Vitamin K reaction
Phytomenadione (Intravenous Vitamin K1)

Vitamin K reactions are adverse side effects that may occur after injection with vitamin K.[1] The liver utilizes vitamin K to produce coagulation factors that help the body form blood clots which prevent excessive bleeding.[2][3] Vitamin K injections are administered to newborns as a preventative measure to reduce the risk of hemorrhagic disease of the newborn (HDN).[4][5]

The coagulation pathway helps the body stop active bleeds by using vitamin K dependent clotting factors (factors II, VII, IX, and X) which are synthesized by the liver.[2][3][6] Vitamin K can be delivered into the body via the oral, subcutaneous, intramuscular, or intravenous routes of administration.[7]

Vitamin K can influence bone health, coagulation, and insulin sensitivity, but it can also be effected by bariatric surgery which can result in vitamin K deficiency.[8][9][10][11] Vitamin K reactions, such as dermatological and anaphylactic reactions, can cause itchiness, reddening of superficial skin, difficulty breathing, and changes to blood pressure.[12][6][13]

Background

In 1929, Henrik Dam discovered Vitamin K, also known as phylloquinone, phytonadione, or phytomenadione, which is a fat-soluble vitamin. Vitamin K is a family of structures of the aforementioned molecules and is not a single compound.[14][6] Phytonadione, also known as K1, is synthetically derived, approved by the Food and Drug Administration (FDA) and is available on the market. It is available in many different formulations such as intravenous (IV) route, subcutaneous (SQ) route, intramuscular (IM) route and oral tablet. The package insert for K1 illustrates to avoid the injectable emulsions, however, guidelines advocates for use of injectable emulsions of K1 in urgent situations. Specifically, a boxed warning for IV and IM usage dictates the possible occurrence of mortality or severe reactions.[6] This vitamin is involved in the coagulation pathway and helps create factors II, VII, IX, X, proteins C and S.[6] Vitamin K cannot dissolve in water but fully dissolves in fatty and vegetable oils.[15]

Importance of vitamin K

Roles of vitamin K

Bone health

Many proteins in our body depends on vitamin K especially in the bone by carboxylating an amino acid glutamic acid (Glu) to gamma carboxyglutamic acid (Gla). There are controversial results in many studies that suggest the reduction of bone fracture or and increase of bone fracture. Due to these varying results, there are no conclusion in the usage of vitamin K supplements for bone health.[8]

Coagulation

Blood clotting proteins also depend on vitamin K to stop bleeding.[9]

Bariatric surgery

People with severe obesity may have undergone bariatric surgery, which promotes intense weight loss and they are more prone to have nutritional deficiency such as vitamin K deficiency. Vitamin K supplementations may be recommended in this population.[10]

Insulin sensitivity

There has been some evidence to suggest that vitamin K could increase insulin sensitivity in diabetic men as well as help keep INR values from fluctuating for individuals on warfarin therapy.[11]

Vitamin K administration routes

Vitamin K can be administered orally, intravenously (IV), subcutaneously (SQ), and intramuscularly (IM). Of these, intramuscular administration is the least recommended because it can result in hematomas.

Vitamin K that is injected is available as a glass ampule, so a filter should be used prior to administration to avoid glass particles getting into the human body. Unpreserved vitamin K should be used in nursing mothers to eliminate the chance of benzyl alcohol exposure via breastmilk.

No matter the form of administration, supplemental vitamin K should be monitored in people who are on medication for anticoagulation.[7]

Dermatological reactions

There are two patterns of injection site reactions, (1) a reaction may occur several days to 2 weeks after injection with skin lesions that are pruritic, red patches and plaques that can deep-seated, involving the dermis and subcutaneous tissue, or (2) with subcutaneous sclerosis with or without fasciitis, that appears at the site of injection many months after treatment.[1]: 123  The latter reaction is known as Texier's disease and lasts several years.[1]: 123 [16] Vitamin K reactions can occur on the skin but due to its varying presentation, healthcare providers have a difficult time diagnosing it.[17] After Vitamin K injection is administered there are two potential cutaneous effects that can occur. The first is a local reaction of itchiness, eczema-like texture, indurated erythema on the skin at the injection site. The second is a generalized reaction that can show up as a skin lesion resembling a cyst. The localized reaction takes 4–14 days to develop and can take months to heal.[12]

Anaphylactic reactions

There has been rare reports of oral vitamin K adverse effects. Intravenous vitamin K admission had reports of low blood pressure, shortness of breath, flushing, and other serious allergic reactions.[6][13] Vitamin K needs to be diluted to an aqueous solution for administration as a it is a fat-soluble vitamin. Reports of hypersensitivity of the diluent with the vitamin K such as castor oil lead to cardiorespiratory arrest.[6][18]

Parental Vitamin K1 Reactions

Phytonadione, also known as parental vitamin K1, is a therapeutic that is used to reverse the effects of anticoagulants. There are many severe reactions that can occur within or during 20 minutes post-administration of parental vitamin K1 such as very low heart rate, very high heart rate, very low blood pressure, cardiac arrest, difficult breathing, and death. These type of reactions have been more commonly observed in those that are administered parental vitamin K1 through an IV versus SQ, IM or oral tablets. The emulsion notes of Vitamin K1 prescribing notes dictates that people taking vitamin K1 have reported skin reactions, pain, variable flushing, and interference in taste. Most of the reactions that are observed, can be maintained by polyoxyethylated caster oil. This oil is composed by reacting castrol oil with ethylene oxide. This emulsifier can act as a stabilizer for other medications like cyclosporine, clotrimazole, miconazole, teniposide and paclitaxel. The reactions mentioned earlier do not happen often at a rate of 3 per 10,000 doses when administered via an IV. More importantly, such cases have been associated with mortality which is why the prescribing guidelines indicate and recommends SQ for parental vitamin K1. On the other hand, the British Committee for Standards in Haematology as well as the ACCP guidelines discourages SQ and IM because they have variable and unforeseeable absorption. Higher doses of vitamin K1 administration can cause more reactions to occur when it is not properly diluted, fastly injected, or given at a very high dose. Even with proper administration of vitamin K, people can still have the serious reactions mentioned above.[6]

Pediatrics

Vitamin K may be given to children in the case of deficiency, hemorrhagic disease of newborn, malabsorption syndrome, cystic fibrosis, biliary atresia, hepatic failure, and an antidote to warfarin. However, adverse reactions may ensue. In pediatrics, these reactions may present as changes in taste, skin flushing, feeling dizzy, fast heart rate, excessive sweating, a drop in blood pressure, shortness of breath, and blue coloring of the skin. Less commonly, respiratory and cardiac arrest may result. In the case where the child has a history of severe liver disease, decreased liver function and a decrease in prothrombin production.

Specifically in neonates, an excess dose of vitamin K may result in hyperbilirubinemia, consequences of which are deadly.[19]

Hemorrhagic Disease of the Newborn (HDN)

The underdeveloped liver of a newborn coupled with poor placental distribution and an uncolonized gastrointestinal tract can result in insufficient vitamin K levels due to the body not being able to use stored vitamin K which increases the risk of HDN.[4] Additional risk factors include 1) infants who never got a vitamin K shot at birth, even more so if they were solely breastfed, 2) infants who had mothers taking medications to treat seizures since these affect how the body uses vitamin K, 3) infants with diarrhea, cystic fibrosis, and celiac disease because this makes it hard to absorb vitamins from foods.[20]

HDN, sometimes referred to as Vitamin K Deficiency Bleeding (VKDB), can lead to serious consequences, such as damage to the brain as a result of uncontrolled bleeding or potentially more fatal outcomes in newborns. Preventative use of vitamin K injections can help reduce risk of HDN.[21] Some parents may refuse the vitamin K shot given at birth to help reduce risk of HDN, and in these cases oral vitamin K can be administered. This alternative is evaluated on a case-by-case basis as there are no guidelines for oral vitamin K for infants in the U.S.[22] Vitamin K supplementation via the oral route of administration may require higher doses in newborns if affected by cholestasis or malabsorption.[23]

Treatment

Adverse effects typically goes away after discontinuing the administration of Vitamin K as the body adjusts to the dose. Severe reactions should be seen by a medical provider for further treatment.[24][25][13]

Vitamin K as reversal agent for vitamin K antagonists

Vitamin K antagonists (VKAs), like warfarin, are often used in those with elevated risks for blood clot formation.[26] VKAs diminish vitamin K levels in the body and inhibit the synthesis of vitamin K dependent clotting factors.[27] Thus, by inhibiting vitamin K, a key element by which the body produces clots, the risk of prolonged bleeding increases.[28] Traditionally, vitamin K has been used as a reversal agent for VKAs. The intravenous (IV) route of administration has a faster onset of action when compared to the oral and subcutaneous routes, thus IV vitamin K is more appropriate in critical situations.[26][27] However, the intravenous route of administration of vitamin K still takes hours before the vitamin K dependent coagulation factors can be produced by the liver, thus it requires more time for the body to suspend bleeding.[26][28] In situations where rapid reversal is necessary for those on warfarin, such as in the case of major hemorrhage or surgery, 4-factor prothrombin complex concentrate (4F-PCC) is used with vitamin K to neutralize the effects of VKAs.[28] 4F-PCC is composed of clotting factors that allow for quick reversal of VKAs, thus it compensates for the slow reversal time of vitamin K when administered together.[26][28]

Precautions

Intravenous administration of vitamin K should only be done by a healthcare facility under the care of a healthcare professional that can provide proper observation of the person in case of an adverse vitamin K reaction. Intravenous vitamin K should only be given in emergencies where benefits outweigh risks when compared to alternative options, as in the case of oral anticoagulant overdose.[6] Adverse effects can be avoided with appropriate dosing, dilution, and slow administration.[6]

See also

References

  1. 1 2 3 James W, Berger T, Elston D (2005). Andrews' Diseases of the Skin: Clinical Dermatology (10th ed.). Saunders. ISBN 978-0-8089-2351-0.
  2. 1 2 Zhang Y, Bala V, Mao Z, Chhonker YS, Murry DJ (May 2019). "A concise review of quantification methods for determination of vitamin K in various biological matrices". Journal of Pharmaceutical and Biomedical Analysis. 169: 133–141. doi:10.1016/j.jpba.2019.03.006. PMC 6496949. PMID 30861405.
  3. 1 2 Mahtani KR, Heneghan CJ, Nunan D, Roberts NW, et al. (Cochrane Heart Group) (May 2014). "Vitamin K for improved anticoagulation control in patients receiving warfarin". The Cochrane Database of Systematic Reviews (5): CD009917. doi:10.1002/14651858.CD009917.pub2. PMID 24832594.
  4. 1 2 Jullien S (September 2021). "Vitamin K prophylaxis in newborns". BMC Pediatrics. 21 (Suppl 1): 350. doi:10.1186/s12887-021-02701-4. PMC 8424792. PMID 34496783.
  5. ↑ "FAQs About Vitamin K Deficiency Bleeding | CDC". Centers for Disease Control and Prevention. 2019-12-19. Archived from the original on 2023-07-26. Retrieved 2023-07-27.
  6. 1 2 3 4 5 6 7 8 9 10 Britt RB, Brown JN (January 2018). "Characterizing the Severe Reactions of Parenteral Vitamin K1". Clinical and Applied Thrombosis/Hemostasis. 24 (1): 5–12. doi:10.1177/1076029616674825. PMC 6714635. PMID 28301903.
  7. 1 2 Ingold CJ, Sergent SR (2023). "Phytonadione (Vitamin K1)". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID 32491554. Archived from the original on 2023-06-29. Retrieved 2023-07-27.
  8. 1 2 Rodríguez-Olleros Rodríguez C, Díaz Curiel M (2019-12-31). "Vitamin K and Bone Health: A Review on the Effects of Vitamin K Deficiency and Supplementation and the Effect of Non-Vitamin K Antagonist Oral Anticoagulants on Different Bone Parameters". Journal of Osteoporosis. 2019: 2069176. doi:10.1155/2019/2069176. PMC 6955144. PMID 31976057.
  9. 1 2 Girolami A, Ferrari S, Cosi E, Santarossa C, Randi ML (December 2018). "Vitamin K-Dependent Coagulation Factors That May be Responsible for Both Bleeding and Thrombosis (FII, FVII, and FIX)". Clinical and Applied Thrombosis/Hemostasis. 24 (9_suppl): 42S–47S. doi:10.1177/1076029618811109. PMC 6714837. PMID 30428703.
  10. 1 2 Gasmi, Amin; Bjørklund, Geir; Mujawdiya, Pavan Kumar; Semenova, Yuliya; Peana, Massimiliano; Dosa, Alexandru; Piscopo, Salva; Gasmi Benahmed, Asma; Costea, Daniel Ovidiu (2021-07-23). "Micronutrients deficiences in patients after bariatric surgery". European Journal of Nutrition. 61 (1): 55–67. doi:10.1007/s00394-021-02619-8. ISSN 1436-6215. PMID 34302218. S2CID 236203803.
  11. 1 2 DiNicolantonio JJ, Bhutani J, O'Keefe JH (October 2015). "The health benefits of vitamin K". Open Heart. 2 (1): e000300. doi:10.1136/openhrt-2015-000300. PMC 4600246. PMID 26468402.
  12. 1 2 Zhang, Miao; Chen, Jia; Wang, Chun-Xiao; Lin, Nai-Xuan; Li, Xin (2022-10-16). "Cutaneous allergic reaction to subcutaneous vitamin K 1 : A case report and review of literature". World Journal of Clinical Cases. 10 (29): 10742–10754. doi:10.12998/wjcc.v10.i29.10742. ISSN 2307-8960. PMC 9602232. PMID 36312487.
  13. 1 2 3 Ensina LF, da Cunha FS, Bastos PG, Nunes FA, Camelo-Nunes IC (2020-01-14). "Vitamin-Induced Anaphylaxis". Current Treatment Options in Allergy. 7 (1): 84–92. doi:10.1007/s40521-020-00246-y. ISSN 2196-3053. S2CID 210168554.
  14. ↑ Jäpelt RB, Jakobsen J (February 2016). "Analysis of vitamin K1 in fruits and vegetables using accelerated solvent extraction and liquid chromatography tandem mass spectrometry with atmospheric pressure chemical ionization". Food Chemistry. 192: 402–408. doi:10.1016/j.foodchem.2015.06.111. PMID 26304366.
  15. ↑ Vermeer C, Schurgers LJ (April 2000). "A comprehensive review of vitamin K and vitamin K antagonists". Hematology/Oncology Clinics of North America. 14 (2): 339–353. doi:10.1016/S0889-8588(05)70137-4. PMID 10806559.
  16. ↑ Memar EH, Safavi M, Moradinejad MH, Ziaee V (January 2022). "The First Presentation of Localized Scleroderma at Birth: Scleroderma as a Differential Diagnosis of Congenital Skin Lesion". Journal of Child Science. 12 (1): e1–e4. doi:10.1055/s-0041-1741055. ISSN 2474-5871. S2CID 246761908.
  17. ↑ Zhang M, Chen J, Wang CX, Lin NX, Li X (October 2022). "Cutaneous allergic reaction to subcutaneous vitamin K1: A case report and review of literature". World Journal of Clinical Cases. 10 (29): 10742–10754. doi:10.12998/wjcc.v10.i29.10742. PMC 9602232. PMID 36312487.
  18. ↑ Kang SY, Sohn KH, Lee JO, Kim SH, Cho SH, Chang YS (July 2015). "Intravenous tacrolimus and cyclosporine induced anaphylaxis: what is next?". Asia Pacific Allergy. 5 (3): 181–186. doi:10.5415/apallergy.2015.5.3.181. PMC 4521168. PMID 26240796.
  19. ↑ "Vitamin-k - Mechanism, Indication, Contraindications, Dosing, Adverse Effect, Interaction, Renal Dose, Hepatic Dose | Drug Index | Pediatric Oncall". www.pediatriconcall.com. Archived from the original on 2023-07-26. Retrieved 2023-07-26.
  20. ↑ "What is Vitamin K Deficiency Bleeding? | CDC". Centers for Disease Control and Prevention. 2023-02-10. Archived from the original on 2023-07-26. Retrieved 2023-07-28.
  21. ↑ "Protect Your Baby from Bleeds". Centers for Disease Control and Prevention. 2019-12-26. Archived from the original on 2023-07-05. Retrieved 2023-07-26.
  22. ↑ Dekker R (2019-04-09). "Evidence on: The Vitamin K Shot in Newborns". Evidence Based Birth®. Archived from the original on 2017-07-10. Retrieved 2023-07-27.
  23. ↑ Ceratto S, Savino F (March 2019). "Vitamin K deficiency bleeding in an apparently healthy newborn infant: the compelling need for evidence-based recommendation". Italian Journal of Pediatrics. 45 (1): 30. doi:10.1186/s13052-019-0625-y. PMC 6399912. PMID 30832683.
  24. ↑ Mladěnka P, Macáková K, Kujovská Krčmová L, Javorská L, Mrštná K, Carazo A, et al. (March 2022). "Vitamin K - sources, physiological role, kinetics, deficiency, detection, therapeutic use, and toxicity". Nutrition Reviews. 80 (4): 677–698. doi:10.1093/nutrit/nuab061. PMC 8907489. PMID 34472618.
  25. ↑ "Vitamin K (Class) (Oral Route, Parenteral Route) Side Effects - Mayo Clinic". www.mayoclinic.org. Archived from the original on 2023-07-26. Retrieved 2023-07-26.
  26. 1 2 3 4 Milling TJ, Refaai MA, Sengupta N (November 2021). "Anticoagulant Reversal in Gastrointestinal Bleeding: Review of Treatment Guidelines". Digestive Diseases and Sciences. 66 (11): 3698–3714. doi:10.1007/s10620-020-06728-y. PMC 9245141. PMID 33403486.
  27. 1 2 Heestermans M, Poenou G, Hamzeh-Cognasse H, Cognasse F, Bertoletti L (October 2022). "Anticoagulants: A Short History, Their Mechanism of Action, Pharmacology, and Indications". Cells. 11 (20): 3214. doi:10.3390/cells11203214. PMC 9600347. PMID 36291080.
  28. 1 2 3 4 Milling TJ, Ziebell CM (February 2020). "A review of oral anticoagulants, old and new, in major bleeding and the need for urgent surgery". Trends in Cardiovascular Medicine. 30 (2): 86–90. doi:10.1016/j.tcm.2019.03.004. PMC 6763385. PMID 30952383.
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