Coumarin toxicology: literature review and case study of the 4-hydroxycoumarin derivatives poisoning
Keywords:anticoagulant rodenticides, poisoning, review
AbstractBackground. The widespread use of coumarin-based anticoagulant rodenticides in most countries of the world and in Ukraine determines the regular occurrence of poisonings among the population. Purpose of the work: to familiarize general practitioners with the biological and toxic effects of 4-hydroxycoumarin derivatives using a separate clinical observation. Materials and methods. The analysis was performed of modern sources of scientific information about the biological and toxic effects of coumarins over the past 20 years. A clinical case of poisoning with 4-hydroxycoumarin derivatives in a 40-year-old woman undergoing treatment at the toxicology department of City Emergency Hospital in Mykolaiv was considered. The methods of analytical, systemic and comparative analysis were applied. Results. On the basis of 4-hydroxycoumarin, a number of substances with anticoagulant properties of different efficacy were synthesized: brodifacoum, dicoumarol, warfarin, which are used as drugs for the prevention of thrombosis and embolism in a number of diseases, and pesticides — means of deratization. Rodenticides belonging to the 4-hydroxycoumarin group (superwarfarins) are used to kill rats and mice. Superwarfarins block vitamin K-dependent γ-carboxylation of glutamic acid residues in prothrombin precursors 100 times stronger (in equimolar ratio) than warfarin. In addition, their half-life reaches 120 days, and for warfarin it is 42 hours. The plasma content of factors II, VII, IX and X is reduced. As the concentration of coagulation factors decreases, clinical manifestations of their deficiency occur (usually on day 2 or day 3). Swallowing a small amount of poison can hardly harm the body. Multiple doses over several days or weeks can lead to serious poisoning and even death. Bleedings in the urogenital system, gastrointestinal tract, nosebleeds occur most often. The mechanism of coumarin anticoagulant intoxication is disrupting the cellular recirculation of the blood clotting factor — vitamin K, which results in secondary coagulopathy. This class of substances is characterized by high biological activity and toxicity. Case study. Patient D., a 40-year-old woman, was urgently admitted to the ENT department of the Mykolaiv City Hospital 4 with nosebleed in June 2018. The patient was treated in the ENT department during 2 days, but nosebleed recurred. Due to the negative changes in urine tests, acute haemorrhagic cystitis was diagnosed. The patient was examined by urologist and gynaecologist, but she refused hospitalization to the urological department and was referred to the therapeutic department for further treatment. However, due to the progressive coagulopathy (prothrombin index 65 %), the patient D. was transferred to the intensive care unit. Haemostatics, antibiotics, intravenous injection of crystalloids, single-donor plasma were used. However, the patient’s condition continued to worsen, coagulopathy was progressing (prothrombin index < 5 %; international normalized ratio > 10). The cause of severe coagulopathy remained unclear. The medical history of the patient was re-examined by doctors, and it was found that patient D. had schizophrenia. One year before, she has similar symptoms and was treated in the haematology department with the symptoms of coagulopathy during one week. Combining these facts, doctors suspected poisoning with unknown substance with a clear anticoagulant effect. A detailed survey of the patient’s mother revealed that shortly before the disease, patient D. had purchased a rat poison based on 4-hydroxycoumarin derivatives, and may have taken it for several days. This version was later confirmed. In the intensive care unit, patient D. was treated for 14 days, and after that she was transferred to the toxicology department of the Mykolaiv City Emergency Hospital, where she was treated and underwent rehabilitation for 25 days. Unfortunately, it was not possible to accurately determine the dose and period of poison use. During the entire period of stay in the toxicology department, symptomatic treatment for coagulopathy was performed with the use of vitamin K (vikasol, 20 mg, 3–4 times a day) and other haemostatics and symptomatic therapy. Prolonged nasal tamponade caused complications such as nasal septum perforation and pressure ulcer of the upper lip and nostrils on the left, which led to a long period of treatment by the ENT doctor. After wound healing and stabilization of laboratory parameters, patient D. was transferred to a psychiatric hospital with the diagnosis: acute rodenticide (4-hydroxycoumarin derivative) poisoning. Suicidal attempt. Toxic coagulopathy. Repeated nosebleeds. Haemorrhagic cystitis. Post-haemorrhagic anaemia. Pressure ulcer of the left sinus and upper lip on the left. Nasal septum perforation. Mental illness. This case demonstrated that clinical diagnosis of secondary coagulopathy is sometimes challenging. If it is impossible to carry out chemical and analytical studies (liquid chromatography — mass spectrometry) on the coumarin content in the patient’s blood, then the quality of collecting anamnesis vitae and anamnesis morbi, dynamic monitoring of haemostatic parameters, blood biochemical indices and clinical parameters of the blood and urine play a key role in establishing the diagnosis. Conclusions. The problem of acute poisonings with 4-hydroxycoumarin derivatives remains relevant in clinical practice. The use of an antidote (vitamin K) gives a positive result with timely treatment of a patient. Biological markers of the toxic process are international normalized ratio, prothrombin index, platelet count, and other haemostatic parameters, which characterize the coagulation system. It should be remembered that severe coagulopathy with the development of internal bleeding complicates the diagnosis of acute poisoning with anticoagulants and is often the reason why surgical complications such as bleeding are interpreted as the underlying disease.
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