Vitamin K Deficiency

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Practice Essentials

Vitamin K (VK) deficiency can occur in any age group but is encountered most often in infancy. 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. (See Etiology and Epidemiology.)

The 3 main types of VK are K-1 (also known as phylloquinone or phytonadione), which is derived from plants; K-2 (menaquinone), which is produced by the intestinal flora; and K-3 (menadione), which is a synthetic, water-soluble form used for treatment.

Infants with VK deficiency are at 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. Vitamin K deficiency bleeding (VKDB) in infants is classified according to the time of presentation: early (3</ref>[5, 6, 7] (See Etiology, Treatment, and Medication.)

Bleeding is the major symptom, especially in response to minor or trivial trauma. On physical examination, ecchymosis, petechiae, hematomas, and oozing of blood at surgical or puncture sites are observed.

Because diet is the main source of VK, an adult's daily requirement has been estimated at 100-200 mcg/day. 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-functioning villi of the ileum, are necessary for the effective uptake of VK. If a healthy person is subject to a complete dietary absence of VK, his/her VK reserve is adequate for 1 week. (See Etiology below.)

Measurements of serum prothrombin time (PT) tend to be elevated, and activated partial thromboplastin time (aPTT) is usually normal.[8]  Both PT and aPTT can be elevated in more severe deficiency states. The most sensitive marker that is elevated in VK deficiency states is des-gamma-carboxy prothrombin (DCP), also known as protein induced by vitamin K absence/antagonist-II (PIVKA-II).[9]  PIVA-II levels reflect the functional marker of coagulation.

The medical therapy for VK deficiency depends on the severity of the associated bleeding and the underlying disease state. The most effective approach to correcting the deficiency also depends on the nature of the bleeding and the risk of inducing a local hematoma at the VK injection site. In life-threatening bleeds, fresh frozen plasma should be administered prior to VK.[10]  There is no evidence of increased risk for adverse events associated with vitamin K prophylaxis. The risk of developing VK deficiency bleeding is 81 times greater in infants who do not receive a vitamin K injection.[11]

Physiology

Vitamin K (VK) acts as a cofactor; it is needed for the conversion of 10-12 glutamic acid residue on the NH2 -terminal of precursor coagulation proteins into the action form of gamma-carboxyglutamic acid (which occurs via VK-dependent gamma-glutamyl carboxylase).[12, 13, 14] 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.

Vitamin K is required in the synthesis of 4 clotting factors in the liver: factors II,VII, IX, and X. It is also essential in the production of protein C and S, which are anticoagulant proteins.[5]

Bone matrix proteins, specifically osteocalcin, undergo gamma carboxylation with calcium much the way coagulation factors do; this process also requires VK.

Etiology

In infants, the low transmission of vitamin K (VK) across the placenta, liver prematurity with prothrombin synthesis, lack of VK in breast milk, and the sterile gut in neonates account for VK deficiency.[2, 3, 4, 15]  Neonatal diseases that cause cholestasis can result in VK deficiency.[5]  Parental refusal of VK prophylaxis at childbirth can result in bleeding sequela.[5]

In adults, the causes of VK deficiency include the following[15, 16] :

The synthesis of VK-dependent factors are decreased by parenchymal liver diseases, such as cirrhosis secondary to viral hepatitis, alcohol intake, and other infiltrative diseases; hepatic malignancy; amyloidosis; Gaucher disease; and alpha-1 antitrypsin deficiency. Therefore, supplementation with VK is not effective unless a patient has severe bleeding and fresh frozen plasma is administered in addition to correcting 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 result in poor absorption of VK (which can be corrected with VK supplementation).[8]

Cystic fibrosis patients who have pancreatic insufficiency, excessive or chronic antibiotic usage, or short bowel due to intestinal resection are at increased risk for vitamin K deficiency due to malabsorption.[18]

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, such as VK.[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, alcoholics, and 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. Warfarin 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 their mechanism of action in this condition is unknown.

Because 2 main sources of VK exist, neither dietary deficiency nor gut sterilization produces significant coagulopathy in a healthy person.

Epidemiology

Vitamin K (VK) deficiency can occur in any age group, but it is encountered most often in infancy. In the United States, the prevalence of 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. 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.

Comparing incidences of VK deficiency between different countries is difficult because countries have different criteria to acquire their national incidences. Among countries that share the same methodologies, western European countries have an incidence of late VK deficiency bleeding in infants of approximately 5 cases per 105 live births; the incidence is 11 cases per 105 live births in Japan; and the incidence is 72 cases per 105 live births in Thailand.[19]

Prognosis

Patients with VK deficiency have a very good prognosis if the condition is recognized early and treated appropriately. No mortalities from VK deficiency have been reported. However, severe bleeding can occur if the deficiency is left untreated. Morbidity correlates with the severity of vitamin K deficiency. The risk of developing vitamin K deficiency bleeding is 81 times greater in infants who do not receive a  prophylactic vitamin K injection.[11]

In 50% of patients with late vitamin K deficiency bleeding (VKDB), the bleeding location involves an intracranial hemorrhage, which is associated with high mortality and morbidity.

History

The clinical manifestations of vitamin K (VK) 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.[20]

Physical Examination

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. Infants may present with nontraumatic intracranial bleeding with signs such as vomiting, poor intake, anemia, seizures, and bleeding in mucosal sites.

Complications

The characteristics of vitamin K (VK) deficiency vary according to the age of onset. In infants, its deficiency causes hemorrhagic disease of newborn, resulting in intracranial and retroperitoneal bleeding, which can occur at 1-7 days postpartum. Late hemorrhagic disease of newborn can occur as late as 3 months postpartum. (See Presentation and Workup.)[21, 22]

Because VK is involved in gamma carboxylation of osteocalcin, which is important in bone synthesis, osteoporosis is associated with VK deficiency.[23, 24, 25]  Osteocalcin is important in the remodeling and mineralization of bone.

Laboratory Studies

Measurements of serum prothrombin time (PT) tend to be elevated and activated partial thromboplastin time (aPTT) is usually normal.[8]  Both PT and aPTT can be elevated in more severe deficiency states.

The most sensitive marker that is elevated in VK deficiency states is des-gamma-carboxy prothrombin (DCP), also known as protein induced by vitamin K absence/antagonist-II (PIVKA-II).[9]  PIVA-II levels reflect the functional marker of coagulation.

The plasma level of VK, serum phylloquinone, (0.2-1.0 ng/mL) can be measured; however, the level of VK depends on the oral intake of VK, which can vary. However, a low serum phylloquinone (< 0.15 mcg/L) suggests low tissue body stores.[19]

A clearly prolonged PT (INR > 3.5) along with normal fibrinogen concentration and platelet count is highly suggestive ofvitamin K deficiency-related bleeding (VKDB). Confirmation of the diagnosis requires measurement of the specific vitamin K-dependent factors (II, VII, IX, X) whose levels are rapidly corrected by the parenteral administration of 1 mg vitamin K.[3]

Approach Considerations

The medical therapy for vitamin K (VK) deficiency depends on the severity of the associated bleeding and the underlying disease state. The most effective approach to correcting the deficiency also depends on the nature of the bleeding and the risk of inducing a local hematoma at the VK injection site. In life-threatening bleeds, fresh frozen plasma should be administered prior to VK.

In adults, VK-1 should be administered subcutaneously or intramuscularly. If the PT does not normalize after VK supplementation, then consideration should be made for the presence of liver disease or DIC.

If there is a high risk for hematoma formation with intramuscular or subcutaneous VK administration, then an oral form of VK can be administered in 5- to 20-mg doses, 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 (VK-1) can be dissolved in a 5% dextrose or 0.9% normal saline to be administered intravenously at a rate not to exceed 1 mg/mL to prevent a hypersensitive or anaphylactic reaction. When giving VK in the 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.

There is currently no consensus on dosing for chronic supplementation for patients with cystic fibrosis. However, because of limited stores of vitamin K and its fast turnover in the body, daily supplementation is recommended. Dosages for all ages range from 0.3 to 1 mg/day.[18, 26]

Consultations

Consultations should be considered with a hematologist and a gastroenterologist.

A hematologist can exclude conditions that can mimic vitamin K (VK) deficiency. Bleeding time, PT/aPTT, and serum DCP level (PIVKA level) are ordered to assist the physician in diagnosing the VK deficiency. A hematologist can aid in the interpretation of laboratory results.

A gastroenterologist is consulted when the hematologic or dietary causes of VK deficiency are excluded. They can help diagnose inflammatory bowel disease, malabsorption, and parenchymal liver disease that can cause a VK-deficient state.

Diet

The main sources of VK are plants. The following are rich in vitamin K:

No consensus has been reached on a recommended daily allowance for VK. Current adequate intake (AI) index for VK in the United States is 90 mcg/day for women and 120 mcg/day for men. The AI for pregnant and lactating women are 75 mcg/day and 90 mcg/day, respectively.[19] AI recommendations for VK only fulfill the requirement for coagulation function.

For patients on parenteral nutrition, 150 mcg/day of phylloquinone is provided in a multivitamin preparation. Careful monitoring of the international normalized ratio (INR) is needed in patients who are on anticoagulation and receiving high supplemental dosing of VK, because this can create a warfarin-resistant state.[19]

Prevention

Vitamin K injection at birth is highly effective in preventing vitamin K deficiency bleeding in infants, and since 1961, the American Academy of Pediatrics (AAP, has recommended a prophylactic dose of intramuscular vitamin K be given up to 6 hours after birth.[10] There is no evidence of increased risk for adverse events associated with vitamin K prophylaxis. The risk of developing vitamin K deficiency bleeding is 81 times greater in infants who do not receive a vitamin K injection.[11, 27, 28]

Although a study in the early 1990s found an association between vitamin K injection and childhood cancer, these results were never replicated in subsequent studies.[29, 30] The AAP reviewed the evidence regarding vitamin K and cancer risk in 1993, and again in 2003, and reaffirmed its recommendation for intramuscular injection both times.[10]  Nevertheless, in 2013 the CDC investigated a cluster of large cranial bleeds caused by vitamin K deficiency in infants who had not received prophylaxis at birth because of parental concerns of cancer risk or toxic effects of preservatives.[31] Parents of infants who opt out of the vitamin K injection report being unaware that the risk for vitamin K deficiency bleeding lasts up to 6 months.[31, 32]

Universal neonatal vitamin K prophylaxis is further by complicated by state public health laws that can be inconsistent with the AAP guidelines. According to the CDC, 20 states lack statutes related to neonatal vitamin K prophylaxis, and among the 30 states that do, there is significant variability in the framework for administration of prophylaxis.[11]

Similarly, although the World Health Organization has released recommendations for intramuscular vitamin K for newborns, there is no agreement globally of the optimal dose, route, and frequency of administration of vitamin K. Among developed countries, there is a variety of oral and intramuscular (IM) regimens of vitamin K administration at birth being utilized.[33]

Guidelines Summary

Vitamin K prophylaxis in neonates

The following organizations have issued guidelines for the administration of vitamin K prophylaxis in neonates:

According to the AAP guidelines, all newborns should be given an intramuscular (IM) dose of 0.5 to 1 mg of vitamin K within 6 hours after birth. The Canadian Paediatric Society Committee/College of Family Physicians of Canada guidelines are in concurrence with AAP with the recommendation of IM administration of vitamin K within the first 6 hours after birth, with dosages of 0.5 mg for birthweights up to 1,500 g and a 1-mg dose for birthweights over 1,500 g.[34]  The WHO recommends 1 mg of vitamin K intramuscularly up to 6 hours after birth for all infants.[35]

Medication Summary

In vitamin K (VK) deficiency, the goals of pharmacotherapy are to correct the deficiency, reduce morbidity, and prevent complications. Newborns commonly are given VK-1 injections intramuscularly to prevent bleeding problems. In adults, VK-1 should be administered subcutaneously or intramuscularly. If the PT does not normalize, good evidence exists for the presence of liver disease or DIC. Vitamin K is necessary for the function of clotting factors in the coagulation cascade.[3, 4, 36]

Some small studies have suggested that prophylaxis with VK in newborn patients may increase the risk of cancer, but large, observational trials have found no such correlation.[30]

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. In Japan, high oral doses of VK (45mg/day) are given to prevent osteoporosis with little known side effects.[19]

Phytonadione (Mephyton)

Clinical Context:  Phytonadione promotes the synthesis of clotting factors in the liver. 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). The injectable form should be protected from light at all times (it may be autoclaved).

Class Summary

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.

Fresh frozen plasma

Clinical Context:  Fresh frozen plasma is for use in patients with blood product deficiencies.

Class Summary

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

Author

Dieu-Thu Nguyen-Khoa, MD, FACP, Associate Clinical Professor of Medicine, University of California, Los Angeles, David Geffen School of Medicine; Physician Specialist, Department of Primary Care and Community Medicine, ValleyCare Olive View-UCLA Medical Center

Disclosure: Nothing to disclose.

Coauthor(s)

Mageda Mikhail, MD, Assistant Professor, Department of Medicine, Division of Endocrinology, The School of Medicine at Stony Brook University Medical Center

Disclosure: Nothing to disclose.

Pankaj Patel, MD, Fellow, Department of Gastroenterology, Winthrop University Hospital and The School of Medicine at Stony Brook University Medical Center

Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor Emeritus of Medicine, St Louis University School of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Hampton Roy, Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences

Disclosure: Nothing to disclose.

Acknowledgements

Romesh Khardori, MD, PhD, FACP Professor of Endocrinology, Director of Training Program, Division of Endocrinology, Diabetes and Metabolism, Strelitz Diabetes and Endocrine Disorders Institute, Department of Internal Medicine, Eastern Virginia Medical School

Romesh Khardori, MD, PhD, FACP is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, and Endocrine Society

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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