vitamin-k-semiquinone-radical and coumarin

Many natural coumarins and their chemically synthesized analogs and derivatives exert diverse properties, such as anticancer, antioxidant, anti-inflammatory, or anticoagulant, with the latter being of the utmost importance. The widely used warfarin, acenocoumarol, and phenprocoumon exert anticoagulant properties by inhibiting the vitamin K epoxide reductase complex. In this interdisciplinary review, we present biochemical principles of the coagulation processes and possible methods for their tuning based on the use of coumarins. We also summarize chemical methods of synthesis of coumarins and discuss structures and properties of those that have been used for a long time, as well as newly synthesized compounds. Brief information on the clinical use of coumarins and other anticoagulant drugs is given, including the severe effects of overdosing and methods for reversing their action.

Topics: Animals; Cardiovascular Diseases; Coumarins; Factor Xa Inhibitors; Humans; Vitamin K

Vitamin K antagonists are highly effective antithrombotic drugs. However, appropriate dosing is difficult to establish owing to its narrow therapeutic window as well as widespread inter- and intra-individual variability in dosage. Compared with dosing solely based on clinical information, pharmacogenetics can help improve the therapy with coumarins by decreasing the time to reach a stable dose and reducing the risk of bleeding. Most of the studies about genotyping of patients using vitamin K antagonists have focused on predicting the stable dose. Two genes have been shown to have the most influence on dosing: VKORC1 and CYP2C9. Furthermore, genotyping of more genes, such as CYP4F2 and APOE, is also being included in some dosing algorithms. The role of genotype beyond the initial dose-titration phase is less clear. Thus, a proven genetically determined risk of unstable dose or bleeding could help with the selection of patients who require more frequent monitoring of dose. On the other hand, patients who have a genetically determined stable dose could self-monitor their international normalized ratio (INR), making the therapy less expensive and more convenient.

Topics: Anticoagulants; Coumarins; Dose-Response Relationship, Drug; Genotype; Humans; Pharmacogenetics; Vitamin K

Numerous factors affect the response to vitamin K antagonists (VKA) including age, dietary vitamin K, other drugs, pharmacogenetics, and disease states. In antithrombotic guidelines, fever is mentioned as a factor that may increase response to VKA. The purpose of this article is to review the available evidence regarding the effect of fever on response to VKA, and to discuss possible mechanisms of this effect. We performed a search of the English literature from 1943 to June 2014, using the key words fever AND warfarin, acenocoumarol, phenprocoumon, coumarin anticoagulants and VKA; fever AND vitamin K dependent clotting factors II, VII, IX, and X. One animal investigation and 6 studies in humans suggest fever increases response to VKA, but one study did not find a significant effect. The magnitude of this effect is variable. Possible mechanisms for the increased effect of VKA associated with fever are increased catabolism of vitamin K dependent clotting factors, decreased vitamin K intake, and inhibition of VKA metabolism. More rigorous studies are needed to confirm that fever increases response to warfarin and other VKA.

Topics: Acenocoumarol; Animals; Anticoagulants; Clinical Trials as Topic; Coumarins; Fever; Hemorrhage; Humans; International Normalized Ratio; Phenprocoumon; Rats; Risk Factors; Treatment Outcome; Vitamin K; Warfarin

Inflammatory plaques at injection sites are frequent side effects of heparin treatment and a clinical symptom of delayed-type hypersensitivity (DTH) to heparin. In most cases, changing the subcutaneous therapy from unfractionated to low-molecular-weight heparin or treatment with heparinoids does not provide improvement because of extensive cross-reactivity. Because of their completely different chemical structure, hirudins are a safe alternative for anticoagulation. Despite DTH to subcutaneously injected heparins, patients tolerate heparin intravenously. Therefore, in case of therapeutic necessity and DTH to heparins, the simple shift from subcutaneous to intravenous heparin administration is justified. Skin necrosis is a rare complication of anticoagulation. Heparin-induced skin necrosis is 1 of the symptoms of immune-mediated heparin-induced thrombocytopenia and should result in the immediate cessation of heparin therapy to prevent potentially fatal thrombotic events. This is in contrast to coumarin-induced skin necrosis, where therapy may be continued or restarted at a lower dose.

Topics: Anaphylaxis; Anticoagulants; Coumarins; Drug Eruptions; Fibrinolytic Agents; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Hypersensitivity, Delayed; Polysaccharides; Thrombin; Thrombocytopenia; Vitamin K

The recent identification of vitamin K epoxid-reductase complex (VKORC1) contributed significantly to our mechanistic understanding of the vitamin K cycle. VKORC1 protein is targeted by Coumarins. Its enzymatic activity represents the rate-limiting step in the vitamin K cycle and gamma-carboxylation of vitamin K dependent proteins. Possibly, VKORC1 is the only component of VKOR activity. Mutations as well as polymorphisms in coding and non-coding regions of the VKORC1 gene have been shown to cause both partial to total coumarin resistance and coumarin sensitivity. Availability of molecular diagnostics (VKORC1, CYP2C9) and laboratory analysis by HPLC (determination of coumarin, vitamin K and vitamin K epoxide levels) is helpful in detection of hereditary and acquired factors influencing coumarin therapy. In the future, these tools might lead to an individualized and safer oral anticoagulation therapy. Furthermore, daily low-dose vitamin K supplementation may improve stability of coumarin-based anticoagulation. In the perspective of the coming new oral anticoagulants, the efficacy and safety profile of the "old" anticoagulants is of major importance. The well established and oeconomic coumarin drugs will benefit from a pharmacogenetic and nutritive adjusted optimization of therapy.

Topics: Anticoagulants; Coumarins; Drug Hypersensitivity; Humans; Mixed Function Oxygenases; Vitamin K; Vitamin K Epoxide Reductases

Vitamin K is a collective term for lipid-like naphthoquinone derivatives synthesized only in eubacteria and plants and functioning as electron carriers in energy transduction pathways and as free radical scavengers maintaining intracellular redox homeostasis. Paradoxically, vitamin K is a required micronutrient in animals for protein posttranslational modification of some glutamate side chains to gamma-carboxyglutamate. The majority of gamma-carboxylated proteins function in blood coagulation. Vitamin K shuttles reducing equivalents as electrons between two enzymes: VKORC1, which is itself reduced by an unknown ER lumenal reductant in order to reduce vitamin K epoxide (K>O) to the quinone form (KH2); and gamma-glutamyl carboxylase, which catalyzes posttranslational gamma-carboxylation and oxidizes KH2 to K>O. This article reviews vitamin K synthesis and the vitamin K cycle, outlines physiological roles of various vitamin K-dependent, gamma-carboxylated proteins, and summarizes the current understanding of clinical phenotypes caused by genetic mutations affecting both enzymes of the vitamin K cycle.

Topics: Animals; Blood Coagulation; Calcium; Carbon-Carbon Ligases; Coumarins; Homeostasis; Humans; Mixed Function Oxygenases; Osteoporosis; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Epoxide Reductases

Vitamin K's effects extend beyond blood clotting to include a role in bone metabolism and potential protection against osteoporosis. Vitamin K is required for the gamma-carboxylation of osteocalcin. Likewise, this gamma-carboxylation also occurs in the liver for several coagulation proteins. This mechanism is interrupted by coumarin-based anticoagulants in both the liver and bone.. A thorough review of the literature on vitamin K, osteocalcin and their role in bone metabolism and osteoporosis, as well as the potential bone effects of anticoagulant therapy was conducted.. Epidemiological studies and clinical trials consistently indicate that vitamin K has a positive effect on bone mineral density and decreases fracture risk. Typical dietary intakes of vitamin K are below the levels associated with better BMD and reduced fracture risk; thus issues of increasing dietary intakes, supplementation, and/or fortification arise. To effectively address these issues, large-scale, intervention trials of vitamin K are needed. The effects of coumarin-based anticoagulants on bone health are more ambiguous, with retrospective studies suggesting that long-term therapy adversely affects vertebral BMD and fracture risk. Anticoagulants that do not affect vitamin K metabolism are now available and make clinical trials feasible to answer the question of whether coumarins adversely affect bone. The research suggests that at a minimum, clinicians should carefully assess anticoagulated patients for osteoporosis risk, monitor BMD, and refer them to dietitians for dietary and supplement advice on bone health. Further research is needed to make more efficacious decisions about vitamin K intake, anticoagulant therapy, and bone health.

Topics: Anticoagulants; Bone and Bones; Bone Density; Coumarins; Humans; Nutritional Requirements; Osteocalcin; Osteoporosis; Risk Factors; Time Factors; Vitamin K; Vitamin K Deficiency

Coumarins belong to drugs widely used and the spectrum of their use is going to grow. From this point of view and/or because the coumarins are adminstrated in patients who are treated for the other diseases--medical or surgical--at the same time, it is necessary to modify, interrupt or replace peroral anticoagulant treatment in the dependence on various aspects. It requires to compound different algorithms for given situations solution. It is always to decide, if the situation is imperative from the view of solution planed, what risk brings proposed treatment and what is the risk of anticoagulant treatment modification.

Topics: Anticoagulants; Coumarins; Hemorrhage; Humans; International Normalized Ratio; Postoperative Hemorrhage; Preoperative Care; Risk Factors; Thromboembolism; Vitamin K; Warfarin

Excessive anticoagulation is a frequent complication of anticoagulant therapy. The risk of hemorrhage approximately doubles for each one point increase in the International Normalized Ratio (INR) above 3.0. Reducing a prolonged INR to within the desired therapeutic range requires that oral anticoagulants be withheld. In addition, vitamin K may be administered. Since this latter treatment can produce rapid reductions in the INR, it must be carefully tailored to meet individual needs, balancing the risk of bleeding against the potential risk of causing thromboembolism.. To review available literature on the management of coumarin-associated coagulopathy in asymptomatic patients, a Medline search was carried out and papers published in English from 1966 and 2003 were identified. All available information on the management of asymptomatic patients presenting with coumarin-associated coagulopathy was analyzed.. Following the results of clinical studies that only used an elevated INR as a surrogate end-point for the risk of bleeding, low dose oral vitamin K appears as the preferable strategy for rapidly restoring therapeutic INR levels in asymptomatic patients who present with an excessively prolonged INR due to warfarin therapy. For the treatment of patients with asymptomatic acenocoumarol-induced coagulopathy, vitamin K does not add any benefit to the strategy of simply withholding oral anticoagulant treatment.. Large randomized trials using clinical end-points are now required to provide evidence-based treatment recommendations for patients with coumarin-associated coagulopathy.

Topics: Anticoagulants; Antifibrinolytic Agents; Blood Coagulation Disorders; Costs and Cost Analysis; Coumarins; Hemorrhage; Humans; International Normalized Ratio; Risk Factors; Vitamin K; Warfarin; Withholding Treatment

From injury through healing, thrombin has several important functions in blood clotting, subsequent clot lysis, and tissue repair. These include edema, inflammation, cell recruitment, cellular releases, transformations, mitogenesis, and angiogenesis. Thrombin also participates in disease states, such as venous thrombosis, coronary thrombosis, stroke, and pulmonary emboli, among others and is implicated in atherosclerosis, the growth and metastasis of certain cancers, Alzheimer's disease, and perhaps other conditions. Thrombin must be continually generated to sustain normal and pathogenic processes. This is because of a variety of consumptive mechanisms. Unlike other activated factors in thrombotic and fibrinolytic pathways, and because thrombin promotes its own generation (feedback and cellular activation), thrombin is a primary target for therapeutics. Besides recombinant hirudins, Argatroban (Novastan) and Bivalirudin (Hirulog) are promising thrombin-directed inhibitors for antithrombotic intervention.

Topics: Blood Coagulation; Blood Coagulation Factors; Coumarins; Enzyme Activation; Factor VIII; Fibrinolytic Agents; Heparin; Hirudins; Humans; Prothrombin; Thrombin; Thromboplastin; Vitamin K

This article reviews the published original sources of information on interactions of oral anticoagulants with dietary factors, points out deficiencies in our knowledge of these interactions, and suggests applications for this information in the clinical setting. As with many drug-nutrient interactions, the original references include a few experimental studies and many case reports. Deciding which interactions of oral anticoagulants with dietary factors are clinically relevant and determining the appropriate dietary prescription concerning each interaction involves, in most cases, an educated opinion rather than a conclusion based on extensive research. Enough information exists on the vitamin K content of foods and the quantity of vitamin K that alters coagulation status from the therapeutic range to provide the patient with advice concerning a group of foods to avoid and a group of foods to limit to one serving per day. With respect to other dietary factors that may interact with oral anticoagulants, the patient should be cautioned concerning supplements of vitamins A, E, and C and alcohol used chronically or ingested in large quantities.

Topics: Administration, Oral; Alcoholic Beverages; Allium; Anticoagulants; Beverages; Caffeine; Coumarins; Dietary Fats; Food-Drug Interactions; Humans; Peptide Hydrolases; Silicones; Vitamin K; Vitamins

Topics: Administration, Oral; Adult; Animals; Anticoagulants; Coumarins; Drug Eruptions; Drug Hypersensitivity; Female; Fibrinolytic Agents; Hemorrhagic Disorders; Heparin; Humans; Male; Osteoporosis; Pregnancy; Pregnancy Complications, Cardiovascular; Risk Factors; Thrombocytopenia; Thrombolytic Therapy; Vitamin K

Prothrombin complex concentrate (PCC) can substantially shorten the time needed to reverse antivitamin K oral anticoagulant therapy (OAT). OBJECTIVES. To determine the effectiveness and safety of emergency OAT reversal by a balanced pasteurized nanofiltered PCC (Beriplex P/N) containing coagulation factors II, VII, IX, and X, and anticoagulant proteins C and S.. Patients receiving OAT were eligible for this prospective multinational study if their International Normalized Ratio (INR) exceeded 2 and they required either an emergency surgical or urgent invasive diagnostic intervention or INR normalization due to acute bleeding. Stratified 25, 35, or 50 IU kg(-1) PCC doses were infused based on initial INR. Study endpoints included INR normalization (

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Coumarins; Drug Combinations; Emergencies; Europe; Factor IX; Factor VII; Factor X; Female; Hemorrhage; Hemostatics; Humans; International Normalized Ratio; Israel; Male; Middle Aged; Prospective Studies; Prothrombin; Pulmonary Embolism; Vitamin K

Topics: Administration, Oral; Adult; Animals; Anticoagulants; Coumarins; Drug Eruptions; Drug Hypersensitivity; Female; Fibrinolytic Agents; Hemorrhagic Disorders; Heparin; Humans; Male; Osteoporosis; Pregnancy; Pregnancy Complications, Cardiovascular; Risk Factors; Thrombocytopenia; Thrombolytic Therapy; Vitamin K

Among the vitamin K antagonists (VKA), indanedione-derived VKA is suspected to induce an immunoallergic risk. One indanedione-derived VKA, fluindione, is still being used in France. The aim of this study was to evaluate the contribution of VKA to acute and chronic nephritis.. Twenty-four cases of biopsy proven acute interstitial nephritis (AIN) were retrospectively selected, based on a first intake of VKA within the previous 12 months as well as an increase of at least 50% of the basal level of serum creatinine. The 24 cases were all treated with fluindione VKA and not with coumarinic VKA.. The subjects studied included 20 men and 4 women, with a mean age of 73.0±9.3 years (range: 44-84). The delay between fluindione introduction and the appearance of an AIN, proven by biopsy when available, was 11.9±6.9 weeks (range: 3-28). Creatinine increased from 123.0±56.4 μmol/L (range: 56-335) at fluindione introduction to 460.7±265.3 μmol/L (range: 109-1200) at the time of AIN discovery. The treatment then consisted of stopping the fluindione and introducing steroids for 21 patients. If a VKA was necessary, fluindione was replaced by a coumarinic VKA. After 6 months, 1 patient died and 15 patients presented severe chronic kidney disease (CKD Stages 4-5). Two patients still required chronic dialysis after 6 months and five patients after 3 years. Patients with pre-existing kidney disease were more prone to develop severe CKD with fluindione.. In this large study, arguments are presented to incriminate fluindione in the induction of acute and chronic nephritis.

Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Anticoagulants; Coumarins; Drug Hypersensitivity; Female; Follow-Up Studies; France; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Nephritis, Interstitial; Phenindione; Prognosis; Retrospective Studies; Vitamin K

Topics: Animals; Anticoagulants; Atrial Fibrillation; Calcinosis; Coumarins; Humans; Mice; Quality-Adjusted Life Years; Renal Dialysis; Vitamin K

In 2006 a case report was published in this journal describing partial acenocoumarol- and phenprocoumon resistance in a 78-year-old man. A mutation in the VKORC1 gene was suggested to be the cause of the observed resistance. We examined the patient and found a new and hitherto unknown mutation in the VKORC1 gene which may well explain the observed resistance. The mutation concerns a polymorphism in exon 2 that predicts the substitution of tryptophan at position 59 of the VKOR protein by arginine, the p.Trp59Arg mutation. Meanwhile, we have detected the same p.Trp59Arg mutation in another patient with coumarin derivative resistance. The fact that this mutation did not occur in 100 individuals who responded well to coumarin derivatives, together with the knowledge that amino acid 59 is conserved among species, renders it likely that p.Trp59Arg was the cause of the partial acenocoumarol- and phenprocoumon resistance observed in these two patients.

Topics: Anticoagulants; Coumarins; Drug Resistance; Humans; Mixed Function Oxygenases; Mutation, Missense; Vitamin K; Vitamin K Epoxide Reductases

A survey is given on pharmacology and indications for the treatment with vitamin K antagonists. The therapeutic handling and self control by the patient is described.

Topics: Administration, Oral; Anticoagulants; Arrhythmias, Cardiac; Coumarins; Drug Interactions; Humans; International Normalized Ratio; Myocardial Infarction; Thromboembolism; Vitamin K

In most countries hypersensitivity to vitamin K antagonists (VKA) is considered to be a rare congenital bleeding diathesis. It occurs in patients with FIX propeptide mutations at locus -10. We present a Swiss family with two patients who suffered major bleedings under oral anticoagulant treatment in the presence of therapeutic or subtherapeutic INR levels and abnormally prolonged aPTT. In both patients a mutation in the propeptide of FIX at locus -10 with substitution of alanine by threonine (Ala-10Thr) was found. In one patient FIX clotting activity was found to be severely reduced (2%). The observed bleeding tendency is related to this--compared to the other vitamin K dependent factors (FII, FVII, FX)--excessively and disproportionately low level of FIX. Three generations of this family were tested for propeptide mutations, which are transmitted in an X-chromosomal recessive mode of inheritance. Apart from the two symptomatic male patients we found another male with the mutation who has not been exposed to VKA, six female carriers and four potential male carriers in the fourth generation who have not been tested. A founder effect for this mutation has been previously described for cases in Switzerland and Germany.. FIX propeptide mutation-associated hypersensitivity to VKA is a rare occurrence in Switzerland. The severity of associated bleeding complications and the reversible nature of the bleeding diathesis may nonetheless warrant increased awareness on the part of primary care physicians in Switzerland.

Topics: Aged; Alanine; Amino Acid Substitution; Anticoagulants; Coumarins; Drug Hypersensitivity; Factor IX; Heart Valve Prosthesis Implantation; Hemorrhage; Heterozygote; Humans; International Normalized Ratio; Male; Mutation; Partial Thromboplastin Time; Pedigree; Protein Precursors; Switzerland; Threonine; Vitamin K

Topics: Aged; Coumarins; Female; Humans; Male; Middle Aged; Pulmonary Embolism; Recurrence; Registries; Venous Thrombosis; Vitamin K

Topics: Aged, 80 and over; Anticoagulants; Cardiac Surgical Procedures; Coumarins; Extremities; Gangrene; Heparin; Humans; International Normalized Ratio; Male; Middle Aged; Necrosis; Thrombocytopenia; Vitamin K; Warfarin

Thyroid hemorrhage is a relatively frequent event that in most cases causes pain and discomfort only, while rarely can cause significant neck swelling. Even more rarely, however, extensive thyroid hemorrhage can result in a rapidly expanding hematoma with airway compromise. We report a case of a rapidly expanding thyroid hemorrhage that occurred secondary to oral anticoagulation therapy in an 80-year-old patient with a previously existing goiter. The patient presented with acute onset of neck pain, dysphagia, and respiratory distress caused by tracheal compression from the thyroid mass. Computed tomography demonstrated a 6 x 9 x 10 cm mass consistent with an intrathyroidal hematoma projecting into the anterior mediastinum and displacing the trachea to the left. Rapid reversal of the coagulopathy was achieved with fresh frozen plasma and vitamin K. Consequently, the patient was managed conservatively with close observation, antibiotics, and steroids because no progression of airway compromise was manifested. Although the diagnosis can be easily established in these patients, no management guidelines of this condition exist. The potential of rapid airway compromise and the risk for exacerbation of bleeding in the light of significant elevation in the international normalized ratio (INR), make any airway management decisions very difficult. The importance of managing the airway and the haemostatic problem with the help of a multidisciplinary team is discussed.

Topics: Administration, Oral; Aged, 80 and over; Airway Obstruction; Anticoagulants; Coumarins; Female; Goiter; Hematoma; Humans; International Normalized Ratio; Respiration Disorders; Thyroid Gland; Tomography, X-Ray Computed; Treatment Outcome; Vitamin K

Vitamin K is an essential cofactor for the synthesis of several blood coagulation factors. It has been suggested that the apolipoprotein E (ApoE) genotype has profound effects on vitamin K status. Therefore, we investigated whether this common genetic polymorphism influenced dose requirements and effects of coumarin anticoagulants.. We did a cohort study in 1637 patients from an outpatient anticoagulation clinic treated with acenocoumarol or phenprocoumon.. To attain the same level of anticoagulation, patients with genotype epsilon4/epsilon4 and genotype epsilon3/epsilon4 required respectively 3.4 mg (95%CI: -6.0 to -0.9) and 0.8 mg (95%CI: -1.6 to 0.1) acenocoumarol per week less than patients with genotype epsilon3/epsilon3. Patients homozygous for the epsilon2 allele required 3.5 mg (95%CI: 0.1 to 6.9) acenocoumarol per week more than patients with genotype epsilon3/epsilon3. The acenocoumarol maintenance dose showed a gene dose effect of the epsilon4 allele, but not of the epsilon2 allele. No significant dose difference was observed for phenprocoumon, possibly because of low numbers.. The ApoE genotype affects the dose requirements of acenocoumarol.

Topics: Acenocoumarol; Aged; Alleles; Anticoagulants; Apolipoproteins E; Blood Coagulation; Cohort Studies; Coumarins; Female; Genotype; Homozygote; Humans; International Normalized Ratio; Male; Middle Aged; Phenprocoumon; Time Factors; Vitamin K

Generalized osteoporosis is a result of different causes and pathogenic mechanisms, which often combine forces to become clinically relevant. Among the different exogenic factors, drugs play an important role, frequently in connection with other factors such as immobilization or pregnancy. It has been suggested that anticoagulation therapy with heparins or coumarins may induce osteoporotic changes or enhance the development of osteoporosis for other reasons. According to in vitro experiments, preclinical trials, and clinical investigations, it seems reasonable to assume that heparins induce increased bone loss in a time- and dose-related manner. Low-molecular-weight heparins most likely have less effect on bone turnover when compared to unfractionated heparin. Oral anticoagulation therapy with vitamin K-antagonists is believed to have a weak effect on induction of osteoporosis, but clinical studies are contradictory. In spite of the fact that a relevant effect of these drugs on the induction of osteoporosis is questionable, it must be taken into consideration that anticoagulant drugs may enhance the negative effects on bone density of other risk factors capable of inducing osteoporosis such as immobilization, pregnancy, or endocrinological disorders.

Topics: Administration, Oral; Adult; Anticoagulants; Bone and Bones; Bone Density; Clinical Trials as Topic; Coumarins; Double-Blind Method; Female; Fractures, Bone; Heparin; Heparin, Low-Molecular-Weight; Humans; Immobilization; Meta-Analysis as Topic; Middle Aged; Osteoporosis; Osteoporosis, Postmenopausal; Pregnancy; Pregnancy Complications; Prospective Studies; Renal Dialysis; Retrospective Studies; Risk Factors; Time Factors; Vitamin K

The toxicity of allyl alcohol, coumarin and menadione has been studied in precision-cut liver slice cultures. Liver slices were prepared from male Sprague-Dawley rats, male Dunkin-Hartley guinea-pigs and from samples of Cynomolgus monkey and human liver using a Krumdieck tissue slicer. The liver slices were cultured with the test compounds for 24 h in a dynamic organ culture system. Toxicity was assessed by measurement of protein synthesis, potassium content and the MTT assay. At the concentrations examined, menadione produced marked toxicity in liver slices from all four species, whereas rat liver slices were less susceptible to allyl alcohol toxicity. Coumarin produced concentration-dependent toxic effects in rat and guinea-pig liver slices, whereas Cynomolgus monkey and human liver slices were relatively resistant, especially at low coumarin concentrations. At some concentrations of the test compounds examined, the MTT assay appeared to be a less sensitive indicator of toxicity than either protein synthesis or potassium content. These results demonstrate the usefulness of precision-cut liver slices for assessing species differences in xenobiotic-induced toxicity.

Topics: 1-Propanol; Animals; Coloring Agents; Coumarins; Guinea Pigs; Humans; Liver; Macaca fascicularis; Male; Potassium; Propanols; Protein Biosynthesis; Rats; Tetrazolium Salts; Thiazoles; Toxicity Tests; Vitamin K

The sensitivity of the standard prothrombin time (PT) was low when measured on 56 plasmas with a reduced activity of the coagulation factors mainly of the prothrombin complex (factors II, VII and/or X) taken from eight dogs at different times of vitamin K1 therapy after coumarin intoxication. This was demonstrable by use of three different Ca-thromboplastins. With the standard test only plasmas with an excessive decrease of coagulation factor activity (sum of activity decrease of the single factors in relation to the respective reference range [SAD] > 100%) were detectable with sufficient reliability. In contrast, by using a method optimized for dogs (1:20 sample predilution, fibrinogen substitution) and respecting the species specific features of coagulation physiology, pathological PT-values were measured in up to 70% of the samples (dependent on the Ca-thromboplastin) with slight reductions of single factor activity (SAD: 11-25%). Significant differences concerning the sensitivity were seen additionally between the different Ca-thromboplastins. Human placenta thromboplastin in particular, but also rabbit brain thromboplastin, were more sensitive than a preparation of recombinant human tissue factor. The correlation between the PT and the SAD was closer when using the optimized method (r = 0.919-0.954) compared to the standard test (r = 0.771-0.862). In contrast to the standard test, the PT optimized for dogs is, therefore, a reliable screening test to recognize a slight reduction in prothrombin complex. It is especially suitable for monitoring of vitamin K1 therapy after coumarin intoxication.

Topics: Animals; Blood Coagulation Disorders; Coumarins; Dog Diseases; Dogs; Female; Humans; Male; Pregnancy; Prothrombin Time; Reference Values; Sensitivity and Specificity; Vitamin K

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

Topics: 4-Hydroxycoumarins; Animals; Blood Coagulation Factors; Coumarins; Dicumarol; Liver; Male; Microsomes, Liver; Mixed Function Oxygenases; Rats; Rats, Inbred Strains; Vitamin K; Vitamin K Epoxide Reductases; Warfarin

In the liver, it appears that there are two different pathways for vitamin K reduction. One pathway is irreversibly inhibited by coumarin anticoagulant drugs. The other pathway has been shown in the present study to be composed of enzymes that are not effected by physiological 'in vivo' concentrations of these drugs. This pathway appears to be responsible for the antidotal effect of vitamin K in overcoming coumarin poisoning. In rat liver the pathway has been shown to be composed of DT-diaphorase (EC.1.6.99.2) and a microsomal dehydrogenase(s). The activity of the microsomal dehydrogenase(s) was 3.6-fold higher with NADH than with NADPH present in the test system. It appears that this enzyme is the physiologically important enzyme in the pathway. In contrast with DT-diaphorase, this enzyme(s) is shown to be tightly associated with the mirosomal membrane. The enzyme(s) is not identical with either of the quinone-reducing enzymes cytochrome P-450 reductase or cytochrome-b5 reductase. Our data thus postulate the existence of an as-yet-unidentified microsomal dehydrogenase that appears to have an important function in the pathway.

Topics: 4-Hydroxycoumarins; Animals; Anticoagulants; Blood Coagulation; Coumarins; Immunosorbent Techniques; Ligases; Male; Microsomes, Liver; NAD(P)H Dehydrogenase (Quinone); Oxidoreductases; Quinone Reductases; Rats; Rats, Inbred Strains; Salicylates; Salicylic Acid; Vitamin K; Warfarin

Clinical use of antibiotics containing a N-methyl-thiotetrazole (NMTT) side chain has been reported to be associated with an increased incidence of a vitamin K-responsive hypoprothrombinemia. Administration of NMTT to rats decreased the activity of the liver microsomal vitamin K epoxide reductase, increased the liver ratio of vitamin K epoxide to vitamin K, and decreased the rate of metabolism of injected vitamin K epoxide. These responses are the same as those observed following the administration of coumarin anticoagulants. In contrast to the effect of coumarin anticoagulants, NMTT did not inhibit the vitamin K epoxide reductase in vitro. These data suggest that the hypoprothrombinemia which has been observed following use of these antibiotics results from the inactivation of the liver vitamin K epoxide reductase by NMTT or a NMTT metabolite.

Topics: Animals; Azoles; Coumarins; Cytosol; Dithiothreitol; Hypoprothrombinemias; Male; Microsomes, Liver; Mixed Function Oxygenases; Rats; Tetrazoles; Vitamin K; Vitamin K 1; Vitamin K Epoxide Reductases; Warfarin

An elderly woman who had been receiving long-term oral anticoagulant therapy developed skin and subcutaneous fat necrosis on five repeated occasions of extreme hypocoagulability, associated with coinciding periods of congestive cardiac failure. In each episode, the skin necrosis developed within days after the prothrombin time (as determined with Thrombotest) exceeded 200 s (International Normalized Ratio greater than 5.4). Widespread thrombosis in the subcutaneous vasculature and interstitial bleeding, as observed in a skin biopsy specimen, were consistent with a diagnosis of coumarin necrosis. On two occasions, an acquired functional protein C deficiency was present. It is hypothesized that an imbalance between anticoagulant and procoagulant vitamin K-dependent factors contributed to the pathogenesis of coumarin-induced skin necrosis. This imbalance was related to repeated periods of congestive heart failure.

Topics: Biopsy; Blood Coagulation Factors; Coumarins; Female; Humans; Middle Aged; Necrosis; Protein C Deficiency; Prothrombin Time; Skin; Vitamin K

Topics: Amino Acids; Aminoisobutyric Acids; Antimetabolites; Carbon Isotopes; Coumarins; Factor VII; Glycine; In Vitro Techniques; Liver; Metabolism; Naphthoquinones; Pharmacology; Proteins; Rats; Research; Ubiquinone; Vitamin K; Warfarin

Topics: Anticoagulants; Blood; Blood Coagulation Factors; Blood Coagulation Tests; Child; Coumarins; Dicumarol; Diseases in Twins; Drug Tolerance; Genetics, Medical; Geriatrics; Heparin; Humans; Intestinal Absorption; Pharmacology; Phenindione; Vitamin K; Warfarin

Topics: Acenocoumarol; Anticoagulants; Antifibrinolytic Agents; Coumarins; Humans; Vitamin K

Topics: 4-Hydroxycoumarins; Analgesics; Analgesics, Non-Narcotic; Antipyretics; Coumarins; Dicumarol; Vitamin K

Topics: Antifibrinolytic Agents; Blood Coagulation; Coumarins; Factor IX; Humans; Vitamin K

Topics: Antifibrinolytic Agents; Coumarins; Dicumarol; Heparin Antagonists; Humans; Hypoprothrombinemias; Naphthoquinones; Prothrombin; Retinoids; Vitamin K; Vitamin K 1

Topics: Accidents; Anticoagulants; Antifibrinolytic Agents; Coumarins; Hemorrhage; Humans; Thrombosis; Vitamin K; Vitamin K 1

Topics: 4-Hydroxycoumarins; Anticoagulants; Blood Coagulation; Coumarins; Humans; Indenes; Vitamin K

Topics: Anticoagulants; Cell Respiration; Coumarins; Cytochromes c; Liver; NAD; Oxidoreductases; Vitamin K; Vitamin K Deficiency

Topics: Antifibrinolytic Agents; Coagulants; Coumarins; Fibrinogen; Hemostatics; Heparin Antagonists; Humans; Phenprocoumon; Vitamin K

Topics: Antifibrinolytic Agents; Coumarins; Heparin Antagonists; Humans; Phosphorus; Vitamin K

Topics: Anticoagulants; Coumarins; Hemostatics; Humans; Phenindione; Protamines; Thrombosis; Vitamin K

Topics: Antifibrinolytic Agents; Coumarins; Humans; Thromboplastin; Vitamin K; Vitamin K 1

Topics: Anticoagulants; Antidotes; Coumarins; Female; Genital Diseases, Female; Hemorrhage; Humans; Thrombophlebitis; Vitamin K; Vitamin K 1

Topics: Antifibrinolytic Agents; Coumarins; Hemorrhage; Humans; Naphthoquinones; Phenprocoumon; Retinoids; Vitamin K; Vitamin K 1

Topics: Coumarins; Fibrinolytic Agents; Rats; Vitamin K

Topics: Anticoagulants; Coumarins; Female; Genitalia; Genitalia, Female; Gynecology; Humans; Thromboembolism; Vitamin K; Vitamin K 1

Topics: Anticoagulants; Antifibrinolytic Agents; Coumarins; Humans; Phenindione; Vitamin K

Topics: 4-Hydroxycoumarins; Anticoagulants; Antidotes; Antifibrinolytic Agents; Coumarins; Dicumarol; Hemostatics; Vitamin K; Vitamin K 1

Topics: 4-Hydroxycoumarins; Anticoagulants; Antidotes; Coumarins; Female; Hemostatics; Humans; Phenprocoumon; Prothrombin Time; Thrombophlebitis; Vitamin K; Vitamin K 1

Topics: Animals; Antifibrinolytic Agents; Behavior, Animal; Coumarins; Humans; Naphthoquinones; Phenprocoumon; Vitamin K

Topics: Antifibrinolytic Agents; Coumarins; Ethyl Biscoumacetate; Heparin Antagonists; Naphthoquinones; Phenindione; Thromboembolism; Vitamin K; Vitamin K 1

Topics: Antifibrinolytic Agents; Coumarins; Dicumarol; Hemorrhage; Naphthoquinones; Poisoning; Retinoids; Vitamin K; Vitamin K 1

Topics: Anticoagulants; Antidotes; Blood Coagulation; Coumarins; Dicumarol; Hemostatics; Humans; Prothrombin Time; Vitamin K; Vitamin K 1

Topics: Anticoagulants; Antifibrinolytic Agents; Coumarins; Female; Genitalia; Genitalia, Female; Humans; Hypoprothrombinemias; Phenprocoumon; Postpartum Period; Prothrombin; Thrombophlebitis; Vitamin K; Vitamin K 1

Topics: Antifibrinolytic Agents; Cardiovascular Agents; Coumarins; Hexylresorcinol; Humans; Muscle Relaxants, Central; Naphthoquinones; Rosaniline Dyes; Vitamin K

Topics: Coumarins; Hemostatics; Humans; Vitamin K

Topics: Antidotes; Antifibrinolytic Agents; Coumarins; Heparin Antagonists; Naphthoquinones; Retinoids; Vitamin K; Vitamin K 1

Topics: Antifibrinolytic Agents; Coumarins; Ethyl Biscoumacetate; Hemostatics; Humans; Hypoprothrombinemias; Injections, Intravenous; Retinoids; Vitamin K; Vitamin K 1

Topics: Antifibrinolytic Agents; Coumarins; Dicumarol; Hemorrhagic Disorders; Heparin Antagonists; Hypoprothrombinemias; Naphthoquinones; Vitamin K; Vitamin K 1; Vitamin K 3

Topics: Blood Coagulation; Coumarins; Factor VII; Hemostatics; Heparin Antagonists; Humans; Infant, Newborn; Liver; Liver Diseases; Pregnancy; Thromboembolism; Vitamin K

Topics: 4-Hydroxycoumarins; Anticoagulants; Coumarins; Vitamin K

Topics: Anticoagulants; Coumarins; Heparin Antagonists; Humans; Infarction; Lung; Myocardial Infarction; Phenprocoumon; Pulmonary Infarction; Thrombosis; Vitamin K

Topics: 4-Hydroxycoumarins; Antifibrinolytic Agents; Coumarins; Heparin Antagonists; Humans; Naphthoquinones; Retinoids; Rodenticides; Vitamin K; Vitamins

Topics: Coumarins; Ethyl Biscoumacetate; Vitamin K

Topics: Coumarins; Fibrinolytic Agents; Humans; Vitamin K; Vitamin K 1

Topics: Antidotes; Coumarins; Dicumarol; Female; Hemostatics; Humans; Vitamin K; Vitamin K 1

Topics: Anticoagulants; Coumarins; Dicumarol; Ethyl Biscoumacetate; Hemostatics; Humans; Hypoprothrombinemias; Phenindione; Prothrombin; Vitamin K; Vitamin K 1; Vitamin K 3

Topics: Coumarins; Dicumarol; Heart Failure; Humans; Sexually Transmitted Diseases; Vitamin K

Topics: Anticoagulants; Antifibrinolytic Agents; Coumarins; Dicumarol; Ethyl Biscoumacetate; Hemostatics; Heparin Antagonists; Humans; Naphthoquinones; Phenindione; Prothrombin; Vitamin K

Topics: Antifibrinolytic Agents; Coumarins; Dicumarol; Hemostatics; Humans; Hypoprothrombinemias; Naphthoquinones; Prothrombin; Retinoids; Vitamin K; Vitamin K 1; Vitamin K 2

Topics: Antidotes; Antifibrinolytic Agents; Coumarins; Hemostatics; Humans; Prothrombin; Vitamin K

Topics: Antidotes; Antifibrinolytic Agents; Coumarins; Dicumarol; Heparin Antagonists; Naphthoquinones; Prothrombin; Retinoids; Vitamin K; Vitamins

Topics: Antifibrinolytic Agents; Coumarins; Dicumarol; Humans; Hypoprothrombinemias; Vitamin K; Vitamin K Deficiency

Topics: Antifibrinolytic Agents; Coumarins; Dicumarol; Ethyl Biscoumacetate; Hypoprothrombinemias; Naphthoquinones; Prothrombin; Vitamin K

Topics: Coumarins; Dicumarol; Hemostatics; Humans; Hypoprothrombinemias; Prothrombin; Vitamin K

Topics: Antifibrinolytic Agents; Blood Transfusion; Coumarins; Dicumarol; Humans; Vitamin K

Topics: Coumarins; Humans; Hypoprothrombinemias; Prothrombin; Vitamin K

Topics: Animals; Antifibrinolytic Agents; Blood Coagulation; Cats; Coumarins; Dicumarol; Hypoprothrombinemias; Liver; Rabbits; Vitamin K; Vitamin K 1

Topics: Coumarins; Dicumarol; Humans; Vitamin K

Topics: 4-Hydroxycoumarins; Anticoagulants; Coumarins; Hemostatics; Humans; Prothrombin; Vitamin K; Vitamin K 3

Topics: Administration, Intravenous; Antifibrinolytic Agents; Coumarins; Dicumarol; Emergencies; Emulsions; Naphthoquinones; Prothrombin; Vitamin K; Vitamin K 1

Topics: Amino Acids; Antifibrinolytic Agents; Blood Coagulation; Coumarins; Dicumarol; Humans; Methionine; Vitamin K

Topics: Coumarins; Esculin; Humans; Hypoprothrombinemias; Phenindione; Vitamin K

Topics: Coumarins; Dicumarol; Humans; Vitamin K

Topics: Antidotes; Antifibrinolytic Agents; Coumarins; Dicumarol; Humans; Naphthoquinones; Vitamin K; Vitamins