Superwarfarin Poisoning

ORIGINAL INVESTIGATION Superwarfarin Poisoning Jimmy Dy Chua, MD; William R. Friedenberg, MD Background: Superwarfarin sodium exposure or poi- accidentally ingested superwarfarin or attempted sui- soning is a growing public health problem. There were 5133 cide using it were easily diagnosed, while diagnosis was reported cases of superwarfarin exposure and poisoning markedly delayed for the 2 patients with Munchausen in 1988 and 13 423 cases in 1995. Cases may be associ- syndrome. Full reversal of anticoagulation was quickly ated with accidental exposure, suicide attempts, or Mun- achieved in the cases of accidental ingestion and at- chausen syndrome, and may be difficult to diagnose. tempted suicide. We examined and treated the patients with Munchausen syndrome for months before estab- Patients and Methods: Patients from northern Wis- lishing a diagnosis and fully reversing the anticoagula- consin with superwarfarin exposure or poisoning were tion. None of the patients in our study died of superwar- examined at a tertiary referral center in rural Wisconsin farin poisoning. to determine what led to their exposure and to review the clinical manifestations, diagnosis, treatment, and pre- Conclusions: Superwarfarin exposure or poisoning is vention of superwarfarin poisoning. a growing public health problem that should be part of the differential diagnosis of patients who present with a Results: Eleven cases satisfied the criteria for superwar- coagulopathy consistent with vitamin K deficiency in the farin exposure or poisoning. All 7 children included in absence of coumadin therapy, liver disease, or the use of the study had accidentally ingested superwarfarin, 2 adults an inhibitor, and whose conditions do not resolve with had Munchausen syndrome, and 1 teenager and 1 adult large doses of parenteral vitamin K1 therapy. had attempted suicide using superwarfarin. Nine of the 11 cases had taken brodifacoum. The patients who had Arch Intern Med. 1998;158:1929-1932 UPERWARFARINS constitute a tamin K epoxide,3 the inactive form of class of rodenticides devel- vitamin K (Figure 1). Although the events oped in the 1970s to over- that lead to superwarfarin exposure or poi- come resistance to warfarin in soning are diverse, the cause is usually rats.1,2 They are popular and straightforward on admission. Some- Sreadily available in stores and homes. Su- times the diagnosis of superwarfarin poi- perwarfarins are long-acting, fat-soluble soning can be challenging. Multiple ad- anticoagulants with a terminal half-life of missions and evaluations6-9 are reported for at least 24.2 days and are 100 times more this disorder when it is a manifestation of potent than warfarin.3 Superwarfarins and Munchausen syndrome. warfarins concentrate in the liver on in- There have been no epidemiological gestion.4 There are 3 major groups of su- studies of patients with superwarfarin ex- perwarfarins: hydroxy coumarin deriva- posure or poisoning. We reviewed the re- tives with a 4-bromo(1-1 biphenyl) side cords of 11 patients found to have super- chain; coumatetryls; and indanediones. warfarin poisoning over 15 years. We also The most commonly used superwarfarin reviewed the literature on the causes, clini- is brodifacoum, a 4-hydroxy coumarin cal manifestations, diagnosis, treatment, and with a 4-bromo side chain sold as D-Con prevention of brodifacoum poisoning. (Reckitt & Colman, Montvale, NJ.)5 Su- perwarfarins inhibit the carboxylation of RESULTS From the Marshfield Clinic, vitamin K–dependent factors (II, VII, IX, Marshfield, Wis. Dr Chua is and X) in the liver. They specifically in- Eleven cases (7 children, 1 teenager, and now with the Cleveland Clinic hibit the vitamin K 2,3-epoxide reduc- 3 adults) satisfied the criteria of super- Foundation, Cleveland, Ohio. tase enzyme, leading to an increase in vi- warfarin exposure or poisoning. Seven pa- ARCH INTERN MED/ VOL 158, SEP 28, 1998 1929 ©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Vitamin K Metabolism SUBJECTS AND METHODS Epoxidase We reviewed all cases (128 charts) at Marshfield Clinic, Marshfield, Wis, with International Statistical Classi- fication of Diseases, 10th Revision (ICD-10)10 codes 989.4 (toxic effects of other pesticides), including E codes E863.7 (accidental poisoning–rodenticide), E950.6 (suicide-agricultural agent), E962.1 (assault Vitamin K Liver Microsomes poisoning with solid/liquid), and E980.7 (undeter- Vitamin K mined poisoning with agricultural agent), and code Epoxide 286.7 (acquired coagulation factor deficiency) from January 1, 1979, to March 31, 1996. Exposure was defined as any history of oral intake or inhalation of superwarfarin, or superficial con- tact with a superwarfarin near the oral mucosa with- out any biochemical or clinical manifestations of coagulopathy. Reductase (Superwarfarin Blocks) Poisoning was defined by exposure to superwarfarin plus clinical and biochemical changes consis- Figure 1. Vitamin K is converted to vitamin K epoxide (inactive) in the liver. tent with coagulopathy, including an elevated pro- Brodifacoum (a superwarfarin) interferes with vitamin K metabolism by thrombin time (PT), an elevated activated partial inhibiting the 2,3-epoxide reductase enzyme, which increases levels of vitamin K epoxide (inactive vitamin K) and inhibits the synthesis of active thromboplastin time (APTT), an increase in the vi- factors II, VII, IX, and X. tamin K epoxide–vitamin K1 ratio, or depressed levels of vitamin K–dependent coagulation factors (II, VII, IX, and X) with the presence of superwarfarin in tient’s plasma and normal plasma at a ratio of 1:1 cor- the blood. The definitions of exposure and poison- rected the PT to normal. The patient’s plasma was negative ing were established before the epidemiological data for warfarin. His vitamin K epoxide level (following high- were collected. dose vitamin K1 therapy) was 50.2 ng/mL (reference range, ,0.05 ng/mL) and his phylloquinone level (reduced vitamin K) was 9.5 ng/mL (reference range, 0.1-1.0 ng/ mL). The results of his initial screening for superwarfa- tients were male and 4 were female. There were 3 major rins were negative. Subsequently, a specific assay for brodi- categories of exposure or poisoning: accidental inges- facoum revealed a concentration of 78 ng/mL. After the tion (in children), attempted suicide, and deliberate self- patient was confronted with this finding and a possible poisoning with denial (Munchausen syndrome). police investigation, he admitted to taking a handful of All the children in our study were individuals brodifacoum (Talon). The patient received large doses of younger than 6 years who had accidentally ingested parenteral vitamin K1 in addition to fresh frozen plasma superwarfarin. None of the children had documented to reverse his coagulopathy as soon as the initial coagu- elevated PTs, clinical signs of coagulopathy, or compli- lation levels were reported. He was discharged after 11 days cations. One child received 5 mg of vitamin K subcuta- in the hospital, requiring 5 months of outpatient fol- neously, and 5 children received syrup of ipecac. Test re- low-up by a home health nurse and 20 weekly doses of sults showed no PT abnormalities in any of the children subcutaneous vitamin K1 (410 mg) before the coagulopa- on follow-up more than 48 hours after treatment. There thy resolved. Although he had been instructed to take oral was no morbidity or mortality reported in this group over vitamin K1, it was discovered that he never had the pre- many years of follow-up. scription filled. The patient underwent psychiatric evalu- The second group, patients who attempted suicide, ation but refused follow-up visits. included 1 teenager and 1 adult. The teenager presented The second patient, a 50-year-old woman, was ad- with some bruising and a slightly elevated PT with an in- mitted because of easy bruising and a subungual hema- ternational normalized ratio of 1.3. She was sent home and toma. Laboratory studies yielded the following values: PT, found to be normal on follow-up 3 days later with no clini- 39.6 seconds; APTT, 108.2 seconds; factor VII, 7%; and cal signs of coagulopathy. The man who had attempted factor IX, less than 2%. Mixing studies performed as de- suicide had an initial PT of 11.7 seconds and no coagu- scribed earlier corrected the PT to normal. The patient’s lopathy during his 4-day stay. The final outcome of this plasma was negative for warfarin; however, she was found patient was unknown since he was transferred to another to have a brodifacoum level of 310 ng/mL. As a result, she institution on his fourth day at the hospital. was given large doses of parenteral vitamin K1 as well as The third group of patients included those with Mun- fresh-frozen plasma to reverse her coagulopathy, which chausen syndrome. The first patient was a 44-year-old di- resolved after 11 months of outpatient treatment. The treat- vorced man who was admitted with multiple ecchymosis ment included prolonged intake of oral vitamin K and nu- and gross hematuria. Laboratory studies yielded the fol- merous emergency department and clinic visits for fresh- lowing values: PT, greater than 90 seconds; APTT, greater frozen plasma transfusions and parenteral vitamin K1. The than 160 seconds; international normalized ratio, 60.8; fac- patient was suspected of continuing to ingest brodi- tor VII, 1%; and factor X, 4%. Mixing studies with the pa- facoum, but she refused psychiatric referral. ARCH INTERN MED/ VOL 158, SEP 28, 1998 1930 ©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 18,30,34 14 000 orrhage. Sixteen of the 24 reported cases presented with hematuria. Ecchymosis was present in 6 of 12 000 the 24 cases. Workup of brodifacoum poisoning is not a problem in cases of acute poisoning but may be challenging in patients with suspected Munchausen syn- 10 000 drome.

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