CASE REPORTS Brodifacoum exposure
CASE REPORTS
Prolonged coagulopathy after brodifacoum exposure Elizabeth L. Underwood, JoLeigh Sutton, Ira Keith Ellis, Brian Qualls, Jon Zamber, and Brian N. Walker
E
pisodes of human poisoning by a long-acting anticoagulant rodenticide (LAAR) have been reported in the literature for over 30 years.1 LAAR exposures continue to be a growing health concern, with greater than 10,000 exposures reported in 2010.2 These LAAR compounds, coined “superwarfarins,” include bromadiolone, difenacoum, diphacinone, chlorophacinone, and brodifacoum and were developed in response to warfarin resistance in the rat population during the 1970s.3 Brodifacoum is the most common active ingredient in commercially available rodenticides in the United States and may be purchased in numerous retail settings for agricultural, urban, and household uses.3-5 Brodifacoum toxicity may lead to significant morbidity and mortality due to its 100-fold increase in potency over warfarin, prolonged half-life, and extended inhibition of vitamin K 2,3-epoxide reductase.4,6-9 Toxicity occurs via ingestion, inhalation, or topical exposure to brodifacoum, with 95% of cases being ingestion related.3 Most exposures are accidental and involve children younger than 12 years.2,3 Intentional overdose is found primarily in adults as suicide or
Purpose. A case of brodifacoum exposure leading to coagulopathy lasting for approximately one year despite treatment with large doses of phytonadione is reported. Summary. 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
homicide attempts, with an increasing subset of exposures via “lacing” drugs of abuse to prolong euphoric effects. 3,10 A diagnosis of toxicity can be challenging and is generally made only after documentation of an elevated International Normalized Ratio (INR) and the presence of bleeding.
Elizabeth L. Underwood, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Ambulatory Care; and JoLeigh Sutton, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Internal Medicine, Jackson–Madison County General Hospital, Jackson, TN. Ira Keith Ellis, M.D., is Assistant Professor, Family Medicine; Brian Qualls, M.D., is Resident, Family Medicine; and Jon Zamber, M.D., is Resident, Family Medicine, University of Tennessee Health Science Center, Jackson. Brian N. Walker, D.O., is Medical Oncologist, Hematology and Oncology, Cancer Care Center, Jackson.
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. Conclusion. 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. Am J Health-Syst Pharm. 2014; 71:639-42
General treatment of superwar farin coagulopathy has been reported to include phytonadione therapy, blood transfusions, and fresh frozen plasma (FFP).3 Currently, minimal guidance is available for the management of brodifacoum coagulopathy, and published case reports provide differing views on the appropriate
Address correspondence to Dr. Underwood (lizunderwood12@ gmail.com). The authors have declared no potential conflicts of interest. Copyright © 2014, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/14/0402-0639$06.00. DOI 10.2146/ajhp130537
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method to determine treatment endpoint.8,11,12 Monitoring of coagulation values and brodifacoum levels has been reported in the literature as possible methods to adjust phytonadione therapy to attain resolution of coagulopathy. Treatment with oral phytonadione therapy is prolonged and may become a financial burden and lead to compliance dilemmas for both the patient and the provider. We describe the case of a patient who developed long-term coagulopathy after an unknown exposure to the vitamin K antagonist (VKA) brodifacoum. The persistence of the patient’s coagulopathy for over one year despite repeated undetectable brodifacoum levels led to the identification of the case. Case report A 36-year-old African-American man arrived at an outside health care facility with low back pain, hematuria, hematemesis, and melena. He reported no known allergies and a medical history significant for an accidental gunshot wound to the chest 4 years prior. He reported smoking three packs of cigarettes daily and inconsistently described his alcohol consumption as ranging from 2 beers to a 12-pack of beer daily for 4 years. Illicit drug abuse was denied by the patient, but he admitted having contact with people who smoke marijuana. The patient’s height and weight were 180 cm and 83 kg, respectively. The only outpatient medication he reported using was ibuprofen to relieve back pain. The patient’s vital signs on admission included a temperature of 97.8 °F, blood pressure of 185/102 mm Hg, and heart rate of 90 beats/min. Initial laboratory test results included an INR of >9 (normal, 0.9–1.1), a partial thromboplastin time of 102 seconds (normal, 23–33 seconds), a prothrombin time (PT) of >130 seconds (normal, 9.5–11.9 seconds), a platelet count of 235,000 platelets/ mL (normal, 140,000–450,000 plate640
lets/mL), a hemoglobin concentration of 11.6 g/dL (normal, 13–18 g/ dL), a hematocrit of 31.8% (normal, 39–55%), a serum ferritin concentration of 197 ng/mL (normal, 17.9–464 ng/mL), a serum iron saturation level of 5.2% (normal, 11–40%), a serum iron-binding capacity of 271 mg/dL (normal, 261–462 mg/dL), a plasma fibrinogen concentration of 474 mg/dL (normal, 200–424 mg/dL), a serum albumin concentration of 3.3 g/dL (normal, 3.5–4.8 g/dL), and a serum creatinine concentration of 2.3 mg/dL (normal, 0.66–1.25 mg/dL). The direct antiglobulin test result was negative, his liver function test results were within normal limits, and a drug screen detected the presence of opioids. An initial computed tomography (CT) scan without contrast revealed bilateral perinephric hematomas and a retroperitoneal hematoma with a small-to-moderate degree of ascites and associated hemoperitoneum. A CT scan with contrast was performed 12 hours later and confirmed bilateral perinephric hematomas and hemoperitoneum. The original differential diagnosis included disseminated intravascular coagulation, vitamin K deficiency, and alcohol abuse with possible liver damage leading to coagulopathy. During his hospital stay, the patient received 6 units of FFP, 10 units of cryoprecipitate, and 2 units of packed red blood cells, as well as a hematology evaluation. The patient improved with 40 mg of phytonadione orally daily and was discharged after a five-day stay without a firm diagnosis but with no evidence of bleeding and an INR that remained less than 2 while he was receiving phytonadione. Other discharge medications included hydralazine hydrochloride 50 mg three times orally daily for newly diagnosed hypertension and thiamine 100 mg orally daily. The laboratory test results from the full coagulopathy panel were still pending at the time of discharge.
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One week later, the patient was admitted to our facility for phytonadione dosage adjustment and to meet with social services to receive financial assistance with obtaining outpatient oral phytonadione therapy. This was subsequent to a follow-up clinic visit during which the patient’s INR was 5.9. The patient denied ingestion of any VKA or knowledge of a poisoning attempt and reported compliance with his home phytonadione regimen of 40 mg orally daily. The phytonadione dosage was increased to 80 mg orally daily, and 2 units of FFP were given to help correct the continued coagulopathy. The patient continued to have low levels of vitamin K-dependent coagulation factors, including factor II at 24% of normal activity (normal, 75–145%), factor IX at 8% (normal, 65–140%), factor VII at less than 1% (normal, 65–180%), and factor X at 17% (normal, 70–150%), while factor V, factor VIII, and fibrinogen were all within normal limits. The patient experienced no bleeding events during this three-day hospitalization. Financial concerns led to social services assisting the patient in successfully filing for indigent coverage of the oral phytonadione therapy. The patient was discharged with a one-week supply of medication funded by a hospital charitable foundation program. The cause of the coagulopathy remained unknown at discharge, but the hematologist theorized that exposure to a VKA was likely the source of the patient’s condition. During outpatient follow-up at the hematology clinic, the patient’s INR was elevated (1.6–2.3) while receiving phytonadione 80 mg orally daily during the two months after his most recent hospitalization. Results of the original coagulopathy panel returned negative results for the presence of lupus anticoagulant, for the dilute Russell’s viper venom time, and for anticardiolipin antibody. The qualitative serum–plasma brodifacoum analysis performed using high-performance
CASE REPORTS Brodifacoum exposure
liquid chromatography–mass spectrometry was positive, with a level of detection of 10 ng/mL (Quest Diagnostics, Madison, NJ). This confirmed the presence of brodifacoum, though the method of exposure remained unclear. During a visit to the hematology clinic seven months later, the patient reported taking various dosages of oral phytonadione over the past several months but said that he was currently taking 10 mg orally daily. Testing revealed a normal INR of 1.0, and phytonadione therapy was discontinued. Two months later, the patient reported for a repeat INR evaluation and was found to have an INR of >9 and a PT of >93.5 seconds. Oral phytonadione 10 mg daily was prescribed, but the patient came to the hospital one week later without having resumed therapy. During this repeat arrival and subsequent readmission to our hospital, approximately one year after the initial suspicion of brodifacoum coagulopathy, we found continued coagulopathy with an undetectable brodifacoum concentration of 69 seconds, an INR of >9, and a urine drug screen that detected the presence of opioids. The patient’s unemployed status and transportation issues were identified as the primary causes of his inconsistent follow-up over the previous year. The patient was admitted to the intensive care unit and given phytonadione 20 mg i.v. three times daily. The empirical diagnosis of peritonsillar abscess was reconsidered after
his INR value was found to be more than 9. An otolaryngology consultation was obtained due to concerns over possible airway compromise. A radiograph of the neck’s soft tissue revealed a right oropharyngeal hematoma with preserved airway and hemorrhagic right tonsil and uvula. Oral rinses with 0.9% sodium chloride solution were prescribed with no indication for drainage of the oral hematoma. The calf hematoma was found to be stable, and a small hematoma present on the patient’s forearm was also noted with bruising but no active bleeding. Correction of the patient’s coagulopathy was achieved with 2 units of FFP along with continuation of i.v. phytonadione. After a two-day hospital stay, the patient had an INR of 1.2 and a PT of 15 seconds and was considered stable for discharge. Due to reported financial hardship, social services was consulted and an application was successfully filed to acquire the large doses of oral daily phytonadione as an outpatient. The hematology recommendation included continuation of outpatient oral phytonadione 40 mg daily, cessation of all alcohol and illicit drug consumption, and follow-up in the hematology clinic for INR evaluation. Discussion Previous published reports have documented a wide range of phytonadione dosages, routes of administration, and durations of therapy as defined by varying endpoints for the treatment of LAAR coagulopathy.1,7-12 In the limited number of reports that have described the outpatient treatment of prolonged coagulopathy, few reports detailed continued administration of oral phytonadione for longer than one year.7,8,13 In this report, we describe both the acute hospital management and long-term outpatient treatment of brodifacoum-induced coagulopathy, which persisted for over one year. In addition, our patient’s financial
burdens and inconsistent follow-up were found to be barriers to medication adherence. According to the National Poison Data System (NPDS), 10,227 exposures to LAARs occurred in 2010: 9,271 in children, 925 in adults, and 31 in patients of an unknown age.2 In 1985, NPDS reported 5,098 LAAR exposures, highlighting the increasingly relevant problem of LAAR exposure and the need for an evidencebased approach to the treatment of toxicity. Brodifacoum is the most commonly used LAAR in commercially available rodenticides in the United States. LAARs are VKAs reported to be 100-fold more potent than warfarin.3,4,6-9 VKAs inhibit vitamin K 2,3-epoxide reductase, preventing carboxylation of the vitamin K-dependent coagulation factors II, VII, IX, and X into their active, procoagulant form.14 Brodifacoum has a half-life of up to 69 days, which may lead to prolonged inhibition of vitamin K-dependent coagulation factors.10 A pharmacodynamic study in rats suggested that slower systemic clearance is possibly related to enterohepatic cycling of brodifacoum and a volume of distribution approximately six times greater than that of warfarin, with sustained high concentrations in the liver.6 LAAR exposures have been described in the literature for the past several decades to be an increasing public health concern.1 Toxicity is most commonly the result of accidental ingestion in pediatric patients, selfadministration due to Munchausen syndrome, or attempted suicide.15 Possible intentional poisoning by others, industrial exposure, and ingestion due to the lacing of street drugs have also been noted.3,7,10,16 Of the 10,227 LAAR exposures reported in 2010, 9,796 were unintentional, and 331 were intentional; the reasons for 78 exposures were classified as “other.”2 The details of exposure in our patient were never identified.
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CASE REPORTS Brodifacoum exposure
Typical manifestations of toxicity vary and can range from a relatively asymptomatic presentation, through various degrees of bleeding, to death.3,7-13,16 Diffuse ecchymoses, concentrated petechial hemorrhages, and multiple crusted abrasions and hemorrhagic lesions may be found during autopsy.4 Manifestations of minor bleeding have been reported to include easy or spontaneous bruising, bleeding oral mucosa, ecchymoses, and epistaxis. Symptoms of major bleeding have been reported to include hematuria, hematoma with and without compartment syndrome, conjunctival hemorrhage, melena, hematemesis, and menorrhagia.3,7-13,16 Treatment of acute bleeding with parenteral phytonadione and FFP followed by long-term treatment with oral phytonadione seems to have been effective in a number of patients exposed to an LAAR.3,4,7-13,16 For patients with serious bleeding, i.v. administration is preferred, with monitoring for anaphylaxis. For long-term treatment, the oral route of administration is preferred given the risk of hematoma and the potential requirement for intramuscular administration of a large-volume injection of higher doses.10 Long-term oral phytonadione therapy is often tapered over weeks to months based on coagulation parameters such as INR and PT, as was done in this case. Once therapy is discontinued, coagulation parameters are often reassessed. Olmos and López.11 suggested that this coagulation parameterbased strategy places patients at risk of recurrent bleeding if the LAAR is still circulating in the bloodstream and that a more appropriate strategy would include periodic measurement of brodifacoum levels until they are within normal limits. Interestingly, two weeks after discontinuing oral therapy based on normalized coagulation parameters and approximately one year after the initial diagnosis of brodifacoum 642
exposure, our patient demonstrated continued coagulopathy, with a PT of more than 69 seconds and an INR of more than 9 despite the fact that the brodifacoum level was undetectable after a repeat assessment. The reason for this observation is unknown. We theorize this may have been due to the pharmacodynamic property of brodifacoum to undergo enterohepatic cycling and concentrate in the liver or potential ongoing or repeated occult exposures since the original diagnosis.6 Oral phytonadione is available most commonly as 0.1-mg generic tablets or 5-mg brand-name tablets and is relatively inexpensive at usual doses indicated in warfarin reversal. The cost of our patient’s dosage (up to 80 mg orally per day, or 16 5-mg tablets) became a significant issue. The patient reported an average cost of approximately $500 per month solely for phytonadione therapy before financial assistance was obtained. This report highlights the need for clinicians to include LAARs in the differential diagnosis of patients with coagulopathy and deficiency of vitamin K-dependent coagulation factors. Toxicity can occur due to intentional or unintentional exposure or without known exposure to an LAAR, as was the case with our patient. Treatment of acute bleeding should include high-dose i.v. phytonadione and often must be followed by long-term therapy with large doses of oral phytonadione. Conclusion A patient with brodifacoum exposure 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.
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References 1. Barlow AM, Gay AL, Park BK. Difenacoum (Neosorexa) poisoning. Br Med J. 1982; 285:541. 2. Bronstein AC, Spyker DA, Cantilena LR et al. 2010 annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 28th annual report. Clin Toxicol. 2011; 49:910-41. 3. 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. 2007; 45:1-22. 4. Palmer RB, Alakija P, de Baca JE et al. Fatal brodifacoum rodenticide poisoning: autopsy and toxicologic findings. J Forensic Sci. 1999; 44:851-5. 5. Pesticide Action Network North America. Toxicity information for brodifacoum. www.pesticideinfo.org (accessed 2012 Sep 20). 6. Bachmann KA, Sullivan TJ. Dispositional and pharmacodynamic characteristics of brodifacoum in warfarin-sensitive rats. Pharmacology. 1983; 27:281-8. 7. Park BK, Choonara IA, Haynes BP et al. Abnormal vitamin K metabolism in the presence of normal clotting factor activity in factory workers exposed to 4hydroxycoumarins. Br J Clin Pharmacol. 1986; 21:289-93. 8. Hong J, Yhim HY, Bang SM et al. Korean patients with superwarfarin intoxication and their outcome. J Korean Med Sci. 2010; 25:1754-8. 9. Nelson AT, Hartzell JD, More K et al. Ingestion of superwarfarin leading to coagulopathy: a case report and review of the literature. MedGenMed. 2006; 8:41. 10. Spahr JE, Maul JS, Rodgers GM. Superwarfarin poisoning: a report of two cases and review of the literature. Am J Hematol. 2007; 82:656-60. 11. Olmos V, López CM. Brodifacoum poisoning with toxicokinetic data. Clin Toxicol. 2007; 45:487-9. 12. Bruno GR, Howland MA, McMeeking A et al. Long-acting anticoagulant overdose: brodifacoum kinetics and optimal vitamin K dosing. Ann Emerg Med. 2000; 36:262-7. 13. 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; 76:2555-9. 14. Ageno W, Gallus AS, Wittkowsky A et al. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012; 141(suppl):e44S88S. 15. Chua JD, Friedenberg WR. Superwarfarin poisoning. Arch Intern Med. 1998; 158:1929-32. 16. Dolin EK, Baker DL, Buck SC. A 44-yearold woman with hematemesis and cutaneous hemorrhages as a result of superwarfarin poisoning. J Am Osteopath Assoc. 2006; 106:280-4.
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CASE REPORTS
Prolonged coagulopathy after brodifacoum exposure Elizabeth L. Underwood, JoLeigh Sutton, Ira Keith Ellis, Brian Qualls, Jon Zamber, and Brian N. Walker
E
pisodes of human poisoning by a long-acting anticoagulant rodenticide (LAAR) have been reported in the literature for over 30 years.1 LAAR exposures continue to be a growing health concern, with greater than 10,000 exposures reported in 2010.2 These LAAR compounds, coined “superwarfarins,” include bromadiolone, difenacoum, diphacinone, chlorophacinone, and brodifacoum and were developed in response to warfarin resistance in the rat population during the 1970s.3 Brodifacoum is the most common active ingredient in commercially available rodenticides in the United States and may be purchased in numerous retail settings for agricultural, urban, and household uses.3-5 Brodifacoum toxicity may lead to significant morbidity and mortality due to its 100-fold increase in potency over warfarin, prolonged half-life, and extended inhibition of vitamin K 2,3-epoxide reductase.4,6-9 Toxicity occurs via ingestion, inhalation, or topical exposure to brodifacoum, with 95% of cases being ingestion related.3 Most exposures are accidental and involve children younger than 12 years.2,3 Intentional overdose is found primarily in adults as suicide or
Purpose. A case of brodifacoum exposure leading to coagulopathy lasting for approximately one year despite treatment with large doses of phytonadione is reported. Summary. 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
homicide attempts, with an increasing subset of exposures via “lacing” drugs of abuse to prolong euphoric effects. 3,10 A diagnosis of toxicity can be challenging and is generally made only after documentation of an elevated International Normalized Ratio (INR) and the presence of bleeding.
Elizabeth L. Underwood, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Ambulatory Care; and JoLeigh Sutton, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Internal Medicine, Jackson–Madison County General Hospital, Jackson, TN. Ira Keith Ellis, M.D., is Assistant Professor, Family Medicine; Brian Qualls, M.D., is Resident, Family Medicine; and Jon Zamber, M.D., is Resident, Family Medicine, University of Tennessee Health Science Center, Jackson. Brian N. Walker, D.O., is Medical Oncologist, Hematology and Oncology, Cancer Care Center, Jackson.
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. Conclusion. 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. Am J Health-Syst Pharm. 2014; 71:639-42
General treatment of superwar farin coagulopathy has been reported to include phytonadione therapy, blood transfusions, and fresh frozen plasma (FFP).3 Currently, minimal guidance is available for the management of brodifacoum coagulopathy, and published case reports provide differing views on the appropriate
Address correspondence to Dr. Underwood (lizunderwood12@ gmail.com). The authors have declared no potential conflicts of interest. Copyright © 2014, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/14/0402-0639$06.00. DOI 10.2146/ajhp130537
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CASE REPORTS Brodifacoum exposure
method to determine treatment endpoint.8,11,12 Monitoring of coagulation values and brodifacoum levels has been reported in the literature as possible methods to adjust phytonadione therapy to attain resolution of coagulopathy. Treatment with oral phytonadione therapy is prolonged and may become a financial burden and lead to compliance dilemmas for both the patient and the provider. We describe the case of a patient who developed long-term coagulopathy after an unknown exposure to the vitamin K antagonist (VKA) brodifacoum. The persistence of the patient’s coagulopathy for over one year despite repeated undetectable brodifacoum levels led to the identification of the case. Case report A 36-year-old African-American man arrived at an outside health care facility with low back pain, hematuria, hematemesis, and melena. He reported no known allergies and a medical history significant for an accidental gunshot wound to the chest 4 years prior. He reported smoking three packs of cigarettes daily and inconsistently described his alcohol consumption as ranging from 2 beers to a 12-pack of beer daily for 4 years. Illicit drug abuse was denied by the patient, but he admitted having contact with people who smoke marijuana. The patient’s height and weight were 180 cm and 83 kg, respectively. The only outpatient medication he reported using was ibuprofen to relieve back pain. The patient’s vital signs on admission included a temperature of 97.8 °F, blood pressure of 185/102 mm Hg, and heart rate of 90 beats/min. Initial laboratory test results included an INR of >9 (normal, 0.9–1.1), a partial thromboplastin time of 102 seconds (normal, 23–33 seconds), a prothrombin time (PT) of >130 seconds (normal, 9.5–11.9 seconds), a platelet count of 235,000 platelets/ mL (normal, 140,000–450,000 plate640
lets/mL), a hemoglobin concentration of 11.6 g/dL (normal, 13–18 g/ dL), a hematocrit of 31.8% (normal, 39–55%), a serum ferritin concentration of 197 ng/mL (normal, 17.9–464 ng/mL), a serum iron saturation level of 5.2% (normal, 11–40%), a serum iron-binding capacity of 271 mg/dL (normal, 261–462 mg/dL), a plasma fibrinogen concentration of 474 mg/dL (normal, 200–424 mg/dL), a serum albumin concentration of 3.3 g/dL (normal, 3.5–4.8 g/dL), and a serum creatinine concentration of 2.3 mg/dL (normal, 0.66–1.25 mg/dL). The direct antiglobulin test result was negative, his liver function test results were within normal limits, and a drug screen detected the presence of opioids. An initial computed tomography (CT) scan without contrast revealed bilateral perinephric hematomas and a retroperitoneal hematoma with a small-to-moderate degree of ascites and associated hemoperitoneum. A CT scan with contrast was performed 12 hours later and confirmed bilateral perinephric hematomas and hemoperitoneum. The original differential diagnosis included disseminated intravascular coagulation, vitamin K deficiency, and alcohol abuse with possible liver damage leading to coagulopathy. During his hospital stay, the patient received 6 units of FFP, 10 units of cryoprecipitate, and 2 units of packed red blood cells, as well as a hematology evaluation. The patient improved with 40 mg of phytonadione orally daily and was discharged after a five-day stay without a firm diagnosis but with no evidence of bleeding and an INR that remained less than 2 while he was receiving phytonadione. Other discharge medications included hydralazine hydrochloride 50 mg three times orally daily for newly diagnosed hypertension and thiamine 100 mg orally daily. The laboratory test results from the full coagulopathy panel were still pending at the time of discharge.
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One week later, the patient was admitted to our facility for phytonadione dosage adjustment and to meet with social services to receive financial assistance with obtaining outpatient oral phytonadione therapy. This was subsequent to a follow-up clinic visit during which the patient’s INR was 5.9. The patient denied ingestion of any VKA or knowledge of a poisoning attempt and reported compliance with his home phytonadione regimen of 40 mg orally daily. The phytonadione dosage was increased to 80 mg orally daily, and 2 units of FFP were given to help correct the continued coagulopathy. The patient continued to have low levels of vitamin K-dependent coagulation factors, including factor II at 24% of normal activity (normal, 75–145%), factor IX at 8% (normal, 65–140%), factor VII at less than 1% (normal, 65–180%), and factor X at 17% (normal, 70–150%), while factor V, factor VIII, and fibrinogen were all within normal limits. The patient experienced no bleeding events during this three-day hospitalization. Financial concerns led to social services assisting the patient in successfully filing for indigent coverage of the oral phytonadione therapy. The patient was discharged with a one-week supply of medication funded by a hospital charitable foundation program. The cause of the coagulopathy remained unknown at discharge, but the hematologist theorized that exposure to a VKA was likely the source of the patient’s condition. During outpatient follow-up at the hematology clinic, the patient’s INR was elevated (1.6–2.3) while receiving phytonadione 80 mg orally daily during the two months after his most recent hospitalization. Results of the original coagulopathy panel returned negative results for the presence of lupus anticoagulant, for the dilute Russell’s viper venom time, and for anticardiolipin antibody. The qualitative serum–plasma brodifacoum analysis performed using high-performance
CASE REPORTS Brodifacoum exposure
liquid chromatography–mass spectrometry was positive, with a level of detection of 10 ng/mL (Quest Diagnostics, Madison, NJ). This confirmed the presence of brodifacoum, though the method of exposure remained unclear. During a visit to the hematology clinic seven months later, the patient reported taking various dosages of oral phytonadione over the past several months but said that he was currently taking 10 mg orally daily. Testing revealed a normal INR of 1.0, and phytonadione therapy was discontinued. Two months later, the patient reported for a repeat INR evaluation and was found to have an INR of >9 and a PT of >93.5 seconds. Oral phytonadione 10 mg daily was prescribed, but the patient came to the hospital one week later without having resumed therapy. During this repeat arrival and subsequent readmission to our hospital, approximately one year after the initial suspicion of brodifacoum coagulopathy, we found continued coagulopathy with an undetectable brodifacoum concentration of 69 seconds, an INR of >9, and a urine drug screen that detected the presence of opioids. The patient’s unemployed status and transportation issues were identified as the primary causes of his inconsistent follow-up over the previous year. The patient was admitted to the intensive care unit and given phytonadione 20 mg i.v. three times daily. The empirical diagnosis of peritonsillar abscess was reconsidered after
his INR value was found to be more than 9. An otolaryngology consultation was obtained due to concerns over possible airway compromise. A radiograph of the neck’s soft tissue revealed a right oropharyngeal hematoma with preserved airway and hemorrhagic right tonsil and uvula. Oral rinses with 0.9% sodium chloride solution were prescribed with no indication for drainage of the oral hematoma. The calf hematoma was found to be stable, and a small hematoma present on the patient’s forearm was also noted with bruising but no active bleeding. Correction of the patient’s coagulopathy was achieved with 2 units of FFP along with continuation of i.v. phytonadione. After a two-day hospital stay, the patient had an INR of 1.2 and a PT of 15 seconds and was considered stable for discharge. Due to reported financial hardship, social services was consulted and an application was successfully filed to acquire the large doses of oral daily phytonadione as an outpatient. The hematology recommendation included continuation of outpatient oral phytonadione 40 mg daily, cessation of all alcohol and illicit drug consumption, and follow-up in the hematology clinic for INR evaluation. Discussion Previous published reports have documented a wide range of phytonadione dosages, routes of administration, and durations of therapy as defined by varying endpoints for the treatment of LAAR coagulopathy.1,7-12 In the limited number of reports that have described the outpatient treatment of prolonged coagulopathy, few reports detailed continued administration of oral phytonadione for longer than one year.7,8,13 In this report, we describe both the acute hospital management and long-term outpatient treatment of brodifacoum-induced coagulopathy, which persisted for over one year. In addition, our patient’s financial
burdens and inconsistent follow-up were found to be barriers to medication adherence. According to the National Poison Data System (NPDS), 10,227 exposures to LAARs occurred in 2010: 9,271 in children, 925 in adults, and 31 in patients of an unknown age.2 In 1985, NPDS reported 5,098 LAAR exposures, highlighting the increasingly relevant problem of LAAR exposure and the need for an evidencebased approach to the treatment of toxicity. Brodifacoum is the most commonly used LAAR in commercially available rodenticides in the United States. LAARs are VKAs reported to be 100-fold more potent than warfarin.3,4,6-9 VKAs inhibit vitamin K 2,3-epoxide reductase, preventing carboxylation of the vitamin K-dependent coagulation factors II, VII, IX, and X into their active, procoagulant form.14 Brodifacoum has a half-life of up to 69 days, which may lead to prolonged inhibition of vitamin K-dependent coagulation factors.10 A pharmacodynamic study in rats suggested that slower systemic clearance is possibly related to enterohepatic cycling of brodifacoum and a volume of distribution approximately six times greater than that of warfarin, with sustained high concentrations in the liver.6 LAAR exposures have been described in the literature for the past several decades to be an increasing public health concern.1 Toxicity is most commonly the result of accidental ingestion in pediatric patients, selfadministration due to Munchausen syndrome, or attempted suicide.15 Possible intentional poisoning by others, industrial exposure, and ingestion due to the lacing of street drugs have also been noted.3,7,10,16 Of the 10,227 LAAR exposures reported in 2010, 9,796 were unintentional, and 331 were intentional; the reasons for 78 exposures were classified as “other.”2 The details of exposure in our patient were never identified.
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CASE REPORTS Brodifacoum exposure
Typical manifestations of toxicity vary and can range from a relatively asymptomatic presentation, through various degrees of bleeding, to death.3,7-13,16 Diffuse ecchymoses, concentrated petechial hemorrhages, and multiple crusted abrasions and hemorrhagic lesions may be found during autopsy.4 Manifestations of minor bleeding have been reported to include easy or spontaneous bruising, bleeding oral mucosa, ecchymoses, and epistaxis. Symptoms of major bleeding have been reported to include hematuria, hematoma with and without compartment syndrome, conjunctival hemorrhage, melena, hematemesis, and menorrhagia.3,7-13,16 Treatment of acute bleeding with parenteral phytonadione and FFP followed by long-term treatment with oral phytonadione seems to have been effective in a number of patients exposed to an LAAR.3,4,7-13,16 For patients with serious bleeding, i.v. administration is preferred, with monitoring for anaphylaxis. For long-term treatment, the oral route of administration is preferred given the risk of hematoma and the potential requirement for intramuscular administration of a large-volume injection of higher doses.10 Long-term oral phytonadione therapy is often tapered over weeks to months based on coagulation parameters such as INR and PT, as was done in this case. Once therapy is discontinued, coagulation parameters are often reassessed. Olmos and López.11 suggested that this coagulation parameterbased strategy places patients at risk of recurrent bleeding if the LAAR is still circulating in the bloodstream and that a more appropriate strategy would include periodic measurement of brodifacoum levels until they are within normal limits. Interestingly, two weeks after discontinuing oral therapy based on normalized coagulation parameters and approximately one year after the initial diagnosis of brodifacoum 642
exposure, our patient demonstrated continued coagulopathy, with a PT of more than 69 seconds and an INR of more than 9 despite the fact that the brodifacoum level was undetectable after a repeat assessment. The reason for this observation is unknown. We theorize this may have been due to the pharmacodynamic property of brodifacoum to undergo enterohepatic cycling and concentrate in the liver or potential ongoing or repeated occult exposures since the original diagnosis.6 Oral phytonadione is available most commonly as 0.1-mg generic tablets or 5-mg brand-name tablets and is relatively inexpensive at usual doses indicated in warfarin reversal. The cost of our patient’s dosage (up to 80 mg orally per day, or 16 5-mg tablets) became a significant issue. The patient reported an average cost of approximately $500 per month solely for phytonadione therapy before financial assistance was obtained. This report highlights the need for clinicians to include LAARs in the differential diagnosis of patients with coagulopathy and deficiency of vitamin K-dependent coagulation factors. Toxicity can occur due to intentional or unintentional exposure or without known exposure to an LAAR, as was the case with our patient. Treatment of acute bleeding should include high-dose i.v. phytonadione and often must be followed by long-term therapy with large doses of oral phytonadione. Conclusion A patient with brodifacoum exposure 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.
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