Vitamin K is synthesised by plants and bacteria. There are two natural and one synthetic source of vitamin K: Phylloquinones (formerly, K1s). Green plants synthesise the phylloquinones as a normal component of chloroplasts. Menaquinones (MKs, formerly K2s). Bacteria (including those of the normal intestinal microflora) synthesise the menaquinones. Menadione, the formal parent compound of the menaquinone series does not occur naturally, but is a common synthetic form; as is menadione sodium bisulfite complex and menadione pyridi¬nol bisulfite (MPB). Animals cannot synthesise the vitamin which they require for blood clotting, bone formation, and other functions. These needs are critical to good health; yet the preva¬lent microbial synthesis of the menaquinones, including that occurring in the hindgut of humans, results in frank deficiencies of this vitamin being rare. Nevertheless, vitamin K deficiency can occur with certain antibiotics that reduce their hindgut microbial synthesis of the vita¬min (1). Human neonates, particularly premature infants, can also be at risk of haemorrhagic disease by virtue of limited transplacental transfer of the vitamin. The function of vitamin K in blood clotting is widely exploited to reduce risks to post-surgical athrombosis and cardiac patients. Coumarin-based drugs (e.g., warfarin, dicumarol) and other inhibitors of the vitamin K cycle are valuable in this purpose.
The vitamers K are absorbed from the intestine into the lymphatic circulation by processes that first require the formation of mixed micelles, in which they are dissolved. Vitamin K absorption therefore depends on normal pancreatic and biliary function. Conditions resulting in impaired lumenal micelle formation (e.g., dietary mineral oil, pancreatic dysfunction, bile stasis) therefore impair the enteric absorption of vitamin K.
On absorption, vitamin K is transported to the liver. Vitamin K is rapidly taken up by the liver via an apolipoprotein E receptor; it has a relatively short half-life there (about 17 hours) before it is transferred to very HDLs and LDLs, which carry it in the plasma.
When administered as either phylloquinone or MKs, vita¬min K is rapidly taken up by the liver, which is the site of synthesis of the vitamin K-dependent coagula¬tion proteins. In contrast, little menadione is taken up by that organ; instead, it is distributed widely to other tissues. The vitamin is found at low levels in many organs; several tend to concentrate it: adrenal glands, lungs, bone marrow, kidneys, lymph nodes. The transplacental movement of vitamin K is poor; the vitamin is frequently not detectable in the cord blood from mothers with normal plasma levels. For this reason, newborn infants are susceptible to haemorrhage.
The coumarin-type anticoagulants block the regeneration of the vitamin, result¬ing in the accumulation of metabolites and several have been widely used in anticoagulant therapy in clinical medi¬cine, as well as in rodenticides (effective by causing fatal hemorrhaging). The most widely used for each purpose has been warfarin an analogue of the naturally occurring haemorrhagic factor dicumarol and warfarin therapy is prescribed for many millions of patients each year. Resistance to warfarin has been observed in both rats and humans, and has become a significant problem. While coumarin therapy has been important in preventing strokes, it is estimated that 12% of cases experience major bleeding episodes which are fatal in some 2% (2). For this reason, there has been great interest in developing safer anticoagulants.
Vitamin K functions in the modifica¬tion of at least 20 proteins involved in three key functions:-blood clotting, bone mineralisation and vascular health (see below)
The most frequent causes of vitamin K deficiency are factors that interfere with the microfloral production or absorption of the vitamin:
Lipid malabsorption. Diseases of the gastrointestinal tract, biliary stasis, liver disease, cystic fibrosis, celiac disease can interfere with the enteric absorption of vitamin K.
Anticoagulant therapy. Certain types of drugs can impair vitamin K function. These include warfarin and other 4-hydroxycoumarin anticoagulants, and large doses of salicylates, which inhibit the redox cycling of the vita¬min. In each case, high doses of vitamin K are generally effective in normalizing clotting mechanisms. In medi¬cal management of thrombotic disorders, over-antico¬agulation with warfarin is common; this is reversed by warfarin dose reduction coupled with treatment with phylloquinone (3).
Antibiotic therapy. Sulfonamides and broad-spectrum antibiotic drugs can virtually sterilise the lumen of the intestine, thus removing an important source of vitamin K. Therefore, it has been thought that patients on antibiotic therapy can be at risk of vitamin K deficiency. The prevalence of such cases appeared to increase in the 1980s with the intro¬duction of the β-lactam antibiotics. Although these drugs are administered intravenously, it is possible that they may affect enteric bacterial metabolism via biliary release. The cephalosporin-type antibiotics can also produce cou¬marin-like depressions of the activities of the vitamin K-dependent clotting factors. Unlike the coumarins, however, the β-lactam antibiotics are very weak anti¬coagulants, the effects of which are observed only in patients of low vitamin K status.
Neonates are at special risk of vitamin K deficiency for several reasons: Placental transport of the vitamin is poor. Infants have very limited reserves of vitamin K; their serum levels are typically about half those of their mothers; The neonatal intestine is sterile for the first few days of life. The neonatal intestine thus does not provide an enteric microbial source of the vitamin; Biosynthesis of the clotting factors in the liver is inadequate in the young infant. The plasma prothrombin concentrations of foetuses and infants are typically one-quarter those of their mothers; Human milk is an inadequate source of vitamin K. The frequency of vitamin K-responsive haemorrhagic disease in 1-month-old infants is 1/4,000 overall, but 1/1,700 among breastfed infants. For these reasons, some infants will develop haemorrhage if continuing intake of vitamin K is not pro¬vided. This condition of vitamin K deficiency bleeding (VKDB), also called haemorrhagic disease of the new¬born, can present in different ways, depending on the age of the infant.
The major risk factors for VKDB are exclusive breast¬feeding, failure to give vitamin K prophylaxis, and certain maternal drug therapies. Exclusively breastfed infants who have not received vitamin K or who have gastrointestinal disorders involving lipid malabsorption can show signs within several weeks. That infant fed for¬mula diets are at lower risk probably relates to the greater amounts of vitamin K in infant formulas than human milk. Haemorrhagic disease has also been reported for newborns of mothers on anticonvulsant therapy. It has become a common practice in many countries to treat all infants at birth with parentally administered vitamin K (1 mg phylloquinone). This practice has greatly reduced the incidence of haemorrhagic disease of the new¬born, although much lower doses have been found to be effective.
Phylloquinone exhibits no adverse effects when admin¬istered to animals in massive doses by any route. The menaquinones are similarly thought to have negligible tox¬icity. Menadione, however, can be toxic. At high doses, it can produce hemolytic anemia, hyperbilirubinemia, and severe jaundice. Accordingly, phylloquinone has replaced menadione for the vitamin K prophylaxis of neonates.
SOURCES OF VITAMIN K
Green leafy vegetables tend to be rich in vitamin K, whereas fruits and grains are poor sources. The vitamin K activities of meats and dairy products tend to be moderate. Unfortunately, data for the vitamin K contents of foods are limited by the lack of good analytical methods. Nevertheless, it is clear that, because dietary needs for vitamin K are low, most foods contribute significantly to those needs. This is not true for breast milk, which has been found in most studies to be of very low vitamin K content and insufficient to meet the vitamin K needs of infants.
Menaquinones can be synthesised by many anaero¬bic bacteria, including some in the human large intes¬tine. In humans, the daily production of MKs by the gut microflora has been thought to exceed the nutritionally required amount by a substantial margin, which would explain the difficulty in producing clear signs of vitamin K deficiency in normal subjects (4). Little is known about the bioavailability of vitamin K in most foods. It appears, however, that only about 10% of the phylloquione in boiled spinach is absorbed by humans (5). The relative biopotencies of the various vitamers K dif¬fer according to route of administration.
VITAMIN K IN HEALTH AND DISEASE
The best understood metabolic roles of vitamin K are those involved in its anti-haemorrhagic function, which led to the vitamin’s discovery. It has since become clear that vitamin K plays important metabolic roles beyond clotting.
Blood clotting is produced by a complex system of pro¬teins that functions to prevent haemorrhage and leads to thrombus formation. It involves coagulation at the site of injury and curtails the process upon formation of the clot. It is initiated by injury to tissues through the release of col¬lagen fibres and tissue factor, a cell surface protein, where¬upon they interact with vitamin K-dependent proteins in the plasma. These signals are amplified via the clotting pathway, ultimately, to form the clot.
The eight vitamin K-dependent plasma proteins com¬prising this system all require calcium for activity. Most circulate as a zymogen, i.e., an inactive precursor of the respective functional form. Each participates in a cascade of activation of a series of factors leading to the conversion of a soluble protein, fibrinogen, to insoluble fibrin, which cross-links with platelets to form the blood clot. The activation of proteases in this cas¬cade involves the calcium mediated association of the active protein, its substrate, and another protein factor with a phospholipid surface.
The key step in this system is the activation of factor X. This can occur in two ways: by the actions of factor IX which is activated by plasma thromboplastin as the result of a contact with a foreign surface in what is referred to as the intrinsic clotting system, or by the action of factor VII, which is activated by tissue thromboplastin released as the result of injury in what is called the extrinsic clotting system (6).
Once activated, factor X, binding calcium and phos¬pholipid, catalyses the activation of several coagulation factors: prothrombin (factor II) to its active form, thrombin (factor IIa), which catalyses the change in fibrinogen that renders it insoluble (as fibrin) for clot formation; factor V to its active form, factor Va; factor VIII to its active form factor VIIIa. Control of clotting is accomplished by the downregu¬lation of thrombin production via thrombin binding to thrombomodulin, which complex activates protein C, which in turn inactivates factors Va and VIIIa. Two components of this system are proteins S and Z. Protein S is found in the plasma both in free form and as a complex with a regulatory component of the com¬plement system. Individuals with inherited protein S defi¬ciency have been reported to have recurrent thromboses. Protein Z is a cofactor for inhibition of activated factor X. Protein Z deficiency has been associated with a bleeding tendency in patients with factor V mutation.
Diseases of coagulation now associated with vitamin K deficiency were reported in the nineteenth century. These include those that were called “haemorrhagic disease of the newborn,” which differed from hemophilia by its earlier presentation (within a couple of days after birth) and absence of family history. Routine prophylaxis of newborns with vitamin K has made this condition rare.
Hereditary combined vitamin K-dependent clotting fac¬tor deficiency is a rare disorder involv¬ing mutations in the genes for vitamin K-dependent enzymes. This involves subopti¬mal levels of coagulation factors II, VII, IX, and X, as well as proteins C, S, and Z. It results in a range of spon¬taneous bleeding symptoms. High-level vitamin K supple¬mentation is effective in managing the disorder. Low vitamin K status appears to contribute to unstable anticoagulation control in warfarin treatment, which affects as many as half of patients. Interventions with vitamin K have been found to improve anticoagulation control.
The presence of vitamin K-dependent proteins in bone suggests a role in bone health. Three vitamin K-dependent proteins have been identified in calcified tissues:
Osteocalcin. The best characterised vitamin K-dependent protein is osteocal¬cin, which has also been referred to as “bone protein.” The protein binds calcium weakly and hydroxyapatite strongly to maintain its secondary structure and to allow it to bind mineralised bone matrix. Synthesized by osteoblasts, it is the second most abundant pro¬tein in the bone matrix and plasma osteocalcin and can be used as a marker of bone formation (7).
Matrix Gla Protein (MGP). Sometimes referred to as periostin, this is a small, insoluble polypep¬tide structurally related to osteocalcin.
Protein S. That protein S is synthesised by osteoblasts suggests that it may have an activity in bone in addition to its role in clotting.
Several studies have shown individuals with low circulating vitamin K levels or vitamin K intakes to be at elevated risk of osteoporosis or fracture(8-10). The Nurses’ Health Study, a 10-year prospective study of more than 72,000 women, found the age-adjusted risk of hip fracture to be 30% less in women with vitamin K intakes >109 μg/d than in those consuming lower amounts (11). A similar relationship was observed in the Framingham Heart Study (12).
At least a dozen randomised clinical intervention stud¬ies have been conducted to determine the efficacy of vita¬min K supplementation in reducing bone mineral loss and/ or fracture risk. Supplementation with MK has been found to reduce fracture risk and improve bone mineral den¬sity (13,14).
Two proteins appear to play anti-atherogenic roles by impairing calcification: MGP. This is expressed in vascular smooth muscle, and appears to play a dominant role in maintaining the rate of arterial calcification as low as possible. Atherocalcin. It has been suggested that atherocalcin may inhibit a vitamin K-dependent enzyme, which is found in the walls of arteries but not veins, and may be involved in the development of atherosclerosis. Vitamin K-dependent Gla proteins may also play roles in atherogenesis, which involves thrombus-induced coagula¬tion as well as intimal calcification. Osteocalcin, normally expressed only in bone, is upreg¬ulated in arterial calcification. It is possible that increased dietary intakes of the vitamin may be useful in reducing athero¬sclerosis risk.
Obesity appears to impair the utilisation of vitamin K. Adipose tissue stores vitamin K at relatively high lev¬els, and plasma phylloquinone levels have been found to vary inversely with percentage body fat in women.
A 3-year intervention study found that phylloquinone supplementation reduced insulin resistance in men (15-17).
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Keyword-vitamin K, coagulation (clotting factors), bone, cardiovascular disease, obesity, diabetes