Doses Of Vitamin K1 Research Articles

Vitamin K Status Based on K1, MK-4, MK-7, and Undercarboxylated Prothrombin Levels in Adolescent and Adult Patients with Cystic Fibrosis: A Cross-Sectional Study.

The available evidence on vitamin K status in cystic fibrosis (CF) is scarce, lacking data on vitamin K2 (menaquinones-MK). Therefore, we assessed vitamin K1, MK-4 and MK-7 concentrations (LC-MS/MS) in 63 pancreatic insufficient and modulator naïve CF patients, and compared to 61 healthy subjects (HS). Vitamin K1 levels did not differ between studied groups. MK-4 concentrations were higher (median <1st-3rd quartile>: 0.778 <0.589-1.086> vs. 0.349 <0.256-0.469>, p < 0.0001) and MK-7 levels lower (0.150 <0.094-0.259> vs. 0.231 <0.191-0.315>, p = 0.0007) in CF patients than in HS. MK-7 concentrations were higher in CF patients receiving K1 and MK-7 supplementation than in those receiving vitamin K1 alone or no supplementation. Moreover, vitamin K1 concentrations depended on the supplementation regime. Based on multivariate logistic regression analysis, we have found that MK-7 supplementation dose has been the only predictive factor for MK-7 levels. In conclusion, vitamin K1 levels in CF are low if not currently supplemented. MK-4 concentrations in CF patients supplemented with large doses of vitamin K1 are higher than in HS. MK-7 levels in CF subjects not receiving MK-7 supplementation, with no regard to vitamin K1 supplementation, are low. There do not seem to be any good clinical predictive factors for vitamin K status.

Investigation of the protective effect of vitamin K1 on the heart in streptozotocin induced type 1 diabetes model

Maternal and fetal diabetes are directly associated with increased morbidity and mortality risk. Along with this increased risk, the incidence of congenital malformations in newborns also increases depending on the mother’s diabetes. Vitamin K1 is used as a therapeutic and protective agent in diabetes and various clinical conditions. For this reason, it was aimed to investigate the effect of vitamin K1 on chick embryo hearts immunohistochemically and morphologically by creating type 1 diabetes mellitus with streptozotocin in a chick embryo model. In our study, 5 different experimental groups will be created and a total of 50 SPF fertilized eggs, 10 in each group, will be used. The first group will be the control group, the second group will be the diabetes group, and the other three groups will be the treatment groups given different doses of vitamin K1. All solutions will be given on the 12th day ofincubation, and the hearts of all embryos will be analyzed immunohistochemically and morphologically on the 18th day of incubation. It was determined that the weight, length and ventricular thickness of the chick embryo hearts were statistically significantly decreased in the streptozotocin group compared to the control group embryo hearts. It was determined that the heart weights, lengths, and ventricular thicknesses increased depending on the dose of vitamin K1 compared to the streptozotocin group in the groups therapeutically administered vitamin K1 (p&lt;0.05). In addition, caspase-3 expression was also evaluated in our study, and a statistically significant increase was found in the streptozotocin group compared to the control group. Again, as a result of vitamin K1 administration, caspase-3 expressions decreased depending on the applied dose (p&lt;0.05). In conclusion, it was concluded thatthe therapeutically applied vitamin K1 to diabetes mellitus reduces the degenerative and hyperplastic effects of diabetes mellitus.

A novel vitamin K derived anticoagulant tolerant to genetic variations of vitamin K epoxide reductase

BackgroundVitamin K antagonists (VKAs), such as warfarin, have remained the cornerstone of oral anticoagulation therapy in the prevention and treatment of thromboembolism for more than half a century. They function by impairing the biosynthesis of vitamin K‐dependent (VKD) clotting factors through the inhibition of vitamin K epoxide reductase (VKOR). The challenge of VKAs therapy is their narrow therapeutic index and highly variable dosing requirements, which are partially the result of genetic variations of VKOR. ObjectivesThe goal of this study was to search for an improved VKA that is tolerant to the genetic variations of its target enzyme. MethodsA series of vitamin K derivatives with benzyl and related side‐chain substitutions at the 3‐position of 1,4‐naphthoquinone were synthesized. The role of these compounds in VKD carboxylation was evaluated by mammalian cell‐based assays and conventional in vitro activity assays. ResultsOur results showed that replacing the phytyl side‐chain with a methylene cyclooctatetraene (COT) moiety at the 3‐position of vitamin K1 converted it from a substrate to an inhibitor for VKD carboxylation. Strikingly, this COT‐vitamin K derivative displayed a similar inhibition potency in warfarin‐resistant VKOR mutations whose warfarin resistance varied more than 400‐fold. Further characterization of COT‐vitamin K for the inhibition of VKD carboxylation suggested that this compound targets multiple enzymes in the vitamin K redox cycle. Importantly, the anticoagulation effect of COT‐vitamin K can be rescued with high doses of vitamin K1. ConclusionWe discovered a vitamin K analogue that functions as a VKA and is tolerant to genetic variations in the target enzyme.

Finding the optimal dose of vitamin K1 to treat vitamin K deficiency and to avoid anaphylactoid reactions.

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.

Treatment of a long-acting anticoagulant rodenticide poisoning cohort with vitamin K1 during the maintenance period.

Currently, there are few guidelines for the use of vitamin K1 in the maintenance treatment of long-acting anticoagulant rodenticide (LAAR) poisonings. We explored factors in the treatment of LAAR poisoning during the maintenance period in order to suggest feasible treatment models.Data from 24 cases of anticoagulant rodenticide poisoning in our hospital were collected from January 2013 to May 2016. The patients' sex, age, coagulation function, total time from poisoning to treatment with vitamin K1 (prehospital time), vitamin K1 sustained treatment time (VKSTT), anticoagulant rodenticide category, and specific poison dosage were collected. Multivariate analysis was used to evaluate the correlation between vitamin K1 dosage and other factors during the maintenance period.Only VKSTT (partial regression coefficient -1.133, 0.59, P = 0.035) had an obvious influence on the therapeutic dose of vitamin K1 required during the maintenance period.After an initial pulse therapy, the bleeding and coagulation functions were stabilized, and the patients were subsequently treated with vitamin K1 during the maintenance period. Over time, the maintenance dose of vitamin K1 (10-120 mg/d, intravenous drip) was gradually decreased and was not related to toxicant concentration.

Warfarin Poisoning with Delayed Rebound Toxicity

BackgroundIntentional poisoning with warfarin is not the same as over-anticoagulation, for which guidelines exist. The coagulopathy resulting from a warfarin overdose is reversed with vitamin K1, the dose and timing of which is often guided by experience with the management of over-anticoagulation with warfarin therapy, rather than acute overdose. Case ReportWe report a case of a 50-year-old man who ingested an unknown amount of his warfarin, venlafaxine, and paracetamol. He presented with an international normalized ratio (INR) of 2.5, which steadily increased over 24 h to 7, despite receiving an initial 1 mg of vitamin K1. He was then treated with 5 mg vitamin K1, and once the INR returned to 4.5, 40 h post ingestion, he was discharged home. He was also treated with a full course of acetylcysteine for the paracetamol overdose. The following day his INR rebounded to 8.5 and he suffered a spontaneous epistaxis requiring readmission; he was treated with low titrated doses of vitamin K1. The warfarin concentration was 74.6 μg/mL 26 h post ingestion and decreased to 3.7 μg/mL over 72 h. Why Should an Emergency Physician Be Aware of This?Our case highlights the risk of a rebound elevated INR even 3 days after acute warfarin overdose despite treatment with vitamin K1. Understanding the pharmacokinetics of vitamin K1 in comparison with warfarin, repeat INR testing, and continued treatment with oral vitamin K1 may help avoid complications of rebound coagulopathy in warfarin overdose.

Effects of a Single Intramuscular Injection of Vitamin K on the Hematology, Serum Biochemistry and Coagulation Parameters in Healthy Adult Dairy Cows

Abstract Vitamin K1 is commonly administered to dairy cattle suffering from uncontrollable hemorrhage and to cattle with known deficiency of vitamin K dependent coagulation factors. However, a review of recent literature concludes the absence of available information regarding the safety and effects of this drug in dairy cattle. Therefore, this study was carried out to evaluate the safety and effects of a single intramuscular injection of vitamin K1 (2.5 mg/kg) on various clinical, hematological, serum biochemical and coagulation parameters in adult Holstein dairy cows. Six adult Holstein dairy cows were injected a single intramuscular dose of vitamin K1. Cows were then clinically monitored for 24 hours after drug administration for any abnormal behavioral activities. The heart rate, respiration rate, rectal temperature, and rumen motility were also reported before and at each follow-up check point after administration of the drug. Whole blood samples were collected before and again at 15, 30, 60, and 120 minutes and at 24 hours after drug administration. Hematology and serum biochemistry parameters were evaluated to detect any systemic effects. Selected coagulation parameters including the activated partial thromboplastine time (APTT), prothrombin time (PT), thrombin time (TT), D-dimers, platelets count, and fibrinogen concentrations were determined to evaluate the effect of the drug on coagulation mechanisms. There were no abnormal clinical, pathological, or behavioral activities associated with the drug administration in all cows. In the coagulation profile, there was a significant increase in platelets counts starting from 15 minutes after administration and throughout the observation period. Other coagulation parameters were not significantly changed.

The effects of vitamin K supplementation and vitamin K antagonists on progression of vascular calcification: ongoing randomized controlled trials.

BackgroundThe extent and the progression of vascular calcification (VC) are independent predictors of cardiovascular risk in the haemodialysis population. Vitamin K is essential for the activation of matrix gla protein (MGP), a powerful inhibitor of tissue calcification. Functional vitamin K deficiency may contribute to the high VC burden in haemodialysis patients. In addition, haemodialysis patients are frequently treated with vitamin K antagonists, mainly to prevent stroke in atrial fibrillation, potentially compounding the cardiovascular risk in these already vulnerable patients. New oral anticoagulants (NOACs) are valuable alternatives to vitamin K antagonists in the general population, but their use in dialysis has been encumbered by substantial renal clearance. However, a recent pharmacokinetic study provided information on how to use rivaroxaban in haemodialysis patients.MethodsWe conduct a randomized, prospective, multicentre, open-label interventional clinical trial that will include 117 chronic haemodialysis patients with non-valvular atrial fibrillation, treated with or candidates for treatment with vitamin K antagonists. Patients will be randomized to a vitamin K antagonist titrated weekly to an international normalized ratio between 2 and 3, a daily dose of rivaroxaban of 10 mg, or a daily dose of rivaroxaban 10 mg with a thrice weekly supplement of 2000 µg vitamin K2. Cardiac computed tomography, pulse wave velocity (PWV) measurements and MGP sampling will be performed at baseline, 6 months, 12 months and 18 months. Primary endpoints include progression of coronary artery and thoracic aorta calcification and changes in PWV. Secondary endpoints are progression of aortic and mitral valve calcification, all-cause mortality, major adverse cardiovascular events, stroke and bleeding. The ClinicalTrials.gov database was searched to retrieve related trials.ResultsSeven trials, three of which are performed in the haemodialysis population, evaluate whether pharmacological doses of vitamin K1 or K2 retard progression of VC. Five studies compare the effect of warfarin and NOACs on progression of VC, the present study being the only conducted in the dialysis population.ConclusionVitamin K deficiency may be a modifiable cardiovascular risk factor in the haemodialysis population. Conversely, vitamin K antagonists may aggravate VC burden in haemodialysis patients. Several ongoing trials may provide an answer to these questions in the near future.

A simple and sensitive method for determination of vitamins D3 and K1 in rat plasma: application for an in vivo pharmacokinetic study

Purpose: To develop and to validate a simple but sensitive method for determination of vitamins D3 and K1 in rat plasma.Methods: The sample treatment included protein precipitation by cold acetonitrile, evaporation, reconstitution with methanol and filtration. The chromatography conditions included Xterra RP18 3.5 µm 4.6 × 100 mm column at ambient temperature and mobile phase consisting of methanol/water (93/7, v/v) at 0.5 mL/min flow rate. Vitamin D3 and probucol were detected at 265 nm and vitamin K1 at 239 nm. Rats were administered intravenously by 0.1 mg/kg of vitamin D3 or K1 and the blood samples were withdrawn pre-administration and at pre-determined time points post-administration. The pharmacokinetic analysis was performed using a non-compartmental approach.Results: The calibration curves in rat plasma were linear up to 5000 ng/mL for both vitamins. The limit of quantification (LOQ) was 20 ng/mL for vitamin D3 and 40 ng/mL for K1. Inter- and intra-day precision and accuracy were below 15%. The pharmacokinetic parameters of vitamin D3 following intravenous administration were: AUC0−∞ = 11323 ± 1081 h × ng/mL, Vd = 218 ± 80 mL/kg, CL = 8.9 ± 0.8 mL/h/kg, t1/2 = 16.8 ± 5 h; and of vitamin K1: AUC0−∞ = 2495 ± 297 h × ng/mL, Vd = 60 ±24 mL/kg, CL = 40.5 ± 5.1 mL/h/kg, t1/2 = 1.1 ±0.5 h.Conclusion: The developed HPLC–UV assay is a simple and sensitive method for the determination of vitamins D3 and K1 in rat plasma. A higher dose of vitamin K1 should be used in future studies for accurate estimation of pharmacokinetic parameters. The data show the suitability of the assay for pharmacokinetic studies in rats.

Reversal of Overanticoagulation in Very Elderly Hospitalized Patients with an INR above 5.0: 24-Hour INR Response after Vitamin K Administration

Background Reversal of overanticoagulation to minimize the bleeding risk is important in elderly inpatients receiving vitamin K antagonist therapy. However, no study has specifically focused on this population. The objective of this study is to evaluate whether guidelines based on American College of Chest Physicians recommendations for the management of overanticoagulation (international normalized ratio [INR] ≥5.0) can apply to elderly inpatients, and notably allow 24-hour INRs to return to the 1.8-3.2 range in this population. The influence of different factors on the vitamin K response also was evaluated. Methods Inpatients aged ≥75 years with INR ≥5.0 were included in this observational study. INRs were assessed on the day of the overdosage (Day 0) and on the following day (Day 1). Results Of 385 Day 0 INRs ≥5.0 (239 patients; 86 ± 6 years), 217 were managed according to recommendations, with a mean INR decreasing from 6.8 ± 2.4 (range: 5.0-20.0) on Day 0 to 2.7 ± 1.3 (range: 1.1-10.1) on Day 1 ( P < .0001); 55% of INRs were within the 1.8-3.2 range, 20% <1.8, and 25% >3.2. In the subset of Day 0 INRs between 5.0 and 6.0, mean INR decreased from 5.5 ± 0.3 to 2.7 ± 1.0 ( P < .0001) on Day 1 after oral administration of 1 mg vitamin K1 (n = 121) and from 5.3 ± 0.3 to 5.0 ± 1.6 ( P = .149) without vitamin K1 administration (n = 48). Among covariates entered in the multivariate analysis, including co-medications, only the vitamin K1 dose influenced Day 1 INRs, with higher doses of vitamin K1 associated with Day 1 INRs <1.8 ( P < .0001). Conclusion In elderly inpatients with INR ≥5.0, both vitamin K antagonist dose omission and vitamin K1 administration according to recommendations were effective in reversing overanticoagulation, allowing most INRs to return to the 1.8-3.2 range without excessive overcorrection. Therefore, American College of Chest Physicians recommendations may be applied to elderly inpatients.

Urinary Excretion of Vitamin K Metabolites in Term and Preterm Infants: Relationship to Vitamin K Status and Prophylaxis

Little is known about the metabolic turnover and excretion of vitamin K in healthy newborn infants and the metabolic consequences of prophylactic regimens designed to protect against vitamin K deficiency bleeding (VKDB). We measured the excretion of two urinary metabolites (≤ 24 h) of vitamin K (5C- and 7C-aglycones) in term infants before (n = 11) and after (n = 5) a 1000 μg i.m. dose of vitamin K1 (K1) and in preterm infants after 200 μg i.m. (n = 4), 500 μg i.m. (n = 4), or 200 μg i.v. (n = 5). In preterm infants, we also measured serum K1, vitamin K1 2,3-epoxide, and PIVKA-II at 5 d postpartum. Before prophylaxis, the rate of 5C- and 7C-aglycone excretion was 25 times lower than adults, reflecting low vitamin K stores at birth. After prophylaxis, the excretion rate correlated to K1 dose (r = 0.6) but was two orders of magnitude lower than that in adults, probably reflecting the immaturity of neonatal catabolism. All term and 10 of 13 preterm infants mainly excreted 5C-aglycone. We present evidence that increased excretion of the 7C-aglycone was associated with metabolic overload because of the exposure to high-tissue K1 concentrations. Measurement of the 5C- and 7C-aglycones may facilitate longitudinal studies of vitamin K status in neonates and aid the development of improved prophylactic regimens.

Abstract 5407: Inhibitory Raf-1 phosphorylations at Ser-43 and Ser-259 are induced in vitamin K1 enhancement of Sorafenib-mediated HCC cell growth inhibition

Abstract Sorafenib, a multi-kinase inhibitor, is an FDA-approved agent for treatment of human hepatocellular carcinoma (HCC). However, tumor shrinkage is minor. K vitamins can activate protein kinase A (PKA), which in turn can mediate inhibitory Raf phosphorylation. We developed a new strategy to combine naturally occurring K vitamins with Sorafenib to treat HCC, and found that K vitamins were able to enhance the inhibition of HCC cell growth in vitro and in vivo by Sorafenib. To explore the mechanisms involved, we examined the role of Raf-1 kinase, because it has been reported that Sorafenib inhibits tumor cell growth as a direct inhibitor of Raf, whereas vitamin K2 can induce PKA activity, which is a Raf-1 upstream kinase. We found that while lower doses of vitamin K1 (10 μM) or Sorafenib (2.5 μM) alone slightly induced Raf-1 phosphorylation at both Ser-43 and Ser-259 in Hep3B cells, combination vitamin K1 plus Sorafenib treatment resulted in strong Raf-1 phosphorylation at these two Raf-inhibitory serine residues. Raf-1 protein kinase activity assay showed that lower concentrations of vitamin K1 or Sorafenib alone had little, if any effects on Raf-1 activity, combination vitamin K1 plus Sorafenib at the same low concentrations significantly inhibited Raf-1 activity, judged by strong inhibition of MEK, and of ERK phosphorylation, its down stream targets. Since Raf-1 phosphorylation at Ser-43 and Ser-259 can be regulated by either PKA or Akt kinase, we examined the effects of both vitamin K1 and Sorafenib on their phosphorylation. Although both vitamin K1 and Sorafenib alone induced PKA phosphorylation, no synergistic phosphorylation effects on PKA were found using the combination. However, vitamin K1 enhanced Sorafenib-induced Akt phosphorylation, which was associated with enhanced c-Met tyrosine phosphorylation at Tyr-1349, a known phospho-Akt regulator. Our data suggest that enhanced inhibitory Raf-1 phosphorylation at Ser-43 and Ser-259 may play a central role in vitamin K1 plus Sorafenib synergy in inhibiting HCC cell growth. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5407.

Post-discharge supplementation of vitamins and minerals for preterm neonates

Ninety percent of premature babies has nutritional deficiency at discharge. It is very important that not only carbohydrates, proteins, fats, but also mineral salts, and vitamins are in quantities and adequate quality according to the needs of the various scientific neonatal and nutrition programs so as to avoid any shortcomings or excess. The growth, neurodevelopmental outcome and quality of life depend on, among other factors, an adequate nutritional supply with essential nutrients including minerals. It is now recommended that all infants and children, including adolescents, have a minimum daily intake of 400 IU of vitamin D beginning soon after birth. The standard initial dose of vitamin K1 for full term infants (1.0 mg) may be too high for premature infants. The addition of folate and especially vitamin B-12 with formula feedings, provided an effective and nontoxic means of reducing anemia of prematurity. Several investigators have reported higher plasma concentrations of selenium and glutathione peroxidase in preterm infants fed with selenium-supplemented formula than in infants fed with unsupplemented formula.

Superwarfarin intoxication: hematuria is a major clinical manifestation

Since superwarfarin is popular and readily available in stores, it may cause intoxication or overexposure, which can result in coagulopathy or abnormal bleeding in humans and, thus, is an important public health problem. We report our clinical experience with superwarfarin intoxication. Nine patients, including eight patients who had histories of ingesting superwarfarin, were studied. Of the patients, hematuria occurred in eight. Laboratory tests among the nine patients showed extremely prolonged prothrombin times and activated partial thromboplastin times, which could be corrected to normal by mixing 1:1 with normal pooled plasma; they also had very low functional levels of factor II, VII, IX, X, and proteins C and S, but normal functional levels of factors V, VIII, fibrinogen, and anti-thrombin III. Large doses of vitamin K1 were needed for 3 months or more to treat and correct the coagulopathy among the patients. The majority of the patients presented with gross hematuria, suggesting that hematuria is probably a major clinical manifestation of superwarfarin intoxication. Prolonged use of large doses of vitamin K1 is needed for the treatment of superwarfarin intoxication.

American Heart Association/American College of Cardiology Foundation guide to warfarin therapy.

### Mechanism of Action of Coumarin Anticoagulant Drugs Warfarin, a coumarin derivative, produces an anticoagulant effect by interfering with the cyclic interconversion of vitamin K and its 2,3 epoxide (vitamin K epoxide). Vitamin K is a cofactor for the carboxylation of glutamate residues to γ-carboxyglutamates (Gla) on the N-terminal regions of vitamin K–dependent proteins (Figure 1).1–6 These proteins, which include the coagulation factors II, VII, IX, and X, require γ-carboxylation by vitamin K for biological activity. By inhibiting the vitamin K conversion cycle, warfarin induces hepatic production of partially decarboxylated proteins with reduced coagulant activity.7,8 Figure 1. The vitamin K cycle and its link to carboxylation of glutamic acid residues on vitamin K–dependent coagulation proteins. Vitamin K1 obtained from food sources is reduced to vitamin KH2 by a warfarin-resistant vitamin K reductase. Vitamin KH2 is then oxidized to vitamin K epoxide (Vit KO) in a reaction that is coupled to carboxylation of glutamic acid residues on coagulation factors. This carboxylation step renders the coagulation factors II, VII, IX, and X and the anticoagulant factors protein C and protein S functionally active. Vit KO is then reduced to Vit K1 in a reaction catalyzed by vitamin KO reductase. By inhibiting vitamin KO reductase, warfarin blocks the formation of vitamin K1 and vitamin KH2, thereby removing the substrate (vitamin KH2) for the carboxylation of glutamic acids. Vitamin K1, either given therapeutically or derived from food sources, can overcome the effect of warfarin by bypassing the warfarin-sensitive vitamin KO reductase step in the formation of vitamin KH2. Carboxylation promotes binding of the vitamin K–dependent coagulation factors to phospholipid surfaces, thereby accelerating blood coagulation.9–11 γ-Carboxylation requires the reduced form of vitamin K (vitamin KH2). Coumarins block the formation of vitamin KH2 by inhibiting the …

Effects of vitamin K on calcium and bone metabolism.

The K vitamins, a group of napthoquinones, are required for the carboxylation of a limited number of proteins including the bone matrix protein osteocalcin. Vitamin K1 (phylloquinone) and vitamin K2 (menaquinones), differ regarding food source (green vegetables and fermented products, respectively), bioavailability and intermediate metabolism. Epidemiological studies provide evidence for an association between a low vitamin K intake and an enhanced osteoporotic fracture risk. Doses of vitamin K1 up to 15 times the current recommended dietary allowance have successfully been used to reduce the percentage of undercarboxylated osteocalcin in the circulation. Studies demonstrating clear beneficial effects on bone health, however, are still lacking. In contrast, therapy with very high pharmacological doses of the vitamin K2 menatetrenone has impressively been used to prevent further bone mineral loss and fracture risk in osteoporotic patients.

Evaluation and survey of intravenous vitamin K1 for treatment of coagulopathy in critically ill patients.

To determine patient factors associated with coagulopathy, to assess variables affecting response to vitamin K1, to describe vitamin K1-associated adverse reactions, and to survey Canadian tertiary care hospitals about vitamin K1 practice patterns in their intensive care units (ICUs). Retrospective chart audit and prospective survey. Medical-surgical ICU with a 23-bed complement in a tertiary care, university-affiliated hospital, and 47 Canadian tertiary care hospitals. Forty-eight critically ill patients with nonconsumptive coagulopathies. Intravenous vitamin K1 utilization over 4 months. The only independent risk factor for elevated baseline international normalized ratios (INRs) was Acute Physiologic and Chronic Health Evaluation (APACHE) II score (r2 = 0.51, p<0.05). The INR values decreased after two doses of vitamin K1 10 mg for patients grouped as a whole (2.14 +/- 0.96 to 1.61 +/- 0.62, p<0.0001) and when patients were stratified according to APACHE II scores below 23 (1.83 +/- 0.44 to 1.34 +/- 0.18, p<0.05). The INRs were not significantly reduced for patients with APACHE II scores of 23 or greater (2.44 +/- 1.23 to 1.82 +/- 0.66). No variables were associated with response, and adverse events were not observed. Of 47 Canadian tertiary care hospitals surveyed, 27 (55%) responded. Twenty-four (89%) indicated that vitamin K1 was administered intravenously, and no adverse events resembling anaphylaxis were reported. Administration of two doses of intravenous vitamin K1 10 mg was associated with reversal of coagulopathies, but variable responses may be expected for patients with high APACHE II scores. Randomized, placebo-controlled studies are necessary to confirm the effectiveness of vitamin K1.

Cutaneous Reactions Associated with Vitamin K1

Vitamin K1 (phytonadione) is a fat-soluble, naturally occurring vitamin used to treat certain coagulation disorders. A review of the adverse cutaneous reactions to Vitamin K1 is important because this diagnosis can be easily overlooked. This is due to their low incidence and because the presentation and morphology can vary considerably. The objective of this article is to summarize the different morphologies, the natural history, and the treatment of the cutaneous reactions reported to Vitamin K1. A case of a patient who developed a localized eczematous plaque at the site of a vitamin K1 injection is outlined. A review of the English medical literature focused on the adverse cutaneous reactions associated with intramuscular or subcutaneous use of vitamin K1. Our patient developed a localized eczematous reaction to subcutaneous vitamin K1. The eruption developed within 7 days of her dose of vitamin K1. The eruption persisted for 18 months despite treatment with topical and intralesional steroids. There are three distinct types of cutaneous reactions to vitamin K1: localized eczematous, localized morphea-form, and, very rarely, diffuse maculopapular eruption. The eczematous type (32 cases) appears at the site of injection, and the median number of days between injection and appearance of the eruption is 13 days. The dose range required to initiate the reaction is broad (10 to 410 mg). Thirteen of 32 cases took more than 2 months to resolve. The morphea-form type (7 cases) is a localized morphea-form patch that appears at the site of injection. The average delay before presentation of morphea-form changes was 8.5 months (range: 5 weeks-1.5 years). The dose range is broad (30-2080 mg), and the prognosis for resolution very poor. The diagnosis of an adverse cutaneous reaction to vitamin K can be made if the possibility is considered. Many of these reactions are very slow to clear up and some may persist as a chronic sclerodermoid change. Managing these reactions may be frustrating for both the patient and the clinician.

Course of the international Normalized Ratio in response to oral vitamin K1 in patients overanticoagulated with phenprocoumon.

Oral vitamin K1 is used for the treatment of excessive anticoagulation. Detailed information on changes in the International Normalized Ratio (INR) in response to vitamin K1 is not available. We therefore measured the INR for the first 7 d following the oral intake of 1-5 mg of vitamin K1 in 24 patients routinely treated with phenprocoumon who had an INR > or =6.0 at presentation. On the first 2 d after administration of vitamin K1, the mean INR decreased by 40% and 23% respectively. After day 2, the day-to-day proportional change in the mean INR depended on the dose of vitamin K1 and varied from a decrease of 12% to an increase of 21%. On day 7 the mean INR was higher than on day 2 in three out of five treatment groups. Between day 2 and day 7, in general, 32% of the patients had an INR value within the target zone, 25% had an INR value > or =6.0 and 8% had an INR value <2.0. These findings suggest that our routine treatment of overanticoagulation in patients on phenprocoumon should be intensified to improve its efficacy.

Prospective Evaluation of Anticoagulant Reversal With Oral Vitamin K1 While Continuing Warfarin Therapy Unchanged

To study the efficacy and safety of partially correcting therapeutic anticoagulation by administering oral vitamin K1. Prospective interventional trial. Outpatient anticoagulation clinic. Patients who required reversal of their normal or excessive therapy with oral anticoagulant drugs were recruited. All patients received a single oral dose of vitamin K1. The dose was calculated using a regression formula and was intended to decrease the international normalized ratio (INR) to a predetermined value. Patient follow-up continued for 8 weeks. We compared the actual change of the INR to the predicted change. Sixty-five reversals of anticoagulant therapy were initiated in the study group. Sixty-four of the 65 reversals were successful. The mean (+/-SEM) initial INR was 2.6+/-0.1 for the preprocedure patients and 8.4+/-0.5 for the excessively anticoagulated patients. The predicted change in the INR correlated with the actual change (r = 0.92, p < 0.0001). There were no thromboembolic events and only one hemorrhagic complication. The mean (+/-SEM) dose of oral vitamin K1 was 5.0+/-0.3 mg for the preprocedure patients and 10.0+/-1.0 mg for the excessively anticoagulated patients. The administration of a single oral dose of vitamin K1 is a safe and effective method for partially reversing anticoagulant therapy without disrupting the daily maintenance dose of warfarin. A reliable regression formula was developed to predict the dose of vitamin K1 needed to achieve the desired INR.