The Case Files (2013)

A 49-year-old woman presented to our facility as a transfer from an outside hospital with recurrent hematochezia, hematemesis, epistaxis, and ostomy bleeding. Her past medical history was significant for uterine cancer with metastasis to her colon, status post-radiation therapy, and total abdominal hysterectomy approximately three years earlier. She had developed lower gastrointestinal bleeding resulting in diverting colostomy thought to be secondary to radiation proctitis.FigureThe patient reported that she began to develop symptoms five days before presentation to the transferring facility, and staff there noted that she had blood in her ostomy bag and an INR of 16.7; other lab results were PTT 130 sec, PT 163 sec, hemoglobin 7.3 gm/dL, and hematocrit 21.7%. She was transfused six units of FFP and two units of pRBCs, and transferred to our tertiary care facility for further hematologic workup. The patient's vital signs on arrival to our ICU were blood pressure 109/53 mm Hg, heart rate 79, and 96% on 4L/min nasal cannula. Her initial INR was 1.8, PT 20.0 sec, PTT 37 sec, hemoglobin 7.1 gm/dL, hematocrit 21.9%, and platelet count 158,000. Physical exam revealed diffuse abdominal tenderness without evidence of active gastrointestinal bleeding or epistaxis. The patient denied any exposure or ingestion of warfarin or superwarfarin anticoagulants. Surreptitious superwarfarin toxicity was suspected because of her initial INR elevation, and she was started on IV vitamin K1 at 10 mg daily. Psychiatry was consulted, yet the patient continued to deny superwarfarin exposure. Poison control also performed an inspection of the patient's home, and no identifiable anticoagulants were found. Her INR was trended daily and peaked at 6.4 on hospital day five. Her vitamin K1 was increased to 60 mg sub-q with the addition of 60 mg PO on that day. Hematologic workup revealed normal PT and PTT mixing studies, thrombin time, fibrinogen level, Dilute Russell's viper venom test, and undetectable anticardiolipin IgM and IgG. Coagulation factor levels V (0.97 U/ml; range 0.70–1.50) and factor VIII (1.33 U/ml; range 0.60–1.50) were normal. Vitamin K-dependent clotting factors II (0.40 U/ml; range 0.70–1.50), VII (0.06 U/ml; range 0.70–1.60), IX (0.07 U/ml; range 0.60–1.50), and X (0.29 U/ml; range 0.70–1.50) were all found to be low, highly suggestive of superwarfarin anticoagulant toxicity. The patient was then transitioned to 60 mg PO vitamin K1 daily with 60 mg sub-q three times a week to be continued as an outpatient. She was discharged on hospital day nine with an INR of 1.3. A qualitative brodifacoum drug level was subsequently found to be positive by way of high-performance liquid chromatography/tandem mass spectrometry 10 days after outside testing and patient discharge. Superwarfarins are a group of xenobiotic rodenticides developed in the 1970s to address the genetic resistance to warfarin in rats. (Clin Toxicol 2011;49[5]:385.) The most commonly used superwarfarin, brodifacoum, is a 4-hydroxy coumarin with a 4-bromo side chain, which accounts for most human exposures in the United States. (Clin Toxicol 2007;45[1]:1; Arch Intern Med 1998;158[17]:1929.) Brodifacoum products include Talon-G, Havoc, and D-Con, which are formulated at 0.005% active ingredient. (Arch Intern Med 1993;153[16]:1925.) The superiority of superwarfarins as rodenticides are secondary to higher lipid solubility and concentrations in the liver, making them 100 times more potent than warfarin with a half-life of 10–70 days in humans. (Arch Intern Med 1998;158[17]:1929; Clin Toxicol 2011;49[5]:385; Goldfrank's Toxicologic Emergencies. Ninth Edition. New York: McGraw-Hill Companies, Inc., pp. 865–9.) Intestinal and cutaneous absorption can occur. After accumulation in the liver, superwarfarins block hepatic carboxylation of vitamin K-dependent factors (II, VII, IX, and X) by inhibition of the vitamin K 2,3-epoxide reductase enzyme, leading to increased levels of inactive vitamin K epoxide. The resulting coagulopathy induces life-threatening hemorrhage in rodents, humans, and other animals. Presentation of superwarfarin-induced coagulopathy can include epistaxis, vaginal bleeding, hematuria, gingival bleeding, gastrointestinal bleeding, spontaneous abortion, hemoptysis, and intracranial hemorrhage. (Arch Intern Med 1998;158[17]:1929.) Because of brodifacoum's prolonged half-life, single ingestions may result in coagulopathies lasting five to six months. (Clin Toxicol 2011;49[5]:385; Clin Toxicol 2007;45[5]:487.) Typically, prolonged, high-dose vitamin K therapy is required in amounts ranging from 15-800 mg/day until adequate superwarfarin elimination is achieved. (Pharmacotherapy 2003;23[9]:1186.) Intentional and unintentional brodifacoum exposures require a high index of suspicion to detect, particularly in cases of surreptitious poisoning. Qualitative and quantitative brodifacoum serum detection tests are available, but they frequently must be sent to outside facilities. Results may take more than seven days, making initiation of long-term vitamin K therapy challenging without a definitive diagnosis. Vitamin K-dependent coagulation factor activity levels have been shown to be decreased in instances of brodifacoum toxicity. (J Toxicol Clin Toxicol 1988;26[3–4]:233; Conn Med 2008;72[4]:207; Am J Emerg Med 2006;24[3]:383.) Coagulation factor levels can typically be performed at local institutions with results in two to three days. Vitamin K-dependent factor activity measures may serve as a surrogate for detecting superwarfarin poisoning, allowing for earlier initiation of long-term vitamin K therapy. Brodifacoum-induced coagulopathy may present with a variety of reported clinical manifestations, which in cases of surreptitious exposure, may be particularly challenging to detect, as with our patient. Although a public health concern, brodifacoum poisonings are rarely reported in the literature. (Clin Toxicol 2011;49[5]:385.) Early initiation of long-term vitamin K therapy is imperative to prevent recurrent life-threatening hemorrhage because of the prolonged coagulation even after a single exposure or ingestion. (Ann Emerg Med 2000;36[3]:262; Clin Toxicol 2007;45[1]:1; Arch Intern Med 1998;158[17]:1929 and Arch Intern Med 1993;153[16]:1925; Ann Emerg Med 2002;40[1]:73; Goldfrank's Toxicologic Emergencies. Ninth Edition. New York: McGraw-Hill Companies, Inc., pp. 865–9; Pharmacotherapy 2003;23[9]:1186.) Direct serum brodifacoum measures often require lengthy waits for results, and it is often not feasible to wait for results before beginning long-term vitamin K therapy. Our case confirms brodifacoum-induced vitamin K -2,3-epoxide reductase inhibition will demonstrate low coagulation factor II, VII, IX, and X levels while factors VIII and V and thrombin time will remain within normal limits. Coagulation factor assays are readily available at many local hospital laboratory facilities and turnaround time for results are rapid, allowing coagulation factor activity levels to be used to diagnose brodifacoum-induced coagulopathy.