InteractionsGuide Index Page

 
Case Analysis Toolclose
Enter Each Substance:


Analysis Search Terms:

Vitamin K

Nutrient Name: Vitamin K.
Synonyms: Phylloquinone, phytonadione.
Related Substances: Phylloquinone, phytomenadione or phytonadione (K1), menaquinone (K2), menadione (K3).

Summary Table
nutrient description

Chemistry and Forms

Vitamin K refers to a family of compounds exhibiting the activity of phytomenadione. Phylloquinone (or phytomenadione) is the K1form naturally occurring in plants and fish. Bacteria synthesize menaquinone (K2), a fat-soluble form. Menadione (K3), the water-soluble parent compound, does not occur naturally.

Physiology and Function

Vitamin K serves as a coenzyme during the synthesis of many proteins involved in blood clotting and bone metabolism. Vitamin K1is fat soluble and requires bile salts for absorption in the upper gastrointestinal tract. Vitamin K acts as a cofactor in the final synthesis of proteins with a modified amino acid residue. This modified glutamic acid residue is found in the blood and along vessel walls, along with platelet-derived phospholipid, where it binds and facilitates the action of calcium, and is an integral part of the clotting process. It is also found in bone proteins and can bind onto calcium ions to cause calcification. This role in calcium transport is central to vitamin K's functions within healthy bone formation and blood clotting.

Vitamin K enables both coagulation and fibrinolysis. Vitamin K's central role in blood coagulation involves synthesis of coagulation components, such as prothrombin (factor II), as well as factors VII, IX, and X and proteins C, S, and Z in the liver. Proteins C and S promote fibrinolysis and anticoagulation. Thus, they are involved with reducing inflammation.

Osteocalcin, matrix Gla protein, and protein S are vitamin K–dependent structural and regulatory proteins in bone and vascular metabolism. Vitamin K plays the critical role of allowing calcium ions to bind, thus resulting in the calcification of bone. Osteocalcin metabolism has been implicated in the pathogenesis of osteoporosis through an unknown mechanism that may be linked to suboptimal vitamin K status, resulting in its undercarboxylation and presumed dysfunction.

Probiotic microflora in the intestines, when a healthy microecology is functioning, normally manufacture significant amounts of vitamin K, contributing up to half of daily requirements in some individuals.

nutrient in clinical practice

Historical/Ethnomedicine Precedent

In most cultural traditions, herbs and green leafy vegetables have historically been used to enrich and tonify the blood and support its metabolic functions. Consumption of cultured foods can support vigorous probiotic flora population and healthy gut ecology.

Possible Uses

Acute myeloid leukemia (vitamin K2only), bone loss (risk reduction), calcium oxalate kidney stones (prevention), celiac disease (malabsorption-induced deficiency), coagulation disorders, cystic fibrosis, epistaxis, floaters (in eyes), fractures (risk reduction), gastric bypass with Roux-en- Y (bariatric surgery), hemorrhagic disease of the newborn, inflammatory conditions, myelodysplastic syndromes (vitamin K2only), nausea and vomiting of pregnancy, osteoporosis, phenylketonuria (if deficient), preterm infants (K1prophylaxis), pruritus, rheumatoid arthritis, stroke prevention; vitamin K malabsorption (e.g., with celiac disease or bariatric surgery), warfarin overanticoagulation.

When the clotting mechanism is disrupted by medications such as certain antibiotics, cephalosporin possessing an MTT side chain, or excessive doses of oral anticoagulants (warfarin), vitamin K can be administered to correct the situation.

Deficiency

Symptoms: Easy bruising, small amounts of blood in stool, prolonged bleeding; impaired bone remodeling, and mineralization.

Vitamin K deficiency is rare in the general population, but the risk is significantly greater in infants, especially premature infants and those who are exclusively breast-fed, for whom such a deficiency can be fatal (hemorrhagic disease of the newborn). Adults at increased risk of vitamin K deficiency include individuals with heavy alcohol intake, liver disease, fat malabsorption, or chronic digestive disorders, such as chronic diarrhea, celiac sprue, Crohn's disease or ulcerative colitis, and bariatric surgical procedures that bypass the duodenum.

In recent years, several published papers suggest that the dietary reference intakes (DRIs) for vitamin K are based solely on levels relevant to hepatic synthesis of clotting factors, and that much higher levels (10 mg/day) may be needed for optimal health of the skeletal and vascular systems. Vascular calcification may be related to chronic insufficiency of vitamin K intake. Patients receiving chronic warfarin, essentially an induced vitamin K deficiency, have a higher incidence of vascular calcification.

Dietary Sources

Leafy green vegetables are the single best dietary source of vitamin K because of their high chlorophyll content; the vitamin K content is proportionate to the degree to which the plant parts are green. Kale, green tea, and turnip greens are the most abundant food sources. Spinach, broccoli, lettuce, and cabbage are also rich sources. Other food sources include egg yolk, cow's milk, and liver, as well as soybean oil, olive oil, cottonseed oil, and canola oil.

The probiotic flora inhabiting intestines with a healthy ecology normally manufacture vitamin K2, or menaquinone . Menaquinones (MK- n , with the n determined by the number of prenyl side chains) can also be found in the diet; MK-4 is in meat, and MK-7, -8, and -9 are found in fermented food products such as cheese. The Japanese fermented soy product natto is a rich source of MK-7. Some sources have said that MK-4, also known as menatetrenone, is synthetic vitamin K2, but this is not accurate. However, MK-4 is distinct from other MKs because it is not produced in significant amounts by gut microflora, but it can be derived from vitamin K1in vivo. Hydrogenation of plant oils appears to decrease the absorption and biological effect of vitamin K in bone, possibly as an effect of trans-fatty acids.

Nutrient Preparations Available

Phylloquinone (K1) is the usual form of supplemental vitamin K. Vitamin K2is also used therapeutically, often parenterally. Mixed K1and K2formulations are increasingly available. The natural, long-chain menaquinone-7 (MK-7), derived from natto, exhibits a “very long half-life time,…resulting in much more stable serum levels and accumulation of MK-7 to higher levels (7-8 fold) during prolonged intake,” 1 compared to synthetic vitamin K1. The MK-7 preparation can also induce “more complete carboxylation of osteocalcin,” and thereby also increase activity against vitamin K antagonists. 1

Dosage Forms Available

Capsule, tablet; injectable (prescription only).

Dosage Range

Adult

  • Supplemental/Maintenance:   30 to 100 µg per day.

  • Pharmacological/Therapeutic:   45 to 500 µg per day.

  • Toxic:   None reported or suspected.

Pediatric (<18 years)

Supplemental/Maintenance

    • Infants, birth to 6 months:   5 µg/day
    • Infants, 7 to 12 months:   10 µg/day
    • Children, 1 to 3 years:   15 µg/day
    • Children, 4 to 6 years:   20 µg/day
    • Children, 7 to 10 years:   30 µg/day

  • Pharmacological/Therapeutic:   45 to 150 µg per day.

  • Toxic:   None reported or suspected.

Laboratory Values

Plasma vitamin K: Osteocalcin level is sometimes used as a surrogate test for vitamin K status.

Prothrombin time (PT) and clotting factors (X, IX, VII, and protein C) may also be used as reference values, but PT is not considered a reliable test for vitamin K status. Vitamin K deficiency will prolong PT, but so does hepatic insufficiency (which also results in inadequate levels of clotting factors).

safety profile

Overview

Supplemental vitamin K is generally considered safe when used in accordance with proper dosing guidelines. No adverse effects associated with vitamin K consumption from food or supplements have been reported in humans or animals. This does not mean, however, that no potential exists for adverse effects resulting from high intakes beyond normal dietary or supplemental levels. Because data on the adverse effects of vitamin K are limited, caution may be warranted.

Patients undergoing anticoagulant therapy should monitor vitamin K intake and avoid significant inconsistencies in intake levels. Regular monitoring of coagulation parameters (INR) and dose titration is essential.

Nutrient Adverse Effects

General Adverse Effects

Naturally occurring vitamin K1(phylloquinone) is generally considered nontoxic, whereas menadione (K3), the synthetic derivative, has been associated with potentially severe toxicity reactions at high doses, particularly in infants and other highly vulnerable populations. Flushing and perspiration are the most common, although infrequent, adverse effects reported. Other potential toxicity symptoms include difficulty breathing, tightness in throat or chest, chest pain, hives, rash, or itchy or swollen skin. Rare cases of hemolytic anemia have been reported.

The primary risk associated with vitamin K has been limited to rare reports of cutaneous allergic reaction to intramuscular (IM) vitamin K1.

Less than 1%: Abnormal taste, anaphylaxis, cyanosis, diaphoresis, dizziness (rarely), dyspnea, gastrointestinal upset (oral), hemolysis in neonates and in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, hypersensitivity reactions, hypotension (rarely), pain, tenderness at injection site, transient flushing reaction.

More recently, discussions have arisen concerning potential risk of cirrhosis associated with supplemental intake of vitamin K, but not with food sources, in the treatment of osteoporosis.

Toxicity

Phylloquinone (vitamin K1) is not toxic at 500 times the recommended dietary allowance (RDA, 0.5 mg/kg/day). No toxicities have been reported or suspected as being associated with natural vitamin K at any dose in humans when given orally. Intravenous (IV) administration of vitamin K at doses of 2 to 8 mg/kg has been found to be lethal in horses.

Menadione (vitamin K3) has a finite toxicity resulting from its reaction with sulfhydryl groups. Large doses of menadione may produce hemolytic anemia, hyperbilirubinemia, and kernicterus in the infant. Other signs of synthetic vitamin K toxicity include flushing, sweating, and chest constriction. Most toxicity is associated with IV use and may be related to allergies to various preservatives or excipients.

Adverse Effects Among Specific Populations

Patients receiving anticoagulant therapy should monitor vitamin K intake. Possible risk of aggravation exists among individuals prone to form kidney stones.

Pregnancy and Nursing

No extant reports of adverse effects have been related to fetal development during pregnancy. This fat-soluble vitamin crosses the placenta and is excreted into breast milk.

Infants and Children

Vitamin K can cause a fatal form of jaundice in infants. No adverse effects have been reported among breast-fed infants.

Contraindications

Patients undergoing anti–vitamin K anticoagulant therapy, except within the context of appropriate professional supervision; some premature infants.

interactions review

Strategic Considerations

The primary interactions of clinical significance involving vitamin K and pharmaceutical agents derive from interference of vitamin K with the therapeutic action of certain anticoagulant medications and the adverse effect of antimicrobial medications on normal vitamin K synthesis by gut bacterial flora. Although vitamin K's role in coagulation receives attention regularly, its influence on fibrinolysis also needs to be considered. The critical issue with anticoagulants is monitoring and managing the proportionate effects of the medication and dietary or supplemental sources of vitamin K. Strategic administration of probiotic flora and restoration of a healthy gut ecology can compensate for the tactical use of antimicrobial agents in the suppression of infectious bacteria. The interactions involving vitamin K provide challenging opportunities for reframing the constituent elements of medical intervention within the context of a dynamic and evolving individualized process emphasizing strategic goals and comprehensive clinical outcomes, such as improved function, decreased risk, and enhanced quality of life.

Oral Anticoagulant Overdose

Clinical surveys have found that a substantial number of anticoagulation clinics underutilize oral phytonadione for patients with supratherapeutic international normalized ratio (INR) values. These data indicate that such clinics do not comply with the guidelines for vitamin K use developed at the American College of Chest Physicians (ACCP) Fifth Consensus Conference on Antithrombotic Therapy, as published in 1998.

nutrient-drug interactions
Antibiotics/Antimicrobial Agents (Systemic)
Bile Acid Sequestrants
Corticosteroids, Oral, Including Prednisone
Mineral Oil
Phenytoin, Phenobarbital, and Other Anticonvulsant Medications
Warfarin and Related Oral Vitamin K Antagonist Anticoagulants
  • Evidence: Warfarin (Coumadin, Marevan, Warfilone).
  • Extrapolated, based on similar properties: Anisindione (Miradon), dicumarol, ethyl biscoumacetate (Tromexan), nicoumalone (acenocoumarol; Acitrom, Sintrom), phenindione (Dindevan), phenprocoumon (Jarsin, Marcumar).
Drug-Induced Effect on Nutrient Function, Supplementation Contraindicated, Professional Management Appropriate
Bimodal or Variable Interaction, with Professional Management
Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern
Adverse Drug Effect on Herbal Therapeutics, Strategic Concern
Drug-Induced Adverse Effect on Nutrient Function, Coadministration Therapeutic, with Professional Management

Probability: 1. Certain
Evidence Base: Consensus

Effect and Mechanism of Action

Coumarins are vitamin K antagonists that produce their anticoagulant effect by interfering with the cyclic interconversion of vitamin K and its 2,3-epoxide (vitamin K epoxide). Vitamin K is primarily located in hepatic microsomes, where the vitamin K–dependent gamma-carboxylation as the final step in synthesis of prothrombin and factors VII, IX, and X occurs. Gamma-carboxylation is linked to vitamin K metabolism, specifically the cyclic interconversion of vitamin K and vitamin K epoxide. The primary site of action of warfarin and indandione anticoagulants appears to be an inhibition of the conversion of epoxide to vitamin K in this cycle. Warfarin's anticoagulant effect is based on the the drug being structurally a vitamin K “mimic” that binds to the vitamin K–dependent enzymes more avidly than does vitamin K, but does not allow the enzyme its active form, thus preventing gamma-carboxylation of coagulation factors II, VII, IX, and X; paradoxically, warfarin can exert a procoagulant response by interfering with proteins C and S. Without the gamma-carboxylation step, the factors lack adequate activity in the coagulation cascade. This vitamin K–epoxide cycle occurs in extrahepatic tissues such as kidney, spleen, and lung and is inhibited by warfarin. Thus, vitamin K epoxide is an intermediary metabolite of vitamin K that accumulates when it cannot be utilized, and thus is a marker of warfarin effect. There is a correlation between the inhibition of prothrombin synthesis and the regeneration of vitamin K from the epoxide by anticoagulants.

Gamma-carboxylation of glutamyl residues, facilitated by vitamin K, not only activates clotting factors but also activates osteocalcin and other bone matrix proteins. By inhibiting this process, vitamin K antagonists such as warfarin impair bone metabolism and increase the risk of osteoporotic fractures. 51

Research

The simple issue of whether or not vitamin K, alone or in plant materials, interacts with warfarin and similar anticoagulants appears inherent and formulaic, which it is to a major degree. However, the nuances and complexities of individual variations and competing therapeutic agendas reveal a wider range of hidden risks and clinical options than initially evident. Moreover, a review of the research literature indicates that a significant gap exists between the therapeutic guidelines and prevailing clinical practices regarding the use of vitamin K for treatment of warfarin-associated coagulopathy.

A long-term debate as to the safest and most effective form of vitamin K for stabilizing an excessively elevated INR has recently approached an evidence-based consensus. 52 A series of randomized controlled trials, particularly those by Crowther et al. 53,54 and Lubetsky et al., 55 have determined that oral vitamin K (phytonadione) lowers the INR more rapidly than subcutaneous vitamin K. Moreover, in some compromised ill patients, subcutaneous absorption, due to shunting of blood away from the skin, may actually be even less effective. Oral delivery also carries a substantially reduced risk of adverse reactions. In particular, intravenous administration carries a risk of anaphylaxis, although this may be significantly reduced by infusing over 30 minutes.

Clinical surveys, including ongoing research by Libby and Garcia 56 at the University of New Mexico, have determined that despite published reports of its safety and efficacy and established clinical protocols, a substantial number of anticoagulation clinics underutilize oral phytonadione in treating patients taking warfarin whose INR values are above therapeutic levels. In a 2002 paper, 100 separate anticoagulation clinics in the southwestern United States were surveyed with respect to the implementation of the recommendations for phytonadione use from the ACCP Fifth Consensus Conference on Antithrombotic Therapy. Of 53 respondents, 13 (25%) indicated that their clinics never use oral phytonadione. Eighteen (34%) indicated that their clinics use subcutaneous phytonadione, despite the absence of a recommendation for this in the 1998 ACCP guidelines. Only 17 respondents (32%) provided all four answers consistent with the ACCP recommendations. 56 The reasons for and implications of this apparent pattern of practice warrant broader and more in-depth research, in addition to confirming whether the observed phenomenon is representative of other geographic regions.

Individual sensitivity to warfarin is not consistent or fixed and appears to be influenced by vitamin K status, drug protein binding, and warfarin metabolism, among other variables. Reduced dietary vitamin K 1 intake potentiates the effect of warfarin in sick patients treated with antibiotics and IV fluids without vitamin K coadministration and in states of fat malabsorption. Hepatic dysfunction potentiates the response to warfarin through impaired synthesis of coagulation factors. Hypermetabolic states produced by fever or hyperthyroidism increase warfarin responsiveness, probably by increasing the catabolism of vitamin K–dependent coagulation factors. Lubetsky et al. 57 followed 50 patients commencing warfarin and consuming their regular diets for 8 weeks and concluded that in 32% (16/50) of anticoagulated patients under usual dietary conditions, sensitivity to warfarin is decreased by vitamin K intake of 250 µg/day or greater. Similarly, Cushman et al. 58 investigated the association of vitamin K status with warfarin sensitivity among 40 orthopedic patients beginning perioperative algorithm-dosed warfarin and found that dietary and biochemical measures of vitamin K status were associated with early warfarin sensitivity.

As Iqbal, Linder, and others have discussed, the pharmacodynamics of warfarin are subject to significant genetic and environmental variability. 59-62 Research by O’Reilly, Aggeler, et al., 64-66 as well as by Alving et al., 67 found that hereditary resistance to warfarin occurs in rats as well as humans. Individuals with genetic warfarin resistance require doses fivefold to 20-fold higher than average to achieve an anticoagulant effect. This pharmacogenomic pattern of response is attributed to altered affinity of the receptor for warfarin because the plasma warfarin levels required to achieve an anticoagulant effect are increased. Furthermore, Scordo et al. 68 evaluated the influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance in 93 Italian outpatients receiving long-term warfarin anticoagulant therapy. They concluded that “CYP2C9 genetic polymorphisms markedly influence warfarin dose requirements and metabolic clearance of the S-warfarin enantiomer, although non-genetic factors may also contribute to their large interindividual variability.”

Overall, a greater clinical understanding of, and development of experience with, the dynamic equilibrium between vitamin K intake and anticoagulant medications, with a heightened appreciation for and responsiveness to individual variability, physiological dynamics, and evolving health status, will enable safer and more effective utilization of anticoagulant therapy and reduce unrealistic assumptions of static physiological states. 69-71 Sconce, Kamali, et al. 72,73 have published a series of papers proposing an appraisal of current vitamin K–dosing algorithms for the reversal of overanticoagulation with warfarin, providing evidence to support vitamin K administration to “improve stability of anticoagulation for patients with unexplained variability in response to warfarin,” and emphasizing the “need for a more tailored dosing regimen.” Such an evolution of clinical practice will enable greater flexibility and reveal opportunities for support of a broader criterion for health than simple disease management as defined by INR levels, including integrative therapeutic strategies incorporating more robust dietary options and appropriate therapeutic application of herbal preparations, aimed at enhancing healthy function, reducing cardiovascular risk, and reducing reliance on anticoagulants over time.

Clinical Implications and Adaptations

By design, warfarin and similar anticoagulant medications achieve their therapeutic effect by interfering with vitamin K function and metabolism. Conversely, vitamin K therapy can be employed to antidote excessive effects of such anticoagulant therapies. Within the clinical practice of integrative medicine, warfarin therapy presents significant challenges to the implementation of botanical and nutritional therapeutics, let alone maintaining a simple healthy diet rich in nutritive plant foods. However, through communication, collaboration, and coordination, seemingly contraindicated therapies can be used together through high levels of vigilance, close monitoring, and responsive management within a context of integrative care bringing together medical practitioners trained and experienced in nutritional therapeutics, herbal medicine, and conventional pharmacology. As Jaffer and Bragg 74 judiciously pointed out in a 2003 review of warfarin dosing and monitoring: “There is no evidence that consuming less vitamin K is more beneficial in maintaining anticoagulation control than consuming more.”

Although the actions of anticoagulant medications and supplements, herbs, or foods containing vitamin K may be antagonistic on a tactical level, achieving and maintaining stability of coagulation factors are more important than mere presence or intake levels. More fundamentally, the primary strategic goals of disease prevention and health optimization must always remain clear and central. Amid valid concerns for effective anticoagulant protection, many physicians who prescribe coumadin anticoagulation instruct their patients to avoid consuming anything high in vitamin K, a practice that deprives them of many health-promoting phytonutrients. Consequently, from whatever source of information, many patients have been misinformed or otherwise come to believe that substances rich in vitamin K should be avoided if they are taking warfarin. However, simply eliminating plant foods rich in vitamin K and prohibiting use of therapeutically beneficial herbal prescriptions will not necessarily guarantee normalized INR values or support long-term medical objectives. Foods, herbs, and nutritional supplements inherently contain variable amounts of vitamin K and need to be evaluated with a thorough dietary assessment; the phylloquinone content of a wide range of foodstuffs has been listed by Sadowski et al. 75 Green leafy vegetables, such as kale, Swiss chard, spinach, broccoli, and mustard and turnip greens, are the foods that contain the highest amount of vitamin K per serving and thus are most likely to cause fluctuations in the INR. 76 Furthermore, in warfarinized patients any sudden reduction in intake of vitamin K from any of these sources is contraindicated because it may induce increased anticoagulation and increase bleeding risk through enhanced unopposed action of the medication.

Ultimately, the fundamental clinical management concern is maintaining a dynamic balance between vitamin K intake and warfarin, as represented in the INR; as such, however, the INR itself is secondary, if not irrelevant, to clinical outcomes and patient health, whether the patient reaches a therapeutic INR with 3 mg of warfarin, or 5, or 10, or even 20 mg. Warfarin itself is inexpensive and, unlike many pharmacological agents of its therapeutic potency, has no inherent toxicity or dose-related adverse effects, apart from its effects on vitamin K--related functions. Maintaining fairly constant vitamin K levels from both endogenous and exogenous sources is the key to stable anticoagulation with vitamin K antagonist anticoagulants. Thus, therapeutic agents containing vitamin K, whose actions are desirable for other reasons, are not necessarily contraindicated and can be used in the presence of anticoagulant medications if the individual has been stable during coadministration of such substances and anticoagulants, or if gradual, staged introduction of such agents is closely supervised and regularly monitored. Trust, communication, and education, along with systematic monitoring and flexible responses, are pivotal in the safe and effective management of vitamin K intake and INR stability within the context of a healthy diet and therapeutic use of herbal and nutritional therapies.

Management of a proper equilibrium between vitamin K intake and warfarin levels can be a challenging balancing act for both health care providers and patients, given the clinical importance of effective anticoagulant therapy and warfarin's narrow therapeutic index. Excessive vitamin K consumption can promote increased production of the vitamin K clotting factors, decreasing the anticoagulant response to warfarin. On the other hand, decreased vitamin K consumption can increase the anticoagulant response to warfarin. Normally it is sufficient to inform individuals taking warfarin to maintain a moderate and consistent level of vitamin K in their diet, to avoid binge eating of vitamin K–rich foods, and to report any significant changes in diet, supplement, or herbal intake to their anticoagulant management team. During the course of coadministration of vitamin K–rich herbs (or foods) and warfarin, the anticoagulant dose will need to be titrated, based on recognition that the effects of a dose adjustment on a given day will be seen in the INR 2 days later. In general, it would be reasonable to monitor the PT and INR more frequently when any dietary change, herbal therapy, or drug therapy is added or withdrawn from the regimen of a patient treated with an oral anticoagulant. Evidence from randomized controlled trials continues to support the use of less-intense warfarin treatment for many indications. For most patients, within an INR range of 2.0 to 3.0, the lower level generally is safer and equally effective. Whenever possible, it can be beneficial for patients undergoing warfarin therapy to have a home monitor so that they can monitor their INR daily during such transitional processes. However, the increasing availability of oral, direct thrombin inhibitors, such as Exanta, may soon reduce the risk of drug interactions and the need to restrict vitamin K intake, as well as provide a sufficiently predictable effect that high levels of monitoring become unnecessary.

Exercise is important in the elderly population and in individuals with cardiovascular disease. Clinical care needs to emphasize measures to counter the adverse effects of warfarin and other vitamin K antagonists on normal bone metabolism and subsequent elevation in the risk of osteoporotic fractures. Thus, particularly when prescribing anticoagulants to elderly individuals or others at high risk of falling, health care providers are advised to instruct patients to wear stable shoes, exercise regularly, maintain adequate intake of calcium and vitamin D, employ walking aids, and discontinue unnecessary and potentially complicating medications.

theoretical, speculative, and preliminary interactions research, including overstated interactions claims
Acetylsalicylic Acid (Aspirin) and Salicylates
Olestra
Orlistat
nutrient-nutrient interactions
Vitamin C
Vitamin E
Citations and Reference Literature
  • 1.Schurgers LJ, Teunissen KJ, Hamulyak K et al. Vitamin K–containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7. Blood 2006;109(8):3279-3283.View Abstract
  • 2.Cummings JH, Macfarlane GT. Role of intestinal bacteria in nutrient metabolism. JPEN J Parenter Enteral Nutr 1997;21:357-365.View Abstract
  • 3.Hill MJ. Intestinal flora and endogenous vitamin synthesis. Eur J Cancer Prev 1997;6 Suppl 1:S43-S45.View Abstract
  • 4.Shirakawa H, Komai M, Kimura S. Antibiotic-induced vitamin K deficiency and the role of the presence of intestinal flora. Int J Vitam Nutr Res 1990;60:245-251.View Abstract
  • 5.Stieger R, Baumgartner K, Neff U. [Dangerous hypoprothrombinemic hemorrhage in antibiotic therapy]. Helv Chir Acta 1992;58:775-778.View Abstract
  • 6.Kimura S, Satoh H, Komai M. The roles of intestinal flora and intestinal function on vitamin K metabolism. J Nutr Sci Vitaminol (Tokyo) 1992;Spec No:425-428.View Abstract
  • 7.Conly J, Stein K. Reduction of vitamin K2 concentrations in human liver associated with the use of broad spectrum antimicrobials. Clin Invest Med 1994;17:531-539.View Abstract
  • 8.Clark J, Hochman R, Rolla AR et al. Coagulopathy associated with the use of cephalosporin or moxalactam antibiotics in acute and chronic renal failure. Clin Exp Dial Apheresis 1983;7:177-190.View Abstract
  • 9.Spurling NW, Harcourt RA, Hyde JJ. An evaluation of the safety of cefuroxime axetil during six months oral administration to beagle dogs. J Toxicol Sci 1986;11:237-277.
  • 10.Schafer H, Naber K, Adam D. [Hemostasis disturbance caused by cephalosporins with an N-methylthiotetrazole side chain: a randomized pilot study]. Arzneimittelforschung 1989;39:1156-1162.View Abstract
  • 11.Kaiser CW, McAuliffe JD, Barth RJ, Lynch JA. Hypoprothrombinemia and hemorrhage in a surgical patient treated with cefotetan. Arch Surg 1991;126:524-525.View Abstract
  • 12.Peetermans W, Verbist L. [Coagulation disorders caused by cephalosporins containing methylthiotetrazole side chains]. Acta Clin Belg 1990;45:327-333.View Abstract
  • 13.Breen GA, St Peter WL. Hypoprothrombinemia associated with cefmetazole. Ann Pharmacother 1997;31:180-184.View Abstract
  • 14.Lipsky JJ. Nutritional sources of vitamin K. Mayo Clin Proc 1994;69:462-466.View Abstract
  • 15.Macfarlane GT, Cummings JH. Probiotics, infection and immunity. Curr Opin Infect Dis 2002;15:501-506.View Abstract
  • 16.Montalto M, Arancio F, Izzi D et al. [Probiotics: history, definition, requirements and possible therapeutic applications]. Ann Ital Med Int 2002;17:157-165.View Abstract
  • 17.Morelli L. Probiotics: clinics and/or nutrition. Dig Liver Dis 2002;34 Suppl 2:S8-S11.View Abstract
  • 18.Ouwehand A, Vesterlund S. Health aspects of probiotics. IDrugs 2003;6:573-580.View Abstract
  • 19.Reid G, Jass J, Sebulsky MT, McCormick JK. Potential uses of probiotics in clinical practice. Clin Microbiol Rev 2003;16:658-672.View Abstract
  • 20.Blum S, Schiffrin EJ. Intestinal microflora and homeostasis of the mucosal immune response: implications for probiotic bacteria? Curr Issues Intest Microbiol 2003;4:53-60.
  • 21.Olson RE. Vitamin K. In: Shils ME, Olson JA, Shike M, eds. Modern Nutrition in Health and Disease. 9th ed. Media, Pa: Williams & Wilkins; 1999:363-380.
  • 22.Vermeer C, Schurgers LJ. A comprehensive review of vitamin K and vitamin K antagonists. Hematol Oncol Clin North Am 2000;14:339-353.View Abstract
  • 23.Verho M, Malerczyk V, Rosenkranz B, Grotsch H. Absence of interaction between ofloxacin and phenprocoumon. Curr Med Res Opin 1987;10:474-479.
  • 24.Conly JM, Stein K, Worobetz L, Rutledge-Harding S. The contribution of vitamin K2 (menaquinones) produced by the intestinal microflora to human nutritional requirements for vitamin K. Am J Gastroenterol 1994;89:915-923.View Abstract
  • 25.Bandrowsky T, Vorono AA, Borris TJ, Marcantoni HW. Amoxicillin-related postextraction bleeding in an anticoagulated patient with tranexamic acid rinses. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;82:610-612.View Abstract
  • 26.Huilgol VR, Markus SL, Vakil NB. Antibiotic-induced iatrogenic hemobilia. Am J Gastroenterol 1997;92:706-707.View Abstract
  • 27.Suzuki K, Fukushima T, Meguro K et al. Intracranial hemorrhage in an infant owing to vitamin K deficiency despite prophylaxis. Childs Nerv Syst 1999;15:292-294.View Abstract
  • 28.Jones CB, Fugate SE. Levofloxacin and warfarin interaction. Ann Pharmacother 2002;36:1554-1557.View Abstract
  • 29.Davydov L, Yermolnik M, Cuni LJ. Warfarin and amoxicillin/clavulanate drug interaction. Ann Pharmacother 2003;37:367-370.View Abstract
  • 30.West RJ, Lloyd JK. The effect of cholestyramine on intestinal absorption. Gut 1975;16:93-98.View Abstract
  • 31.Hathcock JN. Metabolic mechanisms of drug-nutrient interactions. Fed Proc 1985;44:124-129.View Abstract
  • 32.Watkins DW, Khalafi R, Cassidy MM, Vahouny GV. Alterations in calcium, magnesium, iron, and zinc metabolism by dietary cholestyramine. Dig Dis Sci 1985;30:477-482.View Abstract
  • 33.Roe DA. Drug-Induced Nutritional Deficiencies. 2nd ed. Westport, Conn: Avi Publishing; 1985.
  • 34.Knodel LC, Talbert RL. Adverse effects of hypolipidaemic drugs. Med Toxicol 1987;2:10-32.View Abstract
  • 35.Roe DA. Drug and nutrient interactions in the elderly diabetic. Drug Nutr Interact 1988;5:195-203.View Abstract
  • 36.Tonstad S, Sivertsen M, Aksnes L, Ose L. Low dose colestipol in adolescents with familial hypercholesterolaemia. Arch Dis Child 1996;74:157-160.View Abstract
  • 37.Booth SL, Broe KE, Gagnon DR et al. Vitamin K intake and bone mineral density in women and men. Am J Clin Nutr 2003;77:512-516.View Abstract
  • 38.Yonemura K, Kimura M, Miyaji T, Hishida A. Short-term effect of vitamin K administration on prednisolone-induced loss of bone mineral density in patients with chronic glomerulonephritis. Calcif Tissue Int 2000;66:123-128.View Abstract
  • 39.Inoue T, Sugiyama T, Matsubara T et al. Inverse correlation between the changes of lumbar bone mineral density and serum undercarboxylated osteocalcin after vitamin K2 (menatetrenone) treatment in children treated with glucocorticoid and alfacalcidol. Endocr J 2001;48:11-18.
  • 40.Elmstahl S, Ekstrom H, Galvard H et al. Is there an association between inhaled corticosteroids and bone density in postmenopausal women? J Allergy Clin Immunol 2003;111:91-96.
  • 41.Leone FT, Fish JE, Szefler SJ, West SL. Systematic review of the evidence regarding potential complications of inhaled corticosteroid use in asthma: collaboration of American College of Chest Physicians, American Academy of Allergy, Asthma, and Immunology, and American College of Allergy, Asthma, and Immunology. Chest 2003;124:2329-2340.
  • 42.Suissa S, Baltzan M, Kremer R, Ernst P. Inhaled and nasal corticosteroid use and the risk of fracture. Am J Respir Crit Care Med 2004;169:83-88.View Abstract
  • 43.Clark JH, Russell GJ, Fitzgerald JF, Nagamori KE. Serum beta-carotene, retinol, and alpha-tocopherol levels during mineral oil therapy for constipation. Am J Dis Child 1987;141:1210-1212.
  • 44.Diarrhea and constipation. In: Berkow R, Fletcher AJ, Beers MH et al, eds. The Merck Manual of Diagnosis and Therapy. 16th ed. Rahway, NJ: Merck Research Laboratories; 1992:810.
  • 45.Keith DA, Gallop PM. Phenytoin, hemorrhage, skeletal defects and vitamin K in the newborn. Med Hypotheses 1979;5:1347-1351.View Abstract
  • 46.Howe AM, Lipson AH, Sheffield LJ et al. Prenatal exposure to phenytoin, facial development, and a possible role for vitamin K. Am J Med Genet 1995;58:238-244.View Abstract
  • 47.Keith DA, Gundberg CM, Japour A et al. Vitamin K–dependent proteins and anticonvulsant medication. Clin Pharmacol Ther 1983;34:529-532.View Abstract
  • 48.Cornelissen M, Steegers-Theunissen R, Kollee L et al. Increased incidence of neonatal vitamin K deficiency resulting from maternal anticonvulsant therapy. Am J Obstet Gynecol 1993;168:923-928.View Abstract
  • 49.Kaaja E, Kaaja R, Matila R, Hiilesmaa V. Enzyme-inducing antiepileptic drugs in pregnancy and the risk of bleeding in the neonate. Neurology 2002;58:549-553.View Abstract
  • 50.Hey E. Effect of maternal anticonvulsant treatment on neonatal blood coagulation. Arch Dis Child Fetal Neonatal Ed 1999;81:F208-F210.View Abstract
  • 51.Gage BF, Birman-Deych E, Radford MJ et al. Risk of osteoporotic fracture in elderly patients taking warfarin: results from the National Registry of Atrial Fibrillation 2. Arch Intern Med 2006;166:241-246.View Abstract
  • 52.Hirsh J, Fuster V, Ansell J, Halperin JL. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. J Am Coll Cardiol 2003;41:1633-1652.View Abstract
  • 53.Crowther MA, Julian J, McCarty D et al. Treatment of warfarin-associated coagulopathy with oral vitamin K: a randomised controlled trial. Lancet 2000;356:1551-1553.View Abstract
  • 54.Crowther MA, Douketis JD, Schnurr T et al. Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of warfarin-associated coagulopathy: a randomized, controlled trial. Ann Intern Med 2002;137:251-254.View Abstract
  • 55.Lubetsky A, Yonath H, Olchovsky D et al. Comparison of oral vs intravenous phytonadione (vitamin K1) in patients with excessive anticoagulation: a prospective randomized controlled study. Arch Intern Med 2003;163:2469-2473.View Abstract
  • 56.Libby EN, Garcia DA. A survey of oral vitamin K use by anticoagulation clinics. Arch Intern Med 2002;162:1893-1896.View Abstract
  • 57.Lubetsky A, Dekel-Stern E, Chetrit A et al. Vitamin K intake and sensitivity to warfarin in patients consuming regular diets. Thromb Haemost 1999;81:396-399.View Abstract
  • 58.Cushman M, Booth SL, Possidente CJ et al. The association of vitamin K status with warfarin sensitivity at the onset of treatment. Br J Haematol 2001;112:572-577.View Abstract
  • 59.Lappegard KT. [Hereditary warfarin resistance]. Tidsskr Nor Laegeforen 2000;120:3257-3258.View Abstract
  • 60.Linder MW. Genetic mechanisms for hypersensitivity and resistance to the anticoagulant warfarin. Clin Chim Acta 2001;308:9-15.View Abstract
  • 61.Linder MW, Valdes R Jr. Genetic mechanisms for variability in drug response and toxicity. J Anal Toxicol 2001;25:405-413.View Abstract
  • 62.Iqbal O. Pharmacogenomics in anticoagulant drug development. Pharmacogenomics 2002;3:823-828.View Abstract
  • 63.O’Reilly RA, Aggeler PM, Hoag MS et al. Hereditary transmission of exceptional resistance to coumarin anticoagulant drugs: the first reported kindred. N Engl J Med 1964;271:809-815.
  • 64.O’Reilly RA, Aggeler PM. Coumarin anticoagulant drugs: hereditary resistance in man. Fed Proc 1965;24:1266-1273.
  • 65.O’Reilly RA, Pool JG, Aggeler PM. Hereditary resistance to coumarin anticoagulant drugs in man and rat. Ann NY Acad Sci 1968;151:913-931.
  • 66.O’Reilly RA. The second reported kindred with hereditary resistance to oral anticoagulant drugs. N Engl J Med 1970;282:1448-1451.
  • 67.Alving BM, Strickler MP, Knight RD et al. Hereditary warfarin resistance: investigation of a rare phenomenon. Arch Intern Med 1985;145:499-501.View Abstract
  • 68.Scordo MG, Pengo V, Spina E et al. Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance. Clin Pharmacol Ther 2002;72:702-710.
  • 69.Cohen H, Scott SD, Mackie IJ et al. The development of hypoprothrombinaemia following antibiotic therapy in malnourished patients with low serum vitamin K1 levels. Br J Haematol 1988;68:63-66.View Abstract
  • 70.Feldstein AC, Smith DH, Perrin N et al. Reducing warfarin medication interactions: an interrupted time series evaluation. Arch Intern Med 2006;166:1009-1015.View Abstract
  • 71.Sconce EA, Daly AK, Khan TI et al. APOE genotype makes a small contribution to warfarin dose requirements. Pharmacogenet Genomics 2006;16:609-611.View Abstract
  • 72.Sconce EA, Kamali F. Appraisal of current vitamin K dosing algorithms for the reversal of over-anticoagulation with warfarin: the need for a more tailored dosing regimen. Eur J Haematol 2006;77:457-462.View Abstract
  • 73.Sconce E, Avery P, Wynne H, Kamali F. Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin. Blood 2006.View Abstract
  • 74.Jaffer A, Bragg L. Practical tips for warfarin dosing and monitoring. Cleve Clin J Med 2003;70:361-371.View Abstract
  • 75.Sadowski JA, Booth SL, Mann KG et al. Structure and mechanism of activation of vitamin K antagonists. In: Poller L et al, eds. Oral anticoagulants. London: Arnold; 1996:439-442.
  • 76.Franco V, Polanczyk CA, Clausell N, Rohde LE. Role of dietary vitamin K intake in chronic oral anticoagulation: prospective evidence from observational and randomized protocols. Am J Med 2004;116:651-656.View Abstract
  • 77.Harrell CC, Kline SS. Vitamin K–supplemented snacks containing olestra: implication for patients taking warfarin. JAMA 1999;282:1133-1134.View Abstract
  • 78.McDuffie JR, Calis KA, Booth SL et al. Effects of orlistat on fat-soluble vitamins in obese adolescents. Pharmacotherapy 2002;22:814-822.View Abstract
  • 79.Merkel RL. The use of menadione bisulfite and ascorbic acid in the treatment of nausea and vomiting of pregnancy: a preliminary report. Am J Obstet Gynecol 1952;64:416-418.View Abstract
  • 80.Venugopal M, Jamison JM, Gilloteaux J et al. Synergistic antitumour activity of vitamins C and K3 against human prostate carcinoma cell lines. Cell Biol Int 1996;20:787-797.View Abstract
  • 81.Gilloteaux J, Jamison JM, Arnold D et al. Cancer cell necrosis by autoschizis: synergism of antitumor activity of vitamin C: vitamin K3 on human bladder carcinoma T24 cells. Scanning 1998;20:564-575.View Abstract
  • 82.Zhang W, Negoro T, Satoh K et al. Synergistic cytotoxic action of vitamin C and vitamin K3. Anticancer Res 2001;21:3439-3444.View Abstract
  • 83.Gilloteaux J, Jamison JM, Arnold D et al. Ultrastructural aspects of autoschizis: a new cancer cell death induced by the synergistic action of ascorbate/menadione on human bladder carcinoma cells. Ultrastruct Pathol 2001;25:183-192.View Abstract
  • 84.Gilloteaux J, Jamison JM, Arnold D, Summers JL. Autoschizis: another cell death for cancer cells induced by oxidative stress. Ital J Anat Embryol 2001;106:79-92.View Abstract
  • 85.Booth SL, Golly I, Sacheck JM et al. Effect of vitamin E supplementation on vitamin K status in adults with normal coagulation status. Am J Clin Nutr 2004;80:143-148.View Abstract
  • .[No authors listed.] ACCP-NHLBI National Conference on Antithrombotic Therapy: American College of Chest Physicians and the National Heart, Lung and Blood Institute. Chest 1986;89(2 Suppl):1S-106S.
  • .[No author listed.] Aquamephyton (phytonadione), product prescribing information. Whitehouse Station, NJ: Merck and Co, Inc; 2001.
  • .[No author listed.] Coumadin (warfarin), product prescribing information. Wilmington, DE: DuPont Pharma; 2001.
  • .Ageno W, Crowther M, Steidl L, et al. Low dose oral vitamin K to reverse acenocoumarol-induced coagulopathy: a randomized controlled trial. Thromb Haemost 2002;88(1):48-51.
  • .Aisaka K, Uesato T, Miwa, et al. Evaluation of vitamin K2 (menatetrenone) administration with hormone replacement therapy on prevention of osteoporosis in climacteric women. Ninth International Menopause Society World Congress on the Menopause: Yokohama, Japan, Oct 1999:79-83.
  • .Alberts MJ, Massey EW, Dawson D. A multicenter study of anticoagulation parameters when using heparin and warfarin. Arch Neurol 1987;44(12):1229-1231.
  • .Alexander KP, Chen AY, Roe MT, et al. Excess dosing of antiplatelet and antithrombin agents in the treatment of non-ST-segment elevation acute coronary syndromes. JAMA 2005;294:3108-3116.
  • .Allison AC. The possible role of vitamin K deficiency in the pathogenesis of Alzheimer’s disease and in augmenting brain damage associated with cardiovascular disease. Med Hypotheses 2001;57(2):151-155.
  • .Allison PM, Mummah-Schendel LL, Kindberg CG, et al. Effects of a vitamin K-deficient diet and antibiotics in normal human volunteers. J Lab Clin Med 1987;110(2):180-188.
  • .Alperin JB. Coagulopathy caused by vitamin K deficiency in critically ill, hospitalized patients. JAMA 1987;258(14):1916-1919.
  • .Andersen P, Godal HC. Predictable reduction in anticoagulant activity of warfarin by small amounts of vitamin K. Acta Med Scand 1975;198:269-270.
  • .Ansell JE. The perioperative management of warfarin therapy. Arch Intern Med 2003;163:881-883.
  • .Anonymous. New examples of vitamin K-drug interaction. Nutr Rev 1984;42(4):161-163. (Review)
  • .Arunachalam K, Gill HS, Chandra RK. Enhancement of natural immune function by dietary consumption of Bifidobacterium lactis (HN019). Eur J Clin Nutr 2000;54:263-267.
  • .Avery RA, Duncan WE, Alving BM. Severe vitamin K deficiency induced by occult celiac disease BR96-026. Am J Hematol 1996;53(1):55.
  • .Barash P, Kitahata LM, Mandel S. Acute cardiovascular collapse after intravenous phytonadione. Anesth Analg 1976;55(2):304-306.
  • .Bell RG. Metabolism of vitamin K and prothrombin synthesis: anticoagulants and the vitamin K-epoxide cycle. Fed Proc 1978;37(12):2599-2604. (Review)
  • .Bell RG, Caldwell PT, Holm EE. Coumarins and the vitamin K-K epoxide cycle: lack of resistance to coumatetralyl in warfarin-resistant rats. Biochem Pharmacol 1976;25(9):1067-1070.
  • .Bell RG, Ren P. Inhibition by warfarin enantiomers of prothrombin synthesis, protein carboxylation, and the regeneration of vitamin K from vitamin K epoxide. Biochem Pharmacol 1981;30(14):1953-1958.
  • .Bengmark S. Ecological control of the gastrointestinal tract: the role of probiotic flora. Gut 1998;42(1):2-7. (Review)
  • .Binkley N, Suttie J. Vitamin K nutrition and osteoporosis. J Nutr 1995;125:1812-1821.
  • .Blum S, Haller D, Pfeifer A, et al. Probiotics and immune response. Clin Rev Allergy Immunol 2002;22(3):287-309.
  • .Bodin L, Verstuyft C, Tregouet D-A, et al. Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity. Blood 2005;106:135-140.
  • .Booth SL, Broe KE, Gagnon DR, et al. Vitamin K intake and bone mineral density in women and men. Am J Clin Nutr 2003;77(2):512-516.
  • .Booth SL, Broe KE, Peterson JW, et al. Associations between vitamin K biochemical measures and bone mineral density in men and women. J Clin Endocrinol Metab 2004;89(10):4904-4909.
  • .Booth SL, Charnley JM, Sadowski JA, et al. Dietary vitamin K1 and stability of oral anticoagulation: proposal of a diet with a constant vitamin K1 content. Thromb Haemost 1997;77:504-509.
  • .Booth SL, Lichtenstein AH, O’Brien-Morse M, et al. Effects of a hydrogenated form of vitamin K on bone formation and resorption. Am J Clin Nutr 2001;74(6):783-790.
  • .Booth SL, Martini L, Peterson JW, et al. Dietary phylloquinone depletion and repletion in older women. J Nutr 2003;133(8):2565-2569.
  • .Booth SL, Broe KE, McLean RR, et al. Low vitamin K status is associated with low bone mineral density and quantitative ultrasound in men. Presentation at 24th Annual Meeting of the American Society for Bone and Mineral Research. San Antonio, Sep 23, 2002.
  • .Bovill EG, Lawson J, Sadowski J, et al. Mechanisms of vitamin K metabolism and vitamin K-dependent hemostasis: implications for warfarin therapy. In: Ezekowitz, MD, ed. The heart as a source of systemic embolisation. New York: Martin Dekker; 1992.
  • .Braam LA, Knapen MH, Geusens P, et al. Vitamin K1 supplementation retards bone loss in postmenopausal women between 50 and 60 years of age. Calcif Tissue Int 2003;73(1):21-26.
  • .Brown CH, Natelson EA, Bradshaw MW, et al. The hemostatic defect produced by carbenicillin. N Engl J Med 1974;291:265-270.
  • .Burnier JP, Borowski M, Furie BC, et al. Gamma-carboxyglutamic acid. Mol Cell Biochem 1981;39:191-207.
  • .Byrd DC, Stephens MA, Hamann GL, et al. Subcutaneous phytonadione for reversal of warfarin-induced elevation of the international normalized ratio. Am J Health Syst Pharm 1999;56(22):2312-2315.
  • .Canfield AE, Farrington C, Dziobon MD, et al. The involvement of matrix glycoproteins in vascular calcification and fibrosis: an immunohistochemical study. J Pathol 2002;196(2):228-234.
  • .Chu K, Wu SM, Stanley T, et al. A mutation in the propeptide of factor IX leads to warfarin sensitivity by a novel mechanism. J Clin Invest 1996;98:1619-1625.
  • .Clarke P, Mitchell SJ, Wynn R, et al. Vitamin K prophylaxis for preterm infants: a randomized, controlled trial of 3 regimens. Pediatrics 2006;118:1657-1666.
  • .Cockayne S, Adamson J, Lanham-New S, et al. Vitamin K and the prevention of fractures: systematic review and meta-analysis of randomized controlled trials. Arch Intern Med 2006;166:1256-1261. (Meta-analysis)
  • .Combs AB, Porter TH, Folkers K. Anticoagulant activity of a naphthoquinone analog of vitamin K and an inhibitor of coenzyme Q10-enzyme systems. Res Commun Chem Pathol Pharmacol 1976;13(1):109-114.
  • .Conly JM, Stein K, Worobetz L, et al. The contribution of vitamin K2 (menaquinones) produced by the intestinal microflora to human nutritional requirements for vitamin K. Am J Gastroenterol 1994;89(6):915-923.
  • .Corallo CE, Gillett M. Anaphylactic shock following intravenous vitamin K1. Aust J Hosp Pharm 1997;27:146-147.
  • .Corrigan JJ Jr. The effect of vitamin E on warfarin-induced vitamin K deficiency. Ann N Y Acad Sci 1982;393:361-368.
  • .Cornelissen M, Steegers-Theunissen R, Kollee L, et al. Supplementation of vitamin K in pregnant women receiving anticonvulsant therapy prevents neonatal vitamin K deficiency. Am J Obstet Gynecol 1993;168(3 Pt 1):884-888.
  • .Covington T, ed. Nonprescription drug therapy guiding patient self-care. St Louis: Facts and Comparisons; 1999:467-545.
  • .Craciun AM, Wolf J, Knapen MH, et al. Improved bone metabolism in female elite athletes after vitamin K supplementation. Int J Sports Med 1998;19(7):479-484.
  • .Cummings JH, Macfarlane GT. Role of intestinal bacteria in nutrient metabolism. JPEN J Parenter Enteral Nutr 1997;21(6):357-365. (Review)
  • .De Simone C, Vesely R, Bianchi SB, et al. The role of probiotics in modulation of the immune system in man and in animals. Int J Immunother 1993;9:23-28.
  • .DeZee KJ, Shimeall WT, Douglas KM, et al. Treatment of excessive anticoagulation with phytonadione (vitamin K): a meta-analysis. Arch Intern Med 2006;166:391-397.
  • .Diab F, Feffer S. Hereditary warfarin resistance. South Med J 1994;87(3):407-409. (Review)
  • .Dunn AS, Turpie AGG. Perioperative management of patients receiving oral anticoagulants: a systematic review. Arch Intern Med 2003;163:901-908. (Review)
  • .Engelse MA, Neele JM, Bronckers AL, et al. Vascular calcification: expression patterns of the osteoblast-specific gene core binding factor alpha-1 and the protective factor matrix gla protein in human atherogenesis. Cardiovasc Res 2001;52(2):281-289.
  • .Erickson KL, Hubbard NE. Probiotic immunomodulation in health and disease. J Nutr 2000;130(2S Suppl):403S-409S. (Review)
  • .Feldstein AC, Smith DH, Perrin N, et al. Reducing warfarin medication interactions: an interrupted time series evaluation. Arch Intern Med 2006;166:1009-1015.
  • .Feskanich D, Weber P, Willett WC, et al. Vitamin K intake and hip fractures in women: a prospective study. Am J Clin Nutr 1999;69(1):74-79.
  • .Franco V, Polanczyk CA, Clausell N, et al. Role of dietary vitamin K intake in chronic oral anticoagulation: prospective evidence from observational and randomized protocols. Am J Med 2004;116(10):651-656. 
  • .Frey UH, Aral N, Muller N, et al. Cooperative effect of GNB3 825C>T and GPIIIa PI(A) polymorphisms in enhanced platelet aggregation. Thromb Res 2003;109(5-6):279-286.
  • .Fuller R, Gibson GR. Modification of the intestinal microflora using probiotics and prebiotics. Scand J Gastroenterol Suppl 1997;222:28-31.
  • .Fuller R. Probiotics in human medicine. Gut 1991;32(4):439-442. (Review)
  • .Gage BF, Birman-Deych E, Radford MJ, et al. Risk of osteoporotic fracture in elderly patients taking warfarin: results from the National Registry of Atrial Fibrillation. Arch Intern Med 2006;166:241-246.
  • .Garcia D, Libby E. A survey examining oral vitamin K use among anticoagulation clinics in the southwestern United States. Presented at the Eighteenth Congress of the International Society on Thrombosis and Haemostasis (ISTH). Paris, Jul 8, 2001.
  • .Gibson GR. Dietary modulation of the human gut microflora using probiotics. Br J Nutr 1998;80(Suppl 2):S209-S212.
  • .Gilloteaux J, Jamison JM, Arnold D, et al. Autoschizis: another cell death for cancer cells induced by oxidative stress. Ital J Anat Embryol 2001;106(2 Suppl 1):79-92.
  • .Gilloteaux J, Jamison JM, Arnold D, et al. Cancer cell necrosis by autoschizis: synergism of antitumor activity of vitamin C: vitamin K3 on human bladder carcinoma T24 cells. Scanning 1998;20(8):564-575.
  • .Gilloteaux J, Jamison JM, Arnold D, et al. Ultrastructural aspects of autoschizis: a new cancer cell death induced by the synergistic action of ascorbate/menadione on human bladder carcinoma cells. Ultrastruct Pathol 2001;25(3):183-192.
  • .Glasheen JJ, Fugit RV, Prochazka AV. Effect of levofloxacin coadministration on the international normalized ratios during warfarin therapy: a comment. Pharmacotherapy 2003;23(8):1079-1080. (Letter)
  • .Goss TF, Walawander CA, Grasela TH Jr, et al. Prospective evaluation of risk factors for antibiotic-associated bleeding in critically ill patients. Pharmacotherapy 1992;12(4):283-291.
  • .Harrell CC, Kline SS. Oral vitamin K1: an option to reduce warfarin’s activity. Ann Pharmacother 1995;29(12):1228-1232.
  • .Harris JE. Interaction of dietary factors with oral anticoagulants: review and application. J Am Diet Assoc 1995;95(5):580-584. (Review)
  • .Harrison RL, Alperin JB, Kumar D. Concurrent lupus anticoagulants and prothrombin deficiency due to phenytoin use. Arch Pathol Lab Med 1987;111(8):719-722.
  • .Hart JP, Shearer MJ, Klenerman L, et al. Electrochemical detection of depressed circulating levels of vitamin K in osteoporosis. J Clin Endocrinol Metab 1985;60(6):1268-1269.
  • .Hart RG. Atrial fibrillation and stroke prevention [perspective]. N Engl J Med 2003;349:1015-1016. (Editorial)
  • .Hathcock JN. Metabolic mechanisms of drug-nutrient interactions. Fed Proc 1985;44(1 Pt 1):124-129. (Review)
  • .Heck AM, DeWitt BA, Lukes AL. Potential interactions between alternative therapies and warfarin. Am J Health Syst Pharm 2000;57:1221-1230.
  • .Hey E. Vitamin K: what, why, and when. Arch Dis Child Fetal Neonatal Ed 2003;88(2):F80-83.
  • .Hill MJ. Intestinal flora and endogenous vitamin synthesis. Eur J Cancer Prev 1997;6(Suppl 1):S43-45. (Review)
  • .Hillman MA, Wilke RA, Caldwell MD, et al. Relative impact of covariates in prescribing warfarin according to CYP2C9 genotype. Pharmacogenetics 2004;14(8):539-547.
  • .Hillman MA, Wilke RA, Yale SH, et al. A prospective, randomized pilot trial of model-based warfarin dose initiation using CYP2C9 genotype and clinical data. Clin Med Res 2005;3(3):137-145.
  • .Hirsh J, Dalen J, Guyatt G. The sixth (2000) ACCP guidelines for antithrombotic therapy for prevention and treatment of thrombosis: American College of Chest Physicians. Chest 2001;119(1 Suppl):1S-370S.
  • .Hirsh J, Dalen J, Anderson DR, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001;119(1 Suppl):8S-21S. (Review)
  • .Hirsh J, Fuster V, Ansell J, et al; American Heart Association; American College of Cardiology Foundation. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. Circulation 2003;107(12):1692-711. (Review)
  • .Hodges SJ, Pilkington MJ, Shearer MJ, et al. Age-related changes in the circulating levels of congeners of vitamin K2, menaquinone-7 and menaquinone-8. Clin Sci (Colch) 1990;78(1):63-66.
  • .Holbrook AM, Pereira JA, Labiris R, et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med 2005;165;1095-1106.
  • .Holt RJ, Freytes CO. Familial warfarin resistance. Drug Intell Clin Pharm 1983;17(4):281-283.
  • .Holzapfel WH, Haberer P, Snel J, et al. Overview of gut flora and probiotics. Int J Food Microbiol 1998;41(2):85-101. (Review)
  • .Howe AM, Webster WS, Lipson AH, et al. Binder’s syndrome due to prenatal vitamin K deficiency: a theory of pathogenesis. Aust Dent J 1992;37(6):453-460.
  • .Hulse ML. Warfarin resistance: diagnosis and therapeutic alternatives. Pharmacotherapy 1996;16(6):1009-1017. (Review)
  • .Humpl T, Bruhl K, Brzezinska R, et al. Fatal late vitamin K-deficiency bleeding after oral vitamin K prophylaxis secondary to unrecognized bile duct paucity. J Pediatr Gastroenterol Nutr 1999;29(5):594-597.
  • .Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003;349:1019-1026.
  • .Igarashi O. Vitamin K. Nippon Rinsho Apr 1993;51(4):910-918.
  • .Iwamoto I, Kosha S, Noguchi S, et al. A longitudinal study of the effect of vitamin K2 on bone mineral density in postmenopausal women a comparative study with vitamin D3 and estrogen-progestin therapy. Maturitas 1999;31(2):161-164.
  • .Jaffer A, Bragg L. Practical tips for warfarin dosing and monitoring. Cleve Clin J Med 2003;70(4):361-371.
  • .Jie KS, Bots ML, Vermeer C, et al. Vitamin K intake and osteocalcin levels in women with and without aortic atherosclerosis: a population-based study. Atherosclerosis 1995;116(1):117-123.
  • .Jie KS, Gijsbers BL, Knapen MH, et al. Effects of vitamin K and oral anticoagulants on urinary calcium excretion. Br J Haematol 1993;83(1):100-104.
  • .Jorgensen MJ, Cantor AB, Furie BC, et al. Recognition site directing vitamin K-dependent-carboxylation resides on the propeptide of factor IX. Cell 1987;48:185-191.
  • .Kanai T, Takagi T, Masuhiro K, et al. Serum vitamin K level and bone mineral density in post-menopausal women. Int J Gynaecol Obstet 1997;56(1):25-30.
  • .Kasper H. Protection against gastrointestinal diseases: present facts and future developments. Int J Food Microbiol 1998;41(2):127-131.
  • .Kempin SJ. Warfarin resistance caused by broccoli. N Engl J Med 1983;308(20):1229-1230. (Letter)
  • .Kendall MJ, Chan K. Drug-induced malabsorption. Xenobiotica 1973;3(11):727-744. (Review)
  • .Keough GC, English JC, Meffert JJ. Eczematous hypersensitivity from aqueous vitamin K injection. Cutis 1998;61:81-83.
  • .Ketteler M, Vermeer C, Wanner C, et al. Novel insights into uremic vascular calcification: role of matrix Gla protein and alpha-2-Heremans Schmid glycoprotein/fetuin. Blood Purif 2002;20(5):473-476.
  • .Kikuchi S, Ando A, Minato K. [Acquired coagulopathy caused by administration of parenteral broad-spectrum antibiotics.] Rinsho Byori 1991;39(1):83-90. [Japanese]
  • .Kimura S, Satoh H, Komai M. The roles of intestinal flora and intestinal function on vitamin K metabolism. J Nutr Sci Vitaminol (Tokyo) 1992;Spec No:425-428.
  • .Knapen MH, Hamulyak K, Vermeer C. The effect of vitamin K supplementation on circulating osteocalcin (bone Gla protein) and urinary calcium excretion. Ann Intern Med 1989 D15;111(12):1001-1005.
  • .Kohlmeier M, Saupe J, Shearer MJ, et al. Bone health of adult hemodialysis patients is related to vitamin K status. Kidney Int 1997;51:1218-1221.
  • .Lackey L, Ozawa T. Cephalosporins and coagulopathy. J Tenn Med Assoc 1986;79(10):613-615. (Review)
  • .Laupacis A. Oral vitamin K reversed warfarin-associated coagulopathy faster than subcutaneous vitamin K. ACP J Club 2003;138(1):10.
  • .Lee AW, Proudfoot WH, Griffen WO Jr. Coagulopathy associated with broad spectrum antibiotic therapy. J Ky Med Assoc 1984;82(3):125-126.
  • .Lee CR. Warfarin initiation and the potential role of genomic-guided dosing. Clin Med Res 2005;3(4):205-206. (Editorial)
  • .Lefrere JJ, Guyon F, Horellou MH, et al. [Resistance to vitamin K antagonists: 6 cases.] Ann Med Interne (Paris) 1986;137(5):384-390. [French]
  • .Linzenmeier G, Haralambie E, Dermoumi H. [Short-term oral chemoprophylaxis before intestine surgery: quantitative determination of bacteria and fungi in stool specimens.] Zentralbl Bakteriol [Orig A] 1979;243(2-3):326-335. [German]
  • .Lipkin EW, Kowdley KV. Vitamin K replacement in osteoporosis associated with cirrhosis: another reason to “eat your vegetables?” Am J Gastroenterol 2002;97(4):786-788. (Editorial)
  • .Lipsky JJ. Nutritional sources of vitamin K. Mayo Clin Proc 1994;69(5):462-466. (Review)
  • .Lubetsky A, Shasha Y, Olchovsky D, et al. Impact of pre-treatment INR level on the effect of intravenous low dose vitamin K in patients with excessive anticoagulation. Thromb Haemost 2003;90(1):71-76.
  • .Matteuzzi D, Crociani F, Brigidi P. Antimicrobial susceptibility of bifidobacterium. Ann Microbiol (Paris) 1983;134A(3):339-349.
  • .McKeown NM, Jacques PF, Gundberg CM, et al. Dietary and nondietary determinants of vitamin K biochemical measures in men and women. J Nutr 2002;132(6):1329-1334.
  • .McLean RR, Booth SL, Kiel DP, et al. Association of dietary and biochemical measures of vitamin K with quantitative ultrasound of the heel in men and women. Osteoporos Int 2006;17(4):600-607.
  • .Merkel R. The use of menadione bisulfite and ascorbate in the treatment of nausea and vomiting of pregnancy. Am J Obstet Gynecol 1952:416-418.
  • .Miki T, Nakatsuka K, Naka H, et al. Vitamin K(2) (menaquinone 4) reduces serum undercarboxylated osteocalcin level as early as 2 weeks in elderly women with established osteoporosis. J Bone Miner Metab 2003;21(3):161-165.
  • .Monagle P, Michelson AD, Bovill E, et al. Antithrombotic therapy in children. Chest 2001;119(1 Suppl):344S-370S.
  • .Nagashima R, O’Reilly RA, Levy G. Kinetics of pharmacologic effects in man: the anticoagulant action of warfarin. Clin Pharmacol Ther 1969;10(1):22-35.
  • .Nakamura K, Toyohira H, Kariyazono H, et al. Anticoagulant effects of warfarin and kinetics of K vitamins in blood and feces. Artery 1994;21(3):148-160.
  • .Nieuwenhuys CM, Feijge MA, Vermeer C, et al. Vitamin K-dependent and vitamin K-independent hypocoagulant effects of dietary fish oil in rats. Thromb Res 2001;104(2):137-147.
  • .Noto V, Taper HS, Jiang YH, et al. Effects of sodium ascorbate (vitamin C) and 2-methyl-1,4-naphthoquinone (vitamin K3) treatment on human tumor cell growth in vitro: I: synergism of combined vitamin C and K3 action. Cancer 1989;63(5):901-906.
  • .Oldenburg J, Quenzel E-M, Harbrecht V, et al. Missence mutations at ALA-10 in the factor IX propeptide: an insignificant variant in normal life but a decisive cause of bleeding during oral anticoagulant therapy. Br J Haematol 1997;98:240-244.
  • .Olson JA. Recommended dietary intakes (RDI) of vitamin K in humans. Am J Clin Nutr 1987;45(4):687-692.
  • .Olson RE. Vitamin K. In: Shils ME, Olson JA, Shike M, eds. Modern nutrition in health and disease. 9th ed. Media, PA: Williams & Wilkins; 1999:363-380.
  • .O’Reilly RA, Aggeler PM, Hoag MS, et al. Hereditary transmission of exceptional resistance to coumarin anticoagulant drugs: the first reported kindred. N Engl J Med 1964;271:809-815.
  • .O’Reilly R, Rytand D. Resistance to warfarin due to unrecognized vitamin K supplementation. N Engl J Med 1980;303:160-161.
  • .Panel on Micronutrients, Subcommittees on Upper Reference Levels of Nutrients and of Interpretation and Use of Dietary Reference Intakes, and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board. Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, DC: National Academy Press; 2001:144.
  • .Panneerselvam S, Baglin C, Lefort W, et al. Analysis of risk factors for over-anticoagulation in patients receiving long-term warfarin. Br J Haematol 1998;103(2):422-424.
  • .Patel RJ, Witt DM, Saseen JJ, et al. Randomized, placebo-controlled trial of oral phytonadione for excessive anticoagulation. Pharmacotherapy 2000;20(10):1159-1166.
  • .Price PA, Faus SA, Williamson MK. Warfarin causes rapid calcification of the elastic lamellae in rat arteries and heart valves. Arterioscler Thromb Vasc Biol 1998;18(9):1400-1407.
  • .Ramsey PS, Rouse DJ. Therapies administered to mothers at risk for preterm birth and neurodevelopmental outcome in their infants. Clin Perinatol 2002;29(4):725-743. (Review)
  • .Ravnan SL, Locke C. Levofloxacin and warfarin interaction. Pharmacotherapy 2001;21(7):884-885.
  • .Richards, RK. Influence of fever upon the action of 3,3-methylene bis-(4-hydroxoycoumarin). Science 1943;97:313-316.
  • .Riegert-Johnson DL, Volcheck GW. The incidence of anaphylaxis following intravenous phytonadione (vitamin K1): a 5-year retrospective review. Ann Allergy Asthma Immunol 2002;89(4):400-406. (Review)
  • .Ringstrom E, Long H. Oral vitamin K for warfarin-associated coagulopathy. Ann Intern Med 2003;138(7):610-611. (Letter)
  • .Robinson JN, Banerjee R, Thiet MP. Coagulopathy secondary to vitamin K deficiency in hyperemesis gravidarum. Obstet Gynecol 1998;92(4 Pt 2):673-675.
  • .Roe DA. Drug-induced nutritional deficiencies. 2nd ed. Westport, CT: Avi Publishing; 1985:158-159.
  • .Roe DA. Drug and nutrient interactions in the elderly diabetic. Drug Nutr Interact 1988;5(4):195-203. (Review)
  • .Roe DA. Risk factors in drug-induced nutritional deficiencies. In: Roe DA, Campbell T, eds. Drugs and nutrients: the interactive effects. New York: Marcel Decker; 1984:505-523.
  • .Sachdev GP, Ohlrogge KD, Johnson CL. Review of the Fifth American College of Chest Physicians Consensus Conference on Antithrombotic Therapy: outpatient management for adults. Am J Health Syst Pharm 1999;56(15):1505-1514. (Review)
  • .Sadowski JA, Booth SL, Mann KG, et al. Structure and mechanism of activation of vitamin K antagonists. In: Poller L, Hirsh J, eds. Oral anticoagulants. London: Arnold; 1996:9-29.
  • .Schiffrin EJ, Blum S. Interactions between the microbiota and the intestinal mucosa. Eur J Clin Nutr 2002;56(Suppl 3):S60-64. (Review)
  • .Schulman S. Care of patients receiving long-term anticoagulant therapy. N Engl J Med 2003;349(7):675-683. (Review, Tutorial)
  • .Schurgers LJ, Aebert H, Vermeer C, et al. Oral anticoagulant treatment: friend or foe in cardiovascular disease? Blood 2004;104:3231-3232.
  • .Schurgers LJ, Dissel PE, Spronk HM, et al. Role of vitamin K and vitamin K-dependent proteins in vascular calcification. Z Kardiol 2001;90(Suppl 3):57-63.
  • .Schurgers LJ, Shearer MJ, Hamulyák K, et al. Effect of vitamin K intake on the stability of oral anticoagulant treatment: dose-response relationships in healthy subjects. Blood 2004;104:2682-2689.
  • .Schurgers LJ, Spronk HMH, Soute BAM, et al. Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats. Blood 2006;doi:10.1182/blood-2006-07-035345.
  • .Schurgers LJ, Teunissen KJF, Hamulyák K, et al. Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7. Blood 2006;doi:10.1182/blood-2006-08-040709.
  • .Schurgers LJ, Vermeer C. Differential lipoprotein transport pathways of K-vitamins in healthy subjects. Biochim Biophys Acta 2002;1570(1):27-32.
  • .Sconce E, Avery P, Wynne H, et al. Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin. Blood 2006. Epub ahead of print.
  • .Sconce EA, Daly AK, Khan TI, et al. APOE genotype makes a small contribution to warfarin dose requirements. Pharmacogenet Genomics 2006;16(8):609-611.
  • .Sconce EA, Kamali F. Appraisal of current vitamin K dosing algorithms for the reversal of over-anticoagulation with warfarin: the need for a more tailored dosing regimen. Eur J Haematol 2006;77(6):457-462.
  • .Sconce EA, Khan TI, Daly AK, et al. The impact of simvastatin on warfarin disposition and dose requirements. J Thromb Haemost 2006;4(6):1422-1424.
  • .Scordo MG, Pengo V, Spina E, et al. Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance. Clin Pharmacol Ther 2002;72(6):702-710.
  • .Shanahan CM, Proudfoot D, Farzaneh-Far A, et al. The role of Gla proteins in vascular calcification. Crit Rev Eukaryot Gene Expr 1998;8(3-4):357-375. (Review)
  • .Shearer MJ. Role of vitamin K and Gla proteins in the pathophysiology of osteoporosis and vascular calcification. Curr Opin Clin Nutr Metab Care 2000;3(6):433-438. (Review)
  • .Shearer MJ. The roles of vitamins D and K in bone health and osteoporosis prevention. Proc Nutr Soc 1997;56(3):915-937. (Review)
  • .Shearer MJ. Vitamin K. Lancet 1995;345(8944):229-234.
  • .Shearer MJ, Bach A, Kohlmeier M. Chemistry, nutritional sources, tissue distribution and metabolism of vitamin K with special reference to bone health. J Nutr 1996;126(4 Suppl):1181S-1186S. (Review)
  • .Shearer MJ, Bechtold H, Andrassy K, et al. Mechanism of cephalosporin-induced hypoprothrombinemia: relation to cephalosporin side chain, vitamin K metabolism, and vitamin K status. J Clin Pharmacol 1988;28(1):88-95.
  • .Shiraki M, Shiraki Y, Aoki C, Miura M. Vitamin K2 (menatetrenone) effectively prevents fractures and sustains lumbar bone mineral density in osteoporosis. J Bone Miner Res 2000;15(3):515-521.
  • .Slaviero KA, Clarke SJ, Rivory LP. Inflammatory response: an unrecognised source of variability in the pharmacokinetics and pharmacodynamics of cancer chemotherapy. Lancet Oncol 2003;4(4):224-233.
  • .Spronk HM, Soute BA, Schurgers LJ, et al. Matrix Gla protein accumulates at the border of regions of calcification and normal tissue in the media of the arterial vessel wall. Biochem Biophys Res Commun 2001;289(2):485-490.
  • .Streif W, Andrew M, Marizinotto V, et al. Analysis of warfarin therapy in pediatric patients: a prospective cohort study of 319 patients. Blood 1999;94(9):3007-3014.
  • .Suttie JW, Muhah-Schendel LL, Shah DV, et al. Vitamin K deficiency from dietary vitamin K restriction in humans. Am J Clin Nutr 1988;47:475-480.
  • .Tam DA Jr, Myer EC. Vitamin K-dependent coagulopathy in a child receiving anticonvulsant therapy. J Child Neurol 1996;11(3):244-246. 
  • .Taper HS, de Gerlache J, Lans M, et al. Non-toxic potentiation of cancer chemotherapy by combined C and K3 vitamin pre-treatment. Int J Cancer 1987;40(4):575-579.
  • .Taper HS, Keyeux A, Roberfroid M. Potentiation of radiotherapy by nontoxic pretreatment with combined vitamins C and K3 in mice bearing solid transplantable tumor. Anticancer Res 1996;16(1):499-503.
  • .Tapson VF. The evolution and impact of the American College of Chest Physicians consensus statement on antithrombotic therapy. Clin Chest Med 2003;24(1):139-151,vii.
  • .Thorp JA, O’Connor M, Belden B, et al. Effects of phenobarbital and multiple-dose corticosteroids on developmental outcome at age 7 years. Obstet Gynecol 2003;101(2):363-373.
  • .Tsugawa N, Shiraki M, Suhara Y, et al. Vitamin K status of healthy Japanese women: age-related vitamin K requirement for gamma-carboxylation of osteocalcin. Am J Clin Nutr 2006;83:380-386.
  • .van Dongen CJJ, Vink R, Hutten BA, et al. The incidence of recurrent venous thromboembolism after treatment with vitamin K antagonists in relation to time since first event: a meta-analysis. Arch Intern Med 2003;163:1285-1293.
  • .van Haarlem LJ, Knapen MH, Hamulyak K, et al. Circulating osteocalcin during oral anticoagulant therapy. Thromb Haemost 1988;60(1):79-82.
  • .Vanscoy GJ, McAuley JW. Exaggerated warfarin sensitivity: a case report. Vet Hum Toxicol 1991;33(3):270-271.
  • .Venugopal M, Jamison JM, Gilloteaux J, et al. Synergistic antitumor activity of vitamins C and K3 on human urologic tumor cell lines. Life Sci 1996;59(17):1389-1400.
  • .Vermeer C, Braam L. Role of K vitamins in the regulation of tissue calcification. J Bone Miner Metab 2001;19(4):201-206. (Review)
  • .Vermeer C, Schurgers LJ. A comprehensive review of vitamin K and vitamin K antagonists. Hematol Oncol Clin North Am 2000;14(2):339-353.
  • .Visser LE, Penning-van Bees FJ, Kasbergen AA, et al. Overanticoagulation associated with combined use of antibacterial drugs and acenocoumarol or phenprocoumon anticoagulants. Thromb Haemost 2002;88(5):705-710.
  • .Voora D, Eby C, Linder MW, et al. Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype. Thromb Haemost 2005;93(4):700-705.
  • .Voora D, McLeod HL, Eby C, et al. The pharmacogenetics of coumarin therapy. Pharmacogenomics 2005;6(5):503-513.
  • .Voora D, McLeod HL, Eby C, et al. Use of pharmacogenetics to guide warfarin therapy. Drugs Today (Barc) 2004;40(3):247-257.
  • .Wallin R, Cain D, Sane DC. Matrix Gla protein synthesis and gamma-carboxylation in the aortic vessel wall and proliferating vascular smooth muscle cells: a cell system which resembles the system in bone cells. Thromb Haemost 1999;82(6):1764-1767.
  • .Weber P. Vitamin K and bone health. Nutrition 2001;17(10):880-887.
  • .Weibert RT, Le DT, Kayser SR, et al. Correction of excessive anticoagulation with low-dose oral vitamin K1. Ann Intern Med 1997;126(12):959-962.
  • .Weideman R, Patel AP. Oral vitamin K for warfarin-associated coagulopathy. Ann Intern Med 2003;138(7):610. (Letter)
  • .Wells PS, Holbrook AM, Crowther NR, et al. Interactions of warfarin with drugs and food. Ann Intern Med 1994;121(9):676-683. (Review)
  • .Wilke RA, Berg RL, Vidaillet HJ, et al. Impact of age, CYP2C9 genotype and concomitant medication on the rate of rise for prothrombin time during the first 30 days of warfarin therapy. Clin Med Res 2005;3(4):207-213.
  • .Wong DA, Freeman S. Cutaneous allergic reaction to intramuscular vitamin K1. Australas J Dermatol 1999;40:147-152.
  • .Yamreudeewong W, Lower DL, Kilpatrick DM, et al. Effect of levofloxacin coadministration on the international normalized ratios during warfarin therapy. Pharmacotherapy 2003;23(3):333-338.
  • .Yerby MS. Problems and management of the pregnant woman with epilepsy. Epilepsia 1987;28(Suppl 3):S29-36. (Review)
  • .Zhang W, Negoro T, Satoh K, et al. Synergistic cytotoxic action of vitamin C and vitamin K3. Anticancer Res 2001;21(5):3439-3444.