eMedicine Specialties > Endocrinology > Metabolic Disorders
Vitamin K Deficiency
Updated: Dec 18, 2008
Introduction
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 in oils, such as soybean, cottonseed, canola, and olive oils.[1 ]VK is also synthesized by 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 newborn, caused by a lack of VK reaching the fetus across the placenta, the low level of VK in breast milk, and low colonic bacterial synthesis.[2,3,4 ]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 vegetables and other foods; the recycling ability of VK, which helps to conserve the body's supply; and adequate gut flora to produce VK.
Pathophysiology
Vitamin K (VK) acts as a cofactor; it 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 (which occurs via VK-dependent gamma-glutamyl carboxylase).[5,6,7 ]This essential reaction allows the VK-dependent proteins to bind to surface phospholipids through calcium ion channel – mediated binding, in order 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, osteoporosis is associated with VK deficiency.[8 ]
If a healthy person is subject to a complete dietary absence of VK, his/her VK reserve is adequate for 1 week. Because diet is the main source of VK, an adult's daily requirement has been estimated at 100-200 mcg/d. 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.
The characteristics of VK deficiency vary according to the age of onset. In infants, it causes hemorrhagic disease of newborn, resulting especially in 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 breast milk, and the sterile gut in neonates account for VK deficiency in infants.[2,3,4,9 ]Late hemorrhagic disease of newborn can occur as late as 3 months postpartum.
In adults, low dietary intake of VK 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.[9,10 ]Because 2 main sources of VK exist, neither dietary deficiency nor gut sterilization produces significant coagulopathy in a healthy person.
Frequency
United States
The prevalence of vitamin K (VK) deficiency varies by geographic region.[3 ]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 VK prophylaxis.
International
Internationally, the incidence of vitamin K deficiency is similar to that in the United States.
Mortality/Morbidity
Morbidity correlates with the severity of vitamin K deficiency; severe bleeding can be fatal.
Race
There is no race predilection for vitamin K deficiency.
Sex
Vitamin K deficiency occurs with equal frequency in males and females.
Age
Vitamin K deficiency can occur in any age group, but it is encountered most often in infancy.
Clinical
History
The clinical manifestations of vitamin K deficiency 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, so manifestations can include mucosal and subcutaneous bleeding, such as epistaxis, hematoma, gastrointestinal bleeding, menorrhagia, hematuria, gum bleeding, and oozing from venipuncture sites. Easy bruisability also is observed.[11 ]
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 vitamin K – 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 vitamin K (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, bacterial overgrowth, chronic pancreatitis, and short bowel syndrome resulting from multiple abdominal surgeries can be involved in lack of absorption of VK (which can be corrected with VK supplementation).[12 ]
- 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.[4 ]In addition, surgery and T-tube drainage of the bile duct 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).
- Various drugs, such as cholestyramine, bind to bile acids, thus preventing fat-soluble vitamin absorption. Coumadin blocks the effect of 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.
Differential Diagnoses
| Acute Lymphoblastic Leukemia | Immune Thrombocytopenic Purpura |
| Acute Myelogenous Leukemia | Scurvy |
| Chronic Lymphocytic Leukemia | Thrombotic Thrombocytopenic Purpura |
| Chronic Myelogenous Leukemia | von Willebrand Disease |
| Disseminated Intravascular Coagulation | |
| Dysfibrinogenemia | |
| Glanzmann Thrombasthenia |
Other Problems to Be Considered
Any bleeding disorder should prompt an investigation to exclude vitamin K deficiency. The best way to differentiate bleeding related to vitamin K (VK) deficiency from that related to hepatocellular failure is through determination of the patient's factor V level. Factor V is synthesized by the liver and is not a VK-dependent factor. In patients with severe liver disease, factor V and VK-dependent factors are low, but in VK deficiency, the factor V level is within the reference range.
Workup
Laboratory Studies
- An elevation in the level of serum PT and of activated partial thromboplastin time (aPTT) may be found in patients with vitamin K (VK) deficiency. However, it is not uncommon for these patients to have an elevated PT level and a normal aPTT level.[12 ]
- The most sensitive marker is the high level of des-gamma-carboxy prothrombin (DCP), protein in VK absence (PIVKA), measured with appropriate antibodies.[13 ]
- 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 patients.
Treatment
Medical Care
The medical therapy for vitamin K (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 the 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 VK 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 compound 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, the 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 those with a hematologist and a gastroenterologist.
- A hematologist can exclude other conditions that can mimic vitamin K (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 accurately interpret the laboratory results of such tests.
- A gastroenterologist is consulted only if the hematologic or dietary causes of VK deficiency are excluded. Inflammatory bowel disease, malabsorption, and parenchymal liver disease are among the causes of a VK-deficient state.
Diet
Oils, such as olive, canola, cottonseed, and soybean oils, as well as green, leafy vegetables, are rich sources of vitamin K (VK). Common vegetables, including green peas and beans, watercress, asparagus, spinach, and broccoli, as well as oats and whole wheat, are rich in VK.
Medication
In cases of vitamin K deficiency, the goals of pharmacotherapy are to correct the deficiency, reduce morbidity, and prevent complications.
Fat-soluble vitamins
These are used to supplement existing levels of essential vitamins or to replace essential vitamins that are not obtained in sufficient quantities in the diet. Vitamin K is necessary for the function of clotting factors in the coagulation cascade.[3,4,14 ]
Phytonadione (AquaMEPHYTON, Mephyton, Konakion)
Promotes liver synthesis of clotting factors. The oral form requires the presence of bile in the small intestine for absorption and is therefore not used in emergency situations. Metabolism occurs in the liver, and elimination occurs in bile and urine. Phytonadione has a more rapid and prolonged effect than does menadione (water soluble). Protect the injectable form from light at all times (it may be autoclaved).
Dosing
Adult
5-25 mg/d PO, usual dose is 5-10 mg/d for blood clotting or dietary supplement; may repeat in 12-48 h
10 mg/d IM; may repeat in 8-12 h
Pediatric
Hemorrhagic disease of newborn: 1-2 mg/d IM/SC; 0.5-1 mg within 1 h of birth for prophylaxis
VK deficiency:
2.5-5 mg/d PO
1-2 mg IM/SC once
Interactions
Effects of warfarin, anisindione, and dicumarol are antagonized by phytonadione; mineral oil and cholestyramine may decrease GI absorption of oral form
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Severe anaphylaxis or hypersensitivity reactions have occurred rarely during administration of IV form despite proper rate control and dilution; IV form should be administered only in ED or ICU; adverse effects (<1%) include transient flushing, hypotension (rarely), cyanosis, dizziness, tenderness at site of injection, diaphoresis, and hemolysis in neonates and in patients with G-6-PD deficiency
Blood products
Plasma is the fluid compartment of blood containing the soluble clotting factors.
Fresh frozen plasma
For use in patients with blood product deficiencies.
Dosing
Adult
Dose depends on severity of coagulopathy
Initially, 2 units are administered, then more is administered as needed to control bleeding; after 4-6 U of FFP, the prothrombin level should be checked to guide further need for FFP
Pediatric
Administer as in adults; administer 2 units initially; further administration depends on the severity of coagulopathy
Interactions
None reported
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
A - Fetal risk not revealed in controlled studies in humans
Precautions
Viral contamination and infection are possible but unlikely due to prescreening; ineffective in patients with factor IX inhibitors; may induce an anamnestic response
Follow-up
Complications
- Severe bleeding can occur if vitamin K deficiency is left untreated.
Prognosis
- Patients with vitamin K (VK) deficiency have a very good prognosis if the condition is recognized early and treated appropriately.
- No mortalities from VK deficiency have been reported.
Miscellaneous
Medicolegal Pitfalls
- Some small studies have suggested that prophylaxis with vitamin K (VK) in newborn patients may increase the risk of cancer, but large, observational trials have found no such correlation.[15 ]
- Newborns commonly are administered VK-1 injection to prevent bleeding problems.
- Another observational study (Nurse's Health Study) found that a higher dietary intake of VK is associated with a significantly reduced risk of hip fracture.
References
Suttie JW. Vitamin K. In: Machlin L, ed. Handbook of Vitamins. New York, NY: Marcel Dekker; 1984:147.
Van Winckel M, De Bruyne R, Van De Velde S, et al. Vitamin K, an update for the paediatrician. Eur J Pediatr. Nov 4 2008;[Medline].
Shearer MJ. Vitamin K deficiency bleeding (VKDB) in early infancy. Blood Rev. Sep 18 2008;[Medline].
van Hasselt PM, de Koning TJ, Kvist N, et al. Prevention of vitamin K deficiency bleeding in breastfed infants: lessons from the Dutch and Danish biliary atresia registries. Pediatrics. Apr 2008;121(4):e857-63. [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; 1995:1481-5.
Furie B, Furie BC. Molecular basis of vitamin K-dependent gamma-carboxylation. Blood. May 1 1990;75(9):1753-62. [Medline]. [Full Text].
Udall JA. Human sources and absorption of vitamin K in relation to anticoagulation stability. JAMA. Oct 11 1965;194(2):127-9. [Medline].
Furie B. Vitamin K: metabolism and disorders. In: Hoffman R, Benz EJ, Shattil SJ, et al, eds. Hematology: Basic Principles and Practice. 3rd ed. New York, NY: Churchill Livingstone; 2000:1958-62.
Booth SL, Al Rajabi A. Determinants of vitamin K status in humans. Vitam Horm. 2008;78:1-22. [Medline].
Ansell JE, Kumar R, Deykin D. The spectrum of vitamin K deficiency. JAMA. Jul 4 1977;238(1):40-2. [Medline].
Lee GR, Bithell TC, Forester J. Acquired coagulation disorders. In: Wintrobe's Clinical Hematology. 1993. Baltimore, Md: Williams & Wilkins; 1473-80.
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]. [Full Text].
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].
Merli GJ, Fink J. Vitamin K and thrombosis. Vitam Horm. 2008;78:265-79. [Medline].
Klebanoff MA, Read JS, Mills JL, et al. The risk of childhood cancer after neonatal exposure to vitamin K. N Engl J Med. Sep 23 1993;329(13):905-8. [Medline]. [Full Text].
Keywords
vitamin K deficiency, vitamin, vitamin deficiency, coagulation, vitamin nutrition, vitamin supplement, prothrombin, vitamin k nutrition, vitamin deficiencies, vitamin symptoms, vitamin K newborns, vitamin K sources, vitamin K injection, vitamin K supplement, vitamin K supplements, clotting factor, clotting factors, coagulation factor, factor II, coagulation factors, vitamin supplementation, vitamin K1, vitamin K-1, deficiency of vitamin K, hemorrhagic disease of newborn, phylloquinone, vitamin K2, vitamin K-2, menaquinone, vitamin K3, vitamin K-3, menadione, coagulation proteins, fresh frozen plasma
Contributor Information and Disclosures
Author
Pankaj Patel, MD, Fellow, Department of Gastroenterology, Winthrop University Hospital and SUNY-Stony Brook
Pankaj Patel, MD is a member of the following medical societies: American College of Gastroenterology and American College of Physicians-American Society of Internal Medicine
Disclosure: Nothing to disclose.
Coauthor(s)
Mageda Mikhail, MD, Assistant Professor, Department of Medicine, Division of Endocrinology, State University of New York at Stony Brook
Mageda Mikhail, MD is a member of the following medical societies: Endocrine Society
Disclosure: Nothing to disclose.
Medical Editor
Udaya M Kabadi, MD, Professor, Department of Medicine, University of Iowa College of Medicine
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Romesh Khardori, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Medical Association, American Society of Andrology, Endocrine Society, and Illinois State Medical Society
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CME Editor
Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
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Chief Editor
George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
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