Vitamin K2 Supplementation in Hospitalised COVID-19 Patients: A Randomised Controlled Trial
Margot P J Visser, Anton S M Dofferhoff, Jody M W Va Den Ouwelan, Pim A De Jong, Piet Zanen, Henny Van Daal, Eline B Theeuwen, Cornelis Kramers, Rob Janssen, Jona Walk
doi:10.3390/jcm13123476
Background: In observational studies, high levels of desphospho-uncarboxylated matrix gla protein (dp-ucMGP) that result from vitamin K deficiency were consistently associated with poor clinical outcomes during COVID-19. Vitamin K-activated matrix gla protein (MGP) is required to protect against elastic fibre degradation, and a deficiency may contribute to pathology. However, intervention trials assessing the effects of vitamin K supplementation in COVID-19 are lacking. Methods: This is a single-centre, phase 2, double-blind, randomised, placebo-controlled trial investigating the effects of vitamin K2 supplementation in 40 hospitalised COVID-19 patients requiring supplemental oxygen. Individuals were randomly assigned in a 1:1 ratio to receive 999 mcg of vitamin K2-menaquinone-7 (MK-7)-or a placebo daily until discharge or for a maximum of 14 days. Dp-ucMGP, the rate of elastic fibre degradation quantified by desmosine, and hepatic vitamin K status quantified by PIVKA-II were measured. Grade 3 and 4 adverse events were collected daily. As an exploratory objective, circulating vitamin K2 levels were measured. Results: Vitamin K2 was well tolerated and did not increase the number of adverse events. A linear mixed model analysis showed that dp-ucMGP and PIVKA-II decreased significantly in subjects that received supplementation compared to the controls (p = 0.008 and p = 0.0017, respectively), reflecting improved vitamin K status. The decrease in dp-ucMGP correlated with higher plasma MK-7 levels (p = 0.015). No significant effect on desmosine was found (p = 0.545). Conclusions: These results demonstrate that vitamin K2 supplementation during COVID-19 is safe and decreases dp-ucMGP. However, the current dose of vitamin K2 failed to show a protective effect against elastic fibre degradation.
Institutional Review Board Statement: The study was approved by the ethical review board CMO Arnhem-Nijmegen on the 15th of February 2021 (NL74583.091.20). The local review committee of the Canisius-Wilhelmina Hospital approved the protocol (CWZ-nr. 107-2021). This trial is registered at ClinicalTrials.gov, identifier NCT04770740. Informed Consent Statement: Informed consent was obtained from all 40 participants involved in the study. Conflicts of Interest: R.J. discloses the application of a patent on vitamin K in COVID-19 that is held by Emphysema Solutions Bv of which R.J. and J.W. are owners. M.P.J.V., J.W., R.J. and A.S.M.D. had a scientific collaboration with Kappa Bioscience A.S., which is a manufacturer of vitamin K2 (MK-7). R.J. and J.M.W.O. are owners of Desmosine.com. H.D., P.A.J., P.Z., E.B.T. and C.K. declare no competing interests.
Abbreviations COVID-19: Coronavirus Disease 2019; dp-uc, desphospho-uncarboxylated; MGP, matrix gla protein; SARS-CoV, severe acute respiratory syndrome coronavirus; MK-7, menaquinone-7; PIVKA-II, protein induced by vitamin K absence or antagonist-II; PCR, Polymerase Chain Reaction; LMWH, low-molecular-weight heparin; eCRF, electronic Case Report Form; SMC, Safety Monitoring Committee; IL-6, interleukin-6; CT, Computed Tomography; LC-MS/MS, liquid chromatography with tandem mass spectrometry; ITT, intention to treat; AIC, Akaike's Information Criterion; BMI, Body Mass Index; ICU, Intensive Care Unit.
References
Akbulut, Pavlic, Petsophonsakul, Halder, Maresz et al., Vitamin k2 needs an RDI separate from vitamin k1, Nutrients,
doi:10.3390/nu12061852Booth, Martini, Peterson, Saltzman, Dallal et al., Dietary phylloquinone depletion and repletion in older women, J. Nutr,
doi:10.1093/jn/133.8.2565Burstyn-Cohen, Heeb, Lemke, Lack of protein s in mice causes embryonic lethal coagulopathy and vascular dysgenesis, J. Clin. Investig,
doi:10.1172/JCI39325Cho, Lee, Sia, Koo, Tan et al., Extrapulmonary manifestations and complications of severe acute respiratory syndrome coronavirus-2 infection: A systematic review, Singap. Med. J,
doi:10.11622/smedj.2021100Cranenburg, Koos, Schurgers, Magdeleyns, Schoonbrood et al., Characterisation and potential diagnostic value of circulating matrix GLA protein (MGP) species, Thromb. Haemost,
doi:10.1160/TH09-11-0786Cui, Chen, Li, Liu, Wang, Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia, J. Thromb. Haemost,
doi:10.1111/jth.14830De Vriese, Caluwé, Pyfferoen, De Bacquer, De Boeck et al., Multicenter randomized controlled trial of vitamin k antagonist replacement by rivaroxaban with or without vitamin k2 in hemodialysis patients with atrial fibrillation: The valkyrie study, J. Am. Soc. Nephrol,
doi:10.1681/ASN.2019060579Desai, Dirajlal-Fargo, Durieux, Tribout, Labbato et al., Vitamin k & d deficiencies are independently associated with COVID-19 disease severity, Open Forum Infect. Dis
Dofferhoff, Piscaer, Schurgers, Visser, Van Den Ouweland et al., Reduced vitamin k status as a potentially modifiable risk factor of severe COVID-19, Clin. Infect. Dis,
doi:10.1093/cid/ciaa1258Huang, Bolton, Miller, Tal-Singer, Rabinovich et al., Age-dependent elastin degradation is enhanced in chronic obstructive pulmonary disease, Eur. Respir. J,
doi:10.1183/13993003.01125-2016Irwin, Adie, Sandison, Alsomairy, Brancaccio, Warfarin dose requirements in adults hospitalized with COVID-19 infection: A retrospective case series, J. Pharm. Pract,
doi:10.1177/08971900211000705Jaminon, Dai, Qureshi, Evenepoel, Ripsweden et al., Matrix GLA protein is an independent predictor of both intimal and medial vascular calcification in chronic kidney disease, Sci. Rep,
doi:10.1038/s41598-020-63013-8Kumric, Borovac, Ticinovic Kurir, Martinovic, Frka Separovic et al., Role of matrix GLA protein in the complex network of coronary artery disease: A comprehensive review, Life,
doi:10.3390/life11080737Leisman, Ronner, Pinotti, Taylor, Sinha et al., Cytokine elevation in severe and critical COVID-19: A rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes, Lancet Respir. Med,
doi:10.1016/S2213-2600(20)30404-5Linneberg, Kampmann, Israelsen, Andersen, Jørgensen et al., The association of low vitamin k status with mortality in a cohort of 138 hospitalized patients with COVID-19, Nutrients,
doi:10.3390/nu13061985Luo, Ducy, Mckee, Pinero, Loyer et al., Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein, Nature,
doi:10.1038/386078a0Ma, Turino, Hayashi, Yanuma, Usuki et al., Stable deuterium internal standard for the isotope-dilution lc-ms/ms analysis of elastin degradation, Anal. Biochem,
doi:10.1016/j.ab.2013.05.014Mangge, Prueller, Dawczynski, Curcic, Sloup et al., Dramatic decrease of vitamin k2 subtype menaquinone-7 in COVID-19 patients, Antioxidants,
doi:10.3390/antiox11071235Mccann, Ames, Vitamin k, an example of triage theory: Is micronutrient inadequacy linked to diseases of aging?, Am. J. Clin. Nutr,
doi:10.3945/ajcn.2009.27930Mitsui, Effect of natto including bacillus subtilis k-2 (spore) on defecation and fecal microbiota and safety of excessive ingestion in healthy volunteers, Jpn. Pharmacol. Ther
Molfino, Anastasi, Assanto, Toccini, Imbimbo et al., Association between serum levels of GDF-15, SUPAR, PIVKA-ii, SDLDL and clinical outcomes in hospitalized COVID-19 patients, Intern. Emerg. Med,
doi:10.1007/s11739-024-03630-7Mulder, Schellens, Sels, Van Rosmalen, Hulshof et al., Higher levels of circulating desphospho-uncarboxylated matrix GLA protein over time are associated with worse survival: The prospective maastricht intensive care covid cohort, J. Intensive Care,
doi:10.1186/s40560-023-00712-0Padda, Patel, Citla Sridhar, Protein, Statpearls, None
Piscaer, Janssen, Franssen, Schurgers, Wouters, The pleiotropic role of vitamin k in multimorbidity of chronic obstructive pulmonary disease, J. Clin. Med,
doi:10.3390/jcm12041261Popa, Bigman, Rusu, The role of vitamin k in humans: Implication in aging and age-associated diseases, Antioxidants,
doi:10.3390/antiox10040566Proskuriakova, Jasaraj, Shrestha, Reddy, Khosla, Acute portal vein thrombosis as an initial presentation of protein c deficiency: A case report, Cureus,
doi:10.7759/cureus.40407Rucker, Calcium binding to elastin, Adv. Exp. Med. Biol
Speed, Patel, Byrne, Roberts, Arya, A perfect storm: Root cause analysis of supra-therapeutic anticoagulation with vitamin k antagonists during the COVID-19 pandemic, Thromb. Res,
doi:10.1016/j.thromres.2020.05.024Staufer, Gupta, Hernandez Bücher, Kohler, Sigl et al., Synthetic virions reveal fatty acid-coupled adaptive immunogenicity of SARS-CoV-2 spike glycoprotein, Nat. Commun,
doi:10.1038/s41467-022-28446-xSumi, Accumulation of vitamin k (menaquinone-7) in plasma after ingestion of natto and natto bacilli (B. subtilis natto), Food Sci. Technol. Res,
doi:10.3136/fstr.5.48Tsukamoto, Ichise, Kakuda, Yamaguchi, Intake of fermented soybean (natto) increases circulating vitamin k2 (menaquinone-7) and gamma-carboxylated osteocalcin concentration in normal individuals, J. Bone Miner. Metab,
doi:10.1007/s007740070023Turck, Bresson, Burlingame, Dean, Fairweather-Tait et al., Dietary reference values for vitamin k, Efsa J
Visser, Dofferhoff, Van Den Ouweland, Van Daal, Kramers et al., Effects of vitamin d and k on interleukin-6 in COVID-19, Front. Nutr,
doi:10.3389/fnut.2021.761191Visser, Walk, Vermeer, Bílková, Janssen et al., Enhanced vitamin k expenditure as a major contributor to vitamin k deficiency in COVID-19, Int. J. Infect. Dis,
doi:10.1016/j.ijid.2022.10.030Yamaguchi, Kakuda, Gao, Tsukamoto, Prolonged intake of fermented soybean (natto) diets containing vitamin k2 (menaquinone-7) prevents bone loss in ovariectomized rats, J. Bone Miner. Metab,
doi:10.1007/s007740050014Zhan, Zha, Lin, Mao, Yang et al., Protective role of vitamin k3 on SARS-CoV-2 structural protein-induced inflammation and cell death, Pharmaceuticals,
doi:10.3390/ph16081101Zhou, Yu, Du, Fan, Liu et al., Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study, Lancet,
doi:10.1016/S0140-6736(20)30566-3
