vitamin-k-1 and bromfenacoum

We report the deliberate ingestion of a superwarfarin product, brodifacoum, in a 39-y-old male. He presented with prothrombin and partial thromboplastin times of 150 and 113 sec, respectively. His coagulopathy was corrected by administration of blood products and phytonadione. To maintain normal clotting studies this patient required the highest maintenance dose of phytonadione, 200 mg/d, reported to date. The patient was able to tolerate this dose for 5 mo without adverse effects.

Topics: 4-Hydroxycoumarins; Adult; Blood Coagulation Disorders; Chronic Disease; Humans; Male; Partial Thromboplastin Time; Prothrombin Time; Rodenticides; Suicide, Attempted; Vitamin K 1

Newer Rodenticides of the long-acting anticoagulant or "superwarfarin" class are gaining popularity. Since few cases of severe, prolonged anticoagulation after ingestion have been reported, the course of toxicity is not precisely understood. In this case of an intentional ingestion of brodifacoum, a longitudinal analysis of specific coagulation factor derangements was carried out in an attempt to guide a future treatment strategy for this type of toxicity. Results of this analysis demonstrated a profound decrease in levels of factors II, VII, IX, and X, lasting at least 43 days post ingestion. Treatment with subcutaneous vitamin K1 in doses up to 100 milligrams per day was without complication and was effective in reversing the coagulopathy produced by brodifacoum.

Topics: 4-Hydroxycoumarins; Adult; Blood Coagulation Factors; Delayed-Action Preparations; Humans; Male; Prothrombin Time; Rodenticides; Vitamin K 1

Topics: 4-Hydroxycoumarins; Drug Administration Schedule; Humans; Poisoning; Vitamin K 1

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 K

Topics: 4-Hydroxycoumarins; Administration, Inhalation; Adult; Aftercare; Anticoagulants; Antifibrinolytic Agents; Blood Coagulation Disorders; Cannabinoids; Chicago; Female; Hemorrhage; Humans; International Normalized Ratio; Lost to Follow-Up; Male; Medication Adherence; Middle Aged; Patient Compliance; Synthetic Drugs; Vitamin K 1

Patients exposed to long acting anticoagulant rodenticides (LAARs) are typically administered large amounts of oral vitamin K1 (VK1) to counteract life-threatening anticoagulant effects. Although VK1 treatment effectively prevents mortality, additional methods are needed to reduce the long duration of VK1 treatment which can last for months at high expense. We developed a model of brodifacoum (BDF) poisoning, one of the most potent LAARs, in adult male New Zealand White (NZW) rabbits. The LD50 for oral BDF was determined to be 192 μg/kg, similar to that calculated for adult rats. However, in contrast to rats, NZW rabbits exhibited severe internal hemorrhage including in the brain, symptoms which mimic what occurs in cases of human poisoning. Similar to warfarin, BDF and other LAARs undergo enterohepatic recirculation which contributes to their long half-lives. We therefore tested effects of cholestyramine (CSA), an FDA-approved bile sequestrant, on BDF-induced mortality. When given daily (0.67 g/kg, oral) starting the day of BDF administration, CSA reduced mortality from 67% to 11%. At the same CSA prevented the increase in clotting time, and reduced the decrease in core body temperature due to BDF. Given its excellent safety record and that it is approved for children older than 6 years, these findings suggest CSA could be considered as an adjunct to VK1 for treatment of LAAR poisoning.

Topics: 4-Hydroxycoumarins; Animals; Anticoagulants; Bile Acids and Salts; Cholestyramine Resin; Hemorrhage; Lethal Dose 50; Male; Rabbits; Rodenticides; Survival Analysis; Vitamin K 1

Topics: 4-Hydroxycoumarins; Animals; Blood Transfusion; Dog Diseases; Dogs; Female; Gastrointestinal Hemorrhage; Plasma; Rodenticides; Stomach; Stomach Diseases; Vitamin K 1; Whole Blood Coagulation Time

A case of brodifacoum exposure leading to coagulopathy lasting for approximately one year despite treatment with large doses of phytonadione is reported.. 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.. 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.

Topics: 4-Hydroxycoumarins; Adult; Anticoagulants; Antifibrinolytic Agents; Blood Coagulation Disorders; Follow-Up Studies; Humans; International Normalized Ratio; Male; Rodenticides; Severity of Illness Index; Time Factors; Vitamin K 1

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.

Topics: 4-Hydroxycoumarins; Adolescent; Antifibrinolytic Agents; Emergency Service, Hospital; Humans; Intestinal Obstruction; Male; Plasma; Rodenticides; Tomography, X-Ray Computed; Vitamin K 1

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.

Topics: 4-Hydroxycoumarins; Adult; Aged; Aged, 80 and over; Anticoagulants; Antifibrinolytic Agents; Environmental Exposure; Female; Hemorrhage; Humans; Male; Middle Aged; Partial Thromboplastin Time; Prothrombin Time; Republic of Korea; Treatment Outcome; Vitamin K 1

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.

Topics: 4-Hydroxycoumarins; Adult; Aged; Blood Coagulation Tests; Female; Hematuria; Humans; Male; Middle Aged; Rodenticides; Suicide, Attempted; Vitamin K 1; Vitamins; Young Adult

Topics: 4-Hydroxycoumarins; Anticoagulants; Blood Coagulation; Blood Coagulation Tests; Blood Component Transfusion; Contusions; Epistaxis; Female; Gastrointestinal Hemorrhage; Humans; Middle Aged; Rodenticides; Vitamin K 1

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.

Topics: 4-Hydroxycoumarins; Adult; Blood Coagulation Disorders; Deglutition; Drug Packaging; Glass; Humans; International Normalized Ratio; Male; Patient Compliance; Rodenticides; Vitamin K 1

Hemorrhage resulting from ingestion of anticoagulant rodenticides may be evident at any traumatized site or in any body cavity. It is important for clinicians to include coagulopathies among the differential diagnoses for pericardial effusion and to evaluate clotting function before routine pericardiocentesis is performed.

Topics: 4-Hydroxycoumarins; Animals; Anti-Arrhythmia Agents; Blood Coagulation Disorders; Blood Transfusion; Cardiac Tamponade; Diagnosis, Differential; Dog Diseases; Dogs; Electrocardiography; Female; Lidocaine; Partial Thromboplastin Time; Pericardial Effusion; Quinidine; Radiography, Thoracic; Rodenticides; Vitamin K 1

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

A captive white-winged wood duck (Cairina scutulata) with bilateral epistaxis and anemia (packed cell volume = 16%) was treated with injectable and oral vitamin K1 and transfused with 40 ml whole blood. Brodifacoum was detected in blood at 0.002 ppm. The bird made an uneventful recovery. This report illustrates the risk of anticoagulant pest control products in a zoological setting.

Topics: 4-Hydroxycoumarins; Administration, Oral; Animals; Anticoagulants; Antifibrinolytic Agents; Bird Diseases; Blood Transfusion; Ducks; Epistaxis; Female; Male; Rodenticides; Vitamin K 1

We report the case of a 17-year-old boy with a significant history of drug and alcohol abuse, which included smoking marijuana mixed with brodifacoum. As a consequence, the patient developed a prolonged coagulopathy that persisted for more than 1 year. To our knowledge, this is the first case reported in the literature in which super-warfarin intoxication has been associated with marijuana smoking. This report should increase the awareness of pathologists and clinicians when examining a patient with a history of drug abuse who exhibits persistent vitamin K1-dependent coagulopathy.

Topics: 4-Hydroxycoumarins; Adolescent; Blood Coagulation; Blood Coagulation Factors; Factor X Deficiency; Humans; Male; Marijuana Smoking; Prothrombin Time; Rodenticides; Vitamin K 1

Brodifacoum is a readily available, second-generation anticoagulant rodenticide (superwarfarin) that causes extended depletion of vitamin K1-dependent clotting factors. Brodifacoum ingestions are being reported with increasing frequency. For the first time, we compare plasma brodifacoum concentration to prothrombin levels over time in a case of brodifacoum poisoning. Brodifacoum was eliminated according to a two-compartment model, with an initial half-life of 0.75 days and a terminal half-life of 24.2 days. On admission, the brodifacoum level was 731 micrograms/L and the patient suffered severe urinary tract hemorrhage, requiring transfusion of blood products. Persistently increased prothrombin times necessitated treatment with phytonadione up to 80 mg/d for 4 months, until the brodifacoum level reached 10 micrograms/L. These data may help project the duration of phytonadione treatment required in future cases of brodifacoum poisoning. Superwarfarin exposure must be suspected in an otherwise unexplained vitamin K1-deficient coagulopathy.

Topics: 4-Hydroxycoumarins; Adult; Blood Transfusion; Half-Life; Humans; Male; Poisoning; Prothrombin Time; Rodenticides; Vitamin K 1

To present the diagnosis and management of superwarfarin ingestion, a cause of serious and prolonged coagulopathy.. Specific identification of the anticoagulant was made by high-pressure liquid chromatography.. A 24 month-old child developed bruises and a prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT) after receiving multiple doses of brodifacoum, a superwarfarin rodenticide. The coagulopathy was treated successfully with large doses of parenteral and oral vitamin K1; fresh frozen plasma was administered as a precautionary measure on two occasions. After the first 10 days of the child's hospitalization, the mother was identified as the source of brodifacoum, exemplifying the behavior described as Munchausen syndrome by proxy. Oral vitamin K1 was initiated and continued in an outpatient setting with tapering doses over nine months, using the PT as a guide for therapy.. This report emphasizes the necessity of recognizing rodenticide poisoning and investigating its source. Frequent monitoring of the PT is essential to prevent hemorrhagic complications due to repeat exposure, inadequate vitamin K1 therapy, or noncompliance.

Topics: 4-Hydroxycoumarins; Adult; Blood Coagulation Factors; Blood Coagulation Tests; Child Abuse; Child, Preschool; Chromatography, High Pressure Liquid; Combined Modality Therapy; Ecchymosis; Female; Humans; Male; Munchausen Syndrome by Proxy; Plasma; Vitamin K 1

Topics: 4-Hydroxycoumarins; Adult; Drug Overdose; Factitious Disorders; Female; Humans; Prothrombin Time; Vitamin K 1

We have investigated the pharmacokinetics and procoagulant activity of a new, mixed-micellar preparation of vitamin K1 (MM-K) in male New Zealand White rabbits. Oral administration of MM-K alone caused a significant (P less than 0.01) increase in the plasma concentrations of vitamin K1 as measured by normal-phase high-performance liquid chromatography (HPLC). Maximum plasma concentrations of vitamin K1 (450 ng mL-1, range 133-824 ng mL-1) were recorded at 3.3 h (range 3-5 h), and were significantly (P less than 0.05) greater than those seen after administration of an existing polyethoxylated castor oil preparation (PE-K; Konakion), which were 260 ng mL-1, range 198-390 ng mL-1 (tmax 0.8 h, range 0.4-1.2 h). AUC after MM-K (4.6 micrograms mL-1 h-1, range 2.1-6.3 micrograms ML-1 h-1) was also significantly (P less than 0.05) greater than after PE-K (1.6 micrograms mL-1 h-1, range 1.0-2.1 micrograms ML-1 h-1). However, the bioavailability of vitamin K1 after administration of MM-K was poor (9.4%), and there was considerable intra-individual variability between the concentrations of vitamin K1 recorded in the plasma samples. Both preparations of vitamin K1 stimulated clotting factor synthesis in rabbits anticoagulated with the potent and long-acting coumarin, brodifacoum. Maximum stimulation of clotting factor synthesis by vitamin K1 after MM-K was 87%, range 44-124% (%PCA). The maximum was seen later (tmax 12 h) than after PE-K (PCA 82%, range 47-125%; tmax 5 h). However, there was considerable intra-individual variability in response to both MM-K and PE-K.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 4-Hydroxycoumarins; Animals; Anticoagulants; Biological Availability; Blood Coagulation; Coumarins; Half-Life; In Vitro Techniques; Male; Micelles; Rabbits; Vitamin K 1

1. The relationship between pharmacological response and disposition of a dose of vitamin K1 (10 mgkg-1, i.v.) in normal rabbits and in rabbits treated with the coumarin anticoagulant brodifacoum, has been studied. 2. High performance liquid chromatography (h.p.l.c.) with electrochemical detection (EC) was used to determine concentrations of vitamin K1 in plasma, whole liver homogenate, and liver microsomes. 3. After intravenous administration of vitamin K1, plasma concentrations of the vitamin declined in a tri-exponential fashion. There were no differences between the two groups over the first 24 h of the experiment. However, between 24 h and the end of the study, plasma concentrations of vitamin K1 in the presence of brodifacoum were significantly (P less than or equal to 0.05) below those of vehicle-treated rabbits. 4. Seventy-two hours after administration of vitamin K1, plasma concentrations of the vitamin were not different from normal. 5. Three hours after administration of vitamin K1, the concentrations of the vitamin in whole liver were 46.6 +/- 4.3 micrograms g-1 in the presence of brodifacoum, and 32.8 +/- 6.4 micrograms g-1 in the absence of brodifacoum; and were significantly (P less than or equal to 0.05) greater than normal (127.7 +/- 44.3 ng g-1). Likewise, microsomal concentrations of vitamin K1 (4.00 +/- 2.38 micrograms mg-1 protein, and 2.65 +/- 1.01 micrograms mg-1 protein, in the presence and absence of brodifacoum, respectively) were significantly (P less than or equal to 0.01) greater than normal (16.0 +/- 3.5 ng mg-1 protein). 6 In conclusion, there appears to be no direct effect of coumarins on clearance of vitamin K1 from either plasma or liver; the need for large doses of vitamin K1 during coumarin poisoning is due to a greatly increased requirement for the vitamin.

Topics: 4-Hydroxycoumarins; Animals; Chromatography, High Pressure Liquid; Coumarins; Electrochemistry; Liver; Male; Microsomes, Liver; Prothrombin; Rabbits; Rodenticides; Vitamin K 1

The case histories of two patients exposed to the novel anticoagulants brodifacoum and difenacoum are reported. Abnormal vitamin K1 metabolism, as indicated by elevated vitamin K1 2,3-epoxide plasma concentrations after i.v. administration of vitamin K1, could be detected for more than 18 months after exposure to the anticoagulants. There was a marked prolongation of prothrombin time (greater than 50 s) in both cases, at the time of exposure. However, subsequent haematological investigations (prothrombin time and vitamin K-dependent clotting factor activity) have been shown to be normal in both cases for at least 18 months. These cases confirm the long-acting nature of brodifacoum and difenacoum and present an apparent dissociation between the effect of coumarin anticoagulants on vitamin K1 metabolism and clotting factor activity.

Topics: 4-Hydroxycoumarins; Adult; Blood Coagulation Disorders; Blood Coagulation Tests; Humans; Male; Occupational Diseases; Prothrombin Time; Vitamin K 1

Topics: 4-Hydroxycoumarins; Animals; Blood Coagulation Factors; Dose-Response Relationship, Drug; Drug Resistance; Male; Rats; Vitamin K 1; Warfarin