At a Glance

Deficiency of vitamin K (VK) in healthy individuals is very rare because of adequate intake of a wide variety of food items, especially green leafy vegetables (e.g., kale, spinach, broccoli), recycling of VK within hepatocytes, and normal gut flora. Its daily requirement is 100-200 ug (microgram), and the body’s reserve is adequate for 1 week. There are seven types of VK: VK1 is of plant origin (90%), and VK2 is of bacterial origin (10%); VK3-7 are synthetic. VK is a fat soluble vitamin, requires bile salts for emulsification to be absorbed from the terminal ileum.

Absorbed VK is reduced by vitamin K reductase in the liver, which is its active form. In the presence of reduced VK, a carboxylase causes carboxylation of γ glutamic acid residues on coagulation factors II, VII, IX and X, and natural anticoagulants protein C and S. During this reaction, reduced VK gets oxidized to VK epoxide, which, in turn, is converted back to original VK by an epoxide reductase (VK recycling).

Carboxylation is required for a calcium-dependent conformational change in these proteins, which allows binding of factors to phospholipids on various cell surfaces to participate in coagulation cascade.

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Coumarin derivatives, similar in structure to VK, block predominantly epoxide reductase and inhibit regeneration cycle of VK to function as an anticoagulant. During therapeutic anticoagulation, carboxylation of coagulations factors is reduced by 70-85%, which corresponds to an international normalized ratio (INR) of 2-3.

VK deficiency occurs frequently in patients who are very sick with poor dietary intake (e.g., intensive care unit [ICU] patients). Antibiotic therapy kills gut flora, further reducing VK supply. Diseases affecting ileum and liver also cause VK deficiency. In the ICU, sick patients gradually show prolongation of prothrombin time (PT), especially those who are on total parental nutrition, which generally does not supply adequate amount of VK. Similarly, a patient with severe malnutrition will occasionally present to the emergency department with some bleeding tendency and prolonged PT and partial thromboplastin time (PTT). These scenarios suggest the abnormal coagulation test results are due to acquired coagulopathy.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

The patients described with poor nutritional status should be suspected of having VK deficiency and undergo step-by-step testing, if time permits, otherwise should be given 10 mg of VK1 intravenously as a slow infusion over 15-30 minutes in 25-50 cc normal saline, because this approach is both diagnostic (PT gets corrected within 2-6 hours supporting diagnosis of VK deficiency) and therapeutic, preventing unnecessary testing. However, if the differential diagnosis of coagulopathy is liver disease, versus vitamin K, then FV (to assess synthetic function of the liver), FVII, and FII levels (to assess vitamin K status) should be performed.

FVII has the shortest half-life (6 hours) and reflects acute VK status, whereas FII has the longest half-life (60 hours) reflecting long-term VK status. If the FV is normal and FVII and/or FII are reduced, then the coagulopathy is due to VK deficiency. However, if FV is also reduced, then the coagulopathy is due to liver disease. Differentiating between liver disease and VK deficiency is important, because VK deficiency is easily treated with VK1 supplementation, whereas liver disease may need plasma therapy.

Many textbooks still recommend performing PT and/or PTT mixing study to differentiate factor deficiency from an inhibitor as the cause of prolonged test results. However, isolated prolonged PT in such a setting clearly indicates either VK deficiency or liver disease, because FVII inhibitor is extremely rare and such patients present with very long PT and significant bleeding. Performing a mixing study often delays the diagnosis and treatment by at least 1 day.(Table 1)

Table 1.
FV Normal Reduced
FII Reduced Reduced
FVII Reduced Reduced
Interpretation VK deficiency Liver disease

What Lab Results Are Absolutely Confirmatory?

As shown in the table, reduced levels of VK dependent factors and normal FV confirms the diagnosis of VK deficiency.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Rarely, severe VK deficiency results from rat poisoning (suicidal or accidental) in which case PT and PTT are markedly prolonged. In such a case, a very good clinical history is absolutely essential. All vitamin K dependent factors are severely reduced (<5%), including protein C and S with normal FV. The test for superwarfarin (brodifacoum) should be sent out for confirmation.

Because of the very long half-life of superwarfarin (several months), these patients require very high doses of daily VK (20-50mg) for months before showing correction of coagulopathy. Their bleeding should be treated with prothrombin complex concentrates that contain VK dependent factors (FII, VII, IX, and X) or plasma.