Abstract 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. brodifacoum, ingestion, overdose, rat poison, supratherapeutic INR, vitamin K deficiency Clinical History A 40-year-old Caucasian woman presented to the hospital, having had persistent abdominal pain and diarrhea with no clear etiology for the previous 2 years. She had tried a gluten-free and dairy-free diet, antibiotics, mesalamine, and corticosteroids, without relief. In the 2 years before admission, she had undergone repeated endoscopic procedures, a cholecystectomy, and an exploratory laparotomy without satisfactory elucidation of the cause of her abdominal pain. On presentation, the patient had hematuria and anemia, with a hemoglobin level of 11 g per dL (mean corpuscular volume [MCV], 94 fL/cell and mean cell hemoglobin concentration [MCHC], 34 g/dL). Her platelet count was 224,000 per μL. During her stay, laboratory test results revealed she had a coagulopathy. The results of a mixing study showed full correction, and the factor levels are presented in Table 1, which are consistent with a vitamin K deficiency, despite no history of warfarin prescription or malabsorption. The patient admitted to possible rat-poison ingestion and did not comment on the possibility of accidental ingestion. A serum rat-poison panel was requested to be performed at a reference laboratory via liquid chromatography/tandem mass spectrometry. The test results were negative (<100 ng/mL), with the limit of detection reported as 100 ng per mL. This result surprised us, based on the suspicions mentioned earlier herein. Table 1. Laboratory Testing During Admission Test Result Reference Range On admission PT 90 sec 12-14 sec INR 12 NA PTT 135 sec 25-35 sec TT 15 sec <21 sec Fibrinogen 484 mg/dL 220-498 mg/dL D-dimer 114 ng/mL 110-240 ng/mL 2 days later PT 96 sec 12-14 sec INR >12 NA PTT >200 sec 25-35 sec Factor II 4% 70%-120% Factor V 122% 50%-150% Factor VII <3% 50%-150% Factor X 16% 50%-150% Test Result Reference Range On admission PT 90 sec 12-14 sec INR 12 NA PTT 135 sec 25-35 sec TT 15 sec <21 sec Fibrinogen 484 mg/dL 220-498 mg/dL D-dimer 114 ng/mL 110-240 ng/mL 2 days later PT 96 sec 12-14 sec INR >12 NA PTT >200 sec 25-35 sec Factor II 4% 70%-120% Factor V 122% 50%-150% Factor VII <3% 50%-150% Factor X 16% 50%-150% PT, prothrombin time; INR, international normalized ratio; NA, nonapplicable; PTT, partial thromboplastin time; TT, thrombin time View Large Table 1. Laboratory Testing During Admission Test Result Reference Range On admission PT 90 sec 12-14 sec INR 12 NA PTT 135 sec 25-35 sec TT 15 sec <21 sec Fibrinogen 484 mg/dL 220-498 mg/dL D-dimer 114 ng/mL 110-240 ng/mL 2 days later PT 96 sec 12-14 sec INR >12 NA PTT >200 sec 25-35 sec Factor II 4% 70%-120% Factor V 122% 50%-150% Factor VII <3% 50%-150% Factor X 16% 50%-150% Test Result Reference Range On admission PT 90 sec 12-14 sec INR 12 NA PTT 135 sec 25-35 sec TT 15 sec <21 sec Fibrinogen 484 mg/dL 220-498 mg/dL D-dimer 114 ng/mL 110-240 ng/mL 2 days later PT 96 sec 12-14 sec INR >12 NA PTT >200 sec 25-35 sec Factor II 4% 70%-120% Factor V 122% 50%-150% Factor VII <3% 50%-150% Factor X 16% 50%-150% PT, prothrombin time; INR, international normalized ratio; NA, nonapplicable; PTT, partial thromboplastin time; TT, thrombin time View Large As a result, the Pathology team decided to send another serum specimen, which was an aliquot of the one sent to the first laboratory, for testing at a different reference laboratory. This time, the qualitative result was positive for brodifacoum (a quantitative result was not included), with the limit of detection reported as 10 ng per mL, a 10-fold lower limit of detection than that of the first reference laboratory. The Psychiatry service was consulted to evaluate for possible factitious disorder and for treatment recommendations for moderate depression, which were given. After cessation of the hematuria, the patient was discharged with instructions per the Hematology service to continue taking oral vitamin K, 10 milligrams daily, with follow-up scheduled at an outside facility. It was concluded that the diarrhea she had been experiencing may represent diarrhea-predominant irritable bowel syndrome. We have not seen her at our institution since she was discharged. Discussion and Laboratory Role in Diagnosis In laboratory testing, brodifacoum poisoning presents in a form similar to vitamin K deficiency, with or without clinical bleeding.1–8 The differential diagnosis for vitamin K deficiency includes malabsorption, recent broad-spectrum antibiotic use (from destruction of gut bacteria that produces vitamin K), ingestion of a vitamin K antagonist, and a hereditary deficiency.4 If ingestion of a vitamin K antagonist is suspected, it is pertinent to consider whether the agent was a short- or long-acting coumarin or indandione (Table 2).9–20 The superwarfarins have much longer half-lives, and patients who have ingested them require longer treatment, sometimes even months after initial diagnosis.1,2,7–9,21,22 Superwarfarins were produced after rodents developed increased resistance to warfarin, including via a vitamin K epoxide reductase VKORC1 mutation, so that although the vitamin K epoxide reductase (VKOR) enzyme still remains functional, it can display a reduced amount and/or activity for the competitive (ingested) substrate.21,23–25 In 2013, there were more than 8000 reports of long-acting anticoagulant rodenticide poisonings, compared with less than 200 cases of warfarin-type rodenticide poisoning.26 Case reports in the literature1,2,4,7,22,26–31 have demonstrated the need for high daily doses of vitamin K for treatment, sometimes for many months, until the prothrombin (PT) and partial thromboplastin time (PTT) normalize. Table 2. Vitamin K Antagonists Short-Acting 4-Hydroxycoumarins Long-Acting Coumarins Indandiones acenocoumarol brodifacoum* chlorophacinone* coumatetralyl bromadiolone diphacinone* dicumarol* difenacoum phenindione† ethyl biscoumacetate flocoumafen NA warfarin* phenprocoumon NA Short-Acting 4-Hydroxycoumarins Long-Acting Coumarins Indandiones acenocoumarol brodifacoum* chlorophacinone* coumatetralyl bromadiolone diphacinone* dicumarol* difenacoum phenindione† ethyl biscoumacetate flocoumafen NA warfarin* phenprocoumon NA NA indicates nonapplicable; *, anticoagulants tested for at the reference laboratory for the case presented; †, an indandione derivative. View Large Table 2. Vitamin K Antagonists Short-Acting 4-Hydroxycoumarins Long-Acting Coumarins Indandiones acenocoumarol brodifacoum* chlorophacinone* coumatetralyl bromadiolone diphacinone* dicumarol* difenacoum phenindione† ethyl biscoumacetate flocoumafen NA warfarin* phenprocoumon NA Short-Acting 4-Hydroxycoumarins Long-Acting Coumarins Indandiones acenocoumarol brodifacoum* chlorophacinone* coumatetralyl bromadiolone diphacinone* dicumarol* difenacoum phenindione† ethyl biscoumacetate flocoumafen NA warfarin* phenprocoumon NA NA indicates nonapplicable; *, anticoagulants tested for at the reference laboratory for the case presented; †, an indandione derivative. View Large Patients who present with bleeding, especially disproportionate to the level of the injury sustained, with elevated PT and PTT, no signs of disseminated intravascular coagulation, and with no factor inhibitor as the cause, should be investigated for the possibility of rat poisoning. In fact, as low as 4 ng per mL of brodifacoum has been detected in the serum of a patient who was found to have ingested the toxin.6 Social services and/or law enforcement agencies should get involved, to evaluate for abuse and intentional poisoning, if it is considered a possibility. Failure to consider this diagnosis or the discharge of a patient without a thorough investigation (even if a test must be repeated) for rat poisoning, if suspected, may be considered a failure to establish an accurate and timely diagnosis. In an attempt to learn from this near-miss and to reduce errors in the future, we reviewed the recommendations published in 2015 by an expert committee assembled by the National Academies of Sciences, Engineering, and Medicine that proposed recommendations to improve diagnosis.32 The authors of this case report believe that this case demonstrates key decisions that were made to resolve the underlying cause. Without investigation, the correct diagnosis of our patient could have been missed. A challenging evaluation reinforces the importance of toxicology in the differential report and of repeating laboratory tests with unexpected results. One should consider the limit of detection of the assay used to confirm a diagnosis of rat poisoning when high suspicion of the diagnosis exists. Conclusion The incidence of rat poisoning is low, and detection is affected by clinical suspicion and the limit of detection of the laboratory. Providers seeking to effectively diagnose and treat patients with this disorder must consider that the limit of detection could be too high, even in reference laboratories, for these poisons. With this realization in mind, they must work together with their laboratory colleagues to problem solve, even if it means repeating the test at a different laboratory facility. Patients who have ingested rat poison should be followed up by the Hematology department (and the Psychiatry department if the ingestion was intentional) for recommendations on daily vitamin K replacement until their coagulation study results normalize, which could be months from the time of ingestion. References 1. Bruno GR , Howland MA , McMeeking A , Hoffman RS . Long-acting anticoagulant overdose: brodifacoum kinetics and optimal vitamin K dosing . Ann Emerg Med . 2000 ; 36 ( 3 ): 262 – 267 . 2. Hollinger BR , Pastoor TP . Case management and plasma half-life in a case of brodifacoum poisoning . Arch Intern Med . 1993 ; 153 ( 16 ): 1925 – 1928 . 3. MacNicoll AD . A comparison of warfarin resistance and liver microsomal vitamin K epoxide reductase activity in rats . Biochim Biophys Acta . 1985 ; 840 ( 1 ): 13 – 20 . 4. Schulman S , Furie B . How I treat poisoning with vitamin K antagonists . Blood . 2015 ; 125 ( 3 ): 438 – 442 . 5. Thijssen HH , Janssen CA , Drittij-Reijnders MJ . The effect of S-warfarin administration on vitamin K 2,3-epoxide reductase activity in liver, kidney and testis of the rat . Biochem Pharmacol . 1986 ; 35 ( 19 ): 3277 – 3282 . 6. Travis SF , Warfield W , Greenbaum BH , Molokisher M , Siegel JE . Spontaneous hemorrhage associated with accidental brodifacoum poisoning in a child . J Pediatr . 1993 ; 122 ( 6 ): 982 – 984 . 7. Weitzel JN , Sadowski JA , Furie BC , et al. Surreptitious ingestion of a long-acting vitamin K antagonist/rodenticide, brodifacoum: clinical and metabolic studies of three cases . Blood . 1990 ; 76 ( 12 ): 2555 – 2559 . 8. Leck JB , Park BK . A comparative study of the effects of warfarin and brodifacoum on the relationship between vitamin K1 metabolism and clotting factor activity in warfarin-susceptible and warfarin-resistant rats . Biochem Pharmacol . 1981 ; 30 ( 2 ): 123 – 128 . 9. Caravati EM , Erdman AR , Scharman EJ , et al. Long-acting anticoagulant rodenticide poisoning: an evidence-based consensus guideline for out-of-hospital management . Clin Toxicol (Phila) . 2007 ; 45 ( 1 ): 1 – 22 . 10. Wojciechowski VV , Calina D , Tsarouhas K , et al. A guide to acquired vitamin K coagulophathy diagnosis and treatment: the Russian perspective . Daru . 2017 ; 25 ( 1 ): 10 . 11. Fourel I , Hugnet C , Goy-Thollot I , Berny P . Validation of a new liquid chromatography-tandem mass spectrometry ion-trap technique for the simultaneous determination of thirteen anticoagulant rodenticides, drugs, or natural products . J Anal Toxicol . 2010 ; 34 ( 2 ): 95 – 102 . 12. Reitsma PH , van der Heijden JF , Groot AP , Rosendaal FR , Büller HR . A C1173T dimorphism in the VKORC1 gene determines coumarin sensitivity and bleeding risk . PLoS Med . 2005 ; 2 ( 10 ): e312 . 13. Thijssen HH , Drittij MJ , Vervoort LM , de Vries-Hanje JC . Altered pharmacokinetics of R- and S-acenocoumarol in a subject heterozygous for CYP2C9*3 . Clin Pharmacol Ther . 2001 ; 70 ( 3 ): 292 – 298 . 14. Vesell ES , Page JG . Genetic control of dicumarol levels in man . J Clin Invest . 1968 ; 47 ( 12 ): 2657 – 2663 . 15. Perlík F , Patzelová V . Pharmacokinetics of ethyl biscoumacetate and its metabolite 7-hydroxy ethyl biscoumacetate in healthy volunteers . Int J Clin Pharmacol Ther . 1994 ; 32 ( 11 ): 622 – 624 . 16. Jähnchen E , Meinertz T , Gilfrich HJ , Groth U , Martini A . The enantiomers of phenprocoumon: pharmacodynamic and pharmacokinetic studies . Clin Pharmacol Ther . 1976 ; 20 ( 3 ): 342 – 349 . 17. Kelly JG , O’Malley K . Clinical pharmacokinetics of oral anticoagulants . Clin Pharmacokinet . 1979 ; 4 ( 1 ): 1 – 15 . 18. Boettcher S , Wacker A , Moerike K , et al. Acquired coagulopathy caused by intoxication with the superwarfarin-type anticoagulant rodenticide flocoumafen . Eur J Haematol . 2011 ; 86 ( 2 ): 173 – 175 . 19. Burucoa C , Mura P , Robert R , Boinot C , Bouquet S , Piriou A . Chlorophacinone intoxication. A biological and toxicological study . J Toxicol Clin Toxicol . 1989 ; 27 ( 1-2 ): 79 – 89 . 20. Godbillon J , Richard J , Gerardin A , Meinertz T , Kasper W , Jähnchen E . Pharmacokinetics of the enantiomers of acenocoumarol in man . Br J Clin Pharmacol . 1981 ; 12 ( 5 ): 621 – 629 . 21. Bachmann KA , Sullivan TJ . Dispositional and pharmacodynamic characteristics of brodifacoum in warfarin-sensitive rats . Pharmacology . 1983 ; 27 ( 5 ): 281 – 288 . 22. Booth GS , Mody PZ . Brodifacoum inhalation and its clinical manifestations in a 21-Year-Old Caucasian man . Lab Med . 2016 ; 47 ( 1 ): 63 – 66 . 23. Hadler MR , Redfern R , Rowe FP . Laboratory evaluation of difenacoum as a rodenticide . J Hyg (Lond) . 1975 ; 74 ( 3 ): 441 – 448 . 24. Rieder MJ , Reiner AP , Gage BF , et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose . N Engl J Med . 2005 ; 352 ( 22 ): 2285 – 2293 . 25. Rost S , Fregin A , Ivaskevicius V , et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2 . Nature . 2004 ; 427 ( 6974 ): 537 – 541 . 26. Mowry JB , Spyker DA , Brooks DE , McMillan N , Schauben JL . 2014 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 32nd Annual Report . Clin Toxicol (Phila) . 2015 ; 53 ( 10 ): 962 – 1147 . 27. Babcock J , Hartman K , Pedersen A , Murphy M , Alving B . Rodenticide-induced coagulopathy in a young child. A case of Munchausen syndrome by proxy . Am J Pediatr Hematol Oncol . 1993 ; 15 ( 1 ): 126 – 130 . 28. Chong LL , Chau WK , Ho CH . A case of ‘superwarfarin’ poisoning . Scand J Haematol . 1986 ; 36 ( 3 ): 314 – 315 . 29. Haesloop O , Tillick A , Nichol G , Strote J . Superwarfarin ingestion treated successfully with prothrombin complex concentrate . Am J Emerg Med . 2016 ; 34 ( 1 ): 116.e111 – 116.e112 . 30. Jones EC , Growe GH , Naiman SC . Prolonged anticoagulation in rat poisoning . JAMA . 1984 ; 252 ( 21 ): 3005 – 3007 . 31. Lipton RA , Klass EM . Human ingestion of a ‘superwarfarin’ rodenticide resulting in a prolonged anticoagulant effect . JAMA . 1984 ; 252 ( 21 ): 3004 – 3005 . 32. Ball JR , Balogh E . Improving diagnosis in health care: highlights of a report from the National Academies of Sciences, Engineering, and Medicine . Ann Intern Med . 2016 ; 164 ( 1 ): 59 – 61 . Abbreviations MCV mean corpuscular volume MCHC mean cell hemoglobin concentration VKOR vitamin K epoxide reductase PT prothrombin PTT partial thromboplastin time INR international normalized ratio NA nonapplicable TT thrombin time © American Society for Clinical Pathology 2018. All rights reserved. For permissions, please e-mail: firstname.lastname@example.org This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
Laboratory Medicine – Oxford University Press
Published: Jan 22, 2018
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