In chronic kidney disease, vitamin K-dependent proteins, including the calcification inhibitor matrix Gla protein, are largely uncarboxylated indicating that functional vitamin K deficiency may contribute to uremic vascular calcification. Since the effects of uremia on the vitamin K cycle are unknown, we investigated the influence of uremia and vitamin K supplementation on the activity of the vitamin K cycle and extraosseous calcification. Uremia was induced in rats by an adenine-supplemented diet and vitamin K1 or K2 was administered over 4 and 7 weeks. After 4 weeks of adenine diet, the activity of the vitamin K cycle enzyme γ-carboxylase but not the activities of DT-diaphorase or vitamin K epoxide reductase were reduced. Serum levels of undercarboxylated matrix Gla protein increased, indicating functional vitamin K deficiency. There was no light microscopy-detectable calcification at this stage but chemically determined aortic and renal calcium content was increased. Vitamin K treatment reduced aortic and renal calcium content after 4 weeks. Seven weeks of uremia induced overt calcification in the aorta, heart, and kidneys; however, addition of vitamin K restored intrarenal γ-carboxylase activity and overstimulated it in the liver along with reducing heart and kidney calcification. Thus, uremic vitamin K deficiency may partially result from a reduction of the γ-carboxylase activity which possibly contributes to calcification. Pharmacological vitamin K supplementation restored the vitamin K cycle and slowed development of soft tissue calcification in experimental uremia.

We conducted a systematic review to evaluate the burden of late vitamin K deficiency bleeding (VKDB) and the effect of vitamin K prophylaxis on the incidence of VKDB. We searched MEDLINE and other electronic databases, and included all observational studies including population surveys as well as randomized controlled trials (RCT). The median (interquartile range) burden of late VKDB was 35 (10.5 to 80) per 100 000 live births in infants who had not received prophylaxis at birth; the burden was much higher in low- and middle-income countries as compared with high-income countries-80 (72 to 80) vs 8.8 (5.8 to 17.8) per 100 000 live births. Two randomized trials evaluated the effect of intramuscular (IM) prophylaxis on the risk of classical VKDB. Although one trial reported a significant reduction in the incidence of any bleeding (relative risk (RR) 0.73, 95% confidence interval (CI) 0.56 to 0.96) and moderate to severe bleeding (RR 0.19, 0.08 to 0.46; number needed to treat (NNT) 74, 47 to 177), the other trial demonstrated a significant reduction in the risk of secondary bleeding after circumcision in male neonates (RR 0.18, CI 0.08 to 0.42; NNT 9, 6 to 15). No RCTs evaluated the effect of vitamin K prophylaxis on late VKDB. Data from four surveillance studies indicate that the use of IM/subcutaneous vitamin K prophylaxis could significantly reduce the risk of late VKDB when compared with no prophylaxis (pooled RR 0.02; 95% CI 0.00 to 0.10). When compared with IM prophylaxis, a single oral dose of vitamin K increased the risk of VKDB (RR 24.5; 95% CI 7.4 to 81.0) but multiple oral doses did not (RR 3.64; CI 0.82 to 16.3). There is low-quality evidence from observational studies that routine IM administration of 1 mg of vitamin K at birth reduces the incidence of late VKDB during infancy. Given the high risk of mortality and morbidity in infants with late VKDB, it seems appropriate to administer IM vitamin K prophylaxis to all neonates at birth. Future studies should compare the efficacy and safety of multiple oral doses with IM vitamin K and also evaluate the optimal dose of vitamin K in preterm neonates.

We looked at existing recommendations and supporting evidence on the effectiveness of vitamin K given after birth in preventing the haemorrhagic disease of the newborn (HDN).We conducted a literature search up to the 10th of December 2019 by using key terms and manual search in selected sources. We summarized the recommendations and the strength of the recommendation when and as reported by the authors. We summarized the main findings of systematic reviews with the certainty of the evidence as reported.All newborns should receive vitamin K prophylaxis, as it has been proven that oral and intramuscular prophylactic vitamin K given after birth are effective for preventing classical HDN. There are no randomized trials looking at the efficacy of vitamin K supplement on late HDN. There are no randomized trials comparing the oral and intramuscular route of administration of prophylactic vitamin K in newborns. From older trials and surveillance data, it seems that there is no significant difference between the intramuscular and the oral regimens for preventing classical and late HDN, provided that the oral regimen is duly completed. Evidence assessing vitamin K prophylaxis in preterm infants is scarce.

Vitamin K (VK) is a fat-soluble vitamin whose deficiency disrupts coagulation and may disturb bone and cardiovascular health. However, the scale and systems affected by VK deficiency in pediatric populations remains unclear. We conducted a study of the plasma proteome of 500 Nepalese children 6-8 years of age (male/female ratio = 0.99) to identify proteins associated with VK status. We measured the concentrations of plasma lipids and protein induced by VK absence-II (PIVKA-II) and correlated relative abundance of proteins quantified by mass spectrometry with PIVKA-II. VK deficiency (PIVKA-II>2 μg/L) was associated with a higher abundance of low-density lipoproteins, total cholesterol, and triglyceride concentrations (p<0.01). Among 978 proteins observed in >10% of the children, five proteins were associated with PIVKA-II and seven proteins were differentially abundant between VK deficient versus sufficient children, including coagulation factor-II, hemoglobin, and vascular endothelial cadherin, passing a false discovery rate (FDR) threshold of 10% (q<0.10). Among 27 proteins associated with PIVKA-II or VK deficiency at a less stringent FDR (q<0.20), a network comprised of hemoglobin subunits and erythrocyte anti-oxidative enzymes were highly and positively correlated each other (all r>0.7). Untargeted proteomics offers a novel systems approach to elucidating biological processes of coagulation, vascularization, and erythrocyte oxidative stress related to VK status. The results may help elucidate subclinical metabolic disturbances related to VK deficiency in populations.

Although known for its importance in the coagulation cascade, vitamin K has other functions. It is an essential vitamin for bone health, taking part in the carboxylation of many bone-related proteins, regulating genetic transcription of osteoblastic markers, and regulating bone reabsorption. Vitamin K deficiency is not uncommon, as deposits are scarce and dependent upon dietary supplementation and absorption. Vitamin K antagonist oral anticoagulants, which are prescribed to many patients, also induce vitamin K deficiency. Most studies find that low serum K1 concentrations, high levels of undercarboxylated osteocalcin (ucOC), and low dietary intake of both K1 and K2 are associated with a higher risk of fracture and lower BMD. Studies exploring the relationship between vitamin K supplementation and fracture risk also find that the risk of fracture is reduced with supplements, but high quality studies designed to evaluate fracture as its primary endpoint are needed. The reduction in risk of fracture with the use of non-vitamin K antagonist oral anticoagulants instead of warfarin is also of interest although once again, the available evidence offers disparate results. The scarce and limited evidence, including low quality studies reaching disparate conclusions, makes it impossible to extract solid conclusions on this topic, especially concerning the use of vitamin K supplements.

The extent and the progression of vascular calcification (VC) are independent predictors of cardiovascular risk in the haemodialysis population. Vitamin K is essential for the activation of matrix gla protein (MGP), a powerful inhibitor of tissue calcification. Functional vitamin K deficiency may contribute to the high VC burden in haemodialysis patients. In addition, haemodialysis patients are frequently treated with vitamin K antagonists, mainly to prevent stroke in atrial fibrillation, potentially compounding the cardiovascular risk in these already vulnerable patients. New oral anticoagulants (NOACs) are valuable alternatives to vitamin K antagonists in the general population, but their use in dialysis has been encumbered by substantial renal clearance. However, a recent pharmacokinetic study provided information on how to use rivaroxaban in haemodialysis patients.

Patients with chronic kidney disease (CKD) have an increased risk of developing vascular calcifications, as well as bone dynamics impairment, leading to a poor quality of life and increased mortality. Certain vitamin K dependent proteins (VKDPs) act mainly as calcification inhibitors, but their involvement in the onset and progression of CKD are not completely elucidated. This review is an update of the current state of knowledge about the relationship between CKD and four extrahepatic VKDPs: matrix Gla protein, osteocalcin, growth-arrest specific protein 6 and Gla-rich protein. Based on published literature in the last ten years, the purpose of this review is to address fundamental aspects about the link between CKD and circulating VKDPs levels as well as to raise new topics about how the interplay between molecular weight and charge could influence the modifications of circulating VKDPs at the glomerular level, or whether distinct renal etiologies have effect on VKDPs. This review is the output of a systematic literature search and may open future research avenues in this niche domain.

Vitamin K antagonists (VKA) and non-vitamin K oral antagonist anticoagulants (NOAC) are used in the clinic to reduce risk of thrombosis. However, they also exhibit vascular off-target effects. The aim of this study is to compare VKA and NOAC on atherosclerosis progression and calcification in an experimental setup.

Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder in which calcification of connective tissue leads to pathology in skin, eye and blood vessels. PXE is caused by mutations in ABCC6. High expression of this transporter in the basolateral hepatocyte membrane suggests that it secretes an as-yet elusive factor into the circulation which prevents ectopic calcification. Utilizing our Abcc6 (-/-) mouse model for PXE, we tested the hypothesis that this factor is vitamin K (precursor) (Borst et al. 2008, Cell Cycle). For 3 months, Abcc6 (-/-) and wild-type mice were put on diets containing either the minimum dose of vitamin K required for normal blood coagulation or a dose that was 100 times higher. Vitamin K was supplied as menaquinone-7 (MK-7). Ectopic calcification was monitored in vivo by monthly micro-CT scans of the snout, as the PXE mouse model develops a characteristic connective tissue mineralization at the base of the whiskers. In addition, calcification of kidney arteries was measured by histology. Results show that supplemental MK-7 had no effect on ectopic calcification in Abcc6 ( -/- ) mice. MK-7 supplementation increased vitamin K levels (in skin, heart and brain) in wild-type and in Abcc6 (-/-) mice. Vitamin K tissue levels did not depend on Abcc6 genotype. In conclusion, dietary MK-7 supplementation increased vitamin K tissue levels in the PXE mouse model but failed to counteract ectopic calcification. Hence, we obtained no support for the hypothesis that Abcc6 transports vitamin K and that PXE can be cured by increasing tissue levels of vitamin K.

Vitamin K antagonists (VKA) are not recommended during pregnancy because warfarin (a first-generation VKA) is associated with a malformation syndrome "the fetal warfarin syndrome" (FWS). VKA are also used for rodent management worldwide. Recently, the Committee for Risk Assessment responsible for the European chemical legislation for advances on the safe use of chemicals had classed 8 anticoagulant used as rodenticides in the reprotoxic category 1A or 1B. This classification emerges from a read-across prediction of toxicity considering the warfarin malformation syndrome. Herein, our study explores the teratogenicity of warfarin at the human therapeutic dose and that of bromadiolone, a second-generation anticoagulant rodenticide. Using a rat model, our study demonstrates that warfarin used at the therapeutic dose is able to induce teratogenicity, while in the same conditions bromadiolone does not induce any teratogenic effect, challenging the classification of all VKA as reprotoxic molecules.

ATP-binding cassette protein G5 (ABCG5)/ABCG8 heterodimer exports cholesterol from cells, while Niemann-Pick C1-like 1 (NPC1L1) imports cholesterol and vitamin K. We examined whether ABCG5/ABCG8 transports vitamin K similar to NPC1L1. Since high concentrations of vitamin K3 show cytotoxicity, the cytoprotective effects of ABCG5/ABCG8 were examined. BHK cells expressing ABCG5/ABCG8 were more resistant to vitamin K3 cytotoxicity than control cells, suggesting that ABCG5/ABCG8 transports vitamin K3 out of cells. The addition of vitamin K1 reversed the effects of ABCG5/ABCG8, suggesting that vitamin K1 competitively inhibits the transport of vitamin K3. To examine the transport of vitamin K1 by ABCG5/ABCG8, vitamin K1 levels in the medium and cells were measured. Vitamin K1 levels in cells expressing ABCG5/ABCG8 were lower than those in control cells, while vitamin K1 efflux increased in cells expressing ABCG5/ABCG8. Furthermore, the biliary vitamin K1 concentration in Abcg5/Abcg8-deficient mice was lower than that in wild-type mice, although serum vitamin K1 levels were not affected by the presence of Abcg5/Abcg8. These findings suggest that ABCG5 and ABCG8 are involved in the transport of sterols and vitamin K. ABCG5/ABCG8 and NPC1L1 might play important roles in the regulation of vitamin K absorption and excretion.

Background: A low vitamin K status is common in patients on haemodialysis, and this is considered one of the reasons for the accelerated atherosclerosis in these patients. The vitamin is essential in activation of the protein Matrix Gla Protein (MGP), and the inactive form, dp-ucMGP, is used to measure vitamin K status. The purpose of this study was to investigate possible underlying causes of low vitamin K status, which could potentially be low intake, washout during dialysis or inhibited absorption capacity. Moreover, the aim was to investigate whether the biomarker dp-ucMGP is affected in these patients. Method: Vitamin K intake was assessed by a Food Frequency Questionnaire (FFQ) and absorption capacity by means of D-xylose testing. dp-ucMGP was measured in plasma before and after dialysis, and phylloquinine (vitamin K1) and dp-ucMGP were measured in the dialysate. Changes in dp-ucMGP were measured after 14 days of protein supplementation. Results: All patients had plasma dp-ucMGP above 750 pmol/L, and a low intake of vitamin K. The absorption capacity was normal. The difference in dp-ucMGP before and after dialysis was -1022 pmol/L (p < 0.001). Vitamin K1 was not present in the dialysate but dp-ucMGP was at a high concentration. The change in dp-ucMGP before and after protein supplementation was -165 pmol/L (p = 0.06). Conclusion: All patients had vitamin K deficiency. The reason for the low vitamin K status is not due to removal of vitamin K during dialysis or decreased absorption but is plausibly due to a low intake of vitamin K in food. dp-ucMGP is washed out during dialysis, but not affected by protein intake to a clinically relevant degree.

Hyperemesis gravidarum (HG), severe nausea and vomiting in pregnancy, can lead to vitamin deficiencies. Little is known about HG-related vitamin K deficiency. We aimed to summarise available evidence on the occurrence of HG-related vitamin K deficiency and corresponding maternal and neonatal complications. A systematic review was conducted, searching Medline and EMBASE from inception to 12 November 2020. We identified 1564 articles, of which we included fifteen in this study: fourteen case reports (n 21 women) and one retrospective cohort study (n 109 women). Nine out of twenty-one women reported in case reports had a prolonged prothrombin time (PT). The cohort study measured PT in 39/109 women with HG, of whom 10/39 women (26 %) had prolonged PT. In total, 30-50 % women received vitamin K supplementation after vitamin K deficiency had been diagnosed. Four case reports (n 4 women) reported corresponding maternal complications, all consisting of coagulopathy-related haemorrhage. Nine case reports (n 16 neonates) reported corresponding neonatal complications including intracranial haemorrhage (n 2 neonates) and embryopathy (n 14 neonates), which consisted of Binder phenotype (n 14 neonates), chondrodysplasia punctata (n 9 neonates) and grey matter heterotopia (n 3 neonates). In conclusion, vitamin K deficiency and related complications occur among women with HG. In our systematic review, we were unable to assess the incidence rate.

Vitamin K (VK) is a key nutrient for several biological processes (e.g., blood clotting and bone metabolism). To fulfill VK nutritional requirements, VK action as an activator of pregnane X receptor (Pxr) signaling pathway, and as a co-factor of γ-glutamyl carboxylase enzyme, should be considered. In this regard, VK recycling through vitamin K epoxide reductases (Vkors) is essential and should be better understood. Here, the expression patterns of vitamin K epoxide reductase complex subunit 1 (vkorc1) and vkorc1 like 1 (vkorc1l1) were determined during the larval ontogeny of Senegalese sole (Solea senegalensis), and in early juveniles cultured under different physiological conditions. Full-length transcripts for ssvkorc1 and ssvkorc1l1 were determined and peptide sequences were found to be evolutionarily conserved. During larval development, expression of ssvkorc1 showed a slight increase during absence or low feed intake. Expression of ssvkorc1l1 continuously decreased until 24 h post-fertilization, and remained constant afterwards. Both ssvkors were ubiquitously expressed in adult tissues, and highest expression was found in liver for ssvkorc1, and ovary and brain for ssvkorc1l1. Expression of ssvkorc1 and ssvkorc1l1 was differentially regulated under physiological conditions related to fasting and re-feeding, but also under VK dietary supplementation and induced deficiency. The present work provides new and basic molecular clues evidencing how VK metabolism in marine fish is sensitive to nutritional and environmental conditions.

A wide variety of approaches have been proposed to manage anticoagulant drugs in patients undergoing dental surgery; vitamin K antagonists and novel direct oral anticoagulants have been used. The present study aims to explore the existing evidence concerning the management of patients in anticoagulant therapy undergoing oral surgery procedures and to give suggestions related to peri- and post-operative measures.

Long-term use of warfarin has been shown to be associated with a reduced risk of prostate cancer. Warfarin belongs to the vitamin K antagonist class of anticoagulants, which inhibit vitamin K epoxide reductase (VKOR). The vitamin K cycle is primarily known for its role in γ-carboxylation, a rare post-translational modification important in blood coagulation. Here we show that warfarin inhibits the transcriptional activity of the androgen receptor (AR), an important driver of prostate cancer development and progression. Warfarin treatment or knockdown of its target VKOR inhibits the activity of AR both in cell lines and in mouse prostate tissue. We demonstrate that AR can be γ-carboxylated, and mapped the γ-carboxylation to glutamate residue 2 (E2) using mass spectrometry. However, mutation of E2 and other glutamates on AR failed to suppress the effects of warfarin on AR suggesting that inhibition of AR is γ-carboxylation independent. To identify pathways upstream of AR signaling that are affected by warfarin, we performed RNA-seq on prostates of warfarin-treated mice. We found that warfarin inhibited peroxisome proliferator-activated receptor gamma (PPARγ) signaling, which in turn, inhibited AR signaling. Although warfarin is unfit for use as a chemopreventative due to its anticoagulatory effects, our data suggest that its ability to reduce prostate cancer risk is independent of its anticoagulation properties. Furthermore, our data show that warfarin inhibits PPARγ and AR signaling, which suggests that inhibition of these pathways could be used to reduce the risk of developing prostate cancer.

Phytonadione (vitamin K1, VK) is fat soluble and may be sequestered by adipose tissue, thus potentially altering drug distribution in obese patients requiring warfarin reversal. This single-center retrospective cohort study aimed to determine the effects of obesity (defined as body mass index [BMI] ≥ 30 kg/m2) on warfarin reversal following administration of VK in adult patients. The primary outcome was complete or partial warfarin reversal (defined as an international normalized ratio [INR] ≤ 2.0) within 72 hours post-VK administration. Of 688 identified patients, 215 were included in primary INR analysis. Mean BMIs for obese (n = 84) and nonobese (n = 131) patients were 37.3 and 24.3 kg/m2 ( P < .001), and mean baseline INRs were 4.73 and 4.42 ( P = .534), respectively. Within 72 hours post-VK administration, 70% and 69% of the obese and nonobese groups, respectively, achieved complete or partial warfarin reversal ( P = .904). Multiple logistic regression determined baseline INR and concomitant fresh frozen plasma administration to be factors influencing warfarin reversal. These findings do not suggest obesity is significantly associated with a decreased likelihood of warfarin reversal within 72 hours post-VK administration.

Increased preoperative delay in patients with hip fractures may be responsible for increased morbidity and mortality. We hypothesized that a strategy of reversal of vitamin K antagonist (VKA) by prothrombin complexes concentrates (PCCs), as compared to vitamin K, is safe and reduces preoperative delay and hospital length of stay (LOS).

Menaquinone (vitamin K2) shuttles electrons between membrane-bound respiratory complexes under microaerophilic conditions. In photosynthetic eukaryotes and cyanobacteria, phylloquinone (vitamin K1) participates in photosystem I function. Here we elucidate the evolutionary history of vitamin K metabolism in algae and plants. We show that Chlamydiales intracellular pathogens made major genetic contributions to the synthesis of the naphthoyl ring core and the isoprenoid side-chain of these quinones. Production of the core in extremophilic red algae is under control of a menaquinone (Men) gene cluster consisting of 7 genes that putatively originated via lateral gene transfer (LGT) from a chlamydial donor to the plastid genome. In other green and red algae, functionally related nuclear genes also originated via LGT from a non-cyanobacterial, albeit unidentified source. In addition, we show that 3-4 of the 9 required steps for synthesis of the isoprenoid side chains are under control of genes of chlamydial origin. These results are discussed in the light of the hypoxic response experienced by the cyanobacterial endosymbiont when it gained access to the eukaryotic cytosol.

Current guidelines recommend oral anticoagulation (OAC) following transcatheter aortic valve replacement (TAVR) in patients with clinical indication, but the optimal antithrombotic regimen remains uncertain. We aimed to compare the efficacy and safety of non-vitamin K oral anticoagulants (NOACs) versus vitamin K antagonists (VKAs) in patients undergoing TAVR with concomitant indication of OAC.