Vitamin K Plays A Role In COVID-19


A new study by medical researchers from Canisius-Wilhelmina Hospital-Netherlands, Maastricht University-Netherlands and also involving doctors from University Hospitals Leuven-Belgium has found that Vitamin K play a critical role in preventing COVID-19 disease severity especially involving lung damage and thromboembolism.

The study findings were published in the peer reviewed British Journal of Nutrition.
The COVID-19 caused by the SARS-CoV-2 coronavirus, exerts far-reaching effects on public health and socio-economic welfare. The majority of infected individuals have mild to moderate symptoms, but a significant proportion develops respiratory failure due to pneumonia. Thrombosis is another frequent manifestation of COVID-19 that contributes to poor outcomes.
Vitamin K are fat-soluble vitamers found in foods and marketed as dietary supplements. The human body requires vitamin K for post-synthesis modification of certain proteins that are required for blood coagulation or for controlling binding of calcium in bones and other tissues.

The complete synthesis involves final modification of these so-called “Gla proteins” by the enzyme gamma-glutamyl carboxylase that uses vitamin K as a cofactor.

The presence of uncarboxylated proteins indicates a vitamin K deficiency. Carboxylation allows them to bind (chelate) calcium ions, which they cannot do otherwise.
Importantly without vitamin K, blood coagulation is seriously impaired, and uncontrolled bleeding occurs. Research suggests that deficiency of vitamin K may also weaken bones, potentially contributing to osteoporosis, and may promote calcification of arteries and other soft tissues.
Chemically, the vitamin K family comprises 2-methyl-1,4-naphthoquinone (3-) derivatives. Vitamin K includes two natural vitamers: vitamin K1 (phylloquinone) and vitamin K2 (menaquinone). Vitamin K2, in turn, consists of a number of related chemical subtypes, with differing lengths of carbon side chains made of isoprenoid groups of atoms. The two most studied ones are menaquinone-4 (MK-4) and menaquinone-7 (MK-7).

Vitamin K1 is made by plants, and is found in highest amounts in green leafy vegetables, because it is directly involved in photosynthesis. It is active as a vitam in in animals and performs the classic functions of vitamin K, including its activity in the production of blood-clotting proteins. Animals may also convert it to vitamin K2, variant MK-4. 

Bacteria in the gut flora can also convert K1 into MK-4. All forms of K2 other than MK-4 can only be produced by bacteria, which use these during anaerobic respiration. Vitamin K3 (menadione), a synthetic form of vitamin K, was used to treat vitamin K deficiency, but because it interferes with the function of glutathione, it is no longer used this way in human nutrition.
It has already been known that Vitamin K plays a crucial role in the activation of both pro- and anticlotting factors in the liver and the activation of extrahepatically synthesized protein S which seems to be important in local thrombosis prevention.
However, unknown to many, the role of vitamin K extends beyond coagulation.
Vitamin K is a monofunctional nutrient from a biochemical perspective as its only well-described function is facilitating γ-carboxylation. However, it can be regarded as pleiotropic because it activates proteins with distinct, opposing and not yet fully unravelled functions.
Vitamin K catalyses the carboxylation reaction that transforms glutamic acid into γ-carboxyglutamic (Gla) residues and is well known as an activator of hepatic procoagulant factors II (prothrombin), VII, IX and X. However, vitamin K also activates anticoagulant proteins C and S as well as a number of extrahepatic proteins not involved in blood coagulation.
Importantly the matrix Gla protein (MGP) is a vitamin K-dependent inhibitor of soft tissue calcification and elastic fibre degradation.
Vitamin K-dependent matrix Gla protein (MGP) has been extensively studied as an inhibitor of vascular mineralization; however, its role in the pulmonary compartment seems to be comparable. Besides preventing soft tissue calcification, MGP also protects against elastic fibre degradation. This was demonstrated in MGP knockout mice, which developed severely mineralized as well as fragmented elastic fibres.
Elastic fibres are critical components in the extracellular matrix of dynamic tissues. They provide deformability to lungs and arteries, which facilitates respiration and circulation. Initial elastic fibre development is almost exclusively restricted to the perinatal period. Elastic fibre degradation and repair, however, are continuous processes. The balance between the two is delicate and of vital importance for cardiovascular and pulmonary health.

The rate of proteolytic elastic fibre degradation increases during ageing. This age-related acceleration of elastolysis is enhanced in certain pulmonary conditions such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis.
Severe extrahepatic vitamin K insufficiency was recently demonstrated in COVID-19 patients, with high inactive MGP levels correlating with elastic fibre degradation rates.
These findings suggest that insufficient vitamin K-dependent MGP activation leaves elastic fibres unprotected against SARS-CoV-2-induced proteolysis. In contrast to MGP, COVID-19 patients have normal levels of activated factor II, in line with previous observations that vitamin K is preferentially transported to the liver for activation of procoagulant factors.
The study team also expects that vitamin K-dependent endothelial protein S activation is also compromised, which would be compatible with enhanced thrombogenicity.
Collectively these data has lead the study team to propose a mechanism of pneumonia-induced vitamin K depletion, leading to a decrease in activated MGP and protein S, aggravating pulmonary damage and coagulopathy, respectively.
The study team proposes that intervention trials should be conducted to assess whether vitamin K administration  as COVID-19 Supplements plays a role in the prevention and treatment of severe COVID-19.
Corresponding author, Dr Rob Janssen from the Department of Pulmonary Medicine, Canisius-Wilhelmina Hospital, told Thailand Medical News, “In conclusion, the potential role of vitamin K supplementation to prevent the development and progression of severe COVID-19 remains largely unexplored.

We would argue that the impact of the current crisis warrants thorough evaluation of the therapeutic potential of vitamin K in COVID-19 pathogenesis for two key reasons.

Unlike treatment strategies involving drugs such as remdesivir or dexamethasone for COVID-19, vitamin K does not have any known unfavourable effects in those who do not use VKA (Vitamin K antagonists). Furthermore, it is relatively simple and inexpensive to manufacture contrary to other therapies like remdesivir or convalescent plasma. Taken together this means that effectiveness can be rapidly and cheaply evaluated in clinical trials and easily implemented if proven successful.

It has recently been hypothesized that vitamin K could play a role in COVID-19. We aimed to test the hypotheses that low vitamin K status is a common characteristic of patients hospitalized with COVID-19 compared to population controls and that low vitamin K status predicts mortality in COVID-19 patients.

In a cohort of 138 COVID-19 patients and 138 population controls, we measured plasma dephosphorylated-uncarboxylated Matrix Gla Protein (dp-ucMGP), which reflects the functional vitamin K status in peripheral tissue. Forty-three patients died within 90 days from admission. In patients, levels of dp-ucMGP differed significantly between survivors (mean 877; 95% CI: 778; 995) and non-survivors (mean 1445; 95% CI: 1148; 1820).

Furthermore, levels of dp-ucMGP (pmol/L) were considerably higher in patients (mean 1022; 95% CI: 912; 1151) compared to controls (mean 509; 95% CI: 485; 540). Cox regression survival analysis showed that increasing levels of dp-ucMGP (reflecting low vitamin K status) were associated with higher mortality risk (sex- and age-adjusted hazard ratio per doubling of dp-ucMGP was 1.49, 95% CI: 1.03; 2.24).

The association attenuated and became statistically insignificant after adjustment for co-morbidities (sex, age, CVD, diabetes, BMI, and eGFR adjusted hazard ratio per doubling of dp-ucMGP was 1.22, 95% CI: 0.82; 1.80). In conclusion, we found that low vitamin K status was associated with mortality in patients with COVID-19 in sex- and age-adjusted analyses, but not in analyses additionally adjusted for co-morbidities. Randomized clinical trials would be needed to clarify a potential role, if any, of vitamin K in the course of COVID-19.

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