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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.

Infection with Helicobacter pylori causes chronic inflammation and is a risk factor for gastric cancer. Antibiotic treatment or increased dietary folate prevents gastric carcinogenesis in male INS-GAS mice. To determine potential synergistic effects, H. pylori -infected male INS-GAS mice were fed an amino acid defined (AAD) diet with increased folate and were treated with antibiotics after 18 weeks of H. pylori infection. Antibiotic therapy decreased gastric pathology, but dietary folate had no effect. However, the combination of antibiotics and the AAD diet induced anemia, gastric hemorrhage, and mortality. Clinical presentation suggested hypovitaminosis K potentially caused by dietary deficiency and dysbiosis. Based on current dietary guidelines, the AAD diet was deficient in vitamin K. Phylloquinone administered subcutaneously and via a reformulated diet led to clinical improvement with no subsequent mortalities and increased hepatic vitamin K levels. We characterized the microbiome and menaquinone profiles of antibiotic-treated and antibiotic-free mice. Antibiotic treatment decreased the abundance of menaquinone producers within orders Bacteroidales and Verrucomicrobiales . PICRUSt predicted decreases in canonical menaquinone biosynthesis genes, menA and menD . Reduction of menA from Akkermansia muciniphila, Bacteroides uniformis , and Muribaculum intestinale were confirmed in antibiotic-treated mice. The fecal menaquinone profile of antibiotic-treated mice had reduced MK5 and MK6 and increased MK7 and MK11 compared to antibiotic-free mice. Loss of menaquinone-producing microbes due to antibiotics altered the enteric production of vitamin K. This study highlights the role of diet and the microbiome in maintaining vitamin K homeostasis.

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.

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., (© 2017 Société Française de Pharmacologie et de Thérapeutique.)

Purpose: 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., Methods: 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., Results: 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., Conclusions: (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.

Background: Neonatal intracranial bleedings and birth defects have been reported, possibly related to maternal vitamin K1 deficiency during pregnancy after bariatric surgery. The objective of this study was to investigate the effects of screening and supplementation on K1 serum levels in pregnant women with bariatric surgery, and to compare K1 levels and prothrombin time (PT %) in the first trimester with pregnant women without bariatric surgery., Methods: A prospective cohort study including 49 pregnant women with bariatric surgery. Nutritional deficiencies were prospectively screened. In case of observed low K1 serum levels, supplementation was provided. K1 serum levels and PT (%) during the first trimester were compared with a nonsurgical control group of 27 women., Results: During the first trimester, most women had low K1 serum levels (<0.8 nmol/l). Mean vitamin K1 levels were significantly lower in the surgical group compared to the nonsurgical control group (.44 versus .64 nmol/l; P = .016). PT (%) remained in the normal range, The surgery group showed a higher mean PT compared to the controls (111.3 versus 98.9%; P<.001) Mean K1 serum levels in the study group were higher during the third than during the first trimester (P = .014). PT (%) was significantly higher during the second and third than during the first trimester (P = .004). Most of the coagulation factors, including II, V, VII, IX, and X, remained within normal ranges., Conclusion: Low circulating K1 appears to be common in pregnant women with and without bariatric surgery. Supplementation during pregnancy can restore vitamin K1 in women with bariatric surgery, potentially protecting the fetus and newborn against intracranial hemorrhage., (Copyright © 2014 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Scope: 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., Methods and Results: 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., Conclusion: Excess α-tocopherol decreased extrahepatic PK in rats fed PK but not MK-4 in rats fed MK-4., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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.

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.

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.

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.

Introduction: 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., Data: 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., Conclusions: 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.

Unlabelled: 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., Conclusion: 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.

Aim: 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., Methods: 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., Results: 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., Conclusion: 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.

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).

Aims: The ability of oral vitamin K to eliminate all risk of vitamin K deficiency bleeding during the first three months of life was studied., Methods: 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., Results: 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., Conclusions: 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.

Unlabelled: 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., Conclusion: 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.

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).

Objective: 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., Design, Setting, Subjects: 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., Results: 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)., Conclusions: Subtle vitamin K depletion is common among hospitalized patients and protein-calorie malnutrition does not predict its presence.

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.

Patients with burn injuries exhibit multiple risk factors for the development of vitamin K deficiency, including malabsorption, limited enteral intake, antibiotic therapy, and multiple surgical procedures. A prospective evaluation of 48 children was conducted to evaluate serum vitamin K values during the first 4 postburn weeks. Serum levels were analyzed in relation to clinical course. Days of antibiotic (p < 0.02) and albumin therapy (p < 0.003), percentage body surface area excised (p < 0.006), and the administration of blood products (p < 0.05) were significantly correlated with serum vitamin K levels, and days of diarrhea approached statistical significance (p < 0.06). No relationship was found between serum values and prothrombin time, activated partial thromboplastin time, or serum albumin. Ninety-one percent of the children demonstrated serum values below expected norms. These data suggest a relationship between coagulopathy and an intact functioning gastrointestinal tract. However, the relative importance of dietary versus endogenous vitamin K produced by intestinal bacteria remains to be elucidated.

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.

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.

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.

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?

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.

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.

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.

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.