TY - JOUR
AU - Saleh,, Julie
AB - Abstract Purpose A case of brodifacoum overdose and its treatment with prothrombin complex concentrate (PCC) are reported. Summary A 44-year-old Caucasian woman weighing 62 kg arrived at the emergency department with a chief complaint of lower left leg pain for two days. A computed tomography (CT) scan of the abdomen revealed perihepatic fluid collection (likely a hematoma), a small-bowel intramural hematoma, and blood in the paracolic gutter. A CT scan of the patient’s left foot showed soft tissue swelling without evidence of fracture or dislocation. The patient was diagnosed with left extremity compartment syndrome secondary to hematoma and trauma. The patient had a history of depression and anxiety and eventually admitted to ingesting large doses of brodifacoum the week prior with suicidal intentions. The patient was treated with phytonadione 20 mg i.v., 1 unit of fresh frozen plasma (FFP), and 1 unit of packed red blood cells. Laboratory test values measured in the intensive care unit revealed an International Normalized Ratio (INR) of 15, a prothrombin time of >120 seconds, and a partial prothromboplastin time of >180 seconds. After consulting with a local poison center, phytonadione 50 mg i.v., PCC 3100 units, and 4 units of FFP were immediately administered to reverse the patient’s coagulopathy. The dose of oral phytonadione was lowered based on INR stability. Once the coagulopathy was stabilized, the patient was transferred to an inpatient psychiatric facility on phytonadione 10 mg daily orally to maintain a stable INR. Conclusion A 44-year-old woman who intentionally ingested brodifacoum was successfully treated with phytonadione, PCC, and FFP. Anticoagulants are the most commonly used rodenticides in the United States. Two categories of long-acting anticoagulants were developed in the 1970s to overcome rat resistance to warfarin: indandiones (e.g., diphacinone, pindone, chlorophacinone) and 4-hydroxycoumarin derivatives, also known as superwarfarins (e.g., difenacoum, bromadiolone, brodifacoum). Superwarfarins are available in a variety of forms, including liquids, pellets, blocks, pastes, and powders, and concentrations, usually ranging from 0.005% to 99%. In the past, brodifacoum, commonly available in a 0.005% concentration, was the most commonly used superwarfarin. Over 95% of all rodenticides used in the United States are superwarfarins, increasing the risk of overexposure to and intoxication with these products. 1,–3 Currently, the Environmental Protection Agency has removed from the market some brodifacoum rodenticides. 4 According to the 2013 annual report of the American Association of Poison Centers, 8783 cases of single long-acting anticoagulant rodenticide ingestion were reported between January 1 and September 30, 2013, 180 of which involved exposure to warfarin-type rodenticides. 5 Recent epidemiologic studies revealed that the incidence of cases of human exposure to long-acting anticoagulant rodenticides has increased over the past 10 years. The majority of cases involved accidental ingestion; however, some cases did involve the use of these superwarfarins in suicide attempts and patients with psychiatric disorders. 1,2 We report the case of a woman who developed hematuria and left lower extremity bruising after long-term ingestion of brodifacoum. Case report A 44-year-old Caucasian woman weighing 62 kg arrived at the emergency department with a chief complaint of lower left leg pain for two days. Two days earlier, she had hit her left lower extremity on a recliner. The patient had been transferred from another facility where she sought medical attention a day prior for suprapubic pain and hematuria. While at that facility, the patient was diagnosed with a urinary tract infection and sent home on nitrofurantoin 100 mg orally twice daily for five days. On the day of admission to our facility, the patient had a positive guaiac test result, a hemoglobin concentration of 8.0 mg/dL (normal, 12.0–15.5 mg/dL), a hematocrit level of 20.5% (normal, 34.9–44.5%), and an International Normalized Ratio (INR) of >15 (normal, 0.9–1.1). She had a white blood cell count of 11.9 × 103 cells/μL (normal, 3.5 × 103−10.5 × 103 cells/μL), blood pressure of 109/56 mm Hg (normal, 120/80 mm Hg), a heart rate of 88 beats/min (normal, 60–100 beats/min), and a respiratory rate of 11 breaths/min (normal, 12–20 breaths/min) and was afebrile. A 10-point review of systems was negative except for left foot pain, which the patient rated 10 of 10 in intensity. The patient’s physical examination was unremarkable. A computed tomography (CT) scan of the abdomen revealed perihepatic fluid collection (likely a hematoma), a small-bowel intramural hematoma, and blood in the paracolic gutter. A CT scan of the head showed no evidence of acute intracranial abnormality. The patient had a history of depression and anxiety, which was being treated with sertraline 100 mg once daily, and eventually admitted to ingesting large (self-reported) doses of brodifacoum the week prior with suicidal intentions. She also admitted to ingesting brodifacoum in 2010 and 2013. The patient was treated with phytonadione 20 mg i.v., 1 unit of fresh frozen plasma (FFP), and 1 unit of packed red blood cells. She was subsequently transferred to the intensive care unit (ICU) due to the severity and acuity of her illness. Laboratory test values measured in the ICU revealed an INR of 15, a prothrombin time of >120 seconds (normal, 11–15.2 seconds), and a partial prothromboplastin time of >180 seconds (normal, 23.4–35.5 seconds). The patient’s hemoglobin concentration dropped from 8.0 to 6.8 mg/dL in a 24-hour period. A urinalysis revealed large amounts of red blood cells and protein, and the urine was reddish brown, indicating hematuria. A CT scan of the patient’s left foot showed soft tissue swelling without evidence of fracture or dislocation. The patient was diagnosed with left extremity compartment syndrome secondary to hematoma and trauma. The local poison center was contacted and recommended that gastric decontamination not be performed due to the unclear timeline of brodifacoum ingestion. To reverse the patient’s coagulopathy, phytonadione 50 mg i.v., prothrombin complex concentrate (PCC) 3100 units, and 4 units of FFP were immediately administered. A subsequent INR level measured approximately 30 minutes after initial medication management showed normalization (2.4) (Figure 1). A four-compartment fasciotomy of the left lower extremity with evacuation of hematoma was performed as soon as the bleeding risk was reduced and the patient was hemodynamically stable. The recommendation of the poison center was to continue phytonadione 10 mg every six hours i.v. to maintain an INR of <2. By hospital day 2, the patient’s therapy was switched to phytonadione 20 mg every eight hours orally. On hospital day 3, the patient’s INR increased to 10.3, and her prothrombin time was over 120 seconds; consequently, the oral phytonadione dose was increased to 30 mg every six hours. The dose of oral phytonadione was lowered based on INR stability. There were two other elevations in the INR which corresponded to the dosing of phytonadione. The last two INR spikes (both 2.5) occurred on hospital days 6 and 11 (Figure 1). Once the coagulopathy was stabilized, the patient was transferred to an inpatient psychiatric facility on phytonadione 10 mg daily orally to maintain a stable INR. Phytonadione was to be continued based on laboratory values and clinical response. Discussion Superwarfarins are fat-soluble, long-acting anticoagulants that are 100 times more potent than warfarin. Similar to warfarin, these anticoagulants work by inhibiting vitamin K epoxide reductase, leading to decreased production of coagulation factors II, VII, IX, and X as well as proteins C and S. 1,3,6 Inhibiting vitamin K reductase reactions indirectly inhibits active prothrombin complex formation. Brodifacoum, the most commonly used rodenticide worldwide, has an elimination half-life of 156 hours in rats; in contrast, warfarin’s half-life in rats is just 17 hours. In humans, the half-life of warfarin ranges from 17 to 37 hours, while the half-life of brodifacoum in humans is 243–1656 hours. Brodifacoum’s effect has been reported to last from 51 days up to nine months after ingestion. 1,3,6 During the first 12 hours after ingestion, clinical presentation will be unremarkable in acute exposures. Laboratory evidence of coagulopathy occurs within one to two days after ingestion, and physical evidence of coagulopathy can be delayed for several more days or one to two weeks after ingestion. If untreated, anticoagulation may persist for months, 1,2 which explains why our patient had signs of bleeding a week after her last episode of brodifacoum ingestion. Coagulopathy is the most common clinical sign seen of bleeding from any mucosal site or organ. Gingival bleeding, epistaxis, ecchymosis, gastrointestinal bleeding, hemoptysis, hematuria, and intracranial hemorrhage have all been observed in cases of superwarfarin poisoning. 1,2 In our case, the patient had hematuria, melena, and bruising in her extremities. Based on guidelines from the American Association of Poison Centers, exposure to brodifacoum in patients in whom self-harm, abuse, or misuse is suspected should be referred to an emergency department immediately, regardless of the dose ingested. 7 Before the approval of PCC, phytonadione and FFP were the mainstays of treatment for overdoses of superwarfarin. Administration of PCC rapidly increases plasma levels of vitamin K–dependent coagulation factors II, VII, IX, and X as well as proteins C and S. Despite the cost of PCC, it was used in this patient because it is indicated for the urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonists such as warfarin. 8,9 Although no case reports describing the use of PCC for reversal of rodenticide overdose have been published, studies have shown that PCC can normalize the INR in half the time it would take with FFP for the reversal of warfarin overdose. Woo et al. 8 conducted a retrospective electronic medical record analysis comparing the effectiveness and safety of FFP, factor VIIa, and PCC in combination with phytonadione to rapidly reverse coagulopathy. The primary endpoint was the reversal of the INR to ≤ 1.3 within the first 48 hours. Rates of rebound INR were compared. The authors found mean INR reversal times of 1933 ± 905 minutes with FFP, 784 ± 926 minutes with factor VIIa, and 980 ± 1021 minutes with PCC (p < 0.001; p < 0.01 between FFP and factor VIIa and p < 0.5 between FFP and PCC). PCC had the lowest 48-hour rebound rate, occurring in zero of seven patients, while factor VIIa had a 50% rebound rate (four of eight patients) (p < 0.001). 8 The efficacy of PCC specifically for the reversal of warfarin-associated acute major bleeding was evaluated in a prospective, open-label, active-controlled, noninferiority, multicenter trial. 10 Patients were treated with a single dose of PCC or plasma. PCC doses were based on factor IX concentrations (25, 35, or 50 units/kg). The efficacy endpoints were effective hemostasis, defined as an INR of ≤1.3 and prompt cessation of bleeding or normal hemostasis during surgery. The authors found that PCC was noninferior to plasma in hemostasis, (72.4% versus 65.4%, respectively; 95% confidence interval [CI], −5.8 to 19.9% with noninferiority if lower limit of 95% CI was greater than −10). An additional endpoint showed that reduction of the INR to 1.3 or less at 30 minutes occurred in approximately 60% of patients using PCC and in only 10% of patients receiving plasma. 10 Figure 1. Open in new tabDownload slide Trend in daily International Normalized Ratio (INR) and daily phytonadione use. PCC = prothrombin complex concentrate. Figure 1. Open in new tabDownload slide Trend in daily International Normalized Ratio (INR) and daily phytonadione use. PCC = prothrombin complex concentrate. Another case report demonstrated that PCC administration quickly reversed anticoagulant activity and allowed for invasive procedures, such as the placement of a pacemaker, after i.v. phytonadione failed to reverse anticoagulation. 11 Because our patient ingested brodifacoum, a superwarfarin that works via vitamin K antagonism, PCC administration showed a similar normalization of the INR within 30 minutes. A previously reported case depicted another patient who also ingested brodifacoum in a suicide attempt several weeks before hospital admission. 12 Similar to our case, this patient had leg swelling and an extremely elevated INR (14) and developed compartment syndrome. The patient in that report was initially treated with parenteral phytonadione and 6 units of FFP and was given oral phytonadione for a prolonged period of time to prevent further coagulopathy. PCC was not administered. Because brodifacoum depletes the body of its vitamin K coagulation factors and indirectly inhibits active prothrombin complex formation, administration of PCC should theoretically replete the patient’s vitamin K stores and stabilize the patient faster than if only phytonadione and FFP are given. Due to the cost of PCC, we would only recommend its use in severe cases in which patients are actively bleeding, are in need of urgent or invasive surgery, or have a high probability of imminent or life-threatening deterioration of their condition. More research is needed to ascertain the full benefits of PCC and phytonadione in the treatment of superwarfarin overdoses. Conclusion A 44-year-old woman who intentionally ingested brodifacoum was successfully treated with phytonadione, PCC, and FFP. Footnotes The authors have declared no potential conflicts of interest. References 1 Nelson AT , Hartzell JD , More K , Durning SJ . Ingestion of superwarfarin leading to coagulopathy: a case report and review of the literature . MedGenMed . 2006 ; 8 : 41 . Google Scholar PubMed WorldCat 2 Altay S , Cakmak HA , Boz GC et al. . Prolonged coagulopathy related to coumarin rodenticide in a young patient: superwarfarin poisoning . Cardiovasc J Afr . 2012 ; 23 : e9 – 11 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Lexi-Comp Online . Long-acting anticoagulant rodenticides . http://online.lexi.com/ICO/action/doc/retrieve/docid/lexier/1303021?hl=superwarfarin (accessed 2015 Jan 29). 4 Environmental Protection Agency . Canceling some d-CON mouse and rat control products ( April 2015 ). www2.epa.gov/rodenticides/canceling-some-d-con-mouse-and-rat-control-products (accessed 2015 Jun 22). 5 Mowry JB , Sypker DA , Cantilena LR Jr et al. . 2013 annual report of the American Association of Poison Centers’ National Poison Data System (NPDS): 31st annual report . Clin Toxicol . 2014 ; 52 : 1032 – 283 . Google Scholar Crossref Search ADS WorldCat 6 Schulman S , Furie B . How I treat poisoning with vitamin K antagonists . Blood . 2015 ; 125 : 438 – 42 . Google Scholar Crossref Search ADS PubMed WorldCat 7 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 . Google Scholar Crossref Search ADS WorldCat 8 Woo CH , Patel N , Conell C et al. . Rapid warfarin reversal in the setting of intracranial hemorrhage: a comparison of plasma, recombinant activated factor VII, and prothrombin complex concentrate . World Neurosurg . 2014 ; 81 : 110 – 5 . Google Scholar Crossref Search ADS PubMed WorldCat 9 Kcentra (prothrombin complex concentrate) package insert . Kankakee, IL : CSL Behring ; 2014 Jul . WorldCat COPAC 10 Pabinger-Fasching I . Warfarin-reversal: results of a phase III study with pasteurised, nanofiltrated prothrombin complex concentrate . Thromb Res . 2008 ; 122 ( suppl 2 ): S19 – 22 . Google Scholar Crossref Search ADS PubMed WorldCat 11 Di Fusco SA , Aspromonte N , Aquilani S et al. . Emergency reversal of vitamin-K antagonists related to over-anticoagulation: case report and brief overview on the role of prothrombin complex concentrate . Monaldi Arch Chest Dis . 2013 ; 80 : 184 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat 12 Tahir M , Khan MF , Tourbaf K . Impending compartment syndrome and hemothorax after brodifacoum ingestion . South Med J . 2008 ; 101 : 1277 . Google Scholar Crossref Search ADS PubMed WorldCat Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights reserved.
TI - Treatment of brodifacoum overdose with prothrombin complex concentrate
JO - American Journal of Health-System Pharmacy
DO - 10.2146/ajhp150233
DA - 2016-01-01
UR - https://www.deepdyve.com/lp/oxford-university-press/treatment-of-brodifacoum-overdose-with-prothrombin-complex-concentrate-g0QRhIAEXw
SP - e14
VL - 73
IS - 1
DP - DeepDyve
ER -