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Anticoagulant rodenticide poisoning: Clinical manifestations and diagnostic evaluation

Anticoagulant rodenticide poisoning: Clinical manifestations and diagnostic evaluation
Literature review current through: Jan 2024.
This topic last updated: Jul 22, 2023.

INTRODUCTION — This topic reviews the clinical manifestations and diagnosis of anticoagulant rodenticide (also called long-acting anticoagulant rodenticide; LAAR) poisoning.

The management of anticoagulant rodenticide poisoning and an overview of rodenticide poisonings other than anticoagulant rodenticides is provided separately.

(See "Anticoagulant rodenticide poisoning: Management".)

(See "Overview of rodenticide poisoning".)

EPIDEMIOLOGY — Anticoagulant compounds are the most commonly used rodenticides in most of the world. The process of controlling rodent populations is imperative to human health but poses challenges when the rodenticide compounds used are also toxic to humans and domestic animals. The ideal rodenticide is highly toxic to rodents in small amounts but relatively nontoxic in small quantities to non-target species. The anticoagulant rodenticides best fit this criteria [1]. Anticoagulant rodenticides came into use in the 1940s with the use of warfarin. The emergence of warfarin-resistant rats prompted the development of superwarfarins, or long-acting anticoagulants such as brodifacoum, bromadiolone, and chlorophacinone. Because of their availability, anticoagulant rodenticides are also the most common cause of rodenticide poisoning exposures reported annually in resource-rich countries such as the United States and the United Kingdom [2,3].

In the United States, brodifacoum remains common although use may be declining due to increased use of bromethalin [3]; however, global differences exist. In the United Kingdom, difenacoum, brodifacoum, and bromadiolone are most common [4]. In the developing world, the use of warfarin rodenticides has led to tragic inadvertent exposures in newborns as well as the ingestion of contaminated foodstuff with resultant fatalities [5,6].

In the United States during 2018, there was an outbreak of anticoagulant rodenticide poisoning; there were reports of over 150 patients with serious bleeding and at least seven deaths from use of synthetic cannabinoids contaminated with brodifacoum [7-11]. In Israel during 2021 to 2022, there was a similar outbreak involving 98 patients and four deaths [12].

Throughout the world, the overwhelming majority of anticoagulant rodenticide exposures occur in young children, who generally ingest small volumes and have no significant coagulopathy [3,6,13,14]. However, patients with intentional or occupational exposures develop coagulopathy much more frequently.

PHARMACOLOGY

Formulations and chemical agents — Anticoagulant rodenticides are widely used in domestic, industrial and agricultural settings. It is essential to identify the specific anticoagulant rodenticide involved with any exposure to accurately determine potential toxicity.

Product formulations include [6]:

Cereal bait

Pellets

Loose grain

Blocks

Paste

Tracking powder

Wax block

Baits may be treated with brightly colored dye and bittering agents (such as denatonium benzoate) to decrease the appeal to non-target species. Warfarin baits are generally 0.025 to 0.05 percent active ingredient. Most long-acting rodenticide baits are sold at a lower concentration to the public, typically 0.0025 percent [6]. However, high concentration formulations that have >90 percent anticoagulant ingredients are commercially available [15].

First-generation anticoagulants such as warfarin and coumatetralyl have been in use as rodenticides since the 1940s. However, the appearance of warfarin-resistant rat populations prompted the development and use of second-generation agents, which due to the presence of a polycyclic side chain and higher lipid solubility are more potent with a longer duration of action [16,17]. While many days of feeding on warfarin may be needed to kill a rodent, a single day's exposure to a second-generation agent is usually lethal [18].

Also called "superwarfarins" or "long-acting" agents, the second generation anticoagulant rodenticides include the following:

The 4-hydroxycoumarin derivatives: brodifacoum (D-Con), bromadiolone, difenacoum, and flocoumafen

The indanedione derivatives: chlorophacinone and diphacinone

Mechanism of action — Both first- and second-generation anticoagulants work by inhibiting vitamin K-1,25 epoxide reductase, which is required for the regeneration of vitamin K and subsequent activation (gamma-carboxylation) of vitamin K-dependent clotting factors II, VII, IX, and X, and proteins C, S, and Z (figure 1). As such, immediate effects are not seen even after massive exposure to these agents, as time is required for the existing coagulation factor supply to decrease and fail to replenish. Laboratory evidence of coagulopathy is typically delayed for 24 to 48 hours after exposure. (See "Vitamin K-dependent clotting factors: Gamma carboxylation and functions of Gla" and 'Toxicokinetics' below.)

Toxicokinetics — The toxicokinetics of anticoagulant rodenticides are as follows:

Absorption – Both warfarin and long-acting anticoagulants are well-absorbed orally and extensively protein-bound. Most undergo hepatic p450 metabolism [6,16,19-21]. Inhalational absorption can occur with occupational exposure. Dermal absorption has also been described in a fatal newborn epidemic of warfarin-contaminated talcum powder and in adults with prolonged dermal exposure [5,22]. However, poisoning with coagulopathy most commonly occurs after ingestion.

Onset of action – The onset of coagulopathy requires coagulation factor activity to drop below 30 percent of normal. The depletion of factor VII, the vitamin K-dependent factor with the shortest plasma half-life (three to five hours), produces the first signs of coagulopathy. Laboratory evidence of coagulopathy (elevated prothrombin time [PT] and international normalized ratio [INR], decreased prothrombin concentrations) is usually evident within 48 hours after exposure; however, long-acting rodenticide poisoning may exhibit significant latency of several days [6]. Second-generation agents have a much longer duration of effect, which is attributable to a number of factors including hepatic accumulation, high lipid solubility, and prolonged elimination [6,18].

Duration of effect and elimination – The duration of effect depends upon the elimination rate of a given compound. Although kinetics distort unpredictably in overdose, warfarin has a much shorter elimination half-life than long-acting anticoagulants, and there is significant variability between long-acting agents. In overdose, warfarin follows a first-order elimination curve with a half-life of 21.7 hours [23]. Second-generation anticoagulants demonstrate zero-order, saturation-dependent kinetics in overdose. Half-lives of brodifacoum in overdose demonstrate a biphasic pattern, with initial values of 0.75 days followed by a half-life ranging from 16 to 62 days [24-26].

Toxic dose — We encourage consultation with a regional poison control center to help determine the potential toxicity of any anticoagulant rodenticide exposure. (See 'Regional poison control centers' below.)

There is no predictable relationship between dose ingested and serum concentrations for anticoagulant rodenticides. A single overdose of warfarin up to 1 mg/kg, or 0.7 mg/kg in a child, which corresponds to the typical pediatric ingestion of less than one packet of a low concentration anticoagulant rodenticide, can be expected to have little effect. The prothrombin time may elevate within 24 hours and normalize within five days [16]. There is less predictability surrounding long-acting anticoagulant dose-response relationships.

CLINICAL MANIFESTATIONS

History — During the history, the clinician should determine the following:

Specific agent ingested

Amount ingested

Time of ingestion

Any coingestions

The clinician should also make every effort to identify the specific rodenticide and the circumstances of the exposure to guide care. In regions where a "signal word" appears on the product label, anticoagulant rodenticides are identified by the word "Caution." A regional poison control center can also assist with product identification. (See "Overview of rodenticide poisoning", section on 'Definition and classification' and 'Regional poison control centers' below.)

The clinician should also maintain vigilance for intentional ingestion or administration of anticoagulant rodenticides when evaluating patients with spontaneous bleeding of unclear etiology. These agents have been well described as a means of producing bleeding in cases of malicious poisoning, factitious disorder (Munchausen syndrome), and medical child abuse (Munchausen syndrome by proxy). Specific concentrations of anticoagulant rodenticides can be obtained when these diagnoses are suspected to confirm exposure. (See "Factitious disorder imposed on self (Munchausen syndrome)" and "Medical child abuse (Munchausen syndrome by proxy)".)

The past medical history should also determine whether the patient has an increased risk of bleeding because of concurrent liver disease, anticoagulant therapy, or a coagulation disorder.

Physical examination — Patients with anticoagulant rodenticide exposure should have assessment of vital signs and a complete physical examination. Patients examined within 24 hours of exposure will not have yet developed coagulopathy and should not be expected to have signs of bruising or bleeding. (See 'Toxicokinetics' above.)

Large ingestions, often suicidal in nature and involving consumption of bait pellets by adolescents and adults, can lead to profound and prolonged anticoagulation with serious or life-threatening hemorrhage, including gastrointestinal, genitourinary, and intracranial bleeding commencing at 24 to 48 hours after exposure [18,24,26,27]. The most common area of significant bleeding seen after exposure is frank hematuria with abdominal or flank pain [6,18,24,25,28]. After ingestion of second-generation agents (superwarfarins), coagulopathy may be present for many months and recurrent bleeding is possible [18,29]. (See 'Toxicokinetics' above.)

Bleeding is assessed according to the site, rate of hemorrhage, and amount of blood loss. We define serious/major bleeding as bleeding that is potentially associated with significant blood loss requiring blood transfusion or bleeding into a critical closed space (eg, intracranial bleeding, compartment syndrome). Major bleeding may also include bleeding requiring an intervention for management (eg, surgery, interventional radiology procedures, endoscopic treatments). Major bleeding has a significant risk of immediate morbidity, regardless of the cause. Various definitions of major bleeding are presented in the table (table 1).

Patients with major bleeding may demonstrate signs of hemorrhagic shock (eg, pallor, tachycardia, tachypnea, narrowed pulse pressure, and hypotension) and for patients with intracranial bleeding, signs of increased intracranial pressure (eg, bradycardia, hypertension, irregular respirations, coma, and focal neurologic deficits). (See "Evaluation of and initial approach to the adult patient with undifferentiated hypotension and shock", section on 'Features of shock' and "Evaluation and management of elevated intracranial pressure in adults", section on 'Clinical manifestations'.)

Minor, but still clinically significant, bleeding includes bleeding requiring a health care assessment or less invasive treatment, such as epistaxis, gum or oral bleeding, easy bruising/ecchymosis, or heavy menstrual bleeding.

Patients with repeated chronic ingestions may also have signs of bruising and minor or major bleeding.

ANCILLARY STUDIES

Acute or chronic exposure — The laboratory evaluation of patients with anticoagulant rodenticide exposure varies according to the estimated ingested dose and the type of exposure. We encourage consultation with a regional poison control center to assist in determining whether the ingested dose is toxic or nontoxic. (See 'Regional poison control centers' below.)

The suggested approach is as follows:

Unintentional nontoxic exposures — No laboratory assessment is needed in children or older patients with clearly unintentional ingestion of nontoxic amounts of anticoagulant rodenticides and who are not on anticoagulant therapy. In the past, some experts suggested that all of these patients undergo testing of prothrombin time (PT) and international normalized ratio (INR) at 48 hours based upon small case series that document occasional instances of coagulopathy [30]. However, serious bleeding has not been reported with ingestion of less than one packet of anticoagulant rodenticide despite regional poison center documentation of thousands of such exposures over the past 40 years [6,31,32].

Asymptomatic patients on anticoagulant therapy who have an unintentional small exposure to anticoagulant rodenticides warrant a baseline measurement of PT and INR with a repeated measurement 48 to 72 hours after exposure.

Unintentional toxic exposures — Patients with unintentional toxic exposures and who are otherwise healthy and not receiving anticoagulant therapy warrant measurement of PT and INR at 48 to 72 hours after exposure. (See 'Toxic dose' above.)

Patients on anticoagulant therapy or with underlying medical conditions (eg, liver disease) that may be associated with abnormal coagulation should have a baseline measurement of PT and INR as soon as possible after the ingestion and repeated measurement 48 to 72 hours after exposure.

Intentional or chronic exposures — We recommend that patients with intentional (self-harm, abuse, or malicious intent) or chronic ingestions, regardless of reported amount, undergo measurement of a PT, an INR, and a partial thromboplastin time (aPTT) during the initial presentation to the emergency department. Soon after ingestion of an anticoagulant rodenticide, these studies will be normal, but measurement will provide a baseline value.

For acute exposures, the PT and INR should then be repeated at 36 to 48 hours. With ingestions likely to cause anticoagulation and/or bleeding, the PT and INR will typically become abnormal at 12 to 24 hours and peak at 36 to 72 hours after ingestion [24]. If no coagulopathy or bleeding is present at 36 to 48 hours after exposure, no further measurement is indicated.

Patients who are suicidal should also undergo laboratory assessment for coingestants based upon clinical findings and warrant measurement of an acetaminophen concentration even if asymptomatic.

Patients with coagulopathy or bleeding — Coagulopathy from rodenticide poisoning is characterized by prolongation of the PT, INR, and aPTT.

Additional studies should be obtained in patients with any evidence of bleeding on physical examination or coagulopathy on laboratory testing and include the following:

Complete blood count with differential

Type and screen for blood products or, if significant bleeding, type and cross match

Urine dipstick for blood

Plasma fibrinogen and serum fibrin degradation products

Stool for guaiac

Other laboratory or imaging studies may also be indicated depending upon the specific sites of bleeding (eg, electrolytes, blood urea nitrogen, serum creatinine, and ultrasound or computed tomography [CT] of the abdomen for major genitor-urinary bleeding; CT of the head for intracranial bleeding).

The definitive test for anticoagulant rodenticide poisoning is quantitative concentration measurement by liquid chromatography-tandem mass spectrometry in serum [33]. However, these tests are difficult to obtain in a timely fashion to guide clinical management of acute overdoses, and are primarily used to confirm exposure (eg, patients with factitious disorder or deliberate administration of a rodenticide as part of medical child abuse or other criminal activity). A brodifacoum or bromadiolone concentration <10 ng/mL has been associated with normal coagulation parameters and is likely safe, although an evidence-based safe threshold does not exist [18,34].

Some parameters that may be of use to assess toxicity beyond standard coagulation testing include clotting factor activity, prothrombin activity and Vitamin K 2,3 epoxide concentration with epoxide:Vitamin K1 ratio. These may elucidate the diagnosis if there is not a clear history of rodenticide exposure. The utility of vitamin K 2,3 epoxide and the epoxide:Vitamin K1 ratio is mostly limited to the setting of occupational monitoring.

Occupational monitoring — Workplace exposure has been observed in patients involved in the manufacture and application of anticoagulant rodenticides, in particular when appropriate industrial hygiene is not performed [22,35]. Industrial exposure may result in persistent abnormalities in vitamin K metabolism for many months after cessation of exposure and resolution of coagulopathy [6,17,35,36]. A vitamin K 2,3-epoxide concentration may be a better long-term marker of exposure than standard coagulation parameters. After a vitamin K challenge, a normal epoxide concentration should be <30 ng/mL [16].

DIAGNOSIS — The diagnosis of anticoagulant rodenticide exposure is made based upon history.

The diagnosis of anticoagulant rodenticide poisoning is made when coagulopathy is identified by clinical bruising and bleeding and/or prolonged prothrombin time (PT) and international normalized ratios (INRs) obtained 36 to 48 hours after ingestion. In patients without a history of exposure but unexplained bruising or bleeding, the presence of measurable rodenticide concentrations in the serum also establishes the diagnosis.

DIFFERENTIAL DIAGNOSIS — In patients who develop coagulopathy or bleeding, the diagnosis of anticoagulant rodenticide is usually obtained from the history.

However, some patients present with unexplained bleeding. The diagnostic approach to these patients includes consideration of other causes of bleeding and is discussed separately. (See "Approach to the child with bleeding symptoms", section on 'Diagnostic approach'.)

MANAGEMENT — The management of anticoagulant rodenticide poisoning is discussed separately. (See "Anticoagulant rodenticide poisoning: Management".)

ADDITIONAL RESOURCES

Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)

In addition, some hospitals have clinical and/or medical toxicologists available for bedside consultation and/or inpatient care. Whenever available, these are invaluable resources to help in the diagnosis and management of toxic exposures.

Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: General measures for acute poisoning treatment" and "Society guideline links: Treatment of acute poisoning caused by specific agents other than drugs of abuse".)

SUMMARY AND RECOMMENDATIONS

Mechanism of action – Anticoagulants rodenticides (warfarins and "superwarfarins") work by inhibiting vitamin K-1,25 epoxide reductase, which is required for the regeneration of vitamin K and subsequent activation (gamma-carboxylation) of vitamin K-dependent clotting factors II, VII, IX, and X, and proteins C, S, and Z. (See 'Formulations and chemical agents' above and 'Mechanism of action' above.)

Clinical manifestations – Large ingestions, often suicidal in nature and involving consumption of bait pellets by adolescents and adults, can lead to profound and prolonged anticoagulation with serious or life-threatening hemorrhage, including gastrointestinal, genitourinary, and intracranial bleeding commencing at 24 to 48 hours after exposure. The most common area of significant bleeding seen after exposure is frank hematuria with abdominal or flank pain. (See 'Clinical manifestations' above.)

Patients examined within 24 hours of exposure will not have yet developed coagulopathy and should not be expected to have signs of bruising or bleeding.

Role of ancillary studies – Laboratory evidence of coagulopathy is typically delayed for 24 to 48 hours after exposure. The laboratory evaluation of patients with anticoagulant rodenticide exposure varies according to the estimated ingested dose and the type of exposure (see 'Ancillary studies' above):

Unintentional nontoxic exposures – No laboratory assessment is needed in children or older patients with clearly unintentional ingestion of nontoxic amounts of anticoagulant rodenticides who are not on anticoagulant therapy or who do not have an underlying medical condition (eg, liver disease) that is associated with abnormal coagulation. (See 'Unintentional nontoxic exposures' above.)

Unintentional toxic exposures – Patients with unintentional toxic exposures and who are otherwise healthy and not receiving anticoagulant therapy warrant measurement of prothrombin time (PT) and international normalized ratio (INR) at 48 to 72 hours after exposure. Patients on anticoagulant therapy or with underlying medical conditions (eg, liver disease) that may be associated with abnormal coagulation should have a baseline measurement of PT and INR as soon as possible after the ingestion and repeated measurement 48 to 72 hours after exposure. (See 'Unintentional toxic exposures' above.)

Intentional or chronic exposures – We recommend that patients with intentional (self-harm, abuse, or malicious intent) or chronic ingestions, regardless of reported amount, undergo measurement of a PT, an INR, and a partial thromboplastin time (aPTT) during the initial presentation to the emergency department. Patients who are suicidal should also undergo laboratory assessment for coingestants based upon clinical findings and warrant measurement of an acetaminophen concentration even if asymptomatic. (See 'Intentional or chronic exposures' above.)

Patients with coagulopathy or bleeding – Additional studies should be obtained in patients with any evidence of bleeding on physical examination or coagulopathy on laboratory testing and include the following (see 'Patients with coagulopathy or bleeding' above):

-Complete blood count with differential

-Type and screen for blood products or, if significant bleeding, type and cross match

-Urine dipstick for blood

-Plasma fibrinogen and serum fibrin degradation products

-Stool for guaiac

Other laboratory or imaging studies may also be indicated depending upon the specific sites of bleeding (eg, electrolytes, blood urea nitrogen, serum creatinine, and ultrasound or computed tomography [CT] of the abdomen for major genitor-urinary bleeding; CT of the head for intracranial bleeding).

Role of anticoagulant concentrations – Specific anticoagulant concentrations are difficult to obtain in a timely fashion to guide clinical management of acute overdoses, and are primarily used to confirm exposure (eg, patients with factitious disorder or deliberate administration of a rodenticide as part of medical child abuse or other criminal activity). (See 'Acute or chronic exposure' above.)

Diagnosis – The diagnosis of anticoagulant rodenticide exposure is made based upon history. The diagnosis of anticoagulant rodenticide poisoning is made when coagulopathy is identified by clinical bruising and bleeding and/or prolonged PT and INRs obtained 36 to 48 hours after ingestion. The presence of measurable rodenticide concentrations in the blood also establishes the diagnosis. (See 'Diagnosis' above.)

Management – The management of anticoagulant rodenticide poisoning is discussed separately. (See "Anticoagulant rodenticide poisoning: Management".)

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