Vitamin K and Its Role Against Arterial Calcification

Vitamin K is a group of vitamins that includes vitamins K₁ and K₂, which, in its turn, comprise other forms, too. Vitamin K₁ is called phylloquinone and is synthesized by plants. The forms of vitamin K₂ are called menaquinones and are synthesized by bacteria in the human hindgut or found in animal products (WHO, 2004, p. 108). In general, vitamin K is a fat-soluble vitamin needed for blood clotting, bone formation, and the metabolism of both calcified and noncalcified tissues (Combs, 2008, p. 214).

Vitamin K was discovered in the 1930s and demonstrated many useful properties (Merli & Fink, 2008, p. 266). For the present essay the most important is its role in the inhibition of arterial calcification. These properties of vitamin K were found not long ago. Until recently, it was mostly believed to play an important role in blood clotting process. However, the discovery of warfarin and its anticoagulant qualities in the 1950s created a new field for the usage of vitamin K (p. 266). Being an antagonist of vitamin K, warfarin impairs the vitamin K function. Patients with prosthetic heart valves, atrial fibrillation, deep vein thrombosis, and pulmonary embolism are proscribed anticoagulant therapy to thin the blood and prevent blockages in arteries. Such treatments include large doses of salicylates, warfarin and other anticoagulants which inhibit the redox-cycling of the vitamin K. (Combs, 2008, p. 228).

Judith E. Brown (2010) gives an example of how and why vitamin K taken together with warfarin becomes a problem: “Big portions of broccoli and greens for a few weeks in summer will decrease the effectiveness of warfarin and thus increase potential for blood clotting and another stroke” (p. 499). Therefore, nutrition counselors should advise patients on how to take vitamin K correctly without interfering with the warfarin therapy. In order to normalize clotting mechanisms vitamin K is prescribed in high doses. Meanwhile “over-anticoagulation with warfarin” is neutralized by the interruption of warfarin therapy or “warfarin dose reduction coupled with treatment with phylloquinone” (Combs, 2008, p. 228).

More recently, vitamin K metabolism was applied to the field of arteriovascular health. It was found out that one of the vitamin K-dependent proteins matrix Gla protein (MGP) may protect soft tissues against calcification (Combs, 2008, p. 225). There were animal lab researches made, and scientists found out that mice kept with MGP-deficiency developed abnormalities and died within 2 months from the rupture of the aorta, connected to arterial calcification (p. 226). “Although the roles of vitamin K-dependent factors in atherogenesis remain unclear, it is possible that increased dietary intake of the vitamin may be useful in reducing atherosclerosis risk” (p. 226). Thus, it was found out that vitamin K acts to prevent mineralization of connective tissues.

Postmenopausal women may come across a curious phenomenon of “the calcification paradox,” a combination of osteoporosis and atherosclerosis in a patient. There are cases when a patient suffers from arterial calcification and at the same time has a deficiency of calcium in bones. The reason for that is that different types of vitamin K are responsible for different functions. While bone mineralization is assisted by vitamin K₁, arterial calcification is prevented by matrix Gla protein (Heiss et al., 2008, p. 423). Having conducted experiments on mice, scientists found out that among other potential calcification inhibitors such as fetuin-A and pyrophosphates was matrix Gla protein. It regulates arterial calcification by inhibiting it and at the same time assists in calcification of bone matrix (Combs, 2008, p. 225).

Matrix Gla protein is the strongest inhibitor of tissue calcifications known. Functional defects in MGP result in the Keutel syndrome, a rare autosomal disorder characterized by midfacial hypoplasia and ectopic abnormal cartilage calcification (Merli & Fink, 2008, p. 274). In healthy tissues, the levels of matrix Gla protein are high only in areas of arterial calcification, which “may serve as a marker of cardiovascular disease in the near future” (p. 275).

According to scholars, prescribing vitamin K₁ and warfarin may be clinically challenging because “vitamin K₁ supplementation will require concordant warfarin adjustment” resulting “in an increased dosing of warfarin, which would exhaust the vitamin K stores in the arterial walls” (Merli & Fink, 2008, p. 275). The experiment with rats receiving vitamin K₁ and the warfarin therapy demonstrated that they develop extensive arterial calcification within 2-4 weeks (p. 275). In contrast, there were conducted researches with different forms of vitamin K₂. MK-4 and MK-7 were proposed for patients on the warfarin therapy. “The stability of their International Normalized Ratio (INR) value over time, bone density, and vascular calcification will be the endpoints of the trial” (p. 276).

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Vitamin K deficiency is diagnosed with blood tests. The deficiency may be found in infants. Now infant formulas are fortified with vitamin K supplements. Therefore, formula-fed infants receive about 100-fold higher intake of phylloquinone than breastfed infants, who receive less than 1 mg/ day (WHO, 2004, p.118). In fact, formula-fed infants have an excess of vitamin K with the average intake of US infants 2–6 months of age 63 mg/ day (Booth & Rajabi, 2008, p. 6). Meanwhile, the adequate intake (AI) for infants is 2–2.5 mg/day, and exclusively breast-fed infants have an average daily intake of 0.5–2.6 mg (p. 6). Very low levels of vitamin K in infants threaten with the condition of vitamin K deficiency bleeding (VKDB), also called hemorrhagic disease of the newborn (Combs, 2008, p. 229). In many countries, it is prevented by administering injections of vitamin K (1 mg phylloquinone) to all infants at birth (p. 229).

For adults, the AI for vitamin K is set at 120 and 90 mg/ day for men and women, respectively. The recent surveys showed that in the last two decades there was a decrease in the phylloquinone intake in the North America and in the United Kingdom (Booth & Rajabi, 2008, p. 7). It may be explained by the fact that few salads with useful vegetable oils are consumed in those regions. In general, it corresponds to the tendency to eat fast food and unhealthy food in some strata of the population (p. 7). In contrast, there are studies about Germany, the Netherlands, Japan, and Northern China, having average phylloquinone intakes among adults within the current dietary recommendations (p. 7).

For healthy functioning of the human organism, it is enough to receive vitamin K through the food in the form of phylloquinone and through the absorption of menaquinones synthesized by bacteria in the intestine (Combs, 2008, p. 215). Phylloquinone is found in different concentrations in all foods of plant origin. Green leafy vegetables are very good sources of vitamin K because plants synthesize it. It is normally in the range 400–700mg/ 100g, with kale and spinach having 274 and 266 mg/ 100g respectively (WHO, 2004, p. 115). Meanwhile fruits and grains have very limited amounts of it (Combs, 2008, p. 215).

Even better levels of vitamin K are demonstrated by some vegetable oils. For example, canola (rapeseed) oil is 830 mg/ 100g, soybean oil is 200 mg/ 100g while olive oil is 58 mg/ 100g. Other vegetable oils, such as sunflower, peanut, and corn contain lower amounts of phylloquinone (1–10mg/100g). With this regard, it seems quite difficult to calculate the vitamin K content in the foods when the nutrition specialist does not know what type of oil was used (Combs, 2008, p. 215).

Apart from the synthesis of menaquinones in the intestine, people obtain menaquinones from foods of animal origin. Meats and dairy products contain moderate amounts of vitamin K. Those foods that are bacteria fermented are rich in menaquinones (WHO, 2004, p. 115). It is not related to yeasts; they do not synthesize menaquinones. In the Western diets, fermented foods are cheeses and yogurts. Other sources of nutritionally significant menaquinones are egg yolks and animal livers. In the Asian diets, fermented soybeans have more menaquinones than green leafy vegetables have phylloquinone (p. 115). However, the contents of menaquinones may vary in different countries. Menaquinones can be synthesized in animal tissues from menadione (MK4), an artificial version of vitamin K, that is supplied in animal feed (p. 115).

In the issue of dietary intake, the bioavailability of the K vitamins from foods should be taken into consideration. There is not much information on it yet. However, it was estimated that only 10% of the phylloquinone in boiled spinach is absorbed by human organism (Combs, 2008, p. 216). In comparison, it is “an estimated 80% when phylloquinone is given in its free form” (WHO, 2004, p. 116). Such a poor absorption of vitamin K from phylloquinone-rich green leafy vegetables may relate to its tight association with the thylakoid membrane and its location in chloroplasts. To compare, menaquinones from butter enriched with menadione are twice more bioavailable than the phylloquinone from spinach (p. 116). Thus, other foods may become more important sources of phylloquinone. It means that despite the fact that leafy vegetables have the best levels of phylloquinone, it may be considered more rational to consume other categories of foods, even if they are poorer in the phylloquinone content. For example, in oils the vitamin K is not tightly bound and, therefore, bioavailability of it is higher. “Even before bioavailability was taken into account, fats and oils that are contained in mixed dishes were found to make an important contribution to the phylloquinone content of the United States diet” (p. 117).

Now it can be seen that for human consumption greater bioavailability of vitamin K is very important. “Interestingly, the menaquinone MK4, which is present in only small amounts in the diet, can be synthesized from phylloquinone in tissue, and MK4 is present in much higher amounts than phylloquinone in some organs (e.g., brain)” (Berkner, 2008, p. 134). In terms of protection against arterial calcification, not phylloquinone but synthetically synthesized MK4 showed its abilities in warfarin-treated rats (Berkner, 2008, p. 134).

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Summing up, it can be said that vitamin K plays a major role in preventing arterial calcification. Vitamin K absorption depends on normal function of liver and pancreatic gland (Combs, 2008, p. 217). Being partly synthesized in the intestines and partly received from dietary intake, the needs for vitamin K can usually be satisfied by a balanced nutrition. A healthy diet should include plenty of green leafy vegetables, vegetable oils, and meats. Infants are the only age group at high risk of vitamin K deficiency. However, in their case the risk relates to blood-clotting properties of vitamin K, rather than its ability to inhibit calcification of blood vessels. Insofar as arterial calcification may develop over years, it is connected to the aging process. Therefore, older adults and postmenopausal women are at risk of arterial calcification due to conflicts between vitamin K supplements and blood-thinning drugs and the calcification paradox.

Calcium supplements for older adults and postmenopausal women should include vitamin K to reduce bone fractures and arterial calcification. Bone-strengthening supplements for older adults on the anticoagulant therapy need to monitor vitamin K intake and to include the form K₂ rather than K₁. By having vitamin K synthesized by the intestines, received from foods and dietary supplements, there is a risk of an excessive intake. There were no adverse effects registered from phylloquinone and the menaquinones when tried on animals (Combs, 2008, p. 229).

The significance of vitamin K and vitamin K-dependent proteins remains a field for extensive and deep research. Scholars and scientists note that there are many issues concerning cardiovascular health that are to be studied in future (Booth & Rajabi, 2008, p. 17).