vitamin-k-1 and Vitamin-K-Deficiency

Vitamin K occupies a unique and often obscured place among its fellow fat-soluble vitamins. Evidence is mounting, however, that vitamin K (VK) may play an important role in the visual system apart from the hepatic carboxylation of hemostatic-related proteins. However, to our knowledge, no review covering the topic has appeared in the medical literature. Recent studies have confirmed that matrix Gla protein (MGP), a vitamin K-dependent protein (VKDP), is essential for the regulation of intraocular pressure in mice. The PREDIMED (Prevención con Dieta Mediterránea) study, a randomized trial involving 5860 adults at risk for cardiovascular disease, demonstrated a 29% reduction in the risk of cataract surgery in participants with the highest tertile of dietary vitamin K1 (PK) intake compared with those with the lowest tertile. However, the specific requirements of the eye and visual system (EVS) for VK, and what might constitute an optimized VK status, is currently unknown and largely unexplored. It is, therefore, the intention of this narrative review to provide an introduction concerning VK and the visual system, review ocular VK biology, and provide some historical context for recent discoveries. Potential opportunities and gaps in current research efforts will be touched upon in the hope of raising awareness and encouraging continued VK-related investigations in this important and highly specialized sensory system.

Topics: Animals; Mice; Sense Organs; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency; Vitamins

Vitamin K (VK) plays many important functions in the body. The most important of them include the contribution in calcium homeostasis and anticoagulation. Vascular calcification (VC) is one of the most important mechanisms of renal pathology. The most potent inhibitor of this process-matrix Gla protein (MGP) is VK-dependent. Chronic kidney disease (CKD) patients, both non-dialysed and hemodialysed, often have VK deficiency. Elevated uncarboxylated matrix Gla protein (ucMGP) levels indirectly reflected VK deficiency and are associated with a higher risk of cardiovascular events in these patients. It has been suggested that VK intake may reduce the VC and related cardiovascular risk. Vitamin K intake has been suggested to reduce VC and the associated cardiovascular risk. The role and possibility of VK supplementation as well as the impact of anticoagulation therapy on VK deficiency in CKD patients is discussed.

Topics: Anticoagulants; Blood Coagulation; Bone and Bones; Calcium; Calcium-Binding Proteins; Cardiovascular Diseases; Extracellular Matrix Proteins; Humans; Matrix Gla Protein; Renal Dialysis; Renal Insufficiency, Chronic; Vascular Calcification; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

Chronic kidney disease (CKD) is commonly associated with vitamin K deficiency. Some of the serious complications of CKD are represented by cardiovascular disease (CVD) and skeletal fragility with an increased risk of morbidity and mortality. A complex pathogenetic link between hormonal and ionic disturbances, bone tissue and metabolism alterations, and vascular calcification (VC) exists and has been defined as chronic kidney disease-mineral and bone disorder (CKD-MBD). Poor vitamin K status seems to have a key role in the progression of CKD, but also in the onset and advance of both bone and cardiovascular complications. Three forms of vitamin K are currently known: vitamin K1 (phylloquinone), vitamin K2 (menaquinone), and vitamin K3 (menadione). Vitamin K plays different roles, including in activating vitamin K-dependent proteins (VKDPs) and in modulating bone metabolism and contributing to the inhibition of VC. This review focuses on the biochemical and functional characteristics of vitamin K vitamers, suggesting this nutrient as a possible marker of kidney, CV, and bone damage in the CKD population and exploring its potential use for promoting health in this clinical setting. Treatment strategies for CKD-associated osteoporosis and CV disease should include vitamin K supplementation. However, further randomized clinical studies are needed to assess the safety and the adequate dosage to prevent these CKD complications.

Topics: Bone and Bones; Cardiovascular Diseases; Chronic Kidney Disease-Mineral and Bone Disorder; Female; Humans; Male; Renal Insufficiency, Chronic; Vascular Calcification; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

Cardiovascular disease (CVD) is a major cause of death in patients with chronic kidney disease (CKD). Both conditions are rising in incidence as well as prevalence, creating poor outcomes for patients and high healthcare costs. Recent data suggests CKD to be an independent risk factor for CVD. Accumulation of uremic toxins, chronic inflammation, and oxidative stress have been identified to act as CKD-specific alterations that increase cardiovascular risk. The association between CKD and cardiovascular mortality is markedly influenced through vascular alterations, in particular atherosclerosis and vascular calcification (VC). While numerous risk factors promote atherosclerosis by inducing endothelial dysfunction and its progress to vascular structural damage, CKD affects the medial layer of blood vessels primarily through VC. Ongoing research has identified VC to be a multifactorial, cell-mediated process in which numerous abnormalities like mineral dysregulation and especially hyperphosphatemia induce a phenotype switch of vascular smooth muscle cells to osteoblast-like cells. A combination of pro-calcifying stimuli and an impairment of inhibiting mechanisms like fetuin A and vitamin K-dependent proteins like matrix Gla protein and Gla-rich protein leads to mineralization of the extracellular matrix. In view of recent studies, intercellular communication pathways via extracellular vesicles and microRNAs represent key mechanisms in VC and thereby a promising field to a deeper understanding of the involved pathomechanisms. In this review, we provide an overview about pathophysiological mechanisms connecting CKD and CVD. Special emphasis is laid on vascular alterations and more recently discovered molecular pathways which present possible new therapeutic targets.

Topics: Animals; Atherosclerosis; Cardio-Renal Syndrome; Disease Models, Animal; Endothelium, Vascular; Extracellular Vesicles; Heart Disease Risk Factors; Humans; Incidence; Inflammation; Mice; MicroRNAs; Myocytes, Smooth Muscle; Rats; Renal Insufficiency, Chronic; Tunica Media; Vascular Calcification; Vitamin K 1; Vitamin K Deficiency

Vitamin K, well known for its role in coagulation, encompasses 2 major subgroups: vitamin K1 is exclusively synthesized by plants, whereas vitamin K2 mostly originates from bacterial synthesis. Vitamin K serves as a cofactor for the enzyme γ-glutamyl carboxylase, which carboxylates and thereby activates various vitamin K-dependent proteins. Several vitamin K-dependent proteins are synthesized in bone, but the role of vitamin K for bone health in chronic kidney disease patients, in particular the prevention of osteoporosis, is still not firmly established. Herein, we focus on another prominent action of vitamin K, in particular vitamin K2 (namely, the activation of matrix γ-carboxyglutamic acid protein, the most potent inhibitor of cardiovascular calcifications). Multiple observational studies link relative vitamin K deficiency or low intake to cardiovascular calcification progress, morbidity, and mortality. Patients with advanced chronic kidney disease are particularly vitamin K deficient, in part because of dietary restrictions but possibly also due to impaired endogenous recycling of vitamin K. At the same time, this population is characterized by markedly accelerated cardiovascular calcifications and mortality. High-dose dietary supplementation with vitamin K2, in particular the most potent form, menaquinone 7, can potently reduce circulating levels of dephosphorylated uncarboxylated (i.e., inactive matrix γ-carboxyglutamic acid protein) in patients with end-stage kidney disease. However, despite this compelling data basis, several randomized controlled trials with high-dose menaquinone 7 supplements in patients with advanced chronic kidney disease have failed to confirm cardiovascular benefits. Herein, we discuss potential reasons and solutions for this.

Topics: Humans; Renal Dialysis; Renal Insufficiency, Chronic; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

Vitamin K and its essential role in coagulation (vitamin K [Koagulation]) have been well established and accepted the world over. Many countries have a Recommended Daily Intake (RDI) for vitamin K based on early research, and its necessary role in the activation of vitamin K-dependent coagulation proteins is known. In the past few decades, the role of vitamin K-dependent proteins in processes beyond coagulation has been discovered. Various isoforms of vitamin K have been identified, and vitamin K2 specifically has been highlighted for its long half-life and extrahepatic activity, whereas the dietary form vitamin K1 has a shorter half-life. In this review, we highlight the specific activity of vitamin K2 based upon proposed frameworks necessary for a bioactive substance to be recommended for an RDI. Vitamin K2 meets all these criteria and should be considered for a specific dietary recommendation intake.

Topics: Diet; Dietary Supplements; Humans; Recommended Dietary Allowances; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

The assessment of the vitamin K status and its effects on clinical outcomes in kidney transplantation (KT) patients has sparked interest, but it is still largely unfulfilled. In part, this is due to difficulties in laboratory measurements of vitamin K, especially K2 vitamers. Vitamin K status is currently best assessed by measuring undercarboxylated vitamin-K-dependent proteins. The relative contribution of vitamin K1 and K2 to the health status of the general population and CKD (chronic kidney disease) patients, including KT patients, is also poorly studied. Through a complete and first review of the existing literature, we summarize the current knowledge of vitamin K pathophysiology and its potential role in preventing KT complications and improving organ survival. A specific focus is placed on cardiovascular complications, bone fractures, and the relationship between vitamin K and cancer. Vitamin K deficiency could determine adverse outcomes, and KT patients should be better studied for vitamin K assessment and modalities of effective therapeutic approaches.

Topics: Cardiovascular Diseases; Fractures, Bone; Humans; Kidney Transplantation; Neoplasms; Nutritional Status; Postoperative Complications; Preoperative Period; Renal Insufficiency, Chronic; Treatment Outcome; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

The cardinal biological role of vitamin K is to act as cofactor for the carboxylation of a number of vitamin K-dependent proteins, some of which are essential for coagulation, bone formation and prevention of vascular calcification. Functional vitamin K deficiency is common and severe among dialysis patients and has garnered attention as a modifiable risk factor in this population. However, no single biochemical parameter can adequately assess vitamin K status. For each biological function of vitamin K, the degree of carboxylation of the relevant vitamin K-dependent protein most accurately reflects vitamin K status. Dephosphorylated uncarboxylated matrix Gla protein (dp-ucMGP) is the best biomarker for vascular vitamin K status when cardiovascular endpoints are studied. Dp-ucMGP levels are severely elevated in haemodialysis patients and correlate with markers of vascular calcification and mortality in some but not all studies. The aetiology of vitamin K deficiency in haemodialysis is multifactorial, including deficient intake, uraemic inhibition of the vitamin K cycle and possibly interference of vitamin K absorption by phosphate binders. The optimal vitamin K species, dose and duration of supplementation to correct vitamin K status in dialysis patients are unknown. Dp-ucMGP levels dose-proportionally decrease with supraphysiological vitamin K2 supplementation, but do not normalize even with the highest doses. In the general population, long-term vitamin K1 or K2 supplementation has beneficial effects on cardiovascular disease, bone density and fracture risk, and insulin resistance, although some studies reported negative results. In haemodialysis patients, several trials on the effects of vitamin K on surrogate markers of vascular calcification are currently ongoing.

Topics: Biomarkers; Dietary Supplements; Humans; Longitudinal Studies; Renal Dialysis; Risk Factors; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency; Vitamins

Vitamins D and K are lipid-phase nutrients that are pleiotropic - endowed with versatile homeostatic capacities at the organ, tissue, and cellular levels. Their metabolic and physiologic roles overlap considerably, as evidenced in the bone and cardiovascular systems. Vitamin D₃ (cholecalciferol, D₃) is the prehormone for the vitamin D endocrine system. Vitamin D₃ undergoes initial enzymatic conversion to 25-hydroxyvitamin D (25D, calcidiol), then to the seco-steroid hormone 1alpha, 25-dihydroxyvitamin D (1,25D, calcitriol). Beyond its endocrine roles in calcium homeostasis, 1,25D likely has autocrine, paracrine, and intracrine effects. At least 17 tissues likely synthesize 1,25D, and 35 carry the vitamin D receptor (VDR). Vitamin D functional deficiency is widespread in human populations. Vitamin K₁ (phylloquinone) is more abundant in foods but less bioactive than the vitamin K₂ menaquinones (especially MK-4, menatetrenone). Menadione (vitamin K₃) has minimal K activity. Vitamin K compounds undergo oxidation-reduction cycling within the endoplasmic reticulum membrane, donating electrons to activate specific proteins via enzymatic gamma-carboxylation of glutamate groups before being enzymatically re-reduced. Warfarin inhibits this vitamin K reduction, necessitating K supplementation during anticoagulation therapy. Along with coagulation factors (II, VII, IX, X, and prothrombin), protein C and protein S, osteocalcin (OC), matrix Gla protein (MGP), periostin, Gas6, and other vitamin K-dependent (VKD) proteins support calcium homeostasis, facilitate bone mineralization, inhibit vessel wall calcification, support endothelial integrity, are involved in cell growth control and tissue renewal, and have numerous other effects. This review updates vitamin D and K skeletal and cardiovascular benefits and evidence for their synergy of action.

Topics: Bone and Bones; Bone Density; Bone Diseases; Calcification, Physiologic; Cardiovascular Diseases; Cardiovascular System; Cholecalciferol; Fractures, Bone; Humans; Nutritional Physiological Phenomena; Osteoblasts; Osteocytes; Vitamin D Deficiency; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K 3; Vitamin K Deficiency

This review summarizes current knowledge on vitamin K for the paediatrician. Vitamin K is a fat-soluble vitamin, present in plants as phylloquinone and produced by bacteria as menaquinone. It is acting as a co-factor for gamma-glutamyl carboxylase. This enzyme is responsible for post-translational modification of some glutamate side chains to gamma-carboxyglutamate. The majority of gamma-carboxylated proteins function in blood coagulation; others play a role in calcium homeostasis.. Newborn babies are at particular risk of vitamin K deficiency, as placental transfer is limited and human milk is a poor source. Vitamin K prophylaxis at birth effectively prevents vitamin K deficiency bleeding (VKDB), formerly known as "haemorrhagic disease of the newborn". Recent epidemiological studies provide data on the effectiveness of different administration routes and dosing schemes. Infants of mothers taking drugs that inhibit vitamin K are at risk of early VKDB and should receive 1 mg intramuscular (i.m.) as soon as possible after birth. Classic VKDB is prevented by intramuscular as well as by oral administration of 1 mg vitamin K. In exclusively breast-fed infants, single i.m. administration at birth is also effectively preventing (rare) late VKDB but single oral administration is not. If given orally, prophylaxis should be continued by either weekly administration of 1 mg till 12 weeks or repeating 2 mg at weeks 1 and 4. Daily administration of 25 microg offers insufficient protection. The only infants not fully protected in this way are those with yet unrecognised liver disease.. Further work is needed before firm recommendations can be made regarding dose in preterm infants and in patients with fat malabsorption/cholestasis or regarding the role of vitamin K in the prevention of osteoporosis.

Topics: Administration, Oral; Blood Coagulation; Breast Feeding; Calcium; Dose-Response Relationship, Drug; Drug Administration Schedule; Homeostasis; Humans; Infant, Newborn; Infant, Premature, Diseases; Injections, Intramuscular; Liver; Risk Factors; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency; Vitamin K Deficiency Bleeding

A protective role for vitamin K in bone health has been suggested based on its role as an enzymatic cofactor. In observational studies, vitamin K insufficiency is generally associated with lower bone mass and increased hip fracture risk. However, these findings are not supported in randomized controlled trials (RCT) of phylloquinone (vitamin K(1)) supplementation and bone loss at the hip in the elderly. This suggests that increased vegetable and legume intakes may simultaneously improve measures of vitamin K status and skeletal health, even though the mechanisms underlying these improvements may be independent of each other. Menaquinone-4 (vitamin K(2)), when given at pharmacological doses, appears to protect against fracture risk and bone loss at the spine. However, there are emerging data that suggest the efficacy of vitamin K supplementation on bone loss is inconclusive.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bone and Bones; Bone Density; Child; Child, Preschool; Dietary Supplements; Female; Humans; Male; Middle Aged; Osteoporosis; Randomized Controlled Trials as Topic; Vitamin K; Vitamin K 1; Vitamin K Deficiency

Naturally occurring vitamin K compounds comprise a plant form, phylloquinone (vitamin K(1)) and a series of bacterial menaquinones (MKs) (vitamin K(2)). Structural differences in the isoprenoid side chain govern many facets of metabolism of K vitamins including the way they are transported, taken up by target tissues, and subsequently excreted. In the post-prandial state, phylloquinone is transported mainly by triglyceride-rich lipoproteins (TRL) and long-chain MKs mainly by low-density lipoproteins (LDL). TRL-borne phylloquinone uptake by osteoblasts is an apoE-mediated process with the LRP1 receptor playing a predominant role. One K(2) form, MK-4, has a highly specific tissue distribution suggestive of local synthesis from phylloquinone in which menadione is an intermediate. Both phylloquinone and MKs activate the steroid and xenobiotic receptor (SXR) that initiates their catabolism, but MK-4 specifically upregulates two genes suggesting a novel MK-4 signalling pathway. Many studies have shown specific clinical benefits of MK-4 at pharmacological doses for osteoporosis and cancer although the mechanism(s) are poorly understood. Other putative non-cofactor functions of vitamin K include the suppression of inflammation, prevention of brain oxidative damage and a role in sphingolipid synthesis. Anticoagulant drugs block vitamin K recycling and thereby the availability of reduced vitamin K. Under extreme blockade, vitamin K can bypass the inhibition of Gla synthesis in the liver but not in the bone and the vessel wall. In humans, MK-7 has a greater efficacy than phylloquinone in carboxylating both liver and bone Gla proteins. A daily supplement of phylloquinone has shown potential for improving anticoagulation control.

Topics: Animals; Anticoagulants; Blood Proteins; Hepatocytes; Humans; Osteocytes; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

Topics: Aging; Anti-Bacterial Agents; Biomarkers; Chromatography, High Pressure Liquid; Electrochemistry; Humans; Kidney Diseases; Neoplasms; Protein Precursors; Prothrombin; Reference Values; Risk Factors; Specimen Handling; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

Hemorrhagic disease of the newborn is a disease of breast-fed infants. We have followed 119 exclusively breast-fed infants for up to 6 months of age, who received 1 mg of vitamin K, intramuscularly at birth. As vitamin K is undetectable in cord blood, the only other source in breast-fed infants is human milk. We found persistently low vitamin K1 plasma concentrations in these infants by 4 weeks, and vitamin K concentrations at 2, 4, 6, 8, 12, and 26 weeks averaged 1.18+/-0.99, 0.50+/-0.70, 0.16 +/-0.07, 0.20+/-0.20, 0.25+/-0.34, and 0.24+/-0.23 ng/mL, respectively (lower limit of adult normal = 0.5ng/mL). Vitamin K, in breast milk at 2, 6, 12, and 26 weeks was also very low, averaging 1.17+/-0.70, 0.95+/-0.50, 1.15+/-0.62, and 0.87+/-0.50 mg/mL, respectively. This may be secondary to low maternal vitamin K1 intakes or inability of vitamin K1 to penetrate human milk. We had previously reported a relatively high mean vitamin K intake of 316+/-548 microg in 20 lactating women during the first 6 months of lactation (mean of 60, 3-day dietary recalls) which greatly exceeded the recommended daily allowance of 1 microg/kg/day. The vitamin K content of foods was recently revised downward utilizing newer analytical methods (Booth et al. 1995). Recalculating maternal vitamin K intakes in this original cohort resulted in a dramatic decrease in intake to 74+/-57 microg/day, an amount closely approximating 1 microg/kg/day. We have completed 69 new dietary recalls in 23 lactating women and, combining these data with the previous study, determined a maternal vitamin K1 mean intake of 65+/-48 microg/day (0.8-1.3 microg/kg/day). Other than plasma vitamin K1 concentrations, PIVKA (undercarboxylated prothrombin produced in the absence of vitamin K) is a marker of vitamin K deficiency. We measured PIVKA in 156 cord bloods of full-term infants. Seventy-five (48%) had a significantly elevated PIVKA (> or =0.1 absorption units per milliliter). Seventy-seven of these infants who were exclusively breast-fed subsequently had no detectable PIVKA at 4 weeks, but by 8 weeks, 3 were again positive for PIVKA (prothrombin times were normal). Breast-fed infants may benefit from increased maternal vitamin K intakes (>1 microg/kg/day) during pregnancy and lactation. A supplement of 5 mg of vitamin K to lactating mothers will increase the concentration in human milk to 80.0+/-37.7 ng/mL and significantly increase infant plasma vitamin K (Greer et al. 1997).

Topics: Breast Feeding; Diet; Humans; Infant; Infant, Newborn; Milk, Human; Vitamin K 1; Vitamin K Deficiency; Vitamin K Deficiency Bleeding

Oral and intramuscular phytomenadione (vitamin K1) prophylaxis became an issue following the report of a potential carcinogenic effect of intramuscular but not oral phytomenadione prophylaxis. There is increasing evidence, however, that oral phytomenadione prophylaxis is less effective for the prevention of late vitamin K deficiency bleeding (VKDB) than intramuscular prophylaxis. Following a report of an increased cancer risk after intramuscular phytomenadione, a series of papers on this issue appeared. Although an increased risk for solid tumours could almost certainly be excluded, a potential risk for acute lymphatic leukaemia in childhood could not be ruled out definitively. Almost all cases of late VKDB are preventable with intramuscular phytomenadione prophylaxis administered once at birth, whereas a single oral dose given at birth is much less effective. Repeated oral phytomenadione doses given to breast-fed infants either weekly (1 mg) or daily (25 microg) seem to be as effective as intramuscular phytomenadione prophylaxis. The efficacy of 3 oral 2mg doses with the new mixed micellar preparation ('Konakion MM') remains to be established. Although a number of studies have failed to confirm a cancer risk with phytomenadione, these studies have been unable to rule out a risk definitely because absence of evidence is not evidence of absence. A meta-analysis of the available studies might provide 95% confidence intervals narrow enough to exclude even a small cancer risk with some certainty. Oral prophylaxis will probably be as safe as the intramuscular prophylaxis if given daily (25 microg) or weekly (1 mg).

Topics: Administration, Oral; Adult; Antifibrinolytic Agents; Blood Coagulation Disorders; Child; Humans; Injections, Intramuscular; Vitamin K 1; Vitamin K Deficiency

(1) Haemorrhagic disease of the newborn is due to vitamin K deficiency. Although rare, it is life-threatening and can have neurological sequelae. Prevention is based on routine vitamin K1 administration at birth. (2) The oral route is suitable for healthy term neonates, but dosing must be repeated if the infant is mainly breastfed. (3) The intramuscular route is reserved for neonates at risk (prematurity, neonatal disease, maternal treatment with antiepileptics or antibiotics), because of a possible risk of carcinogenicity.

Topics: Antifibrinolytic Agents; Humans; Infant, Newborn; Perinatal Care; Vitamin K 1; Vitamin K Deficiency; Vitamin K Deficiency Bleeding

Topics: Biological Transport; Blood Coagulation; Bone and Bones; Bone Development; Calcium; Food Analysis; Humans; Infant, Newborn; Nutritional Requirements; Osteocalcin; Risk Factors; Tissue Distribution; Vitamin K; Vitamin K 1; Vitamin K Deficiency; Vitamin K Deficiency Bleeding

The microsomal mixed function oxidase system metabolizes xenobiotics (Phase I) to products that, if not activated and conjugated for excretion (Phase II), are capable of forming conjugates with cellular macromolecules, including DNA, resulting in toxic, mutagenic, or carcinogenic events. Benzo(a)pyrene (BP), a polycyclic aromatic hydrocarbon, is a model carcinogen for this system. Vitamin K1 (phylloquinone) is a regulator of BP metabolism. These studies demonstrate that K1 is capable of increasing Phase I metabolism and decreasing glutathione transferase activity (Phase II) in chick embryo liver; that deprivation of K1 reduces BP/DNA adducts in mouse liver and reduces tumor formation in mice given intraperitoneal BP; and that K1 supplementation increases BP induced tumor formation in mice. However, epidemiologic studies indicate that children of mothers who smoke during pregnancy may not be at increased risk of cancer. It is known that the placentas from these pregnancies exhibit markedly increased levels of arylhydrocarbon hydroxylase induced by the polycyclic aromatic hydrocarbons in tobacco smoke, but there is no corresponding increase in this enzyme activity in the fetus in such pregnancies. We suggest that the low vitamin K level is a secondary protective mechanism for xenobiotics, such as BP, that may escape the primary placental screen. The recently described role of vitamin K-dependent Gla protein as ligands for receptor tyrosine kinases, also establishes K as a link in cell growth and transformation. It is proposed that the small total body pool of K1 in the adult, which is sufficient only to meet continuing needs, and the even smaller pool in the fetus are protective. This protective effect of low K1 levels is particularly important in the presence of the high mitotic rates and rapid cell turnover in the avian embryo and mammalian fetus.

Topics: 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; Adult; Animals; Biotransformation; Carcinogens; Chick Embryo; Cocarcinogenesis; DNA Adducts; Female; Fetal Diseases; Fetus; Humans; Infant, Newborn; Liver; Maternal Exposure; Maternal-Fetal Exchange; Mice; Mice, Inbred ICR; Microsomes, Liver; Mixed Function Oxygenases; Neoplasms; Neoplasms, Experimental; Placenta; Pregnancy; Prenatal Exposure Delayed Effects; Smoking; Vitamin K; Vitamin K 1; Vitamin K Deficiency; Warfarin; Xenobiotics

Topics: Adult; Aged; Bleeding Time; Blood Platelet Disorders; Cephalosporins; Child; Humans; Hypoprothrombinemias; Infant; Moxalactam; Partial Thromboplastin Time; Platelet Aggregation; Prothrombin Time; Vitamin K 1; Vitamin K Deficiency

Since the discovery of gamma-carboxyglutamic acid a decade ago, great progress has been made in advancing our knowledge of the function and metabolism of vitamin K. The distribution of this new amino acid in proteins of diverse origin and the presence of the vitamin K-dependent carboxylase in diverse tissues have emphasized the widespread significance in biology of a new triad: vitamin K, Gla, and calcium. New knowledge has been obtained on the importance of the utilization and reutilization of vitamin K, whose body pools are extremely low for a fat-soluble vitamin, for the posttranslational carboxylation of peptide-bound glutamate residues in the vitamin K-dependent proteins. The regulation of the activation of the vitamin K-vitamin K-epoxide cycle by drugs and nutrients appears to be the key to controlling the synthesis of vitamin K-dependent proteins, eight of which are involved in blood coagulation. The purification of the vitamin K-dependent gamma-glutamyl carboxylase has turned out to be a more formidable task than anyone had imagined. Many of the questions about its complicated mechanism, utilizing as it does four substrates (KH2, O2, CO2, and a Glu-containing peptide), cannot be answered until the enzyme is homogeneous. Basically, the vitamin K-dependent carboxylase system consists of a specialized microsomal electron transport system coupled to a carbon dioxide fixation. The reaction does not require ATP but apparently utilizes the energy of vitamin KH2 oxidation to perform the chemical work required in Gla synthesis. Why a quinone is employed in this system when other mechanisms exist for CO2 fixation is still mysterious unless the whole process goes by one electron transport. Whether the final CO2 addition to the gamma-methylene group of glutamic acid is a radical reaction is unsettled. Since this enzyme is an intrinsic membrane-bound protein, the scientific attack on its structure and function is at one of the present frontiers of molecular biology. A view of the synthesis of vitamin K-dependent proteins in the RER is shown in Figure 9. Finally, the nutritional requirements for vitamin K in humans are unknown. An unknown fraction of vitamin K in humans is derived from menaquinone biosynthesis in the intestinal flora. Contributions from diet and biosynthesis have not yet been quantitated. Sensitive HPLC methods for measuring plasma phylloquinone are now available, and related methods for measuring long-chain menaquinones can be developed.

Topics: 4-Hydroxycoumarins; Amino Acid Sequence; Animals; Carbon-Carbon Ligases; DNA; DNA, Recombinant; Electron Transport; Genetic Variation; Humans; Immunologic Techniques; Intestinal Absorption; Kinetics; Ligases; Microsomes, Liver; Mixed Function Oxygenases; Nutritional Requirements; Peptides; Protein Binding; Protein Precursors; Protein Sorting Signals; Prothrombin; Quinone Reductases; RNA, Messenger; Salicylates; Tissue Distribution; Vitamin A; Vitamin E; Vitamin K; Vitamin K 1; Vitamin K Deficiency; Vitamin K Epoxide Reductases

Topics: Adult; Animals; Blood Coagulation Factors; Drug Interactions; Humans; Male; Vitamin E; Vitamin K; Vitamin K 1; Vitamin K Deficiency; Warfarin

Topics: Alcoholism; alpha-Tocopherol; Animals; Calcifediol; Factor VII; Humans; Hydroxycholecalciferols; Intestinal Absorption; Liver Diseases, Alcoholic; Prothrombin Time; Tocopherols; Vitamin D; Vitamin D Deficiency; Vitamin E; Vitamin E Deficiency; Vitamin K; Vitamin K 1; Vitamin K Deficiency

Total cranial vault craniosynostosis repairs often require additional blood transfusions in the intensive care unit. Vitamin K1 participates in hepatic production of procoagulant proteins, and body stores of vitamin K1 are limited and dietary dependent. Surgical stress and diet interference may place infants at risk for vitamin K deficiency. Through design of a surgically stratified, randomized, placebo-controlled, blinded pilot study, we evaluated impact of vitamin K1 supplementation on coagulation parameters in infants after craniosynostosis repair. Patients received intramuscular vitamin K1 or placebo coincident with surgical incision. Serum vitamin K1 levels, protein induced in vitamin K absence-prothrombin, and factor VII were obtained at predetermined intervals after surgery. Patients received blood products in the intensive care unit in accordance with transfusion thresholds. Fifteen patients (vitamin K1 = 6, placebo = 9) completed the study procedures. Despite group assignment, patients received an average of 3 postoperative transfusions. Variations were observed with respect to intraoperative resuscitation of patients between comparably trained pediatric anesthesiologists. Thirty-three percent of patients were vitamin K1 deficient on 1 or more laboratory specimens. All breast-fed patients became deficient. Compared with placebo, elevated serum vitamin K1 levels at 6, 12, and 24 hours in the active drug group (P < 0.0001) were not associated with increased factor VII levels or reduced need for postoperative blood products. However, lack of a standardized intraoperative resuscitation plan may contribute to postoperative coagulopathy and is a major study limitation.

Topics: Adolescent; Blood Loss, Surgical; Blood Transfusion; Breast Feeding; Craniosynostoses; Double-Blind Method; Female; Humans; Infant; Injections, Intramuscular; Male; Pilot Projects; Prospective Studies; Prothrombin; Vitamin K 1; Vitamin K Deficiency

Subclinical deficiencies of vitamin K are universally present in unsupplemented cystic fibrosis (CF) patients. The dose required to prevent deficiencies cannot be estimated from the existing literature. The aim of this study is determine if a supplemental dose of 1 mg/day or 5 mg/day vitamin K1 per day would normalize vitamin K status in a population of children with cystic fibrosis.. Fourteen pancreatic insufficient CF children, between the ages of 8 to 18 years old, were randomized to receive either 1 mg/day or 5 mg/day vitamin K1 per day, for one month. Fasting blood tests were done at baseline and after one month of the intervention. The degree of undercarboxylation of osteocalcin (%Glu-OC), and serum vitamin K1, were evaluated by descriptive statistics and nonparametric Wilcoxon matched-pair test and Mann-Whitney U test.. Of the 50% of subjects who were below the optimal serum vitamin K1 at baseline, all rose into the normal range with supplementation. Supplementation also significantly reduced the overall %Glu-OC from a median of 46.8 to 29.1% (p<0.0003).. Our results suggest that both 1 mg and 5 mg of vitamin K1, given over a one-month period in pancreatic insufficient pediatric cystic fibrosis patients improve vitamin K status.

Topics: Adolescent; Child; Cystic Fibrosis; Female; Humans; Male; Treatment Outcome; Vitamin K 1; Vitamin K Deficiency; Vitamins

Vitamin K has bone and cartilage effects, and previously shown to be associated with radiographic osteoarthritis. We evaluated vitamin K's effect on hand osteoarthritis in a randomised controlled trial.. This was an ancillary study to a randomised controlled trial assessing the effects of phylloquinone supplementation (vitamin K arm) versus placebo on bone loss and vascular calcification among older adults regardless of their vitamin K status. At the final 3-year study visit, we assessed the effects of vitamin K versus placebo on hand x-ray features of osteoarthritis using logistic regression and intention to treat, and also restricted analysis to the subgroup that had insufficient vitamin K concentrations at baseline.. This ancillary study had 378 participants (193 in vitamin K arm, 185 in placebo arm). There were no effects of randomisation to vitamin K for radiographic osteoarthritis outcomes. Those with insufficient vitamin K at baseline who attained sufficient concentrations at follow-up had trends towards 47% less joint space narrowing (p = 0.02).. There was no overall effect of vitamin K on radiographic hand osteoarthritis.. that were insufficient in vitamin K at baseline who attained sufficient concentrations at follow-up may have had a benefit in joint space narrowing. A clinical trial in those who are vitamin K insufficient may be warranted.. NCT00183001.

Topics: Aged; Dietary Supplements; Double-Blind Method; Female; Follow-Up Studies; Hand Joints; Humans; Male; Middle Aged; Osteoarthritis; Radiography; Vitamin K 1; Vitamin K Deficiency

To compare efficacy of intramuscular phytomenadione (fat soluble vitamin K or vitamin K1) with menadione (water soluble vitamin K or vitamin K3) in prevention of subclinical vitamin K deficiency.. A doubleblind randomized controlled trial.. Tertiary care hospital.. Healthy term neonates were randomized to receive 1 mg of either phytomenadione (Group I, n = 85) or menadione (Group II, n = 85) intramuscularly within 2 hours of birth. PIVKA-II, a sensitive and specific marker of vitamin K deficiency was measured by ELISA method (Diagnostica Stago, France). Plasma level > 2 ng/mL was labeled as detectable PIVKA-II.. Birth weight (2914 +/- 318 vs 2958 +/- 312 g), gestation (38.4 +/- 1.2 vs 38.4 +/- 1.0 wk) and other baseline variables were comparable between the two groups. 48.2% (41/85) neonates in Group I and 44.7%(38/85) neonates in Group II had detectable PIVKAII levels ([Relative Risk (95% confidence interval): 1.1 (0.8-1.5); P = 0.76]). Median PIVKA-II levels in Group I and Group II were 1.99 ng/mL and 1.97 ng/mL respectively (P = 0.26). At 72 +/- 12 h of age, mean packed cell volume and mean serum bilirubin levels were comparable in the two groups.. Comparable PIVKAII detection rate and PIVKAII levels in neonates receiving phytomenadione or menadione indicate their similar efficacy in prevention of vitamin K deficiency. However, high PIVKAII detection rate observed with both preparations indicates recent vitamin K deficiency and may be due to either inadequate dose of vitamin K or persistence of PIVKAII of fetal origin.

Topics: Biomarkers; Humans; Infant, Newborn; Protein Precursors; Prothrombin; Vitamin K 1; Vitamin K 3; Vitamin K Deficiency; Vitamins

Vitamin K has been implicated in increased bone fracture risk. Despite a potential role of vitamin K in bone, little is known about the effects of altered dietary phylloquinone intake on the underlying components of bone and mineral metabolism.. A 84-day in-house dietary phylloquinone (vitamin K) depletion-repletion study was undertaken in 21 postmenopausal women (mean age: 70 years) to assess the effects of altered vitamin K status on intestinal calcium (Ca) absorption, urinary and serum Ca and phosphorus (P), serum calcemic hormones, and serum biomarkers of bone turnover [osteocalcin and N-telopeptide type 1 collagen cross-links (NTx)] and the response to 1,25-dihydroxyvitamin D treatment (1 microg/dayx7 d).. The group receiving calcitriol treatment (n=11) had higher Ca absorption, urinary Ca, urinary and serum P and serum osteocalcin and lower serum parathyroid hormone (PTH). There were no significant effects of acute (4-week) phylloquinone depletion on response to 1,25-dihydroxyvitamin D treatment or on measures of bone formation or mineral metabolism. However, phylloquinone treatment had a significant effect (p<0.04) on serum NTx. Phylloquinone repletion, up to five times (450 microg phylloquinone per day) the currently recommended adequate intake level of dietary phylloquinone for women, significantly reduced serum NTx (16.8+/-0.9 nmol bone collagen equivalents (BCE) per liter following repletion vs 18.4+/-1.1 nmol BCE per liter following depletion; p<0.01).. These findings suggest that altering vitamin K status in postmenopausal women by manipulating phylloquinone intake does not have an acute affect on intestinal Ca absorption, renal mineral excretion, or bone formation, but high phylloquinone intake may modestly reduce bone resorption. The impact of high phylloquinone intake on bone mineral density and fracture risk needs to be ascertained in randomized clinical trials.

Topics: Aged; Aged, 80 and over; Biomarkers; Calcitriol; Calcium; Collagen Type I; Female; Humans; Middle Aged; Osteocalcin; Osteoporosis, Postmenopausal; Parathyroid Hormone; Peptides; Phosphorus; Vitamin K 1; Vitamin K Deficiency; Vitamins

Most multivitamin supplements contain far less vitamin K(1) than thought to affect warfarin anticoagulation. Having described 3 patients with multivitamin-warfarin interactions, we hypothesized that vitamin K(1)-depleted patients are sensitive to even small increments. Therefore, we compared the effect of a vitamin K(1)-containing multivitamin on warfarin anticoagulation between patients with low versus normal vitamin K(1) status. We screened 102 warfarin-treated patients and recruited nine with "low" (< 1.5 mcg/L, 10(th) percentile) (group 1) and 7 with "normal" (>4.5 mcg/L, median) (group 2) total vitamin K(1) plasma levels (vitamin K(1) + vitamin K(1) 2,3-epoxide). Patients received one multivitamin tablet containing 25 mcg of vitamin K(1) daily, for 4 weeks (period 1). A predefined algorithm was used to adjust warfarin doses if the INR was outside the therapeutic range. Patients requiring warfarin increments were then switched to 4 weeks of a vitamin K(1)-free multivitamin supplement (period 2). During period 1, subtherapeutic INRs occurred in 9/9 and 1/7 patients in group 1 and 2, respectively (p <0.001). In group 1, INR decreased by a median of 0.51 (p <0.01), and warfarin dose had to be raised by 5.3% (p <0.01), whereas INR and warfarin dose did not change significantly in group 2. During period 2 (7 patients), there were trends towards decreased total vitamin K(1) and rising INRs associated with significantly lower warfarin doses. We conclude that vitamin K(1)-containing multivitamins reduce INR in patients with low vitamin K(1) status. Our study suggests that vitamin K-depleted patients are sensitive to even small changes in vitamin K(1) intake.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Dietary Supplements; Drug Antagonism; Drug Monitoring; Female; Humans; International Normalized Ratio; Male; Middle Aged; Nonprescription Drugs; Vitamin K 1; Vitamin K Deficiency; Warfarin

To compare the pharmacokinetics and efficacy of oral versus intravenous mixed micellar vitamin K prophylaxis in infants with cholestatic liver disease, a known risk factor for vitamin K deficiency bleeding.. Prospective randomised controlled study.. Paediatric Liver Unit.. Forty four infants less than 6 months of age with conjugated hyperbilirubinaemia.. Serum concentrations of vitamin K(1) and undercarboxylated prothrombin (PIVKA-II; a sensitive functional indicator of vitamin K status) before and for up to four days after a single dose of mixed micellar K(1) 1 mg intravenously or 2 mg orally. Comparison of K(1) levels 24 hours after oral K(1) with those from 14 healthy newborns given the same dose.. At admission, 18 infants (41%) had elevated levels of serum PIVKA-II and eight (18%) had low K(1) concentrations, indicative of subclinical vitamin K deficiency. Median serum K(1) concentrations were similar in the oral and intravenous groups at baseline (0.92 v 1.15 ng/ml), rising to 139 ng/ml six hours after intravenous K(1) but to only 1.4 ng/ml after oral administration. In the latter group, the low median value (0.95 ng/ml) and wide range (< 0.15-111 ng/ml) of serum K(1) compared unfavourably with the much higher levels (median 77, range 11-263 ng/ml) observed in healthy infants given the same oral dose, and suggested impaired and erratic intestinal absorption in cholestatic infants. The severity of malabsorption was such that only 4/24 (17%) achieved an incremental rise in serum K(1) > 10 ng/ml.. The intestinal absorption of mixed micellar K(1) is unreliable in infants with conjugated hyperbilirubinaemia. Given the strong association between cholestasis and late vitamin K deficiency bleeding, these data provide an explanation for the failure of some oral vitamin K(1) prophylaxis regimens in infants with latent cholestasis.

Topics: Administration, Oral; Antifibrinolytic Agents; Female; Humans; Hyperbilirubinemia; Infant; Infant, Newborn; Injections, Intravenous; Intestinal Absorption; Male; Micelles; Prospective Studies; Vitamin K 1; Vitamin K Deficiency; Vitamin K Deficiency Bleeding

The administration of menaquinone-4 (MK-4), one of subclasses of vitamin K2, significantly reduces bone loss in postmenopausal osteoporotic women. However, concerns have been raised about whether vitamin K administration alters the hemostatic balance by inducing a thrombotic tendency. We investigated were whether the administration of vitamin K in the form of MK-4 induced a thrombotic tendency in 29 elderly patients with osteoporosis (5 men, 24 women; age range 78.7+/-5.1 years). Patients were administered 45 mg/day (three times a day, 30 min after each meal) of MK-4 for 12 weeks. Blood samples were obtained from the patients at 0, 4 and 12 weeks after the start of MK-4 administration. A number of hemostatic parameters remained stable under the markedly increased plasma levels of MK-4. However, in patients with suspected vitamin K deficiency, whose plasma levels of vitamin K or factor VII were low, vitamin-K-dependent clotting factors such as factor VII and prothrombin were gradually increased after administration of MK-4. No changes in the sensitive molecular markers such as TAT and F1+2, which reflect the amount of thrombin generated in the blood stream, were observed, even in those patients with suspected vitamin K deficiency. These results indicate that MK-4 can be administered safely, with regard to maintaining the hemostatic balance, to osteoporotic patients receiving no anticoagulant therapy.

Topics: Aged; Aged, 80 and over; Blood Coagulation Factors; Cyanoacrylates; Female; Hemostasis; Hemostatics; Humans; Male; Osteoporosis; Osteoporosis, Postmenopausal; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

This randomized, controlled study evaluated the bioavailability of phylloquinone from an intravenous lipid emulsion. A mild vitamin K deficiency was induced in 12 healthy adult men and women by dietary restriction of phylloquinone (40 microg/d, days 1-11) and by administration of warfarin (1.0 mg/d, days 5-11). On day 11, subjects received a 500-mL intravenous solution of either lipid or saline, both of which contained 154 microg phylloquinone. Bioavailability was assessed by serial measurements of plasma phylloquinone, vitamin K1-2,3-epoxide. PIVKA-II (proteins induced by vitamin K absence or antagonists-II), and percentage undercarboxylated osteocalcin. As a result of vitamin K deficiency and minidose warfarin, vitamin K1-2,3-epoxide, PIVKA-II, and percentage undercarboxylated osteocalcin increased significantly between days 1 and 11 (P = 0.05, 0.016, and 0.001, respectively). With the infusions, plasma phylloquinone increased in both groups (P = 0.001). After the infusions vitamin K,-2,3-epoxide decreased in both groups (P = 0.002). Changes in plasma phylloquinone and vitamin K1-2,3-epoxide were no different in the two groups (mean areas under the curves +/- SEM: 116+/-13 nmol x h/L for the saline group and 102+/-20 nmol x h/L for the lipid group for phylloquinone; 38.6+/-7.5 nmol x h/L for the saline group and 31.3+/-9.0 nmol x h/L for the lipid group for vitamin K1-2,3-epoxide). PIVKA-II decreased significantly from baseline values (P = 0.005) in both groups after the infusions. Intravenous lipid reversed the effects of minidose warfarin and of dietary restriction of phylloquinone on hemostasis and vitamin K nutritional status. This reversal was no different from that seen with the infusion of phylloquinone in a saline solution.

Topics: Adult; Biological Availability; Biomarkers; Diet; Fat Emulsions, Intravenous; Female; Humans; Male; Osteocalcin; Protein Precursors; Prothrombin; Vitamin K 1; Vitamin K Deficiency; Warfarin

Subjects taking a hydrogen pump blocking agent (omeprazole) develop bacterial overgrowth of the small intestine. We tested the hypothesis that this bacterial overgrowth produces menaquinones, which would meet the vitamin requirement in situations of vitamin K deficiency. In a crossover-type design, 13 healthy volunteers eating a phylloquinone-restricted diet for 35 d were randomly assigned to take omeprazole during the first period of study or starting on day 15 until the end of the study. Coagulation times, serum osteocalcin [total osteocalcin and undercarboxylated osteocalcin (ucOC)], plasma phylloquinone, urinary gamma-carboxyglutamic acid, and plasma undercarboxylated prothrombin (PIVKA-II) were measured. Plasma phylloquinone concentrations declined 82% with dietary phylloquinone restriction (P < 0.05) and were not significantly different in the period when the diet was combined with omeprazole treatment (P > 0.05). The mean value for PIVKA-II during the phylloquinone-restricted diet significantly increased 5.7-fold from baseline (P < 0.05); however, the combination of omeprazole treatment and the phylloquinone-restricted diet significantly reduced PIVKA-II values by 21% (P < 0.05) compared with the diet period alone. There were no alterations in total or percentage ucOC concentrations during the phylloquinone-restricted diet or during the period of diet plus omeprazole treatment. Our data support the hypothesis that bacterial overgrowth results in the synthesis and absorption of menaquinones. These menaquinones contribute to vitamin K nutriture during dietary phylloquinone restriction, but not enough to restore normal vitamin K status.

Topics: 1-Carboxyglutamic Acid; Achlorhydria; Adult; Aged; Bacteria; Biomarkers; Cross-Over Studies; Diet; Drug Interactions; Humans; Intestine, Small; Middle Aged; Omeprazole; Osteocalcin; Protein Precursors; Prothrombin; Vitamin K; Vitamin K 1; Vitamin K Deficiency

Significant reduction in bone mineral density (BMD) occurs in stroke patients on the hemiplegic and contralateral sides, correlating with the degree of paralysis and vitamin D and K deficiency due to malnutrition, and increasing the risk of hip fracture. We evaluated the efficacy of vitamin K2 (menatetrenone: menaquinone-4; MK-4) in maintaining BMD by comparing serum biochemical indices of bone metabolism between treated and untreated patients. In a random and prospective study, of 108 hemiplegic patients following stroke, 54 received 45 mg menatetrenone daily (MK-4 group, n = 54) for 12 months, and the remaining 54 (untreatment group) did not. Nine patients excluded from the study. The BMD in the second metacarpals and serum indices of bone metabolism were determined. BMD on the hemiplegic side increased by 4.3% in the MK-4 group and decreased by 4.7% in the untreated group (p < 0.0001), while BMD on the intact side decreased by 0.9% in the MK-4 group and by 2.7% in the untreated group (p < 0.0001). At baseline, patients of both groups showed vitamin D and K1 deficiencies, high serum levels of ionized calcium, pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP), and low levels of parathyroid hormones (PTH) and bone Gla proteins (BGP), indicating that immobilization-induced hypercalcemia inhibits renal synthesis of 1, 25-dihydroxyvitamin D (1, 25-[OH]2D) and compensatory PTH secretion. Both vitamins K1 and K2 increased by 97.6% and 666.9%, respectively, in the MK-4 group. Correspondingly, a significant increase in BGP and decreases in both ICTP and calcium were observed in the MK-4 group, in association with a simultaneous increase in both PTH and 1, 25-[OH]2D. One patient in the untreated group suffered from a hip fracture, compared with none in the MK-4 group. The treatment with MK-4 can increase the BMD of disused and vitamin D- and K-deficient hemiplegic bone by increasing the vitamin K concentration, and it also can decrease calcium levels through inhibition of bone resorption, resulting in an increase in 1, 25-[OH]2D concentration.

Topics: Aged; Biomarkers; Bone Density; Bone Diseases, Metabolic; Cerebrovascular Disorders; Female; Hemiplegia; Hemostatics; Humans; Male; Metacarpus; Middle Aged; Prospective Studies; Vitamin D Deficiency; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

To establish recommendations for prevention of vitamin K deficiency in healthy breastfed infants.. Prospective clinical trials of different methods of vitamin K prophylaxis.. Study of vitamin K1 and proteins induced by vitamin K absence (PIVKA)-II concentrations, and some coagulation factors at the ages of 2, 4, 8 and 12 weeks in healthy breastfed infants with either once 1 mg vitamin K1 orally (n = 165) or intramuscularly (n = 166), or weekly 1 mg orally (n = 48), or daily 25 micrograms orally (n = 58).. Despite significantly higher vitamin K1 plasma concentrations after intramuscular administration, there was no difference in activities of coagulation factors VII and X, and PIVKA-II concentrations between oral and intramuscular administration. The two single administrations of 1 mg could not prevent the appearance of PIVKA-II after the age of 1 month. When vitamin K was administered as 1 mg per week or 0.025 mg per day, significantly higher concentrations of vitamin K1 were found and no PIVKA-II was detectable.. A single administration of 1 mg vitamin K1 orally or intramuscularly may not afford complete protection against late vitamin K deficiency in healthy breastfed infants. A regimen of 1 mg per week or 25 micrograms vitamin K1 per day proved to be effective in prevention of vitamin K deficiency and the latter is recommended for breastfed infants during the first three months of life.

Topics: Biomarkers; Blood Coagulation Factors; Breast Feeding; Chromatography, High Pressure Liquid; Humans; Infant; Infant, Newborn; Prospective Studies; Protein Precursors; Prothrombin; Vitamin K 1; Vitamin K Deficiency

The plasma disposition of a new mixed-micellar preparation (KONAKION MM, Roche) of phylloquinone (vitamin K1) has been studied in 25 healthy, fully breast-fed, newborn babies, randomized to receive a single dose of either 1.5 mg i.m. (11 babies) or 3 mg p.o. (14 babies). Venous blood samples were collected at 25 h, 4 days, and 24 days. After p.o. administration, the median plasma phylloquinone concentration increased to 89 ng/ml after 24 h, then decreased to 51 ng/ml after 4 days; the respective concentrations after i.m. injection were 146 ng/ml and 34 ng/ml. The higher plasma phylloquinone level in the i.m. group after 24 h was not statistically significant compared with that of the p.o. group, but the reversed higher concentration in the p.o. group after 4 days was significant (p < 0.01). After 24 days the median plasma phylloquinone had decreased to 0.44 ng/ml (range 0.19-1.44) and 1.05 ng/ml (range 0.37-1.87) in the p.o. and i.m. groups, respectively. There was a significant difference between these plasma concentrations (p < 0.01). They were within or above the reference adult fasting range (0.17-0.68 ng/ml). The narrow range of plasma concentrations at 24 h and 4 days suggests a greater consistency of absorption from this micellar preparation than from other emulsion-based preparations. Further studies are required to assess the long-term protection of a single oral dose against late hemorrhagic disease of the newborn. Until such time, breast-fed babies given this preparation orally should receive (an) additional dose(s).

Topics: Administration, Oral; Breast Feeding; Female; Half-Life; Humans; Infant, Newborn; Injections, Intramuscular; Male; Micelles; Random Allocation; Time Factors; Vitamin K 1; Vitamin K Deficiency

A randomised clinical trial was conducted to establish the effects of oral and intramuscular administration of vitamin K at birth on plasma concentrations of vitamin K1, proteins induced by vitamin K absence (PIVKA-II), and clotting factors. Two groups of about 165 healthy breast fed infants who received at random 1 mg vitamin K1 orally or intramuscularly after birth were studied at 2 weeks and 1 and 3 months of age. Although vitamin K1 concentrations were statistically significantly higher in the intramuscular group, blood coagulability, activities of factors VII and X and PIVKA-II concentrations did not reveal any difference between the two groups. At 2 weeks of age vitamin K1 concentrations were raised compared with reported unsupplemented concentrations and no PIVKA-II was detectable. At 3 months vitamin K1 concentrations were back at unsupplemented values and PIVKA-II was detectable in 11.5% of infants. Therefore, a repeated oral prophylaxis will be necessary to completely prevent (biochemical) vitamin K deficiency beyond the age of 1 month.

Topics: Administration, Oral; Biomarkers; Blood Coagulation; Breast Feeding; Female; Humans; Infant; Infant, Newborn; Injections, Intramuscular; Male; Protein Precursors; Prothrombin; Vitamin K; Vitamin K 1; Vitamin K Deficiency

Serum concentration of vitamin K1 and activity of vitamin-K-dependent factors II, VII, IX and X were determined before and after vitamin K1 administration in infants. The babies received vitamin K1 intramuscularly or orally. 12 hours after vitamin K1 treatment the mean concentration was increased in the groups receiving vitamin K1 intramusculary or orally, respectively. Serum level of vitamin K1 fell exponentially, the mean half life was about 30 hours in both groups. Activity of vitamin K-dependent clotting factors did not change significantly after intramuscular or oral vitamin K1 administration during the first four-five days of life. It was no direct correlation between the concentration of vitamin K1 and the activity of vitamin-K-dependent clotting factors. This study suggest that oral administration of vitamin K1 is as effective as the intramuscular route.

Topics: Administration, Oral; Blood Coagulation Factors; Breast Feeding; Clinical Trials as Topic; Erythroblastosis, Fetal; Fetal Blood; Humans; Infant, Newborn; Injections, Intramuscular; Milk, Human; Vitamin K 1; Vitamin K Deficiency

In 34 cancer patients with 40 neutropenic febrile episodes requiring broad-spectrum antimicrobial therapy, detailed dietary assessments revealed that deficient and severely deficient phylloquinone intakes (less than or equal to 70 and less than or equal to 25 micrograms/d) were identified during 88% and 38% of all days recorded, respectively. Serum phylloquinone levels and serial prothrombin times (PT) drawn in a similar group of 32 patients revealed that an elevated PT (greater than or equal to 2 s beyond control) was significantly associated (p less than 0.01) with a serum phylloquinone level of less than 4.4 nmol/L. Patients on antimicrobial regimens that suppressed menaquinone-producing intestinal microflora and that contained an N-methylthiotetrazole (NMTT) moiety had an elevated PT significantly more often than did patients receiving antimicrobial agents that preserved the microflora and contained no NMTT moiety (3 of 10 vs 10 of 11, respectively; p = 0.02 Fisher's exact). These data suggest that these patients have a profound deficiency of oral vitamin K intake that may be further augmented by antimicrobial therapy.

Topics: Agranulocytosis; Anti-Bacterial Agents; Diet; Fever; Humans; Hypoprothrombinemias; Intestines; Neoplasms; Neutropenia; Prothrombin Time; Vitamin K; Vitamin K 1; Vitamin K Deficiency

Vitamin K is required for the maintenance of normal hemostatic function. Ten college-aged male subjects chose diets restricted in vitamin K content for 40 d. Median phylloquinone intakes based on analysis of food composites dropped from 82 micrograms/d during the prestudy period to 40 and 32 micrograms/d at d 9 and 27 of dietary restriction, respectively. Serum phylloquinone concentrations fell from a mean of 0.87 to 0.46 ng/mL during a 21-d period of vitamin K restriction. Supplementation with 50 micrograms phylloquinone/d for 12 d increased serum phylloquinone to 0.56 ng/mL, and supplementation with 500 micrograms phylloquinone/d increased serum phylloquinone to 1.66 ng/mL. Vitamin K restriction resulted in alterations in a functional clotting assay that detects undercarboxylated prothrombin species in plasma and in a decrease in urinary gamma-carboxyglutamic acid. Supplementation with either 50 or 500 micrograms of phylloquinone restored both these indices to near normal values. These data are consistent with a human dietary vitamin K requirement of approximately 1 microgram/kg body wt/d.

Topics: Adult; Blood Coagulation; Humans; Male; Time Factors; Vitamin K; Vitamin K 1; Vitamin K Deficiency

Vitamin K acts a cofactor for the gamma-carboxylation of several proteins in the coagulation cascade. The clinical spectrum of vitamin K deficiency (VKD) can be asymptomatic to a significant bleeding. VKD is classically seen in newborns. However, this can manifest later in patients with risks such as sub-optimal nutrition, fat malabsorption, medications including antibiotics. A 17-year-old male with spinal muscular atrophy (SMA) Type 1, tracheostomy with ventilator dependent, gastrostomy tube feeding was seen by the gastroenterologist following treatment for small intestinal bacterial overgrowth (SIBO). Investigations showed coagulopathy following which he was transferred to the Pediatric ICU. Labs revealed prothrombin time (PT) 114 s [Normal 9.4-12.5 s], INR (International normalized ratio) 12.6 [Normal < 1.1] and partial thromboplastin time (PTT) 90 s [Normal 25.1-36.5 s]. Mixing studies and coagulation assays were consistent with VKD (low Factor VII and Factor IX with normal Factor V). His home blenderized feeding regimen met the caloric requirement but not the adequate intake (AI) values for vitamin K and other minerals. He received intravenous vitamin K (phytonadione) for five consecutive days with resolution of the coagulopathy (PT 13.2 s, PTT 37.1 s, INR 1.2). The patient was discharged on enteral vitamin K and additional supplements following dietary review by a nutritionist. Clinicians should be cognizant of VKD in patients on blenderized tube feeds which may not meet the adequate intake (AI) goals. In patients who are not receiving nutritionally complete formulas or receiving inadequate volumes, it is important to monitor macro and micronutrients.

Topics: Adolescent; Child; Dietary Supplements; Enteral Nutrition; Humans; Infant, Newborn; Male; Vitamin K; Vitamin K 1; Vitamin K Deficiency

Vitamin K is an essential fat-soluble vitamin for the human body and its functions, such as promoting blood coagulation, bone health and preventing atherosclerosis, have attracted increasing attention. However, there is no recognized indicator and corresponding reference range for evaluating vitamin K status of different populations at present. The aim of this study is to establish a reference range for vitamin K evaluating indicators in healthy women of childbearing age in China.. The population sample in this study was from the Chinese Adult Chronic Disease and Nutrition Surveillance (CACDNS) 2015-2017. A total of 631 healthy women of childbearing age (18-49 years) were included using a series of strict inclusion and exclusion criteria. The concentrations of VK1, MK-4 and MK-7 in serum were detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The other commonly-reported indicators evaluating vitamin K nutritional status, including undercarboxylated osteocalcin (ucOC), osteocalcin (OC), matrix Gla protein (MGP), desphosphorylated undercaboxylated MGP (dp-ucMGP) and protein induced by vitamin K absence II (PIVKA-II), were measured by enzyme-linked immunosorbent assay (ELISA). The reference range was obtained by calculating the 2.5% to 97.5% interval of the vitamin K evaluating indicators in the reference population.. The reference ranges of VK1, MK-4 and MK-7 in serum were 0.21-3.07 ng/mL, 0.02-0.24 ng/mL and 0.12-3.54 ng/mL, respectively. The reference ranges of ucOC, %ucOC, dp-ucMGP and PIVKA-II were 1.09-2.51 ng/mL, 5.80-22.78%, 2.69-5.88 ng/mL and 3.98-8.40 ng/mL, respectively. The cut-off values that can be used to evaluate subclinical vitamin K deficiency were as follows: VK1 < 0.21 ng/mL, MK-7 < 0.12 ng/mL, ucOC > 2.51 ng/mL, %ucOC > 22.78%, dp-ucMGP > 5.88 ng/mL and PIVKA-II > 8.40 ng/mL.. The reference range of VK1, MK-4, MK-7 and vitamin K-related indicators for healthy women of childbearing age established in this study could be used to assess the nutritional and health status of this population.

Topics: Adolescent; Adult; Biomarkers; Chromatography, Liquid; East Asian People; Female; Humans; Middle Aged; Osteocalcin; Reference Values; Tandem Mass Spectrometry; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency; Vitamins; Young Adult

Nutritional support is essential for patients with severe motor and intellectual disabilities (SMID) to ensure the smooth provision of medical care. These patients often require long-term tube feeding with enteral formulas, potentially leading to deficiencies in vitamins and trace elements. Additionally, frequent antibiotic use for infections often disrupts gut microbiota, inhibiting vitamin K2 production by intestinal bacteria. We assessed the serum protein induced by vitamin K absence or antagonists-II (PIVKA-II) and undercarboxylated osteocalcin (ucOC) levels to assess the vitamin K status in 20 patients with SMID (median age: 44.1 years, 11 men and 9 women) undergoing long-term tube feeding for durations ranging from 3 to 31 years. Thirteen (65%) and nine (45%) patients had elevated PIVKA-II (<40 mAU/mL) and serum ucOC levels (reference value < 4.50 ng/mL), respectively. Dietary vitamin K1 intake did not differ between patients with and without elevated PIVKA-II levels. Vitamin K2 supplementation for 3 months decreased serum PIVKA-II levels near those within the reference range. Approximately half of the patients with SMID on tube feeding had subclinical vitamin K deficiency. Further studies are needed to ascertain if long-term vitamin K2 supplementation effectively prevents vitamin K deficiency-induced hypercoagulation, osteoporosis, and vascular calcification in patients with SMID.

Topics: Adult; Biomarkers; Dietary Supplements; Enteral Nutrition; Female; Humans; Intellectual Disability; Male; Osteocalcin; Prothrombin; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

Hyperphosphataemia is strongly associated with cardiovascular disease and mortality. Recently, phosphate binders (PBs), which are used to bind intestinal phosphate, have been shown to bind vitamin K, thereby potentially aggravating vitamin K deficiency. This vitamin K binding by PBs may offset the beneficial effects of phosphate reduction in reducing vascular calcification (VC). Here we assessed whether combining PBs with vitamin K2 supplementation inhibits VC.. We performed 3/4 nephrectomy in rats, after which warfarin was given for 3 weeks to induce vitamin K deficiency. Next, animals were fed a high phosphate diet in the presence of low or high vitamin K2 and were randomized to either control or one of four different PBs for 8 weeks. The primary outcome was the amount of thoracic and abdominal aorta VC measured by high-resolution micro-computed tomography (µCT). Vitamin K status was measured by plasma MK7 levels and immunohistochemically analysed in vasculature using uncarboxylated matrix Gla protein (ucMGP) specific antibodies.. The combination of a high vitamin K2 diet and PB treatment significantly reduced VC as measured by µCT for both the thoracic (P = 0.026) and abdominal aorta (P = 0.023), compared with MK7 or PB treatment alone. UcMGP stain was significantly more present in the low vitamin K2-treated groups in both the thoracic (P < 0.01) and abdominal aorta (P < 0.01) as compared with high vitamin K2-treated groups. Moreover, a high vitamin K diet and PBs led to reduced vascular oxidative stress.. In an animal model of kidney failure with vitamin K deficiency, neither PB therapy nor vitamin K2 supplementation alone prevented VC. However, the combination of high vitamin K2 with PB treatment significantly attenuated VC.

Topics: Animals; Calcium-Binding Proteins; Extracellular Matrix Proteins; Female; Male; Models, Animal; Phosphates; Rats; Renal Dialysis; Renal Insufficiency; Vascular Calcification; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency; X-Ray Microtomography

Chronic kidney disease (CKD) is accompanied with extensive cardiovascular calcification, in part correlating with functional vitamin K deficiency. Here, we sought to determine causes for vitamin K deficiency beyond reduced dietary intake. Initially, vitamin K uptake and distribution into circulating lipoproteins after a single administration of vitamin K1 plus K2 (menaquinone 4 and menaquinone 7, respectively) was determined in patients on dialysis therapy and healthy individuals. The patients incorporated very little menaquinone 7 but more menaquinone 4 into high density lipoprotein (HDL) and low-density lipoprotein particles than did healthy individuals. In contrast to healthy persons, HDL particles from the patients could not be spiked with menaquinone 7 in vitro and HDL uptake was diminished in osteoblasts. A reduced carboxylation activity (low vitamin K activity) of uremic HDL particles spiked with menaquinone 7 vs. that of controls was confirmed in a bioassay using human primary vascular smooth muscle cells. Kidney menaquinone 4 tissue levels were reduced in 5/6-nephrectomized versus sham-operated C57BL/6 mice after four weeks of a vitamin K rich diet. From the analyzed enzymes involved in vitamin K metabolism, kidney HMG-CoA reductase protein was reduced in both rats and patients with CKD. In a trial on the efficacy and safety of atorvastatin in 1051 patients with type 2 diabetes receiving dialysis therapy, no pronounced vitamin K deficiency was noted. However, the highest levels of PIVKA-II (biomarker of subclinical vitamin K deficiency) were noted when a statin was combined with a proton pump inhibitor. Thus, profound disturbances in lipoprotein mediated vitamin K transport and metabolism in uremia suggest that menaquinone 7 supplementation to patients on dialysis therapy has reduced efficacy.

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Mice; Mice, Inbred C57BL; Rats; Renal Insufficiency, Chronic; Tissue Distribution; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

There is near-global consensus that all newborns be given parenteral vitamin K. To assess the prevalence of functional VK insufficiency in preterm infants based on elevated under-γ-carboxylated (Glu) species of Gla proteins, factor II (PIVKA-II), and osteocalcin (GluOC), synthesized by liver and bone, respectively.. Preterm infants who remain exclusively or predominantly human breastmilk-fed after neonatal unit discharge are at high risk of developing subclinical VK deficiency in early infancy. Routine postdischarge VK

Topics: Aftercare; Hemorrhage; Humans; Infant; Infant, Newborn; Infant, Premature; Milk, Human; Patient Discharge; Prospective Studies; Vitamin K; Vitamin K 1; Vitamin K Deficiency

Chronic kidney disease (CKD) commonly occurs with vitamin K (VK) deficiency and impaired bone mineralization. However, there are no data explaining the metabolism of endogenous VK and its role in bone mineralization in CKD. In this study, we measured serum levels of phylloquinone (VK1), menaquinone 4 and 7 (MK4, MK7), and VK-dependent proteins: osteocalcin, undercarboxylated osteocalcin (Glu-OC), and undercarboxylated matrix Gla protein (ucMGP). The carboxylated osteocalcin (Gla-OC), Glu-OC, and the expression of genes involved in VK cycle were determined in bone. The obtained results were juxtaposed with the bone mineral status of rats with CKD. The obtained results suggest that the reduced VK1 level observed in CKD rats may be caused by the accelerated conversion of VK1 to the form of menaquinones. The bone tissue possesses all enzymes, enabling the conversion of VK1 to menaquinones and VK recycling. However, in the course of CKD with hyperparathyroidism, the intensified osteoblastogenesis causes the generation of immature osteoblasts with impaired mineralization. The particular clinical significance seems to have a finding that serum osteocalcin and Glu-OC, commonly used biomarkers of VK deficiency, could be inappropriate in CKD conditions, whereas Gla-OC synthesized in bone appears to have an adverse impact on bone mineral status in this model.

Topics: Animals; Biomarkers; Bone and Bones; Minerals; Osteocalcin; Rats; Renal Insufficiency, Chronic; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

Vitamin K, especially its K2 form, is considered to be a protective factor against developing vascular changes and bone lesions that are common complications in kidney transplant (KTx) recipients. There is a growing number of studies showing that KTx patients are at risk of vitamin K deficiency. The aim of this study was to evaluate the intake of vitamin K1 and K2 in the diet of patients in the late period after KTx. During a routine visit at one outpatient transplantation clinic in Central Europe, a diet survey questionnaire was filled in by 151 clinically stable KTx recipients and compared with medical history, anthropometric measurements and laboratory tests. Mean vitamin K1 intake was 120.9 ± 49 μg/day and vitamin K2 (MK, menaquinone) intake 28.69 ± 11.36 μg/day, including: MK-4: 25.9 ± 9.9 μg/day; MK-5: 0.1 ± 0.2 μg/day; MK-6: 0.2 ± 0.4 μg/day; MK-7: 0.2 ± 0.23 μg/day; MK-8: 1 ± 1.9 μg/day; MK-9: 0.9 ± 2.3 μg/day; and MK-10: 0.2 ± 0.5 μg/day. Our study showed that KTx recipients' diets contained adequate amounts of vitamin K1, whereas the intake of vitamin K2 seemed insufficient.

Topics: Diet; Humans; Kidney Transplantation; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

Vitamin K is a fat-soluble vitamin that plays an important role in blood coagulation and bone formation. Vitamin K has homologues due to differences in the side chain structure, phylloquinone (abbreviated as vitamin K

Topics: Animals; Blood Coagulation; Dimethylallyltranstransferase; Humans; Mice, Knockout; Neurodegenerative Diseases; Osteogenesis; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

Infection with

Topics: Amino Acids; Anemia; Animals; Anti-Bacterial Agents; Bacteria; Diet; Dietary Supplements; Dysbiosis; Folic Acid; Food, Formulated; Gastrointestinal Hemorrhage; Gastrointestinal Microbiome; Helicobacter Infections; Helicobacter pylori; Liver; Male; Mice; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

Vitamin K (VK) is a co-factor in the post-translational gamma glutamic carboxylation of Gla-proteins. VK-dependent coagulation factors are carboxylated in the liver by VK1. Osteocalcin and Matrix-Gla protein (MGP) are carboxylated in extrahepatic tissues by VK2. A model of VK deficiency would be suitable for studying extrahepatic Gla-proteins provided that severe bleeding is prevented.. The aim of this work was to adapt an established protocol of vascular calcification by warfarin-induced inactivation of MGP as a calcification inhibitor, in an attempt to create a broader state of subclinical VK deficiency and to verify its safety.. Two consecutive experiments, each lasting 4 weeks, were required to modify the dosing schedule of warfa-rin and VK1 and to adapt it to the Wistar rats used. The original high doses of warfarin used initially had to be halved and the protective dose of VK1 to be doubled, in order to avoid treatment-induced hemorrhagic deaths. The second experiment aimed to confirm the efficacy and safety of the modified doses. To verify the VK deficiency, blood vessels were examined histologically for calcium deposits and serum osteocalcin levels were mea-sured.. The original dosing schedule induced VK deficiency, manifested by arterial calcifications and dramatic changes in carboxyl-ated and uncarboxylated osteocalcin. The modified dosing regimen caused similar vascular calcification and no bleeding.. The modified protocol of carefully balanced warfarin and VK1 doses is an effective and safe way to induce subclinical VK deficiency that can be implemented to investigate VK-dependent proteins like osteocalcin.

Topics: Animals; Anticoagulants; Antifibrinolytic Agents; Arteries; Asymptomatic Diseases; Calcium-Binding Proteins; Carbon-Carbon Ligases; Disease Models, Animal; Extracellular Matrix Proteins; Matrix Gla Protein; Osteocalcin; Rats; Vascular Calcification; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency; Warfarin

In the article intended for neonatologists, general practitioners and family doctors, the main causes of hemostatic disorders that lead to the development of hemorrhagic syndrome in newborns and infants are given. The emphasis is on the different forms of neonatal hemorrhagic disease (HD), which is based on the deficiency of vitamin K1, and therefore the bleeding that is observed in children who are breastfed in the first half of life is mostly associated, namely, with vitamin K deficiency. Risk factors of HD depending from the time of the beginning, of the action of one or another factor. The main clinical manifestations of both early and late forms of HD are described, it is shown which of them are mistakenly diagnosed that lead to the appointment of the wrong treatment. The assessment of the need for prevention of late form of bleeding associated with vitamin K deficiency is carried out by determining the concentration in the blood of a functional coagulation marker - PIVKA II. Modern methods of prevention of late bleeding associated with vitamin K1 deficiency, based on nosological units - chronic cholestasis, cystic fibrosis, are presented. The current recommendations on the use of vitamin K1 in newborns and infants of the American Academy of Pediatrics, the scientific community of Canada, Netherlands, Switzerland, Germany, France, the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), the World Health Organization, which are clearly followed by the effects of local peculiarities are described and interpreted. on approaches to the prevention of bleeding associated with vitamin K1 deficiency, which affects the choice of a single dose, the duration of the prophylactic course and the route of administration of vitamin in K1 (phytomenadion). The role of parents in the prevention of vitamin K deficiency is emphasized.

Topics: Breast Feeding; Child; Female; Germany; Humans; Infant; Infant, Newborn; Male; Treatment Outcome; Vitamin K; Vitamin K 1; Vitamin K Deficiency; Vitamin K Deficiency Bleeding

In children diagnosed with celiac disease, fat soluble vitamin levels were aimed to be evaluated and it was intended to determine whether fat soluble vitamin levels were needed to be assessed routinely in these patients during diagnosis.. Between May 2015-May 2016, diagnosis symptoms of celiac patients (CD) in newly diagnosed pediatric group were questioned, fat soluble vitamin levels simultaneous with intestinal biopsies were evaluated. Vitamin levels were compared with those of healthy control group.. A total of 52 patients involving 27 female (51.9%), 25 male (48.1%); and a total of 50 healthy control group including 25 female (50%), 25 male (50%) were evaluated. The average age of patients was 9 ± 4.3 years, and their average weight was determined as 16.2 ± 6.3 kg. Growth retardation was the most frequent symptom in our patients (61.5%). Abdominal pain (51.9%) and diarrhea (11.5%) are among the other most commonly seen symptoms. In the histological examination of patients, Marsh 3B n = 23 (45.1%) was mostly established. Vitamin A and vitamin D levels of patients were determined significantly lower compared to those of control group. Vitamin A and vitamin D deficiencies were identified significantly higher compared to those of healthy control group. Vitamin D insufficiency was observed in 48 patients (92.3%) and vitamin D deficiency was determined in 32 (61.5%) out of 48. Vitamin A deficiency was established in 17 (32.7%) patients. Vitamin E and vitamin K1 deficiency were determined in no patients. In the healthy control group, vitamin D deficiency was seen in 2 (4%) patients, vitamin D insufficiency was determined in 9 (18%) patients. Other vitamin levels were identified at normal levels in the healthy group.. In newly diagnosed children with CD, a significant lowness was established in vitamin D and A. The evaluation of vitamin A and D levels will be helpful in the course of diagnosis in these patients.

Topics: Adolescent; Avitaminosis; Case-Control Studies; Celiac Disease; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Intestines; Male; Vitamin A Deficiency; Vitamin D Deficiency; Vitamin E Deficiency; Vitamin K 1; Vitamin K Deficiency

Previous studies have shown that α-tocopherol intake lowers phylloquinone (PK) concentration in some extrahepatic tissues in rats. The study's aim was to clarify the effect of α-tocopherol intake on vitamin K concentration in bone, as well as the physiological action of vitamin K. Male Wistar rats were divided into 4 groups. Over a 3-mo period, the K-free group was fed a vitamin K-free diet with 50 mg RRR-α-tocopherol/kg, the E-free group was fed a diet containing 0.75 mg PK/kg without vitamin E, the control group was fed a diet containing 0.75 mg PK/kg with 50 mg RRR-α-tocopherol/kg, and the E-excess group was fed a diet containing 0.75 mg PK/kg with 500 mg RRR-α-tocopherol/kg. PK concentration in the liver was higher in E-excess rats than in E-free rats, was lower in the tibias of control rats than in those of E-free rats, and was lower in E-excess rats than in control rats. Menaquinone-4 (MK-4) concentration in the liver was higher in E-excess rats than in E-free and control rats. However, MK-4 concentrations in the tibias of E-free, control, and E-excess rats were almost the same. Blood coagulation activity was lower in K-free rats than in the other rats but was not affected by the level of α-tocopherol intake. Additionally, dietary intake of PK and α-tocopherol did not affect uncarboxylated-osteocalcin concentration in the serum, femur density, or expression of the genes related to bone resorption and formation in the femur. These results suggest that α-tocopherol intake decreases PK concentration in bone but does not affect bone metabolism in rats.

Topics: alpha-Tocopherol; Animals; Biomarkers; Bone and Bones; Bone Density; Bone Development; Diet; Dietary Supplements; Energy Metabolism; Gene Expression Regulation, Developmental; Liver; Male; Organ Specificity; Osteocalcin; Rats, Wistar; Specific Pathogen-Free Organisms; Tibia; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency; Vitamin K Deficiency Bleeding; Weight Gain

We have reported that vitamin E intake lowers phylloquinone (PK) concentration in extrahepatic tissues of rats. In this study, we aimed to clarify the characteristic of the distribution of menaquinone-7 (MK-7), a vitamin K contained in fermented foods, by comparison with other vitamin K distributions and to clarify the effect of vitamin E intake on MK-7 concentration in rats. Rats were fed a vitamin K-free diet (Free group), a diet containing 0.75 mg PK/kg (PK group), a 0.74 mg menaquinone-4 (MK-4)/kg diet (MK-4 group), a 1.08 mg MK-7/kg diet (MK-7 group), or a 0.29 mg menadione (MD)/kg diet (MD group) for 16 wk. MK-7 mainly accumulated in the liver, spleen, and adrenal gland of the MK-7 group, although PK accumulated in the serum and all tissues of the PK group. Conversely, MK-4 was present in all tissues of the PK, MK-4, MK-7, and MD groups. MK-4 concentration in the serum, liver, adipose tissue, and spleen was higher in the MK-4 group than in the other groups; however, MK-4 concentration in the kidney, testis, tibia, and brain was lower in the MK-4 group than in the PK, MK-7, and MD groups. Next, vitamin E- and K-deficient rats were orally administered MK-7 with or without α-tocopherol. α-Tocopherol did not affect MK-7 or MK-4 concentration in the serum and various tissues. These results suggested that MK-7 is particularly liable to accumulate in the liver, and MK-7 concentration is not affected by vitamin E intake.

Topics: alpha-Tocopherol; Animals; Diet; Fermented Foods; Liver; Male; Nutritional Status; Rats, Wistar; Tissue Distribution; Vitamin K 1; Vitamin K 2; Vitamin K 3; Vitamin K Deficiency

Vitamin K1 injection induces severe dose-related anaphylactoid reactions and overdose for the treatment of vitamin K deficiency. We aimed to find an optimal and small dose of vitamin K1 injection to treat vitamin K deficiency and avoid anaphylactoid reactions in animal. Rats were administered a vitamin K-deficient diet and gentamicin to establish vitamin K deficiency model. Behaviour tests were performed in beagle dogs to observe anaphylactoid reactions. The results showed an increased protein induced by vitamin K absence or antagonist II (PIVKA-II) levels, a prolonging of prothrombin time (PT) and activated partial thromboplastin time (APTT) and a decrease in vitamin K-dependent coagulation factor (F) II, VII, IX and X activities in the model group. In vitamin K1 0.01 mg/kg group, the liver vitamin K1 levels increased fivefold and the liver vitamin K2 levels increased to the normal amount. Coagulation markers PT, APTT, FVII and FIX activities returned to normal. Both in the 0.1 and 1.0 mg/kg vitamin K1 groups, coagulation functions completely returned to normal. Moreover, the amount of liver vitamin K1 was 40 (0.1 mg/kg) or 100 (1.0 mg/kg) times as in normal. Vitamin K2 was about 4 (0.1 mg/kg) or 5 (1.0 mg/kg) times as the normal amount. There was no obvious anaphylactoid symptom in dogs with the dose of 0.03 mg/kg, which is equivalent to the dose of 0.01 mg/kg in rats. These results demonstrated that a small dose of vitamin K1 is effective to improve vitamin K deficiency and to prevent anaphylactoid reactions, simultaneously.

Topics: Anaphylaxis; Animals; Blood Coagulation; Dose-Response Relationship, Drug; Female; Male; Rats; Rats, Sprague-Dawley; Vitamin K 1; Vitamin K Deficiency

Vitamin K acts as a coenzyme in the γ-carboxylation of vitamin K-dependent proteins, including coagulation factors, osteocalcin, matrix Gla protein (MGP), and the growth arrest-specific 6 (GAS6) protein. Osteocalcin is a key factor for bone matrix formation. MGP is a local inhibitor of soft tissue calcification. GAS6 activity prevents the apoptosis of vascular smooth muscle cells. Few data on vitamin K intake in chronic kidney disease patients and no data in patients on a Mediterranean diet are available. In the present study, we evaluate the dietary intake of vitamin K1 in a cohort of patients undergoing haemodialysis.. In this multi-centre controlled observational study, data were collected from 91 patients aged >18 years on dialysis treatment for at least 12 months and from 85 age-matched control subjects with normal renal function. Participants completed a food journal of seven consecutive days for the estimation of dietary intakes of macro- and micro-nutrients (minerals and vitamins).. Compared to controls, dialysis patients had a significant lower total energy intake, along with a lower dietary intake of proteins, fats, carbohydrates, fibres, and of all the examined minerals (Ca, P, Fe, Na, K, Zn, Cu, and Mg). With the exception of vitamin B12, vitamins intake followed a similar pattern, with a lower intake in vitamin A, B1, B2, C, D, E, folates, K1 and PP. These finding were confirmed also when normalized for total energy intake or for body weight. In respect to the adequate intakes recommended in the literature, the prevalence of a deficient vitamin K intake was very high (70-90%) and roughly double than in controls. Multivariate logistic model identified vitamin A and iron intake as predictors of vitamin K deficiency.. Haemodialysis patients had a significantly low intake in vitamin K1, which could contribute to increase the risk of bone fractures and vascular calcifications. Since the deficiency of vitamin K intake seems to be remarkable, dietary counselling to HD patients should also address the adequacy of vitamin K dietary intake and bioavailability. Whether diets with higher amounts of vitamin K1 or vitamin K supplementation can improve clinical outcomes in dialysis patients remains to be demonstrated.

Topics: Aged; Body Mass Index; Case-Control Studies; Diet; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Female; Humans; Male; Micronutrients; Middle Aged; Nutrition Assessment; Nutritional Status; Prevalence; Recommended Dietary Allowances; Renal Dialysis; Renal Insufficiency, Chronic; Retrospective Studies; Vitamin K 1; Vitamin K Deficiency; Waist Circumference

The present study investigated the risk of incident hip fractures according to serum concentrations of vitamin K1 and 25-hydroxyvitamin D in elderly Norwegians during long-term follow-up. The results showed that the combination of low concentrations of both vitamin D and K1 provides a significant risk factor for hip fractures.. This case-cohort study aims to investigate the associations between serum vitamin K1 and hip fracture and the possible effect of 25-hydroxyvitamin D (25(OH)D) on this association.. The source cohort was 21,774 men and women aged 65 to 79 years who attended Norwegian community-based health studies during 1994-2001. Hip fractures were identified through hospital registers during median follow-up of 8.2 years. Vitamins were determined in serum obtained at baseline in all hip fracture cases (n = 1090) and in a randomly selected subcohort (n = 1318). Cox proportional hazards regression with quartiles of serum vitamin K1 as explanatory variable was performed. Analyses were further performed with the following four groups as explanatory variable: I: vitamin K1 ≥ 0.76 and 25(OH)D ≥ 50 nmol/l, II: vitamin K1 ≥ 0.76 and 25(OH)D < 50 nmol/l, III: vitamin K1 < 0.76 and 25(OH)D ≥ 50 nmol/l, and IV: vitamin K1 < 0.76 and 25(OH)D < 50 nmol/l.. Age- and sex-adjusted analyses revealed an inverse association between quartiles of vitamin K1 and the risk of hip fracture. Further, a 50 % higher risk of hip fracture was observed in subjects with both low vitamin K1 and 25(OH)D compared with subjects with high vitamin K1 and 25(OH)D (HR 1.50, 95 % CI 1.18-1.90). The association remained statistically significant after adjusting for body mass index, smoking, triglycerides, and serum α-tocopherol. No increased risk was observed in the groups low in one vitamin only.. Combination of low concentrations of vitamin K1 and 25(OH)D is associated with increased risk of hip fractures.

Topics: Aged; Cohort Studies; Female; Follow-Up Studies; Hip Fractures; Humans; Male; Norway; Risk Factors; Vitamin D; Vitamin D Deficiency; Vitamin K 1; Vitamin K Deficiency

Functional vitamin K deficiency (both K1 and K2) is postulated to be one of the most relevant links between chronic kidney disease and vascular calcification in hemodialysis (HD) patients. Recommended dietary restrictions in HD patients superimposed on diversity of eating habits across the countries may affect the prevalence of functional vitamin K deficiency. The aim of this study was to determine the level of functional vitamin K deficiency and its relation to vitamin K1 intake in HD patients in Upper Silesia in Poland.. Protein-induced vitamin K absence or antagonist-II (PIVKA-II) and undercarboxylated matrix Gla protein (ucMGP) were assessed by ELISA in 153 stable, prevalent HD patients and 20 apparently healthy adults (to establish normal ranges for PIVKA-II and ucMGP). Daily phylloquinone intake was assessed using a food frequency questionnaire.. PIVKA-II and ucMGP levels were increased in 27.5 and 77.1 % of HD patients in comparison with the reference ranges in apparently healthy controls, respectively. In 45 % of cases, the increased PIVKA-II level was explained by insufficient phylloquinone intake for Polish population (recommended intake: >55 μg for women and >65 µg for men). Applying ROC analysis, we showed that vitamin K1 intake below 40.2 µg/day was associated with increased PIVKA-II levels. There was no correlation between vitamin K1 intake and plasma concentration of ucMGP, or between PIVKA-II and ucMGP.. (1) Functional vitamin K1 deficiency is explained by low vitamin K1 intake in less than half of HD patients. (2) Undercarboxylated matrix Gla protein level is a poor surrogate for functional vitamin K1 deficiency.

Topics: Biomarkers; Calcium-Binding Proteins; Case-Control Studies; Diet; Extracellular Matrix Proteins; Female; Humans; Male; Matrix Gla Protein; Middle Aged; Poland; Protein Precursors; Prothrombin; Renal Dialysis; Renal Insufficiency, Chronic; ROC Curve; Vitamin K 1; Vitamin K Deficiency

The main vitamin K-deficient model, minidose warfarin, is different from the pathological mechanism of vitamin K deficiency, which is a shortage of vitamin K. The objective of this study was to establish a new method of vitamin K-deficient model combining a vitamin K-deficient diet with the intragastrical administration of gentamicin in rats. The clotting was assayed by an automated coagulation analyser. The plasma PIVKA-II was assayed by ELISA. The vitamin K status was detected by an HPLC-fluorescence system. In the diet- and gentamicin-induced vitamin K-deficient 14-day group, the rats had undetected vitamin K1 and vitamin K2 in the liver and a prolonged APTT. In the 21-day group, there was also a prolonged PT and a decrease of the FIX activities. In the 28-day group, the undetected vitamin K1 and vitamin K2, the prolonged PT and APTT, and the decrease of the FII, FVII, FIX, and FX activities prompted the suggestion that there were serious deficiencies of vitamin K and vitamin K-dependent coagulation in rats. It is suggested that the diet- and gentamicin-induced vitamin K-deficient 14-day or 21-day model can be used for studies related to the status of vitamin K. The vitamin K-deficient 28-day model can be applied to research involving both the status of vitamin K and of vitamin K-dependent coagulation. In conclusion, the combination of a vitamin K-deficient diet with the administration of gentamicin results in a useful model of vitamin K-deficieny.

Topics: Animals; Blood Coagulation; Blood Coagulation Factors; Blood Coagulation Tests; Diet; Disease Models, Animal; Female; Gentamicins; Liver; Male; Partial Thromboplastin Time; Prothrombin Time; Rats, Sprague-Dawley; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

There has been limited characterization of biological variables that impact vitamin K metabolism. This gap in knowledge can limit the translation of data obtained from preclinical animal studies to future human studies.. The purpose of this study was to determine the effects of diet, sex, and housing on serum, tissue, and fecal vitamin K concentrations and gene expression in C57BL6 mice during dietary vitamin K manipulation.. C57BL6 4-mo-old male and female mice were randomly assigned to conventional or suspended-wire cages and fed control [1400 ± 80 μg phylloquinone (PK)/kg] or deficient (31 ± 0.45 μg PK/kg) diets for 28 d in a factorial design. PK and menaquinone (MK) 4 plasma and tissue concentrations were measured by HPLC. Long-chain MKs were measured in all matrices by LC-atmospheric pressure chemical ionization-mass spectrometry. Gene expression was quantified by reverse transcriptase-polymerase chain reaction in the liver, brain, kidney, pancreas, and adipose tissue.. Male and female mice responded differently to dietary manipulation in a tissue-dependent manner. In mice fed the control diet, females had ∼3-fold more MK4 in the brain and mesenteric adipose tissue than did males and 100% greater PK concentrations in the liver, kidney, and mesenteric adipose tissue than did males. In mice fed the deficient diet, kidney MK4 concentrations were ∼4-fold greater in females than in males, and there were no differences in other tissues. Males and females differed in the expression of vitamin K expoxide reductase complex 1 (Vkorc1) in mesenteric adipose tissue and the pancreas and ubiA domain-containing protein 1 (Ubiad1) in the kidney and brain. There was no effect of housing on serum, tissue, or fecal concentrations of any vitamin K form.. Vitamin K concentrations and expression of key metabolic enzymes differ between male and female mice and in response to the dietary PK concentration. Identifying factors that may impact study design and outcomes of interest is critical to optimize study parameters examining vitamin K metabolism in animal models.

Topics: Adipose Tissue; Animals; Brain; Diet; Dimethylallyltranstransferase; Female; Housing; Housing, Animal; Kidney; Liver; Male; Membrane Proteins; Mesentery; Mice, Inbred C57BL; Pancreas; Sex Factors; Tissue Distribution; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency; Vitamin K Epoxide Reductases

Vitamin K-dependent (VKD) proteins, including the mineralization inhibitor matrix-gla protein (MGP), are found in joint tissues including cartilage and bone. Previous studies suggest low vitamin K status is associated with higher osteoarthritis (OA) prevalence and incidence.. To clarify what joint tissues vitamin K is relevant to in OA, we investigated the cross-sectional and longitudinal association between vitamin K status and knee OA structural features measured using magnetic resonance imaging (MRI).. Plasma phylloquinone (PK, vitamin K1) and dephosphorylated-uncarboxylated MGP ((dp)ucMGP) were measured in 791 older community-dwelling adults who had bilateral knee MRIs (mean ± SD age = 74 ± 3 y; 67% female). The adjusted odds ratios (and 95% confidence intervals) [OR (95%CI)] for presence and progression of knee OA features according to vitamin K status were calculated using marginal models with generalized estimating equations (GEEs), adjusted for age, sex, body mass index (BMI), triglycerides and other pertinent confounders.. Longitudinally, participants with very low plasma PK (<0.2 nM) were more likely to have articular cartilage and meniscus damage progression after 3 years [OR (95% CIs): 1.7(1.0-3.0), 2.6(1.3-5.2) respectively] compared to sufficient PK (≥ 1.0 nM). Higher plasma (dp)ucMGP (reflective of lower vitamin K status) was associated with higher odds of meniscus damage, osteophytes, bone marrow lesions, and subarticular cysts cross-sectionally [ORs (95% CIs) comparing highest to lowest quartile: 1.6(1.1-2.3); 1.7(1.1-2.5); 1.9(1.3-2.8); 1.5(1.0-2.1), respectively].. Community-dwelling men and women with very low plasma PK were more likely to have progression of articular cartilage and meniscus damage. Plasma (dp)ucMGP was associated with presence of knee OA features but not progression. Future studies are needed to clarify mechanisms underlying vitamin Ks role in OA.

Topics: Aged; Calcium-Binding Proteins; Cartilage, Articular; Cohort Studies; Cross-Sectional Studies; Decarboxylation; Disease Progression; Extracellular Matrix Proteins; Female; Humans; Incidence; Longitudinal Studies; Magnetic Resonance Imaging; Male; Matrix Gla Protein; Menisci, Tibial; Odds Ratio; Osteoarthritis, Knee; Osteophyte; Phosphorylation; Vitamin K 1; Vitamin K Deficiency

All newborns require phylloquinone after birth to prevent vitamin K deficiency bleeding. Babies born prematurely may be at particular risk of deficiency without adequate supplementation during infancy. The main sources of phylloquinone in preterm babies during the neonatal period are the prophylactic dose of phylloquinone given at birth, and that derived from parenteral and/or enteral feeding. This observational study formed part of a prospective, multicentre, randomised, controlled trial that examined the vitamin K status of preterm infants after random allocation to one of three phylloquinone prophylactic regimens at birth (0.5 or 0.2 mg intramuscularly or 0.2 mg intravenously). In this nutritional sub-study we quantified the proportional and total phylloquinone intakes of preterm infants within the neonatal period from all sources. Almost all infants had average daily phylloquinone intakes that were in excess of the currently recommended amounts. In infants who did not receive parenteral nutrition, the bolus dose of phylloquinone given at birth was the major source of phylloquinone intake, whereas in infants who received parenteral nutrition, the intake from the parenteral preparation exceeded that from the bolus dose by a ratio of approximately 3:1. Our study supports the concern of others that preterm infants who receive current parenteral nutrition formulations may be receiving excessive vitamin K.

Topics: Enteral Nutrition; Gestational Age; Humans; Infant Nutritional Physiological Phenomena; Infant, Newborn; Infant, Premature; Parenteral Nutrition; Recommended Dietary Allowances; Vitamin K 1; Vitamin K Deficiency

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.

Topics: Animals; Aorta; Calcinosis; Calcium-Binding Proteins; Carbon-Carbon Ligases; Extracellular Matrix Proteins; Kidney; Liver; Male; Matrix Gla Protein; NAD(P)H Dehydrogenase (Quinone); Rats; Rats, Wistar; Uremia; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

The effects of vitamin E on vitamin K metabolism were elucidated by comparing the effect of tocopherol intake on vitamin K concentrations in rats fed phylloquinone (PK) or menaquinone (MK)-4.. Initially, the dietary effect of RRR-α-tocopherol, but not RRR-γ-tocopherol, in decreasing extrahepatic PK concentrations was confirmed. Subsequently, rats were fed a PK or MK-4-containing diet (0.75 mg/kg) with RRR-α-tocopherol (0, 10, 50, or 500 mg/kg) for 6 weeks. In rats fed PK, α-tocopherol consumption decreased PK in kidney, lung, heart, muscle, testis, and brain but not in serum and liver. However, in rats fed MK-4, α-tocopherol consumption did not decrease MK-4 in serum and tissues. Finally, vitamin K- and E-depleted rats were administered PK or MK-4 (0.2 mg) with RRR-α-tocopherol (0, 1, or 10 mg) by gavage. After PK administration, α-tocopherol was observed to decrease PK in kidney, adrenal gland, lung, testis, and brain but not in serum and liver, whereas, after MK-4 administration, α-tocopherol did not affect MK-4 in serum and tissues.. Excess α-tocopherol decreased extrahepatic PK in rats fed PK but not MK-4 in rats fed MK-4.

Topics: alpha-Tocopherol; Animals; Dietary Supplements; Down-Regulation; gamma-Tocopherol; Male; Organ Specificity; Rats, Wistar; Specific Pathogen-Free Organisms; Vitamin E Deficiency; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

The influence of excess α-tocopherol (α-T) on tissue depletion of phylloquinone (PK) and menaquinone-4 (MK-4) was evaluated.. Rats (n = 5 per group) were fed deuterium-labeled PK (2 μmol/kg diet) for 17 days, thereby labeling the conversion from deuterium-labeled PK to d₄-MK-4. Then they were injected subcutaneously daily for the last 7 days with saline, vehicle, or α-T (100 mg/kg body weight). α-T injections (i) increased α-T concentrations by tenfold in liver, doubled them in plasma and most tissues, but they were unchanged in brain; (ii) increased the α-T metabolite, carboxyethyl hydroxychromanol (α-CEHC) concentrations: >25-fold in liver and kidney, tenfold in plasma and lung, and 50-fold in heart; brain contained detectable α-CEHC (0.26 ± 0.03 nmol/g) only in α-T-injected animals; and (iii) depleted most tissues' vitamin K. Compared with vehicle-injected rats, brains from α-T rats contained half the total vitamin K (10.3 ± 0.5 versus 21 ± 2 pmol/g, p = 0.0002) and one-third the d₄-MK-4 (5.8 ± 0.5 versus 14.6 ± 1.7 pmol/g, p = 0.0002). Tissues with high PK concentrations (liver, 21-30 pmol/g and heart, 28-50 pmol/g) were resistant to K depletion.. We propose that α-T-dependent vitamin K depletion is likely mediated at an intermediate step in MK-4 production; thus, tissues with high PK are unaffected.

Topics: alpha-Tocopherol; Animals; Biotransformation; Brain; Deuterium; Injections, Subcutaneous; Kidney; Liver; Male; Neurons; Organ Specificity; Rats, Sprague-Dawley; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency; Vitamins

Early infant (1-60 days of life) male circumcision is being trialed in Africa as a human immunodeficiency virus prevention strategy. Postcircumcision bleeding is particularly concerning where most infants are breastfed, and thus these infants are at increased risk of vitamin K deficiency bleeding.. During a circumcision trial, one infant bled for 90 minutes postprocedure. After discovering he had not received standard prophylactic vitamin K, we gave 2 mg phytomenadione (vitamin K1) intramuscularly; bleeding stopped within 30 minutes.. Vitamin K's extremely rapid action is not commonly appreciated. Neonatal vitamin K has been shown to be cost-effective. To increase availability and promote awareness of its importance, especially in low-resource settings where blood products and transfusions are limited, vitamin K should be included in the World Health Organization's Model List of Essential Medicines for Children.

Topics: Africa; Circumcision, Male; Hemorrhage; Humans; Infant, Newborn; Male; Vitamin K 1; Vitamin K Deficiency; Vitamins

This study examined the relationships among ethnicity/race, lifestyle factors, phylloquinone (vitamin K₁) intake, and arterial pulse pressure in a nationally representative sample of older adults from four ethnic/racial groups: non-Hispanic Whites, non-Hispanic Blacks, Mexican Americans, and other Hispanics. This was a cross-sectional study of U.S. representative sample with data from the National Health and Nutrition Examination Surveys, 2007-2008 and 2009-2010 of adults aged 50 years and older (N = 5296). Vitamin K intake was determined by 24-hour recall. Pulse pressure was calculated as the difference between the averages of systolic blood pressure and diastolic blood pressure. Compared to White non-Hispanics, the other ethnic/racial groups were more likely to have inadequate vitamin K₁ intake. Inadequate vitamin K₁ intake was an independent predictor of high arterial pulse pressure. This was the first study that compared vitamin K₁ inadequacy with arterial pulse pressure across ethnicities/races in U.S. older adults. These findings suggest that vitamin K screening may be a beneficial marker for the health of older adults.

Topics: Aged; Aged, 80 and over; Biomarkers; Blood Pressure; Cross-Sectional Studies; Diet; Ethnicity; Female; Humans; Male; Mental Recall; Middle Aged; Nutrition Assessment; Nutrition Surveys; Racial Groups; United States; Vascular Stiffness; Vitamin K 1; Vitamin K Deficiency; Vitamins

Coronary artery calcification is a recognised risk factor for ischaemic heart disease and mortality. Evidence is now strong that Mönckeberg's arteriosclerosis, a form of vascular calcification, can be attributable to vitamin K deficiency, but that vitamin K-2, especially the MK-4 form from foods like cheese can be protective. Warfarin blocks the recycling of hepatic and peripheral vitamin K leading to secondary vitamin K deficiency with adverse effects on vasculature, bone, kidneys, brain and other tissues and systems (inflammatory, immune function and neoplasia at least). There is individual susceptibility to vitamin K deficiency and warfarin sensitivity, partly explicable in terms of genetic polymorphisms, epigenetics, diet and pharmacotherapy. The emergence of extensive coronary calcification in a man with atrial fibrillation treated for a decade with warfarin is described by way of illustration and to raise the present clinical management conundrums. Finally, a putative set of recommendations is provided.

Topics: Calcinosis; Coronary Artery Disease; Diet; Factor Xa Inhibitors; Humans; Male; Middle Aged; Monckeberg Medial Calcific Sclerosis; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency; Warfarin

It has been demonstrated that single nucleotide polymorphism (SNP) (R325Q, 974G>A) in the gamma-glutamyl carboxylase (GGCX) gene is associated with the bone mineral density (BMD). In the present study, we investigated the effect of GGCX polymorphism (974G>A) on the correlations among the vitamin K in-take, level of serum vitamin K, and ratio of undercarboxylated osteocalcin (ucOC) to intact osteocalcin (OC) in healthy young Japanese subjects.. Healthy young adult subjects (n=189) were genotyped for the poly-morphism, and we measured the levels of serum vitamin K, intact OC, ucOC, and dietary nutrient intakes.. Dietary vitamin K intake from vegetables was significantly correlated with the level of serum phylloquinone (PK), and vitamin K intake from fermented beans, natto, was also significantly correlated with the level of serum menaquinone-7 (MK-7). Moreover, the total dietary vitamin K intake showed a significant negative correlation with the ratio of ucOC to intact OC. Interestingly, on grouping by the GGCX genotype, there was a significant interaction between the ratio of ucOC to intact OC with vitamin K intake in homozygotes (GG-type) and heterozygotes (GA-type) (p<0.001). These results suggest that an adequate nutritional strategy is necessary for people with high-risk genotypes (GG- or GA-type).. We demonstrated the effects of SNP (974G>A) in the GGCX gene on the correlation between dietary vitamin K intake and gamma-carboxylation of serum OC. Our data may be useful for planning strategies to prevent osteoporosis.. 前言：γ-麩胺醯羧化酶(GGCX)基因的單核苷酸多型性(SNP)與骨骼礦物質密度 (BMD)之相關性已被證實。本篇研究探討，在日本的健康年輕受試者中，其 GGCX 多型性(974G>A)對於維生素K 攝取、血清中維生素K 濃度和羧化不全骨 鈣素(ucOC)與完整骨鈣素(OC)比值之間關聯性的影響。方法：共有189 位健康 年輕成人進行基因多型性檢測，並測量其血清中維生素K、OC、ucOC 濃度和 飲食中營養素攝取量。結果：飲食中攝取來自蔬菜的維生素K 與血清中維生素 K1(PK；葉綠醌)有顯著相關；而攝取來自發酵豆類-納豆的維生素K 也與血清中 維生素K2(MK-7；甲萘醌-7)有顯著相關。此外，從飲食中攝取的總維生素K 和 ucOC 與OC 比值有顯著負相關。值得注意的是，將GGCX 基因型分組時發現， 同型結合子(GG-type)和異型結合子(GA-type)兩組的ucOC 與OC 比值和維生素 K 攝取有顯著交互作用(p<0.001)。以上結果顯示，適當的營養策略對於具有高 風險基因型(GG-或GA-type)的人是必要的。結論：本研究證實GGCX 基因中的 SNP(974G>A)多型性對於飲食維生素K 攝取與血清骨鈣素γ-羧化相關性之效 應。本資料對於規劃預防骨質疏鬆症之策略也許會有幫助。

Topics: Carbon-Carbon Ligases; Diet; Genotype; Humans; Japan; Male; Nutritional Status; Osteocalcin; Polymorphism, Single Nucleotide; Soy Foods; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency; Young Adult

Vitamin K is essential for the activity of γ-carboxyglutamate (Gla)-proteins including matrix Gla28 protein and osteocalcin; an inhibitor of vascular calcification and a bone matrix protein, respectively. Insufficient vitamin K intake leads to the production of non-carboxylated, inactive proteins and this could contribute to the high risk of vascular calcification in hemodialysis patients. To help resolve this, we measured vitamin K(1) and K(2) intake (4-day food record), and the vitamin K status in 40 hemodialysis patients. The intake was low in these patients (median 140 μg/day), especially on days of dialysis and the weekend as compared to intakes reported in a reference population of healthy adults (mean K(1) and K(2) intake 200 μg/day and 31 μg/day, respectively). Non-carboxylated bone and coagulation proteins were found to be elevated in 33 hemodialysis patients, indicating subclinical hepatic vitamin K deficiency. Additionally, very high non-carboxylated matrix Gla28 protein levels, endemic to all patients, suggest vascular vitamin K deficiency. Thus, compared to healthy individuals, hemodialysis patients have a poor overall vitamin K status due to low intake. A randomized controlled trial is needed to test whether vitamin K supplementation reduces the risk of arterial calcification and mortality in hemodialysis patients.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Calcium-Binding Proteins; Diet; Dietary Supplements; Extracellular Matrix Proteins; Female; Humans; Liver; Male; Matrix Gla Protein; Middle Aged; Netherlands; Nutrition Policy; Nutritional Status; Osteocalcin; Protein Precursors; Prothrombin; Renal Dialysis; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency; Young Adult

Although hip fracture is considered to be associated with hypovitaminosis D and K, few reports have previously studied both of them. We have studied the vitamin D- and K-status as well as the general nutritional status in ninety-nine patients with hip fracture. Mean serum concentration of 25hydroxy-vitamin D (25OH-D) in female fractured patients was only approximately 9 ng/mL, suggesting severe vitamin D deficiency. There was no significant difference between the two groups in serum concentration of intact parathyroid hormone in both genders and serum 25OH-D levels in the male subjects. Plasma concentrations of phylloquinone (vitamin K1; PK) and menaquinone-7 (MK-7) were significantly lower in the fractured group than in the control group in both genders. Logistic regression analysis indicated that circulating concentrations of albumin, PK and 25OH-D were the significant and independent determinants of fracture risk, with their higher concentrations associated with decreased fracture risk. Finally, principal component analysis (PCA) was performed to summarize the clinical parameters into smaller numbers of independent components. Three components were obtained, each representing the overall nutritional status, the vitamin D status, and the vitamin K status. In conclusion, our study has shown that patients with hip fracture have vitamin D and K deficiency independent of general malnutrition.

Topics: Aged; Aged, 80 and over; Female; Hip Fractures; Humans; Logistic Models; Male; Parathyroid Hormone; Risk Factors; Vitamin D; Vitamin D Deficiency; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

A case of coagulopathy in a pre-adolescent with cerebral palsy that developed after chronic prophylactic antibiotic use is reported.. An 11-year-old boy with cerebral palsy was brought to the emergency department experiencing restlessness and decreased oxygen saturation. Evaluation of the patient revealed gallstone-related pancreatitis, with elevated serum amylase and lipase concentrations and abnormal liver function test results. At the time of the initial evaluation, the International Normalized Ratio (INR) was 6.54 (normal range, 0.8-1.2), and the activated partial thromboplastin time was 53.8 seconds (normal range, 24.4-34.8 seconds). The boy's medication history included use of azithromycin 200 mg every other day for about two years for antiinflammatory therapy. On confirmation of the elevated INR 2 hours after the initial evaluation, azithromycin was discontinued, and a single dose of phytonadione 2 mg was administered. About 14 hours after phytonadione administration, the INR had declined to 0.94; 43 hours later, the INR remained within the normal range without further phytonadione therapy. Using the probability scale of Naranjo and colleagues, this case was rated as a probable drug-related adverse event. Previous reports have linked the development of vitamin K deficiency and impaired coagulation to long-term antibiotic use, but not specifically to use of azithromycin or other macrolide antibiotics.. An elevated INR in a child with cerebral palsy was evidently related to long-term therapy with azithromycin. The abnormal INR normalized after discontinuation of azithromycin and administration of one dose of phytonadione.

Topics: Anti-Bacterial Agents; Antifibrinolytic Agents; Azithromycin; Blood Coagulation Disorders; Cerebral Palsy; Child; Humans; International Normalized Ratio; Male; Time Factors; Vitamin K 1; Vitamin K Deficiency

Vitamin K, vitamin K-dependent proteins, and vitamin D may be involved in the regulation of calcification in chronic kidney disease (CKD).. Vitamin K and D status was measured as dietary intake, plasma phylloquinone, serum percent uncarboxylated osteocalcin (%ucOC), proteins induced by vitamin K absence (PIVKA-II), Vitamin K Epoxide Reductase single-nucleotide polymorphism, apolipoprotein E genotype, and plasma 25-hydroxyvitamin D (25(OH)D) in 172 subjects with stage 3 to 5 CKD. Nutritional status was determined by subjective global assessment.. Subclinical vitamin K deficiency criteria was met by 6% (phylloquinone), 60% (%ucOC), and 97% (PIVKA-II) of subjects, whereas 58.3% and 8.6% had 25(OH)D insufficiency and deficiency, respectively. Dietary vitamin K intake was associated with higher phylloquinone and lower PIVKA-II. There were positive correlations between phylloquinone and the presence of stable weight, and the absence of subcutaneous fat loss or muscle wasting. 25(OH)D levels were positively associated with stable weight and albumin (P < 0.001). PIVKA-II levels were associated with apolipoprotein E genotype. Higher %ucOC and lower 25(OH)D were similarly associated with CKD stage, parameters of mineral metabolism, and urine albumin to creatinine ratio.. These data indicate that a suboptimal vitamin K and D status is prevalent in patients with CKD. Sufficiency of both vitamins K and D was similarly predicted by measures of overall improved nutritional status. Proteinuria was associated with both a suboptimal vitamin D status as well as worse peripheral vitamin K status.

Topics: Adult; Aged; Aged, 80 and over; Apolipoproteins E; Biomarkers; Chronic Disease; Cross-Sectional Studies; Diet; Female; Genetic Markers; Genotype; Humans; Kidney Diseases; Linear Models; Male; Middle Aged; Mixed Function Oxygenases; Nutritional Status; Osteocalcin; Polymorphism, Single Nucleotide; Protein Precursors; Proteinuria; Prothrombin; Vitamin D; Vitamin D Deficiency; Vitamin K; Vitamin K 1; Vitamin K Deficiency; Vitamin K Epoxide Reductases; Young Adult

Plasma vitamin K1 (phylloquinone) determination is commonly used for the diagnosis of vitamin K deficiency in patients suffering from lipid malabsorption. Moreover, current evidence that adequate vitamin K intake, and correspondingly adequate plasma vitamin K1 concentration, could also be of importance in relation to bone and brain diseases emphasizes the need to improve the current analytical methods. We developed a liquid chromatography coupled to tandem mass spectrometry method using a stable isotope ring-D4-labeled internal standard of vitamin K1 and operating in the multiple reaction monitoring mode by the selection of a precursor and product ions. The atmospheric pressure chemical ionization (APCI) method was shown to be more sensitive than electrospray ionization. After a single-step extraction with cyclohexane, chromatographic separation was performed on a C18 column with an isocratic mobile phase. The linearity was up to 5400ng/L, and the limit of detection was 14ng/L. Intra- and interrun precision were 2.4% and 8.3%, respectively, for the lower limit of the reference range. Recovery was better than 98%. The method is simple and reliable, allowing accurate vitamin K1 measurement in plasma samples from healthy subjects and patients suffering from vitamin K deficiency.

Topics: Chromatography, High Pressure Liquid; Cyclohexanes; Humans; Isotope Labeling; Tandem Mass Spectrometry; Vitamin K 1; Vitamin K Deficiency

There have been methodological problems for studying hypovitaminosis D and K in the elderly. First, studies were done either by evaluating food intake or measuring their circulating levels, but rarely by both in Japan. In this paper, vitamin D and K intakes and their circulating levels were simultaneously determined. Second issue is whether hypovitaminosis D and K are independent of general malnutrition, prevalent in the elderly. We tried to statistically discriminate them by principal component analysis (PCA). Fifty institutionalized elderly were evaluated for their circulating 25 hydroxy-vitamin D (25OH-D), intact parathyroid hormone (PTH), phylloquinone (PK), menaquinone-7 (MK-7) levels, and their food intake. Although average vitamin D intake (7.0 microg/day) exceeded the Japanese Adequate Intake (AI) of 5.0 microg/day, average serum 25OH-D concentration was in the hypovitaminosis D range (11.1 ng/mL). Median vitamin K intake was 168 microg/day, approximately 2.5 times as high as AI for vitamin K. Nevertheless, plasma PK and MK-7 concentrations were far lower than those of healthy Japanese elderly over 70 years old. PCA yielded four components; each representing overall nutritional, vitamin K2, vitamin D, and vitamin K1 status, respectively. Since these components are independent of each other, vitamin D- and K-deficiency in these subjects could not be explained by overall malnutrition alone. In summary, institutionalized elderly had a high prevalence of hypovitaminosis D and K, and the simultaneous determination of their circulating level and dietary intake is mandatory in such studies. PCA would yield fruitful results for eliminating the interference by confounders in a cross-sectional study.

Topics: 25-Hydroxyvitamin D 2; Aged; Aged, 80 and over; Biomarkers; Body Mass Index; Calcifediol; Diet; Female; Humans; Institutionalization; Japan; Male; Malnutrition; Nutritional Status; Parathyroid Hormone; Principal Component Analysis; Sex Characteristics; Vitamin D Deficiency; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

Des-gamma-carboxy prothrombin (DCP) is an abnormal prothrombin, increased in serum of patients with hepatocellular carcinoma (HCC) as result of an acquired defect of post-translational carboxylation of prothrombin's precursor. It is unclear if the reduced activity of gamma-carboxylase is secondary to vitamin K deficiency or to an altered gene encoding this enzyme. The aim of this study was to evaluate the effect of vitamin K administration on DCP and alpha-fetoprotein (AFP) levels, to identify a relationship between vitamin K and DCP serum levels and to investigate mechanisms of serum elevation of DCP levels.. The authors determined DCP and AFP serum levels and vitamin K concentration in 64 cirrhotics with HCC and in 60 cirrhotic subjects without HCC. In HCC subjects DCP and AFP levels were measured before and after vitamin K administration. A t-test for unpaired data was applied (P values <0.05 statistically significant).. Only HCC patients had detectable levels of DCP and significant AFP levels. Administration of vitamin K reduced DCP but not AFP levels in HCC patients. No correlation was observed between vitamin K concentration and DCP levels: vitamin K concentration was similar both in HCC patients and in control group without HCC; HCC patients had the same vitamin K concentration regardless of elevated o reduced DCP levels after vitamin K administration.. DCP detectable serum levels are the result not only of vitamin K deficiency or selective defects of carboxylase, because probably alterations of membrane receptors or cytoplasmatic transfers, that are necessary for the function of vitamin K, are involved.

Topics: Aged; alpha-Fetoproteins; Biomarkers; Carcinoma, Hepatocellular; Case-Control Studies; Female; Humans; Injections, Intravenous; Liver Neoplasms; Male; Middle Aged; Protein Precursors; Prothrombin; Up-Regulation; Vitamin K; Vitamin K 1; Vitamin K Deficiency

Idiopathic vitamin K deficiency in infancy or acquired prothrombin complex deficiency (APCD) is a serious bleeding disorders in infants. It leads to a high mortality rate and permanent neurological sequele among the survivors. A low vitamin K intake by infants is suggested to have a major role in the pathogenesis. To reduce the incidence of this syndrome, its risk factors have to be identified.. To determine the risk factors of the acquired prothrombin complex deficiency syndrome in the early infantile period.. A case-control study was conducted in 20 cases and 60 age- and sex-matched controls who were admitted to the Queen Sirikit National Institute of Child Health in Bangkok during August 1991 to August 1993. Feeding type, maternal history of herb-liquor extracts (herbal medicine) use and no history of vitamin K1 prophylactics at birth were identified to be risk factors of the syndrome. All subjects were fed by breast milk with or without formula milk. None of the subjects fed by formula milk were in the case group (Chi-square for trend = 14.77, p = 0.001).. The rate of a maternal history of herb-liquor extracts use in the case group was significantly higher than that of the control group (p = 0.03). Vitamin K2MK4 level in breast milk obtained from the mothers of the infants with maternal history of herb-liquor extracts use was lower than that obtained from the mothers of the infants without maternal history of herb-liquor extracts use (p = 0.03). No infant with history of intramuscular K1 prophylactics was in the case group. Three out of eight infants with history of oral vitamin K1 regimen were cases. Although vitamin K1 and K2MK4 level in breast milk obtained from the cases' mothers were significantly lower than that obtained from the controls' mothers (p = 0.015 and p = 0.003 respectively), there was an overlapping of vitamin K levels among these two groups.. This study demonstrated that vitamin K in breast milk has a main role in the pathogenesis of this disease. Herb-liquor extracts may be a cause of the APCD syndrome. Intramuscular vitamin K1 prophylactics should be routinely given to all newborn babies who will receive breast feeding. Effectiveness of oral vitamin K1 prophylactics regimen must be studied urgently.

Topics: Adult; Breast Feeding; Case-Control Studies; Chi-Square Distribution; Confidence Intervals; Female; Humans; Infant; Infant, Newborn; Middle Aged; Milk, Human; Odds Ratio; Pregnancy; Risk Factors; Thailand; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

Many patients with advanced cancer are malnourished. Anorexia is common, as is the use of chemotherapy, which may cause nausea and poor appetite. Ten per cent of these patients experience haemorrhagic events.. Since vitamin K deficiency (VKD) causes bleeding, to establish the prevalence of VKD in patients with advanced cancer receiving palliative care.. Serum concentrations of vitamin K(1) and undercarboxylated factor II (PIVKA-II) were determined in 46 (17 male/29 female) inpatients aged 26-85 (mean 58) years. INR and liver function tests (bilirubin, ALT, GGT and ALP) were also performed.. Vitamin K(1) was below the lower limit of the reference range (0.33 nmol/l) in 22% of patients. 78% of patients had some degree of functional VKD indicated by raised (>0.2 AU/ml) PIVKA-II. Six patients (13%) had a prolonged INR, all of whom had raised PIVKA-II and GGT; 4 also had vitamin K(1) <0.33 nmol/l. Three patients (6.5%) had clinically significant VKD characterised by INR >1.5, PIVKA-II >10 AU/ml, and undetectable vitamin K(1).. Patients with advanced cancer are prone to VKD which, while usually subclinical, may develop to a clinically relevant prolongation of the INR. Serum measurements of vitamin K(1) and PIVKA-II can be used to detect VKD and monitor vitamin K status before an increased risk of bleeding develops.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Female; Hemostatic Disorders; Humans; International Normalized Ratio; Male; Middle Aged; Neoplasms; Palliative Care; Protein Precursors; Prothrombin; Vitamin K 1; Vitamin K Deficiency

Polymorphisms in the apolipoprotein E (APOE) gene are associated with fracture risk, and a potential mechanism is through vitamin K transport.. We investigated the relation between dietary vitamin K(1) intake, APOE polymorphisms, and markers of bone health.. We measured bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN) in a cohort of Scottish women aged 49-54 y in 1990-1994 (baseline) and in 1997-2000 (visit 2). At visit 2, bone markers (urinary pyridinoline crosslinks and serum N-terminal propeptide of type 1 collagen) were measured, 3199 women completed a food-frequency questionnaire, and 2721 women were genotyped for APOE.. Compared with quartile 3 (Q3) of energy-adjusted vitamin K(1) intake (mean: 116 microg/d), women in the lowest quartile (mean: 59 microg/d) had lower BMD (analysis of variance; FN, Q1: 0.831 +/- 0.122 g/cm(2); Q3: 0.850 +/- 0.126 g/cm(2); P < 0.001; LS, Q1: 1.000 +/- 0.170 g/cm(2); Q3: 1.020 +/- 0.172 g/cm(2); P = 0.009), remaining significant at the FN after adjustment for age, weight, height, menopausal status or use of hormone replacement therapy, socioeconomic status, and physical activity (P = 0.04). Vitamin K(1) intake was associated with reduced concentrations of pyridinoline crosslinks (Q1: 5.4 +/- 2.0 nmol/mmol; Q4: 5.1 +/- 1.9 nmol/mmol; P = 0.003). Carriers of the E2 allele had greater LS BMD at visit 2 and lost less BMD than did carriers of the E4 allele (E2: -0.50 +/- 1.22%/y; E4: -0.71 +/- 1.17%/y; P = 0.05). After adjustment for confounders, the P value for BMD loss (0.03 for LS and 0.04 for FN) did not reach the level of significance required for multiple testing (P = 0.012). No interaction was observed between dietary vitamin K and APOE on BMD.. Vitamin K(1) intake was associated with markers of bone health, but no interaction was observed with APOE alleles on BMD or markers of bone turnover.

Topics: Absorptiometry, Photon; Amino Acids; Analysis of Variance; Apolipoproteins E; Bone and Bones; Bone Density; Bone Resorption; Collagen Type I; Diet; Exercise; Factor Analysis, Statistical; Female; Humans; Middle Aged; Peptides; Polymerase Chain Reaction; Polymorphism, Genetic; Postmenopause; Scotland; Surveys and Questionnaires; Vitamin K 1; Vitamin K Deficiency

Subclinical vitamin K deficiency increasingly is associated with extraosseous calcification in healthy adults. Nondietary determinants of vitamin K status include apolipoprotein E (apoE) genotype, which may influence vitamin K transport to peripheral tissues.. Serum phylloquinone concentrations and percentage of uncarboxyated osteocalcin (%ucOC) were measured by means of high-performance liquid chromatography and radioimmunoassay in 142 hemodialysis patients, respectively. ApoE phenotype was determined by means of isoelectric focusing of delipidated serum samples and Western blot analysis. Clinical and laboratory data were obtained by using chart review.. Mean age was 62.6 +/- 14.8 (SD) years. Mean phylloquinone level was 0.99 +/- 1.12 nmol/L; 29% of patients had levels less than 0.4 nmol/L. There was no association between phylloquinone level and %ucOC. There were positive correlations between phylloquinone and total cholesterol (P = 0.017), triglyceride (P = 0.022), and ionized calcium levels (P = 0.019). There was a negative correlation between phylloquinone level and dialysis adequacy (P = 0.002). Mean %ucOC was 51.1% +/- 25.8%, and 93% of subjects had values greater than 20%. There were positive correlations between %ucOC and dialysis vintage (P < 0.001), phosphate level (P < 0.001), parathyroid hormone level (P < 0.001), albumin level (P = 0.035), and ionized calcium level (P = 0.046). Seventeen percent of patients were apoE4. Mean %ucOC was significantly greater in apoE4 carriers compared with all other apoE phenotypes (60.1% +/- 28.4% versus 47.8% +/- 24.4%; P = 0.035). In multiple regression analysis with phylloquinone level forced in, independent predictors of %ucOC were phosphate level, dialysis vintage, parathyroid hormone level, and apoE4.. These data indicate suboptimal vitamin K status in hemodialysis patients, shown by low phylloquinone concentrations and high %ucOC in 29% and 93% of subjects, respectively. The apoE4 allele influences osteocalcin gamma-carboxylation in hemodialysis patients.

Topics: Aged; Alleles; Apolipoproteins E; Biological Transport; Cohort Studies; Cross-Sectional Studies; Female; Humans; Male; Middle Aged; Osteocalcin; Phenotype; Regression Analysis; Renal Dialysis; Vitamin K 1; Vitamin K Deficiency

Topics: Antifibrinolytic Agents; Blood Coagulation Tests; Diagnosis, Differential; Diagnostic Imaging; Echoencephalography; Epistaxis; Hematoma, Subdural; Humans; Infant, Newborn; Magnetic Resonance Imaging; Male; Melena; Subarachnoid Hemorrhage; Vitamin K 1; Vitamin K Deficiency

Germfree mice died when they were fed a purified diet of AIN-76 formula sterilized by gamma-irradiation. Vitamin K deficiency was suspected and this study was performed to confirm the cause of the death. Germfree mice were fed purified diets of AIN-76 or AIN-93M formula, which were pelleted and sterilized by gamma-irradiation at a dose of 50 kGy. One half of the mice fed the AIN-76 diet died within two weeks and the surviving animals were also in poor health, while 91% of mice fed the AIN-93M diet survived. No hemorrhage was observed grossly in any organs of the surviving animals. Histologically, degeneration with inflammatory cell infiltration was observed as well as hemorrhage and fibrosis in the heart muscles of mice fed the AIN-76 diet. No microscopic lesions were observed in the other organs. Prothrombin time (PT) and activated partial thromboplastin time (APTT) were extremely prolonged when mice were fed the AIN-76 diet. The animals totally recovered when they were intragastrically administered 1 microg/day of vitamin K(3) from the third day of feeding of the AIN-76 diet, except for PT and APTT which were still slightly longer than in mice fed the AIN-93M diet. The concentration of vitamin K(3) supplied in the AIN-76 diet decreased to an undetectable level after gamma-irradiation, while the AIN-93M diet contained 240 microg/kg of vitamin K(1). These results indicate that the deaths of the germfree mice fed the gamma-irradiated AIN-76 diet were caused by vitamin K deficiency. Vitamin K deficiency may cause fatal degeneration of cardiac muscle cells.

Topics: Animal Feed; Animals; Food, Formulated; Gamma Rays; Germ-Free Life; Heart; Heart Ventricles; Hemorrhage; Longevity; Mice; Mice, Inbred BALB C; Myocardium; Partial Thromboplastin Time; Prothrombin Time; Sterilization; Survival Rate; Vitamin K 1; Vitamin K 3; Vitamin K Deficiency

Vitamin K deficiency is associated with low bone mineral density and increased risk of bone fracture. Phylloquinone (K1) and menaquinone 4 (MK-4) and 7 (MK-7) are generally observed in human plasma; however, data are limited on their circulating concentrations and their associations with bone metabolism or with gamma-carboxylation of the osteocalcin molecule.. The objectives were to measure the circulating concentrations of K1, MK-4, and MK-7 in women and to ascertain whether each form of vitamin K is significantly associated with bone metabolism.. Plasma concentrations of K1, MK-4, MK-7, undercarboxylated osteocalcin (ucOC; measured by using the new electrochemiluminescence immunoassay), intact osteocalcin (iOC), calcium, and phosphorus; bone-derived alkaline phosphatase activity; and concentrations of urinary creatinine, N-terminal telopeptide, and deoxypyridinoline were measured in healthy women (n = 396).. On average, MK-7 and MK-4 were the highest and lowest, respectively, of the 3 vitamers in all age groups. K1 and MK-7 correlated inversely with ucOC, but associations between nutritional basal concentration of MK-4 and ucOC were not observed. Multiple regression analysis indicated that not only K1 and MK-7 concentrations but also age were independently correlated with ucOC concentration and the ratio of ucOC to iOC. The plasma K1 or MK-7 concentration required to minimize the ucOC concentration was highest in the group aged > or =70 y, and it decreased progressively for each of the younger age groups.. The definite role of ucOC remains unclear. However, if submaximal gamma-carboxylation is related to the prevention of fracture or bone mineral loss, circulating vitamin K concentrations in elderly people should be kept higher than those in young people.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Aging; Biomarkers; Bone and Bones; Bone Density; Carboxylic Acids; Female; Fractures, Bone; Humans; Japan; Middle Aged; Nutritional Requirements; Nutritional Status; Osteocalcin; Risk Factors; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency; Vitamins

The aim of this study was to assess vitamin K status in an unselected population of children with cystic fibrosis (CF) and to investigate any vitamin K effect on bone turnover and bone mineral status.. Children > or =5 years of age who were attending the CF unit were invited to enter the study. Fasting blood samples were analyzed for levels of vitamin K1 and prothrombin produced in vitamin K absence; total, undercarboxylated, and carboxylated osteocalcin (OC); and bone-specific alkaline phosphatase and procollagen I carboxy-terminal propeptide (bone formation markers). Levels of N-telopeptide and free pyridinoline and deoxypyridinoline (bone breakdown products) were measured in urine samples. Bone mineral density and bone mineral content were measured at the lumbar spine and for the total body with a GE Lunar Prodigy densitometer. Statistical analyses were performed with Minitab version 9.1.. One hundred six children entered the study. Sixty-five of 93 children (70%) from whom blood samples were obtained showed suboptimal vitamin K status, on the basis of low serum vitamin K1 levels, increased prothrombin produced in vitamin K absence levels, or both abnormalities. Vitamin K1 levels showed a significant negative correlation with undercarboxylated OC levels but showed no significant correlation with any marker of bone turnover or measurement of bone mineral status. Undercarboxylated OC levels were correlated significantly with bone turnover markers, which themselves showed a significant negative correlation with measurements of bone mineral density and content. There were no significant correlations between carboxylated or undercarboxylated OC levels and bone density measurements.. Vitamin K1 deficiency is common among children with CF, and routine supplements should be considered. Through its role in the carboxylation of OC, vitamin K deficiency may be associated with an uncoupling of the balance between bone resorption and bone formation. A cause-effect relationship between vitamin K deficiency and low bone mass has not been proved.

Topics: Absorptiometry, Photon; Alkaline Phosphatase; Biomarkers; Bone Density; Bone Remodeling; Child; Cystic Fibrosis; Humans; Osteocalcin; Prothrombin; Vitamin K; Vitamin K 1; Vitamin K Deficiency

The common bile duct-ligated (CBDL) rat, which is widely used as a model of human cirrhosis, rapidly develops secondary biliary cirrhosis (SBC) within 4 weeks. The CBDL rat shows poor viability, however, a detailed examination of the causes of its death has not been made. In this study, we investigated the outcome of bile duct ligation in detail and attempted to extend the life span of this model by feeding the animals a diet supplemented with nutrients. Survival rate, blood chemistry, blood cell counts, plasma levels of K vitamins and liver histology were compared among CBDL rats fed a standard diet and an enriched diet. Sham-operated rats were used as a control. Six out of 18 CBDL rats fed the standard diet died within 32 days of operation. The cause of death was massive internal hemorrhage in various organs or body cavities. All CBDL rats fed the enriched diet survived more than 31 days, but the viability of CBDL rats was not significant between those fed the standard diet and the enriched diet. The degree of anemia correlated significantly with the prolongation of prothrombin time. Plasma vitamin K1 levels in CBDL rats were significantly lower than those in sham-operated rats, but vitamin K2 levels were similar. We suggest that massive hemorrhage, which was the direct cause of death, is caused by the impairment of hemostasis resulting from vitamin K deficiency. The enriched diet with vitamin K nutritional supplements seemed to contribute to the prolongation of the life span of CBDL rats.

Topics: Animals; Disease Models, Animal; Hemorrhage; Hemostasis; Ligation; Liver Cirrhosis, Biliary; Male; Rats; Rats, Sprague-Dawley; Survival Rate; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

To investigate the vitamin K status of preterm infants who have a prolonged prothrombin time (PT) in the first month of life.. Measures of vitamin K status were assessed in 21 preterm infants who were found to have an abnormal PT, despite 0.2-0.5 mg vitamin K(1) prophylaxis at birth.. All infants had normal or supraphysiological vitamin K(1) concentrations and undetectable or, in one infant, insignificant PIVKA-II, indicating adequate vitamin K status.. In preterm infants born at <32 wk gestation who received > or = 0.2 mg vitamin K(1) after delivery, a prolonged PT in the first month of life is unlikely to be due to vitamin K deficiency.

Topics: Biomarkers; Humans; Infant, Newborn; Infant, Premature; Protein Precursors; Prothrombin; Prothrombin Time; Randomized Controlled Trials as Topic; Vitamin K 1; Vitamin K Deficiency; Vitamins

To evaluate oral vitamin K prophylaxis at birth by giving 2 mg phytomenadione, followed by weekly oral vitamin K prophylaxis; 1 mg was administered by the parents until 3 mo of age.. A total of 507850 live babies were born in Denmark during the study period, November 1992 to June 2000. Of these infants, 78% and 22% received oral and intra-muscular prophylaxis, respectively; i.e. about 396000 neonates received oral prophylaxis at birth. Weekly oral prophylaxis was recommended for all infants as long as they were mainly breastfed. A survey of possible cases of vitamin K deficiency bleeding (VKDB) was carried out by repeated questionnaires to all Danish paediatric departments and by checking the National Patient Register.. No cases of VKDB were revealed, i.e. the incidence was 0-0.9:100000 (95% CI). The questionnaires were used to evaluate compliance with the regimen. Parents of 274 infants participated. A dose of vitamin K was regarded as having been given if the infant received a drop of vitamin K or was mostly formula-fed that week, and the prophylaxis was regarded as completed if the infant had received at least 9 doses. Compliance was good, with 94% of the infants completing the course of prophylaxis.. Weekly oral vitamin K supplementation during the first 3 mo of life was an efficient prophylaxis against VKBD. Parental compliance with the regimen was good.

Topics: Antifibrinolytic Agents; Breast Feeding; Child Health Services; Denmark; Drug Administration Schedule; Drug Therapy, Combination; Food, Fortified; Health Promotion; Humans; Incidence; Infant Welfare; Infant, Newborn; Patient Compliance; Preventive Health Services; Surveys and Questionnaires; Vitamin K; Vitamin K 1; Vitamin K Deficiency; Vitamin K Deficiency Bleeding

In 1995, a new form of vitamin K prophylaxis with two oral doses of 2 mg mixed micellar phylloquinone (Konakion MM) on the 1st and 4th day of life was introduced in Switzerland. It was hoped that this new galenic preparation of phylloquinone would protect infants with insufficient or absent bile acid excretion from late vitamin K deficiency bleeding (VKDB). Subsequently, the occurrence of VKDB was monitored prospectively between July 1, 1995 and June 30, 2001 with the help of the Swiss Paediatric Surveillance Unit (SPSU). Over a period of 6 years (475,000 deliveries), there were no cases of early (<24 h of age), one case of classical (2-7 days of life), and 18 cases of late (1-12 weeks) VKDB fulfilling standard case definitions. In 13/18 patients with late VKDB there was pre-existing liver disease and in 4/18 patients, parents had refused prophylaxis. The incidence of late VKDB for infants with completed Konakion MM prophylaxis was 2.31/100,000 (95% CI: 1.16-4.14) and for the entire population 3.79/100,000 (95% CI: 2.24-5.98). There was only one case of late VKDB after complete prophylaxis in an infant without underlying liver disease.. two oral doses of 2 mg of a mixed micellar vitamin K preparation failed to abolish VKDB. The recommendations for vitamin K prophylaxis in Switzerland have therefore been changed to include a third dose at 4 weeks of age. Starting on January 1, 2004, the incidence of vitamin K deficiency bleeding will again be monitored prospectively by the Swiss Paediatric Surveillance Unit.

Topics: Administration, Oral; Hemorrhagic Disorders; Humans; Incidence; Infant, Newborn; Micelles; Prospective Studies; Switzerland; Vitamin K 1; Vitamin K Deficiency

Vitamin K deficiency is a known cause of coagulopathy in hospitalized patients, but the extent of the problem has not been well assessed. This noninterventional, prospective observational study of 35 adults was undertaken in the intensive care unit (ICU) and examined the incidence of and the methods for diagnosing vitamin K deficiency. Measurements of prothrombin time, Echis time and plasma concentrations of under-carboxylated prothrombin (proteins induced in vitamin K absence or antagonism, PIVKA-II), vitamin K1 and ferritin were made during the 48 h after admission to the unit and repeated if coagulopathy developed later. Plasma vitamin K1 was low in 15 admissions (43%), in 11 cases of patients with coagulopathy and in four cases without coagulopathy. PIVKA-II was present in 12 cases (34%), of whom four had low vitamin K1 levels. All of the eight patients with raised PIVKA-II but normal vitamin K concentration were hyperferritinaemic. We conclude that low plasma vitamin K levels, suggestive of low tissue stores, are common in intensive care patients with or without coagulopathy. As 34% of patients had a raised PIVKA-II, this suggests that vitamin K stores may be insufficient to maintain full gamma-carboxylation of prothrombin and emphasize the need to anticipate vitamin K deficiency in the ICU setting by appropriate supplementation.

Topics: Adolescent; Adult; Aged; Biomarkers; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Female; Ferritins; Humans; Intensive Care Units; International Normalized Ratio; Male; Middle Aged; Prospective Studies; Protein Precursors; Protein Processing, Post-Translational; Prothrombin; Viper Venoms; Vitamin K 1; Vitamin K Deficiency

The difference between vitamin K metabolism in the liver and that in the bone of vitamin K-deficient rats was examined. After 17 d administration of vitamin K-deficient food, vitamin K in the liver was almost depleted, and prothrombin time (PT) was prolonged. Serum total osteocalcin level was slightly decreased by vitamin K deficiency, whereas serum undercarboxylated osteocalcin level did not change. The level of menaquinone (MK)-4 as well as that of phylloquinone was decreased, but approximately 40 % of the initial level still existed in the femur after the 17 d period. A single-dose administration of vitamin K (250 nmol/kg body weight) markedly increased vitamin K level in the liver but not in the femur. These results suggest that the turnover of vitamin K in the bone is slower than that in the liver, and bone metabolism may be little affected by the short period of intake of vitamin K-deficient food. However, intake of a larger amount of vitamin K is required for its accumulation in the bone than in the liver. Furthermore, the counteracting effect of MK-7 on prolonged PT in vitamin K-deficient rats was found to be higher than phylloquinone or MK-4.

Topics: Animals; Bone and Bones; Cyanoacrylates; Indoleacetic Acids; Liver; Male; Osteocalcin; Partial Thromboplastin Time; Prothrombin Time; Rats; Rats, Sprague-Dawley; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

The ability of oral vitamin K to eliminate all risk of vitamin K deficiency bleeding during the first three months of life was studied.. Babies (n=182,000) in the north of England judged well enough to be offered milk within 12 hours of birth were given 1 mg of phytomenadione (vitamin K(1)) suspended in a medium chain triglyceride oil by mouth at delivery between 1993 and 1998. The parents of those who were breastfed were given a further three doses to give to the baby once every two weeks after discharge.. Four breastfed babies developed late vitamin K deficiency bleeding. In two, staff failed to follow policy guidelines, and in two there was undiagnosed alpha(1) antitrypsin deficiency. Audit suggested that 93% of breastfed babies had all four doses, as advised.. An oral product that parents can administer themselves would be popular if licensed, but the total dose offered may need to be more than in this study if babies with undiagnosed liver disease are to be protected.

Topics: Administration, Oral; alpha 1-Antitrypsin Deficiency; Bottle Feeding; Breast Feeding; Chemoprevention; Confidence Intervals; Hemorrhage; Humans; Infant, Newborn; Medical Audit; Patient Compliance; Practice Guidelines as Topic; Risk Factors; Self Administration; Vitamin K 1; Vitamin K Deficiency

Topics: Antifibrinolytic Agents; Coumarins; Hemorrhagic Disorders; Humans; Vitamin K 1; Vitamin K Deficiency

Gender differences in relation to vitamin K were investigated in the rat. Hepatic phylloquinone and menaquinone (MK-1 to MK-10) concentrations, gamma-carboxyglutamic acid (Gla) excretion, plasma phylloquinone and percent prothrombin were measured in male and female rats on a chow diet (24.5 ng phylloquinone and 8.8 microgram menadione), and on phylloquinone-deficient and -supplemented purified diets (0.38 and 1400 ng phylloquinone/g, respectively). Mean hepatic phylloquinone concentrations varied with dietary intake and ranged from 6.8+/-9.0 pmol/g in the deficient male, to 171. 1+/-56.9 pmol/g in the supplemented female. Menaquinones accounted for a large proportion of total vitamin K in the liver of males and females with MK-4, MK-6, and MK-10 present in highest concentrations. On the chow and supplemented diets, females had significantly higher MK-4, MK-6, and MK-10 concentrations in their livers (P<0.05). On the phylloquinone-deficient diet (-K1), hepatic phylloquinone, MK-4, and to a lesser extent MK-6 (but not MK-10) were significantly reduced (P<0.05). In the phylloquinone-supplemented male and female groups, which did not receive menadione during the experimental period, MK-4 increased above that in the chow groups suggesting synthesis of MK-4 from phylloquinone which was statistically significant in the female (P<0.01). A significant gender difference (P<0.05) was also observed for urinary Gla excretion with less Gla excreted by the females indicating that females may require less dietary phylloquinone than males of the same body weight.

Topics: 1-Carboxyglutamic Acid; Animals; Chromatography, High Pressure Liquid; Diet; Humans; Liver; Male; Prothrombin; Rats; Rats, Sprague-Dawley; Sex Factors; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

In 1995, a new water-soluble mixed-micellar analogue of vitamin K1 (Konakion MM paediatric) was introduced in Switzerland to replace the formerly used fat-soluble Konakion drops for the prevention of vitamin K1-deficiency-bleeding (VKDB) in infants. According to the new guidelines, an oral dose of 2 mg is given after birth and again on the 4th day of life. We examined the compliance with these guidelines and the impact on the incidence of VKDB. To assess compliance, questionnaires were sent to all hospitals with delivery services 6 months after the introduction of the new guidelines. Using the database of the Swiss Paediatric Surveillance Unit (SPSU) which records rare paediatric diseases, we assessed the incidence of VKDB in Switzerland between July 1995 and June 1998. In addition, we determined the precise circumstances under which the episodes of VKDB occurred. More than 99% of infants received vitamin K1 prophylaxis. Since July 1995, 93% of newborns have received prophylaxis according to the new guidelines; the remaining infants were given fat-soluble Konakion drops or parenteral vitamin K1. Within 3 years, one case of classical and 12 cases of late-onset VKDB (11 confirmed, 1 probable) were reported to the SPSU. Of the 11 confirmed late-onset cases, 7 received the recommended prophylaxis, whereas 3 had not and 1 had been given fat-soluble Konakion drops. All confirmed cases of late-onset VKDB occurred in fully breast-fed infants and 8 of 11 had hepatobiliary disease.. With the introduction of two oral doses of a mixed-micellar vitamin K1 preparation administered in the 1st week of life, the incidence of late vitamin K1-deficiency-bleeding has decreased from 7.2:100,000 between 1986-1987 to 2.8:100,000 between 1995 and 1998. This regimen may be suitable for prophylaxis of vitamin K1-deficiency-bleeding, however, it does not fully protect infants with cholestatic disease from late-onset bleeding. If oral prophylaxis is considered for these infants, vitamin K1 has to be administered repeatedly to all infants during the breast feeding period.

Topics: Administration, Oral; Antifibrinolytic Agents; Child Health Services; Female; Follow-Up Studies; Guidelines as Topic; Health Surveys; Hemorrhagic Disorders; Humans; Incidence; Infant, Newborn; Male; Primary Prevention; Registries; Switzerland; Treatment Outcome; Vitamin K 1; Vitamin K Deficiency

Topics: Antifibrinolytic Agents; Breast Feeding; Humans; Incidence; Infant, Newborn; United Kingdom; Vitamin K 1; Vitamin K Deficiency; Vitamins

Two forms of vitamin K [phylloquinone (K1) and menaquinone-4 (MK-4)] were added to vitamin K-deficient rat food in varying amounts. These diets were given as the sole source of nutrition to rats for one week. The minimal dietary requirements (MDR) to attain maximal prothrombin synthesis were determined to be 0.6 and 6-10 microg/g of food for K1 and MK-4, respectively. The difference between both vitamers could be explained by the limited hepatic accumulation of MK-4. Next, vitamin K was offered to rats at concentrations ranging between 0.6 and 3000 microg/g of food, and the tissue distribution of vitamin K was investigated after one week of administration. Accumulation of K1 and MK-4 was found in all tissues investigated, but both the absolute tissue concentration and the ratio between K1 and MK-4 were tissue-dependent. Highest values were found in liver and in heart, but since the heart contains no gamma-glutamylcarboxylase, the function of vitamin K in this tissue remains obscure. High tissue concentrations of MK-4 were also found in pancreas and testis after a diet containing K1 exclusively. The data indicate that this conversion is tissue-specific, but neither the reason nor its mechanism are known.

Topics: Animal Nutritional Physiological Phenomena; Animals; Carbon-Carbon Ligases; Diet; Dietary Supplements; Liver; Male; Myocardium; Prothrombin; Rats; Rats, Inbred Strains; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

To elucidate the role of intestinal bacteria in the conversion of phylloquinone into menaquinone-4 (MK-4) we investigated the tissue distribution of vitamin K in germ-free rats. The rats were made vitamin K deficient by feeding a vitamin K-free diet for 13 days. In a subsequent period of 6 days, phylloquinone and menadione were supplied via the drinking water in concentrations of 10 and 50 micromol l(-1). Menadione supplementation led to high levels of tissue MK-4, particularly in extrahepatic tissues like pancreas, aorta, fat and brain. Liver and serum were low in MK-4. Phylloquinone supplementation resulted in higher phylloquinone levels in all tissues when compared with vitamin K-deficient values. The main target organs were liver, heart and fat. Remarkably, tissue MK-4 levels were also higher after the phylloquinone supplementation. The MK-4 tissue distribution pattern after phylloquinone intake was comparable with that found after menadione intake. Our results demonstrate that the conversion of phylloquinone into MK-4 in extrahepatic tissues may occur in the absence of an intestinal bacterial population and is tissue specific. A specific function for extrahepatic MK-4 or a reason for this biochemical conversion of phylloquinone into MK-4 remains unclear thus far.

Topics: Animals; Diet; Germ-Free Life; Intestines; Male; Rats; Rats, Wistar; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

Vitamin K is a group name for a number of prenylated 2-methyl-1,4-naphtoquinones, which may differ in their ability to function as a cofactor for prothrombin biosynthesis. To quantify the bioactivity of different forms of vitamin K, two experimental animal systems are frequently used: vitamin K-deficient rats and anticoagulated rats. In this paper both models are compared, and it is shown that the results obtained depend on the model used. The main reason for this discrepancy is the difference in recycling of vitamin K-epoxide, which results in a 500 times higher vitamin K requirement in anticoagulated rats. Absorption and hepatic accumulation of long chain menaquinones seem to be restricted to a maximum, whereas also the lipophilic nature of long chain menaquinones may hamper the quinone-quinol reduction in anticoagulated animals. If these data may be extrapolated to patients, food items rich in K1 and MK-4 would be expected to influence the stability of oral anticoagulation to a much larger extent than food items primarily containing higher menaquinones.

Topics: 4-Hydroxycoumarins; Absorption; Animals; Anticoagulants; Blood Coagulation; Disease Models, Animal; Male; Prothrombin; Rats; Rats, Inbred Lew; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

Recent studies suggest that subtle vitamin K depletion has far-reaching consequences. As this entity is not associated with prothrombin time elevation, it is important to determine whether alternate methods can help identify it. We investigated subtle vitamin K depletion in a hospital setting and determined whether protein calorie malnutrition predicts its presence.. Using a high-pressure liquid chromatography (HPLC) assay of plasma phylloquinone and a food frequency questionnaire for phylloquinone intake, we examined the phylloquinone status of 27 hospitalized patients with normal coagulation parameters, no liver disease, and no recent warfarin use. We assessed protein-calorie nutritional status with Reilly's criteria and anthropometrics.. 51% of patients (95% CI = 31% to 70%) had evidence of subtle vitamin K depletion as defined by a subnormal plasma phylloquinone concentration. Patients whose phylloquinone intake was less than the Recommended Daily Allowance (RDA) over the preceding year had lower plasma phylloquinone concentrations when compared to other patients: median (range) 0.106 nmol/l (0.022-0.461) versus 0.301 nmol/l (0.067-3.928), respectively (P = 0.023). Plasma phylloquinone concentrations were no different, however, between well-nourished and malnourished patients: median (range) 0.245 nmol/l (0.022-0.522) versus 0.188 nmol/l (0.067-3.928), respectively (P=0.782).. Subtle vitamin K depletion is common among hospitalized patients and protein-calorie malnutrition does not predict its presence.

Topics: Adult; Anthropometry; Chromatography, High Pressure Liquid; Female; Hospitalization; Humans; Male; Middle Aged; Nutritional Status; Protein-Energy Malnutrition; Prothrombin Time; Serum Albumin; Surveys and Questionnaires; Vitamin K 1; Vitamin K Deficiency

Atrophic gastritis patients have intestinal bacterial overgrowth which could produce menaquinones. The aim of this study was to evaluate the interaction between a diet low in phylloquinone and minidoses of warfarin in subjects with and without bacterial overgrowth. Subjects with atrophic gastritis (indicated by serum pepsinogen ratio) and healthy volunteers were studied while fed a restrictive phylloquinone diet and while receiving a minidose of warfarin. Coagulation times, serum osteocalcin, serum undercarboxylated osteocalcin, plasma phylloquinone, plasma K-epoxide, plasma undercarboxylated prothrombin (PIVKA)-II and urinary gamma-carboxyglutamic acid (Gla) were measured. At baseline, there were no differences between groups for any variable measured. Comparisons between baseline and post intervention in both groups, showed significant increases in circulating levels of K-epoxide, PIVKA II and undercarboxylated osteocalcin. However, no differences were observed when comparisons were made between groups. Our data do not support the hypothesis that bacterial synthesis of menaquinones in patients with bacterial overgrowth due to atrophic gastritis confers considerable resistance to the effect of warfarin.

Topics: Aged; Anticoagulants; Bacteria, Anaerobic; Diet; Female; Food-Drug Interactions; Gastritis, Atrophic; Humans; Hydrogen-Ion Concentration; Intestines; Male; Middle Aged; Vitamin K; Vitamin K 1; Vitamin K Deficiency; Warfarin

Vitamin K is involved in the biosynthesis of a number of blood coagulation factors and bone proteins. It has been suggested that the vitamin K requirement of bone tissue is higher than that of the liver. Here we report that in rats very high doses of vitamin K affected neither the blood coagulation characteristics nor the blood platelet aggregation rate. This was observed for both phylloquinone and menaquinone-4. Both vitamers were also tested for their effects on the arterial thrombosis tendency in the rat aorta loop model. The mean obstruction times were prolonged at a high intake of menaquinone-4 (250 mg/kg body weight/day), and shortened after a similarly high phylloquinone regimen. Since (a) both vitamers only differ in their aliphatic side chains; and (b) a similar trend was observed after administration of phytol and geranylgeraniol, we conclude that the modulation of the arterial thrombosis tendency is accomplished by the side chain of vitamin K.

Topics: Animals; Blood Coagulation; Diet; Dietary Fats, Unsaturated; Disease Models, Animal; Disease Susceptibility; Diterpenes; Dose-Response Relationship, Drug; Male; Phytol; Platelet Aggregation; Rats; Rats, Wistar; Thrombosis; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

To clarify the origin of organ menaquinone-4 (MK-4), the distributions of phylloquinone and MK-4 were investigated in rats fed diets containing phylloquinone, MK-4 or menadione (1.1, 2.2 and 31 mumol/kg diet, respectively, 6 rats per group). Warfarin (2 x 1 mg/kg subcutaneously) was given (3 rats per group) to study the effect of vitamin K cycle blockage. In rats fed phylloquinone the vitamin accumulated mainly in liver and heart. Additionally, the diet resulted in significantly higher organ MK-4 concentrations compared with the vitamin K-deficient controls. The epoxide of MK-4 also was significantly higher in some organs. The MK-4 diet increased MK-4 concentration primarily in the heart, liver and lung. Rats fed menadione had significantly higher MK-4 and MK-4 epoxide concentrations in all organs examined. The greatest accumulations were in nonhepatic organs, particularly the pancreas, salivary gland and brain. Generally, liver and plasma had low MK-4 concentrations. Warfarin treatment lowered significantly the MK-4 concentrations, whereas MK-4 epoxide accumulated. The study shows the following: 1) dietary phylloquinone is accumulated mainly in the heart and liver, 2) the MK-4 accumulation in nonhepatic organs is due to synthesis rather than uptake and 3) MK-4 rather than phylloquinone may be the functional vitamin in nonhepatic organs.

Topics: Animals; Brain Chemistry; Liver; Lung; Male; Myocardium; Pancreas; Rats; Rats, Wistar; Salivary Glands; Vitamin K; Vitamin K 1; Vitamin K Deficiency; Warfarin

Rats were made vitamin K-deficient by feeding them a diet devoid of vitamin K and by rigorously preventing coprophagy. After one week, circulating prothrombin concentrations were between 5 and 10% of initial values, and various amounts of phylloquinone, menaquinone-4, and menaquinone-9 were given in a single dose either subcutaneously, orally, or colorectally. The relative 'vitamin K activities' of these compounds were assessed by comparing their ability to support prothrombin synthesis after subcutaneous injection. Intestinal and colonic absorption were deduced from the difference between subcutaneous and either oral or colorectal administration of the vitamers. It is concluded that the colonic absorption of all three forms of vitamin K is extremely poor, suggesting that physiological menaquinones in the colon do not contribute substantially to vitamin K status in rats. Furthermore, the stimulation of prothrombin synthesis by menaquinone-9 lasted much longer than that by the two other K-vitamers, resulting in a substantially higher 'vitamin K activity' of menaquinone-9.

Topics: Animals; Biological Availability; Hemostatics; Intestinal Absorption; Male; Prothrombin; Rats; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

Topics: Anticoagulants; Blood Loss, Surgical; Cardiopulmonary Bypass; Humans; Plasma; Preanesthetic Medication; Vitamin K 1; Vitamin K Deficiency; Warfarin

It is unclear whether menaquinones produced by the intestinal microflora play any role in human nutrition. Reports of coagulopathy due to vitamin K deficiency occurring in patients receiving broad spectrum antibiotics indirectly suggest that vitamin K2 produced by the gut microflora may be utilized by the host. We analyzed the vitamin K1 (phylloquinone) and vitamin K2 (menaquinone) content in a convenience sample of 22 human post-mortem liver samples, including 9 individuals who had been receiving broad spectrum antimicrobials prior to death and 13 individuals who had been victims of sudden, unexpected deaths. There were no significant differences in the mean (+/- SEM) phylloquinone content between the 2 groups [21.9 (+/- 15.5) vs. 16.0 (+/- 9.3) pmol/g wet weight (excluding those who had received supplemental vitamin K1)] but there was a significant difference (p < 0.05) in the total menaquinone (MK) content, 70.0 (+/- 23.3) vs. 423.1 (+/- 141) pmol/g between the 2 groups. These findings suggest an association between receipt of broad spectrum antibiotics and a reduction in hepatic menaquinone concentration, lending support to the hypothesis that a reduction in the gut microflora responsible for their production leads to reduced hepatic stores of this form of the vitamin.

Topics: Adult; Aged; Anti-Bacterial Agents; Cadaver; Female; Humans; Intestines; Liver; Male; Middle Aged; Vitamin K; Vitamin K 1; Vitamin K Deficiency

Eleven patients with cholestatic jaundice had measurements of plasma vitamin K1 performed. Seven of these 11 (64%) had subnormal levels. The prothrombin time (PT) was prolonged in three of 15 patients with cholestasis (20%), the patient with the longest PT had the lowest vitamin K1 level. A single intramuscular (im) dose of 10 mg vitamin K1 lowered the PT in 9/15 patients (includes correcting the three prolonged PTs). The initial mean plasma vitamin K1 level rose 24 h later, to a mean plasma level which was 33 times the upper limit of the normal physiological range. These preliminary results suggest that a majority of patients presenting with cholestatic jaundice have low tissue reserves of vitamin K1, and that guidelines for vitamin K1 therapy in patients with cholestatic jaundice should be revised.

Topics: Adult; Aged; Aged, 80 and over; Alkaline Phosphatase; Blood Coagulation Disorders; Blood Coagulation Tests; Cholestasis; Digestive System Neoplasms; Female; Humans; Male; Middle Aged; Prospective Studies; Vitamin K 1; Vitamin K Deficiency

Rats were made vitamin K-deficient by feeding them a 1:1 (w/w) mixture of a commercial vitamin K-depleted diet and boiled white rice. After one week of treatment the rats had developed severe vitamin K deficiency, resulting in Thrombotest values of 5-10% of the initial values. In this experimental system the efficacy of phylloquinone (K1) was compared with that of menaquinone-4 (MK-4) by measuring the extent to which the Thrombotest was normalized after the administration of varying doses of the respective vitamins. Oral administration of the vitamins showed that the efficacy of K1 was at least two-fold higher than that of MK-4. As comparable results were obtained after subcutaneous administration of the vitamins, we conclude that after oral administration the intestinal absorption had been quick and nearly complete. A less pronounced effect of K1 and MK-4 was found after colorectal administration. For both forms of vitamin K relatively high amounts (well above the physiological concentration) were required before significant effects on the Thrombotest could be observed. Therefore these data demonstrate the importance of sufficient dietary vitamin K consumption in rats. The efficacy of other menaquinones may be investigated in the same experimental animal model system.

Topics: Administration, Oral; Animals; Blood Coagulation Factors; Injections, Subcutaneous; Male; Rats; Rats, Inbred Lew; Rectum; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

Vitamin K prophylaxis has been developed to prevent classic haemorrhagic disease of the newborn. Single vitamin K administration after birth has been reported to fail, resulting in late haemorrhagic disease of the newborn. The preventive effect of oral administration of vitamin K1 1 mg, repeated weekly during the first three months of life, was studied in 48 healthy breast-fed infants, by determination of thrombotest, PIVKA-II and vitamin K1 concentrations at the age of 4, 8 and 12 weeks. All infants showed normal thrombotest values and PIVKA-II was not detectable. Vitamin K1 concentrations were negatively correlated with the number of days elapsed since the most recent vitamin K administration. Six to seven days after the latest application, mean levels were 1223, 927 and 748 pg/ml at ages 4, 8 and 12 weeks, respectively. In conclusion, weekly administration of vitamin K1 1 mg offers complete protection against vitamin K deficiency and does not result in an accumulation of vitamin K1 in the blood.

Topics: Biomarkers; Blood Proteins; Breast Feeding; Drug Evaluation; Female; Humans; Infant; Infant, Newborn; Male; Protein Precursors; Prothrombin; Prothrombin Time; Time Factors; Vitamin K; Vitamin K 1; Vitamin K Deficiency; Vitamin K Deficiency Bleeding

To assess the effect of prenatal vitamin K1 on the coagulation status of newborns.. We measured noncarboxylated prothrombin and performed the Normotest in two groups of 5-day-old infants whose mothers were given oral vitamin K1, 10 mg/day for 2 weeks at least 10 days before delivery, or were untreated.. Noncarboxylated prothrombin was found in one of 74 treated women and 13 of 186 controls, a nonsignificant difference. The mean (+/- standard deviation) Normotest value was 59.6 +/- 10.1% (range 38.9-84.4) for the treated group and 53.4 +/- 9.9% (range 16.3-89.9) for the controls, a statistically significant difference (P < .001).. Based on the Normotest results, we suggest that vitamin K crosses the placenta and persists to activate the vitamin K-dependent coagulant factors until at least the fifth day of life. Thus, prenatal vitamin K1 administration may replace prophylaxis at birth.

Topics: Adult; Female; Humans; Infant, Newborn; Maternal-Fetal Exchange; Pregnancy; Prenatal Care; Vitamin K 1; Vitamin K Deficiency; Vitamin K Deficiency Bleeding

Topics: Breast Feeding; Cerebral Hemorrhage; Cholestasis; Exchange Transfusion, Whole Blood; Female; Humans; Infant; Male; Vitamin K 1; Vitamin K Deficiency

Cutaneous reactions to vitamin K1 injections are reported infrequently. Most previously reported cases have been associated with liver disease, primarily alcoholic cirrhosis and viral hepatitis. Four new cases are reported. One patient had polycythemia vera and the Budd-Chiari syndrome, the second such report in the literature. The other three patients had no known hepatic disease. The reactions consisted of erythematous plaques at the injection site without progression to sclerodermatous plaques. Histopathologic examination in three cases showed spongiotic changes and mononuclear infiltrates typical of cutaneous reactions to vitamin K1. In one instance a neutrophilic infiltrate was associated with the reaction site. Our findings support the observation that liver disease is not a necessary condition for the occurrence of vitamin K1 hypersensitivity.

Topics: Adult; Budd-Chiari Syndrome; Drug Eruptions; Female; Humans; Injections, Intramuscular; Middle Aged; Vitamin K 1; Vitamin K Deficiency

After optimizing conditions for maximal production of menaquinones (MK), S. aureus and B. vulgatus were grown in batches, harvested and extracted for qualitative and quantitative MK content utilizing HPLC (high performance liquid chromatography) until a total of 6 mg was available. Five normal healthy male volunteers were placed on a vitamin K1 deficient diet (< or = 25 micrograms/day) and were subsequently warfarinized to maintain a prothrombin time (PT) 1.5-2 times control. Following stabilization of daily warfarin dosage 1 mg doses of the extracted MK were orally administered. As a control, the same volunteers were later warfarinized but no MK was given. Within 24 h of MK administration the prothrombin time (PT) decreased (mean +/- SEM) 3.6 +/- 1.0 s (p < 0.005) and the Factor VII level increased 0.36 +/- 0.3 u/ml (p < 0.005) vs a PT increase of 1.0 +/- 1.0 s (p > 0.1) and a Factor VII level increase of 0.03 +/- 0.1 u/ml (p > 0.1) in the control phase. Within 48 h of MK administration the PT was normal in all subjects but remained > or = 1.5 times control in the control phase. These data demonstrate for the first time the absorption and bioactivity of bacterially synthesized vitamin K in humans.

Topics: Administration, Oral; Adult; Bacteroides; Factor VII; Humans; Intestinal Absorption; Male; Prothrombin; Prothrombin Time; Staphylococcus aureus; Vitamin K; Vitamin K 1; Vitamin K Deficiency; Warfarin

Topics: Administration, Oral; Animals; Germ-Free Life; Intestines; Male; Mice; Mice, Inbred ICR; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

Topics: Foot Injuries; Fractures, Closed; Humans; IgA Vasculitis; Male; Middle Aged; Shoulder Fractures; Vitamin K 1; Vitamin K Deficiency

Sprague-Dawley rats were given daily subcutaneous doses of sodium warfarin (100 mg/kg) and vitamin K1 (10 mg/kg) for up to 12 weeks, starting on the day after birth. This dosing regimen creates an extrahepatic vitamin K deficiency while preserving the vitamin K-dependent processes of the liver. Control rats received either vitamin K1 only or were untreated. All rats survived without any signs of hemorrhage. The warfarin-treated rats developed a marked maxillonasal hypoplasia associated with a 11-13% reduction in the length of the nasal bones compared with controls. The length of the posterior part of the skull was not significantly different from controls. In the warfarin-treated rats, the septal cartilage of the nasal septum showed large areas of calcification, not present in controls, and abnormal calcium bridges in the epiphyseal cartilages of the vertebrae and long bones. The ectopic calcification in the septal cartilage may have been the cause of the reduced longitudinal growth of the nasal septum and the associated maxillonasal hypoplasia. It is proposed that (1) the facial features of the human warfarin embryopathy are caused by reduced growth of the embryonic nasal septum, and (2) the septal growth retardation occurs because the warfarin-induced extrahepatic vitamin K deficiency prevents the normal formation of the vitamin K-dependent matrix gla protein in the embryo.

Topics: Animals; Animals, Newborn; Calcinosis; Cartilage Diseases; Female; Growth Plate; Male; Maxilla; Models, Biological; Nasal Bone; Nasal Septum; Rats; Rats, Sprague-Dawley; Skull; Species Specificity; Vitamin K 1; Vitamin K Deficiency; Warfarin

Topics: Cerebral Hemorrhage; Female; Humans; Infant, Newborn; Time Factors; Vitamin K; Vitamin K 1; Vitamin K Deficiency; Vitamin K Deficiency Bleeding

Liver and serum concentrations of vitamin K active compounds were measured in two groups of (deficient and normal) broilers after administration of phylloquinone 1 mg/kg. Assays were performed by HPLC after extraction and purification of these compounds. The only menaquinone found in the chicken was menaquinone-4. In the deficient group, the chickens exhibited hepatic concentrations of vitamin K1, vitamin K1 epoxide and menaquinone-4 markedly lower than those of the control group. After administration of phylloquinone, vitamin K and vitamin K epoxide levels fell sharply. There is no hepatic storage of vitamin K comparable to that of vitamin A. However, while menaquinone levels were found to be stable in the control group, they rose significantly in the deficient group after vitamin K injection. The question is: is there a transformation of vitamin K into menaquinone and/or is there a preferential utilization of one of the vitamin K active compounds?

Topics: Animals; Chickens; Diet; Female; Injections, Intravenous; Liver; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

Cephalosporin antibiotics with N-methyl-thio-tetrazole (NMTT) side chains have been known to be associated with the development of hypoprothrombinemia. However, it has not been fully established whether these symptoms are induced by an inhibition of vitamin K production by intestinal microorganisms or by an inhibitory action of these antibiotics on endogenous vitamin K metabolism. Therefore, an attempt has been made to clarify the above-mentioned ambiguity by using germfree mice in which primary vitamin K deficiency can be established within a short experimental period. Germfree (GF) and conventional (CV) ICR male mice, 8-13 weeks old were used in this experiment. Vitamin K deficient (Def) and menaquinone-4 supplemented diet (MK-4) were fed to the mice in both rearing conditions. In the antibiotic-treated group, sodium latamoxef (LMOX, 300 mg/kg B.W./day) was intraperitoneally administered once a day, and in the control group the same volume of saline (Saline) was administered. Severe vitamin K deficient symptoms were observed in the GF-K-Def-LMOX group, and both prothrombin time (PT) and activated-partial thromboplastin time (APTT) values were prolonged on the 8th day of the experimental period compared with the GF-K-Def-Saline group. Furthermore the mortality rate of GF-K-Def-LMOX group was comparatively higher than that of the Saline group. This study has provided evidence that vitamin K deficiency is amplified by an administration of LMOX even in the absence of intestinal flora.

Topics: Animals; Anti-Bacterial Agents; Bacteroides; Blood Coagulation; Diet; Escherichia coli; Germ-Free Life; Intestinal Mucosa; Intestines; Liver; Male; Mice; Moxalactam; Partial Thromboplastin Time; Prothrombin Time; Vitamin K; Vitamin K 1; Vitamin K Deficiency

We studied whether the administration of vitamin K to mothers could increase the concentration of vitamin K in breast milk and prevent idiopathic vitamin K deficient bleeding in breast-feeding infants. Sixty puerperal women were divided into three groups, the control group, Menaquinone-4 (MK-4) administered group and vitamin K1 administered group. We measured the concentrations of vitamin K1, MK-4 and MK-7 in maternal plasma and breast milk on the fourth day after delivery. In the MK-4 group, the concentrations of MK-4(2.13 ng/ml in plasma, 49.3 ng/ml in milk) were significantly higher than in the control group (0.28 ng/ml, 1.51 ng/ml). In the vitamin K1 group, the concentrations of vitamin K1 (49.0 ng/ml in plasma, 71.6 ng/ml in milk) were significantly higher than in the control group (1.17 ng/ml, 2.41 ng/ml). The concentration rates (milk/plasma ratio) of vitamin K1, MK-4 and MK-7 were 2.52, 5.43 and 0.52 in the control group, 1.60, 40.2 and 0.67 in the MK-4 group and 1.65, 10.8 and 0.71 in the vitamin K1 group, respectively. The concentration rate of MK-4 was higher than that of vitamin K1 and was increased by MK-4 administration. After delivery, the daily concentration of MK-4 in milk was increased from 1.69 ng/ml on the first day to 49.3 ng/ml on the fourth day in the MK-4 group. These results indicate that MK-4 is accumulated and concentrated into breast milk, and continuous MK-4 administration can increase the concentration of vitamin K in milk, preventing idiopathic vitamin K deficient bleeding in infants.

Topics: Female; Humans; Infant; Milk, Human; Postpartum Period; Pregnancy; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

The relationship between dietary phylloquinone, serum and liver concentrations of phylloquinone, and various indices of vitamin K adequacy have been studied in male rats fed a purified diet containing various levels of phylloquinone. In excess of 500 micrograms phylloquinone/kg diet was needed to prevent the most sensitive signs of vitamin K deficiency. Liver phylloquinone concentrations were shown to be correlated with dietary phylloquinone intake. Serum phylloquinone was not correlated with either diet or liver concentration of phylloquinone and did not increase with increased dietary intake until the liver contained sufficient vitamin to maintain optimal synthesis of vitamin K-dependent proteins. Because of the rapid loss of vitamin from the liver, prior ingestion of a high level of vitamin K had little influence on liver vitamin K concentrations beyond the first 2 d of a deficient period. When rats consumed a diet containing 500 micrograms phylloquinone/kg diet in 3 h, liver and serum phylloquinone concentrations fluctuated drastically following this feeding period. During the subsequent 24-h period, liver phylloquinone concentrations decreased to a level that would not support maximal activity of the hepatic vitamin K-dependent carboxylase.

Topics: Animals; Diet; Liver; Male; Nutritional Requirements; Prothrombin Time; Rats; Vitamin K 1; Vitamin K Deficiency

Topics: Administration, Oral; Breast Feeding; Drug Administration Schedule; Female; Humans; Infant; Infant, Newborn; Vitamin K 1; Vitamin K Deficiency

A group of nine well-nourished patients, with normal serum vitamin K1 levels (mean 546, range 310-1350 pg/ml), maintained normal prothrombin times (PTs) and factor VII clotting activities throughout a 7 d course of i.v. cefotetan disodium, an N-methyl-thiotetrazole (NMTT) containing cephalosporin antibiotic. However, 11 of 20 patients, with acute intra-abdominal sepsis and initially normal PTs who underwent emergency surgery, developed prolonged PTs (INR 1.4-3.1) associated with reduction in factor VII activities (0.74-0.38 u/ml) after 3-7 d of antibiotic therapy. Nine of these 11 patients had clinical evidence of malnutrition and nine had subnormal serum vitamin K1 levels (mean 119, range 43-354 pg/ml) on admission. Seven received cefotetan but four were treated with a non-NMTT-containing cephalosporin or antibiotics belonging to other groups. The nine patients who maintained normal PTs all had normal nutritional status and normal serum vitamin K1 levels (mean 279, range 103-915 pg/ml) at presentation. The PT is a relatively insensitive indicator of vitamin K stores, and malnourished patients with low serum vitamin K1 levels are at risk of developing hypoprothrombinaemia following intravenous antibiotic therapy.

Topics: Adult; Aged; Aged, 80 and over; Blood Coagulation Tests; Cefotetan; Cephamycins; Humans; Hypoprothrombinemias; Middle Aged; Nutrition Disorders; Vitamin K 1; Vitamin K Deficiency

Topics: Humans; Hypoprothrombinemias; Infant; Infant, Newborn; Milk, Human; Syndrome; Vitamin K; Vitamin K 1; Vitamin K Deficiency

We have evaluated a boy who had excessive bleeding and bruising from birth and showed markedly prolonged prothrombin times, partially correctable by oral vitamin K administration. Additional laboratory studies demonstrated decreased activities of plasma factors II, VII, IX, and X; near normal levels of immunologically detected and calcium binding-independent prothrombin; undercarboxylation of prothrombin; excess circulating vitamin K epoxide; decreased excretion of carboxylated glutamic acid residues; and abnormal circulating osteocalcin. These results all are consistent with effects resulting from decreased posttranslational carboxylation secondary to an inborn deficiency of vitamin K epoxide reductase. This individual also had nasal hypoplasia, distal digital hypoplasia, and epiphyseal stippling on infant radiographs, all of which are virtually identical to features seen secondary to first-trimester exposure to coumarin derivatives. Therefore, by inference, the warfarin embryopathy is probably secondary to warfarin's primary pharmacologic effect (interference with vitamin K-dependent posttranslational carboxylation of glutamyl residues of various proteins) and may result from undercarboxylation of osteocalcin or other vitamin K-dependent bone proteins.

Topics: 1-Carboxyglutamic Acid; Abnormalities, Drug-Induced; Calcium-Binding Proteins; Child; Chromatography, High Pressure Liquid; Female; Fetal Diseases; Fingers; Humans; Male; Nose; Osteocalcin; Phenotype; Pregnancy; Prothrombin; Radiography; Vitamin K; Vitamin K 1; Vitamin K Deficiency; Warfarin

Decreased concentrations of vitamin K-dependent plasma clotting factors are a well-documented response of vitamin K-deprived patients administered broad-spectrum antibiotics. It has recently been claimed that antibiotics containing a N-methylthiotetrazole (NMTT) side chain cause this response through a direct effect of NMTT on the vitamin K-dependent posttranslational carboxylation of these clotting factors. To further study these relationships, 11 groups of three volunteers were fed a synthetic vitamin K-free diet for 2 weeks. During the last 10 days of vitamin K restriction, seven of the volunteer groups received a therapeutic dose of antibiotics not containing NMTT: ampicillin, sulfamethoxazole-trimethoprim (Bactrim), cefoxitin, cefotaxime, ceftazidime, clindamycin, and piperacillin, and three groups received NMTT-containing antibiotics: moxalactam, cefamandole, and cefoperazone. Serum phylloquinone (vitamin K1) concentrations reflected dietary intake and fell from 1.4 +/- 0.9 ng/ml after 3 days of hospital diet to 0.4 +/- 0.3 ng/ml after 13 days of vitamin K-free diet. Median stool excretion of phylloquinone was 19 micrograms/day while subjects consumed the hospital diet, and fell to 3 micrograms/day by day 6 on vitamin K-free diet. Prothrombin times remained within the normal range throughout the study. Suppression of vitamin K-dependent clotting factor biosynthesis was evident by decreased factor VII levels in seven of the volunteers and by an increased concentration of des-gamma-carboxy (abnormal) prothrombin in 21 of the volunteers. The changes occurred in the control subjects and in subjects receiving all nine of the 10 antibiotics with no consistent pattern.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Anti-Bacterial Agents; Blood Coagulation Factors; Humans; Male; Middle Aged; Prothrombin Time; Tetrazoles; Vitamin K 1; Vitamin K Deficiency

The efficacy and tolerability of a conventional vitamin K1 preparation containing polyoxyethylated castor oil as solubilizer were compared with those of a new compound containing mixed micelles as solubilizer in 30 patients. A statistically significant increase in the thrombotest was detected after treatment in both groups. No hematological or chemical toxicity was observed during the observation period. One patient had an anaphylactoid reaction after intravenous injection of the mixed micelles preparation. Intradermal testing yielded positive results. The authors conclude that intravenous administration of vitamin K preparations should be reserved for acute emergencies.

Topics: Adult; Aged; Aged, 80 and over; Anaphylaxis; Blood Coagulation Tests; Excipients; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Vitamin K 1; Vitamin K Deficiency

The levels of the vitamin K-dependent clotting factors are markedly lower in the human fetus and newborn than in older infants and adults. Direct measurement of vitamin K1 in cord plasma records low or undetectable levels. This phenomenon, although the norm, is referred to as vitamin K deficiency and is a significant risk factor for hemorrhage in the fetus and newborn. Sister chromatid exchange (SCE), which may be used as an index of mutagenic activity, was assayed in cultured leukocytes of placental and adult blood following phytohemagglutinin stimulation. The mean number of SCEs per metaphase in human placental blood was 3.32 +/- SE 0.219 as compared with levels of 5.13 +/- SE 0.273 in young adults (p less than 0.01), and in the presence of added vitamin K1 at a concentration of 1 X 10(-6) M the SCE increased significantly in both adult and placental cells. In vitro SCE dose response curves to K1 in the blood of fetal and maternal sheep were obtained. When five fetal sheep were given 1 mg of K1 by catheter into the femoral vein the SCE increased from 3.94 +/- SE 0.15 preinjection to 5.38 +/- SE 0.23 at 24 h postinjection (p less than 0.01). In the pretreatment fetal sheep, serum vitamin K1 was below detectable levels in all seven animals in which it was assayed and reached levels as high as 0.3 X 10(-6) M 1 h post-K1 injection. The low level of K1 in the fetus may in fact confer some biological advantage by reducing the risk of mutagenic events during a period of rapid cell proliferation.

Topics: Adult; Animals; Cells, Cultured; Female; Fetal Blood; Humans; Infant, Newborn; Lymphocytes; Sheep; Sister Chromatid Exchange; Vitamin K 1; Vitamin K Deficiency

Topics: Age Factors; Breast Feeding; Factor IX; Factor VII; Factor X; Female; Humans; Infant; Infant Nutritional Physiological Phenomena; Infant, Newborn; Pregnancy; Prothrombin; Risk; Vitamin K; Vitamin K 1; Vitamin K Deficiency; Vitamin K Deficiency Bleeding

Topics: Anti-Bacterial Agents; Blood Coagulation Factors; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature, Diseases; Parenteral Nutrition; Parenteral Nutrition, Total; Vitamin K 1; Vitamin K Deficiency

Hydroxy vitamin K [3(2)-hydroxy-2,3- dihydrovitamin K1] has been identified as a quantitatively important metabolite of injected vitamin K epoxide in vivo. The metabolite has been isolated and identified by comparison of its UV, mass spectra and high-performance liquid chromatography (HPLC) retention times with those of synthetic standards, and by its characteristic conversion to vitamin K quinone on treatment with the base triethylamine. This metabolite is formed from the vitamin K epoxide, not from the vitamin K quinone and can represent up to 3.5% of dose and 13% of hexane-extractable metabolites present in liver 1 hour after injection of 330 micrograms vitamin K1 epoxide per kilogram body weight. It is formed in both normal and warfarin-resistant rat strains, but to a significantly greater extent in the latter. Unlike the hydroxy vitamin K formed by warfarin-resistant rat liver microsomes in vitro, the metabolite formed from racemic vitamin K epoxide in vivo was not optically active, nor was its formation inhibited by coumarin anticoagulants under conditions that completely blocked vitamin K epoxide reduction in vivo. On this basis, hydroxy vitamin K formation in vivo differs from its formation in vitro; it is not a product of vitamin K epoxide reductase in vivo, but of some other possibly non-enzymatic reaction.

Topics: Animals; Chromatography, High Pressure Liquid; Drug Resistance; Liver; Male; Mixed Function Oxygenases; Rats; Vitamin K; Vitamin K 1; Vitamin K Deficiency; Vitamin K Epoxide Reductases; Warfarin

Vitamin K3 inhibits the conversion of benzo(a)pyrene to its more polar metabolites in an in vitro rat liver microsomal system. Vitamin K3 also inhibits benzo(a)pyrene metabolism in rat liver fragments and reduces its mutagenicity in the Ames test. Higher concentrations of vitamin K3 are required to comparably reduce benzo(a)pyrene metabolism when the microsomal system has been induced with 3-methylcholanthrene. High pressure liquid chromatography analysis of the products of benzo(a)pyrene metabolism shows a uniform reduction of all the metabolic products. When tumors were induced in ICR/Ha female mice by the intraperitoneal injection of benzo(a)pyrene, those mice given vitamin K3 before or both before and after benzo(a)pyrene had a slower rate of tumor appearance and tumor death rate as compared with those receiving benzo(a)pyrene alone. However, vitamin K1 increased the rate of tumor death while vitamin K deprivation and warfarin decreased the rate of tumor appearance and death in benzo(a)pyrene-injected mice. These studies indicate that vitamin K3 is an inhibitor of aryl hydrocarbon hydroxylase and reduces the carcinogenic and mutagenic metabolites in vitro, and inhibits benzo(a)pyrene tumorigenesis in vivo. That vitamin K1 enhances the benzo(a)pyrene effect while warfarin and vitamin K deficiency inhibit benzo(a)pyrene tumorigenesis indicates that vitamin K1, vitamin K deprivation, or possibly blockade of its metabolic cycle also modulates benzo(a)pyrene metabolism in vivo but by a mechanism or at a site different from the vitamin K3 effect. The vitamin K series should be considered as capable of serving a regulatory function in the metabolism of benzo(a)pyrene and possibly other compounds metabolized through the mixed function oxidase system.

Topics: Aflatoxin B1; Aflatoxins; Animals; Benzo(a)pyrene; Benzopyrenes; Female; Male; Mice; Mice, Inbred ICR; Microsomes, Liver; Mutagenicity Tests; Mutation; Neoplasms, Experimental; Rats; Rats, Inbred Strains; Vitamin K; Vitamin K 1; Vitamin K 3; Vitamin K Deficiency

Topics: Breast Feeding; Female; Humans; Infant; Infant, Newborn; Male; Vitamin K 1; Vitamin K Deficiency; Vitamin K Deficiency Bleeding

Vitamin K-1 epoxide, the major metabolite of vitamin k-1, has similar activity to vitamin K-1 in inducing prothrombin synthesis and protein carboxylation. The high activity of K-1 epoxide could be due to its conversion to vitamin K-1 hydroquinone without going through vitamin K-1. A logical intermediate in this conversion would be vitamin K-1 epoxide-1,4-diol. The epoxide diol was synthesized and clearly stimulated prothrombin synthesis in vitamin K deficient rats at a minimum dose of 100 micrograms/kg body weight. Since vitamin K-1 produced a similar response at a minimum dose of 1 microgram/kg, the epoxide diol had about 1% of the activity of vitamin K-1. [3H]K-1 or [3H]epoxide could not be detected as metabolites of [3H]epoxide diol indicating that the activity of epoxide diol was probably not due to its conversion to K-1 hydroquinone, since any [3H]hydroquinone formed would be oxidized in air to [3H]K-1 during analysis. Vitamin K-1 epoxide diol represents a new type of structure possessing vitamin K activity. It is probably not active itself but has to be converted to an active compound since there is a delay in the response to the diol and the activity is completely blocked by Warfarin.

Topics: Animals; Prothrombin; Rats; Vitamin K; Vitamin K 1; Vitamin K Deficiency; Warfarin

The cis and trans isomers of vitamin K1 have been prepared at a purity of better than 99.5% and tested for effect on plasma level of factor VII in coumarin anticoagulant-pretreated and vitamin K-deficient rats. Both isomers show activity, but in coumarin anticoagulant-pretreated animals the cis isomer has approximately 10% and in vitamin K-deficient approximately 1% of the activity of the trans isomer. The cis isomer also shows slower onset and rate of increase of the response. Reduction of the 2',3'-double bond of the phytyl side chain of either isomer to the same 2',3'-dihydro derivative of vitamin K1 leaves the activity of the trans isomer unchanged but increases the activity of the cis isomer to that of the trans isomer. The results suggest that the phytyl side chain not only serves to increase lipid solubility, but may play a more direct functional role.

Topics: Animals; Dose-Response Relationship, Drug; Drug Interactions; Factor VII; Oxidation-Reduction; Rats; Stereoisomerism; Time Factors; Vitamin K 1; Vitamin K Deficiency; Warfarin

Topics: Blood Coagulation; Blood Coagulation Tests; Female; Humans; Infant, Newborn; Injections, Intramuscular; Male; Mass Screening; Sex Factors; Vitamin K 1; Vitamin K Deficiency; Vitamin K Deficiency Bleeding

Topics: Animals; Carboxy-Lyases; Kinetics; Male; Microsomes, Liver; Oligopeptides; Rats; Vitamin K; Vitamin K 1; Vitamin K Deficiency

The vitamin K-dependent hemostatic factors are present in reduced quantities at birth and may decrease further in the first few days of life. Administration of vitamin K1 on day 1 prevents hemorrhagic disease of the newborn. Maternal ingestion of anticonvulsants puts the newborn at greater risk from hemorrhage, possibly as a result of induction of fetal microsomal enzymes with a resultant increased oxidative degradation of vitamin K which gives rise to a vitamin K deficiency and other concomitant clinical results, for example skeletal defects. Evidence for this sequence of events is presented and the widespread effect of vitamin K deficiency on the fetus is discussed.

Topics: Abnormalities, Drug-Induced; Animals; Blood Coagulation Factors; Bone and Bones; Chick Embryo; Female; Hemostasis; Humans; Maternal-Fetal Exchange; Microsomes, Liver; Oxidation-Reduction; Phenytoin; Pregnancy; Vitamin K 1; Vitamin K Deficiency; Vitamin K Deficiency Bleeding; Warfarin

Topics: Animals; Chickens; Female; Liver; Male; Protein Precursors; Prothrombin; Rats; Vitamin K; Vitamin K 1; Vitamin K Deficiency

Two-week-old chicks adequate in vitamin K showed a relative lack of vitamin K-dependent clotting factors when compared with the rat, cow, and man. Chick prothrombin was 50%, IX 8%, and X 6% of respective levels in the rat. Factor VII was not detectable in chick plasma. When 1-day-old chicks were fed a vitamin K-deficient diet, prothrombin levels fell to 5% in 5 days, whereas factors IX and X fell to only 60% of normal. After warfarin administration to normal chicks, prothrombin levels fell to 20% in 6 hours, whereas factors IX and X fell to 60%. When cycloheximide was given to normal chicks, all vitamin K-dependent factors fell at the same relative rate with a half time of 2 hours. Cycloheximide also completely blocked the effect of physiological doses (10 mug) of phylloquinone upon prothrombin synthesis, but only partially blocked the effect of pharmacological doses (2.5 mg) of phylloquinone, suggesting an antagonism between cycloheximide and vitamin K at the ribosomal level. Puromycin was effective in blocking the action of vitamin K at both physiological and pharmacological doses. In the chick, unlike the rat, it appears that (1) cycloheximide is fully effective in blocking the action of physiological doses of vitamin K and (2) the regulatory systems for factors IX and X appear to have a higher affinity for vitamin K and a lower affinity for warfarin than the regulatory system for prothrombin.

Topics: Animals; Blood Coagulation Tests; Chickens; Cycloheximide; Dactinomycin; Factor IX; Factor X; Protein Biosynthesis; Prothrombin; Puromycin; Species Specificity; Time Factors; Vitamin K; Vitamin K 1; Vitamin K Deficiency; Warfarin

A dietary deficiency of vitamin K has been demonstrated in the Syrian hamster. This species has also been shown to be relatively resistant to the action of the indirect anticoagulant Warfarin, and very sensitive to the anticoagulant action of the vitamin K antagonist chloro-K. These observations, and the hamster's apparently high requirement for the vitamin, indicate that it responds to vitamin K and vitamin K antagonists in the same fashion as Warfarin-resistant strains of rats.

Topics: Animals; Anticoagulants; Blood Coagulation; Cricetinae; Diterpenes; Drug Tolerance; Male; Naphthoquinones; Prothrombin; Species Specificity; Vitamin K; Vitamin K 1; Vitamin K Deficiency; Warfarin

The oxidation of phylloquinone to the 2,3-epoxide (by phylloquinone epoxidase) was studied in liver from control and warfarin-resistant rats. The reaction requires microsomal fraction, soluble protein, a heat-stable soluble factor and O(2). It is not inhibited by CO or CN(-). Epoxidase activity was stimulated if plasma prothrombin was lowered either by anticoagulants or the absence of vitamin K. The activity of the enzyme rapidly returned to normal values after the administration of vitamin K to hypoprothrombinaemic rats. These differences in the activity of the enzyme occur in the microsomal fraction and not the cytosol. A thrombin-generating polypeptide that accumulates in microsomal fraction of hypothrombinaemic rats correlated directly with epoxidase activity. These data support the view that enzymic interconversion of phylloquinone and its 2,3-epoxide participates in the biological activity of vitamin K.

Topics: Animals; Anticoagulants; Blood Coagulation; Carbon Monoxide; Cyanides; Drug Resistance; Edetic Acid; Epoxy Compounds; Female; Flavin-Adenine Dinucleotide; Hypoprothrombinemias; Kinetics; Male; Microsomes, Liver; NAD; NADP; Oxidoreductases; Oxygenases; Proteins; Prothrombin; Rats; Vitamin K; Vitamin K 1; Vitamin K Deficiency; Warfarin

Topics: Animals; Endoplasmic Reticulum; Liver; Male; Microscopy, Electron; Polyribosomes; Prothrombin; Rats; Ribosomes; RNA; Vitamin K 1; Vitamin K Deficiency; Warfarin

Topics: Animals; Carbon Radioisotopes; Castration; DDT; Estradiol; Ethers, Cyclic; Female; Gonadal Steroid Hormones; Hydrolases; Male; Methylcholanthrene; Microsomes, Liver; Oxidoreductases; Phenobarbital; Progesterone; Prothrombin; Rats; Sex Factors; Testosterone; Time Factors; Vitamin K 1; Vitamin K Deficiency

Topics: Animals; Anticoagulants; Coumarins; Ethers, Cyclic; Hypoprothrombinemias; Male; Microsomes, Liver; Prothrombin; Rats; Structure-Activity Relationship; Tritium; Vitamin K; Vitamin K 1; Vitamin K Deficiency; Warfarin

Topics: Animals; Binding Sites; Biological Assay; Cell Nucleus; Isomerism; Kidney; Liver; Male; Microsomes, Liver; Mitochondria, Liver; Muscles; Myocardium; Prothrombin; Rats; Ribosomes; Time Factors; Tritium; Vitamin K; Vitamin K 1; Vitamin K Deficiency

Topics: Animals; Binding Sites; Carbon Isotopes; Centrifugation, Density Gradient; Chlorine; Male; Membranes; Microsomes, Liver; Osmolar Concentration; Phospholipases; Phospholipids; Protein Binding; Rats; Rats, Inbred Strains; Ribosomes; RNA; Vitamin K 1; Vitamin K Deficiency; Warfarin

Topics: Animals; Blood Proteins; Cycloheximide; Enzyme Induction; Hydrocortisone; Male; Metabolism; Prothrombin; Rats; Time Factors; Tyrosine Transaminase; Vitamin K; Vitamin K 1; Vitamin K Deficiency

Topics: Animals; Blood Proteins; Carbon Isotopes; Cycloheximide; Depression, Chemical; In Vitro Techniques; Kinetics; Leucine; Liver; Metabolism; Perfusion; Protein Biosynthesis; Prothrombin; Puromycin; Rats; Ribosomes; Stimulation, Chemical; Vitamin K 1; Vitamin K Deficiency

Topics: Adsorption; Amino Acids; Animals; Barium Sulfate; Carbon Isotopes; Male; Prothrombin; Rats; Tritium; Vitamin K; Vitamin K 1; Vitamin K Deficiency

Topics: Animals; Carbon Isotopes; Male; Oxides; Prothrombin; Rats; Time Factors; Tritium; Vitamin K; Vitamin K 1; Vitamin K Deficiency; Warfarin

Topics: Animals; Blood Coagulation Tests; Cycloheximide; Dactinomycin; Depression, Chemical; Liver; Male; Metabolism; Naphthoquinones; Protein Biosynthesis; Prothrombin; Rats; RNA; Stimulation, Chemical; Time Factors; Tritium; Vitamin K; Vitamin K 1; Vitamin K Deficiency; Warfarin

Coumarin anticoagulants inhibit the release of plasma clotting factor VII by vitamin K in liver slices from vitamin K-deficient animals without inhibition of protein synthesis. When the ratio of vitamin K to coumarin anticoagulant is kept constant, but the concentrations are increased, the inhibition disappears. This suggests that the pharmacological action of coumarin anticoagulants depends on irreversible inhibition of normal vitamin K transport to its site of action. At higher concentrations of vitamin K the inhibition can be surmounted, because vitamin K can enter the cell by an alternate route that is not inhibited by coumarin anticoagulants.

Topics: Animals; Anticoagulants; Biological Transport; Carbon Isotopes; Coumarins; Depression, Chemical; Factor VII; In Vitro Techniques; Leucine; Liver; Protein Biosynthesis; Rats; Vitamin K; Vitamin K 1; Vitamin K Deficiency; Warfarin

Topics: Animals; Cell Nucleus; Centrifugation; Chromatography; Detergents; Endoplasmic Reticulum; Liver; Microsomes; Mitochondria, Liver; Naphthoquinones; Prothrombin; Rats; Ribosomes; Solubility; Spleen; Time Factors; Tritium; Vitamin K; Vitamin K 1; Vitamin K Deficiency; Warfarin

Topics: Animals; Biological Assay; Cattle; Chickens; Chromatography, Paper; Lipid Metabolism; Lipids; Liver; Mitochondria, Liver; Naphthoquinones; Prothrombin Time; Rabbits; Spectrophotometry; Swine; Ultraviolet Rays; Vitamin E; Vitamin K 1; Vitamin K Deficiency

Topics: Administration, Oral; Adult; Aged; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Coumarins; Hemorrhage; Humans; Male; Suicide; Vitamin K 1; Vitamin K Deficiency

Topics: Animals; Arachis; Escherichia coli; Fats; Germ-Free Life; Ginsenosides; Intestines; Oils; Rats; Vitamin K; Vitamin K 1; Vitamin K Deficiency; Vitamins

Topics: Antifibrinolytic Agents; Humans; Naphthoquinones; Retinoids; Vitamin K; Vitamin K 1; Vitamin K Deficiency

Topics: Humans; Vitamin K 1; Vitamin K Deficiency

Topics: Animals; Antifibrinolytic Agents; Chickens; Naphthoquinones; Vitamin K; Vitamin K 1; Vitamin K 3; Vitamin K Deficiency

Topics: Animals; Antifibrinolytic Agents; Chickens; Hemostatics; Vitamin K; Vitamin K 1; Vitamin K 3; Vitamin K Deficiency