bromfenacoum and Vitamin-K-Deficiency

Superwarfarins are anticoagulant rodenticides similar to warfarin, but which have various substituted phenyl groups replacing the terminal methyl group, resulting in a fat-soluble, long-acting anticoagulant that is nearly 100 times more potent than the parent compound. Since their development, many accidental and intentional cases of consumption have been reported. We describe two cases of consumption, one related to unknown etiology, and the other related to utilization of the superwarfarin to potentiate a drug of abuse. The clinical manifestations including bleeding symptoms and abnormal coagulation assays are discussed. The differential diagnosis is quite broad, and includes all causes of vitamin K deficiency, factor deficiency or inhibitor, disseminated intravascular coagulation (DIC), and liver disease. Differentiating superwarfarin ingestion from the other causes can be quite difficult, but extremely important, as management requires prolonged administration of vitamin K. Other treatment options are discussed as well including, fresh frozen plasma (FFP), and recombinant factor VIIa. Finally, the significance of "lacing" drugs of abuse with superwarfarin to potentiate their effect is discussed, as well as the complications that could develop from such a habit.

Topics: 4-Hydroxycoumarins; Adult; Blood Coagulation Disorders; Diagnosis, Differential; Humans; Male; Middle Aged; Pain; Platelet Count; Prothrombin Time; Thromboplastin; Time Factors; Vitamin K Deficiency

Rat poisoning should be considered in the differential diagnosis of a patient presenting with signs and symptoms of vitamin K deficiency without a more likely explanation. However, confirming this diagnosis may be difficult due to the varying sensitivities of available assays. A 40-year-old Caucasian woman presented to our hospital with chronic abdominal pain, hematuria, and a history of diarrhea of unknown etiology, despite an extensive work-up. Her laboratory evaluation results were consistent with vitamin K deficiency. Because she reported that she had not ingested warfarin, rat poisoning was suspected; however, the results of the first assay were negative. A second specimen was sent to another reference laboratory with a more sensitive assay, and the diagnosis of brodifacoum poisoning was confirmed. The patient was treated with oral vitamin K. If a patient presents with unexplained signs and symptoms of vitamin K deficiency, toxicological evaluation should be performed and repeat testing may be warranted, depending on the sensitivity of the original testing method.

Topics: 4-Hydroxycoumarins; Adult; Female; Humans; International Normalized Ratio; Poisoning; Rodenticides; Vitamin K Deficiency

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

A 71-year-old man presented with a recurrent bleeding diathesis requiring frequent blood transfusions, vitamin K and fresh frozen plasma. Extensive investigations revealed vitamin K deficiency. After repeated interviews the patient admitted to deliberately ingesting rat poison. Superwarfarins are an uncommon cause of deranged clotting and specialised tests are available to identify them. They can cause prolonged coagulation abnormalities and may require treatment with oral vitamin K for several months after just a single dose.

Topics: 4-Hydroxycoumarins; Aged; Gastrointestinal Hemorrhage; Humans; Male; Middle Aged; Rodenticides; Suicide, Attempted; Vitamin K Deficiency

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

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

Because of the emergence of warfarin resistance in rodents, second-generation anticoagulants named "superwarfarins" were developed and marketed in over-the-counter rodenticide products. The availability of these compounds has resulted in accidental or intentional human ingestions, which cause severe bleeding. The methods for diagnosis and treatment of patients using superwarfarins are different from those for patients taking the regular warfarins. We report a case of intentional superwarfarin ingestion that caused petechiae and hematuria. Although the patient denied taking anticoagulant, the persistence of vitamin K-dependent factor deficiency led us to investigate the serum for anticoagulant rodenticides. We found high levels of brodifacoum, a superwarfarin compound. This case emphasizes the need for suspicion of superwarfarin poisoning in patients who show unexplained bleeding due to deficiency of vitamin K-dependent factors and resistance to treatment.

Topics: 4-Hydroxycoumarins; Adult; Blood Coagulation Tests; Hematuria; Humans; Male; Poisoning; Rodenticides; Vitamin K Deficiency; Warfarin