Sudden nasal bleeding and brodifacoum: A case of accidental exposure or attempted homicide?

A 50-year-old man was admitted to the emergency department with abrupt massive epistaxis. An accurate anamnesis and physical evaluation could not reveal any other anomalies, while coagulation tests showed potentially life threatening prolonged prothrombin time, with activated partial thromboplastin and thrombin time, with fibrinogen and antithrombin III within limits. Despite the prompt pharmacological and compressive local treatment, bleeding continued and the patient was therefore hospitalized. Highly specific coagulation and toxicological testing-among others high-performance liquid chromatography assessment on plasma-were performed, leading to the unexpected identification of brodifacoum. Police and criminal justice authorities revealed the source of exposure to brodifacoum after several months of investigation, residing in his everyday life. Brodifacoum is a long-lasting anticoagulant, acting as a vitamin K antagonist, and belongs to the family of superwarfarins. Brodifacoum use is authorized as rodenticide in many countries worldwide, but has been reported as cause of severe coagulopathies in humans, both intentional or involuntary, even consumed as a contaminant of herbal drugs, such as cannabis. The original contribution of this case to the knowledges of human brodifacoum intoxication resides in the multidisciplinary approach and the collaborative interplay of clinical and toxicology experts as well as judicial authorities.

Effects of vitamin K1 treatment on plasma concentrations of long-acting anticoagulant rodenticide enantiomers following inhalation of contaminated synthetic cannabinoids.

Background: An outbreak of synthetic cannabinoid (SC)-associated coagulopathy and bleeding in Illinois, USA was determined to be due to inhalation of SC contaminated with brodifacoum (BDF), difenacoum (DiF), and bromadiolone (BDL), highly potent long-acting anticoagulant rodenticides (LAARs). Treatment with high-dose vitamin K1 (VK1) prevented mortality; however, plasma LAAR levels were not measured risking recurrence of coagulopathy and bleeding due to premature discontinuation. The goal of this study was to determine if plasma LAAR levels were reduced following standard of care treatment to normalize coagulopathy.Methods: Blood samples were collected from a cohort of 32 patients, and ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) analysis used to quantify plasma LAAR levels including enantiomers.Results: BDF was detected in 31 samples; 30 also contained DiF and 18 contained BDL. Initial plasma levels were 581 ± 87, 11.0 ± 1.9, and 14.9 ± 5.9 ng/mL for BDF, DiF, and BDL, respectively (mean ± SE). At discharge plasma, BDF levels remained elevated at 453 ± 68 ng/mL. Plasma half-lives for BDF, DiF, and BDL were 7.5 ± 1.3, 7.2 ± 1.9, and 1.8 ± 0.3 days, respectively. The half-life for trans-BDF enantiomers (5.7 ± 0.8 days) was shorter than for cis-enantiomers (7.6 ± 1.9 days). BDF half-lives were shorter, and coagulopathy normalized faster in patients receiving intravenous VK1 as compared to oral VK1. Patients prescribed VK1 at discharge had fewer re-admittances.Conclusions: These results demonstrate that plasma LAAR levels at discharge were elevated in poisoned patients despite normal coagulation, and that the route of VK1 administration affected LAAR pharmacokinetics and INR normalization. We propose plasma LAAR levels and coagulation be monitored concomitantly during follow-up of patients with LAAR poisoning. KEY POINTSIn patients treated with high-dose vitamin K1 for LAAR poisoning, plasma levels remained 40-fold above safe levels upon discharge from hospital.LAAR half-lives, normalization of coagulopathy, and readmittances were reduced by treatment with intravenous vitamin K1.

Adherence to Long-Term Follow-Up of Patients with Life-Threatening, Inhaled Synthetic Cannabinoids-Associated Coagulopathy in Chicago.

A large-scale outbreak of life-threatening, inhaled synthetic cannabinoids (Spice/K2)-associated coagulopathy with bleeding complications was recently reported in Illinois. The causative agents were brodifacoum, difenacoum, and bromadiolone, potent, long-acting, 4-hydroxycoumarin anticoagulant rodenticides (LAAR) that were mixed with Spice/K2 products procured and then inhaled by the victims. We report on 3 poisoned patients who reside in underserved, socioeconomically disadvantaged neighborhoods of Chicago that were admitted and treated successfully at two inner-city, tertiary care hospitals in Chicago. The patients were discharged from the hospitals on daily long-term high-dose oral vitamin K1 (VK1), provided free of charge. However, 2 patients were lost to follow-up prior to safe discontinuation of oral VK1 therapy. The third patient was treated and followed successfully for 7 months when VK1 was discontinued. We conclude that prolonged oral VK1 therapy and follow-up of acute, life-threatening LAAR poisoning are variable and present challenges to healthcare providers. Appropriate practice guidelines to improve patient access and adherence to daily high-dose oral VK1 therapy and follow-up should be developed and implemented.

Should Cytochrome P450 Inducers be Used to Accelerate Clearance of Brodifacoum from Poisoned Patients?

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.

Brodifacoum-contaminated synthetic marijuana: clinical and radiologic manifestations of a public health outbreak causing life-threatening coagulopathy.

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.

Prolonged coagulopathy after brodifacoum exposure.

PURPOSE: A case of brodifacoum exposure leading to coagulopathy lasting for approximately one year despite treatment with large doses of phytonadione is reported. SUMMARY: A 36-year-old man was diagnosed with severe coagulopathy. He was treated and discharged on 40 mg of oral phytonadione daily. The cause of the coagulopathy remained unknown at discharge, but the hematologist theorized that exposure to a vitamin K antagonist was likely the source of the patient's condition. The patient was rehospitalized one week later with an International Normalized Ratio (INR) of 5.9 despite self-reported medication compliance. Oral phytonadione was increased to 80 mg daily. The patient was seen at an outpatient hematology clinic for several months and continued on tapering dosages of oral phytonadione. A coagulopathy panel from the original hospitalization confirmed the presence of brodifacoum, though the method of exposure remained unclear. He was lost to follow-up until approximately nine months later, when he reported taking 10 mg daily of oral phytonadione and had an INR of 1. Oral phytonadione was discontinued. Two months later, his INR was greater than 9, despite an undetectable level of brodifacoum. He was rehospitalized with oropharyngeal hematoma approximately 1 year after the initial coagulopathy diagnosis. The patient was discharged on 40 mg oral phytonadione daily with outpatient follow-up. CONCLUSION: A patient with brodifacoum exposure ingested brodifacoum had coagulopathy that lasted approximately one year despite long-term treatment with large dosages of oral phytonadione. The coagulopathy persisted even when brodifacoum was undetectable in the serum. Long-term treatment with high-dose phytonadione is expensive, which may influence medication compliance.

Superwarfarin intoxication: two case reports and review of pathophysiology and patient management.

Superwarfarin vitamin K antagonists are found in rat poisons and are readily available. Pediatric exposures are common but are usually asymptomatic without significant coagulopathy. Superwarfarin intoxication must be considered in any adult who presents with an unexplained coagulopathy with extreme elevation of prothrombin time and partial thromboplastin time with associated depletion of vitamin K dependent factors. If superwarfarin toxicity is confirmed, intentional ingestion should be considered, as a large quantity of ingested rat poison is necessary to induce a coagulopathy. Patients with superwarfin induced coagulopathy require several months of high dose oral and parenteral vitamin K supplementation. We describe two patients with superwarfarin toxicity treated at Louisiana State University Health in Shreveport and review pathophysiology and patient management.

Management of intentional superwarfarin poisoning with long-term vitamin K and brodifacoum levels.

CONTEXT: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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.

Korean patients with superwarfarin intoxication and their outcome.

This observational study aimed at evaluating recent superwarfarin intoxication of Korean patients. Ten patients were diagnosed as or highly suspicious for superwarfarin intoxication. Case report forms described by attending hematologists of the patients were collected and analyzed. Bleeding symptoms were varied among the patients. Patients uniformly showed prolonged prothrombin time (PT) and activated thromboplastin time (aPTT) with decreased activity of vitamin K dependent coagulation factors. Positive serum brodifacoum test results in 4 of 5 requested patients contributed to confirmatory diagnosis. Psychiatric interview revealed an attempted ingestion in one patient. High dose vitamin K1 therapy promptly corrected prolonged PT and aPTT, but hasty discontinuation caused repeated bleeding diathesis in 6 patients. Route of intoxication was unknown or not definite among 8 of 10 patients. Three patients had a possibility of environmental exposure considering their occupations: there might be intoxication by transdermal absorption or inhalation. Therefore, high dose and prolonged use of vitamin K1 therapy is necessary for effective detoxification. Further detailed investigation on environmental exposure and efforts to improve availability of the blood level test in clinic are requested.

Superwarfarin poisoning as a cause of intestinal obstruction.

A 17-year-old boy was brought to our department with nausea, vomiting, absence of flatus or bowel movements, abdominal distension, and pain for about 5 days. Emergency abdominal CT scan showed extensive gas-fluid levels in the intestinal tract and intestinal wall swelling that indicated acute intestinal obstruction. Routine coagulation tests revealed abnormality and further provided evidence of superwarfarin poisoning. With high dosage of vitamin K1 and fresh frozen plasma therapy, surgery was avoided.

Korean Patients with Superwarfarin Intoxication and Their Outcome

This observational study aimed at evaluating recent superwarfarin intoxication of Korean patients. Ten patients were diagnosed as or highly suspicious for superwarfarin intoxication. Case report forms described by attending hematologists of the patients were collected and analyzed. Bleeding symptoms were varied among the patients. Patients uniformly showed prolonged prothrombin time (PT) and activated thromboplastin time (aPTT) with decreased activity of vitamin K dependent coagulation factors. Positive serum brodifacoum test results in 4 of 5 requested patients contributed to confirmatory diagnosis. Psychiatric interview revealed an attempted ingestion in one patient. High dose vitamin K1 therapy promptly corrected prolonged PT and aPTT, but hasty discontinuation caused repeated bleeding diathesis in 6 patients. Route of intoxication was unknown or not definite among 8 of 10 patients. Three patients had a possibility of environmental exposure considering their occupations: there might be intoxication by transdermal absorption or inhalation. Therefore, high dose and prolonged use of vitamin K1 therapy is necessary for effective detoxification. Further detailed investigation on environmental exposure and efforts to improve availability of the blood level test in clinic are requested.

Superwarfarin intoxication: hematuria is a major clinical manifestation.

Since superwarfarin is popular and readily available in stores, it may cause intoxication or overexposure, which can result in coagulopathy or abnormal bleeding in humans and, thus, is an important public health problem. We report our clinical experience with superwarfarin intoxication. Nine patients, including eight patients who had histories of ingesting superwarfarin, were studied. Of the patients, hematuria occurred in eight. Laboratory tests among the nine patients showed extremely prolonged prothrombin times and activated partial thromboplastin times, which could be corrected to normal by mixing 1:1 with normal pooled plasma; they also had very low functional levels of factor II, VII, IX, X, and proteins C and S, but normal functional levels of factors V, VIII, fibrinogen, and anti-thrombin III. Large doses of vitamin K1 were needed for 3 months or more to treat and correct the coagulopathy among the patients. The majority of the patients presented with gross hematuria, suggesting that hematuria is probably a major clinical manifestation of superwarfarin intoxication. Prolonged use of large doses of vitamin K1 is needed for the treatment of superwarfarin intoxication.

Mosquito repellents and superwarfarin rodenticides--are they really toxic in children?

PURPOSE OF REVIEW: In many United States households, there are many substances used to control the exposure of our children to mosquitoes, mice and rats. This review provides information on common mosquito repellents and rodenticides used in households and discusses their toxicity, in order to help pediatricians better advise their patients of their proper use. RECENT FINDINGS: A recent study has demonstrated that many continue to have practices of applying DEET (N,N-diethyl-3-methylbenzamide) based repellents that may lead to undesirable effects. Picaridin and oil of lemon eucalyptus are two products that have recently been shown to have an efficacy similar to that of DEET-based repellents. Studies within the last five years show that most unintentional superwarfarin ingestions can be managed at home with close outpatient follow-up. There does not appear to be a benefit of prophylactic vitamin K or gastrointestinal decontamination in patients with relatively small ingestions of superwarfarins. SUMMARY: With education and correct usage, mosquito repellents and the superwarfarin rodenticides can help protect children from significant vector-borne diseases. Not all exposures lead to significant morbidity or mortality. With recognition of the current literature, most of these exposures can be managed safely at home or as an outpatient, ultimately saving healthcare costs.

Effect of supplementary feeding of vitamin K1 on difethialone treated Indian gerbil, Tatera indica Hardwicke in laboratory.

Two dosages (1 and 2 mg/kg) of vitamin K1 supplementation for 5 and 15 days were given to Indian gerbil T. indica fed on difethialone bait (0.0025%) for one day. The results indicated that the lower dosage could not reverse the anticoagulation process, however the period of mortality was considerably increased from 3-9 days (in control) to 5-14 days (5 days supplementation regime). Subsequently when the vitamin K1 dosage was doubled and given for 15 days, there was 100% reversal of anticoagulation process and all the test gerbils became normal within a month of poisoning with difethialone bait.

Superwarfarin and glass ingestion with prolonged coagulopathy requiring high-dose vitamin K1 therapy.

A 23-year-old man was brought to the emergency department after eating four boxes of brodifacoum-containing rodenticide over a 4-day interval and pieces from approximately two bottles of glass over the previous 2 weeks. He was asymptomatic but his prothrombin time was markedly elevated with an international normalized ratio (INR) of 37.8. A plain abdominal film showed diffuse radiopaque foreign bodies, presumably glass, in the large and distal small intestines. Treatment for ingested glass consisted of stool softeners and bulk-forming laxatives. The patient developed mild gingival bleeding and received fresh frozen plasma (FFP) infusions and vitamin K1 orally. At a vitamin K1 dosage of 300 mg/day, the INR corrected to less than 2.0 and the patient was discharged taking that dosage. He returned 26 days later with hematuria and flank pain, and his INR was 189. He was administered FFP and packed red blood cells, and his vitamin K1 dosage was increased to 800 mg/day; his INR returned to baseline. Compliance with taking the vitamin K1, which required ingestion of 60-160 tablets/day, was a serious problem, requiring numerous follow-up calls and visits to the patient at home and work. At 5-month follow he was doing well. Compliance with large daily doses of vitamin K1 for treatment of "superwarfarin" ingestion may be poor because of the duration of treatment and large number of pills required. A more concentrated formulation may be advantageous for management of patients with brodifacoum poisoning.

Long-acting anticoagulant overdose: brodifacoum kinetics and optimal vitamin K dosing.

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.

[Anticoagulant activity of coumarins from Ferula communis L]. / Activité anticoagulante des coumarines de Ferula communis L.

Ferula communis is an ombelliferous plant of the Mediterranean regions. It is represented in Morocco by two varieties: brevifolia and genuina. The later is very rich in a soap or resinous gum. This product, collected from the roots, is largely used in traditional medicine. It is know as fessoukh in Morocco and other Arab countries. This plant is also well known for its toxicity and its anticoagulant activity. In the present review, are discussed: (1) the ethnobotany of the plant, especially medicinal uses of fessoukh in traditional medicine as well as alimentary use of young stems as legumes; (2) clinical and biochemical data of intoxication by this plant, which are dominated by haemorrhage as a consequence of blood coagulation disturbance; (3) 4-hydroxycoumarins isolated from Ferula communis L. and their anticoagulant activity; (4) the role of vitamin K1 in the treatment of poisoning by this plant.

Superwarfarin poisoning.

BACKGROUND: 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 AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

'Superwarfarin' poisoning leading to prolonged coagulopathy.

An elderly Chinese was admitted for haemetemesis. Investigations revealed markedly prolonged clotting times that recurred every few days despite administration of fresh frozen plasma and vitamin K. The derangement in coagulation lasted more than 3 months. In view of the absence of liver disease or malabsorption syndromes, long-acting anticoagulant ('superwarfarin') ingestion was suspected. The diagnosis of rodenticide poisoning was hampered by the lack of available assays. Diagnosis of brodifacoum intoxication using HPLC was confirmed only months after prolonged treatment with high dose vitamin K1. Superwarfarin poisoning should be suspected in cases of deranged coagulation refractory to treatment since these over-the-counter rodenticides are easily available.

Combined superwarfarin and ethylene glycol ingestion. A unique case report with misleading clinical history.

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.