Chemistry and Forms

Vitamin K refers to a family of compounds exhibiting the activity of phytomenadione. Phylloquinone (or phytomenadione) is the K1form naturally occurring in plants and fish. Bacteria synthesize menaquinone (K2), a fat-soluble form. Menadione (K3), the water-soluble parent compound, does not occur naturally.

Physiology and Function

Vitamin K serves as a coenzyme during the synthesis of many proteins involved in blood clotting and bone metabolism. Vitamin K1is fat soluble and requires bile salts for absorption in the upper gastrointestinal tract. Vitamin K acts as a cofactor in the final synthesis of proteins with a modified amino acid residue. This modified glutamic acid residue is found in the blood and along vessel walls, along with platelet-derived phospholipid, where it binds and facilitates the action of calcium, and is an integral part of the clotting process. It is also found in bone proteins and can bind onto calcium ions to cause calcification. This role in calcium transport is central to vitamin K's functions within healthy bone formation and blood clotting.

Vitamin K enables both coagulation and fibrinolysis. Vitamin K's central role in blood coagulation involves synthesis of coagulation components, such as prothrombin (factor II), as well as factors VII, IX, and X and proteins C, S, and Z in the liver. Proteins C and S promote fibrinolysis and anticoagulation. Thus, they are involved with reducing inflammation.

Osteocalcin, matrix Gla protein, and protein S are vitamin K–dependent structural and regulatory proteins in bone and vascular metabolism. Vitamin K plays the critical role of allowing calcium ions to bind, thus resulting in the calcification of bone. Osteocalcin metabolism has been implicated in the pathogenesis of osteoporosis through an unknown mechanism that may be linked to suboptimal vitamin K status, resulting in its undercarboxylation and presumed dysfunction.

Probiotic microflora in the intestines, when a healthy microecology is functioning, normally manufacture significant amounts of vitamin K, contributing up to half of daily requirements in some individuals.

Historical/Ethnomedicine Precedent

In most cultural traditions, herbs and green leafy vegetables have historically been used to enrich and tonify the blood and support its metabolic functions. Consumption of cultured foods can support vigorous probiotic flora population and healthy gut ecology.

Possible Uses

Acute myeloid leukemia (vitamin K2only), bone loss (risk reduction), calcium oxalate kidney stones (prevention), celiac disease (malabsorption-induced deficiency), coagulation disorders, cystic fibrosis, epistaxis, floaters (in eyes), fractures (risk reduction), gastric bypass with Roux-en- Y (bariatric surgery), hemorrhagic disease of the newborn, inflammatory conditions, myelodysplastic syndromes (vitamin K2only), nausea and vomiting of pregnancy, osteoporosis, phenylketonuria (if deficient), preterm infants (K1prophylaxis), pruritus, rheumatoid arthritis, stroke prevention; vitamin K malabsorption (e.g., with celiac disease or bariatric surgery), warfarin overanticoagulation.

When the clotting mechanism is disrupted by medications such as certain antibiotics, cephalosporin possessing an MTT side chain, or excessive doses of oral anticoagulants (warfarin), vitamin K can be administered to correct the situation.

Deficiency

Symptoms: Easy bruising, small amounts of blood in stool, prolonged bleeding; impaired bone remodeling, and mineralization.

Vitamin K deficiency is rare in the general population, but the risk is significantly greater in infants, especially premature infants and those who are exclusively breast-fed, for whom such a deficiency can be fatal (hemorrhagic disease of the newborn). Adults at increased risk of vitamin K deficiency include individuals with heavy alcohol intake, liver disease, fat malabsorption, or chronic digestive disorders, such as chronic diarrhea, celiac sprue, Crohn's disease or ulcerative colitis, and bariatric surgical procedures that bypass the duodenum.

In recent years, several published papers suggest that the dietary reference intakes (DRIs) for vitamin K are based solely on levels relevant to hepatic synthesis of clotting factors, and that much higher levels (10 mg/day) may be needed for optimal health of the skeletal and vascular systems. Vascular calcification may be related to chronic insufficiency of vitamin K intake. Patients receiving chronic warfarin, essentially an induced vitamin K deficiency, have a higher incidence of vascular calcification.

Dietary Sources

Leafy green vegetables are the single best dietary source of vitamin K because of their high chlorophyll content; the vitamin K content is proportionate to the degree to which the plant parts are green. Kale, green tea, and turnip greens are the most abundant food sources. Spinach, broccoli, lettuce, and cabbage are also rich sources. Other food sources include egg yolk, cow's milk, and liver, as well as soybean oil, olive oil, cottonseed oil, and canola oil.

The probiotic flora inhabiting intestines with a healthy ecology normally manufacture vitamin K2, or menaquinone . Menaquinones (MK- n , with the n determined by the number of prenyl side chains) can also be found in the diet; MK-4 is in meat, and MK-7, -8, and -9 are found in fermented food products such as cheese. The Japanese fermented soy product natto is a rich source of MK-7. Some sources have said that MK-4, also known as menatetrenone, is synthetic vitamin K2, but this is not accurate. However, MK-4 is distinct from other MKs because it is not produced in significant amounts by gut microflora, but it can be derived from vitamin K1in vivo. Hydrogenation of plant oils appears to decrease the absorption and biological effect of vitamin K in bone, possibly as an effect of trans-fatty acids.

Nutrient Preparations Available

Phylloquinone (K1) is the usual form of supplemental vitamin K. Vitamin K2is also used therapeutically, often parenterally. Mixed K1and K2formulations are increasingly available. The natural, long-chain menaquinone-7 (MK-7), derived from natto, exhibits a “very long half-life time,…resulting in much more stable serum levels and accumulation of MK-7 to higher levels (7-8 fold) during prolonged intake,” ¹ compared to synthetic vitamin K1. The MK-7 preparation can also induce “more complete carboxylation of osteocalcin,” and thereby also increase activity against vitamin K antagonists. ¹

Dosage Forms Available

Capsule, tablet; injectable (prescription only).

Dosage Range

Adult

• Supplemental/Maintenance:   30 to 100 µg per day.

• Pharmacological/Therapeutic:   45 to 500 µg per day.

• Toxic:   None reported or suspected.

Pediatric (<18 years)

Supplemental/Maintenance

• • Infants, birth to 6 months:   5 µg/day
• • Infants, 7 to 12 months:   10 µg/day
• • Children, 1 to 3 years:   15 µg/day
• • Children, 4 to 6 years:   20 µg/day
• • Children, 7 to 10 years:   30 µg/day

• Pharmacological/Therapeutic:   45 to 150 µg per day.

• Toxic:   None reported or suspected.

Laboratory Values

Plasma vitamin K: Osteocalcin level is sometimes used as a surrogate test for vitamin K status.

Prothrombin time (PT) and clotting factors (X, IX, VII, and protein C) may also be used as reference values, but PT is not considered a reliable test for vitamin K status. Vitamin K deficiency will prolong PT, but so does hepatic insufficiency (which also results in inadequate levels of clotting factors).

Overview

Supplemental vitamin K is generally considered safe when used in accordance with proper dosing guidelines. No adverse effects associated with vitamin K consumption from food or supplements have been reported in humans or animals. This does not mean, however, that no potential exists for adverse effects resulting from high intakes beyond normal dietary or supplemental levels. Because data on the adverse effects of vitamin K are limited, caution may be warranted.

Patients undergoing anticoagulant therapy should monitor vitamin K intake and avoid significant inconsistencies in intake levels. Regular monitoring of coagulation parameters (INR) and dose titration is essential.

Nutrient Adverse Effects

General Adverse Effects

Naturally occurring vitamin K1(phylloquinone) is generally considered nontoxic, whereas menadione (K3), the synthetic derivative, has been associated with potentially severe toxicity reactions at high doses, particularly in infants and other highly vulnerable populations. Flushing and perspiration are the most common, although infrequent, adverse effects reported. Other potential toxicity symptoms include difficulty breathing, tightness in throat or chest, chest pain, hives, rash, or itchy or swollen skin. Rare cases of hemolytic anemia have been reported.

The primary risk associated with vitamin K has been limited to rare reports of cutaneous allergic reaction to intramuscular (IM) vitamin K1.

Less than 1%: Abnormal taste, anaphylaxis, cyanosis, diaphoresis, dizziness (rarely), dyspnea, gastrointestinal upset (oral), hemolysis in neonates and in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, hypersensitivity reactions, hypotension (rarely), pain, tenderness at injection site, transient flushing reaction.

More recently, discussions have arisen concerning potential risk of cirrhosis associated with supplemental intake of vitamin K, but not with food sources, in the treatment of osteoporosis.

Toxicity

Phylloquinone (vitamin K1) is not toxic at 500 times the recommended dietary allowance (RDA, 0.5 mg/kg/day). No toxicities have been reported or suspected as being associated with natural vitamin K at any dose in humans when given orally. Intravenous (IV) administration of vitamin K at doses of 2 to 8 mg/kg has been found to be lethal in horses.

Menadione (vitamin K3) has a finite toxicity resulting from its reaction with sulfhydryl groups. Large doses of menadione may produce hemolytic anemia, hyperbilirubinemia, and kernicterus in the infant. Other signs of synthetic vitamin K toxicity include flushing, sweating, and chest constriction. Most toxicity is associated with IV use and may be related to allergies to various preservatives or excipients.

Adverse Effects Among Specific Populations

Patients receiving anticoagulant therapy should monitor vitamin K intake. Possible risk of aggravation exists among individuals prone to form kidney stones.

Pregnancy and Nursing

No extant reports of adverse effects have been related to fetal development during pregnancy. This fat-soluble vitamin crosses the placenta and is excreted into breast milk.

Infants and Children

Vitamin K can cause a fatal form of jaundice in infants. No adverse effects have been reported among breast-fed infants.

Contraindications

Patients undergoing anti–vitamin K anticoagulant therapy, except within the context of appropriate professional supervision; some premature infants.

Strategic Considerations

The primary interactions of clinical significance involving vitamin K and pharmaceutical agents derive from interference of vitamin K with the therapeutic action of certain anticoagulant medications and the adverse effect of antimicrobial medications on normal vitamin K synthesis by gut bacterial flora. Although vitamin K's role in coagulation receives attention regularly, its influence on fibrinolysis also needs to be considered. The critical issue with anticoagulants is monitoring and managing the proportionate effects of the medication and dietary or supplemental sources of vitamin K. Strategic administration of probiotic flora and restoration of a healthy gut ecology can compensate for the tactical use of antimicrobial agents in the suppression of infectious bacteria. The interactions involving vitamin K provide challenging opportunities for reframing the constituent elements of medical intervention within the context of a dynamic and evolving individualized process emphasizing strategic goals and comprehensive clinical outcomes, such as improved function, decreased risk, and enhanced quality of life.

Oral Anticoagulant Overdose

Clinical surveys have found that a substantial number of anticoagulation clinics underutilize oral phytonadione for patients with supratherapeutic international normalized ratio (INR) values. These data indicate that such clinics do not comply with the guidelines for vitamin K use developed at the American College of Chest Physicians (ACCP) Fifth Consensus Conference on Antithrombotic Therapy, as published in 1998.

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