Brodifacoum Poisoning: A New Risk in the Use of Synthetic Cannabinoids

Brodifacoum Poisoning: A New Risk in the Use of Synthetic Cannabinoids

By Kristen C. Lee, PharmD, BCPS and Madison Schwartz, PharmD | Clinical Toxicology/EM Fellows at Florida/USVI Poison Information Center—Jacksonville

A 27-year-old female presents to the emergency department complaining of increased bruising over the past few weeks and dark stool for the last three days. She has no prior medical history and is not on any prescription or overthe-counter medications. Her vital signs are within normal limits. Her urine drug screen is positive for cocaine and THC. Initial coagulation studies reveal an INR of 8.5 and a PTT of 85.7 sec. Upon further questioning, the patient admits to “occasional” cocaine use, as well as “intermittent” use of synthetic cannabinoid products that may include K2 or Spice.

What is the connection between the patient’s use of synthetic cannabinoids and her current presentation?

Synthetic cannabinoids, including those sold under the names “K2” or “Spice,” are synthetically-derived compounds that agonize the cannabinoid receptor. In March 2018, the Illinois Poison Center alerted the Illinois Department of Public Health to a series of cases of patients presenting to emergency departments with unexplained bleeding, elevated INRs from 5 to >20 and recent use of synthetic cannabinoids. Blood samples in subsequent cases seen throughout the U.S. were found to be positive for brodifacoum. [1]

Brodifacoum is a long-acting anticoagulant rodenticide (LAAR) in the same pharmacologic class as warfarin, with a chemical structure differentiated by a longer polycyclic hydrocarbon side chain. Brodifacoum is considered a “superwarfarin” because, like warfarin, it blocks formation of the active form of vitamin K to inhibit production of clotting factors II, VII, IX and X. However, its high lipid solubility and ability to concentrate heavily in the liver confers activity 100 times that of warfarin, with a longer duration of action. [2] The terminal elimination half-life of brodifacoum in human cases has ranged from 24 to 31 days. [3, 4] In animal models, brodifacoum has demonstrated a half-life of up to 120 days. [5]

Patients who present with signs or symptoms of bleeding— including hematemesis, hemoptysis, bruising, epistaxis, unusually heavy menstrual bleeding, melena, hematuria, bleeding gums, or bleeding disproportionate to injury— should be questioned about use of synthetic cannabinoids including K2/Spice in the last three months. Laboratory diagnostics should include an INR ≥ 2 or an abnormal coagulation profile with no alternative clinical cause, or identification of an LAAR through high-performance liquid chro¬matography–tandem mass spectrometry of blood samples. [1]

Life-threatening bleeds due to brodifacoum should be managed similarly to warfarin toxicity, with rapid reversal of anticoagulation using fresh frozen plasma (FFP), prothrombin complex (PCC) or recombinant factor VIIa. [6] To sustain the INR reversal achieved by FFP or factor products, vitamin K 5-10 mg (up to 400 mg has been needed) should be administered intravenously. [7] Slower infusions (i.e. 1 mg/min) may reduce the risk of anaphylactoid reactions. In patients with elevated INR in the absence of significant bleeding, intravenous vitamin K alone can be given at the above-mentioned dosages. Caution should be used in patients on an anticoagulant for medical reasons.

Once INR reversal is achieved, vitamin K should be continued orally and can be treated on an outpatient basis with regular follow-up for laboratory assessment once coagulation abnormalities have stabilized. While dosing strategies are variable based on response, one approach is 25-50 mg PO vitamin K 3-4 times daily for 1-2 days, with regular INR monitoring for adjustment of dosing. 7 Serial serum concentrations of brodifacoum may also be useful in guiding duration of therapy, but may require analysis by independent laboratories and take multiple days to result. [8]

Because of the long duration of action of brodifacoum, patients should be followed to the resolution of coagulopathy, which may require weeks to months of observation. Serial INR measurements may guide tapering of vitamin K. [2]

Cases of brodifacoum-tainted synthetic cannabinoids have been reported in at least nine states and are being monitored by Centers for Disease Control and Prevention (CDC). Since the outbreak, at least 300 cases have been reported, including at least seven deaths. Given the multi-state outbreaks, a variety of public safety announcements have been created by CDC and poison centers around the country to spread awareness about the dangers of brodifacoum-tainted synthetic cannabinoids. Consider questioning patients with a history of drug abuse regarding use of synthetic cannabinoids, and drawing a coagulation panel in patients with signs or symptoms of synthetic cannabinoid toxicity. ■

References

1. Moritz E, et al. Notes from the Field: Outbreak of Severe Illness Linked to the Vitamin K Antagonist Brodifacoum and Use of Synthetic Cannabinoids - Illinois, March-April 2018. MMWR Morb Mortal Wkly Rep. 2018 Jun 1;67(21):607- 608.

2. Chen BC, Su M. Antithrombotics. In: Hoffman RS, Howland M, Lewin NA, Nelson LS, Goldfrank LR. eds. Goldfrank's Toxicologic Emergencies, 10e New York, NY: McGraw-Hill; 2015. http://accesspharmacy.mhmedical.com/content. aspx?bookid=1163&sectionid=65096168. Accessed October 09, 2018.

3. Hollinger BR & Pastoor TP: Case management and plasma half-life in a case of brodifacoum poisoning. Arch Intern Med 1993; 153:1925-1928.

4. Pavlu J, Harrington DJ, Voong K, et al: Superwarfarin poisoning. Lancet 2005; 365:628.

5. Lipton RA & Klass EM: Human ingestion of a "superwarfarin" rodenticide resulting in a prolonged anticoagulant effect. JAMA 1984; 252:3004-3007.

6. Holbrook A, Schulman S, Witt DM et al.: Evidence-based management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e152S–e184S.

7. Howland MA. Antidotes in Depth: Vitamin K1. In: Nelson LS, Hoffman RS, Lewin NA, Goldfrank LR, Howland MA, Flomenbaum NE editors. Goldfrank’s Toxicologic Emergencies. 9th ed. New York: McGraw-Hill: 2011. p. 876- 879.

8. Bruno GR, Howland MA, McMeeking A, Hoffman RS: Longacting anticoagulant overdose: brodifacoum kinetics and optimal vitamin K dosing. Ann Emerg Med. 2000;36:262– 267.

FPICN toxicologists are available 24 hours a day at 1-800-222-1222 to assist emergency physicians in the treatment of all toxic exposures, including management of coagulopathy suspected to be secondary to brodifacoumcontaminated synthetic cannabinoids.