Vitamin K Deficiency

Pathogenesis

Vitamin K is a group of compounds that have a common naphthoquinone ring structure (see Table 64.1 ). Phylloquinone , called vitamin K ₁ , is present in a variety of dietary sources, with green leafy vegetables, liver, and certain legumes and plant oils having the highest content. Vitamin K ₁ is the form used to fortify foods and as a medication in the United States. Vitamin K ₂ is a group of compounds called menaquinones , which are produced by intestinal bacteria. There is uncertainty regarding the relative importance of intestinally produced vitamin K ₂ . 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 posttranslational 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 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 (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. Evidence suggests 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. Thus, symptomatic vitamin K deficiency can develop within weeks when there is inadequate supply because of low intake or malabsorption.

There are 3 forms of vitamin K deficiency bleeding (VKDB) of the newborn (see Chapter 124.4 ). 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 as a result of 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 K ₂ because the newborn gut is sterile. Early VKDB occurs mostly in breastfed infants as a consequence of the low vitamin K content of breast milk (formula is fortified). Delayed feeding is an additional risk factor.

Late VKDB most often occurs at 2-12 wk of age, although cases can occur up to 6 mo after birth. Almost all cases are in breastfed infants because of 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, α ₁ -antitrypsin deficiency). Without vitamin K prophylaxis, the incidence is 4-10 per 100,000 newborns.

The third form of VKDB of the newborn occurs at birth or shortly thereafter. It is secondary to maternal intake of medications (warfarin, phenobarbital, phenytoin) that cross the placenta and interfere with vitamin K function.

VKDB as a result of fat malabsorption can occur in children of any age. Potential etiologies include cholestatic liver disease, pancreatic disease, and intestinal disorders (celiac sprue, inflammatory bowel disease, short bowel syndrome). Prolonged diarrhea can cause vitamin K deficiency, especially in breastfed infants. Children with cystic fibrosis are most likely to have vitamin K deficiency if they have pancreatic insufficiency and liver disease.

Beyond infancy, low dietary intake by itself never causes vitamin K deficiency. However, the combination of poor intake and the use of broad-spectrum antibiotics that eliminate the intestine's vitamin K ₂ –producing bacteria can cause vitamin K deficiency. This scenario is especially common in the intensive care unit. Vitamin K deficiency can also occur in patients who receive total parenteral nutrition (TPN) without vitamin K supplementation.

Clinical Manifestations

In early VKDB, the most common sites of bleeding are the gastrointestinal (GI) tract, mucosal and cutaneous tissue, umbilical stump, and postcircumcision site; intracranial bleeding is less common. GI blood loss can be severe enough to require a transfusion. In contrast, the most common site of bleeding in late VKDB is intracranial, although cutaneous and GI bleeding may be the initial manifestation. Intracranial bleeding can cause convulsions, permanent neurologic sequelae, or death. In some patients with late VKDB, the presence of an underlying disorder may be suggested by jaundice or failure to thrive (malnutrition). Older children with vitamin K deficiency can present with bruising, mucocutaneous bleeding, or more serious bleeding.