Continuing Education Activity

Vitamin K deficiency is an underrecognized condition affecting newborns and adults that can result in impaired coagulation and bleeding complications ranging from mild laboratory abnormalities to life-threatening hemorrhage. Vitamin K is a fat-soluble vitamin essential for the synthesis of proteins involved in hemostasis, bone metabolism, and vascular health. Newborns face an increased risk due to limited placental transfer, low hepatic stores, and insufficient breast milk concentrations, predisposing to vitamin K deficiency bleeding, whereas adult deficiency commonly arises from malnutrition, fat malabsorption, liver disease, medication effects, or rare inherited disorders such as vitamin K–dependent clotting factor deficiency. This course reviews the etiology, epidemiology, clinical manifestations, diagnostic evaluation, and evidence-based management of vitamin K deficiency across patient populations. Participants gain knowledge to recognize early signs, implement preventive strategies, and guide treatment. Collaboration among clinicians, pharmacists, nurses, and laboratory professionals strengthens early detection and coordinated intervention, improving safety and patient outcomes.

Objectives:

• Determine the risk factors, clinical presentations, and diagnostic features of vitamin K deficiency in both newborns and adults to support timely recognition and management.
• Assess vitamin K status using appropriate laboratory markers, including protein induced by vitamin K absence or antagonist-II, to diagnose deficiency and determine severity.
• Implement evidence-based guidelines and protocols for preventing, diagnosing, and treating vitamin K deficiency, including counseling parents and caregivers on the importance of newborn vitamin K prophylaxis, addressing common concerns, and explaining the risks of vitamin K deficiency bleeding.
• Collaborate with an interprofessional healthcare team on appropriate management strategies for vitamin K deficiency, including prophylaxis, treatment of bleeding, and monitoring for complications across different patient populations.

Introduction

Vitamin K deficiency is an often overlooked condition that affects both adults and newborns and can lead to significant morbidity, primarily due to impaired coagulation. Vitamin K is a fat-soluble vitamin essential for the synthesis of vitamin K–dependent proteins that are involved in hemostasis, bone metabolism, and cardiovascular health. Deficiency can cause bleeding complications, with severity ranging from subtle lab abnormalities to life-threatening hemorrhages, as well as contribute to poor bone development, osteoporosis, and increased cardiovascular disease. According to the National Academy of Sciences Food and Nutrition Board, the recommended adequate dietary intake for healthy adults is 120 μg/day for men and 90 μg/day for women. For children, the recommended range varies from 2  to 75 μg/day, depending on age.

Vitamin K deficiency can occur across the lifespan. In adults, it is typically associated with inadequate dietary intake, fat malabsorption, liver disease, or use of medications that interfere with vitamin K metabolism. In contrast, newborns are at increased risk due to physiologic factors, including low vitamin K stores at birth and limited intake in early life.

Vitamin K deficiency bleeding (VKDB) in newborns is categorized based on the timing of presentation. Early VKDB occurs within 24 hours after birth, classic VKDB presents in the first week of life, and late VKDB occurs between 1 week and 6 months, with a peak incidence between 2 and 8 weeks.[1][2] In addition, hereditary vitamin K-dependent clotting factor deficiency (VKCFD) is a rare congenital disorder that can present in infancy or later in life.[1][3] This activity reviews the etiology, epidemiology, clinical presentation, assessment, and treatment of vitamin K deficiency in both adults and newborns, and discusses current clinical guidelines for newborn prophylaxis to prevent VKDB, as well as the apparent rise in its incidence attributable to parental refusal and the lower efficacy of oral alternatives to parenteral vitamin K.

Etiology

Vitamin K deficiency results from inadequate intake, impaired absorption or metabolism, or increased physiologic demand, with distinct etiologies in neonates and adults.

Neonatal Etiology

Nearly all newborns are vitamin K-deficient due to physiologic factors. These include poor placental transfer of vitamin K, immature hepatic synthesis of vitamin K–dependent clotting factors (estimated at 30%-50% of adult levels), and a lack of intestinal colonization by vitamin K–producing bacteria.[4][5] Exclusive breastfeeding further increases risk, as breast milk contains relatively low concentrations of vitamin K. Historically and in contemporary studies, VKDB occurs predominantly in exclusively breastfed infants who do not receive prophylaxis at birth.[4]

Early-onset VKDB (within the first 24 hours of life) is most commonly associated with maternal use of medications that interfere with vitamin K metabolism, including anticonvulsants, antibiotics, antituberculosis agents, and warfarin. These medications induce hepatic cytochrome P450 enzymes in the fetus, accelerating vitamin K degradation.[4] Classic VKDB occurs between 2 days and 1 week of life, often presenting with postcircumcision or skin bleeding. Risk factors are exclusive breastfeeding and failure to receive vitamin K prophylaxis at birth.

Late-onset VKDB (occurring between 1 week and 6 months of age) is often associated with secondary conditions that impair vitamin K absorption or metabolism. These include hepatobiliary disorders such as biliary atresia or neonatal hepatitis, intestinal malabsorption, chronic diarrhea, antimicrobial therapy, and, rarely, toxin exposures such as rat poison ingestion.[4][5] Rare inherited disorders may also cause vitamin K deficiency. Hereditary VKCFD results from mutations in γ-glutamyl carboxylase or the vitamin K epoxide reductase complex, leading to impaired activation of multiple coagulation factors.[5]

Adult Etiology

In adults, vitamin K deficiency is uncommon but may occur with inadequate intake, malabsorption, or altered metabolism. Poor dietary intake, particularly in individuals with restricted diets, malnutrition, or prolonged periods of no oral intake, is a common contributing factor.[6][7] Malabsorption syndromes are a major cause, especially in conditions affecting fat absorption, such as cholestatic liver disease, biliary obstruction, celiac disease, and inflammatory bowel disease. Because vitamin K is fat-soluble, these conditions significantly impair its absorption.

Medications also play an important role. Broad-spectrum antibiotics can reduce intestinal flora responsible for synthesizing menaquinones (vitamin K2), while drugs that interfere with vitamin K metabolism, such as anticoagulants and anticonvulsants, can exacerbate deficiency.[6][7] Additional contributing factors include hepatic dysfunction, renal insufficiency, malignancy, and chronic illness. Vitamin K deficiency is particularly prevalent in critically ill and hospitalized patients, where multiple factors—such as poor nutritional intake, impaired absorption, antibiotic exposure, and increased metabolic demand—often coexist.[8]

Epidemiology

The epidemiology of vitamin K deficiency varies significantly between neonates and adults. In newborns, deficiency is nearly universal without prophylaxis, whereas in adults, it is relatively uncommon but occurs in specific high-risk populations.

Neonatal Epidemiology

VKDB remains a preventable cause of morbidity in neonates. Without prophylaxis, the incidence of early and classic VKDB ranges from 0.25% to 1.7% of births, while late VKDB occurs in approximately 4.4 to 10.5 per 100,000 live births. The use of oral vitamin K prophylaxis reduces the incidence of late VKDB to 1.5 to 6.4 per 100,000 live births, whereas intramuscular prophylaxis prevents nearly all cases.[5]

Nearly all neonates are physiologically vitamin K-deficient at birth due to poor placental transfer and lack of intestinal colonization by vitamin K–producing bacteria.[5] Late-onset VKDB typically occurs between 1 week and 6 months of age, with peak incidence between 2 and 8 weeks, and is most commonly observed in exclusively breastfed infants who did not receive vitamin K prophylaxis.[4] In the United States, the incidence of VKDB appears to be increasing, largely due to rising parental refusal of intramuscular vitamin K prophylaxis.

The proportion of newborns not receiving prophylaxis has increased from approximately 3% in 2017 to over 5% by 2024.[9] Globally, national surveillance studies from countries including Japan, Germany, Great Britain, and Thailand have demonstrated substantial reductions in late VKDB following the implementation of vitamin K prophylaxis programs.[4] Countries with universal intramuscular prophylaxis have near-elimination of VKDB, whereas those relying on oral regimens or with higher refusal rates continue to report cases.

Adult Epidemiology

Overt vitamin K deficiency is uncommon in healthy adults consuming a typical Western diet and rarely results in clinically significant bleeding. However, subclinical insufficiency is relatively common, and deficiency is prevalent in specific high-risk populations.[7] Population-based dietary data suggest that inadequate vitamin K intake is widespread. In the United States, approximately 55% of adults have intakes below recommended levels, according to data from the National Health and Nutrition Examination Survey.[3] 

Similarly, in a nationally representative Irish cohort, 55% of adults had phylloquinone intake below recommended levels, with younger adults (aged 18–35 years) demonstrating lower vitamin K status and higher levels of undercarboxylated osteocalcin, indicating functional deficiency.[7][10] Vitamin K deficiency is more common in hospitalized and critically ill individuals, where multiple contributing factors coexist. Elevated levels of undercarboxylated proteins (eg, PIVKA-II) are frequently observed in intensive care unit patients, and deficiency has been associated with prolonged hospitalization, mechanical ventilation, and increased mortality.[5][8]

Several high-risk populations have an increased prevalence of deficiency. Individuals with chronic kidney disease are most affected, with approximately 70% demonstrating inadequate intake.[4] Additional at-risk groups include patients receiving prolonged antibiotic therapy (especially cephalosporins), those with malabsorption syndromes such as cholestatic liver disease or biliary obstruction, elderly individuals with malnutrition or polypharmacy, patients with malignancy, those receiving parenteral nutrition without supplementation, and individuals with hepatic dysfunction or advanced illness.[6][7][8] Hemodialysis patients are also at increased risk, often demonstrating low or undetectable vitamin K levels.[11]

Rare Conditions

VKCFD is a rare autosomal recessive disorder, with approximately 50 affected families reported worldwide.[12][13] Overall, vitamin K deficiency in adults is most commonly encountered in the setting of underlying disease, nutritional compromise, or medical interventions that impair vitamin K intake, absorption, or metabolism.

Pathophysiology

Vitamin K is a fat-soluble vitamin composed of a group of 2-methyl-1,4-naphthoquinone compounds with variable side chains. The 2 clinically relevant natural forms are vitamin K1 (phylloquinone) and vitamin K2 (menaquinones). In contrast, the synthetic form, vitamin K3 (menadione), is no longer used due to toxicity, particularly hemolysis in infants with glucose-6-phosphate dehydrogenase deficiency.[2] 

Vitamin K1 is primarily obtained from leafy green vegetables, whereas vitamin K2 is derived from fermented foods and intestinal bacterial synthesis. Both forms are absorbed in the jejunum and ileum via a fat-dependent process that requires bile salts and pancreatic enzymes, and are transported in chylomicrons to the liver. Although gut bacteria produce vitamin K2 in the distal intestine, colonic absorption is limited, making dietary intake the primary source. Conditions that impair fat absorption—such as cholestasis, pancreatic insufficiency, small bowel disease, or bariatric surgery—can reduce vitamin K absorption and lead to deficiency.[14]

Vitamin K serves as a required cofactor for γ-glutamyl carboxylase, an enzyme that activates vitamin K–dependent proteins by adding γ-carboxyglutamate (Gla) residues.[5] This modification allows these proteins to bind calcium, which is necessary for their biological activity. During this process, reduced vitamin K (KH2) is oxidized to vitamin K epoxide, which is then efficiently recycled to its active form by vitamin K epoxide reductase (VKOR) and vitamin K reductase. This recycling explains why only small amounts of dietary vitamin K are needed. Vitamin K antagonists such as warfarin inhibit VKOR, blocking the regeneration of active vitamin K and impairing this activation step.[15]

Vitamin K is required for activation of several key proteins, including coagulation factors II, VII, IX, and X; anticoagulant proteins C, S, and Z; and extrahepatic proteins such as osteocalcin and matrix Gla protein (MGP).[5][16] In vitamin K deficiency, these proteins are produced but remain undercarboxylated and functionally inactive. In the coagulation system, this prevents calcium-dependent binding of clotting factors to phospholipid surfaces, reducing clotting efficiency and leading to a prolonged prothrombin time and, in more severe cases, activated partial thromboplastin time. Undercarboxylated proteins—referred to as proteins induced by vitamin K absence (PIVKA)—accumulate and can serve as a marker of deficiency.[5][7]

Beyond hemostasis, vitamin K deficiency affects bone and vascular health. Undercarboxylated osteocalcin impairs bone mineralization, contributing to reduced bone density and increased fracture risk.[14][16] Similarly, undercarboxylated MGP loses its ability to inhibit vascular calcification, promoting calcium deposition in vascular tissues. Vitamin K does not cross the placenta efficiently, leading to low neonatal stores and increased susceptibility to deficiency, as evidenced by elevated PIVKA-II levels in newborns.[17] Rare inherited defects in γ-glutamyl carboxylase, or VKCFD, result in impaired carboxylation and variable bleeding phenotypes, sometimes accompanied by skeletal abnormalities.

History and Physical

Neonates and Infants with VKDB

History

• Early-onset VKDB (within 24 hours of birth): Typically occurs in infants of mothers taking medications that interfere with vitamin K metabolism, including anticonvulsants, warfarin, antibiotics, and antituberculosis agents. Bleeding is often severe.
• Classic VKDB (2 days to 1 week of life): Usually idiopathic, but may be associated with maternal medication exposure and historically linked to increased postcircumcision bleeding. Breastfed infants are at higher risk than formula-fed infants.
• Late-onset VKDB (1 week to 6 months, peak 2–8 weeks): Most commonly occurs in exclusively breastfed infants who did not receive vitamin K prophylaxis. May also be associated with underlying hepatobiliary disease (eg, biliary atresia, neonatal hepatitis) or malabsorption. A high proportion present with intracranial hemorrhage (ICH).[4]

Key historical factors that increase risk include:

• Refusal of vitamin K prophylaxis at birth
• Exclusive breastfeeding 
• Maternal medication use during pregnancy, including carbamazepine, phenytoin, phenobarbital, primidone, rifampin, isoniazid, and warfarin [4]
• Underlying gastrointestinal or hepatobiliary disease
• Recent illness, such as viral gastroenteritis or chronic diarrhea [4][5] 

Physical Examination

Findings reflect impaired coagulation and range from mild to life-threatening bleeding:

• Cutaneous bruising, petechiae, or ecchymoses
• Mucosal bleeding
• Bleeding from the umbilicus or circumcision site
• Gastrointestinal bleeding
• Large intramuscular hematomas
• Intracranial hemorrhage with bulging anterior fontanelle and neurologic signs (more common in late VKDB and the most serious manifestation) [5][4]

Early VKDB can present with severe internal bleeding (intracranial, intrathoracic, intra-abdominal), whereas classic VKDB more commonly involves skin, umbilical, or gastrointestinal bleeding. Late VKDB frequently presents with intracranial hemorrhage.[4][18]

Adults with Vitamin K Deficiency and VKDB

History

Adults with vitamin K deficiency may present with bleeding or asymptomatic coagulopathy.[19] Higher-risk populations include older adults, patients with cancer, and those with multiple comorbidities, especially in the setting of poor nutrition and antibiotic exposure.[7][20] Important historical factors include:

• Dietary insufficiency: Malnutrition, malabsorption, restricted diets, or low intake of green leafy vegetables [7]
• Antibiotic use: Especially prolonged courses of broad-spectrum antibiotics that reduce intestinal vitamin K production
• Malabsorption syndromes: Cholestatic liver disease, biliary obstruction, celiac disease, inflammatory bowel disease, pancreatic insufficiency, or short bowel syndrome
• Hepatic or renal disease
• Other medications: Warfarin or other vitamin K antagonists, anticonvulsants
• Parenteral nutrition without adequate vitamin K supplementation [6]
• Recent hospitalization or critical illness

Physical Examination

Findings reflect impaired clotting and may include:

• Cutaneous bleeding: ecchymoses, petechiae, purpura
• Mucosal bleeding: epistaxis, gingival bleeding
• Bleeding from venipuncture sites or surgical wounds
• Subcutaneous or intramuscular hematomas
• Gastrointestinal bleeding: melena, hematochezia, hematemesis
• Hematuria [20][21]

Unexplained bruising or bleeding—particularly in the setting of risk factors—should prompt evaluation for vitamin K deficiency.

Evaluation

Across age groups, vitamin K deficiency is characterized by impaired γ-carboxylation of clotting factors, leading to prolonged prothrombin time with normal platelet counts and fibrinogen levels. Measurement of PIVKA-II provides a sensitive indicator of functional deficiency and is particularly useful when standard coagulation tests are inconclusive or after treatment has begun.[5][7][22]

Infants with VKDB

The American Academy of Pediatrics (AAP) recommends a stepwise approach to evaluating suspected VKDB.[5][23]

Step 1: Clinical Suspicion VKDB should be considered in any infant 6 months or younger with unexplained bleeding, particularly in the presence of exclusive breastfeeding, lack of vitamin K prophylaxis at birth, underlying hepatobiliary disease, or maternal use of medications that interfere with vitamin K metabolism.

Step 2: Initial Laboratory Evaluation The diagnosis is suggested by:

• Prothrombin time, often with prolonged activated partial thromboplastin time

  • Prothrombin time is a useful screening test, but it is relatively insensitive; it usually becomes abnormal only after a 50% decrease in prothrombin levels.[22]
• Normal platelet count
• Normal fibrinogen level [5][23]

Step 3: Confirmatory Testing

• Reduced levels of vitamin K–dependent clotting factors (II, VII, IX, X) [5]
• Elevated PIVKA-II, also known as des-γ-carboxy prothrombin (DCP)

  • This is a sensitive marker and remains useful even after vitamin K administration. PIVKA-II levels are commonly elevated in unsupplemented newborns and provide a more sensitive indicator than PT alone.[23][24]

Step 4: Evaluate for medical conditions that predispose to VKDB

• Hepatobiliary disease (eg, biliary atresia, neonatal hepatitis)
• Malabsorption or chronic diarrhea
• Recent antimicrobial therapy
• Warfarin or rat poison exposure [5]

Step 5: Therapeutic ConfirmationA correction of the prothrombin time within 2 to 4 hours after vitamin K administration supports the diagnosis of VKDB.[5]

Adults

Evaluation in adults follows similar principles but incorporates additional laboratory tools to assess both vitamin K status and function.

Initial Laboratory Testing

• Prolonged prothrombin time is the hallmark finding, though it lacks sensitivity and specificity, particularly in subclinical deficiency.[7]
• Serum activated partial thromboplastin time may also be prolonged in a more severe deficiency.

Assessment of Vitamin K Status and Function

• Serum phylloquinone (vitamin K1): Levels <0.15 µg/L suggest deficiency but may fluctuate with recent dietary intake.[7]
• PIVKA-II (DCP): Elevated levels indicate functional hepatic vitamin K deficiency and are less affected by short-term dietary changes.[7]

Using both serum vitamin K levels and PIVKA-II can help distinguish between reduced intake (low levels) and impaired utilization (functional deficiency).

Coagulation Factor Analysis

• Decreased clotting factors II, VII, IX, and X
• Normal factors V and VIII (helping distinguish vitamin K deficiency from advanced liver disease, where multiple clotting factors are reduced) [6]

Specialized Testing

• Factor II functional comparison (FII/FIIE ratio): A ratio <0.86 supports vitamin K deficiency and predicts response to vitamin K therapy [25]

Treatment / Management

Neonatal Prophylaxis

The AAP recommends routine vitamin K prophylaxis for all newborns to prevent VKDB. Intramuscular injection is preferred because it is more effective, especially in preventing late-onset VKDB. The AAP clearly states that oral vitamin K is not recommended because it is absorbed inconsistently and may not achieve sufficient concentrations or stores. 

• Term infants (>1500 g): 1 mg vitamin K1 (phytonadione) intramuscularly within 6 hours of birth
• Preterm infants (≤1500 g): 0.3 to 0.5 mg/kg intramuscularly as a single dose [4]

Oral regimens (eg, 2 mg at birth with repeat doses on days 4–6 and weeks 4–6, or weekly dosing) are less effective. They are associated with breakthrough late VKDB, particularly in infants with prematurity or unrecognized cholestasis. If a newborn vomits or regurgitates an oral dose of vitamin K within 1 hour, the dose should be repeated.[4][26] In contrast to the United States, oral vitamin K prophylaxis is recommended or used in several European countries, including Switzerland, the Netherlands, and Denmark. The European Society for Paediatric Gastroenterology, Hepatology and Nutrition provides guidance allowing either intramuscular or oral prophylaxis in healthy term infants.  

Treatment of VKDB in Infants

Initial Management

• This includes vitamin K1 (phytonadione) 1 mg intramuscularly or subcutaneously. 
• In cases of severe bleeding, fresh-frozen plasma may be required at a dose of 10 to 15 mL/kg.[18]

A measurable improvement in coagulation parameters typically occurs within 2 to 4 hours.[4]

Severe or Life-Threatening Bleeding

• Fresh frozen plasma 10 to 15 mL/kg or
• Prothrombin complex concentrate for rapid factor replacement [18] 

These treatments are indicated in cases requiring immediate correction, such as intracranial hemorrhage. 

Management of Vitamin K Deficiency in Adults

General Approach

Treatment varies based on severity, etiology, and ability to absorb oral vitamin K. Oral supplements are preferred for mild deficiencies, while injections are used for severe cases or for malabsorption. The National Academy of Sciences' Food and Nutrition Board recommends a daily vitamin K intake of at least 120 μg for men and 90 μg for women, through diet or supplements, to treat deficiency in adults. The suggested oral dose for vitamin K1 deficiency is 1 to 2 mg, with a maximum of 25 mg.

Oral Vitamin K1 (Phytonadione)

• Anticoagulant-associated hypoprothrombinemia: 2.5 to 10 mg orally; up to 25 mg initially [15]
• Other causes (eg, antibiotics, malabsorption): 2.5 to 25 mg orally; up to 50 mg as a single dose

Peak effect occurs within approximately 24 hours. If bile production is impaired (eg, obstructive jaundice), bile salt administration may be required to facilitate absorption.[Amneal Pharmaceuticals NY LLC. Phytonadione tablet [package insert]. DailyMed. US National Library of Medicine; 2023.]

Parenteral Vitamin K1

Indicated for patients with malabsorption or when rapid correction is required:

• 2.5 to 10 mg (up to 25–50 mg) via subcutaneous, intramuscularly, or slow intravenous administration
• Intravenous infusion should not exceed 1 mg/min due to the risk of anaphylactoid reactions
• Reassess international normalized ratio within 6 to 8 hours and repeat dosing if needed [Amneal Pharmaceuticals NY LLC. Phytonadione tablet [package insert]. DailyMed. US National Library of Medicine; 2023]

Severe Bleeding or Urgent Reversal

• Fresh-frozen plasma (FFP) or a 4-factor prothrombin complex (PCC) concentrate provides immediate replacement of clotting factors, while vitamin K restores endogenous synthesis. Vitamin K replacement restores hepatic production of functional clotting factors, but because this process takes several hours, blood products (FFP or PCC) are required for immediate correction in severe bleeding.[Amneal Pharmaceuticals NY LLC. Phytonadione tablet [package insert]. DailyMed. US National Library of Medicine; 2023]

Additional Considerations

• Failure to respond to vitamin K suggests underlying liver disease or a congenital coagulation disorder.
• In patients receiving warfarin who will resume anticoagulation, use the lowest effective dose to avoid overcorrection and thromboembolic risk.
• Chronic deficiency is best managed with adequate dietary intake (120 µg/day for men, 90 µg/day for women), supplemented as needed.[27]

Special Situations in Infants and Adults

• Malabsorption or cholestasis: May require higher or repeated dosing; oral therapy (0.3–15 mg/day) can be attempted, but parenteral administration is often necessary if absorption is impaired.[28]
• VKCFD: Typically managed with oral vitamin K1 (eg, 10 mg 2–3 times weekly), with FFP or PCC used perioperatively or during bleeding episodes.[12]

Adverse Effects of Treatment

No known adverse effects are associated with excessive dietary intake of vitamin K. Phytonadione (vitamin K1) is available as an oral formulation and as a parenteral preparation for intravenous, intramuscular, or subcutaneous use. Parenteral administration is generally well tolerated but may cause mild injection site reactions. Anaphylactoid reactions to phytonadione are rare, estimated at 3 cases per 10,000 doses, with a higher likelihood with rapid intravenous administration. Emulsifying agents, particularly polyoxyethylated castor oil, have been identified as the most likely cause of the anaphylactoid reaction.[29]

Differential Diagnosis

The differential diagnosis of vitamin K deficiency in infants and adults includes conditions that either mimic the clinical presentation (bleeding/coagulopathy) or are underlying causes of the deficiency.

Infants

• VKCFD: An exceedingly rare autosomal recessive disorder caused by mutations in the GGCX or VKORC1 genes that may also present with dysmorphic features or skeletal defects in addition to bleeding.
• Hepatocellular dysfunction: Liver disease leads to decreased production of all coagulation factors, including fibrinogen and factor V.
• Disseminated intravascular coagulation (DIC): Distinguished by thrombocytopenia, low fibrinogen, elevated D-dimer, and an underlying trigger (sepsis, trauma).[30] 
• Inherited factor deficiencies: Hemophilia A (factor VIII) and hemophilia B (factor IX) deficiencies with isolated prolonged aPTT, and factor VII deficiency with isolated prolonged prothrombin time.[30] 
• Accidental or intentional warfarin/rodenticide ingestion: "Superwarfarin" oral exposure to rat poison baits, especially in older infants.[5][31]

Older Children and Adults

• Acquired vitamin K deficiency 

  • Malabsorption: Cholestatic liver disease, cystic fibrosis, celiac disease, inflammatory bowel disease (eg, Crohn disease), short bowel syndrome, pancreatic insufficiency, or prior bariatric surgery
  • Prolonged antibiotic use: Disrupts gut flora that synthesizes vitamin K2
  • Malnutrition/poor dietary intake: Alcohol use disorder, restrictive diets
  • Medications: Warfarin, certain cephalosporins (N-methylthiotetrazole side chain), rifampin, isoniazid[32]
• Liver disease 

  • Causes a decrease in the production of all coagulation factors; distinguishes itself from isolated vitamin K deficiency by low factor V (which is not vitamin K-dependent) and by not fully responding to vitamin K treatment.[32]
• DIC

  • Low fibrinogen, elevated D-dimer, thrombocytopenia, and a clinical context of sepsis/trauma [30]
• Hereditary VKCFD

  • May present in adulthood with mild bleeding; diagnosis is often delayed due to phenotypic similarity to acquired deficiency. 

Pertinent Studies and Ongoing Trials

Recent research on vitamin K deficiency has increasingly focused on functional deficiency and extrahepatic effects, particularly vascular calcification, bone health, and metabolic disease, as well as potential symptom-based applications. Ongoing studies listed on ClinicalTrials.gov reflect broad interest in vitamin K and related compounds, including comparisons with anticoagulants and investigations into chronic conditions such as osteoporosis, chronic kidney disease, and diabetes. A randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes demonstrated a modest reduction in the propensity for vascular calcification, suggesting a potential role for vitamin K in modulating the biology of calcification. However, effects on clinical cardiovascular outcomes remain uncertain.[33] Additional ongoing trials in high-risk populations, including patients with chronic kidney disease on dialysis, continue to assess whether vitamin K supplementation reduces vascular calcification and cardiovascular risk.

In bone health, a 2024 systematic review and meta-analysis of randomized trials found that vitamin K supplementation may help maintain or modestly improve lumbar spine bone mineral density, likely through enhanced osteocalcin carboxylation rather than increases in total bone mass.[34] Emerging areas of investigation include nontraditional indications. A 2024 randomized clinical trial reported that vitamin K2 supplementation significantly reduced the frequency, duration, and severity of nocturnal leg cramps in older adults, highlighting a potential novel therapeutic application that remains under active study.[35][36] Overall, while vitamin K replacement is well established for correcting coagulopathy, its role in modifying chronic disease outcomes and symptom burden remains an active, evolving area of investigation, with mixed results across populations.

Prognosis

Infants with VKDB

VKDB is a condition with significant potential for morbidity and mortality, particularly when associated with intracranial hemorrhage (ICH).[4] Prognosis varies by VKDB subtype:

• Early-onset VKDB (within 24 hours): Clinical severity ranges from mild cutaneous bleeding to life-threatening ICH and is often associated with maternal medications that impair vitamin K metabolism.[4]
• Classic VKDB (2 days to 1 week): Prognosis is generally favorable with prompt treatment. Bleeding is typically less severe (eg, postcircumcision, gastrointestinal, or umbilical), and ICH is less common.[4]
• Late-onset VKDB (1 week to 6 months): This form carries the poorest prognosis, with ICH occurring in approximately 30% to 60% of cases, and more than half of affected infants present with ICH.[4][5] These events are associated with high mortality and significant long-term neurologic morbidity.[5]

Key prognostic factors:

• Intracranial hemorrhage is the primary determinant of adverse outcomes.[5]
• Timely prophylaxis, with intramuscular vitamin K administration at birth, prevents nearly all cases of late VKDB.[4]
• Underlying conditions, such as hepatobiliary disease, biliary atresia, chronic diarrhea, or antibiotic exposure, may contribute to secondary VKDB.[5]

Overall, early recognition and treatment significantly improve outcomes. When vitamin K deficiency is promptly identified and treated, the prognosis is generally favorable. In contrast, delayed diagnosis—particularly in late VKDB—often results in permanent neurologic injury or death.[18] VKCFD has a variable prognosis. With appropriate vitamin K supplementation, outcomes are often favorable, although some patients experience significant bleeding or associated skeletal abnormalities.[5][12]

Adults with Vitamin K Deficiency

In adults, the prognosis of vitamin K deficiency depends on the severity of the deficiency, the underlying etiology, and the timeliness of treatment. Mild deficiency is typically reversible with dietary modification or supplementation and is associated with an excellent prognosis and few long-term consequences.[7] However, untreated deficiency can result in significant morbidity, primarily due to bleeding complications. Additional potential consequences include impaired bone health and a possible association with increased vascular calcification, although long-term outcomes in these domains are less clearly defined.

Prognosis may be more guarded in patients with:

• Malabsorption syndromes or chronic liver disease
• Multiple comorbidities or poor nutritional status
• Prolonged antibiotic use or critical illness [6][7]

In most cases, correcting the underlying cause and restoring vitamin K levels result in rapid improvement in coagulation parameters and a favorable clinical outcome.

Complications

Infants

The most serious complications are related to uncontrolled bleeding and its sequelae, particularly in cases of VKDB.

• Intracranial hemorrhage: The most devastating complication, especially in late VKDB, causes permanent neurologic injury, including cerebral palsy, seizures, developmental delay, and hydrocephalus.[4][5]
• Death: Caused by severe hemorrhage, particularly ICH or massive internal bleeding.[4]
• Severe anemia and hypovolemic shock, resulting from significant or recurrent bleeding episodes.
• Complications related to secondary VKDB: Infants with underlying hepatobiliary disease (eg, biliary atresia) may experience delayed diagnosis of their primary condition, leading to worse overall outcomes.[5]

Adults

Complications arise from the failure of vitamin K–dependent proteins across multiple systems—most notably blood clotting, but also bone and vascular health—leading to both immediate life-threatening events and long-term systemic consequences.

• Major hemorrhage: Includes gastrointestinal bleeding, ICH, and postoperative bleeding, particularly in high-risk or anticoagulated individuals.
• Anemia and transfusion dependence: This is from chronic or recurrent bleeding.
• Osteoporosis and fracture risk: Chronic deficiency results in undercarboxylated osteocalcin, which contributes to reduced bone mineralization and increased fracture risk.[37][38]
• Vascular calcification: Impaired activation of matrix Gla protein promotes vascular calcification, which may contribute to cardiovascular morbidity.
• Increased mortality in high-risk populations: Low circulating vitamin K levels have been associated with higher all-cause mortality, particularly in older adults and those with chronic disease.[39][40]
• Critical illness–associated complications: In intensive care unit populations, vitamin K deficiency has been associated with prolonged hospital stays, increased reliance on mechanical ventilation, and higher mortality rates, although causality remains unclear.[8]

Deterrence and Patient Education

Prevention of vitamin K deficiency, particularly VKDB in infants, relies heavily on effective education for parents and caregivers. Intramuscular vitamin K prophylaxis has been the standard of care since the American Academy of Pediatrics' 1961 recommendation and remains the most effective strategy for preventing all forms of VKDB.[4]

Parental Counseling and Refusal Management

A growing clinical concern is the rising rate of parental refusal of intramuscular vitamin K prophylaxis, from approximately 3% in 2017 to over 5% by 2024.[9] This trend has been associated with a resurgence of VKDB cases and highlights a critical need for improved communication strategies.

Parental concerns commonly fall into 3 categories:

• Preference for "natural" birth practices
• Concerns about infant safety (eg, pain, preservatives, outdated cancer risk claims)
• Influence of misinformation from social networks or media [4]

Clinicians should use a nonjudgmental, patient-centered approach, asking open-ended questions and addressing concerns at the caregiver's level of understanding. Key counseling points include:

• Effectiveness: A single intramuscular dose at birth is highly effective at preventing early, classic, and late VKDB, whereas oral regimens are less reliable and require strict adherence to multiple doses.
• Safety: Earlier concerns about a link between vitamin K injections and childhood cancer have been disproven by multiple large studies showing no association.[41]
• Simplicity: Intramuscular administration protects with a single dose, avoiding the need for repeated oral dosing and reducing the risk of missed doses.

Educational materials, such as those from the Centers for Disease Control and Prevention, can reinforce counseling. The AAP recommends documenting informed refusal (eg, with a signed refusal form).[4]

Special Considerations in Breastfed Infants

Emerging evidence suggests that even with IM prophylaxis, exclusively breastfed infants may have lower vitamin K levels after discharge, with biochemical evidence of functional insufficiency (elevated PIVKA-II).[42] Some European countries have adopted additional oral supplementation strategies for breastfed infants (eg, daily dosing regimens) to prevent VKDB, although these are not standard in the United States.[4]

Education in Other Populations

In older children and adults, deterrence and patient education should focus on:

• Maintaining adequate dietary intake (eg, green leafy vegetables)
• Recognizing risk factors such as malabsorption, liver disease, or prolonged antibiotic use
• Understanding medication interactions (eg, anticoagulants and anticonvulsants)

For patients with chronic conditions, clinicians may discuss the evolving evidence on vitamin K and its potential roles in bone and cardiovascular health, while emphasizing that supplementation beyond correcting deficiency remains an area of ongoing research.

Enhancing Healthcare Team Outcomes

Effective management of vitamin K deficiency requires coordinated, interprofessional care focused on prevention, early recognition, and appropriate treatment. In neonates, preventing VKDB is a key priority. Clinicians involved in perinatal care, including physicians, advanced practice practitioners, and nurses, should ensure the timely administration of intramuscular vitamin K prophylaxis soon after birth. Equally important is clear communication with parents to address concerns and emphasize that VKDB is a rare, potentially life-threatening, but preventable condition.

Across all age groups, clinicians should stay aware of at-risk populations, such as exclusively breastfed infants without prophylaxis, patients with malabsorption or hepatobiliary disease, and those on medications that affect vitamin K metabolism. Early detection of deficiency and prompt treatment can prevent serious complications. Pharmacists play a crucial role in reviewing medications, identifying potential drug interactions, and ensuring proper dosing and administration of vitamin K. Nutritionists or dietitians contribute by addressing dietary gaps and supporting long-term nutritional health, especially in patients with chronic illnesses or poor dietary intake.

Specialty collaboration may be necessary in certain cases, such as gastroenterology for malabsorption or hepatobiliary issues; hematology for complex coagulopathies; genetics for suspected inherited conditions; and neurology or neurosurgery when ICH occurs. This team-based approach helps ensure accurate diagnosis, appropriate management of underlying causes, and prevention of recurrence. Overall, coordinated care and patient education are key in reducing morbidity and preventing avoidable complications of vitamin K deficiency.

Review Questions

• Access free multiple choice questions on this topic.
• Click here for a simplified version.
• Comment on this article.

References

1.

Sutor AH. Vitamin K deficiency bleeding in infants and children. Semin Thromb Hemost. 1995;21(3):317-29. [PubMed: 8588159]

2.

Mihatsch WA, Braegger C, Bronsky J, Campoy C, Domellöf M, Fewtrell M, Mis NF, Hojsak I, Hulst J, Indrio F, Lapillonne A, Mlgaard C, Embleton N, van Goudoever J., ESPGHAN Committee on Nutrition. Prevention of Vitamin K Deficiency Bleeding in Newborn Infants: A Position Paper by the ESPGHAN Committee on Nutrition. J Pediatr Gastroenterol Nutr. 2016 Jul;63(1):123-9. [PubMed: 27050049]

3.

Tie JK, Carneiro JD, Jin DY, Martinhago CD, Vermeer C, Stafford DW. Characterization of vitamin K-dependent carboxylase mutations that cause bleeding and nonbleeding disorders. Blood. 2016 Apr 14;127(15):1847-55. [PMC free article: PMC4832504] [PubMed: 26758921]

4.

Hand I, Noble L, Abrams SA. Vitamin K and the Newborn Infant. Pediatrics. 2022 Mar 01;149(3) [PubMed: 35190810]

5.

Carpenter SL, Abshire TC, Killough E, Anderst JD., AAP SECTION ON HEMATOLOGY/ONCOLOGY, THE AMERICAN SOCIETY OF PEDIATRIC HEMATOLOGY AND ONCOLOGY, and the AAP COUNCIL ON CHILD ABUSE AND NEGLECT. Evaluating for Suspected Child Abuse: Conditions That Predispose to Bleeding. Pediatrics. 2022 Oct 01;150(4) [PubMed: 36120799]

6.

Shearer MJ. Vitamin K in parenteral nutrition. Gastroenterology. 2009 Nov;137(5 Suppl):S105-18. [PubMed: 19874942]

7.

Card DJ, Gorska R, Harrington DJ. Laboratory assessment of vitamin K status. J Clin Pathol. 2020 Feb;73(2):70-75. [PubMed: 31862867]

8.

Paulus MC, Drent M, Kouw IWK, Balvers MGJ, Bast A, van Zanten ARH. Vitamin K: a potential missing link in critical illness-a scoping review. Crit Care. 2024 Jul 01;28(1):212. [PMC free article: PMC11218309] [PubMed: 38956732]

9.

Scott K, Miller E, Culhane JF, Greenspan J, Handley SC, Lo JY, Knake LA, McKenney KM, Burris HH, Dysart K. Trends in Vitamin K Administration Among Infants. JAMA. 2026 Jan 20;335(3):272-274. [PMC free article: PMC12687205] [PubMed: 41359326]

10.

Hayes A, Hennessy Á, Walton J, McNulty BA, Lucey AJ, Kiely M, Flynn A, Cashman KD. Phylloquinone Intakes and Food Sources and Vitamin K Status in a Nationally Representative Sample of Irish Adults. J Nutr. 2016 Nov;146(11):2274-2280. [PubMed: 27733530]

11.

Allen LH. Micronutrients - Assessment, Requirements, Deficiencies, and Interventions. N Engl J Med. 2025 Mar 06;392(10):1006-1016. [PubMed: 40043238]

12.

Napolitano M, Mariani G, Lapecorella M. Hereditary combined deficiency of the vitamin K-dependent clotting factors. Orphanet J Rare Dis. 2010 Jul 14;5:21. [PMC free article: PMC2913942] [PubMed: 20630065]

13.

Perrone S, Raso S, Napolitano M. Clinical, Laboratory, and Molecular Characteristics of Inherited Vitamin K-Dependent Coagulation Factors Deficiency. Semin Thromb Hemost. 2025 Mar;51(2):170-179. [PubMed: 39496305]

14.

Shearer MJ, McBurney A, Barkhan P. Studies on the absorption and metabolism of phylloquinone (vitamin K1) in man. Vitam Horm. 1974;32:513-42. [PubMed: 4617407]

15.

Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e44S-e88S. [PMC free article: PMC3278051] [PubMed: 22315269]

16.

Wen L, Chen J, Duan L, Li S. Vitamin K‑dependent proteins involved in bone and cardiovascular health (Review). Mol Med Rep. 2018 Jul;18(1):3-15. [PMC free article: PMC6059683] [PubMed: 29749440]

17.

Greer FR, Mummah-Schendel LL, Marshall S, Suttie JW. Vitamin K1 (phylloquinone) and vitamin K2 (menaquinone) status in newborns during the first week of life. Pediatrics. 1988 Jan;81(1):137-40. [PubMed: 3336580]

18.

Shearer MJ. Vitamin K deficiency bleeding (VKDB) in early infancy. Blood Rev. 2009 Mar;23(2):49-59. [PubMed: 18804903]

19.

Wu Q, Wang L, Zhao R. Neglected vitamin K deficiency causing coagulation dysfunction in an older patient with pneumonia: a case report. BMC Geriatr. 2022 Jul 30;22(1):628. [PMC free article: PMC9338575] [PubMed: 35907829]

20.

Kozák M, Majoros L, Panyiczki Z, Bagoly Z, Hodossy-Takács R, Dobos LV, Várkonyi I. Severe vitamin K deficiency-associated coagulopathy triggered by Clostridioides difficile infection and antibiotic-associated dysbiosis: A case report and literature review. Infection. 2026 Jan 21; [PubMed: 41563580]

21.

Neutze D, Roque J. Clinical Evaluation of Bleeding and Bruising in Primary Care. Am Fam Physician. 2016 Feb 15;93(4):279-86. [PubMed: 26926815]

22.

Sokoll LJ, Sadowski JA. Comparison of biochemical indexes for assessing vitamin K nutritional status in a healthy adult population. Am J Clin Nutr. 1996 Apr;63(4):566-73. [PubMed: 8599321]

23.

Anderst J, Carpenter SL, Abshire TC, Killough E, AAP SECTION ON HEMATOLOGY/ONCOLOGY, THE AMERICAN SOCIETY OF PEDIATRIC HEMATOLOGY/ONCOLOGY, THE AAP COUNCIL ON CHILD ABUSE AND NEGLECT. Consultants. Mendonca EA, Downs SM, Section on Hematology/Oncology executive committee, 2020–2021. Wetmore C, Allen C, Dickens D, Harper J, Rogers ZR, Jain J, Warwick A, Yates A, past executive committee members. Hord J, Lipton J, Wilson H, staff. Kirkwood S, Council on Child Abuse and Neglect, 2020–2021. Haney SB, Asnes AG, Gavril AR, Girardet RG, Heavilin N, Gilmartin ABH, Laskey A, Messner SA, Mohr BA, Nienow SM, Rosado N, cast Council on Child Abuse and Neglect executive committee members. Idzerda SM, Legano LA, Raj A, Sirotnak AP, Liaisons. Forkey HC, Council on Foster Care, Adoption and Kinship Care. Keeshin B, American Academy of Child and Adolescent Psychiatry. Matjasko J, Centers for Disease Control and Prevention. Edward H, Section on Pediatric Trainees. staff. Chavdar M, American Society of Pediatric Hematology/Oncology Board of Trustees, 2020–2021. Di Paola J, Leavey P, Graham D, Hastings C, Hijiya N, Hord J, Matthews D, Pace B, Velez MC, Wechsler D, past board members. Billett A, Stork L, staff. Hooker R. Evaluation for Bleeding Disorders in Suspected Child Abuse. Pediatrics. 2022 Oct 01;150(4) [PubMed: 36180615]

24.

Suttie JW, Mummah-Schendel LL, Shah DV, Lyle BJ, Greger JL. Vitamin K deficiency from dietary vitamin K restriction in humans. Am J Clin Nutr. 1988 Mar;47(3):475-80. [PubMed: 3348159]

25.

Bourguignon A, Mathews N, Tasneem S, Douketis J, Hayward CPM. Rapid diagnosis of coagulopathies from vitamin K deficiency in a consecutive case cohort evaluated by comparative assessment of factor II by 1-stage assays with prothrombin time vs Ecarin reagents. J Thromb Haemost. 2024 Nov;22(11):3059-3069. [PubMed: 39151703]

26.

Witt M, Kvist N, Jørgensen MH, Hulscher JB, Verkade HJ., also. Netherlands Study group of Biliary Atresia Registry (NeSBAR). Prophylactic Dosing of Vitamin K to Prevent Bleeding. Pediatrics. 2016 May;137(5) [PubMed: 27244818]

27.

Lin YL, Hsu BG. Vitamin K and vascular calcification in chronic kidney disease: An update of current evidence. Tzu Chi Med J. 2023 Jan-Mar;35(1):44-50. [PMC free article: PMC9972925] [PubMed: 36866348]

28.

Sathe MN, Patel AS. Update in pediatrics: focus on fat-soluble vitamins. Nutr Clin Pract. 2010 Aug;25(4):340-6. [PubMed: 20702838]

29.

Britt RB, Brown JN. Characterizing the Severe Reactions of Parenteral Vitamin K1. Clin Appl Thromb Hemost. 2018 Jan;24(1):5-12. [PMC free article: PMC6714635] [PubMed: 28301903]

30.

Hughes PR, Lewis MN, Adams SS. Bleeding and Bruising: Primary Care Evaluation. Am Fam Physician. 2024 Nov;110(5):504-514. [PubMed: 39556633]

31.

Chong YK, Mak TW. Superwarfarin (Long-Acting Anticoagulant Rodenticides) Poisoning: from Pathophysiology to Laboratory-Guided Clinical Management. Clin Biochem Rev. 2019 Nov;40(4):175-185. [PMC free article: PMC6892705] [PubMed: 31857739]

32.

Al Dawood R, Hayward CPM. Laboratory diagnosis of congenital and acquired coagulopathies, including challenging-to-diagnose rare bleeding disorders. Pathology. 2025 Oct;57(6):687-695. [PubMed: 40796410]

33.

Meer R, Romero Prats ML, Vervloet MG, van der Schouw YT, de Jong PA, Beulens JWJ. The effect of six-month oral vitamin K supplementation on calcification propensity time in individuals with type 2 diabetes mellitus: A post hoc analysis of a randomized, double-blind, placebo-controlled trial. Atherosclerosis. 2024 Jul;394:117307. [PubMed: 37852868]

34.

Xie C, Gong J, Zheng C, Zhang J, Gao J, Tian C, Guo X, Dai S, Gao T. Effects of vitamin K supplementation on bone mineral density at different sites and bone metabolism in the middle-aged and elderly population. Bone Joint Res. 2024 Dec 11;13(12):750-763. [PMC free article: PMC11631259] [PubMed: 39657786]

35.

Tan J, Zhu R, Li Y, Wang L, Liao S, Cheng L, Mao L, Jing D. Vitamin K2 in Managing Nocturnal Leg Cramps: A Randomized Clinical Trial. JAMA Intern Med. 2024 Dec 01;184(12):1443-1447. [PMC free article: PMC11581596] [PubMed: 39466236]

36.

Li Y, Zhu R, Wang L, Tan J. Effect of vitamin K2 in the treatment of nocturnal leg cramps in the older population: Study protocol of a randomized, double-blind, controlled trial. Front Nutr. 2023;10:1119233. [PMC free article: PMC9996107] [PubMed: 36908924]

37.

Cao Q, Fan J, Ammerman A, Awasthi S, Lin Z, Mierxiati S, Chen H, Xu J, Garcia BA, Liu B, Li W. Structural insights into the vitamin K-dependent γ-carboxylation of osteocalcin. Cell Res. 2025 Oct;35(10):735-749. [PMC free article: PMC12484842] [PubMed: 40890294]

38.

Xu Y, Shen L, Liu L, Zhang Z, Hu W. Undercarboxylated Osteocalcin and Its Associations With Bone Mineral Density, Bone Turnover Markers, and Prevalence of Osteopenia and Osteoporosis in Chinese Population: A Cross-Sectional Study. Front Endocrinol (Lausanne). 2022;13:843912. [PMC free article: PMC9309304] [PubMed: 35898467]

39.

Shea MK, Barger K, Booth SL, Matuszek G, Cushman M, Benjamin EJ, Kritchevsky SB, Weiner DE. Vitamin K status, cardiovascular disease, and all-cause mortality: a participant-level meta-analysis of 3 US cohorts. Am J Clin Nutr. 2020 Jun 01;111(6):1170-1177. [PMC free article: PMC7266692] [PubMed: 32359159]

40.

Lees JS, Chapman FA, Witham MD, Jardine AG, Mark PB. Vitamin K status, supplementation and vascular disease: a systematic review and meta-analysis. Heart. 2019 Jun;105(12):938-945. [PubMed: 30514729]

41.

Fear NT, Roman E, Ansell P, Simpson J, Day N, Eden OB., United Kingdom Childhood Cancer Study. Vitamin K and childhood cancer: a report from the United Kingdom Childhood Cancer Study. Br J Cancer. 2003 Oct 06;89(7):1228-31. [PMC free article: PMC2394315] [PubMed: 14520451]

42.

Perrone S, Beretta V, Petrolini C, Scarpa E, De Bernardo G, Buonocore G. Late Vitamin K Deficiency Bleeding in Infancy: The Time to Ensure Effective Prevention. Nutr Rev. 2025 Nov 16; [PubMed: 41241783]

Disclosure: Sharon Daley declares no relevant financial relationships with ineligible companies.

Disclosure: Reddog Sina declares no relevant financial relationships with ineligible companies.