vitamin-k-semiquinone-radical and bromfenacoum

Topics: 4-Hydroxycoumarins; Administration, Inhalation; Adult; Anticoagulants; Delayed-Action Preparations; Disseminated Intravascular Coagulation; Female; Humans; Pregnancy; Pregnancy Outcome; Pregnancy, High-Risk; Risk Assessment; Vitamin K

The increased prevalence of rodents resistant to warfarin led to the development of the hydroxycoumarin anticoagulant brodifacoum. A 25-year-old man attempted suicide by consuming four boxes of d-CON Mouse-Prufe II; each box contains 42 g of bait that is 0.005% brodifacoum. He presented to a hospital nine days later with syncope, hematochezia, gross hematuria, epistaxis, anemia, and a severe coagulopathy. Radiographic studies were consistent with pleural, pericardial, and mediastinal hemorrhages. Vitamin K and fresh frozen plasma were given, and he was later discharged on oral phytonadione (vitamin K1). The patient's coagulopathy recurred, necessitating multiple plasma transfusions and prolonged treatment with oral phytonadione. Fifteen weeks after hospital discharge, he presented again with a history of additional brodifacoum ingestion. Neurologic status was initially normal, but in the emergency department he suddenly became comatose soon after emesis was induced with syrup of ipecac. Computed tomography of the brain revealed a subarachnoid hemorrhage that led to brain death less than 24 hours later. This case demonstrates the severe and prolonged coagulopathy that can result from ingestion of brodifacoum, a compound that has a toxic potency about 200-fold that of warfarin and a half-life as much as 60 times longer.

Topics: 4-Hydroxycoumarins; Adult; Blood Coagulation Disorders; Blood Transfusion; Drug Overdose; Emergency Service, Hospital; Humans; Ipecac; Male; Partial Thromboplastin Time; Patient Readmission; Phenobarbital; Plasma; Poisoning; Prothrombin Time; Rodenticides; Subarachnoid Hemorrhage; Suicide; Tomography, X-Ray Computed; Vitamin K

For the attention of psychiatric consultants, brodifacoum, a new longer-acting, warfarin-like oral anticoagulant rodenticide, has been used for suicide attempts. The overdose potential with brodifacoum is serious since it is readily available without prescription, and bleeding complications last for weeks to months after a single ingestion. This article reports a case of ingestion and reviews four similar cases from medical literature. Also reviewed are details about mechanism of action, procedures for diagnosis, and treatment requirements. Also, characteristics of persons who ingest long-acting anticoagulants appear to differ from those who ingest short-acting anticoagulants reported from earlier literature.

Topics: 4-Hydroxycoumarins; Anticoagulants; Factitious Disorders; Hemorrhagic Disorders; Humans; Male; Middle Aged; Rodenticides; Suicide, Attempted; Vitamin K

We determine the incidence of clinically important bleeding in children with superwarfarin rodenticide ingestions not treated with gastrointestinal decontamination or prophylactic vitamin K.. We prospectively studied patients younger than 6 years of age who reported to our poison center with acute unintentional superwarfarin ingestions. Patients who received gastrointestinal decontamination or prophylactic vitamin K were excluded. Forty-eight- to 96-hour prothrombin time or international normalized ratio (INR) blood tests were recommended, and telephone contact was attempted at least 3 days after ingestion.. A total of 595 consecutive patients were enrolled during the 16-month study period. Fifty patients were excluded: 8 who were known to have ingested 1 pellet or less; 25 who received activated charcoal; 15 who were treated with induced emesis; and 2 who received prophylactic vitamin K. The resulting study group contained 545 patients. Eighty-two patients were lost to follow-up. Follow-up was obtained for 463 patients, including 222 by telephone contact alone, 62 by 48- to 96-hour INR, and 179 by both methods. None of the patients had clinically important coagulopathy. Two patients had an INR of 1.5 or greater (1.5 and 1.8) without symptoms. Single nosebleeds were reported in another 2 patients with normal 48-hour INRs. Another child had a small amount of blood crusted in the nose with no other symptoms and no laboratory work available. One child with a normal 48-hour INR had blood-streaked stools that were thought to be caused by an anal fissure.. Children with acute unintentional superwarfarin ingestions of less than 1 box may be managed without gastric decontamination or prophylactic vitamin K. Laboratory testing for coagulopathy should be reserved for cases involving clinically evident bleeding abnormalities.

Topics: 4-Hydroxycoumarins; Anticoagulants; Child; Child, Preschool; Decontamination; Female; Follow-Up Studies; Hemorrhage; Humans; International Normalized Ratio; Male; Poisoning; Prospective Studies; Prothrombin Time; Rodenticides; Treatment Outcome; Vitamin K

BACKGROUND As marijuana is being legalized in some states in the United States, there is a growing need for physicians to be aware of potential complications related to various forms of marijuana used in the community. Historically, marijuana has been laced with potentially toxic substances to increase its efficacy, and brodifacoum is one of them. Here, we present the case of a patient with toxicity related to use of brodifacoum-laced synthetic marijuana. CASE REPORT A 30-year-old man with history of polysubstance abuse presented with 5 days of flank pain and hematuria. He reported current use of synthetic marijuana. Vital signs were unremarkable. On physical examination, he had petechiae on bilateral upper extremities. Pertinent lab findings included: leukocytosis of 14 000 K/UL, international normalized ratio (INR) 13, prothrombin time (PT) 134.6 s, activated partial thromboplastin time (aPTT) 58.3 s, and only hematuria on urinalysis. CT scans of the abdomen and pelvis were unremarkable. The initial toxicology screen was negative. Brodifacoum toxicity was suspected. The patient was managed in collaboration with poison control, and he was treated with oral vitamin K and close monitoring of INR. CONCLUSIONS Brodifacoum-laced synthetic marijuana toxicity can lead to potentially lethal complications if not recognized and treated in a timely manner. Hence, physicians should have a high index of suspicion in patients presenting with unexplained coagulation abnormalities.

Topics: 4-Hydroxycoumarins; Adult; Cannabis; Humans; Male; Rodenticides; Vitamin K

Synthetic cannabinoids contain many different chemicals and compounds, which pose new health risks to the population using these drugs. In May of 2018 the Center for Disease Control issued a health alert providing information on a multistate outbreak of coagulopathy from exposure to synthetic cannabinoid products containing a Vitamin K-dependent antagonistic agent such as brodifacoum. Recognizing signs, symptoms and imaging findings related to this outbreak is essential for clinicians caring for patients with a history or suspicion of using synthetic cannabinoids. To our knowledge, there are no studies that report the imaging findings demonstrating the coagulopathic complications associated with these synthetic compounds.

Topics: 4-Hydroxycoumarins; Blood Coagulation Disorders; Cannabinoids; Designer Drugs; Emergency Service, Hospital; Fatal Outcome; Hemorrhage; Humans; Male; Middle Aged; Tomography, X-Ray Computed; Vitamin K

A recent multi-state outbreak of life-threatening bleeding following inhalation of synthetic cannabinoids has been attributed to contamination with the long-acting anticoagulant rodenticide (LAAR) brodifacoum, a second-generation, highly potent, long-acting derivative of the commonly used blood thinner warfarin. While long-term treatment with high-dose vitamin K1 restores coagulation, it does not affect brodifacoum metabolism or clearance, and, consequently, brodifacoum remains in the human body for several months, thereby predisposing to risk of bleeding recurrence and development of coagulation-independent injury in extrahepatic tissues and fetuses. This has prompted the evaluation of pharmacological measures that accelerate brodifacoum clearance from poisoned patients. Since the induction of certain cytochrome P450 (CYP) enzymes accelerates warfarin metabolism, using CYP inducers, such as phenobarbital, to accelerate brodifacoum clearance seems plausible. However, unlike warfarin, brodifacoum does not undergo significant metabolism in the liver, nor have the effects of phenobarbital on vitamin K1 metabolism been previously determined. In addition, the safety of phenobarbital in brodifacoum-poisoned patients has not been established. Therefore, we propose that CYP inducers should not be used to accelerate the clearance of brodifacoum from poisoned patients, but that alternative approaches such as reducing enterohepatic recirculation of brodifacoum, or using lipid emulsions to scavenge brodifacoum throughout the body, be considered.

Topics: 4-Hydroxycoumarins; Anticoagulants; Blood Coagulation; Cytochrome P-450 Enzyme Inducers; Enterohepatic Circulation; Fat Emulsions, Intravenous; Half-Life; Hemorrhage; Humans; Inactivation, Metabolic; Vitamin K

More than 60 types of cannabinoids are found in nature; the remaining are chemically synthesized analogs of natural cannabinoids. Synthetic cannabinoids were first reported in the United States in 2008. These compounds are usually smoked by users and are sold under various names. Synthesized products have clinical effects that are similar to the effects of cannabis, which include tachycardia, conjunctival injection, nystagmus, vomiting, and ataxia. In cases of acute overdose, hyperthermia, acute kidney injury, seizures, and rhabdomyolysis can occur.. Deaths and life-threatening coagulopathies caused by brodifacoum (BDF) adulteration of synthetic cannabinoids have been reported in Illinois and other regions of the United States. BDF is a long-acting vitamin K-dependent antagonist that is often used as rat poison and that can cause massive hemorrhage. BDF is sometimes referred to as "superwarfarin" because the anticoagulant effect is 100 times greater than warfarin on a molar basis and its half-life is 20-130 days, which markedly exceeds that of warfarin. The rationale for lacing synthetic cannabinoids with BDF may be associated with attempts to enhance psychoactive effect of the drug, keeping the user high for a longer period of time because of lipid storage, hepatic metabolism, and slow release. We present the case of a healthy 27-year-old man who developed severe soft tissue hemorrhage and airway obstruction after use of a cannabinoid laced with BDF. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: To date there have been no case reports documenting severe soft tissue hemorrhage leading to airway obstruction and respiratory failure from synthetic cannabinoid use, whether or not the synthetic cannabinoid has been adulterated. Severe complications can arise from use, and treatment includes vitamin K and supportive therapy because the resulting coagulopathy can take days to weeks to resolve.

Topics: 4-Hydroxycoumarins; Adult; Airway Obstruction; Anticoagulants; Cannabinoids; Hemorrhage; Humans; Male; Soft Tissue Injuries; Vitamin K

Warfarin- and superwarfarin-type anticoagulants are commonly used as rodenticides. Exposure to these agents, especially superwarfarins with long-acting anticoagulant effect, can cause life-threatening coagulopathy in humans. Most superwarfarin poisoning cases had an obvious history of exposure, though occult cases without exposure history have also been reported. The current study aims to examine anticoagulant-type rodenticide poisoning in Hong Kong and to identify the similarities and differences between patients with known exposure history and those whose exposure is recognized only through laboratory testing.. The present study was conducted in a tertiary referral clinical toxicology laboratory in Hong Kong. This was a retrospective cohort study of all patients with biochemically confirmed anticoagulant-type rodenticide exposure, from 2010 to 2014.. Superwarfarin was the most common group of anticoagulant-type rodenticides identified (87.8%), in which bromadiolone and brodifacoum were the most frequently encountered. Among the 41 cases identified, 31 had an obvious exposure history, and 10 were occult poisoning in which the context of exposure remained unidentified. All occult poisoning patients without exposure history presented with bleeding events. These occult poisoning cases often went unrecognized by frontline clinicians, leading to delayed investigation and initiation of treatment. This group of patients was associated with a longer time to diagnose coagulopathy (p < 0.001) and confirm rodenticide poisoning (p < 0.05), a higher rate of international normalized ratio (INR) rebound after initiation of antidote (p < 0.001), and a longer time needed for normalizing INR (p < 0.05).. Occult superwarfarin poisoning is an important yet under-recognized differential cause of unexplained coagulopathy. A high index of clinical suspicion and availability of specialized toxicological test for superwarfarins play a vital role in diagnosis and early initiation of appropriate management. The underlying cause of such poisoning remains obscure and warrants further study.

Topics: 4-Hydroxycoumarins; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation Disorders; Cohort Studies; Female; Hemorrhage; Hong Kong; Humans; Infant; International Normalized Ratio; Male; Middle Aged; Poisoning; Retrospective Studies; Rodenticides; Vitamin K; Warfarin; Young Adult

Acute, unintentional drug-related poisonings lead to an estimated 418,313 ED visits in 2014, according to the latest statistics from the Center for Disease Control and Prevention. While most of these were opiate-related poisonings, anticoagulant rodenticides were the most common cause of rodenticide-related poisoning in the United States. Many clinical syndromes and treatment algorithms have been described for patients with anticoagulant rodenticide poisoning. We report a case of an acute ingestion of two anticoagulant rodenticides and successful reversal of coagulation parameters using 4-factor prothrombin complex concentrate in a fixed-dose approach.

Topics: 4-Hydroxycoumarins; Abdominal Pain; Aged; Anticoagulants; Blood Coagulation Disorders; Blood Coagulation Factors; Drug Contamination; Drug Dosage Calculations; Hemorrhage; Humans; Illicit Drugs; Male; Rodenticides; Synthetic Drugs; Treatment Outcome; Vitamin K

Synthetic marijuana is a dangerous substance due to its potency, ever-changing composition, and unpredictable side effects. Recently, brodifacoum-contaminated synthetic marijuana has led to multiple deaths and morbidity throughout the USA from severe coagulopathy associated with use of this strain of the drug (brodifacoum is a rodenticide and potent Vitamin K antagonist/anticoagulant). We describe the clinical and radiologic findings in two patients who were diagnosed with, and treated for, ingestion of this new strain of synthetic marijuana. The radiologic manifestations were most notable for hemorrhagic pyelitis/ureteritis. Both patients required hospitalization with Vitamin K supplementation. The radiologic and clinical pictures in these patients are important for radiologists to recognize in order to help guide appropriate patient management.

Topics: 4-Hydroxycoumarins; Adult; Baltimore; Blood Coagulation Disorders; Cannabinoids; Diagnosis, Differential; Disease Outbreaks; Female; Humans; Illicit Drugs; Male; Middle Aged; Poisoning; Rodenticides; Tomography, X-Ray Computed; Vitamin K

In March and April 2018, more than 150 patients presented to hospitals in Illinois with coagulopathy and bleeding diathesis. Area physicians and public health organizations identified an association between coagulopathy and synthetic cannabinoid use. Preliminary tests of patient serum samples and drug samples revealed that brodifacoum, an anticoagulant, was the likely adulterant.. We reviewed physician-reported data from patients admitted to Saint Francis Medical Center in Peoria, Illinois, between March 28 and April 21, 2018, and included in a case series adult patients who met the criteria used to diagnose synthetic cannabinoid-associated coagulopathy. A confirmatory anticoagulant poisoning panel was ordered at the discretion of the treating physician.. A total of 34 patients were identified as having synthetic cannabinoid-associated coagulopathy during 45 hospitalizations. Confirmatory anticoagulant testing was performed in 15 of the 34 patients, and superwarfarin poisoning was confirmed in the 15 patients tested. Anticoagulant tests were positive for brodifacoum in 15 patients (100%), difenacoum in 5 (33%), bromadiolone in 2 (13%), and warfarin in 1 (7%). Common symptoms at presentation included gross hematuria in 19 patients (56%) and abdominal pain in 16 (47%). Computed tomography was performed to evaluate abdominal pain and revealed renal abnormalities in 12 patients. Vitamin K. Our data indicate that superwarfarin adulterants of synthetic cannabinoids can lead to clinically significant coagulopathy. In our series, in most of the cases in which the patient presented with bleeding diathesis, symptoms were controlled with the use of vitamin K

Topics: 4-Hydroxycoumarins; Abdominal Pain; Adult; Anticoagulants; Blood Coagulation Disorders; Blood Transfusion; Cannabinoids; Female; Hematuria; Hemorrhage; Humans; Illinois; International Normalized Ratio; Male; Middle Aged; Patient Readmission; Vitamin K; Warfarin

Topics: 4-Hydroxycoumarins; Blood Coagulation Disorders; Dissociative Disorders; Eating; Female; Follow-Up Studies; Humans; Middle Aged; Risk Assessment; Suicide, Attempted; Vitamin K

Topics: 4-Hydroxycoumarins; Adult; Anticoagulants; Biopsy; Blood Coagulation; Blood Component Transfusion; Duodenal Diseases; Hematoma; Humans; Intestinal Obstruction; Jejunal Diseases; Male; Risk Factors; Rodenticides; Tomography, X-Ray Computed; Treatment Outcome; Vitamin K

Topics: 4-Hydroxycoumarins; Anticoagulants; Blood Coagulation; Female; Humans; Male; Rodenticides; Vitamin K; Vitamin K Deficiency Bleeding

Recently, many cases of vitamin K-dependent coagulopathy of unknown origin have been reported. Such patients lack any relevant family history and have no systemic disease, raising suspicion of superwarfarin intoxication. We evaluated individual risk factors causing coagulopathy and hemorrhagic symptoms in patients with suspected superwarfarin intoxication. In addition, we determined how to effectively treat vitamin K-dependent coagulopathy caused by suspected superwarfarin intoxication.. Seven patients with suspected superwarfarin intoxication who lacked any definitive history of rodenticide ingestion were included. Thirty-one patients initially diagnosed with rodenticide poisoning were also included. We performed a retrospective chart review of all subjects and examined clinical data including patient demographics and medical histories.. Patients initially diagnosed with rodenticide poisoning were divided into two groups, one of which had a laboratory abnormality (prothrombin time [PT] > 13 seconds) and another group with PTs in the normal range. There was no significant difference between the two groups in any of age, gender, the extent of chronic alcohol consumption, the causative rodenticide, psychiatric problems, ingestion of drugs interacting with warfarin, the extent of intoxication, or the type of ingestion attempt. The albumin level of the former group was significantly lower than that of the latter group (p = 0.014). Furthermore, a significant difference between the two groups was evident in terms of simultaneous ingestion of rodenticide and alcohol (p = 0.023).. Most patients with superwarfarin poisoning did not exhibit any complication. When such complications were evident, they were associated with serum albumin level and coingestion of rodenticide and alcohol.

Topics: 4-Hydroxycoumarins; Adolescent; Adult; Aged; Aged, 80 and over; Alcohol Drinking; Anticoagulants; Blood Coagulation; Child; Child, Preschool; Female; Humans; Male; Middle Aged; Partial Thromboplastin Time; Prothrombin Time; Republic of Korea; Retrospective Studies; Risk Factors; Rodenticides; Serum Albumin; Serum Albumin, Human; Vitamin K; Vitamin K Deficiency Bleeding; Young Adult

Topics: 4-Hydroxycoumarins; Antifibrinolytic Agents; Female; Follow-Up Studies; Hematuria; Humans; Pregnancy; Rodenticides; Stillbirth; Vitamin K; Young Adult

Superwarfarins (brodifacoum, difenacoum, bromodialone and chlorphacinone) are anticoagulant rodenticides that were developed in 1970s to overcome resistance to warfarin in rats. A 26-year-old previously healthy man was admitted to the emergency department with epigastric pain, severe upper and lower gastrointestinal haemorrhage, gingival bleeding and melena. The patient stated that he had been healthy with no prior hospital admissions and no personal or family history of bleeding diathesis. The patient, who later admitted attempted suicide, stated that he had taken 400 g rodenticide including brodifacoum orally for five days prior to admission to hospital. He had oral mucosal bleeding, numerous bruises over the arms, legs and abdomen, and an abdominal tenderness, together with melena. Laboratory tests revealed a haemoglobin level of 12.3 g/dl, leucocyte count of 9.1 × 10(9) /l, haematocrit of 28% and platelet count of 280 × 10(9) /l. The prothrombin time (PT) was > 200 s (normal range 10.5-15.2 s) and the activated partial thromboplastin time (aPTT) was 91 s (normal range 20-45 s). The INR (International normalised ratio) was reported to be > 17 (normal range 0.8-1.2). The thrombin time and plasma fibrinogen levels were in the normal range. The results showed the presence of brodifacoum at a concentration of 61 ng/ml, detected by reversed-phase liquid chromatography.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; 4-Hydroxycoumarins; Adult; Animals; Anti-Ulcer Agents; Anticoagulants; Blood Coagulation Disorders; Emergency Service, Hospital; Gastrointestinal Hemorrhage; Humans; Male; Pantoprazole; Partial Thromboplastin Time; Poisoning; Prothrombin; Rats; Rodenticides; Suicide, Attempted; Treatment Outcome; Vitamin K

Brodifacoum is a widely available superwarfarin used as a commercial rodenticide. Toxicity from long-acting anticoagulant rodenticides, primarily from uncontrolled bleeding, has been reported. Very little published toxicokinetic data are available for human brodifacoum poisoning. Management is also contentious with uncertainty over the dose, frequency, and duration of antidote treatment with vitamin K. The role of brodifacoum levels in guiding management is not entirely established.. A novel, highly sensitive method was developed for measuring all commercially available rodenticide-hydroxycoumarin anti-coagulants. Monthly brodifacoum levels were performed in two patients to determine half-life and expected time for levels to fall below 10 μg/L.. We report two concurrent cases at our clinical toxicology service that required prolonged treatment with oral vitamin K to achieve normalisation of coagulation studies. Brodifacoum elimination appears to follow first-order kinetics. Case 1 had a brodifacoum elimination half-life of 33 days and was treated with vitamin K (100 mg) for 6 months. Case 2 was treated with vitamin K (100 mg) for 3 months with a half-life of 15 days.. Our cases illustrate the positive experience in the utility of brodifacoum levels to confirm diagnosis and aid in directing antidote therapy. Large ingestions of brodifacoum-containing rodenticides are likely to require high-dose oral vitamin K administered daily. A brodifacoum level below 10 μg/L was associated with a normal coagulation profile following completion of vitamin K(1) therapy in our cases; this level may prove to be a safe treatment cessation threshold.

Topics: 4-Hydroxycoumarins; Adult; Female; Humans; Male; Middle Aged; Rodenticides; Suicide; Vitamin K

Patients rarely consult physicians before developing coagulopathy or bleeding in most reported cases of superwarfarin intoxication. A 57-year-old woman ingested red-dyed pellets of anticoagulant rodenticide containing difethialone and warfarin as well as tablets of nitrazepam. Although she presented to the hospital in a comatose state, notable pink-colored excreta hinted at the consumption of anticoagulant rodenticide, which led to the early diagnosis of superwarfarin intoxication. Supplementation of large doses of intravenous and oral vitamin K successfully prevented coagulopathy and bleeding. On the other hand, temporary and reversible myocardial suppression was extremely severe, and required the introduction of percutaneous cardiopulmonary support.

Topics: 4-Hydroxycoumarins; Anticoagulants; Cardiomyopathies; Coloring Agents; Female; Humans; Intra-Aortic Balloon Pumping; Middle Aged; Nitrazepam; Rodenticides; Vitamin K; Warfarin

A female patient with significant coagulopathy is presented for case discussion. This case represented a presumed Munchausen exposure to commercially available rat poison that contained one of the superwarfarin chemicals, brodifacoum. Review of the medical literature is undertaken to discuss the diagnostic approach and treatment of superwarfarin exposure. The accidental or intentional exposure to this group of rodenticide represents a significant public health problem that often is not considered by primary care physicians when confronted with coagulopathy.

Topics: 4-Hydroxycoumarins; Animals; Anticoagulants; Blood Coagulation Disorders; Blood Coagulation Tests; Female; Humans; Middle Aged; Munchausen Syndrome; Rats; Rodenticides; Vitamin K

Topics: 4-Hydroxycoumarins; Adult; Blood Transfusion; Compartment Syndromes; Female; Hemothorax; Humans; Infusions, Intravenous; International Normalized Ratio; Leg; Plasma; Rodenticides; Suicide, Attempted; Ultrasonography, Doppler; Vitamin K

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

Topics: 4-Hydroxycoumarins; Adult; Blood Coagulation Disorders; Blood Coagulation Factors; Humans; Male; Plasma; Rodenticides; Treatment Outcome; Vitamin K; Vitamin K Deficiency

Topics: 4-Hydroxycoumarins; Adult; Anticoagulants; Diagnosis, Differential; Epistaxis; Female; Hematemesis; Humans; Partial Thromboplastin Time; Pesticides; Poisoning; Prothrombin Time; Thrombosis; Unconsciousness; Vitamin K; Vitamin K Deficiency

Superwarfarins are widely used as rodenticides. They are similar to warfarin, but they are more potent and act longer. In case of poisoning, they cause severe bleeding, usually from multiple sites.. A 67-yr-old man was admitted with melaena, epistaxis and haemarthrosis in his left knee. PT, INR and aPTT were markedly increased. Initially, the patient was treated with blood and fresh frozen plasma (FFP) transfusions. However at the second day, PT, INR and aPTT were even worse. The combination of persistent coagulopathy, normal mixing studies, normal liver function tests and absence of hepatic failure or malabsorption syndromes lead to the suspicion of vitK dependent clotting factors deficiency due to superwarfarin poisoning. Indeed, the patient admitted a suicide attempt with rodenticide, although he had previously denied it. Psychiatric evaluation revealed a disturbed personality. Melaena stopped after 7 d. Then, the patient was administered 30 mg of vitK daily for a total period of 4 months.. Superwarfarin poisoning leads to severe bleeding, usually from multiple sites. Prolonged treatment with high doses of vitK is necessary. Haemarthrosis, as a complication of superwarfarin poisoning, is presented here for the first time in literature.

Topics: 4-Hydroxycoumarins; Aged; Blood Coagulation Tests; Hemarthrosis; Hemorrhage; Humans; Male; Rodenticides; Vitamin K; Vitamin K Deficiency

Topics: 4-Hydroxycoumarins; Adult; Humans; Male; Rodenticides; Vitamin K

Ingestion of long-acting anticoagulant rodenticides such as brodifacoum can lead to prolonged and life-threatening coagulopathy. A paucity of conflicting information is available on brodifacoum's half-life and elimination pharmacokinetics. In addition, the optimal dose, duration, and route of administration of vitamin K(1) therapy are unknown. We report the case of a 52-year-old man who ingested eight 43-g boxes of a rodenticide (d-Con Mouse-Prufe II; 0.005% brodifacoum; Reckitt & Colman, Wayne, NJ). This case demonstrates that after stabilization with fresh frozen plasma, high-dose oral vitamin K(1) therapy ( congruent with 7 mg/kg per 24 hours divided every 6 hours) was effective in treating brodifacoum-induced coagulopathy. The concentration of vitamin K(1) required for normal coagulation in this case was less than the accepted value of 1 microg/mL, which is derived from a rabbit model. In this case, brodifacoum appears to follow zero-order elimination pharmacokinetics. In future cases of patients with ingestions of long-acting anticoagulants who present with coagulopathy, it may be useful to obtain serial brodifacoum concentrations to determine elimination curves to help predict the duration of oral vitamin K(1) therapy.

Topics: 4-Hydroxycoumarins; Administration, Oral; Drug Overdose; Follow-Up Studies; Half-Life; Hemorrhage; Humans; Male; Metabolic Clearance Rate; Middle Aged; Plasma; Rodenticides; Suicide, Attempted; Vitamin K

Vitamin K is a group name for a number of prenylated 2-methyl-1,4-naphtoquinones, which may differ in their ability to function as a cofactor for prothrombin biosynthesis. To quantify the bioactivity of different forms of vitamin K, two experimental animal systems are frequently used: vitamin K-deficient rats and anticoagulated rats. In this paper both models are compared, and it is shown that the results obtained depend on the model used. The main reason for this discrepancy is the difference in recycling of vitamin K-epoxide, which results in a 500 times higher vitamin K requirement in anticoagulated rats. Absorption and hepatic accumulation of long chain menaquinones seem to be restricted to a maximum, whereas also the lipophilic nature of long chain menaquinones may hamper the quinone-quinol reduction in anticoagulated animals. If these data may be extrapolated to patients, food items rich in K1 and MK-4 would be expected to influence the stability of oral anticoagulation to a much larger extent than food items primarily containing higher menaquinones.

Topics: 4-Hydroxycoumarins; Absorption; Animals; Anticoagulants; Blood Coagulation; Disease Models, Animal; Male; Prothrombin; Rats; Rats, Inbred Lew; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

Superwarfarin sodium exposure or poisoning is a growing public health problem. There were 5133 reported cases of superwarfarin exposure and poisoning in 1988 and 13 423 cases in 1995. Cases may be associated with accidental exposure, suicide attempts, or Munchausen syndrome, and may be difficult to diagnose.. Patients from northern Wisconsin with superwarfarin exposure or poisoning were examined at a tertiary referral center in rural Wisconsin to determine what led to their exposure and to review the clinical manifestations, diagnosis, treatment, and prevention of superwarfarin poisoning.. Eleven cases satisfied the criteria for superwarfarin exposure or poisoning. All 7 children included in the study had accidentally ingested superwarfarin, 2 adults had Munchausen syndrome, and 1 teenager and 1 adult had attempted suicide using superwarfarin. Nine of the 11 cases had taken brodifacoum. The patients who had accidentally ingested superwarfarin or attempted suicide using it were easily diagnosed, while diagnosis was markedly delayed for the 2 patients with Munchausen syndrome. Full reversal of anticoagulation was quickly achieved in the cases of accidental ingestion and attempted suicide. We examined and treated the patients with Munchausen syndrome for months before establishing a diagnosis and fully reversing the anticoagulation. None of the patients in our study died of superwarfarin poisoning.. Superwarfarin exposure or poisoning is a growing public health problem that should be part of the differential diagnosis of patients who present with a coagulopathy consistent with vitamin K deficiency in the absence of coumadin therapy, liver disease, or the use of an inhibitor, and whose conditions do not resolve with large doses of parenteral vitamin K1 therapy.

Topics: 4-Hydroxycoumarins; Adult; Aged; Anticoagulants; Blood Coagulation Disorders; Diagnosis, Differential; Female; Humans; Incidence; Male; Middle Aged; Munchausen Syndrome; Poisoning; Rodenticides; Suicide, Attempted; United States; Vitamin K; Wisconsin

Topics: 4-Hydroxycoumarins; Blood Transfusion; Depressive Disorder; Drug Monitoring; Emergency Treatment; Female; Humans; Middle Aged; Poisoning; Prothrombin Time; Rodenticides; Suicide, Attempted; Vitamin K

Using the rat as an experimental animal model we have found that prothrombin synthesis reaches its maximal level at a relatively low dietary vitamin K intake. At still higher vitamin K intakes, however, the urinary Gla-excretion was substantially increased, showing a different vitamin K requirement for liver and extrahepatic tissues. The increased urinary Gla-excretion was found for both phylloquinone and menaquinone-4, but not for menaquinone-8, which questions the bioavailability of higher menaquinones for extrahepatic tissues. A discrepancy was found between effects of nutritional vitamin K-deficiency and treatment with a vitamin K-antagonist (brodifacoum). With both regimens plasma prothrombin rapidly decreased to well below 10% of the starting values, but in case of K-deficiency urinary Gla had hardly decreased in 7 days, whereas after 3 days of brodifacoum treatment Gla-excretion had decreased to 17% of the starting values. An explanation for this observation is that prothrombin procoagulant activity does not decrease proportional to the prothrombin Gla-content, but that a wide range of undercarboxylated prothrombins have lost nearly all activity. During vitamin K-deficiency the remaining low levels of vitamin K would mainly give rise to undercarboxylated prothrombin, whereas during brodifacoum treatment only non-carboxylated prothrombin is formed. It seems plausible that in the latter case the urinary Gla originates from proteins with long half-life times, such as the bone Gla-proteins.

Topics: 1-Carboxyglutamic Acid; 4-Hydroxycoumarins; Animals; Anticoagulants; Diet; Dose-Response Relationship, Drug; Male; Prothrombin; Rats; Vitamin K; Vitamin K Deficiency

Increased popularity during the past decade of brodifacoum, an anticoagulant rodenticide, has led to an increase in cases of accidental poisoning in nontarget species, including pets and farm animals. Pharmacokinetics of second-generation anticoagulant rodenticides such as brodifacoum are substantially different from those of first-generation anticoagulant rodenticides such as warfarin. This difference dramatically influences management of exposure in terms of duration and cost of treatment and may affect outcome. The National Poison Control Center reports that approximately 50 cases of brodifacoum exposure have occurred in horses between 1993 and 1997. To our knowledge, this report is the first complete clinical description of accidental ingestion of a potentially lethal dose of brodifacoum in horses. Early recognition of exposure to brodifacoum, subsequent treatment with adequate doses of vitamin K1, and sequential monitoring of clotting times and serum brodifacoum concentration permitted poisoning in these horses to be managed successfully.

Topics: 4-Hydroxycoumarins; Animals; Anticoagulants; Blood Coagulation; Half-Life; Horse Diseases; Horses; Male; Partial Thromboplastin Time; Poisoning; Prothrombin Time; Rodenticides; United States; Vitamin K

Topics: 4-Hydroxycoumarins; Animals; Diagnosis, Differential; Dog Diseases; Dogs; Female; Hemostatics; Laryngeal Edema; Poisoning; Postoperative Hemorrhage; Rodenticides; Tracheostomy; Vitamin K

Brodifacoum is a 4-hydroxycoumarin derivative that is commonly used as a rodenticide. Human exposures have produced severe coagulopathies resulting in hematuria, gastrointestinal bleeding, intracranial hemorrhage, and death. This is the first report of spontaneous hemoperitoneum secondary to brodifacoum ingestion. The patient was successfully managed with fresh frozen plasma, packed red blood cells, and vitamin K1. No surgical intervention was performed. The patient required ongoing daily vitamin K1 therapy for longer than 6 months.

Topics: 4-Hydroxycoumarins; Adult; Blood Component Transfusion; Drug Overdose; Erythrocyte Transfusion; Female; Hemoperitoneum; Humans; Plasma; Poisoning; Rodenticides; Vitamin K

A markedly elevated prothrombin time (PT) and activated partial thromboplastin time (APTT) were observed in a 24-year-old man who was admitted with a history of ethylene glycol ingestion. Further laboratory evaluation suggested that the coagulopathy was related to acquired factor deficiencies. The PT and APTT improved transiently on usual doses of vitamin K, but rapidly became abnormal again. The coagulopathy was controlled only after large doses of vitamin K for at least 37 days. On further questioning, the patient admitted to consuming a large quantity of a rodenticide. The second generation anticoagulant rodenticides (superwarfarins) result in a potent and prolonged anticoagulant effect by reducing the activity of the vitamin K dependent factors (II, XII, IX, and X). To our knowledge, this is the first reported concomitant ingestion of both ethylene glycol and a superwarfarin compound. This case serves to illustrate how a logical laboratory evaluation can lead to the proper diagnosis, despite a misleading clinical history.

Topics: 4-Hydroxycoumarins; Adult; Ethylene Glycol; Ethylene Glycols; Humans; Male; Partial Thromboplastin Time; Prothrombin Time; Renal Dialysis; Rodenticides; Vitamin K

A 36-month-old child had spontaneous hemorrhage from her nose, mouth, and urinary tract, and a fall in hemoglobin of 20 gm/L (2 gm/dl). The prothrombin time and partial thromboplastin time were markedly prolonged with a decrease in the vitamin K-dependent factors. The child had ingested brodifacoum, a long-acting rodenticide. Prolonged follow-up and treatment with vitamin K were necessary.

Topics: 4-Hydroxycoumarins; Child, Preschool; Female; Hemorrhage; Humans; Poisoning; Rodenticides; Vitamin K

1. The long-term (30 days) effects of a single dose of brodifacoum (0.2 mg kg-1, orally) on blood clotting activity and on liver parameters of the vitamin K cycle were investigated in rats. Maximal effect on blood clotting activity was seen on day one. On day seven blood clotting activity had returned to normal. 2. Liver microsomal vitamin KO reductase activity was maximally suppressed (10% of control activity) on day one, steadily recovered to about 40% on day 15 to remain at that level. The same time course was seen for the number of microsomal warfarin binding sites. 3. The persistent inhibition of the vitamin K cycle was also verified in vivo; following vitamin K administration (10 mg kg-1, i.v.) on day 30, the brodifacoum-treated rats accumulated vitamin KO in the liver. 4. Although clotting factor synthesis was normal, brodifacoum-treated rats were highly sensitive to warfarin. 5. Brodifacoum rapidly accumulated in the liver until the saturation of the microsomal binding site. Brodifacoum binding to the target prevented its elimination from the liver; liver content on day 30 was not different from day 7. 6. The results show (1) an over capacity for the hepatocellular vitamin K cycle, (2) a dissociation of the vitamin K epoxidation and the vitamin K-dependent carboxylation, (3) the 'superwarfarin' rodenticides to be extremely persistent due to their binding to the target.

Topics: 4-Hydroxycoumarins; Administration, Oral; Animals; Blood Coagulation; Humans; Liver; Male; Mixed Function Oxygenases; Rats; Rats, Inbred Strains; Rodenticides; Time Factors; Vitamin K; Vitamin K Epoxide Reductases

Because of the emergence of warfarin resistance, new potent long-acting anticoagulants are now readily available in several over-the-counter rodenticide products. The availability of these "superwarfarin" compounds has led to accidental and purposeful human ingestions, one of which has resulted in a death. We summarize the prior case reports and report a second death. In addition, we report the availability of an assay to detect the presence of brodifacoum (a superwarfarin compound) in human plasma and tissues.

Topics: 4-Hydroxycoumarins; Adult; Female; Humans; Kidney; Liver; Osmolar Concentration; Rodenticides; Substance-Related Disorders; Vitamin K; Warfarin

The vitamin K metabolism of three patients with factitious purpura due to brodifacoum ingestion was studied. These patients, who presented with bleeding disorders due to deficiency of the vitamin K-dependent blood clotting proteins, were refractory to vitamin K1 at standard doses and required fresh frozen plasma to control bleeding until large doses of vitamin K1 were used. Metabolic studies demonstrated a blockade in vitamin K utilization, consistent with the presence of a vitamin K antagonist, but the patients denied use of anticoagulants. Warfarin assays were negative. We show that the factitious purpura in each patient was due to the surreptitious ingestion of brodifacoum, a potent second generation long-acting vitamin K antagonist used as a rodenticide. The coagulopathies responded to long-term therapy with large doses of vitamin K1. The serum elimination half-time for brodifacoum ranged from 16 to 36 days in these patients. The anticoagulant effect is of long duration, requiring chronic vitamin K treatment. With increasing availability of new rodenticides, factitious purpura due to surreptitious ingestion of these potent vitamin K antagonists is emerging as a new problem, previously associated with warfarin, with important implications for diagnosis and treatment.

Topics: 4-Hydroxycoumarins; Administration, Oral; Adult; Blood Coagulation; Blood Coagulation Disorders; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Purpura; Rodenticides; Vitamin K; Warfarin

The clinical course of a patient poisoned with the 'superwarfarin' brodifacoum and a method for estimation of plasma levels is described. It was characterised by prolonged depression of Vitamin K-dependent clotting factors poorly responsive to Vitamin K administration.

Topics: 4-Hydroxycoumarins; Adult; Blood Coagulation Tests; Blood Transfusion; Chromatography, High Pressure Liquid; Humans; Male; Poisoning; Rodenticides; Vitamin K

Topics: 4-Hydroxycoumarins; Anticoagulants; Humans; Prothrombin Time; Rodenticides; Vitamin K

A young adult ingested 10 mg brodifacoum (a potent rodenticide) in an attempt to commit suicide. Prolonged bleeding was noted for over 6 months. It required large doses and prolonged use of vitamin K1 to combat this 'superwarfarin' poisoning.

Topics: 4-Hydroxycoumarins; Adult; Humans; Male; Vitamin K

Topics: 4-Hydroxycoumarins; Adult; Blood Coagulation; Drug Therapy, Combination; Ecchymosis; Female; Humans; Phenobarbital; Prothrombin Time; Rodenticides; Time Factors; Vitamin K

Topics: 4-Hydroxycoumarins; Adolescent; Blood Coagulation Factors; Blood Transfusion; Hematoma; Humans; Male; Partial Thromboplastin Time; Plasma; Prothrombin Time; Rodenticides; Thigh; Time Factors; Vitamin K

Topics: 4-Hydroxycoumarins; Animals; Rodenticides; Vitamin K

The pharmacological response to vitamin K1 (Konakion) in anticoagulated (prothrombin complex activity less than 30%) New Zealand white rabbits was determined by measuring prothrombin complex activity (P.C.A.) in peripheral plasma. In animals pretreated with either brodifacoum (1 mg/kg or 10 mg/kg) or difenacoum (0.85 mg/kg or 8.5 mg/kg) P.C.A. reached a maximum 4 hr after administration of vitamin K1 (0.5 mg/kg) and declined at a rate indicating complete inhibition of clotting factor synthesis. A different response to vitamin K1 (0.5 mg/kg) was observed in rabbits pretreated with warfarin (63 mg/kg); after an initial rise P.C.A. appeared to plateau for 11 hr and then fall at a rate which indicated incomplete inhibition of clotting factor synthesis. The response to several doses of vitamin K1(0.5, 1,2.5 and 5.0 mg/kg) was investigated in the same group of brodifacoum (1 mg/kg) anticoagulated animals. There was a linear relationship between the duration of clotting factor synthesis and the logarithm of the dose of the vitamin K; the pharmacological half-life of vitamin K1 was only 1.7 +/- 0.1 hr. The duration of action of brodifacoum and difenacoum was much longer than that of warfarin. Six weeks after administration of brodifacoum (1 mg/kg) animals were still anticoagulated (P.C.A. less than 30%). In conclusion, we have found that brodifacoum and difenacoum are both more potent and persistent antagonists of vitamin K1 than warfarin in vivo. In cases of poisoning with these compounds it will be necessary to give repeated and frequent doses of vitamin K to maintain clotting factor synthesis.

Topics: 4-Hydroxycoumarins; Animals; Anticoagulants; Male; Prothrombin; Rabbits; Time Factors; Vitamin K; Warfarin