Vitamin K Deficiency

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.