Abstract:

Vitamin K is recognized for its important role in blood coagulation. Little did we know that it has other vital functions in the human body. Current research findings show its function in bone mineralization, inhibition of vascular calcification, tumor suppression, and inducing insulin sensitization. These benefits offer novel supportive approach in the management of certain diseases including Covid-19.

Introduction:

Vitamin K is a fat-soluble vitamin and its long time well-known function within the body is in the production of coagulation factors (II, VII, IX, X, protein C, and protein S). Moreover, Vitamin K is also involve in the formation of bones (osteocalcin), anticalcification (matrix-Gla protein), cancer prevention and as an insulin sensitizing molecule. Vitamin K is available naturally as Vitamin K1 (phylloquinone) and Vitamin K2 (menaquinone). Vitamin K1 is mostly found among green leafy vegetables (broccoli, brussels sprouts, cabbage, kale, kai-lan, etc.).1 Dark leaf color has more substantial amount of phylloquinones. The other sources of phylloquinone are found in certain plant oils such as soybean, canola, cottonseed, and olive.2 The recommended adequate intake of phylloquinone is 90 μg/day for women and 120 μg/day for men..3 Menaquinones, on the other hand, are found in foods of animal in origin, like bovine liver, and in foods which are fermented with bacteria such as yogurt and other types of cheese. They differ in structure from phylloquinone in their 3-substituted liphophilic side chain. The major menaquinones has 4-10 repeating isoprenoid designated by MK-4 to MK-10.2 The most important menaquinones which has preventive and therapeutic values are menaquinone-4 (MK-4) and menaquinone-7 (MK-7).4 Natto, a traditional Japanese food, which is made from bacterially fermented soya beans, has the richest source of MK-7 with 10 μg/g. Another form of Vitamin K is Menadione (K3). It is not considered a natural form of Vitamin K but a synthetic equivalent that function as a provitamin. Once absorbed in the body, K3 becomes alkylated into a biologically active isoprenylated menaquinones. The difference of K3 among the other vitamins is that it has limitations in its function. K3 is unable to apply all the functions of the natural forms of Vitamin K.14 However, vitamin K3 has been found out to exhibit antitumor activity.

Vitamin K and Coagulation

The classic role of Vitamin K is in the production of proteins needed for coagulation. This is exemplified in vitamin K deficiency states as seen in newborns. In the classic Hemorrhagic Disease of the Newborn (HDN), vitamin K deficiency may cause unexpected bleeding in 0.25% to 1% neonates in the first week of life.⁵ The administration of a single dose of 0.5 to 1.0 mg of Vitamin K as prophylaxis in newborns has been well-established in the prevention of the classic hemorrhagic disease of newborn. In infants aged 2 to 12 weeks who are exclusively breast-fed and have received no or inadequate vitamin K prophylaxis, a condition known as late hemorrhagic disease of newborn may occur. Infants who have malabsorption defects in the intestine (cholestatic jaundice, cystic fibrosis, etc.) may also manifest with late hemorrhagic disease of the newborn. The administration of parenteral neonatal vitamin K prophylaxis is shown to prevents the development of late HDN. ⁵

Vitamin K and Bone Health:

Vitamin K is an essential cofactor for the carboxylation of osteocalcin that helps in bone formation.⁶ Vitamin K and 1,25-dihydroxyvitamin D [1,25 (OH)₂D; calcitriol] regulate the activation and production of osteocalcin. The transcription of the osteocalcin gene is supported by 1,25 (OH)₂D, while vitamin K assists in the posttranscriptional carboxylation of Gla residues in the osteocalcin propeptide.⁴ Additionally, it was established that 1,25 (OH)₂D complements the activity of γ-glutamyl carboxylase, which implies that the carboxylation of osteocalcin is accelerated by Vitamin D and that MK-4 activates 1,25-dihydroxyvitamin D3-induced mineralization by human osteoblasts. Both vitamin K and vitamin D are involved synergistically on bone health. Thereby, low vitamin K status was identified to be linked with low bone mass, osteoporosis, and fracture risk.⁷ In the Nurses’ health study, which is a 10-year prospective study of women aged 38-63, it was found out that undercarboxylated osteocalcin can be lowered with high intakes of Vitamin K-rich foods and that there is a positive association with risk of hip fractures with undercarboxylated osteocalcin. It was observed that an increased risk of hip fracture was seen in women with lowest vitamin K intake.⁸ In the Framingham offspring study conducted to determine the effect of vitamin K intake in bone mineral density, it was determined that low dietary phylloquinone intake was associated with low bone mineral density. The results of this study promoted support to the assumption that vitamin K is a reversible factor that help reduce bone loss due to aging.⁹ Patients who have chronic renal failure also undergo bone mineral disturbances. In the study conducted by Kohlmeier et al, they investigated a total of 68 patients (33-91 years) on hemodialysis and analyzed the association between biochemical indicators of vitamin K nutrition and bone metabolism, and related fracture risk. After a four-year follow-up period, there were 41 patients who did not develop any fracture and it was notable that these patients have close to three times higher concentrations of phylloquinone than the nine patients with fracture.¹⁰

Vitamin K and Vascular Health:

While vitamin K plays a significant role in the carboxylation of osteocalcin which helps in the formation of bones, the vitamin K-dependent Matrix Gla Protein (cMGP) prevents blood vessels from developing calcification from calcium overload.⁴ The matrix Gla-protein was discovered in human atherosclerotic plaque where its role help prevent the precipitation of calcium as what it does in bone. It was assumed that a diet with insufficient intake of vitamin K may also lead to under carboxylation of vascular matrix Gla protein which may result to calcification of atherosclerotic lesions, and, therefore, a heightened risk of developing coronary heart disease. In the Rotterdam Study conducted to determine the association of dietary intake of Menaquinone with Coronary Heart Disease, they have observed that dietary menaquinone intake has a protective effect from coronary artery disease in older men and women as determined by the inverse association with all-cause mortality. The patients in the highest quartile for K2 intake had a median intake of 40.9 μg/day. Moreover, cancer risk does not rise with high menaquinone dietary intake.¹¹ On the other hand, phylloquinone intake had no association with coronary heart disease, mortality, or in the calcification of aorta. Gast et al also did a study similar to the Rotterdam study, where they also found an inverse relationship with menaquinone dietary intake and coronary heart disease. The protective effect of Vitamin K2 is manifested in subtypes MK-7 through MK-9.¹² However, more studies should be done in the future to determine the adequate dose of Vitamin K in the prevention of coronary heart disease.  

In patients with chronic kidney disease, warfarin is frequently prescribed to inhibit venous thromboembolism, atrial fibrillation and for access-related issues. Warfarin then impedes the vitamin K epoxide reductase enzyme, interrupting the reduction of the epoxide and inhibits the cycling back to the hydroquinone intermediate, which then interrupts the blood coagulation cascade.¹³ The resultant low tissue levels of vitamin K leads to formation of inactive MGP which is not able to counteract vascular calcification. Conversely with a high vitamin K dietary intake, tissue levels of vitamin K are increased then rising the amount of active MGP, and, therefore, heightens the vascular calcification inhibitory action. McCabe et al demonstrated in their study a rodent model of chronic kidney disease (CKD), and the role of vitamin K as a possible treatment option to lessen the development of vascular calcification in CKD. Their study showed that those given with therapeutic doses of warfarin had accelerated vascular calcification in all the vessels studied (renal artery, carotid artery, abdominal aorta, and thoracic aorta) and displayed changes within the circulation (elevated pulse pressure and pulse wave velocity). Their results suggested that in the setting of chronic kidney disease, vitamin K levels are critical in preventing vascular calcification.¹³