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Superwarfarin intoxication: two case reports and review of pathophysiology and patient management.

INTRODUCTION

Ingestion of rat poisons containing superwarfarin (brodifacoum) is an important public health problem in the United States. These poisons are potent and readily available in home and stores. More than 16,000 exposure events are reported in the United States each year. (1) Most exposures occur in children, are accidental, asymptomatic, and of little consequence. Adult exposures occur far less frequently, however, and are more likely to result in serious toxicity because of the large quantities consumed as part of a suicide attempt or intentional poisoning. (2) Superwarfarin exposure must be included in the differential diagnosis when a patient presents with deficiency of vitamin K-dependent clotting factors and has a limited response to vitamin K supplementation. (3) We describe two patients seen at the Louisiana State University Health Sciences Center in Shreveport (LSUHSC-S) with superwarfarin toxicity and review characteristic findings, clinical course, and management.

CASE NO. 1

A 48-year-old white female was transferred to our hospital because of abnormal coagulation studies. She was in her normal state of good health until five days prior to admission, when she presented to her primary care provider complaining of increased urinary frequency, urgency, and dysuria. She was diagnosed with a urinary tract infection and prescribed a five-day course of ciprofloxacin. One day prior to admission, she developed gross hematuria and hematochezia. The bleeding resolved after receiving vitamin K and fresh frozen plasma at an outside facility. The patient denied any anticoagulation therapy and denied any symptoms to suggest a malabsorption syndrome.

She reported that she had a similar episode of gross hematuria in 1992. At that time, she was diagnosed with vitamin K deficiency and received vitamin K subcutaneously for several months. She states that this episode occurred during divorce proceedings that ended her first marriage. Physical exam was remarkable for tenderness in the left lower quadrant of the abdomen without guarding or rebound. Numerous ecchymosis were present on the arms and legs. Laboratory studies obtained prior to transfer revealed a prothrombin time (PT) > 100.0 seconds and activated partial thromboplastin time (aPTT) of 129.1 seconds. She received an unknown quantity of Fresh Frozen Plasma (FFP) and vitamin K prior to transfer to LSUH-S.

Initial laboratory studies at LSUH-S revealed an elevated platelet count (452 x [10.sup.9]/l) and normocytic anemia (hemoglobin concentration 10.1 g/dl). PT was 22.9 seconds (normal = 11.3-15.2 sec), with an INR of 2.05 (normal= 0.8-1.2) and aPTT of 53.0 seconds (normal = 24.7-35.3 sec). Results of electrolyte, renal, and liver-function testing revealed only an elevated total protein (9.1 g/dl, normal = 6.4-8.2 g/dl) presumed related to FFP therapy. Urinalysis revealed trace (25/UL) blood and small (25/UL) leukocyte esterase. Additional coagulation studies were obtained, which revealed: complete normalization of aPTT and PT after mixing control plasma and patient's serum in a 1:1 ratio and decreased levels of all vitamin K dependent factors with normal non-vitamin K dependent factors ([normal range for all assays = 50-150%], Factor II = 30%, Factor V = 97%, Factor VII < 13%, Factor VIII = 152%, Factor IX = 6.5%, and Factor X = 26%). The patient received oral and subcutaneous vitamin K and FFP with improvement of the INR (1.41), PT (17.0 secs) and aPTT (44.8 secs). She was discharged home on two 100 mcg vitamin K tablets taken daily by mouth and phytonadione 10 mg/ml ampules subcutaneously daily. Superwarfarin poisoning was suspected and testing revealed a brodifacoum serum level of 0.1 ug/ ml. Further lab studies were not performed. The patient vehemently denied intentional ingestion of rat or mouse poison. She lived with her husband and denied marital stressors. She did have a history of depression and anxiety. She admitted that she was under stress because of the recent wedding of her oldest daughter, which she missed due to her illness. At her one-month follow-up visit, the patient complained of hematuria. She reported compliance with her vitamin K therapy, however, her INR was 5.41, PT was 49.1 seconds, and aPTT was 86.8 seconds. She was readmitted to our hospital for observed treatment with oral and subcutaneous vitamin K. A source of rodenticide was not identified.

CASE NO. 2

A 48-year-old African-American male with a past medical history of hypertension was transferred to our hospital from an outside facility secondary to an elevated INR and suspected disseminated intravascular coagulation. He was in his usual state of good health until two weeks prior to admission when he noticed decreased exercise tolerance, postural dizziness, blood in his urine and sputum, and one episode of billous vomitus that was blood-streaked. He had a syncopal episode witnessed by his wife. The patient denied injury, anticoagulation therapy, or symptoms to suggest a malabsorption syndrome. He denied any prior abnormal bleeding or bruising and had an uncomplicated tooth extraction 10 years earlier.

[FIGURE 1 OMITTED]

On admission to the intensive care unit, he had gross hematuria, hemoptysis, and stool positive for occult blood. The remainder of the physical exam did not reveal additional information. Initial laboratory studies at LSUHSC-S revealed a normocytic anemia (hemoglobin concentration 9.5 g/dl), PT=128.2 seconds, INR = 18.29, and aPTT =148.4 seconds. Electrolytes, renal, and liver-function tests revealed an elevated BUN and creatinine (159 mg/dl and 3.4 mg/dl) and decreased albumin (2.5 g/dl). Urinalysis revealed large (250/UL) blood and protein (500 A).

Coagulation studies demonstrated correction of aPTT and PT after mixing control plasma and patient's serum in a 1:1 ratio. Factor assays revealed all vitamin K dependent factors to be reduced with non-vitamin K dependent factors normal or elevated (Factor II = 15%, Factor V = 137%, Factor VII = 6.5%, Factor VIII = 300%, Factor IX = 4.1%, and Factor X = 13%). CT scan demonstrated a retroperitoneal bleed with a duodenal hematoma. Surgical intervention was not recommended. The patient received 39 units of FFP and daily parenteral vitamin K during his hospitalization, with improvement in PT (27.6 sec), INR (2.6), and PTT (66.3 sec).

Superwarfarin poisoning was suspected, and testing revealed serum brodifacoum. Further lab studies were not performed. He and his wife denied any potential accidental or intentional ingestion of rat poison. He denied any history of psychiatric problems. His wife remained with him during the entire hospital stay. The patient was discharged on doses of vitamin K at 20 mg orally daily. He was readmitted 19 days later, secondary to an elevated INR of 6.5. His dose of vitamin K was increased to 30 mg every day with the intention of continuing supplementation for six months to one year and weekly monitoring of INR. A source of rodenticide was not identified.

DISCUSSION

The ingestion of superwarfarin containing rodenticides, such as brodifacoum, may result in long lasting and potentially fatal coagulopathy. The superwarfarins found in rat poison are 100 times more potent than warfarin, with a plasma half-life determined to be between 16-69 days (as compared to warfarin's 36-42 hours). (4) Superwarfarins are 4-hydroxy coumarins and have increased potency due to their high lipid solubility. Additionally, they have affinity for hepatic tissue and are very slowly eliminated from the body. (5, 6) Their mechanism of action is believed to be the same as warfarin (Figure 1), which inhibits the action of epoxide reductase. This action prevents the reactivation of vitamin K, therefore depleting the body stores. The coagulation factors II, VII, IX, X, C, S, and Z can no longer be activated by vitamin K-dependent y-carboxylation. The relative lack of inhibition of quinone reductase allows for dietary and parenteral correction. (7,8) (Figure 1)

In a patient with a deficiency of all vitamin-K dependent coagulation factors and without a history of oral anticoagulation ingestion or malabsorption, accidental or intentional ingestion of superwarfarins should be considered. (9) Coagulopathy due to superwarfarins in an adult is almost always the result of intentional ingestion. Most products contain 0.005% of the active ingredient. According to chemical profiles, the dose that is lethal in 50% of 5 kg dogs is 355-1,000 g of bait. If this were extrapolated to a 50-60 kg adult human, then the dose of bait required would be 3,550-10,000 g. Household products typically contain a total of 150 mg. Fatal poisoning would therefore require the consumption of up to 23 packages of rat bait. Accidental ingestions are likely to be of a small amount and are also likely to be asymptomatic. In order for symptoms such as hemorrhage to occur, large quantities must be consumed. This is almost always secondary to deliberate ingestion. It could also, because of the long half-life, be secondary to chronic exposure if basic hygiene standards are ignored. Most cases in the literature are unable to define the source of rodenticide.

Patients with superwarfarin toxicity usually have a very high PT (>100 seconds) and INR, which will correct to normal with 1:1 plasma mixing studies. All vitamin K dependent factors will be decreased, while non-vitamin K dependent factors are normal to elevated. Failure to completely reverse with usual doses of vitamin K is indicative of superwarfarin toxicity. Confirmation can be obtained with serum studies from reference laboratories. (4)

Treatment requires protracted high dose oral and parenteral vitamin K supplementation and will require several months of therapy because of the long half-life. Because superwarfarin toxicity requires the ingestion of very large quantities of commercial products, all patients should be suspected of intentional exposure, and a psychiatric evaluation should be performed on every patient with confirmed superwarfarin toxicity. (10,11)

REFERENCES

(1.) Watson WA, Litovitz TL, Rodgers GC Jr, Klein-Schwartz W, Reid N, Youniss J, et al. 2004 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. 2005;23(5):589-666.

(2.) 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.

(3.) Pavlu J, Harrington DJ, Voong K, Savidge GF, Jan-Mohamed R, Kaczmarski R. Superwarfarin poisoning. Lancet. 2005;356:628.

(4.) Chua JD, Friedenberg WR. Superwarfarin poisoning. Arch Int Med. 1998;158:1929-32.

(5.) Bachmann KA, Sullivan TJ. Dispositional and pharmacodynamics characteristics of brodifacoum in warfarin-sensitive rats. Pharmacology. 1983;27:281-288.

(6.) Mosterd JJ, Thijssen HHW. The long-term effects of the rodenticide, brodifacoum, on blood coagulation and vitamin K metabolism in rats. Br J Pharmacol. 1991;104:531-535.

(7.) Whitlon DS, Sadowski JA, Suttie JW. Mechanism of coumarin action: significance of vitamin K epoxide reductase inhibition. Biochemistry. 1978;17:1371-1377.

(8.) Furie B, Furie BC. Molecular basis of vitamin K dependent y-carboxylation. Blood. 1990;75:1753-1762.

(9.) O'Reilly RA, Aggeler PM. Covert anticoagulation ingestion: study of 25 patients and review of world literature. Medicine. 1976;55:389.

(10.) Murphy MJ, Ray AC, Woody B, Reagor JC. Serum brodifacoum concentrations and coagulopathic effects in anticoagulant poisoned dogs treated with vitamin K. Toxicologist. 1985;5:38.

(11.) Swiger ME, Clemow LP, Saidi P, Kim HC. "Superwarfarin" ingestion. A new problem in covert anticoagulant overdose. Gen Hosp Psychiatry. 1990;12(5):309-312.

Kaylin S. Watson, MSIV; Glenn M. Mills, MD; Gary V. Burton, MD

Ms. Watson is fourth-year medical student at the Louisiana State University Health Sciences Center in Shreveport School of Medicine. Dr. Mills is the Director of the Feist Weiller Cancer Center at LSUHSC-Shreveport. Dr. Burton is with the Feist Weiller Cancer Center at LSUHSC-Shreveport.
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Author:Watson, Kaylin S.; Mills, Glenn M.; Burton, Gary V.
Publication:The Journal of the Louisiana State Medical Society
Article Type:Case study
Geographic Code:1USA
Date:Mar 1, 2012
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