Gender differences in hepatic phylloquinone and menaquinones in the vitamin K-deficient and -supplemented rat.

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.

The interaction between vitamin K nutriture and warfarin administration in patients with bacterial overgrowth due to atrophic gastritis.

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.

The riddle of vitamin K1 deficit in the newborn.

Vitamin K in the fetus and newborn is maintained at levels less than that necessary to achieve full gamma-carboxylation of the K-dependent proteins, including those required for hemostasis. As the infant matures and even into adulthood, there is no significant storage pool for this vitamin, and a K1-deficient state can be produced by placing an adult on a K-deficient diet for 7 to 10 days. Questions arise as to why the level of vitamin K is so rigidly controlled and why the placental gradient in humans and other mammals maintains the fetus in a K-"deficient" state. The evidence is reviewed that suggests that K-dependent proteins are ligands for receptor tyrosine kinases, which, in the rapidly proliferating cell milieu of the fetus, control growth regulation. Increased stimuli may result in growth dysregulation whereas conversely, the further depletion of vitamin K-dependent proteins, as in warfarin toxicity, depletes the required stimuli for normal embryogenesis. These findings argue for the need for tightly controlled levels of vitamin K consistent with normal embryogenesis.

Transient electron paramagnetic resonance of the triplet state of P700 in photosystem I: evidence for triplet delocalization at room temperature.

Spin-polarized EPR spectra of the triplet state of P700, the primary electron donor in photosystem I (PS I), have been measured for the first time at room temperature. The measurements were performed on intact PS I from Synechococcus sp. after prereduction of all iron-sulfur centers and on vitamin K1 depleted PS I from Synechocystis 6803. The two preparations give similar spectra with a polarization pattern which indicates that the triplet state is formed via recombination of a radical pair. The axial and nonaxial zero-field splitting (zfs) parameters are found to be magnitude of D = (284 +/- 15) x 10(-4) cm-1 and magnitude of E = (22 +/- 3) x 10(-4) cm-1, respectively. The E-value is 42% smaller than in monomeric chlorophyll a, while the D-value is nearly the same. Measurements of the Synechocystis 6803 sample at 4.5 K yielded zfs parameters which are identical with those of the chlorophyll monomer, in agreement with previous results. In order to explain this behavior, it is proposed that the triplet excitation is delocalized over the two halves of a chlorophyll dimer at room temperature but appears localized on one half at low temperature. The observed zfs parameters are obtained if (1) the magnetic z-axes of the two chlorophylls are collinear, (2) the magnetic y-axes (and x-axes) of the two chlorophylls make an angle of approximately 55 degrees with each other, and (3) the admixture of charge-transfer states to 3P700 is negligible.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of oral and intramuscular vitamin K prophylaxis on vitamin K1, PIVKA-II, and clotting factors in breast fed infants.

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.

Electron transfer reactions in photosystem I following vitamin K1 depletion by ultraviolet irradiation.

Photosystem I preparations were irradiated with UV to destroy vitamin K1 in situ. The depletion of vitamin K1 resulted in inactivation of NADP+ photoreduction and introduction of a approximately 220 ms component in the flash generated P700+ rereduction at room temperature. The photoreduction of the terminal FeS centers FA and FB in control and vitamin K1-depleted preparations at 7 K were comparable. The data confirm that vitamin K1 is functionally implicated in primary electron transfer reactions in PS I at physiological temperature, and that the anomalous results at cryogenic temperature may be explicable in terms of a by-pass of the vitamin K1 acceptor site or heterogeneity introduced into the photosystem by quinone removal.

Dietary deficiency of phylloquinone and reduced serum levels in febrile neutropenic cancer patients.

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.

The development of hypoprothrombinaemia following antibiotic therapy in malnourished patients with low serum vitamin K1 levels.

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.

Plasma vitamin K1 in mothers and their newborn babies.

Plasma vitamin K1 (phylloquinone) was assayed in normal adults and pregnant women at term and their babies by a method based on high-performance liquid chromatography. The mean plasma concentration in 30 healthy, fasting adults was 0.26 ng/ml (range 0.10-0.66). 8 out of 9 healthy mothers at term had a mean K1 concentration of 0.20 ng/ml (range 0.13-0.29), but K1 was not detected in the cord plasma of their babies. 1 mg vitamin K1 given intravenously to 6 mothers shortly before delivery raised their plasma K1 to 45-93 ng/ml: K1 was then detectable in the cord plasma of 4 of the 6 infants but at a much lower concentration which did not exceed 0.14 ng/ml. The large concentration gradient between maternal and neonatal plasma suggests that vitamin K1 does not cross the placenta readily or that the uptake by fetal plasma is low, perhaps because of low levels of a binding lipoprotein. The low levels of vitamin K in the cord plasma of the normal newborn would explain "physiological" hypoprothrombinaemia and suggest the need to reassess current clinical practice in respect of vitamin K prophylaxis in the early neonatal period.