AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Vitamin K (VK), an essential lipid-soluble vitamin that plays a vital role in the production of coagulation proteins, is found in green leafy vegetables and oils, such as soybean, cottonseed, canola, and olive oil. VK is synthesized by the colonic bacteria. The 3 main types of VK are K-1, which is derived from plants; K-2, menaquinone, which is produced by the intestinal flora; and K-3, which is a synthetic water-soluble form used for treatment. VK deficiency can occur in persons of any age. Infants are at higher risk for hemorrhagic disease of the newborn due to lack of VK reaching to the fetus across the placenta, the low level of VK in breast milk, and low colonic bacterial synthesis. However, a large amount of VK given to a pregnant patient can lead to jaundice in a newborn. In adults, VK deficiency is uncommon due to the intake of a wide variety of food and vegetables; the recycling ability of VK, which helps conserve the body's supply; and adequate gut flora to produce VK.

Pathophysiology

VK acts as a cofactor and is needed for the conversion of 10-12 glutamic acid residue on the NH2-terminal of the precursor coagulation proteins into the action form of gamma-carboxyglutamic acid via VK-dependent gamma glutamyl carboxylase. This essential reaction allows the VK-dependent proteins to bind to surface phospholipids through calcium ion channel–mediated binding to start the normal antithrombotic process. The exact mechanism by which VK functions as cofactor with the carboxylase is not fully understood. In addition to the coagulation factors, bone matrix proteins, specifically osteocalcin, undergo similar gamma carboxylation with calcium that requires VK; therefore, association of osteoporosis with VK deficiency exists.

The body's reserve for VK is adequate for 1 week with complete dietary absence in a healthy patient. Because diet is the main source of VK, the daily requirement has been estimated at 100-200 mcg/d in the adult. About 80-85% of VK is absorbed mainly in the terminal ileum into the lymphatic system; therefore, bile salts and normal fat absorption, as well as normal villi of the ileum, are necessary for the effective uptake of VK.

VK deficiency varies in the age of onset. In infants, it causes the hemorrhagic disease of newborns, especially with intracranial and retroperitoneal bleeding, which can occur at 1-7 days postpartum. The low transmission of VK across the placenta, liver prematurity with the prothrombin synthesis, lack of VK in the breast milk, and the sterile gut in neonates account for VK deficiency in infants. Late hemorrhagic disease of newborns can occur as long as 3 months postpartum.

In the adult, low dietary intake due to chronic illness, malnutrition, alcoholism, multiple abdominal surgeries, long-term parenteral nutrition, malabsorption, cholestatic disease, parenchymal liver disease, cystic fibrosis, inflammatory bowel disease, and drugs (eg, antibiotics [cephalosporin], Coumadin, salicylates, anticonvulsants, certain sulfa drugs) are some of the common causes of VK deficiency. Because 2 main sources of VK exist, neither the dietary deficiency nor the gut sterilization produces significant coagulopathy in a healthy person.

Frequency

United States

Prevalence varies with geographic regions. In infants, VK deficiency without bleeding may occur in as many as 50% of infants younger than 5 days old. The classic hemorrhagic disease occurs in 0.25-1.7% of infants. The prevalence of late hemorrhagic disease in breastfed infants is about 20 cases per 100,000 live births with no prior prophylaxis with VK.

International

International incidence is similar to incidence in the United States.

Mortality/Morbidity

Morbidity correlates with severity of VK deficiency, but severe bleeding can lead to a patient's demise.

Race

All races are affected equally.

Sex

Both sexes are affected with equal frequency.

Age

VK deficiency may occur in any age group, but it is encountered more often in infancy.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The clinical manifestations are evident only if hypoprothrombinemia is present. Bleeding is the major symptom, especially in response to minor or trivial trauma. Any site can be involved, including mucosal and subcutaneous bleeding, such as epistaxis, hematoma, gastrointestinal bleeding, menorrhagia, hematuria, gum bleeding, and oozing from venipuncture sites. Easy bruisability also is observed.

Physical

Ecchymosis, petechiae, hematomas, and oozing of blood at surgical or puncture sites are observed. In infants, some birth defects, such as underdevelopment of the face, nose, bones, and fingers, are linked to a VK-deficient state.

Causes

• Parenchymal liver diseases such as cirrhosis secondary to viral hepatitis, alcohol intake, and other infiltrative diseases; hepatic malignancy; amyloidosis; Gaucher disease; and others decrease the synthesis of VK-dependent factors; therefore, supplementation with VK is not effective unless a patient has severe bleeding and fresh frozen plasma (FFP) is administered in addition to correct the coagulopathy.



• Malabsorption syndrome affects VK absorption in the ileum. Celiac sprue, tropical sprue, Crohn disease, ulcerative colitis, Ascaris infection, short bowel syndrome due to multiple abdominal surgeries, bacterial overgrowth, and chronic pancreatitis can be involved in lack of absorption of VK, which can be corrected with VK supplementation.



• Biliary diseases, such as common duct obstruction due to stones and strictures, primary biliary cirrhosis, cholangiocarcinoma, and chronic cholestasis, cause maldigestion of fat; the decrease in fat absorption leads to a deficiency of fat-soluble vitamins. In addition, T tube drainage of the bile duct and surgery can lead to a VK-deficient state.



• Dietary deficiency occurs in people with malnutrition, including people with alcoholism, as well as patients undergoing long-term parenteral nutrition without VK supplements. A large amount of vitamin E can antagonize VK and prolong the prothrombin time (PT).



• Drugs, such as cholestyramine, bind to bile acids, thus preventing fat-soluble vitamin absorption. Coumadin blocks the effect of both VK epoxide reductase and VK reductase, thereby inducing an intracellular deficiency. Cefamandole, cefoperazone, salicylates, hydantoins, rifampin, isoniazid, and barbiturates are some of the common drugs that are associated with VK deficiency, but the mechanism is unknown.



• Disease with endogenously produced coagulation inhibitors, such as lupus anticoagulant and antithrombins, and paraproteinemias, ie, multiple myeloma, may cause a VK deficient state.



• Miscellaneous causes include massive transfusion, disseminated intravascular coagulation (DIC), polycythemia vera, nephrotic syndrome, cystic fibrosis, and leukemia.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Any bleeding disorder should prompt an investigation to exclude VK deficiency.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Elevated serum PT and activated partial thromboplastin time (aPTT)



• The most sensitive marker is the high level of des-gamma-carboxy prothrombin (DCP), protein in VK absence (PIVKA), measured with appropriate antibodies.



• The plasma level of VK (0.2-1.0 ng/mL) can be measured. The level of VK depends on the oral intake of VK, which varies among the patients.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The medical therapy for VK deficiency depends on the severity of the bleeding and the underlying pathophysiologic disease state. The most effective approach to correct the deficiency also depends on the nature of bleeding and the risk of inducing a local hematoma at the injection site. In life-threatening bleeds, FFP should be administered prior to VK.

In adults, VK-1, a phylloquinone, should be administered subcutaneously or intramuscularly. If the PT does not normalize, good evidence exists for the presence of liver disease or DIC.

Due to the risks of hematoma formation with intramuscular or subcutaneous administration, an oral form of VK can be administered in 5-20 mg, depending on the severity. The absorption with the oral form is variable because it requires bile salts in the ileum for absorption. This form is used in the setting of asymptomatic VK deficiency.

VK-3, a menadione, is a synthetic water-soluble form used to treat VK deficiency associated with maldigestion and malabsorption syndromes; however, it is not used in newborns due to the hemolysis observed with higher doses.

In urgent situations, 10-20 mg of injectable phytonadione can be dissolved in a 5% dextrose or 0.9% isotonic sodium chloride solution to be administered intravenously at a rate not to exceed 1 mg/mL to prevent a hypersensitive or anaphylactic reaction. With an intravenous form, a patient needs to be monitored closely because cardiopulmonary arrest and/or shock can occur in rare cases. The parenteral administration of VK-1 corrects VK deficiency in 12-24 hours.

Consultations

Consultations include a hematologist and a gastroenterologist.

• A hematologist can exclude other conditions that can mimic VK deficiency. Bleeding time, PT/aPTT levels, and serum DCP level (PIVKA level) are ordered to assist the physician in diagnosing the VK deficiency. A hematologist can interpret the laboratory results of such tests accurately.
• A gastroenterologist is consulted only if the hematological or dietary causes of VK deficiency are excluded. Inflammatory bowel disease, malabsorption, parenchymal liver disease, and others can cause a VK deficient state.

Diet

Green leafy vegetables and oils, such as olive, canola, cottonseed, and soybean, are sources rich in VK. Common vegetables, such as green peas and beans, watercress, asparagus, spinach, and broccoli, as well as oats and whole wheat, are rich in VK.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to correct the vitamin deficiency, reduce morbidity, and prevent complications.

Drug Category: Fat-soluble vitamins

Used to replace essential vitamins not obtained in sufficient quantities in the diet or used to further supplement levels. VK is necessary for the function of clotting factors in the coagulation cascade.

Drug Category: Blood products

Plasma is the fluid compartment of blood containing the soluble clotting factors.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Complications

• Severe bleeding can occur if this condition is left untreated.

Prognosis

• Patients have a very good prognosis if the VK deficiency is recognized early and treated appropriately.
• No mortalities have been reported.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Although some small studies suggested that prophylaxis with VK in newborn patients may increase the risk of cancer, recent large observational trials have found no such correlation.
• Newborns commonly are administered VK-1 injection to prevent bleeding problems.
• Another observational study (Nurse's Health Study) found that higher dietary intake of VK is associated with significantly reduced risk of hip fracture.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Ansell JE, Kumar R, Deykin D. The spectrum of vitamin K deficiency. JAMA. Jul 4 1977;238(1):40-2. [Medline].
• Beutler E, Lichtman MA, Coller BS. Disorders of the vitamin K dependent coagulation factors. In: Williams Hematology. 5th ed. New York, NY:. McGraw-Hill Co;1995:1481-1485.
• Furie B, Furie BC. Molecular basis of vitamin K-dependent gamma-carboxylation. Blood. May 1 1990;75(9):1753-62. [Medline].
• Furie B. Vitamin K: Metabolism and Disorders. In: Hoffman R, Benz EJ, et al, eds. Hematology: Basic Principles and Practice. 3rd ed. New York, NY:. Churchill Livingstone, Inc;2000:1958-1962.
• Klebanoff MA, Read JS, Mills JL, Shiono PH. The risk of childhood cancer after neonatal exposure to vitamin K. N Engl J Med. Sep 23 1993;329(13):905-8. [Medline].
• Krasinski SD, Russell RM, Furie BC. The prevalence of vitamin K deficiency in chronic gastrointestinal disorders. Am J Clin Nutr. Mar 1985;41(3):639-43. [Medline].
• Lee GR, Bithell TC, Forester J. Acquired Coagulation Disorders. In: Wintrobe's Clinical Hematology. Baltimore, Md:. William & Wilkins;1993:1473-1480.
• Liebman HA, Furie BC, Tong MJ. Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma. N Engl J Med. May 31 1984;310(22):1427-31. [Medline].
• Suttie JW. Vitamin K. In: Machlin L, ed. Handbook of Vitamins. New York, NY:. Marcel Dekker;1984:147.
• Udall JA. Human sources and absorption of vitamin K in relation to anticoagulation stability. JAMA. Oct 11 1965;194(2):127-9. [Medline].

Article Last Updated: Jun 20, 2006