Vitamin E-induced coagulopathy in a young patient: a case report.

BACKGROUND: High-dose vitamin E intake is known to inhibit vitamin K-derived coagulation factor synthesis, which can cause serious bleeding events such as gastrointestinal bleeding and intracranial hemorrhage. We report a case of coagulopathy induced by marginally increased levels of vitamin E. CASE PRESENTATION: A 31-year-old Indian man presented with oral bleeding, black tarry stools, and bruising over his back. He had been taking non-steroidal anti-inflammatory drugs for low backache and vitamin E for hair loss. He had mild anemia with normal platelet count, thrombin time, and prolonged bleeding time, activated partial thromboplastin time, and prothrombin time. Serum fibrinogen was slightly raised. Mixing studies with pooled normal plasma, aged plasma, and adsorbed plasma were suggestive of deficiency of multiple coagulation factors due to acquired vitamin K deficiency. Serum phylloquinone was normal, while prothrombin induced by vitamin K absence-II level was increased. Serum alpha-tocopherol was slightly raised. Upper gastrointestinal endoscopy showed multiple gastroduodenal erosions. A final diagnosis of vitamin E toxicity-related coagulopathy was made. The patient responded well to pantoprazole, vitamin K supplementation, multiple fresh frozen plasma transfusions, and other supportive treatments besides the discontinuation of vitamin E supplementation. The coagulation parameters normalized, and the patient was discharged with complete resolution of symptoms and remained asymptomatic during the follow-up for 6 months. CONCLUSIONS: Vitamin E-related inhibition of vitamin K-dependent factors with coagulopathy may occur even at marginally increased levels of serum vitamin E. This risk becomes significant in patients receiving other drugs that may increase the risk of bleeding.

Methods to Correct Drug-Induced Coagulopathy in Bleeding Emergencies: A Comparative Review.

OBJECTIVE: Anticoagulant and antiplatelet therapy have become increasingly popular. The goal of therapy is to prevent venous thromboembolism and platelet aggregation, respectively. Traditional anticoagulant and antiplatelet drugs are quickly being replaced with novel medications with more predictable pharmacokinetics. Unfortunately, these drugs carry the risk of uncontrolled hemorrhage because of drug-induced coagulopathy. Uncontrolled hemorrhage continues to be a major cause of preventable death: hemorrhage accounts for approximately 30% of trauma-related deaths, second to brain injury. Controlling hemorrhage while dealing with comorbidities remains a challenge to clinicians. There are many gaps in care and knowledge that contribute to the struggle of treating this patient population. METHODS: This literature review is focused on the most effective ways to achieve hemostasis in a patient with drug-induced coagulopathy. The antiplatelet therapies aspirin, clopidogrel, ticlopidine, pasugrel, and ticagrelor are analyzed. Anticoagulant therapies are also reviewed, including warfarin, rivaroxaban, apixaban, edoxaban, and dabigatran. In addition, viscoelastic testing and platelet function assays are reviewed for their ability to monitor drug effectiveness and to accurately depict the patient's ability to clot. This review focuses on articles from the past 10 years. However, there are limitations to the 10-year restriction, including no new research posted within the 10-year timeline on particular subjects. The most recent article was then used where current literature did not exist (within 10 years). RESULTS: Traditional anticoagulants have unpredictable pharmacokinetics and can be difficult to correct in bleeding emergencies. Vitamin K has been proven to reliably and effectively reverse the effect of vitamin K antagonists (VKAs) while having a lower anaphylactoid risk than frozen plasma. Prothrombin complex concentrates should be used when there is risk of loss of life or limb. Frozen plasma is not recommended as a first-line treatment for the reversal of VKAs. Novel anticoagulants have specific reversal agents such as idarucizumab for dabigatran and andexxa alfa for factor Xa (FXa) inhibitors. Although reliable, these drugs carry a large price tag. As with traditional anticoagulants, cheaper alternative therapies are available such as prothrombin complex concentrates. Finally, static coagulation testing works well for routine therapeutic drug monitoring but may not be appropriate during bleeding emergencies. Viscoelastic testing such as thromboelastography and rotational thromboelastometry depict in vivo hemostatic properties more accurately than static coagulation assays. Adding viscoelastic testing into resuscitation protocols may guide blood product usage more efficiently. CONCLUSION: This review is intended to be used as a guide. The topics covered in this review should be used as a reference for treating the conditions described. This review article also covers laboratory testing and is meant as a guide for physicians on best practices. These findings illustrate recommended testing and reversal techniques based off evidence-based medicine and literature.

Vitamin K for kidney transplant organ recipients: investigating vessel stiffness (ViKTORIES): study rationale and protocol of a randomised controlled trial.

BACKGROUND: Renal transplant recipients (RTRs) exhibit increased vascular stiffness and calcification; these parameters are associated with increased cardiovascular risk. Activity of endogenous calcification inhibitors such as matrix gla protein (MGP) is dependent on vitamin K. RTRs commonly have subclinical vitamin K deficiency. The Vitamin K in kidney Transplant Organ Recipients: Investigating vEssel Stiffness (ViKTORIES) study assesses whether vitamin K supplementation reduces vascular stiffness and calcification in a diverse population of RTR. METHODS AND ANALYSIS: ViKTORIES (ISRCTN22012044) is a single-centre, phase II, parallel-group, randomised, double-blind, placebo-controlled trial of the effect of vitamin K supplementation in 90 prevalent RTR. Participants are eligible if they have a functioning renal transplant for >1 year. Those on warfarin, with atrial fibrillation, estimated glomerular filtration rate <15 mL/min/1.73 m2 or contraindications to MRI are excluded. Treatment is with vitamin K (menadiol diphosphate) 5 mg three times per week for 1 year or matching placebo. All participants have primary and secondary endpoint measures at 0 and 12 months. The primary endpoint is ascending aortic distensibility on cardiac MR imaging. Secondary endpoints include vascular calcification (coronary artery calcium score by CT), cardiac structure and function on MR, carotid-femoral pulse wave velocity, serum uncarboxylated MGP, transplant function, proteinuria and quality of life. The study is powered to detect 1.0×10-3 mm Hg-1 improvement in ascending aortic distensibility in the vitamin K group relative to placebo at 12 months. Analyses will be conducted as between-group differences at 12 months by intention to treat. DISCUSSION: This trial may identify a novel, inexpensive and low-risk treatment to improve surrogate markers of cardiovascular risk in RTR.

A cell-based high-throughput screen identifies drugs that cause bleeding disorders by off-targeting the vitamin K cycle.

Drug-induced bleeding disorders contribute to substantial morbidity and mortality. Antithrombotic agents that cause unintended bleeding of obvious cause are relatively easy to control. However, the mechanisms of most drug-induced bleeding disorders are poorly understood, which makes intervention more difficult. As most bleeding disorders are associated with the dysfunction of coagulation factors, we adapted our recently established cell-based assay to identify drugs that affect the biosynthesis of active vitamin K-dependent (VKD) coagulation factors with possible adverse off-target results. The National Institutes of Health (NIH) Clinical Collection (NCC) library containing 727 drugs was screened, and 9 drugs were identified, including the most commonly prescribed anticoagulant warfarin. Bleeding complications associated with most of these drugs have been clinically reported, but the pathogenic mechanisms remain unclear. Further characterization of the 9 top-hit drugs on the inhibition of VKD carboxylation suggests that warfarin, lansoprazole, and nitazoxanide mainly target vitamin K epoxide reductase (VKOR), whereas idebenone, clofazimine, and AM404 mainly target vitamin K reductase (VKR) in vitamin K redox cycling. The other 3 drugs mainly affect vitamin K availability within the cells. The molecular mechanisms underlying the inactivation of VKOR and VKR by these drugs are clarified. Results from both cell-based and animal model studies suggest that the anticoagulation effect of drugs that target VKOR, but not VKR, can be rescued by the administration of vitamin K. These findings provide insights into the prevention and management of drug-induced bleeding disorders. The established cell-based, high-throughput screening approach provides a powerful tool for identifying new vitamin K antagonists that function as anticoagulants.

Effect of Vitamin K Supplementation on Cardiometabolic Risk Factors: A Systematic Review and Meta-Analysis.

BACKGROUND: Multiple cross sectional and longitudinal studies reported the benefits of vitamin K intake for management of cardiometabolic risk factors so as to minimize the risk of cardiovascular diseases. OBJECTIVE: In present systematic review and meta-analysis, we aimed to evaluate the effect of vitamin K supplementation on cardiometabolic risk factors. METHODOLOGY: A systematic literature search of PubMed, Cochrane central, Clinicaltrials.gov, Google Scholar, Web of Science, EBSCO and Scopus databases was done from inception to November, 2017. A total of 13 trials were selected for inclusion into the present systematic review to evaluate the effect of vitamin K supplementation on cardiometabolic risk factors in healthy or in population at high risk of cardiovascular diseases. RESULTS: Significant beneficial effects of vitamin K supplementation were found only in case of Creactive protein (p = 0.01) and insulin sensitivity index (p <0.001), while no significant effects of vitamin K supplementation were found in case of total cholesterol (p=0.857), low density lipoprotein - cholesterol (p=0.964), high density lipoprotein - cholesterol (p=0.998), interleukin - 6 (p=0.766), systolic blood pressure (p=0.660), diastolic blood pressure (p=0.818), fasting plasma glucose (p=0.362), fasting plasma insulin (p=0.928) and homeostasis model assessment for insulin resistance (p=0.672). CONCLUSION: Presently available evidence are insufficient to ascertain the beneficial effects of vitamin K supplementation for the management of cardiometabolic risk factors. In order to explore the true potential of vitamin K supplementation for management of cardiometabolic diseases, large randomized placebo controlled trials are required in population with disturbed cardiometabolic profile. Present systematic review and meta-analysis is registered with PROSPERO (Registration number: CRD42018084608).

US Pharmacopeial Convention safety evaluation of menaquinone-7, a form of vitamin K.

Vitamin K plays important biological roles in maintaining normal blood coagulation, bone mineralization, soft tissue physiology, and neurological development. Menaquinone-7 is a form of vitamin K2 that occurs naturally in some animal-derived and fermented foods. It is also available as an ingredient of dietary supplements. Menaquinone-7 has greater bioavailability than other forms of vitamin K, which has led to increasing sales and use of menaquinone-7 supplements. This special article reviews the chemistry, nomenclature, dietary sources, intake levels, and pharmacokinetics of menaquinones, along with the nonclinical toxicity data available and the data on clinical outcomes related to safety (adverse events). In conclusion, the data reviewed indicate that menaquinone-7, when ingested as a dietary supplement, is not associated with any serious risk to health or with other public health concerns. On the basis of this conclusion, US Pharmacopeia monographs have been developed to establish quality standards for menaquinone-7 as a dietary ingredient and as a dietary supplement in various dosage forms.

[A Systematic Review of the Acceptable Intake Level of Vitamin K among Warfarin Users].

The interaction of warfarin and vitamin K is a clinically significant issue. This study investigated the acceptable intake level of vitamin K among warfarin users by means of a systematic review. We searched two databases (PubMed and "Igaku chuo zasshi")for articles about adverse events arising from interaction of warfarin and vitamin K, published until October 2014. Of 1,310 citations retrieved, 16 studies met the selection criteria for examination of the upper limit, and 6 studies dealt with amounts below the limit. The intake of vitamin K in warfarin patients was acceptable in the range of 25-325 µg/day, with a maximum daily variation of 292 µg, and a value of 150 µg/day seemed optimum. When these results were applied to usual foods, except for dietary supplements or health foods, the only prohibited foods were fermented soybean (natto) and foods containing it, while green leafy vegetables could be acceptable if their intake is limited.

Probable interaction between an oral vitamin K antagonist and turmeric (Curcuma longa).

We report a probable interaction between a vitamin K antagonist, fluindione, and the herbal medicine turmeric that resulted in the elevation of the international normalized ratio (INR). The case presented here underlines the importance of considering potential exposure to herbal medications when assessing adverse effects.

Two-generation diet-induced obesity model producing mice with increased amount of body fat in early adulthood.

The aim of our study was to develop a model producing obese mice in early adulthood (4-6 weeks) based on their over-nutrition during fetal and early postnatal development. The fertilized dams of the parental generation were fed the standard diet supplemented with high-energy nutritional product Ensure Plus during gestation and lactation. Delivered weanlings were then fed with standard or supplemented diet and assessed for body fat deposits using EchoMRI at the time of early and late adulthood. Maternal over-feeding during the period before weaning had the most significant effect on obesity development in the filial generation. In weanlings, significantly higher body fat deposits and average body weight were recorded. Later, further significant increase in percentage of body fat in both male and female mice was observed. Withdrawal of the Ensure Plus supplement caused a decrease in the percentage of body fat in part of the filial generation. In offspring fed the standard diet, higher fat deposits persisted till the time of late adulthood. We conclude that this diet-induced obesity model might be used in exploration of the effects of elevated body fat on physiological functions of various organ systems during juvenile and early adulthood periods of life of a human being.

Elevated international normalized ratio from vitamin K supplement discontinuation.

OBJECTIVE: To report a case of a critically elevated international normalized ratio (INR) following discontinuation of a vitamin K supplement in a patient receiving warfarin. CASE SUMMARY: A 64-year-old man with atrial fibrillation received warfarin for primary stroke prevention. He was initiated on low-dose vitamin K supplementation therapy secondary to a high level of INR variability. The patient was stabilized on this therapy for approximately 9 months with a mean INR of 2.02 and a warfarin dose ranging from 6.5 to 7.5 mg/week. At a visit with his primary care physician, the patient's INR was subtherapeutic at 1.5. He had not been taking his vitamin K supplement for nearly a week, but had not missed any doses of warfarin. The vitamin K supplement was discontinued and his warfarin dose was increased by 14.3%. Nearly 2 weeks later the patient presented with a critically elevated INR of 8.5, but no acute bleeding. No other factors affecting the INR could be determined. After a dose of 2.5 mg of vitamin K was administered and warfarin was withheld for 2 days, the patient's INR returned to 2.9. Low-dose vitamin K supplementation and warfarin at a lower dose of 7 mg/week were restarted. His INR remained relatively stable, with no ensuing critical INR changes or other sequelae. DISCUSSION: Vitamin K supplement removal was believed to be a major contributor to the critically elevated INR. While the warfarin dose had been increased according to the clinic protocol (14.3% for an INR of 1.5), the timing of the INR elevation following supplement removal follows pharmacodynamic expectations of clotting factor synthesis. This case is labeled a category D error. CONCLUSIONS: Discontinuation of vitamin K supplementation therapy might result in elevation of INR.

Vitamin K the basics--what's new?

Relatively little is known about the vitamin K status and requirements in term and preterm infants, though hemorrhagic disease of the newborn infant continues to be a worldwide problem. This brief review of vitamin K metabolism, vitamin K dependent proteins, and the vitamin K cycle covers some new thoughts about the importance of vitamin K to human health including the preterm infant. A review of perinatal vitamin K metabolism concludes that little vitamin K actually crosses the placenta from mother to infant. The neonatal sources of vitamin K are generally limited to the vitamin K prophylaxis given at the time of birth, dietary sources, and questionable amounts from vitamin K present in the intestinal tract synthesized from bacteria. Preterm infants receive large quantities of vitamin K from prophylaxis, TPN solutions, infant formula and breast milk fortifiers. Thus, vitamin serum concentration in preterm infants is up to one hundred times higher than those found in adults and 10-20 times those found in term formula-fed infants. Though no toxicity has been reported, the elevation of epoxide reductase (VKOR) from the vitamin K cycle found in the serum of preterm infants is worthy of additional study. PIVKA-II (abnormal prothrombin) is not a reliable indicator of vitamin K deficiency in preterm or term infants.

Vitamin K treatment reduces undercarboxylated osteocalcin but does not alter bone turnover, density, or geometry in healthy postmenopausal North American women.

Low vitamin K status is associated with low BMD and increased fracture risk. Additionally, a specific menaquinone, menatetrenone (MK4), may reduce fracture risk. However, whether vitamin K plays a role in the skeletal health of North American women remains unclear. Moreover, various K vitamers (e.g., phylloquinone and MK4) may have differing skeletal effects. The objective of this study was to evaluate the impact of phylloquinone or MK4 treatment on markers of skeletal turnover and BMD in nonosteoporotic, postmenopausal, North American women. In this double-blind, placebo-controlled study, 381 postmenopausal women received phylloquinone (1 mg daily), MK4 (45 mg daily), or placebo for 12 mo. All participants received daily calcium and vitamin D(3) supplementation. Serum bone-specific alkaline phosphatase (BSALP) and n-telopeptide of type 1 collagen (NTX) were measured at baseline and 1, 3, 6, and 12 mo. Lumbar spine and proximal femur BMD and proximal femur geometry were measured by DXA at baseline and 6 and 12 mo. At baseline, the three treatment groups did not differ in demographics or study endpoints. Compliance with calcium, phylloquinone, and MK4 treatment was 93%, 93%, and 87%, respectively. Phylloquinone and MK4 treatment reduced serum undercarboxylated osteocalcin but did not alter BSALP or NTX. No effect of phylloquinone or MK4 on lumbar spine or proximal femur BMD or proximal femur geometric parameters was observed. This study does not support a role for vitamin K supplementation in osteoporosis prevention among healthy, postmenopausal, North American women receiving calcium and vitamin D supplementation.

[New proposals for old vitamins]. / Nouvelles indications pour de vieilles vitamines.

Complementary to their specific metabolic actions, several vitamins are given for new previously unsuspected properties. In addition to its role in calcium absorption, vitamin D has been proven to possess beneficial effects for some autoimmune diseases, several cancers and cardiovascular illnesses. It also increases muscle strength and prevents falls particularly in elderly people. Low dose oral vitamin K supplementation is a new indication for people with unstable coumarinic anticoagulant treatment. Oral vitamin 812 administration is an alternative to the classical parenteral intramuscular administration in pernicious anemia. However, the possible antioxidant beneficial effects of vitamin A and E are largely disputed taking into account an increased mortality associated to their consumption.

Update on fat-soluble vitamins in cystic fibrosis.

PURPOSE OF REVIEW: We review and critique recent scientific advances in the understanding of fat-soluble vitamins and the care of people with cystic fibrosis. RECENT FINDINGS: A shift in the conceptual approach to fat-soluble vitamin status has occurred. Vitamin status in cystic fibrosis had previously been discussed in terms of sufficiency versus insufficiency as compared with healthy populations. The discussion of vitamin status has now shifted to that of suboptimal versus optimal with respect to health outcomes. This is best illustrated by advances in the study of vitamin D. Newer metabolic and immunological roles and biomarkers have been identified. With supplementation of water-miscible formulations of preformed vitamin A, increased serum retinol has been observed, and may increase the risk for toxicity. SUMMARY: A paradigm shift has occurred in defining fat-soluble vitamin status by utilizing different biomarkers and associations with health outcomes. Identification of additional biomarkers, redefining definitions of adequacy, optimal surveillance for toxicity as well as adequacy is needed for care of patients with cystic fibrosis.

Is there a role for reactive oxygen species in arterial medial elastocalcinosis?

Isolated systolic hypertension results from a gradual stiffening of large arteries, to which medial elastocalcinosis (calcification of elastic lamellae) contributes. There is compelling evidence that reactive oxygen species (ROS) are associated with several disease processes affecting the cardiovascular system, including hypertension. The present study was designed to investigate whether the inhibition of ROS production by alpha-lipoic acid can prevent vascular calcification. Sprague-Dawley rats were treated with warfarin (20 mg/kg/day) and vitamin K (15 mg/kg/day) (WVK) for 4 weeks to induce large artery calcification. Subgroups received either a normal diet or a diet supplemented with lipoic acid (1000 mg/kg/day). The WVK treatment produced a small elevation of aortic superoxide levels that did not reach statistical significance. Alpha-lipoic acid reduced the elevation below baseline levels. In rats treated with alpha-lipoic acid, the WVK-induced elevation of pulse wave velocity (an index of arterial stiffness), left ventricular hypertrophy, and aortic, femoral and carotid elastocalcinosis were not prevented. Although a contribution of oxidative stress has been suggested in the aging cardiovascular system, this alteration does not appear to contribute to the calcification process and the subsequent stiffening of large arteries in the animal model tested.

Warfarin and its interactions with foods, herbs and other dietary supplements.

Despite its complex pharmacokinetic and pharmacodynamic profile, warfarin is still one of the most widely used oral anticoagulant agents. Attaining optimal anticoagulation with this agent is clinically challenging in view of its many food and drug interactions. Inappropriate anticoagulation control can expose patients to an increased risk of bleeding or thromboembolic complications, due to over and underanticoagulation, respectively. Fluctuations in dietary vitamin K intake can have a significant effect on the degree of anticoagulation in patients treated with warfarin. In addition, the explosion in use of various dietary supplements and herbal products can lead to undesired outcomes on anticoagulant levels. The aim of this review is to discuss the scope and the potential clinical impact of the most commonly reported food, dietary supplement and herbal interactions with warfarin therapy. Practical steps for patients and providers to minimise these interactions are highlighted.