Vitamin K Deficiency

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Vitamin K deficiency, a frequently overlooked condition, significantly impacts health across various physiological domains. Being a group of fat-soluble compounds, vitamin K is involved in essential processes such as blood clotting, bone metabolism, and cardiovascular health. The absence of vitamin K in the human body can result in a spectrum of complications, including bleeding disorders, impaired bone development, and potential cardiovascular risks. Understanding the intricate interplay between vitamin K and these fundamental physiological functions is crucial for healthcare professionals.

Vitamin K deficiency in newborns presents a distinct and critical concern within the realm of pediatric health care. Newborns with limited vitamin K reserves who do not receive timely intervention are susceptible to developing potentially life-threatening bleeding disorders, referred to as Vitamin K deficiency bleeding (VKDB). Hereditary combined deficiency of vitamin K–dependent clotting factor (VKCFD) is a rare congenital bleeding disorder that can manifest in neonates.

This activity reviews the etiology, clinical manifestations, diagnostic approaches, and effective management strategies for vitamin K deficiency. This activity also highlights the importance of an interprofessional healthcare team in delivering comprehensive patient care.

Objectives:

  • Differentiate between the various causes and forms of vitamin K deficiency, including VKDB and VKCFD, in both adults and newborns.

  • Assess vitamin K status using appropriate markers, such as PIVKA-II, to diagnose deficiency and its severity.

  • Implement evidence-based guidelines and protocols for preventing, diagnosing, and treating vitamin K deficiency, ensuring timely administration.

  • Collaborate with an interprofessional healthcare team to provide comprehensive care for patients with vitamin K deficiency.

Introduction

Vitamin K comprises a group of fat-soluble compounds. Several vitamin K-dependent proteins are involved in essential processes such as blood clotting, bone metabolism, and cardiovascular health. Vitamin K deficiency can contribute to significant bleeding, poor bone development, osteoporosis, and increased cardiovascular disease. According to the National Academy of Science Food and Nutrition Board, the recommended dietary intake for healthy adults is 120 μg/d for men and 90 μg/d for women.

Vitamin K deficiency bleeding (VKDB) in newborns is categorized into 3 groups based on the timing of presentation. Early VKDB manifests within 24 hours after birth, classic VKDB presents within the first week, and late VKDB occurs between 1 week and 6 months of life, with a peak incidence between 2 weeks and 8 weeks.[1][2] Hereditary combined deficiency of vitamin K–dependent clotting factors (VKCFD) is a rare congenital bleeding disorder that can also manifest during the neonatal period.[1][3]

Etiology

Vitamin K deficiency can occur due to various factors, such as insufficient consumption of vitamin K-rich foods, including leafy greens and fermented products, which can be a primary cause. Certain medical conditions that affect fat absorption, such as celiac disease or inflammatory bowel diseases, can impede vitamin K absorption. Furthermore, prolonged use of antibiotics can disrupt the gut bacteria responsible for synthesizing vitamin K. Medications that interfere with vitamin K metabolism, such as blood thinners, can also contribute to deficiency. Understanding these diverse underlying factors is essential for effectively preventing and managing vitamin K deficiency.

VKDB has several etiologies, including maternal medication usage during pregnancy and low vitamin K levels at birth or exclusive breastfeeding.

On the contrary, VKCFD is a rare or infrequent autosomal recessive disorder that leads to reduced levels of coagulation factors II, VII, IX, and X, along with proteins C, S, and Z. 

Epidemiology

Although vitamin K deficiency may be commonly observed in 8% to 31% of typically healthy adults, it rarely causes clinically significant bleeding. Bleeding or hemorrhage typically occurs in individuals with malabsorption syndromes, liver disease, or those receiving medications that interfere with vitamin K metabolism.[4][5][6]

Every neonate has lower vitamin K levels at birth. The initial reports of classic VKDB date back to 1894, which describe a bleeding disorder that occurs on the second or third day of life. Combined with sepsis-induced bleeding, the incidence reached 600 cases per 100,000 infants, resulting in a 62% fatality rate. Early VKDB has been linked to mothers prescribed anticonvulsants or other vitamin K–interfering medications. The incidence of early VKDB without prophylactic neonatal vitamin K is as high as 12%. In the absence of vitamin K supplementation, the current incidence of classic VKDB is estimated to be within the range of 0.25% to 1.7%. Late VKDB affects 4.4 to 72 infants per 100,000 births, with a higher risk observed in exclusively breastfed infants and the highest incidence among Asian populations. The mortality rate for late-onset VKDB ranges from 20% to 50%. In addition, late VKDB also has a significant neurological morbidity rate due to intracranial hemorrhage.[2][7][8][9]

VKCFD is an uncommon autosomal recessive disorder, with fewer than 30 reported cases worldwide, affecting both males and females equally.[10]

Pathophysiology

Vitamin K belongs to a group of fat-soluble derivatives known as 2-methyl-1,4-naphthoquinones. There is a variable alkyl substituent at the third position of the compound. There are, in total, 3 forms of vitamin K. The 2 primary forms are K1 (phylloquinone) and K2 (menaquinone), and the third synthetic form, K3 (menadione), is no longer in use. A synthetic form of vitamin K1 has replaced vitamin K3 because of the potential for toxicity in infants with glucose-6-phosphate dehydrogenase deficiency.[2]

Vitamin K1 is abundant in leafy greens and cruciferous vegetables. The primary sources of vitamin K2 are fermented foods and its synthesis by intestinal flora. Vitamins K1 and K2 have distinct bodily distributions and may impact enzyme activity differently.[4] Vitamin K1 obtained from dietary sources is absorbed in the jejunum and ileum, transported by chylomicrons into the circulation, and depends on bile, pancreatic enzymes, and dietary fat for effective absorption.[11]

Vitamin K is essential for the synthesis of prothrombin and clotting factors II, VII, IX, and X. These factors act as cofactors for the gamma-glutamyl carboxylase and the vitamin K 2,3-epoxide reductase complex in the process of modifying gamma-carboxyglutamic acid on clotting factors II, VII, IX, and X. This modification is essential for cofactors to bind effectively to phospholipids in the platelet membrane. Under-carboxylated clotting factors result in reduced protein activity and excessive bleeding.[4]

Vitamin K is also essential for activating other proteins, including anticoagulants C, S, and Z; osteocalcin; and matrix GLA proteins.[12] Individuals with reduced bone mineral density often exhibit under-carboxylated osteocalcin, which increases fracture rates in older patients.[11][12] Decreased levels of certain vitamin K subtypes result in increased arterial calcification.[4]

Vitamin K does not cross the placenta efficiently, which results in infants being born with low-to-undetectable concentrations of vitamin K and an elevation of protein induced by vitamin K absence or antagonist-II (PIVKA-II). PIVKA is a pre-carboxylated or incompletely carboxylated form of prothrombin.[13]

VKCFD is a rare autosomal recessive disorder caused by mutations in either gamma-glutamyl carboxylase type 1 or vitamin K 2,3-epoxide reductase type 2 complex. These mutations lead to under-carboxylation and reduced vitamin K–dependent protein activity.

History and Physical

Vitamin K deficiency may manifest as bleeding at venipuncture sites or after minor trauma. Patients may also administer antibiotics, anticonvulsants, warfarin, or other prescription medications that interfere with vitamin K metabolism. Physical examination often reveals the presence of ecchymoses or petechiae.

In VKDB, neonates exhibit bleeding and ecchymoses. All types of VKDB are associated with parents who have declined the recommended vitamin K prophylaxis for their newborns. Infants with early VKDB typically experience severe bleeding in the intracranial, intrathoracic, or intra-abdominal areas. Early VKDB is associated with maternal medications that inhibit vitamin K metabolism. Classic VKDB naturally occurs with less severe bleeding from the umbilicus or gastrointestinal tract or after circumcision. Late VKDB frequently manifests as severe intracranial hemorrhage and has a higher incidence among exclusively breastfed infants, primarily due to lower vitamin K content in breast milk than in formula milk.[14] Unexplained bleeding or bruising should always trigger additional investigation through laboratory testing.

Severe cases of VKCFD are usually present in the newborn period with symptoms similar to those of VKDB, whereas milder cases may manifest later in life. The typical presentation includes hemorrhage, which can be spontaneous or associated with surgery. There is often a history of easy bruising, mucosal bleeding, and developmental and skeletal anomalies.[10]

Evaluation

Classic vitamin K deficiency in adults is characterized by elongated prothrombin time (PT) responsive to vitamin K supplementation. PT serves as an indicator of vitamin K status due to its effect on plasma prothrombin levels. Notably, PT is a nonspecific indicator, and an approximate 50% reduction in prothrombin levels is typically required for PT to become abnormal.[15] In the absence of vitamin K, PIVKA-II production occurs, which serves as a more sensitive marker for vitamin K deficiency and is also called Des-gamma-carboxy prothrombin (DCP). PIVKA-II or DCP levels have minimal variability based on factors such as age that influence vitamin K plasma and serum concentrations.[16]

Elevated PIVKA-II levels become evident in individuals who consume less than 60 mcg of vitamin K daily.[17] At birth, elevated PIVKA-II levels are present in 10% to 50% of newborns, and by day 4 or 5 of life, approximately 70% of non-supplemented healthy infants exhibit elevated PIVKA-II levels.[2] The direct measurement of vitamin K plasma levels yields highly variable results, influenced by analytical methods, nutritional and metabolic factors, and the interference of dietary lipid content. Although assessing vitamin K subtypes and concentration levels in patients is valuable, liquid chromatography–tandem mass spectrometry technique may not be easily accessible.[4]

The diagnostic criteria for VKDB comprise a PT that is ≥4 times the normal range and the presence of 1 of the following conditions:

  • Normal or increased platelet count with normal fibrinogen and the absence of degradation products.
  • PT returned to the normal range within 30 minutes after administering intravenous (IV) vitamin K.
  • Elevated levels of PIVKA-II or DCP.[2]

When VKCFD is suspected as the etiology, a research laboratory can perform genotyping of gamma-glutamyl carboxylase and the vitamin K 2,3-epoxide reductase complex to confirm the diagnosis.[10]

Treatment / Management

The treatment and management of conditions related to vitamin K are mentioned below.

Vitamin K deficiency in adults: As per the guidelines set by the National Academy of Science Food and Nutrition Board, a daily vitamin K intake of at least 120 μg for men and 90 μg for women is necessary either through dietary sources or oral supplementation to address vitamin K deficiency in adults. The recommended corrective oral dose for vitamin K1 deficiency ranges from 1 to 2 mg, with a maximum oral dose of 25 mg. Patients taking anticoagulants are typically administered 1 to 10 mg of vitamin K1. The maximum effect of oral administration is generally observed around 24 hours after the dose.

Chronic conditions in adults: Although no established guidelines exist, emerging data from ongoing randomized controlled studies indicate potential benefits from larger doses of vitamins K1 and K2.[18]

Prophylaxis in newborns: Prophylaxis typically involves administering 0.5 to 1 mg of vitamin K1 via intramuscular injection within the first hour of birth.[19] Alternatively, an oral dose of 2 mg of vitamin K1 can be administered to newborns at birth, followed by additional doses between days 4 and 6, and then again between weeks 4 and 6. Another approach is to administer 2 mg of vitamin K1 orally at birth, followed by weekly doses of 1 mg for 3 months. However, it is noteworthy that intramuscular injection is preferred in newborns due to its higher efficacy.[1][2]

Vitamin K deficiency due to malabsorption in infants: In cases of malabsorption, the treatment necessitates daily oral administration of vitamin K1 in high doses, ranging from 0.3 to 15 mg/d, depending on the specific disease. If oral dosing proves ineffective, parenteral administration of vitamin K1 can be considered.[20]

Treatment of neonatal VKDB: The treatment typically involves administering 1 to 2 mg of vitamin K1 via slow IV or subcutaneous infusion. In cases of severe bleeding, fresh frozen plasma may be required at a dosage of 10 to 15 mL/kg.[14]

Treatment of VKCFD: For VKCFD, the treatment regimen involves an oral administration of 10 mg of vitamin K1, typically taken 2 to 3 times per week. In cases where oral dosing is not well tolerated, IV infusion of vitamin K1 can be considered an alternative. During surgical procedures or in cases of severe bleeding, fresh frozen plasma may be necessary, typically administered at a dose of 15 to 20 mL/kg. In certain situations, prothrombin complex concentrates and recombinant factor VII may be administered if necessary.[10]

Differential Diagnosis

Other bleeding disorders, such as factor deficiencies, may mimic the presentation of vitamin K deficiency. The diagnosis can be established by assessing unresponsiveness to vitamin K supplementation and conducting assays of factor activity. Furthermore, it is essential to differentiate between possible drug interactions caused by medications such as warfarin and acquired vitamin K deficiencies resulting from malabsorption, as these need to be distinguished from nutritional deficiencies and VKCFD.

Vitamin K deficiency in adults can contribute to conditions such as osteoporosis, cardiovascular disease, and other chronic diseases. Patients with vitamin K deficiency may exhibit signs and symptoms overlapping with those of other medical conditions, posing diagnostic challenges.

Pertinent Studies and Ongoing Trials

A search on ClinicalTrials.gov has identified at least 402 studies involving vitamin K and vitamin K agonists with 136 ongoing trials. These trials encompass a broad range of topics, including comparisons between vitamin K agonists and novel anticoagulants and exploring the potential benefits of vitamin K in chronic conditions such as osteoporosis, chronic kidney disease, and diabetes.

Notable studies and trials exploring vitamin K status in relation to chronic diseases include the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study, the Longitudinal Aging Study Amsterdam (LASA), the Vitamin K Supplementation in Postmenopausal Women with Osteopenia (ECKO) trial, the Vitamin K Italian (VIKI) Dialysis Study, and the Japanese Osteoporosis Intervention Trial-03.[6][21][22][23][24]

Treatment Planning

For adults, the preferred method of maintaining adequate vitamin K levels and treating minor bleeding is through oral vitamin K supplementation or occasional subcutaneous injection. IV administration is typically reserved for cases of severe bleeding.

Intramuscular vitamin K injection is the recommended prophylactic method for all newborns and infants due to its increased efficacy compared to oral administration. If a newborn vomits or regurgitates an oral dose of vitamin K within 1 hour, it is recommended to give them another dose. Oral vitamin K should be avoided in preterm infants and neonates with cholestasis or intestinal conditions that may interfere with absorption.

Toxicity and Adverse Effect Management

No known adverse effects are associated with excessive dietary intake of vitamin K. Phytonadione is a synthetic derivative of vitamin K1, which is accessible as an oral tablet or an injectable emulsion suitable for IV, intramuscular, or subcutaneous administration. Anaphylactoid reactions from phytonadione are infrequent, estimated to occur in 3 cases per 10,000 doses, with a higher association with the IV route, especially in severe cases. Emulsifying agents, specifically polyoxyethylated castor oil, have been implicated as the most likely cause of the anaphylactoid reaction.[25]

Prognosis

The prognosis for vitamin K deficiency varies based on the severity of the deficiency, its underlying causes, and the promptness of intervention. Evaluating nutritional deficiencies in adults poses challenges due to confounding factors, including overall nutritional status and variations in metabolism influenced by comorbid conditions or genetic factors. Mild cases of vitamin K deficiency can frequently be corrected through dietary modifications and supplementation, resulting in a favorable prognosis with minimal long-term consequences. However, if the deficiency remains untreated, it can lead to severe complications, including excessive bleeding, impaired bone development, and potentially heightened cardiovascular risks.

The prognosis for neonates with vitamin K deficiency is intricately linked to the timely diagnosis and the implementation of appropriate preventive measures. Timely administration of vitamin K at birth significantly reduces the risk of life-threatening bleeding disorders. Late-onset VKDB has the most dire prognosis, with 50% of cases presenting with intracranial hemorrhage.[14] In VKCFD, when appropriate vitamin K supplementation is administered, the prognosis is generally favorable, with a limited impact on the individual's quality of life.[10]

Awareness, early detection, and targeted interventions are pivotal in shaping the overall prognosis and mitigating potential adverse outcomes associated with vitamin K deficiency in adults and neonates.

Complications

Vitamin K deficiency can lead to complications due to its pivotal role in blood clotting, bone health, and cardiovascular function. Insufficient vitamin K impairs the production of critical clotting factors, resulting in an increased risk of bleeding and bruising. Hemorrhage is the most dangerous complication of vitamin K deficiency across all age groups, and in infants, it can have fatal consequences.

Inadequate vitamin K in the body also disrupts bone mineralization, contributing to poor bone development, osteoporosis, and increased fracture rates. Emerging evidence suggests that vitamin K deficiency might also heighten the risk of cardiovascular diseases by affecting arterial calcification and arterial stiffness. Comprehending these complications emphasizes the significance of timely detection and intervention to mitigate the potential adverse effects of vitamin K deficiency.

Consultations

A multidisciplinary approach is necessary to ensure comprehensive care for individuals with vitamin K deficiency. Hematologists play a crucial role in assessing and managing bleeding disorders that result from insufficient clotting factors due to vitamin K deficiency. Nutritionists or dietitians can guide dietary adjustments and supplementation strategies to address the deficiency. Gastroenterologists may become involved in cases where malabsorption disorders contribute to the deficiency, addressing underlying gastrointestinal issues. Collaborating with orthopedic specialists to assess bone health and with cardiologists to evaluate cardiovascular risk can prove beneficial, particularly in more severe cases or when associated conditions are present.

Pediatricians are critical in neonatal care, encompassing early detection, administering prophylactic vitamin K, and ongoing monitoring for neonates with vitamin K deficiency. Genetic consultations are advisable for individuals with suspected or confirmed VKCFD to provide comprehensive guidance and insight into the genetic aspects of the condition. This collaborative approach aids in customizing interventions to address each patient's specific needs, ensuring a comprehensive and effective management of vitamin K deficiency and its potential complications.

Deterrence and Patient Education

To prevent VKDB, educating parents about the significance of vitamin K supplementation for their infants at birth and the rationale behind this intervention in averting a rare but potentially life-threatening hemorrhage is essential. Healthcare providers can discuss with parents the efficacy of intramuscular injection in preventing all forms of VKDB compared to oral supplementation. They should highlight that intramuscular injection requires only a single dose of administration, thereby eliminating the need for repeated oral vitamin K supplementation doses. Parents concerned about a 1990 study suggesting a potential link between neonatal administration of vitamin K and childhood cancers can be reassured that numerous subsequent investigations have found no evidence of such association.[26]

Patients with chronic conditions may find potential benefits in vitamin K supplementation. Engaging in a discussion about ongoing research with patients who express interest in this topic is advisable.

Pearls and Other Issues

Understanding the complexities of vitamin K is essential, as it plays a critical role in various physiological processes.

  • Vitamin K is an indispensable cofactor for coagulation factors II, VII, IX, and X, anticoagulation proteins C, S, and Z, osteocalcin, matrix GLA protein, and numerous other non-hematological proteins.
  • Access to direct vitamin K testing and body concentration can be challenging due to interfering substances, variations in vitamers, and tissue distribution complexities.
  • PIVKA-II is currently the most valuable and readily accessible test for assessing vitamin K status.
  • No reported toxicity is associated with elevated levels of vitamin K.
  • Vitamin K formulations have been associated with rare anaphylactoid reactions.

Enhancing Healthcare Team Outcomes

Vitamin K supplementation in calcific cardiovascular disease and osteoporosis may reduce morbidity and mortality. Patients without contraindications should be considered for vitamin K supplementation.[4] Physicians, advanced practice practitioners, nurses, pharmacists, and nutritionists should collaborate as an interprofessional team to ensure that patients with vitamin K deficiency receive appropriate treatment and monitoring.

VKDB represents a potentially devastating consequence of neonatal vitamin K deficiency. Vitamin K prophylaxis in newborns should occur within an hour of birth to prevent severe bleeding. Infants who do not receive an intramuscular injection should receive repeated oral doses for at least 6 weeks.[2] The interprofessional care team should educate parents about the significance of vitamin K prophylaxis to prevent VKDB, a rare but life-threatening and preventable condition.

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Rina E. Eden

Author

Sharon F. Daley

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Jean M. Coviello

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