in the form of spinach, has a peak height difference of more than 10-fold compared to phylloquinone, with a half-life of 56 hours, compared to 7.5 hours for vitamin K1 (phylloquinone) ⁹⁴. Whereas all forms of vitamin K appear to be initially associated with triglyceride-rich lipoproteins, the longer chain menaquinones including MK-7 and MK-9 are also associated with low-density lipoprotein (LDL). MK-4 has been reported in triglyceride-rich lipoprotein, low-density lipoprotein (LDL) and high density lipoproteins (HDL). These preliminary data suggest that vitamin K2 (menaquinones) have different transport pathways and distribution, which has implications for transport to extra-hepatic tissue such as bone ⁸⁰.

Emerging studies on MK-4 challenge our current understanding of vitamin K. As demonstrated using stable isotopes, MK-4 is a conversion product of vitamin K1 (phylloquinone) via the intermediate, vitamin K3 (menadione) ⁷². There appears to be both local and systemic conversion to MK-4, with the local conversion being the predominant pathway. The implications of this conversion are still the topic of speculation. To add complexity to the interpretation is the observation that this conversion does not occur in all tissues. Whereas the liver contains primarily vitamin K1 (phylloquinone) and very long-chain menaquinones, MK-4 is the predominant form in the brain, pancreas, and glands ⁹⁵. In terms of dietary intakes, MK-4 intakes are low compared to other forms of vitamin K. However, dietary vitamin K1 (phylloquinone) converts to MK-4 in those tissues where MK-4 appears to be required so it is likely that low MK-4 intakes are of little consequence to health when there is adequate dietary vitamin K1 (phylloquinone) available for conversion to MK-4.

In conclusion, much of our understanding of vitamin K nutrition has focused on the primary dietary source, vitamin K1 (phylloquinone). There are comprehensive databases available that contain vitamin K1 (phylloquinone) contents of a variety of foods. Dietary assessment of phylloquinone reveals variation in intakes by age and population subgroups. In contrast, vitamin K2 (menaquinones) are present in the food supply, but there are limited food composition data available. As a corollary, estimates of intakes of vitamin K2 (menaquinones) are very limited and our understanding of their role in vitamin K nutrition is not well understood.

What does Vitamin K do?

Main vitamin K actions in humans include ⁹:

Regulation of blood coagulation activity
Bone protection; prevention of osteoporosis and bone fracture
Prevention of vascular calcifications
Prevention of cancer
Prevention of inflammation

Vitamin K functions as a coenzyme for vitamin K-dependent carboxylase, an enzyme required for the synthesis of proteins involved in hemostasis (blood clotting) and bone metabolism, and other diverse physiological functions ³, ⁴⁷. Vitamin K helps make four of the 13 proteins needed for blood clotting. Vitamin K is required in the synthesis of 4 clotting factors in the liver: factors II,VII, IX, and X. Vitamin K is also essential in the production of anticoagulation proteins C, S, and Z ⁹⁶.

Prothrombin (clotting factor II) is a vitamin K-dependent protein in plasma that is directly involved in blood clotting. Its role in maintaining the clotting cascade is so important that people who take anticoagulants such as warfarin (Coumadin) must be careful to keep their vitamin K intake stable. Warfarin (Coumadin®) and some anticoagulants used primarily in Europe antagonize the activity of vitamin K and, in turn, prothrombin ⁹⁷. For this reason, individuals who are taking these anticoagulants need to maintain consistent vitamin K intakes. Coumarin anticoagulants interfere with the synthesis of vitamin–K dependent coagulation proteins (factors II, VII, IX, and X) in the liver.

Carboxylation is catalyzed by the enzyme gamma-glutamyl carboxylase (GGCX), which utilizes a reduced form of vitamin K hydroquinone, carbon dioxide and oxygen as cofactors (Figure 2). Concomitant with each glutamate modification, vitamin K hydroquinone is oxidized to vitamin K 2,3-epoxide (vitamin K epoxide) ⁹⁸. Vitamin K epoxide is converted back to vitamin K hydroquinone through a two-step reduction (first to vitamin K, then to vitamin K hydroquinone) using the enzymes vitamin K epoxide reductase (VKOR) and vitamin K reductase (VKR) in a pathway known as the vitamin K cycle (Figure 4). Importantly, warfarin interferes with regeneration of vitamin K 2,3-epoxide (vitamin K epoxide) to vitamin K hydroquinone, thus impairing gamma-carboxylation and the activity of vitamin K dependent proteins, including the extra-hepatic proteins Osteocalcin (bone Gla-protein) and matrix Gla-protein (MGP), respectively involved in bone mineralization and inhibition of vascular calcifications. Matrix Gla-protein (MGP), a vitamin K-dependent protein present in vascular smooth muscle, bone, and cartilage, is the focus of considerable scientific research because it might help reduce abnormal calcification ⁴⁷, ⁹⁹, ¹⁰⁰. Osteocalcin (OC) is another vitamin K-dependent protein that is present in bone and may be involved in bone mineralization or turnover ⁴⁷.

If vitamin K is deficient, vitamin K dependent proteins cannot increase their carboxylation status and they become significantly undercarboxylated, losing their capacity to bind calcium, so that bone metabolism may be impaired and the process of vascular calcification enhanced ¹⁰¹.

With the discovery of new gamma-carboxyglutamate (Gla) proteins, vitamin K-dependent carboxylation has been implicated in a number of biological functions beyond coagulation. Osteocalcin is a Gla protein produced by osteoblasts and is important for bone formation ¹⁰². Recent studies suggest that osteocalcin also functions as a hormone affecting glucose metabolism in mice ¹⁰³; whether this is the case in humans still needs to be clarified ¹⁰⁴. The second Gla protein found in bone is matrix Gla protein (MGP), which functions as a strong inhibitor of vascular calcification and connective tissue mineralization ¹⁰⁵. Matrix Gla-protein (MGP), a vitamin K-dependent protein present in vascular smooth muscle, bone, and cartilage, is the focus of considerable scientific research because it might help reduce abnormal calcification ¹⁰⁶. Defects of matrix Gla protein (MGP) carboxylation have been associated with cardiovascular diseases and pseudoxanthoma elasticum syndrome ¹⁰⁷. In addition, MGP has been described as a critical regulator of endothelial cell function, regulating both physiological and tumor-related angiogenesis ¹⁰⁸. Other vitamin K-dependent proteins that are not involved in coagulation include Gas6 (growth arrest-specific protein 6), PRGPs (proline-rich Gla proteins) and TMGs (transmembrane Gla proteins). The metabolic significance of most of these non-coagulation Gla proteins is still poorly understood ¹⁰⁹. A better understanding of the structure-function relationship of the enzymes in the vitamin K cycle will help you to better understand and control a variety of biological processes.

Lately, researchers have demonstrated that vitamin K is also involved in building bone. Low levels of circulating vitamin K have been linked with low bone density, and supplementation with vitamin K shows improvements in biochemical measures of bone health ¹¹⁰. There is a consistent line of evidence in human epidemiologic and intervention studies that clearly demonstrates that vitamin K can improve bone health. The human intervention studies have demonstrated that vitamin K can not only increase bone mineral density in osteoporotic people but also actually reduce fracture rates. Further, there is evidence in human intervention studies that vitamins K and D, a classic in bone metabolism, works synergistically on bone density ¹¹⁰. Several mechanisms are suggested by which vitamin K can modulate bone metabolism. Besides the gamma-carboxylation of osteocalcin, a protein believed to be involved in bone mineralization, there is increasing evidence that vitamin K also positively affects calcium balance, a key mineral in bone metabolism. The Institute of Medicine recently has increased the dietary reference intakes of vitamin K to 90 microg/d for females and 120 microg/d for males, which is an increase of approximately 50% from previous recommendations ¹¹⁰. A report from the Nurses’ Health Study suggests that women who get at least 110 micrograms of vitamin K a day are 30 percent less likely to break a hip than women who get less than that ⁵². Among the nurses, eating a serving of lettuce or other green, leafy vegetable a day cut the risk of hip fracture in half when compared with eating one serving a week. Data from the Framingham Heart Study also shows an association between high vitamin K intake and reduced risk of hip fracture in men and women and increased bone mineral density in women ³², ¹¹¹.

Table 1. Consequences of inhibition of vitamin K-dependent proteins

Coagulation	Prothrombin (factor II) VII, IX, X factors Protein C, S, Z	Bleeding
Blood vessels	MGP Osteocalcin GAS-6	Vascular calcifications
Bone	Osteocalcin MGP Periostin	Inadequate bone mineralization Bone fractures
Cellular proliferation	GAS-6	Action on cellular proliferation, cellular adhesion, inhibition of apoptosis
Inflammation	Not defined	Increase of inflammation

Abbreviations: MGP = matrix Gla protein; BGP = bone Gla protein; GAS = growth arrest specific gene

[Source ⁹ ]

Vitamin K cycle

Vitamin K obtained from the diet is considered to reach the target tissues via lipid absorption and the transport system ¹¹². Once transferred to the cells of the target tissue, vitamin K is metabolized by redox (reduction–oxidation) cycling in the intracellular endoplasmic reticulum body, in a process known as the “vitamin K cycle”, “vitamin K oxidation-reduction cycle” or “vitamin K-epoxide cycle” (Figure 4) ¹¹³. This series of oxidation-reduction reactions begins with conversion of vitamin K from a stable oxidized form (quinone form [KO]) to a vitamin K hydroquinone (reduced form [KH2]) by vitamin K-epoxide reductase (VKOR) ¹¹⁴, ¹¹⁵. Gamma-glutamyl carboxylase (GGCX) carboxylates the glutamic acid residues of vitamin K-dependent proteins (VKDP) to gamma-carboxyglutamate (Gla) using reduced vitamin K (vitamin K hydroquinone), while simultaneously oxidizing the reduced form of vitamin K to a vitamin K epoxide (oxidized form). These reactions that gamma-glutamyl carboxylase (GGCX) catalyzes proceed on the GGCX protein molecule using CO2 and O2; however, the detailed molecular mechanisms are not clear. The epoxide form of vitamin K (oxidized form) is reduced by epoxide reductase (vitamin K epoxide reductase complex 1; VKORC1 or vitamin K epoxide reductase complex 1-like 1; VKORC1L1) to a reduced form and then to the reduced hydroquinone form ¹¹⁶. This reuse system allows for a very small amount of vitamin K in cells to act efficiently as a cofactor of gamma-glutamyl carboxylase (GGCX) in the post-translational carboxylation of vitamin K-dependent proteins (VKDPs). Warfarin, an oral anticoagulant drug, inhibits vitamin K epoxide reductase (VKOR), stops the vitamin K cycle, and prevents the gamma-glutamyl-carboxylated (Gla) conversion of the blood coagulation factors, thus inhibiting coagulation (Figure 4). Activity of both gamma-glutamyl carboxylase (GGCX) and vitamin K epoxide reductase (VKOR) are regulated by calumenin ¹¹⁷. Recent evidence has revealed that GGCX is the only enzyme involved in Gla formation, based on structure and function analyses of GGCX at the gene level and animal studies showing that GGCX gene deficiency causes embryonic lethality from systemic bleeding.

Some oral anticoagulants, such as warfarin (Jantoven, formerly known as Coumadin), inhibit coagulation by inhibiting the action of vitamin K. Warfarin prevents the recycling of vitamin K by blocking vitamin K-epoxide reductase (VKOR) activity, hence preventing vitamin K recycling and therefore creating a functional vitamin K deficiency (Figure 4) ⁵⁵. Inadequate gamma-carboxylation of vitamin K-dependent coagulation proteins interferes with the coagulation cascade, which inhibits blood clot formation. Large quantities of dietary or supplemental vitamin K can overcome the anticoagulant effect of vitamin K antagonists; thus, patients taking oral anticoagulants are cautioned against consuming very large or highly variable quantities of vitamin K (see Drug interactions). Experts now advise a reasonably constant dietary intake of vitamin K that meets current dietary recommendations (90-120 mcμg/day) for patients taking vitamin K antagonists like warfarin ⁵⁷, ¹¹⁸.

Vitamin K acts as a cofactor for gamma-glutamyl carboxylase (GGCX) via the vitamin K cycle and exerts physiological effects through its regulation of vitamin K-dependent proteins (VKDPs) ¹¹⁹. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 (growth arrest-specific protein 6) promotes neural differentiation for signaling and cognitive functions in the brain ¹²⁰, ¹¹⁹. Gamma-glutamyl carboxylase (GGCX) is an enzyme that converts glutamic acid (Glu) residues to gamma-carboxyglutamate (Gla) residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation.

Few studies, however, have addressed derivatives targeting GGCX. Vermeer et al. ¹²¹ found increased gamma-glutamyl carboxylase (GGCX) activity with modifying the side-chain structure of vitamin K to a saturated alkyl side chain with an amide bond. Further modification of the side-chain structure is anticipated from synthesis of vitamin K derivatives that yield stronger GGCX activity. Development of such new derivatives may lead to drug discovery that can enhance the physiological effects associated with GGCX and other factors ¹²².

Figure 4. Vitamin K oxidation-reduction cycle

Footnotes: During vitamin K-dependent carboxylation, glutamate (Glu) is converted to gamma-carboxyglutamte (Gla) by gamma-glutamyl carboxylase (GGCX) using a reduced form of vitamin K hydroquinone, carbon dioxide, and oxygen as cofactors. Vitamin K hydroquinone is oxidized to vitamin K epoxide. Vitamin K epoxide is reduced to vitamin K by vitamin K epoxide reductase (VKOR). The reduction of vitamin K to vitamin K hydroquinone is carried out by vitamin K epoxide reductase (VKOR) and an as-yet-unidentified vitamin K reductase (VKR).

[Source ⁴⁸ ]

Vitamin K derivatives targeting steroid and xenobiotic receptor (SXR)

Both vitamin K1 (phylloquinone) and vitamin K2 (menaquinones) may activate the steroid and xenobiotic receptor (SXR) ⁹. Steroid and xenobiotic receptor (SXR) is a nuclear receptor involved in the transcriptional regulation of enzymes such as cytochrome P450 (in particular the CYP3A4 isoform) ¹²³.

Tabb et al. ¹²⁴ revealed that menaquinone-4 (MK-4) regulates gene expression as a ligand of the nuclear receptor SXR. Steroid and xenobiotic receptor (SXR) is mainly expressed in the liver and intestine and regulates expression of genes encoding enzymes involved in steroid metabolism and detoxification of xenobiotics and of various drugs ¹²⁴. When bound to a ligand, SXR forms a heterodimer with retinoid X receptor, and the resulting complex then binds to an SXR responsive element on the target gene promoter via the DNA-binding domain to exert transcription regulation ¹²⁵. In addition to bile acids (e.g., lithocholic acid), drugs such as rifampicin, SR12813, and hyperforin are ligands involved in this process. Among the vitamin K homologs, menaquinone-4 (MK-4) can activate transcription of the SXR target gene CYP3A4, as a ligand of SXR ¹²⁵. MK-4 plays an important role in osteoblast formation by inducing expression of genes such as matrilin-2 and tsukushi, which are involved in collagen accumulation via SXR ¹²⁶. An in vitro study further showed that overexpression of SXR and its activation by MK-4 inhibits proliferation and migration of liver cancer cells ¹²⁷. More recently, the data showed that vitamin K2 (menaquinone) has a differentiation-promoting effect on myeloid progenitors and an anti-apoptotic effect on erythroid progenitors ¹²⁸.

Thus, menaquinone-4 (MK-4) works via SXR to regulate the expression of various genes at the transcriptional level, resulting in broad physiological effects such as bone formation and liver cancer suppression as well as drug metabolism ⁴⁸. However, to date, MK-4 is the only vitamin K homolog known to exert its activities via SXR, and further research is needed to clarify whether other vitamin K homologs act as SXR ligands. X-ray crystal structure analysis of complexes of human pregnane X receptor (PXR) and ligands (such as rifampicin) have demonstrated that the ligand-binding region of SXR is large, with substantial flexibility ¹²⁹, suggesting that other vitamin K congeners likely could act as SXR ligands.

Because menaquinone-4 (MK-4) is present in the brain at a relatively high concentration, it is thought to have important roles in the brain ¹³⁰. Vitamin K protects neural cells from oxidative stress; however, a crucial role for vitamin K in the brain has not been elucidated ⁴⁸. Neural stem cells engage in continuous self-replication while maintaining the ability to differentiate into neurons and glial cells in the early embryonic and late fetal stages. Neural stem cells can differentiate into neuronal precursor cells and glial precursor cells, and each progenitor cell differentiates into neurons, astrocytes, and oligodendrocytes. The neural stem cells that do not differentiate into neurons differentiate into glial cells before and after birth, at which point differentiation into neurons is complete ¹³¹.

Neuronal progenitor cells differentiate into neurons, while glial progenitor cells differentiate into astrocytes and oligodendrocytes ¹³². Scientists recently reported that vitamin K2 (menaquinone) show weak activity in driving the differentiation of progenitor cells to neuronal cells ¹³³, which depended on the number of isoprene units of the side chain in the vitamin K homolog. If this differentiation activity can be increased by modification of the chemical structure, it would be possible to regulate it with a specific neuronal differentiation inducer based on a low-molecular-weight compound. Such a compound could provide an alternate strategy to conventional gene induction methods used in induced pluripotent stem cells and other types of stem and progenitor cells. Researchers are focusing on the role of vitamin K in the regeneration of neurons, and synthesized vitamin K analogs that could differentiate progenitor cells into neuronal cells.

Vitamin K Health Benefits

Scientists are studying vitamin K to understand how it affects our health. Here are some examples of what this research has shown. However, the US Food and Drug Administration (FDA) has not authorized any health claims for any forms of vitamin K.

Osteoporosis

Osteoporosis, a disorder characterized by porous and fragile bones, is a serious public health problem that affects more than 10 million U.S. adults, 80% of whom are women. Consuming adequate amounts of calcium and vitamin D, especially throughout childhood, adolescence, and early adulthood, is important to maximize bone mass and reduce the risk of osteoporosis ¹³⁴. The effect of vitamin K intakes and status on bone health and osteoporosis has been a focus of scientific research ¹³⁵, ¹³⁶, ¹³⁷.

Vitamin K is a cofactor for the gamma-carboxylation of many proteins, including osteocalcin, one of the main proteins in bone ¹³⁸. Some research indicates that high serum levels of undercarboxylated osteocalcin are associated with lower bone mineral density ⁴⁷, ¹³⁸. Some, but not all, studies also link higher vitamin K intakes with higher bone mineral density and/or lower hip fracture incidence ¹³⁹, ¹⁴⁰, ¹⁴¹, ¹⁴², ¹⁴³, ¹⁴⁴.

Although vitamin K is involved in the carboxylation of osteocalcin, it is unclear whether supplementation with any form of vitamin K reduces the risk of osteoporosis. In 2006, Cockayne and colleagues conducted a systematic review and meta-analysis of randomized controlled trials that examined the effects of vitamin K supplementation on bone mineral density and bone fracture ¹⁴⁵. Most of the trials were conducted in Japan and involved postmenopausal women; trial duration ranged from 6 to 36 months. Thirteen trials were included in the systematic review, and 12 showed that supplementation with either phytonadione or MK-4 improved bone mineral density. Seven of the 13 trials also had fracture data that were combined in a meta-analysis. All of these trials used MK-4 at either 15 mg/day (1 trial) or 45 mg/day (6 trials). MK-4 supplementation significantly reduced rates of hip fractures, vertebral fractures, and all nonvertebral fractures.

A subsequent clinical trial found that MK-7 supplementation (180 mcg/day for 3 years) improved bone strength and decreased the loss in vertebral height in the lower thoracic region of the vertebrae in postmenopausal women ¹⁴⁶. Other randomized clinical trials since the 2006 review by Cockayne et al. have found that vitamin K supplementation has no effect on bone mineral density in elderly men or women ¹⁴⁷, ¹⁴⁸. In one of these studies, 381 postmenopausal women received either 1 mg phylloquinone, 45 mg MK-4, or placebo daily for 12 months ¹⁴⁸. All participants also received daily supplements containing 630 mg calcium and 400 IU vitamin D3. At the end of the study, participants receiving either phylloquinone or MK-4 had significantly lower levels of undercarboxylated osteocalcin compared to those receiving placebo. However, there were no significant differences in bone mineral density of the lumbar spine or proximal femur among any of the treatment groups. The authors noted the importance of considering the effect of vitamin D on bone health when comparing the results of vitamin K supplementation studies, especially if both vitamin K and vitamin D (and/or calcium) are administered to the treatment group but not the placebo group. The administration of vitamin D and/or calcium along with vitamin K could partly explain why some studies have found that vitamin K supplementation improves bone health while others have not.

In Japan and other parts of Asia, a pharmacological dose of MK-4 (45 mg) is used as a treatment for osteoporosis ⁴⁷. The European Food Safety Authority has approved a health claim for vitamin K, noting that “a cause and effect relationship has been established between the dietary intake of vitamin K and the maintenance of normal bone” ¹⁴⁹. The FDA has not authorized a health claim for vitamin K in the United States.

Vitamin K antagonists and bone health

Certain oral anticoagulants, such as warfarin, are known to be antagonists of vitamin K. Few studies have examined chronic use of warfarin and risk of fracture in older women. One study reported no association between long-term warfarin treatment and fracture risk ¹⁵⁰, while another one found a significantly higher risk of rib and vertebral fractures in warfarin users compared to nonusers ¹⁵¹. Additionally, a study in elderly patients with atrial fibrillation reported that long-term warfarin treatment was associated with a significantly higher risk of osteoporotic fracture in men but not in women ¹⁵². A meta-analysis of the results of 11 published studies found that oral anticoagulation therapy was associated with a very modest reduction in bone mineral density (BMD) at the wrist and no change in bone mineral density (BMD) at the hip or spine ¹⁵³. The development of new anticoagulants that do not block vitamin K recycling may offer a safer alternative to the use of vitamin K antagonists ¹⁵⁴.

Osteoarthritis

Osteoarthritis, a degenerative joint condition that affects more than 32 million US adults ¹⁵⁵, is characterized by the breakdown of articular cartilage (i.e., cartilage within the joint). Because several vitamin K-dependent proteins are present in cartilage and in bone ¹⁵⁶, vitamin K deficiency may have a role in the development of osteoarthritis. A few observational studies have investigated a possible link between vitamin K intake or status and osteoarthritis. A cross-sectional study among 719 Japanese older adults found dietary intake of vitamin K to be inversely associated with knee osteoarthritis ¹⁵⁷. In the Framingham Offspring Study (n=672; mean age, 66 years), higher plasma concentrations of phylloquinone were associated with a lower risk of hand, but not knee, osteoarthritis ¹⁵⁸. A longitudinal study of 1,180 US adults (mean age, 62 years) found that low plasma concentrations of phylloquinone (≤0.5 nM) at baseline — indicative of a subclinical vitamin K deficiency — were associated with a 56% increase in risk of knee osteoarthritis after 30 months compared to those with higher plasma concentrations ¹⁵⁹. In a more recent longitudinal study among 523 older US adults participating in the Health, Aging, and Body Composition Study, those with extremely low plasma concentrations of phylloquinone (<0.2 nM) at baseline had increased progression of knee osteoarthritis over three years, assessed by MRI of articular cartilage and the meniscus; those with higher plasma concentrations experienced no significant progression of knee osteoarthritis ¹⁶⁰. Moreover, recent studies have associated use of the vitamin K antagonist drugs (e.g., warfarin and acenocoumarol) with higher risks of osteoarthritis and joint replacement of the knee and hip compared to nonusers ¹⁶¹.

While these observational data are interesting, randomized controlled trials are needed to determine whether vitamin K supplementation in those with low vitamin K status might help prevent or treat osteoarthritis. In an ancillary study of a double-blind, controlled trial examining the effects of vitamin K supplementation on bone loss and vascular calcification in older adults, no effects of phylloquinone supplementation (500 mcg/day) were found on incidence of hand osteoarthritis after three years ¹⁶². Study participants were not screened for vitamin K status, and in a subgroup analysis, those with serum phylloquinone ≤1 nM at baseline that reached >1 nM at year 3 had less joint deterioration. These data infer that only those individuals with low vitamin K status benefit from vitamin K supplementation. Unfortunately, no measures were available for knee osteoarthritis, and it is well established that hand and knee osteoarthritis represent different phenotypes. Additional clinical trials that specifically examine the effect of vitamin K supplementation on osteoarthritis development are needed, especially in those with inadequate vitamin K status.

Coronary heart disease

Scientists are studying whether low blood levels of vitamin K increase the risk of heart disease, perhaps by making blood vessels that feed the heart stiffer and narrower. More research is needed to understand whether vitamin K supplements might help prevent heart disease.

Vascular calcification is one of the risk factors for coronary heart disease because it reduces aortic and arterial elasticity ¹⁶³. Matrix Gla-protein is a vitamin K-dependent protein that may play a role in the prevention of vascular calcification ⁴⁷, ¹⁶⁴. Although the full biological function of matrix Gla-protein is unclear, a hypothesis based on animal data suggests that inadequate vitamin K status leads to undercarboxylated matrix Gla-protein, which could increase vascular calcification and the risk of coronary heart disease. These findings might be particularly relevant for patients with chronic kidney disease because their rates of vascular calcification are much higher than those of the general population ¹⁰⁶.

In an observational study conducted in the Netherlands in 564 postmenopausal women, dietary menaquinone (but not phylloquinone) intake was inversely associated with coronary calcification ¹⁶⁵. Menaquinone intake was also inversely associated with severe aortic calcification in a prospective, population-based cohort study involving 4,807 men and women aged 55 years and older from the Netherlands ¹⁶⁴. Participants in this study who had dietary menaquinone intakes in the mid tertile (21.6–32.7 mcg/day) and upper tertile (>32.7 mcg/day) also had a 27% and 57% lower risk of coronary heart disease mortality, respectively, than those in the lower tertile of intake (<21.6 mcg/day). Phylloquinone intake had no effect on any outcome.

Despite these data, few trials have investigated the effects of vitamin K supplementation on arterial calcification or coronary heart disease risk. One randomized, double-blind clinical trial examined the effect of phylloquinone supplementation in 388 healthy men and postmenopausal women aged 60–80 years ¹⁶⁶. Participants received either a multivitamin (containing B-vitamins, vitamin C, and vitamin E) plus 500 IU vitamin D3, 600 mg calcium, and 500 mcg phylloquinone daily (treatment) or a multivitamin plus calcium and vitamin D3 only (control) for 3 years. There was no significant difference in coronary artery calcification between the treatment and control groups. However, among the 295 participants who adhered to the supplementation protocol, those in the treatment group had significantly less coronary artery calcification progression than those in the control group. Furthermore, among those with coronary artery calcification at baseline, phylloquinone treatment reduced calcification progression by 6% compared to the control group. Based on these findings, the authors did not make any clinical recommendations, and they called for larger studies in other populations ¹⁶⁶.

At this time, the role of the different forms of vitamin K on arterial calcification and the risk of coronary heart disease is unclear, but it continues to be an active area of research in the general population and in patients with chronic kidney disease ⁴⁷, ¹⁰⁶, ¹⁶⁷.

How much vitamin K do you need?

The amount of vitamin K you need depends on your age and sex. Average daily recommended amounts are listed below in micrograms (mcg).

Table 2. Adequate Intakes for Vitamin K

Life Stage	Recommended Amount
Birth to 6 months	2.0 mcg
7–12 months	2.5 mcg
1–3 years	30 mcg
4–8 years	55 mcg
9–13 years	60 mcg
14–18 years	75 mcg
Adult men 19 years and older	120 mcg
Adult women 19 years and older	90 mcg
Pregnant or breastfeeding teens	75 mcg
Pregnant or breastfeeding women	90 mcg

[Source ¹⁶⁸ ]

What foods provide vitamin K?

Food sources of vitamin K1 (phylloquinone) include vegetables, especially green leafy vegetables, vegetable oils, and some fruits. Meat, dairy foods, and eggs contain low levels of vitamin K1 (phylloquinone) but modest amounts of vitamin K2 (menaquinones) ⁶¹. Natto (a traditional Japanese food made from fermented soybeans) has high amounts of vitamin K2 (menaquinones) ⁴⁹, ¹⁶⁹. Other fermented foods, such as cheese, also contain vitamin K2 (menaquinones). However, the forms and amounts of vitamin K in these foods likely vary depending on the bacterial strains used to make the foods and their fermentation conditions ⁷¹. Animals synthesize MK-4 from menadione (vitamin K3) (a synthetic form of vitamin K that can be used in poultry and swine feed) ¹⁷⁰. Thus, poultry and pork products contain MK-4 if menadione (vitamin K3) is added to the animal feed ⁷¹.

The most common sources of vitamin K in the U.S. diet are spinach; broccoli; iceberg lettuce; and fats and oils, particularly soybean and canola oil ⁴⁷, ⁵. Few foods are fortified with vitamin K ⁴⁷; breakfast cereals are not typically fortified with vitamin K, although some meal replacement shakes and bars are.

Vitamin K is found naturally in many foods. You can get recommended amounts of vitamin K by eating a variety of foods, including the following:

Green leafy vegetables, such as spinach, kale, broccoli, and lettuce
Vegetable oils
Some fruits, such as blueberries and figs
Meat, cheese, eggs, and soybeans

Although multiple databases now exist that contain some phylloquinone contents of foods ⁷⁸, ¹⁷¹, the most extensive analysis of phylloquinone in common foods using established food sampling protocols ¹⁷² are found in the United States Department of Agriculture (USDA) Nutrient Database for Standard Reference ¹⁷³.

The U.S. Department of Agriculture’s (USDA’s) FoodData Central website (https://fdc.nal.usda.gov) lists the nutrient content of many foods vitamin K (phylloquinone) arranged by nutrient content (https://ods.od.nih.gov/pubs/usdandb/VitK-Phylloquinone-Content.pdf) and by food name (https://ods.od.nih.gov/pubs/usdandb/VitK-Phylloquinone-Food.pdf), and of foods containing vitamin K (menaquinone) arranged by nutrient content (https://ods.od.nih.gov/pubs/usdandb/VitK-Menaquinone-Content.pdf) and food name (https://ods.od.nih.gov/pubs/usdandb/VitK-Menaquinone-Food.pdf).

Data on the bioavailability of different forms of vitamin K from food are very limited ¹⁷⁴. The absorption rate of phylloquinone in its free form is approximately 80%, but its absorption rate from foods is significantly lower. Phylloquinone in plant foods is tightly bound to chloroplasts, so it is less bioavailable than that from oils or dietary supplements ¹⁷⁴. For example, the body absorbs only 4% to 17% as much phylloquinone from spinach as from a tablet ⁵². Consuming vegetables at the same time as some fat improves phylloquinone absorption from the vegetables, but the amount absorbed is still lower than that from oils. Limited research suggests that long-chain MKs may have higher absorption rates than phylloquinone from green vegetables ⁵.

Several food sources of vitamin K are listed in Table 5. All values in this table are for phylloquinone content, except when otherwise indicated, because food composition data for menaquinones are limited ¹⁷⁴.

Table 3. Selected Food Sources of Vitamin K (Phylloquinone)

Food	Micrograms (mcg) per serving	Percent DV*
Natto, 3 ounces (as MK-7)	850	1062
Collards, frozen, boiled, ½ cup	530	662
Turnip greens, frozen, boiled ½ cup	426	532
Spinach, raw, 1 cup	145	181
Kale, raw, 1 cup	113	141
Broccoli, chopped, boiled, ½ cup	110	138
Soybeans, roasted, ½ cup	43	54
Carrot juice, ¾ cup	28	34
Soybean oil, 1 tablespoon	25	31
Edamame, frozen, prepared, ½ cup	21	26
Pumpkin, canned, ½ cup	20	25
Pomegranate juice, ¾ cup	19	24
Okra, raw, ½ cup	16	20
Salad dressing, Caesar, 1 tablespoon	15	19
Pine nuts, dried, 1 ounce	15	19
Blueberries, raw, ½ cup	14	18
Iceberg lettuce, raw, 1 cup	14	18
Chicken, breast, rotisserie, 3 ounces (as MK-4)	13	17
Grapes, ½ cup	11	14
Vegetable juice cocktail, ¾ cup	10	13
Canola oil, 1 tablespoon	10	13
Cashews, dry roasted, 1 ounce	10	13
Carrots, raw, 1 medium	8	10
Olive oil, 1 tablespoon	8	10
Ground beef, broiled, 3 ounces (as MK-4)	6	8
Figs, dried, ¼ cup	6	8
Chicken liver, braised, 3 ounces (as MK-4)	6	8
Ham, roasted or pan-broiled, 3 ounces (as MK-4)	4	5
Cheddar cheese, 1½ ounces (as MK-4)	4	5
Mixed nuts, dry roasted, 1 ounce	4	5
Egg, hard boiled, 1 large (as MK-4)	4	5
Mozzarella cheese, 1½ ounces (as MK-4)	2	3
Milk, 2%, 1 cup (as MK-4)	1	1
Salmon, sockeye, cooked, 3 ounces (as MK-4)	0.3	0
Shrimp, cooked, 3 ounces (as MK-4)	0.3	0

Footnote: *DV = Daily Value. The U.S. Food and Drug Administration (FDA) developed DVs to help consumers compare the nutrient contents of foods and dietary supplements within the context of a total diet. The DV for vitamin K is 120 mcg for adults and children age 4 years and older ¹⁷⁵. FDA does not require food labels to list vitamin K content unless vitamin K has been added to the food. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.

[Sources ⁶¹, ¹⁶⁹, ¹⁷⁶ ]

Table 4. Vitamin K content of common foods

Food	Major form of vitamin K	Concentration (mcg/100g)
Vegetables
Collards	Phylloquinone	440
Spinach	Phylloquinone	380
Broccoli	Phylloquinone	180
Cabbage	Phylloquinone	145
Iceberg lettuce	Phylloquinone	35
Fats and oils
Soybean oil	Phylloquinone	193
Canola oil	Phylloquinone	127
Cottonseed oil	Phylloquinone	60
Olive oil	Phylloquinone	55
Mixed dishes ^a
Fast food french fries	Dihydrophylloquinone	59
Fast food nachos	Dihydrophylloquinone	60
Frozen, breaded fish sticks	Dihydrophylloquinone	16
Margarine with hydrogenated oil	Dihydrophylloquinone	102
Other foods
Natto	Menaquinone-7 (MK-7)	998
Hard cheeses	Menaquinone-9 (MK-9)	51.1
Soft cheeses	Menaquinone-9 (MK-9)	39.5

Footnote:

^a These data reflect the content when hydrogenated phylloquinone-rich oils are used. When non-hydrogenated oils are used, the predominant form would be phylloquinone.

[Source ⁴⁹ ]

Vitamin K Supplements

Vitamin K is present in most multivitamin or multimineral supplements, typically at values less than 75% of the Daily Value (DV) ¹⁷⁷. It is also available in dietary supplements containing only vitamin K or vitamin K combined with a few other nutrients, frequently calcium, magnesium, and/or vitamin D. These supplements tend to have a wider range of vitamin K doses than multivitamin/mineral supplements, with some providing 4,050 mcg (5,063% of the DV) or another very high amount.

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-7 ¹⁷⁷. Few data are available on the relative bioavailability of the various forms of vitamin K supplements. One study found that both phytonadione and MK-7 supplements are well absorbed, but MK-7 has a longer half-life ¹⁷⁸.

Menadione, which is sometimes called “vitamin K3,” is another synthetic form of vitamin K. It was shown to damage liver cells in laboratory studies conducted during the 1980s and 1990s, so it is no longer used in dietary supplements or fortified foods ³, ⁶⁸. Vitamin K3 (menadione) can interfere with the function of glutathione, one of the body’s natural antioxidants, resulting in oxidative damage to cell membranes. Menadione (vitamin K3) given by injection has induced liver toxicity, jaundice, hyperbilirubinemia, and hemolytic anemia (due to the rupture of red blood cells) in infants and kernicterus in infants; therefore, menadione (vitamin K3) is no longer used for treatment of vitamin K deficiency ⁴², ⁶⁹, ⁷⁰, ⁶¹.

Vitamin K Deficiency causes

In infants, the low transmission of vitamin K across the placenta, liver prematurity with prothrombin synthesis, lack of vitamin K in breast milk, and the sterile gut in neonates account for vitamin K deficiency ¹⁷⁹. Neonatal diseases that cause cholestasis can result in vitamin K deficiency ⁹⁶. Parents refusal of vitamin K prophylaxis at childbirth can result in bleeding complications ⁹⁶.

Hereditary combined vitamin K-dependent clotting factor deficiency (VKCFD) is a rare autosomal recessive congenital bleeding disorder that is characterized by decreased levels of the vitamin K-dependent pro- and anticoagulant factors; and vitamin K-dependent proteins involved in calcium homeostasis, bone and cartilage formation ¹⁸⁰, ¹⁸¹, ¹⁸², ¹⁸³, ¹⁸⁴. The two genes associated with the hereditary combined vitamin K-dependent clotting factor deficiency (VKCFD) are GGCX (gamma-glutamyl carboxylase) and VKORC1 (vitamin K epoxide reductase complex subunit 1) ¹⁸⁵, ¹⁸⁶. Hereditary combined vitamin K-dependent clotting factor deficiency (VKCFD) can manifest as a spectrum of presentations, with severity ranging from mild to severe ¹⁸³. The first case of VKCFD was described in 1966, in a female newborn who exhibited significant bleeding from the first week of life ¹⁸⁷. The child was born from an uncomplicated pregnancy and had symptoms manifesting as bruising beginning at week 1 of life, with recurrent serosanguinous oozing from the umbilical stump throughout the first months of life ¹⁸⁷. The diagnosis of hereditary combined vitamin K-dependent clotting factor deficiency (VKCFD) is extremely rare. Currently, fewer than 30 VKCFD cases worldwide have been reported and affects males and females equally ¹⁸³, ¹⁸⁸, ¹⁸⁹, ¹⁹⁰. Most patients with VKCFD show partial or complete improvement in factor activity, as well as normalization of prothrombin time (PT) and activated partial thromboplastin time (aPTT) with oral or parenteral vitamin K ¹⁹¹, ¹⁹², ¹⁹³. These patients have an excellent prognosis. In some cases, though, vitamin K is ineffective and there is biochemical evidence that the molecules are not fully carboxylated by vitamin K treatment ¹⁹⁴, ¹⁹⁵. The response to vitamin K varies based on the route of administration and the individual’s sensitivity to vitamin K ¹⁹⁶. A fixed therapeutic regimen has not been identified, and no clear correlation exists between clinical severity and responsiveness to vitamin K ¹⁸³. Continued daily treatment with high-dose oral vitamin K has been successful in preventing some bleeding complications and is recommended for patients with VKCFD ¹⁹⁴, ¹⁹². One case report also suggested possible value in administering fresh frozen plasma for VKCFD in pregnancy while another suggested the use of prothrombin complex concentrates, which contain factors II, VII, IX, and X, and proteins C and S ¹⁹², ¹⁹⁷.

In adults, the causes of vitamin K deficiency include the following ¹⁹⁸:

Chronic illness
Malnutrition
Alcoholism
Multiple abdominal surgeries
Long-term parenteral nutrition
Malabsorption syndromes
Infectious diarrhea
Cholestatic disease
Parenchymal liver disease
Cystic fibrosis (CF)
Inflammatory bowel disease
Drugs – Antibiotics (cephalosporin), cholestyramines, warfarin, salicylates, anticonvulsants, and certain sulfa drugs) are some of the common causes of vitamin K deficiency
Massive transfusion
Disseminated intravascular coagulation (DIC) – Severe
Chronic kidney disease/hemodialysis ¹⁹⁹

The synthesis of vitamin K-dependent factors are decreased by parenchymal liver diseases, such as cirrhosis secondary to viral hepatitis, alcohol intake, and other infiltrative diseases; hepatic malignancy; amyloidosis; Gaucher disease; and alpha-1 antitrypsin deficiency. Therefore, supplementation with vitamin K is not effective unless a patient has severe bleeding and fresh frozen plasma is administered in addition to correcting the coagulopathy.

Malabsorption syndrome affects vitamin K absorption in the ileum. Celiac sprue, tropical sprue, Crohn disease, ulcerative colitis, Ascaris infection, bacterial overgrowth, chronic pancreatitis, and short bowel syndrome resulting from multiple abdominal surgeries can result in poor absorption of vitamin K (which can be corrected with vitamin K supplementation) ²⁰⁰.

Cystic fibrosis patients who have pancreatic insufficiency, excessive or chronic antibiotic usage, or short bowel due to intestinal resection are at increased risk for vitamin K deficiency due to malabsorption ²⁰¹.

Biliary diseases, such as common duct obstruction due to stones and strictures, primary biliary cirrhosis, cholangiocarcinoma, and chronic cholestasis, cause maldigestion of fat. The decrease in fat absorption leads to a deficiency of fat-soluble vitamins, such as vitamin K ¹⁷⁹. In addition, surgery and T-tube drainage of the bile duct can lead to a vitamin K-deficient state.

Dietary deficiency occurs in people with malnutrition, alcoholics, and patients undergoing long-term parenteral nutrition without vitamin K supplements. A large amount of vitamin E can antagonize vitamin K and prolong the prothrombin time (PT).

Various drugs, such as cholestyramine, bind to bile acids, thus preventing fat-soluble vitamin absorption. Warfarin blocks the effect of vitamin K epoxide reductase and vitamin K reductase, thereby inducing an intracellular deficiency. Cefamandole, cefoperazone, salicylates, hydantoins, rifampin, isoniazid, and barbiturates are some of the common drugs that are associated with vitamin K deficiency, but their mechanism of action in this condition is unknown.

Because 2 main sources of vitamin K exist, neither dietary deficiency nor gut sterilization produces significant bleeding disorder in a healthy person.

Groups at risk of vitamin K deficiency

Vitamin K deficiency can occur in any age group, but it is encountered most often in infancy. In the United States, the prevalence of vitamin K deficiency varies by geographic region ²⁰². In infants, vitamin K deficiency without bleeding may occur in as many as 50% of infants younger than 5 days. The classic hemorrhagic disease occurs in 0.25-1.7% of infants. The prevalence of late hemorrhagic disease in breastfed infants is about 20 cases per 100,000 live births with no prior vitamin K prophylaxis.

Comparing incidences of vitamin K deficiency between different countries is difficult because countries have different criteria to acquire their national incidences. Among countries that share the same methodologies, western European countries have an incidence of late vitamin K deficiency bleeding in infants of approximately 5 cases per 105 live births; the incidence is 11 cases per 105 live births in Japan; and the incidence is 72 cases per 105 live births in Thailand ²⁰³.

Vitamin K deficiency is uncommon in healthy adults for a number of reasons: (1) vitamin K is widespread in foods (see Food sources); (2) the vitamin K cycle conserves vitamin K (see Vitamin K oxidation-reduction cycle); and (3) bacteria that normally inhabit the large intestine synthesize menaquinones (vitamin K2), although it is unclear whether significant amounts are absorbed and utilized (see Food sources). Adults at risk for vitamin K deficiency include those taking vitamin K antagonists and individuals with significant liver damage or disease ⁷. Additionally, individuals with fat malabsorption disorders, including inflammatory bowel disease and cystic fibrosis, may be at increased risk of vitamin K deficiency ⁸, ²⁹, ³⁰, ³¹.

The following groups are among those most likely to have inadequate vitamin K status.

Newborns not treated with vitamin K at birth

Worldwide, vitamin K deficiency causes infant morbidity and mortality. Vitamin K deficiency causes hemorrhagic disease of the newborn or vitamin K deficiency bleeding (VKDB) of the newborn, which usually occurs 1 to 7 days postpartum ²⁰⁴. In affected neonates, birth trauma can cause bleeding inside the skull (intracranial hemorrhage). A late form of this disease can occur in infants about 2 to 12 weeks old, typically in infants who are breastfed and are not given vitamin K supplements. Newborn babies who are exclusively breast-fed are at increased risk for vitamin K deficiency because human breast milk is relatively low in vitamin K compared to milk formula. Newborn infants, in general, have low vitamin K status for the following reasons: (1) vitamin K transport across the placental barrier is limited; (2) liver storage of vitamin K is very low; (3) the vitamin K cycle may not be fully functional in newborns, especially premature infants; (4) the vitamin K content of breast milk is low, and immature gut flora ²⁰⁵, ²⁰⁶. If the mother has taken phenytoin anticonvulsant medication to prevent seizures, coumarin anticoagulants, or cephalosporin antibiotics, the risk of hemorrhagic disease is increased due to vitamin K deficiency ²⁰⁴. Because hemorrhagic disease of the newborn or vitamin K deficiency bleeding of the newborn is life threatening and easily prevented, the American Academy of Pediatrics and a number of similar international organizations recommend that an intramuscular dose of 0.5 to 1 milligram (mg) of phylloquinone (vitamin K1) be administered to all newborns shortly after birth ²⁰⁷, ²⁰⁸.

Vitamin K transport across the placenta is poor, increasing the risk of vitamin K deficiency in newborn babies. During the first few weeks of life, vitamin K deficiency can cause vitamin K deficiency bleeding, a condition formerly known as “classic hemorrhagic disease of the newborn.” Vitamin K deficiency bleeding is associated with bleeding in the umbilicus, gastrointestinal tract, skin, nose, or other sites ⁵, ²⁰⁸, ²⁰⁹. Vitamin K deficiency bleeding (VKDB) of the newborn also known as “early vitamin K deficiency bleeding” when it occurs in the first week of life. “Late vitamin K deficiency bleeding” occurs at ages 2–12 weeks, especially in exclusively breastfed infants due to the low vitamin K content of breast milk or in infants with malabsorption problems (such as cholestatic jaundice or cystic fibrosis) ⁵. Vitamin K deficiency bleeding, especially late vitamin K deficiency bleeding, can also be manifested as sudden intracranial bleeding, which has a high mortality rate ⁵, ²⁰⁹.

People with malabsorption disorders

People with malabsorption syndromes and other gastrointestinal disorders, such as cystic fibrosis, celiac disease, ulcerative colitis, and short bowel syndrome, might not absorb vitamin K properly ⁴⁷, ²¹⁰. Vitamin K status can also be low in patients who have undergone weight loss surgery (bariatric surgery), although clinical signs may not be present ²¹¹. These individuals might need monitoring of vitamin K status and, in some cases, vitamin K supplementation.

Vitamin K deficiency signs and symptoms

The clinical manifestations of vitamin K deficiency are evident only if hypoprothrombinemia is present. Bleeding is the major symptom, especially in response to minor or trivial trauma. Any site can be involved, so manifestations can include mucosal and subcutaneous bleeding, such as nosebleed (epistaxis), hematoma (abnormal collection of blood outside of a blood vessel), gastrointestinal bleeding with blood in the stool or tarry black stools (melena), extremely heavy menstrual bleeding (menorrhagia), blood in the urine (hematuria), bleeding gums, and oozing from venipuncture sites. Easy bruisability also is observed ⁶. In infants, vitamin K deficiency may result in life-threatening bleeding within the skull (intracranial hemorrhage) ⁷. Vitamin K deficiency bleeding (VKDB) in newborns can separate into three categories based on the timing of the presentation. Early vitamin K deficiency bleeding (VKDB) in newborns presents within 24 hours after birth, classic VKDB presents within the first week, and late VKDB presents between one to twelve weeks of life ⁴⁶.

In vitamin K deficiency bleeding (VKDB), the neonate will present with bleeding. The first reported classic vitamin K deficiency bleeding (VKDB) in newborns was in 1894 as a bleeding disorder that occurred on day 2 or 3 of life ²¹². In combination with sepsis-induced bleeding, the incidence was 600/100,000 infants with a 62% fatality rate ²¹². Late vitamin K deficiency bleeding (VKDB) in newborns occurs in 4.4 to 72 infants per 100,000 births with an increased risk in exclusively breastfed infants and the highest incidence occurring in Asian populations ²¹². Early VKDB has been associated with mothers on anticonvulsants or other vitamin K interfering substances, and incidence without vitamin K supplementation has been reported as high as 12% ²¹². The mortality rate for late vitamin K deficiency bleeding (VKDB) in newborns is 20-50%. Late vitamin K deficiency bleeding (VKDB) in newborns also has a significant neurologic morbidity rate. Without Vitamin K supplementation, the current day incidence of classic VKDB is estimated to be 0.25-1.7% ⁴⁶, ²¹³.

Early vitamin K deficiency bleeding (VKDB) in newborns often presents with intracranial, intrathoracic, intra-abdominal and other severe bleeding conditions. Early VKDB is also often associated with maternal drugs that inhibit vitamin K metabolism. Classis VKDB typically occurs with less severe bleeding such as that of the umbilicus, gastrointestinal tract, and post-circumcision. Late VKDB often presents with severe intracranial bleed. All forms of VKDB have a high incidence of the refusal of vitamin K prophylaxis. Late VKDB has a higher association with exclusively breastfed infants due to the lower dietary intake of vitamin K found in human milk versus formula ²⁰⁴. Warning bleeds or bruising should always prompt further investigation by laboratory testing.

Hereditary combined vitamin K-dependent clotting factor deficiency (VKCFD) presents in the newborn period in severe cases similar to vitamin K deficiency bleeding (VKDB) in newborns but can present later in life in milder cases. Symptoms of VKCFD can vary and correlate with coagulation factor levels ²¹⁴. Affected newborns can be symptomatic at birth with spontaneous intracranial hemorrhage or umbilical stump bleeding ¹⁹⁰, ²¹⁵, ²¹⁶. Alternatively, they can be asymptomatic at first and present later in childhood with spontaneous hemarthrosis or soft-tissue or gastrointestinal bleeds ²¹⁷. Older individuals can have easy bruising or post-surgical bleeding ¹⁹¹, ²¹⁸. Other signs and symptoms in more severely affected children with the hereditary combined vitamin K-dependent clotting factor deficiency (VKCFD) GGCX mutations, include skeletal abnormalities such as bone hypoplasia, conductive hearing loss, and mental retardation ¹⁹³, ²¹⁹, ¹⁸¹, ¹⁸³.

Because vitamin K is required for the carboxylation of osteocalcin in bone, vitamin K deficiency could also reduce bone mineralization and reduce bone strength and increase the risk of getting osteoporosis because the body needs vitamin K for healthy bones ⁸.

Physical examination

Ecchymosis, petechiae, hematomas, and oozing of blood at surgical or puncture sites are observed. In infants, some birth defects, such as underdevelopment of the face, nose, bones, and fingers, are linked to a vitamin K-deficient state. Infants may present with nontraumatic intracranial bleeding with signs such as vomiting, poor intake, anemia, seizures, and bleeding in mucosal sites.

Vitamin K deficiency complications

The characteristics of vitamin K deficiency vary according to the age of onset. In infants, vitamin K deficiency causes hemorrhagic disease of newborn, resulting in intracranial and retroperitoneal bleeding, which can occur at 1-7 days postpartum. Late hemorrhagic disease of newborn can occur as late as 3 months postpartum ²²⁰.

Because vitamin K is involved in gamma carboxylation of osteocalcin, which is important in bone synthesis, osteoporosis is associated with vitamin K deficiency ²²¹. Osteocalcin is important in the remodeling and mineralization of bone. Increased fracture rates and cardiac disease may also be a complication. However, more research is required ²¹².

Vitamin K deficiency diagnosis

Measurements of serum prothrombin time (PT) tend to be elevated and activated partial thromboplastin time (aPTT) is usually normal ²⁰⁰, ²²²). Both PT and aPTT can be elevated in more severe vitamin K deficiency states.

Direct measurement of vitamin K plasma levels shows highly variable data influenced by the analytical method, nutritional and metabolic factors, and interference of lipid content. Liquid chromatography-tandem mass spectrometry is useful for determining vitamin K subtypes and concentration levels but is not readily available ⁹.

The plasma level of vitamin K, serum phylloquinone, (0.2-1.0 ng/mL) can be measured; however, the level of vitamin K depends on the oral intake of vitamin K, which can vary. However, a low serum phylloquinone (< 0.15 mcg/L) suggests low tissue body stores ²⁰³.

A clearly prolonged PT (international normalized ratio (INR) > 3.5) along with normal fibrinogen concentration and platelet count is highly suggestive of vitamin K deficiency-related bleeding. Confirmation of the diagnosis requires measurement of the specific vitamin K-dependent factors (II, VII, IX, X) whose levels are rapidly corrected by the parenteral administration of 1 mg vitamin K ²²³.

Diagnostic criteria for vitamin K deficiency bleeding (VKDB) in newborns includes a prothrombin time (PT) greater than or equal to 4 times the normal value and one of the following ²¹²:

Normal or increased platelet count with normal fibrinogen and absent degradation products
Prothrombin time (PT) normalization within 30 minutes after IV vitamin K administration
Increased levels of PIVKA-II ⁴⁶.

When hereditary combined vitamin K-dependent clotting factor deficiency (VKCFD) is suspected as the cause, a research laboratory can be employed to perform genotyping of gamma-glutamyl carboxylase (GGCX) and VKORC1 (vitamin K epoxide reductase complex subunit 1) ¹⁸³.

Vitamin K deficiency treatment

The medical therapy for vitamin K deficiency depends on the severity of the associated bleeding and the underlying disease state. The most effective approach to correcting the deficiency also depends on the nature of the bleeding and the risk of inducing a local hematoma at the vitamin K injection site. In life-threatening bleeds, fresh frozen plasma should be administered prior to vitamin K.

Phytonadione (vitamin K1)

Whenever possible, phytonadione (vitamin K1) should be given orally or subcutaneously ⁴. The usual adult dose is 1 to 20 mg, depending on the severity. Rarely, even when phytonadione is correctly diluted and given slowly, IV replacement can result in anaphylaxis or anaphylactoid reactions. The absorption with the oral form is variable because it requires bile salts in the ileum for absorption. Oral phytonadione (vitamin K1) is used in the setting of asymptomatic vitamin K deficiency. International normalized ratio (INR) usually decreases within 6 to 12 hours. The dose may be repeated in 6 to 8 hours if INR has not decreased satisfactorily. If the PT does not normalize after vitamin K supplementation, then consideration should be made for the presence of liver disease or disseminated intravascular coagulation (DIC).

Phytonadione 1 to 10 mg orally is indicated for nonemergency correction of a prolonged international normalized ratio (INR) in patients taking anticoagulants. Correction usually occurs within 6 to 8 hours. When only partial correction of INR is desirable (eg, when INR should remain slightly elevated because of a prosthetic heart valve), lower doses (eg, 1 to 2.5 mg) of phytonadione can be given.

In infants, bleeding due to vitamin K deficiency can be corrected by giving phytonadione 1 mg sc or IM once. The dose is repeated if INR remains elevated. Higher doses may be necessary if the mother has been taking oral anticoagulants.

In urgent situations, 10-20 mg of injectable phytonadione (vitamin K-1) can be dissolved in a 5% dextrose or 0.9% normal saline to be administered intravenously at a rate not to exceed 1 mg/mL to prevent a hypersensitive or anaphylactic reaction. When giving vitamin K in the intravenous form, the patient needs to be monitored closely, because cardiopulmonary arrest and/or shock can occur in rare cases. The parenteral administration of vitamin K-1 corrects vitamin K deficiency in 12-24 hours.

There is currently no consensus on dosing for chronic supplementation for patients with cystic fibrosis. However, because of limited stores of vitamin K and its fast turnover in the body, daily supplementation is recommended. Dosages for all ages range from 0.3 to 1 mg/day ²⁰¹.

Prophylaxis in newborns

1 mg of phytonadione (vitamin K1) by intramuscular injection within 1 hour of birth. Alternatively, 2 mg of vitamin K1 orally at birth, at 4-6 days, and at 4-6 weeks. Another alternative oral administration is 2 mg Vitamin K1 at birth and a subsequent weekly dose of 1 mg for three months. Intramuscular injection is preferable for efficacy ⁴⁶.

Vitamin K deficiency bleeding (VKDB) in newborns

1 to 2 mg phytonadione (vitamin K1) by slow intravenous or subcutaneous infusion. Severe bleeding may require fresh frozen plasma at a dose of 10-15 mL/kg ²⁰⁴.

Hereditary combined vitamin K-dependent clotting factor deficiency (VKCFD)

10 mg vitamin K1 2-3 times per week by an oral dose by intravenous infusion. Fresh frozen plasma may be required during surgery or in cases of severe bleeding at a dose of 15-20 mL/kg of body weight given intravenously, to be repeated until clinical efficacy and amelioration of clotting times ²²⁴. The requirement of multiple administrations to reach efficient clotting may be complicated by circulatory overload ²²⁴. Prothrombin Complex Concentrates (products containing factors II, VII, IX and X as well as protein C and protein S at variable concentrations) and recombinant Factor VII (Eptacog alfa (activated)) may also have utility during surgery or severe bleeding ¹⁸³, ²²⁵.

Vitamin K deficiency due to malabsorption

Dependent on the disease. Malabsorption requires daily administration of high doses of oral vitamin K1 0.3 to 15 mg/day. If oral dosing is ineffective, consideration should be for parenteral vitamin K1 ²²⁶.

Vitamin K deficiency in adults due to poor nutrition

At least 120 and 90 mcg/day vitamin K1 for men and women respectively, by diet or oral supplementation to meet the National Academy of Science Food and Nutrition Board recommended intake.

Vitamin K deficiency due to chronic conditions

As more research becomes available, a larger dosage of oral vitamin K1 and K2 may be beneficial. No present guidelines are available ²¹².

Vitamin K deficiency prognosis

Adults with vitamin K deficiency due to nutritional deficiencies in adults are difficult to evaluate given confounding factors such as overall quality of diet and differences in metabolism due to comorbid conditions or genetics but are considered to have an excellent prognosis if the condition is recognized early and treated appropriately. No mortalities from vitamin K deficiency have been reported. However, severe bleeding can occur if the deficiency is left untreated. Morbidity correlates with the severity of vitamin K deficiency. The risk of developing vitamin K deficiency bleeding is 81 times greater in infants who do not receive a prophylactic vitamin K injection ²²⁷.

Prophylaxis with 1 mg of phytonadione (vitamin K1) by intramuscular injection within 1 hour of birth reduces the incidence of vitamin K deficiency bleeding (VKDB) in newborns significantly. Late vitamin K deficiency bleeding (VKDB) in newborns has the worse prognosis, with 50% of cases presenting with intracranial hemorrhage, which is associated with high mortality and morbidity ²⁰⁴.

In hereditary combined vitamin K-dependent clotting factor deficiency (VKCFD), with vitamin K supplementation, there is a good prognosis with a low impact on quality of life, with permanent disabling consequences only resulting in severely affected patients who have been diagnosed after critical events such as intracranial haemorrhage ¹⁸³.

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