vitamin-k-semiquinone-radical and Drug-Hypersensitivity

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

Anaphylactoid reactions in patients receiving intravenously administered vitamin K have been reported in the literature. To summarize the known data on anaphylactoid reactions from administration of vitamin K, we reviewed all published and unpublished reports of this adverse reaction. Published reports were obtained through medline (1966--1999) and EMBASE (1971--1999) searches of the English language literature and review of references from identified case reports. Unpublished reports were obtained using the Spontaneous Reporting System Adverse Reaction database of the United States Food and Drug Administration (FDA) between August 1968 and September 1997. All adverse drug reactions to vitamin K were categorized by route of drug administration, dose and standard adverse reaction code. In the FDA reports, we defined anaphylactoid reactions as any adverse drug reaction coded as either anaphylaxis, allergic reaction, apnea, dyspnea, death, heart arrest, hypotension, shock or vasodilatation. Additionally, all fatal and life-threatening FDA reported reactions were reviewed to determine if they could represent an anaphylactoid reaction missed by the above definition. The literature review uncovered a total of 23 cases (3 fatal) of anaphylactoid reactions from intravenous vitamin K. The FDA database contained a total of 2236 adverse drug reactions reported in 1019 patients receiving vitamin K by all routes of administration. Of the 192 patients with reactions reported for intravenous vitamin K, 132 patients (69 %) had a reaction defined as anaphylactoid, with 24 fatalities (18 %) attributed to the vitamin K reaction. There were 21 patients with anaphylactoid reactions and 4 fatalities reported with doses of intravenous vitamin K of less than 5 mgs. For the 217 patients with reactions reported due to vitamin K via a non-intravenous route of administration, 38 patients had reactions meeting the definition of anaphylactoid (18 %), with 1 fatality (3 %) attributed to the drug. The absolute risk of an anaphylactoid reaction to intravenous vitamin K cannot be determined by this study, but the relatively small number of documented cases despite widespread use of this drug suggest that the reaction is rare. Anaphylactic reactions and case fatality reports were found even when intravenous vitamin K was given at low doses by slow dilute infusion. The pathogenesis of this reaction is unknown and may be multifactorial with etiologies including vasodilation induced by the so

Topics: Adverse Drug Reaction Reporting Systems; Anaphylaxis; Animals; Anticoagulants; Drug Administration Routes; Drug Hypersensitivity; Drug Interactions; Hemorrhage; Humans; United States; United States Food and Drug Administration; Vasodilation; Vitamin K; Vitamin K Deficiency

Topics: Drug Hypersensitivity; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Thrombocytopenia; Thrombosis; Vitamin K

During the initial phase or during treatment with oral anticoagulants, hypersensitivity or resistance may be observed, requiring significant changes in prescribed dosage. A thorough knowledge of the mode of action of vitamin K and its antagonists is useful to improve understanding of unexpected response to oral anticoagulant therapy. These abnormal responses may be due to poor compliance to treatment by the patient, insufficient or excessive vitamin K intake, interference with other drugs or abnormalities of the hepatic enzymes which are the target of oral anticoagulant drugs. The search for a cause is justified by the risks associated with these abnormal responses. It must be rigorously undertaken with an accurate interrogation, use of an anticoagulation monitoring leaflet and, if necessary, measurement of plasma concentrations and pharmacokinetics of the anticoagulant drug.

Topics: 4-Hydroxycoumarins; Algorithms; Anticoagulants; Drug Hypersensitivity; Drug Resistance; Humans; Indenes; 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

Compared with aminoglycosides, chloramphenicol, sulfonamides, tetracyclines, and even penicillins, the cephalosporins represent a remarkably safe class of antibiotics. Among the cephalosporins, the extended spectrum, third generation agents developed generally produce few side effects and appear to be less allergenic than the penicillins. Nephrotoxicity has not been a problem at recommended doses. Some third generation agents can cause hypoprothrombinemia if not administered with vitamin K, and disulfiram-like reactions occur with some agents because of the presence of a thiomethyl tetruzole moiety affixed to the cephem nucleus. There is a greater incidence of diarrhea associated with the agents excreted through a primarily biliary route, and this may contribute to the selection of drug resistant bacteria. Some agents are less active against staphylococci and their use may result in an increased incidence of superinfection or overgrowth of enterococci. If attention is given to the potential for adverse effects, many of these problems can be avoided and the third generation cephalosporins can be used safely in hospitals, nursing homes, and home care settings.

Topics: Bacterial Infections; Cephalosporins; Consumer Product Safety; Drug Hypersensitivity; Humans; Hypoprothrombinemias; Product Surveillance, Postmarketing; Superinfection; Time Factors; Vitamin K

In four patients the development of erythematous plaques after vitamin K injections was apparently due to delayed hypersensitivity reactions. The 36 cases described in the literature indicate that most patients with the reaction received vitamin K injections for liver disease and that a late sclerodermatous reaction develops rarely.

Topics: Adolescent; Adult; Drug Eruptions; Drug Hypersensitivity; Erythema; Female; Humans; Hypersensitivity, Delayed; Pruritus; 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

Calcineurin inhibitors are widely used for the prevention and treatment of graft versus host disease in patients undergoing allogeneic hematopoietic stem cell transplantation, and successful treatment with calcineurin inhibitors is very important for the management of these cases.. A 19-year-old man with thalassemia major experienced hypersensitivity reaction to parenteral vitamin K, cyclosporine, and tacrolimus before hematopoietic stem cell transplantation. All three episodes of reaction appeared a few minutes after administration of offended drugs and cause systemic signs and symptoms of anaphylaxis, i.e. itching, flushing, difficulty in breathing, and hypotension.. Hypersensitivity reaction was fully controlled by immediately discontinuing the drug and administering hydrocortisone, chlorpheniramine, epinephrine, and intravenous fluids. During hospitalization, the patient tolerated oral tacrolimus without any complication.. It appears that Cremophor EL (polyoxyethylated castor oil) which acts as a carrier, solubilizer, and emulsifier in intravenous calcineurin inhibitors is responsible for the occurrence of anaphylactic reaction (anaphylaxis); therefore, it is suggested that the administration of cremophor-containing drug should be avoided in patients with a previous history of hypersensitivity reaction to one of these drugs.

Topics: Administration, Intravenous; Administration, Oral; Cyclosporine; Drug Hypersensitivity; Drug Substitution; Humans; Immunosuppressive Agents; Male; Tacrolimus; Vitamin K; Young Adult

Prothrombin complex concentrates (PCCs) are frequently used to reverse the effect of vitamin K antagonists (VKAs) in patients with non-traumatic intracerebral hemorrhage (ICH). However, information on the rate of thromboembolic events (TEs) and allergic events after PCC therapy in VKA-ICH patients is limited.. Consecutive VKA-ICH patients treated with PCC at our institution between December 2004 and June 2014 were included into this retrospective observational study. We recorded international normalized ratio (INR) values before and after PCC treatment, baseline clinical characteristics including the premorbid modified Rankin Scale (pmRS) score, TE and allergic event that occurred during the hospital stay. All events were classified by 3 reviewers as being 'related', 'probably related', 'possibly related', 'unlikely related' or 'not related' to treatment with PCC. To identify factors associated with TEs, log-rank analyses were applied.. Two hundred and five patients were included. Median INR was 2.8 (interquartile range (IQR) 2.2-3.8) before and 1.3 (IQR 1.2-1.4) after PCC treatment and a median of 1,500 IU PCC (IQR 1,000-2,500) was administered. Nineteen TEs were observed (9.3%); none were classified 'related' but 9 were classified as 'possibly' or 'probably related' to PCC infusion (4.4%). One allergic reaction (0.5%), 'unlikely related' to PCC, was observed. In the whole cohort, PCC doses >2,000-3,000 IU, ICH volumes >40 ml, National Institute of Health Stroke Scale values >10 and a pmRS >2 were associated with the development of TEs (p = 0.031, p = 0.034, p = 0.050 and p = 0.036, respectively).. Overall, INR reversal with PCC appears safe. Though no clear relationship between higher PCC dosing and TEs was observed, PCC doses between >2,000 and 3,000 IU and higher morbidity at ICH onset were associated with TEs. Hence, individual titration of PCC to avoid exposure to unnecessarily high doses using point-of-care devices should be prospectively explored.

Topics: Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation; Blood Coagulation Factors; Cerebral Hemorrhage; Coagulants; Databases, Factual; Disability Evaluation; Drug Hypersensitivity; Female; Germany; Humans; International Normalized Ratio; Kaplan-Meier Estimate; Length of Stay; Male; Predictive Value of Tests; Retrospective Studies; Risk Factors; Thromboembolism; Time Factors; Treatment Outcome; Vitamin K

Successful vitamin K antagonist (eg, warfarin) reversal with 4-factor prothrombin complex concentrate (4F-PCC) without vitamin K (phytonadione) for emergent surgery in a patient at moderate-to-high risk for thromboembolism is reported. This approach may decrease the risk for development of thrombus, as it limits the amount of time the patient's anticoagulation is subtherapeutic. It also may increase the risk of bleeding, so patient selection is essential if this strategy is employed. Caution must be exercised to complete the procedure or surgery in the window of peak 4F-PCC effect (∼1-6 hours postinfusion).

Topics: Accidents, Traffic; Aged; Anticoagulants; Antifibrinolytic Agents; Atrial Fibrillation; Blood Coagulation Factors; Compartment Syndromes; Crush Injuries; Drug Hypersensitivity; Fibula; Fractures, Bone; Humans; International Normalized Ratio; Leg Injuries; Male; Preoperative Care; Stroke; Vitamin K; Warfarin

Topics: 4-Hydroxycoumarins; Aged; Drug Hypersensitivity; Drug Overdose; Female; Humans; Indenes; Jaundice; Urticaria; Vitamin K

We report the case of a woman who developed unexplained warfarin hypersensitivity after undergoing surgery to remove her ovaries. Presurgery, the patient's international normalised ratios (INR) control was stable and uneventful but 11 days after her operation she presented with extremely high (frequently ≥10) INR. Warfarin was discontinued on day 24 postoperation but 11 days later the plasma warfarin concentration was high at 4.8 mg/l (therapeutic range 0.7-2.3 mg/l). After cessation of warfarin, she required frequent doses of oral and intravenous vitamin K1 (totalling 48 mg) as well as two doses of prothrombin complex concentrate to normalise the INR. The patient was switched from warfarin to heparin, then to dabigatran with no further thrombosis or bleeding. While on heparin, the kinetics of warfarin elimination and vitamin K status were found to be normal and the reason for the onset of the extreme sensitivity to warfarin remains unknown.

Topics: Anticoagulants; Blood Coagulation Factors; Dabigatran; Drug Hypersensitivity; Drug Substitution; Female; Heparin; Humans; International Normalized Ratio; Middle Aged; Ovariectomy; Venous Thromboembolism; Vitamin K; Warfarin

Fluindione is an oral vitamin K antagonist (indanedione derivative) exclusively marketed in France and Luxembourg, known to have immuno-allergic adverse effects such as hepatitis, fever or interstitial nephritis. A few cases of drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with fluindione. The aim of the present study was to investigate fluindione-induced DRESS cases reported in France and to describe their characteristics.. We searched for potential cases of DRESS with fluindione reported in the French pharmacovigilance database since 2000.. Thirty-six cases of DRESS were included and concerned 17 women and 19 men. The mean age was 65 years (median: 68 years, range: 28-95 years). Kidneys and liver were the most frequent organs involved. Thirty-five cases were serious. In 5 cases, the effect was life-threatening. Most of the patients recovered. Fluindione was the only medicine suspected in 26 cases. Skin patch tests, performed in 10 cases, were positive with fluindione in 9 cases.. Fluindione is not known to be a frequent cause of DRESS. However, the number of reports found is probably underestimated. The seriousness of DRESS, as all immuno-allergic adverse effects, contraindicates fluindione reintroduction. Coumarinic derivatives are the alternatives in patients who need oral anticoagulant treatment.

Topics: Administration, Oral; Adult; Adverse Drug Reaction Reporting Systems; Aged; Aged, 80 and over; Anticoagulants; Drug Eruptions; Drug Hypersensitivity; Eosinophilia; Female; France; Humans; Male; Middle Aged; Pharmacovigilance; Phenindione; Retrospective Studies; Severity of Illness Index; Skin Tests; 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

A 53 year old female who was maintained on long-term warfarin therapy due to history of pulmonary embolism, repeatedly presents with an abnormally prolonged Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT). After many asymptomatic episodes were corrected with Vitamin K therapy to temporarily reverse the effects of the warfarin, the cause of the apparent coagulopathy was further investigated. Factor Activity Assays of the common pathway factors II, IX, and X all revealed critically low values; below the threshold even a loading dose of warfarin is typically capable of eliciting. The patient tested strongly positive for Tissue Transglutaminase IgA, which is highly suggestive of a gluten-sensitive enteropathy. One effect of this condition is malabsorption due to flattened intestinal villi. The patient was determined to have an acquired vitamin K deficiency secondary to gluten-sensitive enteropathy. Her condition was exacerbated by the long-term warfarin therapy, resulting in the prolonged PT and PTT. The patient was treated with vitamin K therapy, which reversed the deficiency and corrected her abnormal coagulation results.

Topics: Anticoagulants; Blood Coagulation; Blood Coagulation Disorders; Celiac Disease; Drug Hypersensitivity; Female; Humans; International Normalized Ratio; Middle Aged; Partial Thromboplastin Time; Prothrombin Time; Treatment Outcome; Vitamin K; Vitamin K Deficiency; Warfarin

Topics: Blood Coagulation Factors; Drug Hypersensitivity; Factor IX; Heart Valve Prosthesis Implantation; Hematoma; Hemophilia B; Hemorrhage; Hemostasis; Humans; Male; Middle Aged; Mutation, Missense; 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

Cutaneous hypersensitivity reactions to vitamin K are rare. They occur almost exclusively with fat-soluble vitamin K (K1). The lesion is most commonly a pruritic, indurated plaque at the site where the vitamin was injected. Most plaques resolve within 4 to 8 week without sequelae, but some progress to produce scar-like changes that may last for years.

Topics: Adult; Biopsy; Blood Coagulation Disorders; Drug Hypersensitivity; Erythema; Female; Humans; Vitamin K

Serotonin release from rat basophilic leukemia (RBL) cells, sensitized with a DNP-binding monoclonal IgE, was stimulated with solid surface (polystyrene)-bound DNP-amino acids. The stimulatory potency of DNP-amino acids was dependent on the structure of amino acid attached to DNP. Generally, DNP-amino acids with high affinities to the sensitizing IgE (I(50) less than 10 microM) were stimulatory in polystyrene-bound form; DNP-amino acids with lower affinities (Pro, Cys, Trp), and aliphatic aromatic DNP-amino acid derivatives were inactive. In addition to structural analogues of DNP, lymecycline, that is chemically unrelated to DNP but was found to have high affinity to IgE(aDNP), was also stimulatory in this system. This drug, and various quinones (e.g. acenaphthene-quinone) in BSA-conjugated forms also stimulated serotonin release from RBL cells sensitized with IgE(aDNP). These studies suggest that (1) There is a threshold of intrinsic ligand binding affinities at approximately I(50) = 10-100 microM; ligands with lower affinities do not stimulate mediator release even if they are presented in multivalent forms; (2) The above affinity threshold for mediator cell stimulation is valid for various ligands, irrespective of their chemical similarity to the immunogen; (3) Multispecific stimulation of mediator release may contribute to the frequently observed allergic cross-reactions, false positive tests for allergies, and anaphylactic reactions to drugs upon first exposure.

Topics: Acenaphthenes; Animals; Anthraquinones; Cross Reactions; Dinitrophenols; Drug Hypersensitivity; Erythrocytes; Immunoglobulin E; In Vitro Techniques; Leukemia, Basophilic, Acute; Lymecycline; Rats; Serotonin; Vitamin K

Topics: Chromium Isotopes; Drug Hypersensitivity; Erythrocytes; Favism; Female; Glucosephosphate Dehydrogenase Deficiency; Hemolysis; Heterozygote; Humans; Immunogenetics; Mosaicism; Primaquine; Sex Chromosomes; Vitamin K

Topics: Adenine; Adult; Analgesics; Antibodies; Antigens; Aspirin; Blood Group Antigens; Blood Transfusion; Bone Marrow Examination; Dextropropoxyphene; Drug Hypersensitivity; Erythrocyte Count; Humans; Isoantibodies; Lectins; Leukocyte Count; Male; Melena; Nicotinic Acids; Rheumatic Diseases; Vitamin K

Topics: Drug Eruptions; Drug Hypersensitivity; Female; Histamine H1 Antagonists; Humans; Middle Aged; Nitroglycerin; Rutin; Skin Tests; Vitamin K

Topics: Antifibrinolytic Agents; Dermatitis; Dermatitis, Contact; Dermatitis, Occupational; Drug Hypersensitivity; Humans; Toxicology; Vitamin K

Topics: Adrenal Cortex Hormones; Anti-Bacterial Agents; Antibiotics, Antitubercular; Drug Hypersensitivity; Drug Therapy; Histamine H1 Antagonists; Toxicology; Vitamin K; Vitamins

Topics: Adrenal Cortex Hormones; Anesthetics; Anti-Bacterial Agents; Antihypertensive Agents; Digitalis Glycosides; Drug Hypersensitivity; Humans; Preanesthetic Medication; Surgical Procedures, Operative; Sympathomimetics; Toxicology; Vitamin K; Vitamins

Topics: Adrenal Cortex Hormones; Anti-Bacterial Agents; Circumcision, Male; Colistin; Digitalis; Drug Hypersensitivity; Exchange Transfusion, Whole Blood; Humans; Infant, Newborn; Infusions, Parenteral; Injections, Intramuscular; Kanamycin; Male; Nalorphine; Novobiocin; Nurseries, Infant; Penicillins; Punctures; Resuscitation; Sulfonamides; Surgical Procedures, Operative; Tetracycline; Vitamin K