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-antitrypsin deficiency). Without vitamin K prophylaxis, the incidence is 4-10/100,000 newborns.

The 3rd 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.

Vitamin K–deficiency bleeding due to 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 breast-fed 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 K₂-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 without vitamin K supplementation.

Clinical Manifestations

In early VKDB, the most common sites of bleeding are the gastrointestinal (GI) tract, mucosal and cutaneous tissue, the umbilical stump, and the post-circumcision site; intracranial bleeding is less common. Gastrointestinal 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 cases of late VKDB, the presence of an underlying disorder may be suggested by jaundice or failure to thrive. Older children with vitamin K deficiency can present with bruising, mucocutaneous bleeding, or more serious bleeding.

Laboratory Findings

In patients with bleeding due to vitamin K deficiency, the prothrombin time (PT) is prolonged. The PT must be interpreted based on the patient’s age, because it is normally prolonged in newborns (Chapter 469). The partial thromboplastin time (PTT) is usually prolonged, but it may be normal in early deficiency; factor VII has the shortest half-life of the coagulation factors and is the first to be affected by vitamin K deficiency, but isolated factor VII deficiency does not affect the PTT. The platelet count and fibrinogen level are normal.

When there is mild vitamin K deficiency, the PT is normal, but there are elevated levels of the undercarboxylated forms of the proteins that are normally carboxylated in the presence of vitamin K. These undercarboxylated proteins are called proteins induced by vitamin K absence (PIVKA). Measurement of undercarboxylated factor II (PIVKA-II) can be used to detect mild vitamin K deficiency. Determination of blood vitamin K levels is less useful because of significant variation based on recent dietary intake; levels do not always reflect tissue stores.

Diagnosis and Differential Diagnosis

The diagnosis is established by the presence of a prolonged PT that corrects rapidly after administration of vitamin K, which stops the active bleeding. Other possible causes of bleeding and a prolonged PT include disseminated intravascular coagulation (DIC), liver failure, and rare hereditary deficiencies of clotting factors. DIC, which is most commonly secondary to sepsis, is associated with thrombocytopenia, low fibrinogen, and elevated D-dimers. Most patients with DIC have hemodynamic instability that does not correct with restoration of blood volume. Severe liver disease results in decreased production of clotting factors; the PT does not fully correct with administration of vitamin K. Children with a hereditary disorder have a deficiency in a specific clotting factor (I, II, V, VII, X).

Coumarin derivatives inhibit the action of vitamin K by preventing its recycling to an active form after it functions as a cofactor for γ-glutamyl carboxylase. Bleeding can occur with overdosage of the commonly used anticoagulant warfarin or with ingestion of rodent poison, which contains a coumarin derivative. High doses of salicylates also inhibit vitamin K regeneration, potentially leading to a prolonged PT and clinical bleeding.

Treatment

Infants with VKDB should receive 1 mg of parenteral vitamin K. The PT should decrease within 6 hr and normalize within 24 hr. For rapid correction in adolescents, the parenteral dose is 2.5-10 mg. In addition to vitamin K, a patient with severe, life-threatening bleeding should receive an infusion of fresh frozen plasma, which corrects the coagulopathy rapidly. Children with vitamin K deficiency due to malabsorption require chronic administration of high doses of oral vitamin K (2.5 mg twice/wk to 5 mg/day). Parenteral vitamin K may be necessary if oral vitamin K is ineffective.

Prevention

Administration of either oral or parenteral vitamin K soon after birth prevents early VKDB of the newborn. In contrast, a single dose of oral vitamin K does not prevent a substantial number of cases of late VKDB. However, a single intramuscular injection of vitamin K (1 mg), the current practice in the USA, is almost universally effective, except in children with severe malabsorption. This increased efficacy of the intramuscular form is believed to be due to a depot effect. Concerns about an association between parenteral vitamin K at birth and the later development of malignancy are unsubstantiated.

Discontinuing the offending medications before delivery can prevent VKDB due to maternal medications. If this is not possible, administration of vitamin K to the mother may be helpful. In addition, the neonate should receive parenteral vitamin K immediately after birth. If parenteral vitamin K does not correct the coagulopathy rapidly, then the child should receive fresh frozen plasma.

Children at high risk for malabsorption of vitamin K should receive supplemental vitamin K and periodic measurement of the PT.