Serum vitamin K1 concentration and vitamin K-dependent clotting factor activity in maternal and fetal cord blood

An osteoblast-like human osteosarcoma cell line (U2-OS) has been shown to possess a vitamin K-dependent carboxylation system which is similar to the system in human HepG2 cells and in liver and lung from the rat. In an ‘in vitro’ system prepared from these cells, vitamin K1 was shown to overcome warfarin inhibition of gamma-carboxylation carried out by the vitamin K-dependent carboxylase. The data suggest that osteoblasts, the cells involved in synthesis of vitamin K-dependent proteins in bone, can use vitamin K1 as an antidote to warfarin poisoning if enough vitamin K1 can accumulate in the tissue. Five precursors of vitamin K-dependent proteins were identified in osteosarcoma and HepG2 cells respectively. In microsomes (microsomal fractions) from the osteosarcoma cells these precursors revealed apparent molecular masses of 85, 78, 56, 35 and 31 kDa. When osteosarcoma cells were cultured in the presence of warfarin, vitamin K-dependent 14C-labelling of the 78 kDa precursor was enhanced. Selective 14C-labelling of one precursor was also demonstrated in microsomes from HepG2 cells and from rat lung after warfarin treatment. In HepG2 cells this precursor was identified as the precursor of (clotting) Factor X. This unique 14C-labelling pattern of precursors of vitamin K-dependent proteins in microsomes from different cells and tissues reflects a new mechanism underlying the action of warfarin.

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A comparative study of the effects of warfarin and brodifacoum on the relationship between vitamin K1, metabolism and clotting factor activity in warfarin-susceptible and warfarin-resistant rats

Biochemical Pharmacology ◽

10.1016/0006-2952(81)90182-9 ◽

1981 ◽

Vol 30 (2) ◽

pp. 123-128 ◽

Cited By ~ 38

Author(s):

Jacqueline B. Leck ◽

B.Kevin Park

Keyword(s):

Comparative Study ◽

Clotting Factor ◽

Vitamin K1 ◽

Factor Activity ◽

The Relationship

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Vitamin K Antagonism of Coumarin Intoxication in the Rat

Thrombosis and Haemostasis ◽

10.1055/s-0038-1661528 ◽

1986 ◽

Vol 55 (02) ◽

pp. 235-239 ◽

Cited By ~ 16

Author(s):

R Wallin ◽

D Susan ◽

D Patrick ◽

J O Ballard

Keyword(s):

Vitamin K ◽

Liver Microsomes ◽

Clotting Factor ◽

Vitamin K1 ◽

Clotting Factors ◽

Strong Inhibitor ◽

In Vitro System ◽

High Concentrations

SummaryAn in vitro system which expresses all enzyme activities related to vitamin K-dependent carboxylation of blood clotting factors was prepared from livers of rats overdosed with warfarin, difenacoum and dicumarol respectively. In this system, the activities of the two pathways that are known to produce active reduced vitamin K1 cofactor for the carboxylation reaction were measured. Also the ability of high concentrations of vitamin Kx to overcome inhibition of clotting factor synthesis was studied. In the systems prepared from livers of warfarin and difenacoum intoxicated rats, pathway I was inactive. Vitamin K epoxide reductase was also inactive which strongly suggests that this enzyme catalyzes the activity of pathway I in vivo. Reduction of vitamin by pathway II bypassed the inactive pathway I and resulted in carboxylation activity. This pathway therefore mediates the antidotic effect of vitamin K1 in the coumarin intoxicated liver. In the in vitro system prepared from dicumarol intoxicated livers the activity of pathway I was not significantly affected. Dicumarol however was a strong inhibitor when added to liver microsomes in vitro.

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In Search of Normality for Vitamin K1: Establishing Age-Dependent Reference Intervals in the Danish Population

The Journal of Applied Laboratory Medicine ◽

10.1093/jalm/jfaa017 ◽

2020 ◽

Vol 5 (3) ◽

pp. 531-543

Author(s):

Ida Boegh Andersen ◽

Claus Lohman Brasen ◽

Anne Schmedes ◽

Ivan Brandslund ◽

Jonna Skov Madsen

Keyword(s):

Vitamin K ◽

Serum Vitamin ◽

Reference Intervals ◽

Specific Reference ◽

Vitamin K1 ◽

Serum Samples ◽

Lower Serum ◽

Limit Of Quantitation ◽

Significant Difference ◽

Age Dependent

Abstract Background A growing body of evidence suggests that vitamin K has beneficial effects on human health, especially cardiovascular and bone health. Vitamin K1 (phylloquinone), the predominant form of vitamin K in blood, is regarded as an indicator of vitamin K status, but to our knowledge no reference intervals (RIs) have been established for vitamin K1. Methods In this population-based study, vitamin K1 was measured in serum from 3808 Caucasian individuals without diabetes from 26 to 78 years of age. The need for gender- and age-partitioned vitamin K1 reference intervals was evaluated using Lahti’s method, and exclusion criteria were defined to obtain as healthy a study group as possible. The excluded subgroups were tested for differences in mean serum vitamin K1 levels. Serum vitamin K1 levels were quantified using an in-house newly developed, validated, and highly sensitive online SPE-LC-MS/MS method with a limit of quantitation of (LOQ) 0.05 nmol/L. Results The reference interval for serum vitamin K1 was 0.22 to 3.95 nmol/L for individuals aged 26 to 44 years and 0.35 to 3.70 nmol/L for individuals aged 45 to 78. Similar age-specific reference intervals were established for vitamin K1-triglyceride ratio being 0.20 to 3.16 and 0.31 to 3.44, respectively. No significant difference was found between genders. Serum vitamin K1 was detectable in all serum samples. Individuals with known comorbidity were found to have significantly lower serum vitamin K1 compared to those without comorbidity. Current smokers had lower serum vitamin K1 compared to nonsmokers. Conclusion Age-dependent reference intervals were established for serum vitamin K1 and vitamin K1-triglyceride ratio in a well-defined, healthy Caucasian population. Lower serum vitamin K1 levels were found in individuals with known comorbidity, suggesting an association between serum vitamin K1 and disease status. Further studies are needed to determine an optimal serum vitamin K1 level.

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The Effect of Vitamin K on Pivka and its Associated Procoagulant Proteins in Liver Disease

10.1055/s-0039-1682745 ◽

1977 ◽

Author(s):

R.G. Malia ◽

F.E. Preston ◽

E.K. Blackburn

Keyword(s):

Liver Disease ◽

Vitamin K ◽

Intravenous Administration ◽

Procoagulant Activity ◽

Clotting Factor ◽

Vitamin K1 ◽

Clotting Factors ◽

Inhibitor Activity ◽

Normal Individuals ◽

K Deficiency

Vitamin K deficiency is associated with low procoagulant activity of the vitamin K-dependent clotting factors together with normal concentrations of an immunologically cross-reacting protein associated with the appropriate clotting factor.In this study we have examined the response of the clotting factors II, VII and X together with their appropriate related antigens to the intravenous administration of vitamin K1 in 14 patients with various forms of liver disease. We have also related the observed changes to alterations of the inhibitor activity of PIVKA as detected by the modified thrombotest.A relationship has been established between the rate of appearance of procoagulant activity and the rate of disappearance of PIVKA after the intravenous administration of vitamin K1 in those patients with thrombotest inhibitor activity. In this same group of patients it can also be shown that PIVKA is physico-chemically dissimilar to the related protein of normal individuals.Patients without thrombotest inhibitor activity appear to synthesise decreased amounts of a structurally normal protein which is not influenced by vitamin K.

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SERUM VITAMIN K1 LEVELS AS AN EARLY INDICATOR OF HYPOPROTHROMBINAEMIA ASSOCIATED WITH ANTIBIOTIC THERAPY

10.1055/s-0038-1644340 ◽

1987 ◽

Author(s):

S J Machin ◽

H Cohen ◽

I J Mackie ◽

M Shearer ◽

S D Scott

Keyword(s):

Antibiotic Therapy ◽

Prothrombin Time ◽

Vitamin K ◽

Serum Vitamin ◽

Abdominal Sepsis ◽

Normal Serum ◽

Factor Vii ◽

Vitamin K1 ◽

K Deficiency ◽

Cefotetan Disodium

The prothrombin time is an insensitive indicator of early vitamin K deficiency and serum vitamin K1 levels may correlate with liver stores. A random non-fasting range of serum vitamin K1 was established in 45 healthy adults of 150-1,530 pg/ml (mean 412 pg/ml). Nine well nourished patients, with normal serum vitamin K1 levels, (mean 546, range 310-1,350 pg/ml), maintained normal prothrombin times and factor VII clotting activity throughout 7 days therapy with cefotetan disodium, an NMTT-containing cephalosporin antibiotic. However, 11 of 20 patients with acute intra-abdominal sepsis and an initially normal prothrombin time who underwent emergency surgery, developed a raised prothrombin time (INR 1.4-3.1) associated with reduction in factor VII activity (0.74 to 0.38 iu/ml) after 3-7 days of antibiotic therapy and the presence of PIVKA II by crossed-immunoelectrophoresis. Nine of these 11 patients had clinical evidence of malnutrition by anthropometric assessment and subnormal serum vitamin K1 (mean 119, range 43-354 pg/ml) levels on admission. Seven received cefotetan but 4 were treated with other non-NMTT containing antibiotics. The 9 patients who maintained normal prothrombin times and factor VII levels had normal nutritional status and normal serum vitamin K1 levels (mean 279, range 103-915 pg/ml) at presentation. A low serum vitamin K1 level was associated with a high incidence of hypopro-thrombinaemia developing following antibiotic therapy and would appear a more sensitive indicator of reduced vitamin K stores than the prothrombin time.

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Vitamin K–containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7

Blood ◽

10.1182/blood-2006-08-040709 ◽

2006 ◽

Vol 109 (8) ◽

pp. 3279-3283 ◽

Cited By ~ 199

Author(s):

Leon J. Schurgers ◽

Kirsten J. F. Teunissen ◽

Karly Hamulyák ◽

Marjo H. J. Knapen ◽

Hogne Vik ◽

...

Keyword(s):

Vitamin K ◽

Serum Vitamin ◽

Life Time ◽

Serum Levels ◽

Coagulation Factors ◽

Matrix Gla Protein ◽

Vitamin K1 ◽

Blood Coagulation Factors ◽

Oral Anticoagulant Treatment ◽

Over The Counter

Abstract Vitamin K is a cofactor in the production of blood coagulation factors (in the liver), osteocalcin (in bone), and matrix Gla protein (cartilage and vessel wall). Accumulating evidence suggests that for optimal bone and vascular health, relatively high intakes of vitamin K are required. The synthetic short-chain vitamin K1 is commonly used in food supplements, but recently the natural long-chain menaquinone-7 (MK-7) has also become available as an over-the-counter (OTC) supplement. The purpose of this paper was to compare in healthy volunteers the absorption and efficacy of K1 and MK-7. Serum vitamin K species were used as a marker for absorption and osteocalcin carboxylation as a marker for activity. Both K1 and MK-7 were absorbed well, with peak serum concentrations at 4 hours after intake. A major difference between the 2 vitamin K species is the very long half-life time of MK-7, resulting in much more stable serum levels, and accumulation of MK-7 to higher levels (7- to 8-fold) during prolonged intake. MK-7 induced more complete carboxylation of osteocalcin, and hematologists should be aware that preparations supplying 50 μg/d or more of MK-7 may interfere with oral anticoagulant treatment in a clinically relevant way.

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