Vitamin K

Vitamin K is a necessary participant in synthesis of several proteins that mediate both coagulation and anticoagulation. Vitamin K deficiency is manifest as a tendency to bleed excessively. Indeed, many commercially-available rodent poisons are compounds that interfere with vitamin K and kill by inducing lethal hemorrhage.

Structure

At least two naturally-occuring forms of vitamin K have been identified, and these are designated vitamins K₁ and K₂. Both are quinone derivatives. The structure of vitamin K₁ is depicted below.

Physiologic Effects of Vitamin K

Vitamin K serves as an essential cofactor for a carboxylase that catalyzes carboxylation of glutamic acid residues on vitamin K-dependent proteins. The key vitamin K-dependent proteins include:

• Coagulation proteins: factors II (prothrombin), VII, IX and X
• Anticoagulation proteins: proteins C, S and Z
• Others: bone proteins osteocalcin and matrix-Gla protein, and certain ribosomal proteins

These proteins have in common the requirement to be post-translationally modified by carboxylation of glutamic acid residues (forming gamma-carboxyglutamic acid) in order to become biologically active. Prothrombin, for example, has 10 glutamic acids in the amino-terminal region of the protein which are carboxylated. Without vitamin K, the carboxylation does not occur and the proteins that are synthesized are biologically inactive.

What essential function do gamma-carboxyglutamic acid residues endow upon a protein? There appear to be two major effects:

• First, they enable the protein to bind to membrane surfaces. Much of blood clotting is a result of blood-clotting proteins assembling into a complex on the membranes of platelets and endothelial cells; within these complexes, the factors can efficiently contact one another to become activated and participate in clot formation. Additionally, calcium is necessary for the blood clotting reaction. The proposed mechanism involving carboxylation is that gamma-carboxyglutamic acid residues strongly chelate calcium, and positively-charged calcium forms ion bridges to negatively-charged phosphate head groups of membrane phospholipids.
• Second, gamma-carboxyglutamic acid groups appear to participate in forming the necessary structure of such proteins by forming calcium-mediated intrachain interactions that link two gamma-carboxyglutamic acids to a calcium ion (similar to disulfide bridges, but much shorter).

Sources of Vitamin K

Vitamin K is found in a number of foods, including leafy greens, cauliflower and, if you consider it a food, liver. However, the chief source of vitamin K is synthesis by bacteria in the large intestine, and in most cases, absence of dietary vitamin K is not at all deleterious. Vitamin K is a fat-soluble vitamin and both dietary and microbial vitamin K are absorbed into intestinal lymph along with other lipids. The fetus obtains vitamin K from its mother by transplacental transfer.

The Vitamin K Cycle

As a cofactor to the carboxylase that generates gamma-carboxyglutamic acid, Vitamin K undergoes a cycle of oxidation and reduction that allows its reuse. The essential details of this cycle are:

• Vitamin K (usually K1) is reduced to vitamin KH2.
• Oxygenation of vitamin KH2 provides the energy to drive the carboxylation reaction, leading to formation of gamma-carboxyglutamic acid residues and vitamin K oxide.
• Vitamin K oxide is reduced by another reductase back to vitamin K, ready to enter another cycle. Anticoagulants such as Warfarin block the reduction of vitamin K oxide to vitamin K, explaining their antagonistic effects on this cycle.

Vitamin K Deficiencies

Deficiency in vitamin K and resulting hemorrhagic disease can result from several situations:

• Poisoning with vitamin K antagonists: Many of the popular rodenticides act by inducing a vitamin K deficiency which, if severe, leads to death by bleeding. Coumarin derivatives such as Warfarin and dicumarol interfere with recycling of vitamin K (see above) and thereby lead to vitamin K deficiency. Some of the newer types of rodenticides have such long half lives that a single feeding on poison bait can kill not only the rodent, but cause bleeding disease in dogs or cats that subsequently ingest them.
• Liver disease: The liver synthesizes bile acids and secretes them into the small intestine where they play a critical role in absorption of lipids. Vitamin K, as a fat-soluble vitamin, requires proper lipid absorption for its own absorption. Liver disease that results in decreased bile salt synthesis leads to impaired vitamin K absorption and deficiency.
  
  Additionally, a majority of the clotting factors are synthesized almost exclusively in the liver, so liver disease can cause defects in blood clotting by several mechanisms.
• Intestinal disease: diseases that result in lipid malabsorption in the small intestine can lead to defects in absorption of vitamin K, as discussed above for liver.

Two other vitamin K deficiency states have received considerable recent attention:

• Hemorrhagic disease of the newborn results from vitamin K deficiency in human infants, and can lead to death or permanent brain damage. At birth, the liver has essentially no vitamin K reserves and a lack of vitamin K intake or situations that somehow interfere with absorption of bacterially-synthesized vitamin K can lead to this situation. Many infants receive vitamin K supplements to preclude this disorder.
• Increased risk of fractures or reduced bone density may result from inadequate intake of vitamin K, due to its necessary role in production of bone proteins such as osteocalcin. Several clinical trials have supported the proposition that, in certain situations, vitamin K supplements enhance the integrity of bone. It seems clear that use of vitamin K antagonists like Warfarin for purposes of anticoagulation have toxic effects on rapidly-growing bone.

Send comments to Richard.Bowen@colostate.edu