Continuing Education Activity
Vitamin K refers to a group of fat-soluble compounds involved in coagulation, bone development, and cardiovascular health. Vitamin K deficiency can contribute to significant bleeding, poor bone development, osteoporosis, and increased risk of cardiovascular disease. Vitamin K Deficiency Bleeding (VKDB) in newborns can be separated into three categories based on the timing of the presentation. Early VKDB presents within 24 hours of birth, classic VKDB presents within the first week, and late VKDB presents between 1 and 12 weeks of life. This activity reviews the causes, pathophysiology, and presentation of vitamin K deficiency bleeding in newborns and highlights the role of the interprofessional team in its management.
- Identify the causes of vitamin K deficiency bleeding in newborns.
- Explain the typical presentation of a newborn with vitamin K deficiency bleeding.
- Summarize the treatment options for vitamin K deficiency bleeding in newborns.
- Identify strategies to optimize care coordination among interprofessional team members to improve outcomes for newborns affected by vitamin K deficiency bleeding.
Vitamin K refers to a group of fat-soluble compounds. There are several vitamin K-dependent proteins involved in coagulation, bone development, 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 dietary requirements are based on the intake of healthy adults, and the adequate intake is 120 and 90 ug/day for men and women, respectively.
Vitamin K deficiency bleeding (VKDB) in newborns can separate into three categories based on the timing of the presentation. Early VKDB presents within 24 hours after birth, classic VKDB presents within the first week, and late VKDB presents between one to twelve weeks of life.
Vitamin K deficiency occurs in the neonatal period, in hereditary combined vitamin K-dependent clotting factors deficiency (VKCFD), inadequate uptake from diet or because of a chronic disorder, or it can be drug-related.
All neonates have reduced vitamin K at birth. The first reported classic VKDB was in 1894 as a bleeding disorder that occurred on day 2 or 3 of life. In combination with sepsis-induced bleeding, the incidence was 600/100,000 infants with a 62% fatality rate. Late VKDB occurs in 4.4 to 72 infants per 100,000 births with an increased risk in exclusively breastfed infants and the highest incidence occurring in Asian populations. Early VKDB has been associated with mothers on anticonvulsants or other vitamin K interfering substances, and incidence without vitamin K supplementation has been reported as high as 12%. The mortality rate for late VKDB is 20-50%. Late VKDB also has a significant neurologic morbidity rate. Without Vitamin K supplementation, the current day incidence of classic VKDB is estimated to be 0.25-1.7%.
VKCFD is extremely rare with less than 30 cases worldwide and affects males and females equally.
In normal healthy adults, 8-31% have vitamin K deficiency. However, it is very rare to result in clinically significant bleeding. Cases are limited to individuals with malabsorption syndromes and those treated with drugs that interfere with vitamin K metabolism.
Vitamin K is a group of fat-soluble 2-methyl-1,4-naphthoquinone. There is a variable alkyl substituent at the third position and exists in two principal forms: K1 (phylloquinone) and K2 (menaquinone). There is a third, synthetic form K3 (menadione), the use of which has been replaced by a synthetic form of vitamin K1 due to the potential for toxicity in infants with glucose-6-phosphate dehydrogenase deficiency. The primary vitamin K1 is predominantly from leafy greens and vegetables, while the main source of Vitamin K2 is intestinal flora and fermented foods. Vitamins K1 and K2 have different bodily distributions and may have different impacts on enzyme activity. Vitamin K1 is the major source in the human diet and is absorbed in the jejunum and ileum, transported by chylomicrons in circulation, and is dependent on bile, pancreatic enzymes, and dietary fat content. 
These substances are necessary for adequate blood clotting because they are cofactors for gamma-glutamyl carboxylase and vitamin K2,3-epoxide reductase complex in modifying gamma-carboxyglutamic acid on clotting factors II, VII, IX, and X. This modification is required for cofactors to bind to phospholipids in the platelet membrane. Under-carboxylated clotting factors will lead to decreased protein activity and can lead to bleeding.
Vitamin K is also a requirement for various other proteins including anti-coagulant proteins (C, S, and Z), osteocalcin, and matrix GLA protein. Under-carboxylated osteocalcin has shown to increase in individuals with decreased bone mineral density and with increased fracture rates in the elderly. [8,9] Decreased levels of some vitamin K subtypes result in increased arterial calcification.
Vitamin K is not transported across the placenta efficiently, and infants are born with low to undetectable concentrations of Vitamin K and elevation of Protein Induced by Vitamin K Absence or Antagonism (PIVKA). PIVKA is a pre-carboxylated (incompletely carboxylated) form of prothrombin.
VKCFD is an autosomal recessive disorder with mutations in gamma-glutamyl carboxylase (type 1) or vitamin K2,3-epoxide reductase complex (type 2) which results in under-carboxylation and decreased activity of K-dependent proteins.
History and Physical
Vitamin K deficiency can present with a history of bleeding at venipuncture sites or with minor trauma. The patient may also have a history of antibiotic, anticonvulsant, or other prescription drug use. Additionally, during a physical exam, ecchymosis or petechiae may be found.
In VKDB, the neonate will present with bleeding. Early VKDB often presents with intracranial, intrathoracic, intra-abdominal and other severe bleeding conditions. Early VKDB is also often associated with maternal drugs that inhibit vitamin K metabolism. Classis VKDB typically occurs with less severe bleeding such as that of the umbilicus, gastrointestinal tract, and post-circumcision. Late VKDB often presents with severe intracranial bleed. All forms of VKDB have a high incidence of the refusal of vitamin K prophylaxis. Late VKDB has a higher association with exclusively breastfed infants due to the lower dietary intake of vitamin K found in human milk versus formula. Warning bleeds or bruising should always prompt further investigation by laboratory testing.
VKCFD presents in the newborn period in severe cases similar to VKDB but can present later in life in milder cases. Common presentation occurs with severe spontaneous or surgical bleeding events. History of easy bruising and mucosal bleeding is frequent, and there can be developmental and skeletal abnormalities.
Classic vitamin K deficiency is a vitamin-k responsive elongation of prothrombin time or bleeding. Prothrombin time has served as an indicator of vitamin K status because of the effect on plasma prothrombin; however, there must be approximately a 50% decrease in prothrombin before the prothrombin time becomes abnormal and is nonspecific. In the absence of vitamin K, there is a production of PIVKA-II and is a sensitive marker for vitamin K deficiency status. PIVKA-II has minimal variability based on other factors such as age that influence vitamin K plasma and serum concentration. Increased PIVKA-II levels start to become apparent in individuals consuming less than 60 mcg of vitamin K per day. At birth, elevated PIVKA-II levels exist in 10-50% of newborns and 70% of non-supplemented healthy infants on day of life 4 or 5. Direct measurement of vitamin K plasma levels shows highly variable data influenced by the analytical method, nutritional and metabolic factors, and interference of lipid content. Liquid chromatography-tandem mass spectrometry is useful for determining vitamin K subtypes and concentration levels but is not readily available.
Diagnostic criteria for VKDB includes a PT greater than or equal to 4 times the normal value and one of the following:
1. normal or increased platelet count with normal fibrinogen and absent degradation products
2. PT normalization within 30 minutes after IV vitamin K administration
3. Increased levels of PIVKA-II.
When VKCFD is suspected as the cause, a research laboratory can be employed to perform genotyping of gamma-glutamyl carboxylase and vitamin K2,3-epoxide reductase complex for confirmation.
Treatment / Management
Prophylaxis in newborns: 1 mg of vitamin K1 by intramuscular injection within 1 hour of birth. Alternatively, 2 mg of vitamin K1 orally at birth, at 4-6 days, and at 4-6 weeks. Another alternative oral administration is 2 mg Vitamin K1 at birth and a subsequent weekly dose of 1 mg for three months. Intramuscular injection is preferable for efficacy.
VKDB: 1 to 2 mg vitamin K1 by slow intravenous or subcutaneous infusion. Severe bleeding may require fresh frozen plasma at a dose of 10-15 mL/kg.
Vitamin K deficiency due to malabsorption: Dependent on the disease. Malabsorption requires daily administration of high doses of oral vitamin K1 0.3 to 15 mg/day. If oral dosing is ineffective, consideration should be for parenteral vitamin K1.
VKCFD: 10 mg vitamin K1 2-3 times per week by an oral dose by intravenous infusion. Fresh frozen plasma may be required during surgery or in cases of severe bleeding at a dose of 15-20 mL/kg. Prothrombin Complex Concentrates and recombinant Factor VII may also have utility during surgery or severe bleeding.
Vitamin K nutritional deficiency in adults: At least 120 and 90 ug/day for men and women respectively, by diet or oral supplementation to meet the National Academy of Science Food and Nutrition Board recommended intake.
Chronic conditions: As more research becomes available, a larger dosage of oral vitamin K1 and K2 may be beneficial. No present guidelines are available.
Other bleeding disorders, such as factor deficiencies, can present similarly to vitamin K deficiency. Unresponsiveness to vitamin K supplementation and factor activity assays will assist in determining the bleeding cause. Evaluation of possible drug interferences such as warfarin and acquired vitamin K deficiencies caused by malabsorption need differentiation from nutritional deficiencies and VKCFD.
Vitamin K deficiencies can influence osteoporosis, cardiovascular disease, and other chronic diseases, but these are multivariate conditions.
Pertinent Studies and Ongoing Trials
A search of ClinicalTrials.gov shows there are 402 studies concerning Vitamin K and Vitamin K agonists with 136 active trials. These trials are widely variable with study topics concerning vitamin K agonists versus novel anticoagulants and vitamin K benefits and use in chronic conditions such as osteoporosis, chronic kidney disease, and diabetes.
Notable studies and trials exploring vitamin K status and chronic diseases include Prevention of Renal and Vascular End-Stage Disease (PREVEND) study, Longitudinal Aging Study Amsterdam (LASA), Vitamin K Supplementation in Postmenopausal Women with Osteopenia (ECKO) trial, Vitamin K Italian (VIKI) Dialysis Study, and Japanese Osteoporosis Intervention Trial-03.
Prophylaxis in newborns: Intramuscular injection of vitamin K is preferable in all infants due to increased efficacy over oral administration. If orally administered and the newborn vomits or regurgitates within 1 hour of dose, repeating oral dose is appropriate. Oral administration should be avoided in preterm infants, infants with cholestasis, or in infants with other intestinal maladies that may interfere with absorption. Additionally, oral administration should be avoided in infants whose mother was taking Vitamin K interfering medications such as anticonvulsants.
Treatment of minor bleeding and maintenance of vitamin K levels can utilize oral Vitamin K1, but in severe bleeding, an intravenous is the route of choice.
For adults with a risk or diagnosis of osteoporosis and fractures, there should be a consideration of vitamin K administration.
Toxicity and Side Effect Management
There are no known adverse effects of excessive intake of dietary vitamin K. Phytonadione is a synthetic derivative of vitamin K1 and is available as an oral tablet or injectable emulsion that is available for administration by intravenous, intramuscular, or subcutaneous routes. Reports of anaphylactoid reactions are rare but are an estimated incidence of 3/10,000 doses, and associations point to the intravenous route in more severe cases. The emulsifying agents, specifically polyoxyethylated castor oil, have been implicated as the cause of the anaphylactoid reaction in most cases.
Prophylaxis in neonates reduces the incidence of VKDB significantly. Late VKDB has the worse prognosis, with 50% of cases presenting with intracranial hemorrhage. Nutritional deficiencies in adults are difficult to evaluate given confounding factors such as overall quality of diet and differences in metabolism due to comorbid conditions or genetics but are considered to have an excellent prognosis. In VKCFD, with Vitamin K supplementation, there is a good prognosis with a low impact on quality of life.
Bleeding is the most significant complication because of vitamin K deficiency and is often fatal in infants. Increased fracture rates and cardiac disease may also be a complication. However, more research is required.
Clinical pathology, transfusion medicine, internal medicine, and hematology should be part of the interdisciplinary team in Vitamin K deficiency. Individual consultations should be set up in the case of VKCFD with genetics. Neonatology and pediatrics should be involved in VKDB and VKCFD.
Deterrence and Patient Education
For prophylaxis of VKDB, parents should be made aware of the importance of vitamin K supplementation at birth and why the intervention is necessary. There should be discussion regarding intramuscular injection having greater efficacy in the prevention of early, classic, and late VKDB compared to oral supplementation and that it is a one-time dose versus repeated doses.
Patients with chronic conditions may benefit from vitamin K supplementation, and the discussion of the research available should take place with interested patients.
Pearls and Other Issues
- Vitamin K is an essential cofactor for the function of coagulation factors II, VII, IX, and X, anticoagulation proteins C, S, and Z, osteocalcin, matrix GLA protein, and many other non-hematologic proteins.
- Direct vitamin K testing and body concentration are difficult to assess due to interfering substances, different vitamers, and tissue distribution.
- PIVKA-II is currently the best test commonly available to determine vitamin K status.
- There is no known toxicity associated with high levels of vitamin K.
- Formulations of vitamin K have some association with rare anaphylactoid reactions.
Enhancing Healthcare Team Outcomes
VKDB is a potentially devastating consequence of vitamin K deficiency in the neonatal period. 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 a minimum of 6 weeks.(Level I).
Vitamin K supplementation in calcific cardiovascular disease and osteoporosis may reduce morbidity and mortality. Patients without contraindications, such as warfarin administration, should be considered for vitamin K supplementation. [Level 2] Nurses, pharmacists, and clinicians should work together as an interprofessional team to make patients with vitamin K deficiency are treated appropriated and followed up on a regular basis.