Vitamin K prophylaxis in high-dose chemotherapy.
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Bone Marrow Transplantation↗
Biomedical subjects
M J Shearer
Publications and source records attributed to M J Shearer.
Variation of phylloquinone (vitamin K1) concentrations in hemodialysis patients.
Intra- and interindividual variation of phylloquinone (vitamin K1) concentrations was investigated by repeat analysis of serum from 28 hemodialysis patients with different apolipoprotein E genotypes. Phylloquinone concentrations ranged from 0.1 to 9.0 nM, with a mean of 1.08 nM (standard deviation 1.90 nM). Most of the variation in serum phylloquinone concentrations was due to differences between patients; the ratio of intra- to interindividual variation was 0.17. Serum triglyceride concentrations and apoE genotype together accounted for 64% of interindividual variation; in contrast, only 6% of intraindividual variation could be attributed to differences in triglyceride concentrations. The small residual variance implies that different phylloquinone consumption levels contributed relatively little to the variation of serum concentrations ( < 36% of interindividual variance). The results suggest that individual disposition is a more important determinant of serum phylloquinone concentrations than dietary phylloquinone intake.
Aged↗
The extent of vitamin K deficiency in patients with cholestatic jaundice: a preliminary communication.
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.
Adult↗
Fetal intraventricular haemorrhage and maternal warfarin.
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Cerebral Hemorrhage↗
Phylloquinone transport and its influence on gamma-carboxyglutamate residues of osteocalcin in patients on maintenance hemodialysis.
Plasma concentrations of phylloquinone in 42 fasting hemodialysis patients showed a much wider range than in healthy adults. Phylloquinone concentrations were best predicted by the concentration ratio of beta-very-low-density-lipoprotein to low-density-lipoprotein cholesterol (r = 0.71), which is closely related to chylomicron-remnant clearance. Phylloquinone concentrations in plasma were related to apolipoprotein E genotype in the order E2 > E3 > E4. The percentage of carboxylated osteocalcin (HBC) was related to the plasma concentration of phylloquinone in patients with the apolipoprotein E genotype E3/3 (r = 0.52, P < 0.05), and in patients with the genotypes E2/3 and E2/2 (r = 0.23, P < 0.1). Overall, plasma triglyceride concentration was a better predictor for HBC than was the plasma concentration of phylloquinone. These results point to the overriding importance of chylomicrons for the transport of phylloquinone to liver and bone. Delivery to osteocalcin-producing osteoblasts seemed impaired in patients with the low receptor-affinity apolipoprotein variant E2, suggesting a major role of receptor-mediated chylomicron-remnant uptake in the transport of phylloquinone to bone.
1-Carboxyglutamic Acid↗
Vitamin K1 concentration in breast-fed neonates after oral or intramuscular administration of a single dose of a new mixed-micellar preparation of phylloquinone.
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).
Administration, Oral↗
Des-gamma-carboxyprothrombin (PIVKA II) and plasma vitamin K1 in newborns and their mothers.
Assessments of the vitamin K status in newborns and their mothers by means of des-gamma-carboxy-prothrombin (PIVKA II) measurement have given equivocal results. Part of the variability could be attributed to differences in sensitivity (i.e. the ability to detect small concentrations) and validity (i.e. ability to detect vitamin K deficiency) of the methods applied. None of these methods have yet been validated with respect to plasma vitamin K1. In 22 healthy mother/infant pairs PIVKA II was determined using three different assays including ratio Xa/ecarin (Xa/ec), crossed immunoelectrophoresis (CIE), and an ELISA with a monoclonal antibody (MAB). The results were compared with conventional clotting tests and plasma vitamin K1. The following results were obtained: Cord blood: Clotting tests within age-related normal ranges; PIVKA II detection rates: 0/22 (Xa/ec), 1/22 (CIE), 4/22 (MAB); plasma vitamin K1: undetectable in 20/22. Mothers: Clotting tests all within normal range; PIVKA II detection rates: 1/22 (Xa/ec), 0/22 (CIE), 5/22 (MAB); plasma vitamin K1 (pg/ml) for all mothers (median; range): 186; 55-833; for PIVKA II positive mothers: 213; 59-699. PIVKA II detectability in newborns and mothers was not correlated. The results show an increase in sensitivity for PIVKA II detection in the order of MAB >> CIE > Xa/ec. Due to the very low plasma vitamin K1 at birth, no correlation was possible between cord PIVKA II detectability and plasma vitamin K1. However, in mothers at term PIVKA II MAB appears to be unrelated to the vitamin K status.
Adult↗
Vitamin K metabolism and nutriture.
Vitamin K functions as a co-factor for the post-translational carboxylation of specific glutamate residues to gamma-carboxyglutamate (Gla) residues in several blood coagulation factors (II, VII, IX and X) and coagulation inhibitors (proteins C and S) in the liver; as well as a variety of extrahepatic proteins such as the bone protein osteocalcin. This review outlines some recent advances in our understanding of the metabolism of vitamin K and its role in human nutriture. The introduction of new methodologies to measure the low endogenous tissue concentrations of K vitamins and circulating plasma levels of des-gamma-carboxyprothrombin (PIVKA-II) have provided correspondingly more refined indices for the assessment of human vitamin K status. The assays for vitamin K have also been used to study the sources, intestinal absorption, plasma transport, storage and transplacental transfer of K vitamins and the importance of phylloquinone (vitamin K1) versus menaquinones (vitamins K2) to human needs. The ability to biochemically monitor subclinical vitamin K deficiency has reaffirmed the precarious vitamin K status of the newborn and led to an increased appreciation of the risk factors leading to haemorrhagic disease of the newborn and how this may be prevented. Biochemical studies are leading to an increased knowledge of the mode of action of traditional coumarin anticoagulants and how some unrelated compounds (e.g. antibiotics) may also antagonize vitamin K and cause bleeding. There is also an awareness of the possible deleterious effects of vitamin K antagonism or deficiency on non-hepatic Gla-proteins which may play some subtle role in calcium homeostasis.
Humans↗
Serum osteocalcin in the management of myeloma.
We have measured serum osteocalcin, a vitamin K-dependent glycoprotein synthesised by osteoblasts in 62 patients, 49 with myeloma, 26 at presentation and 23 previously treated, 7 with Waldenstrom's macroglobulinaemia (WM), and 6 with monoclonal gammopathy of uncertain significance (MGUS). Osteocalcin levels were normal in WM and MGUS. High values were found in 5/26 (19%) patients with myeloma at presentation. There was no relationship between serum osteocalcin and stage of disease. Osteocalcin was normal in all patients in plateau phase, falling to low levels in relapsed patients who failed to respond to further treatment. Serum osteocalcin may be a useful indicator of bone metabolism in myeloma.
Adult↗
Difenacoum poisoning as a cause of haematuria.
A man presented with frank haematuria and a grossly prolonged prothrombin time. He was later found to have taken an overdose of difenacoum--a 'superwarfarin' rodenticide. The diagnosis was confirmed by a serum concentration of difenacoum of 0.6 micrograms ml-1. Overdosage with superwarfarins is discussed and the need for prolonged treatment with vitamin K1 highlighted.
4-Hydroxycoumarins↗
Comparative aspects of human vitamin K metabolism and nutriture.
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Bacteria↗
Depressed levels of circulating menaquinones in patients with osteoporotic fractures of the spine and femoral neck.
Vitamin K1 functions in the conversion of glutamate residues, present in certain bone peptides, into the putatively active gamma-carboxyglutamate form. We have shown previously that the circulating levels of vitamin K1 are depressed in osteoporotic patients. However, it is known that menaquinones (vitamin K2:MK) may be more effective than vitamin K1 in this conversion of the inactive to active form of glutamate residues. A procedure for measuring such menaquinones has now demonstrated a marked deficiency of MK-7 and MK-8 in patients with osteoporotic fractures. It is suggested that estimates of circulating levels of K1, MK-7, and MK-8 might provide a biochemical risk marker of osteoporotic fractures.
Aged↗
A fibroblast cell culture model to study vitamin K metabolism and the inhibition of vitamin K epoxide reductase by known and suspected antagonists.
The metabolism and antagonism of vitamin K has been studied in cultured fibroblasts. Monolayers of 3T3 mouse fibroblasts (grown in the absence or presence of warfarin or other putative antagonists) were incubated for 24 h with [1',2'-3H2]phylloquinone (K1) or [1',2'-3H2]phylloquinone epoxide (K1O), the cells harvested and lipid extracts fractionated by high performance liquid chromatography. [3H]K1 was converted to [3H]K1O (about 20% of [3H] lipids) and to unidentified polar metabolites (30%). [3H]K1O was converted to [3H]K1 (3%) and to polar metabolites (50%). Cells grown with warfarin showed a marked increase in the [3H]K1O:K1 ratio and in the proportion of polar metabolites. The metabolic interconversion of K1 and K1O and inhibitory response to warfarin provide evidence for a fibroblast pathway analogous to the vitamin K-epoxide cycle in the liver. From the K1O:K1 ratios it was possible to grade the antagonism of vitamin K epoxide reductase activity by known and suspected inhibitors. Inhibitory ratios were seen for racemic warfarin down to 10(-8) M. S-warfarin was a more potent antagonist than the R-enantiomer. Consistently low K1O:K1 ratios were observed for N-methyl-thiotetrazole and antibiotics with (moxalactam) or without (cefotaxime) this side chain suggesting that none of these compounds are direct inhibitors of vitamin K epoxide reductase. Fibroblasts grown in cell culture provide a useful model to study the extrahepatic role of vitamin K and the mode of action of vitamin K antagonists.
Animals↗
Age-related changes in the circulating levels of congeners of vitamin K2, menaquinone-7 and menaquinone-8.
1. Through the vitamin K1 cycle, phylloquinone is now known to play an active role, not only in relation to prothrombin, but also in the synthesis of bone peptides. 2. The recent development of a sensitive method allowed the demonstration of a deficit of vitamin K1 in the circulation of osteoporotic subjects. 3. Vitamin K2, namely the menaquinones of various chain-lengths, has been shown by others to be more effective than vitamin K1 in the curative rat bioassay. 4. Earlier reports had shown that the concentration of menaquinones in human liver may exceed that of vitamin K1. But previous methods were too insensitive for testing the normal circulating levels of menaquinones in the human. 5. The new sensitive method has now been applied to measuring the circulating levels of vitamin K1 and of two of the menaquinones, namely menaquinone-7 and menaquinone-8. 6. In normal individuals, the circulating levels of vitamin K1 were the same, irrespective of age. 7. In young normal subjects, the combined levels of menaquinone-7 and menaquinone-8 were at least the same as the level of vitamin K1. In elderly normal subjects, there was a marked deficit of menaquinone-8.
Adult↗
Dietary modification of potential vitamin K supply from enteric bacterial menaquinones in rats.
Rats given a low-fibre diet based on boiled white rice developed symptoms of severe vitamin K deficiency within 23 d. Inclusion of autoclaved black-eye beans (Vigna unguiculata) in the diet prevented the bleeding syndrome. To test the hypothesis that deficiency resulted from low phylloquinone intake exacerbated by inadequate production of menaquinones by the enteric bacteria, a follow-up experiment was carried out in which groups of rats were given an all-rice diet, a rice + beans diet or a stock diet. Rats on the all-rice diet had significantly lower faecal concentrations of the main menaquinone-producing bacterial species (Bacteroides fragilis and Bacteroides vulgatus) than animals on either of the other two diets. This coupled with the much lower faecal output on this diet suggests that total menaquinone production was low for the all-rice diet. The alterations in faecal flora were associated with several significant changes in caecal metabolism. Rats given the stock diet had much shorter caecal transit times and a considerably greater proportion of butyric acid in volatile fatty acid end-products than did rats on either of the other two diets.
Animals↗
Vitamin K and vitamin K-dependent proteins.
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Humans↗
Mechanism of cephalosporin-induced hypoprothrombinemia: relation to cephalosporin side chain, vitamin K metabolism, and vitamin K status.
The mechanism of cephalosporin-induced hypoprothrombinemia has been investigated in hospitalized patients, with respect to cephalosporin structure, vitamin K metabolism, and vitamin K status. Cephalosporins containing side chains of N-methylthiotetrazole (latamoxef, cefmenoxime, cefoperazone, cefotetan, cefamandole) or methyl-thiadiazole (cefazolin) all caused the transient plasma appearance of vitamin K1 2,3-epoxide in response to a 10-mg intravenous dose of vitamin K1, whereas two cephalosporins without a heterocyclic side chain (cefotaxime and cefoxitin) did not. The plasma accumulation of vitamin K1 2,3-epoxide was qualitatively similar to, but quantitatively less than, that produced by the oral anticoagulant phenprocoumon. Patients eating normally had plasma vitamin K1 concentrations (176 to 1184 pg/mL) that were within the normal range (150 to 1550 pg/mL) and their clotting tests remained consistently normal for all antibiotics tested. Patients on total parenteral nutrition had lower plasma vitamin K1 concentrations (50 to 790 pg/mL) but normal clotting before starting antibiotic therapy. Of 19 parenterally fed patients, all seven treated with latamoxef developed hypoprothrombinemia, PIVKA-II and a decrease of protein C within four days whereas 12 patients treated with cefotaxime or cefoxitin showed no clotting changes. Latamoxef-associated hypoprothrombinemia was readily reversible by 1 mg of vitamin K1 given intravenously, but hypoprothrombinemia and sub-normal plasma vitamin K1 could recur within two to three days. The data suggest that NMTT-cephalosporins are inhibitors of hepatic vitamin K epoxide reductase and that a lower nutritional-vitamin K status predisposes to hypoprothrombinemia.
Adult↗