Vitamin K - Phytonadione

Introducing Vitamin K - Saver of Blood Clotting

Vitamin K is a fat-soluble vitamin. Vitamin K is best known for its role in helping blood clot properly, and in preventing excessive bleeding. It also plays an important role in bone health. The "K" is derived from the German word "koagulation". Coagulation refers to blood clotting, because vitamin K is essential for the functioning of several proteins involved in blood clotting. There are two naturally occurring forms of vitamin K. Plants synthesize phylloquinone, also known as vitamin K1. Bacteria synthesize a range of vitamin K forms, using repeating 5-carbon units in the side chain of the molecule. These forms of vitamin K are designated menaquinone-n (MK-n), where n stands for the number of 5-carbon units. MK-n are collectively referred to as vitamin K2. MK-4 is not produced in significant amounts by bacteria, but appears to be synthesized by animals (including humans) from phylloquinone. MK-4 is found in a number of organs other than the liver at higher concentrations than phylloquinone. This fact, along with the existence of a unique pathway for its synthesis, suggests there is some unique function of MK-4 that is yet to be discovered.

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Why Vitamin K?

The only known biological role of vitamin K is that of the required coenzyme for a vitamin K-dependent carboxylase that catalyzes the carboxylation of the amino acid, glutamic acid, resulting in its conversion to gamma (g)-carboxyglutamic acid (Gla). Although vitamin K-dependent carboxylation occurs only on specific glutamic acid residues in a small number of proteins, it is critical to the calcium-binding function of those proteins. View a simple diagram, illustrating this concept.

Coagulation (clotting): The ability to bind calcium ions (Ca2+) is required for the activation of the seven "vitamin K-dependent" clotting factors in the coagulation cascade. The term, "coagulation cascade," refers to a series of events, each dependent on the other that stops bleeding through clot formation. Vitamin K-dependent gamma (g)-carboxylation of specific glutamic acid residues in those proteins makes it possible for them to bind calcium. Factors II (prothrombin), VII, IX, and X make up the core of the coagulation cascade. Protein Z appears to enhance the action of thrombin (the activated form of prothrombin) by promoting its association with phospholipids in cell membranes. Protein C and protein S are anticoagulant proteins that provide control and balance in the coagulation cascade. Because uncontrolled clotting may be as life threatening as uncontrolled bleeding, control mechanisms are built in to the coagulation cascade. Vitamin K-dependent coagulation factors are synthesized in the liver. Consequently, severe liver disease results in lower blood levels of vitamin K-dependent clotting factors and an increased risk of uncontrolled bleeding (hemorrhage).

Some people are at risk of forming clots, which could block the flow of blood in arteries of the heart, brain, or lungs, resulting in heart attack, stroke, or pulmonary embolism, respectively. Some oral anticoagulants, such as warfarin (also known as coumarin or coumadin) inhibit coagulation through antagonism of the action of vitamin K. Although vitamin K is a fat-soluble vitamin, the body stores very little of it, and its stores are rapidly depleted without regular dietary intake. Perhaps, because of its limited ability to store vitamin K, the body recycles it through a process called "the vitamin K cycle." The vitamin K cycle allows a small amount of vitamin K to function in the g-carboxylation of proteins many times, decreasing the dietary requirement. Warfarin prevents the recycling of vitamin K by inhibiting two important reactions and creating a functional vitamin K deficiency (see diagram). Inadequate g-carboxylation of vitamin K-dependent coagulation proteins interferes with the coagulation cascade, and inhibits blood clot formation. Large quantities of dietary or supplemental vitamin K can overcome the anticoagulant effect of vitamin K antagonists, so patients taking these drugs are cautioned against consuming very large or highly variable quantities of vitamin K in their diets (see Safety). Experts now advise a reasonably constant dietary intake of vitamin K that meets current dietary recommendations (60-80 mcg/day) for patients on vitamin K antagonists, like warfarin.

Bone mineralization: Three vitamin-K dependent proteins have been isolated in bone. Osteocalcin is a protein synthesized by osteoblasts (bone forming cells). The synthesis of osteocalcin by osteoblasts is regulated by the active form of vitamin D, 1,25(OH)2D3 or calcitriol. The mineral-binding capacity of osteocalcin requires vitamin K-dependent g-carboxylation of three glutamic acid residues. The function of osteocalcin is unclear, but is thought to be related to bone mineralization. Matrix Gla protein (MGP) has been found in bone, cartilage, and soft tissue, including blood vessels. The results of animal studies suggest MGP prevents the calcification of soft tissue and cartilage, while facilitating normal bone growth and development. The vitamin K-dependent anticoagulant protein S is also synthesized by osteoblasts, but its role in bone metabolism is unclear. Children with inherited protein S deficiency suffer complications related to increased blood clotting as well as to decreased bone density.

Cell proliferation: Gas6 is a vitamin K-dependent protein that was identified in 1993. It has been found throughout the nervous system, as well in the heart, lungs, stomach, kidneys, and cartilage. Although the exact mechanism of its action has not been determined, Gas6 appears to be a cellular growth regulation factor with cell signaling activities. It may also play important roles in the developing and aging nervous system.

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Food High in Vitamin K and Who are likely to be Deficient

Food high in vitamin K include the following categories:
Asparagus, Brussels Sprouts, Cabbage, Cheddar Cheese, Liver, Seaweed, Spinach and Turnip Greens.

It's different this time, the people who are mostly in danger of being deficient in vitamin K are not the elders, they are the babies. There is a rare disease called Vitamin K deficiency bleeding, which occurs in approximately 1/10,000 babies. In about half of babies who suffer this bleeding problem after the first week of life, many will die or sustain significant brain-damage due to the disease, because of bleeding into the brain. It occurs almost exclusively in breast-fed babies and is almost completely preventable by giving extra vitamin K after birth. The prevention is giving all babies extra vitamin K. The reason is the bleeding shows absolutely no signs ahead of the time. Therefore, general prevention is required.

Deficient in vitamin K may cause inBeside the infants, if you are one of the following people, you may need to take extra vitamin K supplements:
- Those with a portion of the gastrointestinal tract surgically removed
- Anyone taking long-term antibiotics that may destroy normal "friendly" bacteria in the intestinal tract
- People who do not have enough bile to absorb fats
- Infants who are breastfed or fed with milk-substitute formula
- People on mineral oil for constipation

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Vitamin K Deficiency Symptoms

Overt vitamin K deficiency results in impaired blood clotting, usually demonstrated by laboratory tests that measure clotting time. Symptoms include easy bruising and bleeding that may be manifested as nosebleeds, bleeding gums, blood in the urine, blood in the stool, tarry black stools, or extremely heavy menstrual bleeding. In infants, vitamin K deficiency may result in life-threatening bleeding within the skull (intracranial hemorrhage).

Adults: 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, and 3) bacteria that normally inhabit the large intestine synthesize menaquinones (vitamin K2), though it is unclear whether a significant amount is absorbed and utilized. Adults at risk of vitamin K deficiency include those taking vitamin K antagonist anticoagulant drugs and individuals with significant liver damage or disease.

Infants: Newborn babies that are exclusively breast-fed are at increased risk of vitamin K deficiency for the following reasons: 1) human milk is relatively low in vitamin K compared to formula, 2) the newborn's intestines are not yet colonized with bacteria that synthesize menaquinones, and 3) the vitamin K cycle may not be fully functional in newborns, especially premature infants. Infants whose mothers are on anticonvulsant medication to prevent seizures are also at risk of vitamin K deficiency. Vitamin K deficiency in newborns may result in a bleeding disorder called hemorrhagic disease of the newborn (HDN). Because HDN is life threatening and easily prevented, the American Academy of Pediatrics and a number of similar international organizations recommend that an injection of phylloquinone (vitamin K1) be administered to all newborns.

Controversy concerning vitamin K administration and the newborn: Controversy arose regarding the routine use of vitamin K injections for newborns in the early 1990's when two retrospective studies were published suggesting the possibility of an association between vitamin K injections in newborns and the development of childhood leukemia and other forms of childhood cancer. However, two large retrospective studies in the U.S. and Sweden that reviewed the medical records of 54,000 and 1.3 million children, respectively, found no evidence of a relationship between childhood cancers and vitamin K injections at birth. In a policy statement, the American Academy of Pediatrics recommended that routine vitamin K prophylaxis for newborns be continued because HDN is life-threatening and the risks of cancer are unproven and unlikely. Full text of the AAP policy statement on vitamin K and the newborn.

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Recent Studies on Vitamin K and Your Health

Vitamin K and Osteoporosis
The discovery of vitamin K-dependent proteins in bone has led to research on the role of vitamin K in maintaining bone health.

Dietary vitamin K and osteoporotic fracture: Epidemiologic studies have demonstrated a relationship between vitamin K and age-related bone loss (osteoporosis). The Nurses Health Study followed more than 72,000 women for 10 years. Investigators found that women whose vitamin K intake was in the lowest quintile (1/5) had a 30% higher risk of hip fracture than women with vitamin K intakes in the highest four quintiles. A study of over 800 elderly men and women followed in the Framingham Heart Study for 7 years found that men and women with dietary intakes in the highest quartile (1/4) had only 35% of the risk of hip fracture experienced by those with dietary vitamin K intakes in the lowest quartile (approximately 250 mcg vs. 50 mcg of vitamin K). However, the investigators found no association between dietary vitamin K intake and bone mineral density (BMD) in the Framingham subjects. Because the primary dietary source of vitamin K is generally green leafy vegetables, high vitamin K intake could just be a marker for a healthy diet that is high in fruits and vegetables.

Vitamin K-dependent carboxylation of osteocalcin and osteoporotic fracture: Osteocalcin, a bone-related protein that circulates in the blood, has been shown to be a sensitive marker of bone formation. Vitamin K is required for the g-carboxylation of osteocalcin. Undercarboxylation of osteocalcin adversely affects its capacity to bind to bone mineral, and the degree of osteocalcin g-carboxylation has been found to be a sensitive indicator of vitamin K nutritional status. Blood levels of undercarboxylated osteocalcin (ucOC) were found to be higher in postmenopausal women than premenopausal women, and markedly higher in women over the age of 70. In a study of 195 institutionalized elderly women, the relative risk of hip fracture was six times higher in those who had elevated ucOC levels at the beginning of the study. In a much larger sample of 7500 elderly women living independently, blood ucOC was also predictive of fracture risk. Although vitamin K deficiency would seem the most likely cause of elevated blood ucOC, investigators have also documented an inverse relationship between measures of vitamin D nutritional status (25-OH-D) and ucOC levels, as well as a significant lowering of ucOC by vitamin D supplementation. It is also possible that an increased ucOc level is a marker for poor vitamin D or protein nutritional status.

Vitamin K antagonists and osteoporotic fracture: Certain oral anticoagulants, like warfarin (coumarin), are known to be antagonists of vitamin K. Two recent studies examined the chronic use of warfarin and the risk of fracture in older women. One study reported no association between long-term warfarin treatment and fracture risk, while the other found a significantly higher risk of rib and vertebral fractures in warfarin users compared to nonusers. A meta-analysis of the results of 11 published studies found that oral anticoagulation therapy was associated with a very modest reduction in bone density at the wrist, and no change in bone density at the hip or spine.

Vitamin K supplementation studies and osteoporosis: Vitamin K supplementation of 1,000 mcg (1 mg)/day of phylloquinone (Vitamin K1) for 2 weeks (more than 10 times the RDA for vitamin K) resulted in a decrease of ucOC levels in postmenopausal women, as well as increases in several biochemical markers of bone formation. In Japan, intervention trials in hemodialysis patients and osteoporotic women using very high pharmacologic doses (45 mg/day) of menatetranone (MK-4) have reported significant reductions in the rate of bone loss. MK-4 is not found in significant amounts in the diet, but can be synthesized in small amounts by humans from phylloquinone. The dose used in the Japanese study was more than 50 times higher than the U.S. RDA for vitamin K. Experts are not sure whether the effects of such high doses of MK-4 represent a true vitamin K effect. Nutritional supplements in the U.S. do not contain MK-4.

In the absence of long-term interventional studies using nutritionally optimal doses of vitamin K, evidence of a relationship between vitamin K nutritional status and bone health in adults is considered weak. Further investigation is required to determine the physiological function of vitamin K-dependent proteins in bone and the mechanisms by which vitamin K affects bone health and osteoporotic fracture risk.

Vascular calcification and cardiovascular disease: One of the hallmarks of cardiovascular disease is the formation of atherosclerotic plaques in arterial walls. Calcification of atherosclerotic plaques occurs as the the condition progresses, resulting in decreased elasticity of the affected vessels and increased risk of clot formation, the usual cause of a heart attack or stroke. One study of postmenopausal women found low dietary vitamin K intake to be associated with increased risk of aortic calcification, as visualized by chest x-ray. Additionally, laboratory tests examining the vitamin K-dependent g-carboxylation of osteocalcin indicated that elevated blood levels of undercarboxylated osteocalcin (ucOc) were also associated with increased aortic calcification. The mechanism by which vitamin K may promote mineralization of bone, while inhibiting mineralization (calcification) of vessels is not entirely clear. One hypothesis is based on the function of two different bone proteins, osteocalcin and matrix Gla protein (MGP). MGP has been found to inhibit the calcification of cartilage and bone during early embryonic development. Osteocalcin appears later during bone development and appears to promote bone mineralization. Some investigators have hypothesized that high levels of MGP found in calcified vessels may represent a defense against vessel calcification, but that inadequate vitamin K nutritional status results in inadequate carboxylation, and presumably inactive MGP. Inadequate carboxylation of osteocalcin might adversely affect bone mineralization. It is important to note that this line of reasoning is based on animal research and one epidemiologic study in humans. Further investigations are necessary to establish the nature of the role of bone proteins in atherosclerotic plaque calcification.

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Editors' summary on Vitamin K

Vitamin K is a fat-soluble vitamin. It promotes production of active prothrombin, proconvertin and other factors necessary for normal blood clotting. All new borns are suggested to take sufficient vitamin K to prevent vitamin K deficiency bleeding.

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