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Coronavirus disease 2019 (Covid-19), caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2, 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 plays a crucial role in the activation of both pro- and anticlotting factors in the liver and the activation of extrahepatically synthesised protein S which seems to be important in local thrombosis prevention. However, the role of vitamin K extends beyond coagulation. Matrix Gla protein (MGP) is a vitamin K-dependent inhibitor of soft tissue calcification and elastic fibre degradation. Severe extrahepatic vitamin K insufficiency was recently demonstrated in Covid-19 patients, with high inactive MGP levels correlating with elastic fibre degradation rates. This suggests 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. We therefore expect that vitamin K-dependent endothelial protein S activation is also compromised, which would be compatible with enhanced thrombogenicity. Taking these data together, we 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. Intervention trials should be conducted to assess whether vitamin K administration plays a role in the prevention and treatment of severe Covid-19.
The rupture of atherosclerotic plaques is the prerequisite for adverse cardiovascular events. Calcification morphology plays a critical role in plaque stability, therefore accurate calcification classification is essential for favourable patient management. Blood biomarkers may be a worthwhile approach to stratify patients based on calcification phenotype. Vitamin K-dependent Matrix γ-carboxyglutamate (Gla) protein (MGP) is a potent inhibitor of vascular calcification. Recent studies have demonstrated the potential utility of circulating non-functional MGP (dp-ucMGP) measurements to determine arterial stiffness and calcification levels. The objective of this study was to examine the relationship between circulating dp-ucMGP and calcification phenotype within symptomatic atherosclerotic lesions. Consenting patients undergoing standard endarterectomy procedures were recruited (n = 29). Fasting venous blood was collected preoperatively. Circulating plasma levels of dp-ucMGP were quantified using the inaKtif MGP (dp-ucMGP) iSYS kit. A bicinchoninic acid assay was used to standardise the total protein content present in each sample. High-resolution micro-CT imaging was conducted on the excised atherosclerotic specimens postoperatively. ImageJ post-processing was used to accurately quantify the calcification volume (≥ 130 Hounsfield Units) and determine the total number of calcified particles (3D objects counter plugin). Thirteen carotid (average age 71 years, 9 male) and fourteen peripheral lower limb (average age 65 years, 12 male) patients were examined. One patient had a carotid and a peripheral lower limb plaque (age 79, male). Peripheral lower limb specimens have larger volumes of calcification and higher numbers of calcified particles than carotid samples (472 ± 310 vs 85 ± 113mm3, p < 0.0005; 13919 ± 16034 vs 3476 ± 6208, p = 0.061.) While a higher dp-ucMGP value was noted in carotid than peripheral lower limb patients (214 ± 52 vs 169 ± 36pmol/L, p = 0.014) there was no correlation between circulating dp-ucMGP and calcification volume or number of calcified particles (rs = -0.329 and rs = 0.046). Previous research also found that peripheral lower limb lesions contain higher volumes of calcification than carotid lesions. There is currently no published data on calcified particle comparisons. Patients with symptomatic carotid disease are assumed to have a degree of peripheral arterial disease, this could explain the higher levels of circulating dp-ucMGP in carotid patients. The current study did not examine the dietary patterns of individuals with regards to Vitamin K intake or analyse other areas of the vasculature for additional calcification. This may interfere with dp-ucMGP measurements. This study serves as a preliminary investigation into the potential of dp-ucMGP as a blood based biomarker to distinguish between symptomatic atherosclerotic calcification phenotypes.
Population-based studies have shown an inverse association between dietary menaquinones (MK-n, vitamin K2) intake, coronary calcification and CHD risk, suggesting a potential role of vitamin K in vascular health. To date, the effects of increased menaquinone intake on (markers of) vascular health have been investigated using predominantly food supplements. Dairy products contain many essential nutrients and can serve as a good matrix for food fortification in order to support health. We were therefore interested to study the effects of a menaquinone-fortified yogurt drink (menaquinone as menaquinone-7 (MK-7); 28 µg MK-7/yogurt drink) on vitamin K status and markers of vascular health. The yogurt drink was also fortified with n-3 PUFA, vitamin D, vitamin C, Ca and Mg to support vascular and/or general health. Healthy men (n 32) and postmenopausal women (n 28) with a mean age of 56 (sd 5) years received either basic or fortified yogurt drink twice per d for 12 weeks. MK-7 was efficiently absorbed from the fortified yogurt drink. Levels of circulating MK-7 were significantly increased from 0·28 to 1·94 ng/ml. In accordance, intake of the fortified yogurt drink improved vitamin K status, as measured by significant decreases in uncarboxylated osteocalcin and desphospho-uncarboxylated matrix Gla-protein. No effects were, however, seen on markers of inflammation, endothelial dysfunction and lipid metabolism. In summary, consumption of a yogurt drink fortified with low doses of among others MK-7 for 3 months significantly improved vitamin K status in a healthy population.
Recent reports have attributed the potential health benefits of vitamin K beyond its function to activate hepatic coagulation factors. Moreover, several studies have suggested that menaquinones, also known as vitamin K2, may be more effective in activating extra-hepatic vitamin K-dependent proteins than phylloquinone, also known as vitamin K1. Nevertheless, present dietary reference values (DRV) for vitamin K are exclusively based on phylloquinone, and its function in coagulation. The present review describes the current knowledge on menaquinones based on the following criteria for setting DRV: optimal dietary intake; nutrient amount required to prevent deficiency, maintain optimal body stores and/or prevent chronic disease; factors influencing requirements such as absorption, metabolism, age and sex. Dietary intake of menaquinones accounts for up to 25 % of total vitamin K intake and contributes to the biological functions of vitamin K. However, menaquinones are different from phylloquinone with respect to their chemical structure and pharmacokinetics, which affects bioavailability, metabolism and perhaps impact on health outcomes. There are significant gaps in the current knowledge on menaquinones based on the criteria for setting DRV. Therefore, we conclude that further investigations are needed to establish how differences among the vitamin K forms may influence tissue specificities and their role in human health. However, there is merit for considering both menaquinones and phylloquinone when developing future recommendations for vitamin K intake.
Vitamin K is required for the carboxylation of Gla-proteins in the liver (coagulation factors) and extra-hepatic tissues, such as bone (osteocalcin, OC), and arterial wall (matrix Gla-protein, MGP). Although the coagulation factors are essentially fully carboxylated under normal conditions, 10–40 % of OC and MGP remains undercarboxylated. We were therefore interested to study the dose–response effects of extra intake of menaquinones on the carboxylation of the extra-hepatic Gla-proteins. A total of forty-two healthy Dutch men and women aged between 18 and 45 years were randomised into seven groups to receive: placebo capsules or menaquinone-7 (MK-7) capsules at a daily dose of 10, 20, 45, 90, 180 or 360 μg. Circulating uncarboxylated OC (ucOC), carboxylated OC (cOC) and desphospho-uncarboxylated MGP were measured by ELISA. The ucOC:cOC ratio was calculated from circulating ucOC and cOC values. Endogenous thrombin potential and peak height were determined by calibrated automated thrombography. To increase the statistical power, we collapsed the treatment groups into three dosage groups: placebo, low-dose supplementation (doses below RDA, Commission Directive 2008/100/EC), and high-dose supplementation (doses around RDA, Commission Directive 2008/100/EC). MK-7 supplementation at doses in the order of the RDA (Commission Directive 2008/100/EC) increased the carboxylation of circulating OC and MGP. No adverse effects on thrombin generation were observed. Extra MK-7 intake at nutritional doses around the RDA (Commission Directive 2008/100/EC) improved the carboxylation of the extra-hepatic vitamin K-dependent proteins. Whether this improvement contributes to public health, i.e. increasing the protection against age-related diseases needs further investigation in specifically designed intervention trials.
Osteocalcin (OC) is a vitamin K-dependent protein found in bone and in circulation. High serum γ-carboxylated OC reflects a high, and high uncarboxylated OC (ucOC) reflects a low vitamin K status. A revolutionary hypothesis is that ucOC acts as a hormone improving glucose handling and reducing fat mass. The objective was to test the logical extrapolation of the ucOC hormone hypothesis to humans that elevated ucOC is associated with higher body weight, BMI and fat mass. In a cross-sectional analysis, the associations of vitamin K status with circulating adiponectin and body composition were investigated in 244 postmenopausal women (study I). The effects of vitamin K treatment on adiponectin, body weight and BMI were investigated in archived samples from forty-two young men and women who received varying doses of menaquinone-7 during 12 weeks (study II) and from a cohort of 164 postmenopausal women who participated in a 3-year placebo-controlled trial on 45 mg menaquinone-4 (MK-4) (study III). No association was found between vitamin K status and circulating adiponectin before or after vitamin K supplementation. A higher carboxylation of OC was significantly correlated with lower body weight, BMI and fat mass of the trunk. Women taking MK-4 maintained their baseline body weight and BMI, whereas women taking placebo showed significant increases in both indices. These findings demonstrate that a high vitamin K status of bone has no effect on circulating adiponectin in healthy people and long-term vitamin K supplementation does not increase weight in healthy postmenopausal women.
Vitamin K contributes to bone health, probably through its role as cofactor in the carboxylation of osteocalcin. Intervention studies in adults have demonstrated that markedly higher osteocalcin carboxylation is obtained by intakes of vitamin K well above the current recommended dietary intake. However, the relationship between increased vitamin K2 intake and enhanced osteocalcin carboxylation has never been shown in healthy children. The objective was to study the effect of 45 μg menaquinone-7 (MK-7; one of the vitamin K2 species) on the circulating levels of undercarboxylated osteocalcin (ucOC) and carboxylated osteocalcin (cOC) in healthy prepubertal children. We hypothesised that MK-7 supplementation will reduce the ucOC:cOC ratio (UCR), indicating an improved vitamin K status. The present study is a double-blind randomised placebo-controlled trial examining the effect of 8 weeks MK-7 supplementation on the carboxylation of osteocalcin in healthy children (n 55). Serum levels of ucOC, cOC and MK-7 were measured at baseline and after 8 weeks, together with bone markers and coagulation parameters. The UCR was used as an indicator of vitamin K status. In the MK-7-supplemented group (n 28), the circulating concentration of inactive ucOC reduced and the UCR improved whereas the concentration of MK-7 increased. Within the placebo group, ucOC, cOC, UCR and MK-7 did not significantly change over time. In both groups, bone markers and coagulation parameters remained constant over time. These findings demonstrate that in healthy, prepubertal children, modest supplementation with MK-7 increases circulating concentrations of MK-7 and increases osteocalcin carboxylation.
In adult bone, vitamin K contributes to bone health, probably through its role as co-factor in the carboxylation of osteocalcin. In children, the significance of vitamin K in bone-mass acquisition is less well known. The objective of this longitudinal study was to determine whether biochemical indicators of vitamin K status are related to (gains in) bone mineral content (BMC) and markers of bone metabolism in peripubertal children. In 307 healthy children (mean age 11·2 years), BMC of the total body, lumbar spine and femoral neck was determined at baseline and 2 years later. Vitamin K status (ratio of undercarboxylated (ucOC) to carboxylated (cOC) fractions of osteocalcin; UCR) was also measured at both time points. Markers of bone metabolism, sex steroids, vitamin D status and growth hormones were measured at baseline only. Large variations in the levels of the UCR were found at both time-points, indicating a substantial interindividual difference in vitamin K status. Improvement of vitamin K status over 2 years (n 281 children) was associated with a marked increase in total body BMC (r − 49·1, P < 0·001). The UCR was associated with pubertal stage, markers of bone metabolism, sex hormones and vitamin D status. A better vitamin K status was associated with more pronounced increase in bone mass in healthy peripubertal children. In order to determine the significance of these findings for childhood bone health, additional paediatric studies are needed.
While current intakes of phylloquinone (vitamin K1) in many populations are believed to be sufficient to maintain normal blood coagulation, these may be insufficient to cover the requirements for optimal bone metabolism. Therefore, the objective of the present study was to investigate the effect of increasing phylloquinone intakes above the usual dietary intake for 6 weeks on biochemical markers of vitamin K status and bone turnover in postmenopausal women. Thirty-one postmenopausal women completed this 3 × 6-week randomised cross-over study, in which volunteers were supplemented with 0 (placebo), 200, and 500 μg phylloquinone/d. In addition, the volunteers were given 10 μg vitamin D3/d throughout the study period. With increasing phylloquinone intake, the concentration of serum γ-carboxylated and under-γ-carboxylated osteocalcin was significantly increased and decreased, respectively, in a dose-dependent manner (P < 0·001). Mean serum phylloquinone concentration was significantly (P < 0·001) higher with daily supplementation with 500 μg phylloquinone/d compared with that during either of the placebo or 200 μg phylloquinone/d supplementation periods, which did not differ (P = 0·15). Serum total osteocalcin was significantly (P < 0·001) increased in response to daily supplementation with 500 (but not 200) μg phylloquinone compared with placebo. Serum bone-specific alkaline phosphatase as well as the urinary markers of bone resorption (N-telopeptide cross-links of collagen, pyridinoline and deoxypyridinoline) and urinary γ-carboxyglutamate were unaffected by phylloquinone supplementation. In conclusion, while daily supplementation with 200 and 500 μg phylloquinone/d for 6 weeks increased vitamin K status in postmenopausal women, it had no effect on bone turnover.
The aim of the present study was to assess how high doses of dietary vitamin K influence the intestinal profile of K-vitamins in vitamin K-deficient rats, and whether the induced changes are reflected in the hepatic vitamin K store. Vitamin K-deficient rats were fed for 10 d on diets containing different forms of vitamin K, and it was determined how these diets affected the vitamin K concentration at various sites of the instestine, serum, and the liver. It was found that the absorption of phylloquinone from standard food is not more than 10 %, while the absorption of pharmacological doses of oil-solubilized phylloquinone and menaquinone-4 was also far from complete (18 and 55 % respectively). High intakes of phylloquinone suppress the colonic production of all higher menaquinones. High menaquinone-4 intake induces very high menaquinone-8 concentrations, both in the colonic contents as well as in the liver. These data suggest that menaquinone-4 may be converted into menaquinone-8 (but not into other menaquinones) via a metabolic pathway which has not been reported previously.
The human vitamin K requirement is not known precisely, but the minimal requirement is often assumed to be between 0·5 and 1 x 10−6g/kg body weight. In the present study we addressed the question to what extent circulating vitamin K concentrations are influenced by the form in which the vitamer is consumed. The experimental group consisted of five healthy volunteers who received phylloquinone after an overnight fast. On the first day of three successive weeks the participants consumed 1 mg (2·2 µmol) phylloquinone, either in the form of a pharmaceutical preparation (Konakion®), or in the form of spinach + butter, or as spinach without added fat. Circulating phylloquinone levels after spinach with and without butter were substantially lower (7·5- and 24·3-fold respectively) than those after taking the pharmaceutical concentrate. Moreover, the absorption of phylloquinone from the vegetables was 1·5 times slower than from Konakion. In a second experiment in the same five volunteers it was shown that relatively high amounts of menaquinone-4 enter the circulation after the consumption of butter enriched with this vitamer. It is concluded that the bioavailability of membrane-bound phylloquinone is extremely poor and may depend on other food components, notably fat. The bioavailability of dietary vitamin K (phylloquinone+menaquinones) is lower than generally assumed, and depends on the form in which the vitamin is ingested. These new insights may lead to a revision of the recommended daily intake for vitamin K.
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