Continuing Education Activity

Vitamin K is a medication used to manage and treat bleeding due to the coagulation disorder caused by warfarin and vitamin K deficiency. It is in the fat-soluble vitamin class of drugs. This activity outlines the indications, actions, and contraindications for vitamin K as a valuable agent in managing coagulation disorders caused by warfarin or vitamin K deficiency.

Objectives:

• Identify the mechanism of action of vitamin K.
• Describe the contraindications of vitamin K.
• Explain the importance of vitamin K concerning monitoring for patients on warfarin therapy, including target INR levels.
• Outline interprofessional team strategies for improving care coordination and communication for improving outcomes with bleeding using vitamin K.

Indications

Vitamin K is a fat-soluble vitamin that affects coagulation pathways within the body. Vitamin K is found in foods and can be a dietary supplement. Vitamin K is essential for the synthesis of coagulation proteins. It is a co-factor for vitamin K-dependent carboxylation, which includes various enzymes. The process of vitamin K carboxylation allows the coagulation factors to bind calcium ions, which further facilitates the cascade pathways. Vitamin K deficiency impairs the coagulation process leading to issues with bleeding. Recent research has linked vitamin K deficiency to issues with osteoporosis and cystic fibrosis.[1][2]

Vitamin K occurs in two bioactive forms, vitamin K1, and vitamin K2. Vitamin K1, also known as phylloquinone, is a product of plant synthesis. It is most prevalent in green leafy vegetables because it is directly involved in photosynthesis. Vitamin K1 is active in animals and is responsible for the production of coagulation factors. It also can be converted into vitamin K2 in animals.[2][3][4][5]

Vitamin K2 is created in the gut by bacteria. Gut flora converts vitamin K1 into vitamin K2 (menaquinone). A range of vitamin K2 forms can be created. This transformation takes place via the gut bacteria lengthening the isoprenoid side chain. Bacteria are the primary producers of menaquinones, which they use during anaerobic respiration. They differ in structure from phylloquinone due to the 3-substituted lipophilic side chain. The most important forms of menaquinones contain 4 to 10 repeating isoprenoid units. These are indicated by MK-4 to MK-10. The most notable forms include MK-7 to MK-11. The MK-7 and other bacterially derived forms of vitamin K2 exhibit vitamin K activity in animals. The synthetic type of vitamin K, vitamin K3 (menadione), interferes with glutathione, which causes toxicity to animals. For this reason, vitamin K3 is no longer a viable treatment for vitamin K deficiency.[2][6][7][8]

Mechanism of Action

The primary function of vitamin K2 is adding carboxylic acid groups to glutamate residues (Glu) to form gamma-carboxyglutamate residues (Gla) during the creation of clotting factors. The presence of two carboxylic acid groups on a single carbon that resides in the gamma-carboxyglutamate residue allows for the chelation of calcium ions. The binding of calcium ions in this fashion is of crucial importance for vitamin K-dependent clotting factors, permitting the perpetuation of the clotting cascades. Vitamin K is also responsible as a factor in synthesizing prothrombin, factor VII, factor IX, and factor X.[1][9]

Vitamin K becomes reduced in the cell to a metabolic form called vitamin K hydroquinone. The catalyst for this process is the enzyme vitamin K epoxide reductase (VKOR). Subsequently, vitamin K hydroquinone gets oxidized by gamma-glutamyl carboxylase (also known as vitamin K-dependent carboxylase). This enzyme carboxylates Glu to Gla, eventually creating vitamin K epoxide. The carboxylation and epoxidation reactions are supposed coupled (occurring simultaneously). Next, vitamin K epoxide is reconverted to vitamin K by VKOR. This entire process has the name of the vitamin K cycle. Vitamin K1 deficiency is not common in humans because it constantly recycles within cells.[1][10][11]

Warfarin is a compound used for anticoagulation that blocks the action of VKOR and results in decreased amounts of vitamin K and vitamin K hydroquinone, which prevents any efficiency by the glutamyl carboxylase enzyme and prevents the carboxylation reaction from occurring. As a result, clotting factors get produced without an adequate number of Gla amino termini. These ‘inactive” factors can no longer create stable bonds to blood vessels endothelium; therefore, no clot formation will result even after endothelial injury. In conclusion, the enzymes that participate in the vitamin K cycle include gamma-glutamyl carboxylase (GGCX), vitamin K epoxide reductase (VKOR), and an as-yet-unidentified vitamin K reductase (VKR). Vitamin K is a lipophilic compound and leads to the belief that vitamin K cycle enzymes are integral membrane proteins in the endoplasmic reticulum. Mutations in these enzymes result in the patient that possesses bleeding disorders or resistance to anticoagulation.[1][11][12]

Administration

The preferred choice for oral vitamin K supplementation is vitamin K1. The suggested dose is 1 to 2 mg. In cases of severe coagulopathy (i.e., high INR), an oral dose of 5 to 10 mg can be administered. The maximum oral dose is 25 mg. Alternatively, vitamin K1 can be given intravenously. The dose for intravenous administration is 10 to 20 mg. It should be given slowly (no less than 30 min). The effect usually occurs within 2 to 4 hours after administering an intravenous dose. The maximum effect for intravenous administration is 6 to 12 hours, while oral supplementation will take about 24 hours.[13]

Adverse Effects

Currently, there is no known toxicity is associated with high doses of vitamin K1 or vitamin K2. Therefore, there is no designated upper intake level (UL). Despite this, an allergic reaction is possible with either version of vitamin K. Vitamin K1 has had documented associations with bronchospasm and cardiac arrest with IV administration. The oral form of vitamin K does not seem to cause severe reactions.[14][15]  

Vitamin K2 also does not display any adverse effects when ingested orally. Studies have shown that coagulation studies in humans did not show an increased risk of blood clots when ingesting 45 mg per day of vitamin K2 (as MK-4). Researchers observed this in a patient who took upwards of 135 mg per day (45 mg three times per day).[16][17]

The synthetic vitamin K3 is very toxic, and as a result, has been banned from over-the-counter sales in the United States because ingestion could result in allergic reactions, hemolytic anemia, and cytotoxicity in liver cells.[2]

Contraindications

Vitamin K use requires caution in neonates, patients with hereditary hypoprothrombinemia, renal impairment, cases of over anticoagulation due to heparins, and hypersensitivity to vitamin K.

Monitoring

The monitoring of vitamin K administration or levels is usually through prothrombin time (PT) and INR. These values measure the presence of vitamin K-dependent factors, which is especially important to utilize in patients who have warfarin toxicity or vitamin K-related coagulopathies.

Toxicity

Vitamin K toxicity is extremely rare. The only reported toxicity comes from menadione, which has no use in humans. Its toxicity is thought to be associated with its water-soluble properties. When toxicity does occur, it manifests with signs of jaundice, hyperbilirubinemia, hemolytic anemia, and kernicterus in infants.

 The mechanism by which toxicity occurs with menadione is the increased oxygen uptake in the liver, leading to a significant increase in lipid peroxidation, which in turn causes cell damage and death. Hepatocyte damage leads to the associated signs of vitamin K toxicity.[2][14][15][16][17]

Enhancing Healthcare Team Outcomes

Even though there is no toxic dose noted in the literature, patients should not take excessive amounts of vitamin K. Instead, patients should be urged to eat a healthy balanced diet with green leafy vegetables rather than to supplement this vitamin.  

Using vitamin K therapeutically requires the effort of an interprofessional healthcare team that includes clinicians, nursing staff, dieticians, and pharmacists, especially as it pertains to the treatment of coagulopathies. Patients on warfarin need to maintain a steady intake level of vitamin K in their diet to optimize warfarin dosing. Conversely, it serves as the antidote to warfarin toxicity. Pharmacists need to counsel patients regarding this topic and dispel the notion that because they are on warfarin, they should no longer eat green leafy vegetables but instead emphasize a consistent intake is the key. Nursing can perform follow-up with patients and also reinforce the points about dietary intake, and ensure that INR and other values remain in range. Any concerns should be reported to the prescriber of warfarin or vitamin K promptly so that dose and/or regimen adjustments can take place immediately if necessary. The dietician can examine the patient's diet and recommend changes to ensure consistent intake from dietary sources. This interprofessional approach ensures optimal patient outcomes from using vitamin K when needed. [Level 5]

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

Tie JK, Stafford DW. Structural and functional insights into enzymes of the vitamin K cycle. J Thromb Haemost. 2016 Feb;14(2):236-47. [PMC free article: PMC5073812] [PubMed: 26663892]

2.

Booth SL. Vitamin K: food composition and dietary intakes. Food Nutr Res. 2012;56 [PMC free article: PMC3321250] [PubMed: 22489217]

3.

Gross J, Cho WK, Lezhneva L, Falk J, Krupinska K, Shinozaki K, Seki M, Herrmann RG, Meurer J. A plant locus essential for phylloquinone (vitamin K1) biosynthesis originated from a fusion of four eubacterial genes. J Biol Chem. 2006 Jun 23;281(25):17189-17196. [PubMed: 16617180]

4.

Thane CW, Paul AA, Bates CJ, Bolton-Smith C, Prentice A, Shearer MJ. Intake and sources of phylloquinone (vitamin K1): variation with socio-demographic and lifestyle factors in a national sample of British elderly people. Br J Nutr. 2002 Jun;87(6):605-13. [PubMed: 12067431]

5.

McKeown NM, Jacques PF, Gundberg CM, Peterson JW, Tucker KL, Kiel DP, Wilson PW, Booth SL. Dietary and nondietary determinants of vitamin K biochemical measures in men and women. J Nutr. 2002 Jun;132(6):1329-34. [PubMed: 12042454]

6.

Davidson RT, Foley AL, Engelke JA, Suttie JW. Conversion of dietary phylloquinone to tissue menaquinone-4 in rats is not dependent on gut bacteria. J Nutr. 1998 Feb;128(2):220-3. [PubMed: 9446847]

7.

Thijssen HH, Vervoort LM, Schurgers LJ, Shearer MJ. Menadione is a metabolite of oral vitamin K. Br J Nutr. 2006 Feb;95(2):260-6. [PubMed: 16469140]

8.

Elder SJ, Haytowitz DB, Howe J, Peterson JW, Booth SL. Vitamin k contents of meat, dairy, and fast food in the u.s. Diet. J Agric Food Chem. 2006 Jan 25;54(2):463-7. [PubMed: 16417305]

9.

Oldenburg J, Bevans CG, Müller CR, Watzka M. Vitamin K epoxide reductase complex subunit 1 (VKORC1): the key protein of the vitamin K cycle. Antioxid Redox Signal. 2006 Mar-Apr;8(3-4):347-53. [PubMed: 16677080]

10.

Suttie JW. Vitamin K-dependent carboxylase. Annu Rev Biochem. 1985;54:459-77. [PubMed: 3896125]

11.

Presnell SR, Stafford DW. The vitamin K-dependent carboxylase. Thromb Haemost. 2002 Jun;87(6):937-46. [PubMed: 12083499]

12.

Stafford DW. The vitamin K cycle. J Thromb Haemost. 2005 Aug;3(8):1873-8. [PubMed: 16102054]

13.

Wojciechowski VV, Calina D, Tsarouhas K, Pivnik AV, Sergievich AA, Kodintsev VV, Filatova EA, Ozcagli E, Docea AO, Arsene AL, Gofita E, Tsitsimpikou C, Tsatsakis AM, Golokhvast KS. A guide to acquired vitamin K coagulophathy diagnosis and treatment: the Russian perspective. Daru. 2017 Apr 17;25(1):10. [PMC free article: PMC5393004] [PubMed: 28416008]

14.

Rasmussen SE, Andersen NL, Dragsted LO, Larsen JC. A safe strategy for addition of vitamins and minerals to foods. Eur J Nutr. 2006 Mar;45(3):123-35. [PubMed: 16200467]

15.

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]

16.

Ushiroyama T, Ikeda A, Ueki M. Effect of continuous combined therapy with vitamin K(2) and vitamin D(3) on bone mineral density and coagulofibrinolysis function in postmenopausal women. Maturitas. 2002 Mar 25;41(3):211-21. [PubMed: 11886767]

17.

Asakura H, Myou S, Ontachi Y, Mizutani T, Kato M, Saito M, Morishita E, Yamazaki M, Nakao S. Vitamin K administration to elderly patients with osteoporosis induces no hemostatic activation, even in those with suspected vitamin K deficiency. Osteoporos Int. 2001 Dec;12(12):996-1000. [PubMed: 11846334]

Disclosure: Kory Imbrescia declares no relevant financial relationships with ineligible companies.

Disclosure: Zbigniew Moszczynski declares no relevant financial relationships with ineligible companies.