Evaluation of vitamin K status and rationale for vitamin K supplementation in dialysis patients.

The cardinal biological role of vitamin K is to act as cofactor for the carboxylation of a number of vitamin K-dependent proteins, some of which are essential for coagulation, bone formation and prevention of vascular calcification. Functional vitamin K deficiency is common and severe among dialysis patients and has garnered attention as a modifiable risk factor in this population. However, no single biochemical parameter can adequately assess vitamin K status. For each biological function of vitamin K, the degree of carboxylation of the relevant vitamin K-dependent protein most accurately reflects vitamin K status. Dephosphorylated uncarboxylated matrix Gla protein (dp-ucMGP) is the best biomarker for vascular vitamin K status when cardiovascular endpoints are studied. Dp-ucMGP levels are severely elevated in haemodialysis patients and correlate with markers of vascular calcification and mortality in some but not all studies. The aetiology of vitamin K deficiency in haemodialysis is multifactorial, including deficient intake, uraemic inhibition of the vitamin K cycle and possibly interference of vitamin K absorption by phosphate binders. The optimal vitamin K species, dose and duration of supplementation to correct vitamin K status in dialysis patients are unknown. Dp-ucMGP levels dose-proportionally decrease with supraphysiological vitamin K2 supplementation, but do not normalize even with the highest doses. In the general population, long-term vitamin K1 or K2 supplementation has beneficial effects on cardiovascular disease, bone density and fracture risk, and insulin resistance, although some studies reported negative results. In haemodialysis patients, several trials on the effects of vitamin K on surrogate markers of vascular calcification are currently ongoing.

Controllable vitamin K deficiency under high-dose oral menatetrenone administration - a case report.

Vitamin (V) K deficiency may cause severe bleeding tendencies, which necessitates extreme caution. We report a case of a 30-year-old man diagnosed with VK deficiency of unknown etiology. He was treated with intravenous menatetrenone three times a week in an outpatient setting for about 1 year and 9 months. Eventually, he developed an allergic reaction to intravenous menatetrenone and was under steroid therapy. In order to reduce his hospital visits and discontinue steroid use, the pharmacist proposed to change the method of menatetrenone administration from intravenous to oral (high dose). The change in treatment method has greatly improved the patient's quality of life.

Yellow is pale: the complications and challenges of late diagnosis of extrahepatic biliary atresia.

Extrahepatic biliary atresia classically presents in the neonatal period with jaundice and pale stools. The lack of bile pigment in stool can be unrecognised, delaying diagnosis and surgical treatment. Vitamin K is given at birth to reduce the risk of haemorrhagic disease of the newborn, but this may be inadequate to prevent the development of coagulopathy secondary to fat soluble vitamin malabsorption. We present the case of a 3 month old infant who presented with an intracerebral haemorrhage and coagulopathy thought to be secondary to fat malabsorption resulting from delayed diagnosis of extrahepatic biliary atresia. This was despite the perinatal administration of intramuscular vitamin K. His parents did not recognise the stool pallor as being abnormal. This case illustrates the importance of educating parents on the significance of pale stools, and also the risk of coagulopathy in extrahepatic biliary atresia despite perinatal intramuscular vitamin K.

Biological Role of Vitamin K-With Particular Emphasis on Cardiovascular and Renal Aspects.

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.

Improving the harmonisation of the International Normalized Ratio (INR): time to think outside the box?

The prothrombin time (PT) assay is the most often requested coagulation test and used primarily for monitoring Vitamin K antagonist therapy, where results may be expressed as an International Normalised Ratio (INR). The INR is the patient's PT 'mathematically adjusted' or 'standardised' to take into account the specific test system used (i.e., comprising the test reagent/instrument combination). This standardisation or 'adjustment' is achieved by applying two 'correction factors', respectively defined by the 'International Sensitivity Index' (ISI) and the 'mean normal prothrombin time' (MNPT), according to the formula: INR=[patient PT/MNPT](ISI). While some manufacturers provide assigned ISI values for specific PT reagents and instrumentation, the vast number of possible reagent/instrument combinations usually precludes this in most situations. Even when an ISI is provided by the manufacturer, laboratories need to check or validate the assigned value. When a manufacturer does not provide an ISI, the laboratory needs to define its own (local ISI) value. The MNPT usually has to be locally defined, based on the population being tested. Current recommendations for defining ISI values include the classical, but prohibitively complex, World Health Organization (WHO) recommended procedure, and more recently the use of commercial reference-plasma calibration sets. The MNPT can also be defined using the WHO recommended procedure or with calibration sets. However, there is limited information to validate the performance of these in laboratory practice, and there are several unrecognised problems that limit the validity and utility of the ISI and MNPT values that are determined. Thus, it is perhaps time to start thinking outside the box, and to utilise additional methods for determining and/or validating ISI and MNPT values. This may include the use of regression analysis to assess ongoing peer-related performance in external quality assurance programmes, and to compare the behaviour of proposed replacement reagents with that of existing reagents. Such strategies have proven of considerable benefit to local laboratory practice, and should therefore enable other laboratories to optimise their practice in order to provide INRs that better reflect a patient's anticoagulant status, and thus assist in their clinical therapeutic management.

Effect of Fat-Soluble Vitamins A, D, E and K on Vitamin Status and Metabolic Profile in Patients with Fat Malabsorption with and without Urolithiasis.

Patients with intestinal fat malabsorption and urolithiasis are particularly at risk of acquiring fat-soluble vitamin deficiencies. The aim of the study was to evaluate the vitamin status and metabolic profile before and after the supplementation of fat-soluble vitamins A, D, E and K (ADEK) in 51 patients with fat malabsorption due to different intestinal diseases both with and without urolithiasis. Anthropometric, clinical, blood and 24-h urinary parameters and dietary intake were assessed at baseline and after ADEK supplementation for two weeks. At baseline, serum aspartate aminotransferase (AST) activity was higher in stone formers (SF; n = 10) than in non-stone formers (NSF; n = 41) but decreased significantly in SF patients after supplementation. Plasma vitamin D and E concentrations increased significantly and to a similar extent in both groups during intervention. While plasma vitamin D concentrations did not differ between the groups, vitamin E concentrations were significantly lower in the SF group than the NSF group before and after ADEK supplementation. Although vitamin D concentration increased significantly in both groups, urinary calcium excretion was not affected by ADEK supplementation. The decline in plasma AST activity in patients with urolithiasis might be attributed to the supplementation of ADEK. Patients with fat malabsorption may benefit from the supplementation of fat-soluble vitamins ADEK.

Vitamin K-dependent coagulation factors deficiency.

All vitamin K-dependent coagulation factors require normal function of gamma-glutamyl carboxylase and vitamin K epoxide reductase enzyme complex (VKORC1). Heritable dysfunction of gamma-glutamyl carboxylase or of the VKORC1 complex results in the secretion of poorly carboxylated vitamin K-dependent proteins that play a role in coagulation. The following review will summarize the clinical manifestations of vitamin K-dependent coagulation factors deficiency I and II and will provide a detailed explanation about the gene and protein structure, the function of the protein, and an analysis of the previously reported mutations. Laboratory assays used for diagnosis will be discussed, and treatment for various clinical settings will be recommended.

Intracranial hemorrhage due to vitamin K deficiency in infants: a clinical study.

The hospital records of 30 infants with a diagnosis of intracranial hemorrhage (ICH) due to late onset of vitamin K deficiency, seen during a 5-year period (2001-2005) were retrospectively evaluated. Signs and symptoms of the patients were convulsions (80%), poor sucking (50%), irritability (40%), vomiting (47%), acute diarrhea (33%), and fever (40%). On physical examination there were bulging or full fontanel in 19 patients (63%), collapsed fontanel in one (3%), diminished or absent neonatal reflexes in 11 (37%), pallor in 14 (47%), and cyanosis in one (3%) patient. Gastrointestinal disorder, skin hemorrhagic findings, and epistaxis each were noted in two (7%) patients. All the infants had prolonged prothrombin time (PT) and seven had prolonged activated partial thromboplastin time (APTT), both of which were corrected by the administration of vitamin K. All the infants had ICH, with the most common being intraparenchymal hemorrhage, followed by multiple type ICH (27%). Neurosurgical intervention was performed in five patients (17%). The overall case fatality rate was 33%. In conclusion, we would like to stress that ICH due to vitamin K deficiency in infants is still an important health problem in Turkey resulting in high mortality rate.

Characteristics of software used in self-management of vitamin K antagonist therapy: A systematic review.

INTRODUCTION AND GOAL: Currently, 1-2% of the population in developed countries are under treatment with oral anticoagulants. An appropriate strategy to deal with this increase in demand of treatment with oral anticoagulants and to manage the costs is the transfer of part or all of the responsibility for managing treatment to the patients. The use of information technology, particularly electronic health software, can be an appropriate method to improve the quality of self-management of treatment with these drugs. Therefore, this systematic review investigated studies that discuss the characteristics of electronic health software in self-management of oral anticoagulation therapy. METHOD: A systematic review based on PRISMA protocol was conducted. In this study, articles were investigated that were in English. Articles existing in Cochrane, EMBASE and PubMed databases were searched up to 14 May 2017. Then, articles searched through Google Scholar were added to this study. FINDINGS: The common characteristics used in most software included 'encryption in exchanging information', having an 'instruction module' and 'being Android-based'. In terms of functionality, 'communication between the patient and healthcare team' existed in most of the software. CONCLUSION: The results of the study showed that the accuracy of administration of the dose of the drug using computer to reach a target international normalized ratio level was not less than those administered with experienced medical staff. In addition, the results indicated that important characteristics of the software include encryption in exchanging information, instruction module and Android-based instruction module. The most important characteristic was the interaction between the patient and the healthcare team.

Acquired deficiency of vitamin K-dependent clotting factors due to brodifacoum ingestion.

Brodifacoum, also known as a superwarfarin, is a four-hydroxycoumarin derivative. It exerts an anticoagulant effect by inhibiting the reduction of vitamin K-2,3 epoxide, thereby decreasing the production of vitamin K-dependent clotting factors. It is a readily available rodenticide that has been associated with accidental ingestions in children. We report the case of a 21-year-old male who was admitted to the hospital with spontaneous bruising, hematuria and abdominal pain secondary to a perinephric hematoma. The patient was found to have a markedly prolonged prothrombin time and activated partial thromboplastin time that corrected with mixing of normal plasma. He had a normal factor V level; however, factors VII and X were less than 1% and factors II and IX were between 2% and 4% of normal. Ingestion of an anticoagulant was suspected, although the patient denied intentional or accidental ingestion. He was treated with FEIBA (Factor VIII Inhibitor Bypass Activity), fresh frozen plasma and oral vitamin K. The patient was stabilized and discharged from the hospital on oral vitamin K 50 mg twice daily. A serum brodifacoum level was later found to be markedly elevated at 320 ng/ml. We followed the brodifacoum level, which decreased to 31 ng/ml approximately six weeks after initial presentation. The exact length of treatment required to prevent recurrence of the coagulopathy was not determined because the patient did not return for follow-up. Superwarfarin ingestion must be suspected and quickly identified in patients with depletion of vitamin K-dependent clotting factors resulting in potentially catastrophic bleeding.

α-Tocopherol Intake Decreases Phylloquinone Concentration in Bone but Does Not Affect Bone Metabolism in Rats.

Previous studies have shown that α-tocopherol intake lowers phylloquinone (PK) concentration in some extrahepatic tissues in rats. The study's aim was to clarify the effect of α-tocopherol intake on vitamin K concentration in bone, as well as the physiological action of vitamin K. Male Wistar rats were divided into 4 groups. Over a 3-mo period, the K-free group was fed a vitamin K-free diet with 50 mg RRR-α-tocopherol/kg, the E-free group was fed a diet containing 0.75 mg PK/kg without vitamin E, the control group was fed a diet containing 0.75 mg PK/kg with 50 mg RRR-α-tocopherol/kg, and the E-excess group was fed a diet containing 0.75 mg PK/kg with 500 mg RRR-α-tocopherol/kg. PK concentration in the liver was higher in E-excess rats than in E-free rats, was lower in the tibias of control rats than in those of E-free rats, and was lower in E-excess rats than in control rats. Menaquinone-4 (MK-4) concentration in the liver was higher in E-excess rats than in E-free and control rats. However, MK-4 concentrations in the tibias of E-free, control, and E-excess rats were almost the same. Blood coagulation activity was lower in K-free rats than in the other rats but was not affected by the level of α-tocopherol intake. Additionally, dietary intake of PK and α-tocopherol did not affect uncarboxylated-osteocalcin concentration in the serum, femur density, or expression of the genes related to bone resorption and formation in the femur. These results suggest that α-tocopherol intake decreases PK concentration in bone but does not affect bone metabolism in rats.

Chronic Complications of Cholestasis: Evaluation and Management.

Patients with primary biliary cholangitis (PBC) are at risk for various harmful consequences of chronic cholestasis. These include fat-soluble vitamin deficiency, even in the setting of macronutrient sufficiency, as well as metabolic bone disease, including osteoporosis with fractures. Hyperlipidemia is often present and less commonly associated with risk of cardiovascular event; however, the long-term effect of new emerging therapies for PBC remains to be determined. Patients with PBC also have infrequent but notable risk of portal hypertension despite early-stage disease. This review discusses the background, evaluation, and practical management of these complications of chronic cholestasis.

Intracranial hemorrhage due to late hemorrhagic disease in two siblings.

Deficiency of vitamin K predisposes to early, classic or late hemorrhagic disease of the newborn (HDN); late HDN may be associated with serious and life-threatening intracranial hemorrhage. Late HDN is characterized by intracranial bleeding in infants aged 1 week to 6 months due to severe vitamin K deficiency, occurring particularly in exclusively breastfed infants. Late HDN is still an important cause of mortality and morbidity in developing countries where vitamin K prophylaxis is not routinely practiced. In this study, we report on two siblings with intracranial bleeding who were fully breastfed without a routine supplementation of vitamin K. Vitamin K should be given to all newborns as a single, intramuscular dose of 1 mg.

Management of vitamin K deficiency after biliopancreatic diversion with or without duodenal switch.

BACKGROUND: Reduced serum vitamin K levels are frequently observed after biliopancreatic diversion (BPD) and BPD with duodenal switch (BPD/DS). The criteria for treatment are not precisely defined. OBJECTIVES: To assess the effects of standardized vitamin K supplementation in patients who develop vitamin K deficiency after BPD or BPD/DS. SETTING: Teaching hospital specializing in bariatric surgery. METHODS: Serum vitamin K levels, clotting times, and vitamin K-dependent coagulation factors were measured after an overnight fast at baseline and then at 4 days and 1, 4, and 52 weeks after the start of vitamin K supplementation in 10 consecutive patients who had developed severe vitamin K deficiency after BPD or BPD/DS. Vitamin K was administered in a dose of 5 mg/d for 1 week, followed by a maintenance dose of 5 mg once a week. RESULTS: At baseline, all patients had serum vitamin K1 levels below the limit of detection, but none reported symptoms of easy bleeding. Minor prolongation of the prothrombin time and minimal decreases of some coagulation factors were observed in a minority of patients. During the first week of vitamin K loading, median serum vitamin K1 levels rose into the high normal range. During maintenance treatment, median vitamin K1 levels settled in the low normal range. CONCLUSION: Vitamin K1 deficiency in patients with BPD or BPD/DS is not commonly associated with bleeding or clinically relevant decreases in coagulation factor activity. We hypothesize that vitamin K2 production in the large intestine is usually sufficient to compensate for vitamin K1 deficiency and to maintain total liver vitamin K stores within the range required for (near) normal coagulation factor production.

Bleeding disorder as the first symptom of biliary atresia.

Biliary atresia (BA) is occasionally diagnosed in infants whose first symptom is a bleeding disorder, such as intracranial bleeding, nasal bleeding or gastrointestinal bleeding. The authors describe 3 cases in which a bleeding disorder was the first symptom of BA. The presenting symptom was intracranial bleeding in a male on day 55 after birth, nasal bleeding in a female at 65 days, and gastrointestinal bleeding in a female at 25 days. Coagulation studies revealed a vitamin K deficiency in all patients. After the administration of vitamin K, the results of coagulation tests normalized and the bleeding tendency of the infants ceased. Subsequently, BA was suspected to be the cause of these bleeding disorders based on imaging findings. BA should therefore be considered in all infants with sudden onset of a tendency to bleed.

A case of maternal vitamin K deficiency associated with hyperemesis gravidarum: its potential impact on fetal blood coagulability.

Vitamin K deficiency is associated with malnutrition in some complications, such as hyperemesis gravidarum, active gastrointestinal diseases, and psychological disorders. Maternal vitamin K deficiency can cause fetal bleeding, in particular, fetal intracranial hemorrhage. Although fetal hemorrhage is uncommon, severe damage to the fetus may be inevitable. We describe a pregnant woman with vitamin K deficiency possibly due to hyperemesis gravidarum. The patient was treated for the deficiency, and no fetal or neonatal hemorrhagic diseases were manifested.

Evaluation and management of coagulation disorders in elective surgical patients.

This is a review of coagulation disorders in elective surgical patients. The study represents both a personal experience in unusual bleeding and clotting disturbances and, in addition, a 15-year review of unique problems evaluated by the Coagulation Department of a local general hospital. Of this group of cases, 17 were selected to illustrate the purpose of this report. Potential "bleeders" due to coagulation defects may be missed preoperatively both by history and by commonly accepted screening tests. The incidence of this situation is fortunately rare, but unfortunately this dulls the likelihood of early diagnosis with the initiation of specific treatment measures. The limitations of preoperative screening tests were apparent and should not be considered a fail-safe detector of coagulation disorders. Qualitative and quantitative factor assay are the cornerstone for accurate diagnosis and a guide for specific replacement therapy. Although most surgeons will never have an in-depth knowledge of hematology, the importance of having some fundamental awareness is apparent. This study encourages surgeons not to take the hemostatic mechanism for granted, and to see the need for understanding hematologic diagnosis and treatment.

Vitamin K deficiency in severely disabled children.

Vitamin K status was examined in 21 severely disabled children in our hospital from September 2001 to August 2002, and 9 children were found to have a vitamin K deficiency. The 21 patients were divided into two groups: group A, 9 patients with vitamin K deficiency, and group B, 12 patients without vitamin K deficiency. The laboratory data and background factors in the two groups were compared statistically. In group A, all patients received enteral nutrition and anticonvulsants. The protein induced by vitamin K absence-II values were elevated in eight patients. Seven exhibited a bleeding tendency. Six developed vitamin K deficiency in association with infection and four were treated with antibiotics. All showed a good response to the administration of vitamin K. The patients in group A had factors such as use of antibiotics, infection, and elemental nutrition at significantly higher rates than those in group B. Data indicating nutrition factors such as body weight, caloric intake, total protein level, and hemoglobin level were not significantly different between the two groups. Severely disabled children suffer from deficiencies of various nutritional elements. However, vitamin K deficiency in severely disabled children has not been fully investigated. Infection, use of antibiotics, and elemental nutrition are risk factors for vitamin K deficiency in severely disabled children. In severely disabled children, there might be marginal vitamin K intake via enteral nutrition, so more vitamin K supplementation is necessary, especially with infection and use of antibiotics.