Pathogenesis

Vitamin K is a group of compounds that have a common naphthoquinone ring structure. Phylloquinone, called vitamin K₁, is present in a variety of dietary sources, with green leafy vegetables, liver, and certain legumes and plant oils having the highest content. Vitamin K₁ is the form used to fortify foods and as a medication in the USA. Vitamin K₂ is a group of compounds called menaquinones, which are produced by intestinal bacteria. There is uncertainty regarding the relative importance of intestinally produced vitamin K₂. Menaquinones are also present in meat, especially liver, and cheese. A menaquinone is used pharmacologically in some countries.

Vitamin K is a cofactor for γ-glutamyl carboxylase, an enzyme that performs post-translational carboxylation, converting glutamate residues in proteins to γ-carboxyglutamate (Gla). The Gla residues, by facilitating calcium binding, are necessary for protein function.

The classic Gla-containing proteins involved in blood coagulation that are decreased in vitamin K deficiency are factors II (prothrombin), VII, IX, and X. Vitamin K deficiency causes a decrease in proteins C and S, which inhibit blood coagulation, and protein Z, which also has a role in coagulation. All of these proteins are made only in the liver, except for protein S, a product of various tissues.

Gla-containing proteins are also involved in bone biology (e.g., osteocalcin and protein S) and vascular biology (matrix Gla protein and protein S). Based on the presence of reduced levels of Gla, these proteins appear more sensitive than the coagulation proteins to subtle vitamin K deficiency. There is evidence suggesting that mild vitamin K deficiency might have a deleterious effect on long-term bone strength and vascular health.

Because it is fat-soluble, vitamin K requires the presence of bile salts for its absorption. Unlike other fat-soluble vitamins, there are limited body stores of vitamin K. In addition, there is high turnover of vitamin K, and the vitamin K–dependent clotting factors have a short half-life. Hence, symptomatic vitamin K deficiency can develop within weeks when there is inadequate supply due to low intake or malabsorption.

There are 3 forms of vitamin K–deficiency bleeding (VKDB) of the newborn (Chapter 97.4). Early VKDB was formerly called classic hemorrhagic disease of the newborn and occurs at 1-14 days of age. Early VKDB is secondary to low stores of vitamin K at birth due to the poor transfer of vitamin K across the placenta and inadequate intake during the 1st few days of life. In addition, there is no intestinal synthesis of vitamin K₂ because the newborn gut is sterile. Early VKDB occurs mostly in breast-fed infants due to the low vitamin K content of breast milk (formula is fortified). Delayed feeding is an additional risk factor.

Late VKDB most commonly occurs at 2-12 wk of age, although cases can occur up to 6 mo after birth. Almost all cases are in breast-fed infants due to the low vitamin K content of breast milk. An additional risk factor is occult malabsorption of vitamin K, as occurs in children with undiagnosed cystic fibrosis or cholestatic liver disease (e.g., biliary atresia, α₁