Sage Journals: Discover world-class research

Abstract

Introduction:

Development of coagulopathy after anticoagulant rodenticide ingestion varies among patients. This study aimed to identify factors that were associated with coagulopathy after anticoagulant rodenticide ingestion.

Methods:

This was a retrospective cohort study, conducted in the Hong Kong Poison Information Centre. All patients who reported rodenticide exposure and presented to the Accident and Emergency Department from 1 January 2010 to 31 December 2019 were recruited. Coagulopathy was defined as International Normalized Ratio of 1.3 or above.

Results:

One hundred sixty-nine patients were included in the final analysis. The median age was 44 years old. Forty-nine patients developed coagulopathy (International Normalized Ratio ⩾1.3). Univariate analysis (at p < 0.05) showed that age (p = 0.003), ingestion of first-generation anticoagulant rodenticide (p = 0.017), ingestion of more than one pack (p < 0.001), intentional ingestion (p = 0.002), hypoalbuminemia (p < 0.001), elevated alanine aminotransferase level (p = 0.041) and abnormal estimated glomerular filtration rate (p = 0.005) on presentation, and co-ingestion with paracetamol (p = 0.018) were associated with coagulopathy after anticoagulant rodenticide ingestion. Among these, ingestion of more than one pack (p < 0.001; odds ratio = 19.8; 95% confidence interval = 6.78–65.7), ingestion of first-generation anticoagulant rodenticide (p = 0.006; odds ratio = 5.2; 95% confidence interval = 1.96–15.2), hypoalbuminemia (p < 0.001; odds ratio = 22.4; 95% confidence interval = 6.17–99.0) and elevated alanine aminotransferase level on presentation (p = 0.039; odds ratio = 7.11; 95% confidence interval = 1.58–33.1) were statistically significant in the multivariate analysis.

Conclusion:

Ingestion of more than one pack and ingestion of first-generation anticoagulant rodenticides were significantly associated with the development of coagulopathy after anticoagulant rodenticide ingestion. Patients who developed hypoalbuminemia or elevated alanine aminotransferase level as a result of anticoagulant rodenticide ingestion were also significantly associated with the development of coagulopathy.

Keywords

Rodenticide warfarin superwarfarin coagulopathy

Introduction

Rodenticides are products that are designed to kill rodents, mice, and other small animals and are used for control of rodent population. Rodenticides are composed of different agents, from highly toxic agents such as sodium monofluoroacetate (SMFA), tetramine, to less toxic agents such as anticoagulants.

According to the Registered Pesticides List by the Hong Kong Agriculture, Fisheries and Conservation Department (AFCD), rodenticides that are registered in Hong Kong for household use include anticoagulants, cholecalciferol, and cellulose. The most encountered rodenticide poisoning in Hong Kong is anticoagulant rodenticide poisoning.¹ In resource rich countries such as the United Kingdom and the United States, anticoagulants are also the most common cause in rodenticide poisoning.^2,3

Anticoagulant rodenticide works by inhibiting vitamin K-1,25 epoxide reductase, an enzyme required for the regeneration of vitamin K. It interferes with the activation of vitamin K-dependent clotting factors II, VII, IX, and X, and proteins C, S and Z. The development of anticoagulation is delayed until body reserve of vitamin K is depleted and the pre-existing active coagulation factors are consumed.⁴ A new group of anticoagulant rodenticide known as “superwarfarin” or second-generation anticoagulants had been developed in view of warfarin-resistant strain of rats. This includes the second-generation 4-hydroxycoumarins: brodifacoum, bromadiolone, difenacoum, flocoumafen and the indanedione derivatives chlorophacinone and diphacinone. They have a higher potency and longer duration of action due to higher affinity for vitamin K1-epoxide reductase, the ability to disrupt the vitamin K1-epoxide cycle at more than one point, liver accumulation and high lipid solubility and enterohepatic circulation.^5,6

The clinical outcome of anticoagulant rodenticides poisoning varies among patients. Some develop coagulopathy with active bleeding, some have asymptomatic coagulopathy, while some do not develop coagulopathy.

A local epidemiological study in 2014¹ on household rodenticide poisoning with 87 patients from July 2008 to February 2012 showed that development of coagulopathy after rodenticide ingestion was significantly related to ingestion of warfarin group rodenticide and a higher ingestion dose. A study in Korea⁷ on 31 patients with vitamin K-dependent coagulopathy presumed to be caused by brodifacoum showed that coagulopathy was significantly related to lower albumin level and simultaneous ingestion of rodenticide and alcohol.

Currently, there are limited local studies on factors associated with coagulopathy in anticoagulant rodenticide poisoning. This study aimed to investigate risk factors that would predispose patients to coagulopathy in anticoagulant rodenticide poisoning.

Method

Study design

This was a retrospective cohort study based on the territory-wide database of the Hong Kong Poison Information Centre (HKPIC). The database included consultation related to poisoning cases encountered by all healthcare workers in Hong Kong, and surveillance data from voluntary reporting of poisoning cases by all Accident and Emergency Departments (AED) under the Hospital Authority.

Patients who presented to the AED and reported rodenticide exposure from 1 January 2010 to 31 December 2019 were included in the study. The patients were recruited from the database of HKPIC. Exclusion criteria included the following: (1) patients with route of exposure other than oral ingestion, (2) patients who reported exposure to non-anticoagulant type of rodenticide, (3) patients who reported exposure to unknown type of rodenticide, (4) patients with incomplete records, (5) patients with unidentified context of exposure (e.g. cases of occult superwarfarin overdose in which the circumstances of exposure is unknown), and (6) patients with unknown dosage of rodenticide ingested. Formula of rodenticide ingested was based on the clinical history from patients or informants, and/or laboratory tests on urine, serum or rodenticide samples. Cases notes were reviewed by two authors to arrive at the decision of case exclusion.

Study variables included demographic characteristics, clinical presentation, clinical outcome, cause of ingestion, type and dosage of each poison ingested, medical and drug history, laboratory investigations and results, toxicology findings, and treatment. Data were extracted from the Accident and Emergency records and Electronic Patient Record System (ePR) of the Hospital Authority.

Coagulopathy was defined as the International Normalized Ratio (INR) of 1.3 or above. The dosage of rodenticide ingested was documented as packs in this study. According to a previous local study,¹ the mean package weight for one packet of household rodenticide across 15 different brands sold in Hong Kong was weighed to be 60.7 g (range = 42.5–100 g). Dosage documented in grams in the hospital records would be converted to packs based on the mean package size of rodenticide in Hong Kong. Co-ingestion was based on clinical history and/or laboratory findings.

Results from the first liver and renal function test taken after rodenticide ingestion were used for analysis in this study. Hypoalbuminemia was defined by a value smaller than the lower limit of the reference range of the respective laboratory. Elevated alanine aminotransferase (ALT) level, alkaline phosphatase (ALP) level, and bilirubin level were defined as a value higher than the upper limit of the reference range of the respective laboratory.

Estimated glomerular filtration rate (eGFR) was calculated using the four-variable Modification of Diet in Renal Disease (MDRD) Study equation: (eGFR = 175 × standardized serum creatinine − 1.154 × age-0.203 × 1.212 (if black) × 0.742 (if female)).⁸ GFR less than 90 mL/min/1.73 m² was classified as renal impairment according to the Kidney Disease Improving Global Outcomes (KDIGO) classification.⁹

The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement Guideline was implemented in this article. This study was approved by the Hong Kong Hospital Authority Kowloon West Cluster Research Ethics Committee (reference no. KC/KE-20-01300/ER-3).

Statistical analysis

Statistical analysis was performed by R (statistical language program: https://www.r-project.org/about.html). Age and INR level were analyzed by Wilcoxon’s rank sum test to compare the difference in median age and INR level. Categorical factors were analyzed with the chi-square test or with Fisher’s exact test when at least one of the cell values was less than five. A multivariate logistic regression was performed on the significant factors from the univariate analysis. A p-value at <0.05 was regarded as statistically significant.

Results

Two hundred ninety-six patients were recruited into the study. One hundred twenty-seven patients were excluded from the study according to the exclusion criteria (Figure 1). One hundred sixty-nine patients were included in the final analysis.

Figure 1.

Flowchart of exclusion.

The median age was 44 years old (range from 11 months to 101 years old). Ninety patients (53.3%) were male and 79 patients (46.7%) were female. Forty-nine patients (29.0%) developed coagulopathy and 120 patients (71.0%) had normal clotting profiles after ingestion of anticoagulant rodenticide.

The documented rodenticide ingested included first-generation anticoagulant rodenticide: warfarin (n = 22), coumatetralyl (n = 13), bishydroxycoumarin (n = 1); second-generation anticoagulant rodenticide: bromadiolone (n = 98), brodifacoum (n = 23), mixed bromadiolone and brodifacoum (n = 5), unknown superwarfarin (n = 4), and flocoumafen (n = 2). One patient ingested mixed bromadiolone and warfarin.

One hundred forty patients (82.8%) ingested one pack of rodenticide or less, while 29 patients (17.2%) ingested more than one pack of rodenticide. One hundred forty-nine cases (88.1%) were intentional ingestion, and 20 cases were unintentional ingestion (11.8%). All the cases with unintentional ingestion had ingested less than one pack of rodenticide.

Ninety cases (41.4%) had co-ingestion, including alcohol (n = 25), sleeping pills (n = 21), paracetamol (n = 9), psychiatric medication (n = 9), household detergent (n = 8), and carbon monoxide poisoning (n = 5). Other co-ingestions included anti-hypertensive medications, oral hypoglycemic agents, insulin, histamine H2 antagonist, and traditional Chinese medicine.

Seven patients had history of liver disease, including hepatitis B carrier (n = 3), hepatitis C carrier (n = 1), fatty liver (n = 2), and liver cirrhosis (n = 1). Five patients had history of renal diseases.

On presentation, 18 patients (10.7%) had hypoalbuminemia, 72 patients (42.6%) had abnormal eGFR, and 12 patients (7.1%) had elevated ALT level. Forty-nine patients developed coagulopathy after rodenticide ingestion. The median peak INR levels was 2.2 (range = 1.3–8.6). Four patients (8.1%) suffered from bleeding symptoms (hemothorax, gum bleeding, hematuria, eye bruising, hemoptysis, and gastrointestinal bleeding); 45 patients (91.8%) were asymptomatic. Forty-one patients (83.7%) received vitamin K1 treatment. Two patients (4.1%) received fresh frozen plasma (both with INR >6.0).

Statistical analysis: deranged INR group versus normal INR group

Univariate analysis

Clinical characteristics were compared between the group that developed coagulopathy and the group that had normal clotting profile after ingestion. Age (p = 0.003), ingestion of first-generation anticoagulant rodenticide (p = 0.017), ingestion of more than one pack (p < 0.001), intentional ingestion (p = 0.002), hypoalbuminemia (p < 0.001), elevated ALT level (p = 0.041) and abnormal eGFR (p = 0.005) on presentation and co-ingestion with paracetamol (p = 0.018) had a statistically significant impact on development of coagulopathy after anticoagulant rodenticide ingestion (Table 1).

Table 1.

Comparison of clinical characteristics between the group with outcome of deranged INR and the other group.

Characteristics	Deranged INR (n = 49)	Normal INR (n = 120)	p-value
Age			0.003 ^a
Median age (years)	52	40	0.003 ^a
Gender			0.709^b
Male	25 (27.8%)	65 (72.2%)
Female	24 (30.4%)	55 (69.6%)
Formula of ingested rodenticide			0.017^b (first generation vs second generation)
First generation	16 (44.4%)	20 (55.6%)
Second generation	32 (24.4%)	100 (75.8%)
First + second generation	1 (100%)	0
Rodenticide detected in serum			0.236^b (first generation vs second generation)
First generation	11 (64.7%)	6 (35.3%)
Second generation	24 (48.0%)	26 (52.0%)
First + second generation	2 (100%)	0
Not done	7 (9.2%)	69 (90.8%)
Not detected	5 (20.8%)	19 (79.2%)
Rodenticide detected in urine			1^c (first generation vs second generation)
First generation	10 (62.5%)	6 (37.5%)
Second generation	4 (57.1%)	3 (42.9%)
Not done	13 (21.3%)	48 (78.7%)
Not detected	22 (25.9%)	63 (74.1%)
Amount of ingestion			<0.001 ^b
⩽1 pack	27 (19.3%)	113 (80.7%)
>1 pack	22 (75.9%)	7 (24.1%)
Cause of ingestion			0.002 ^c
Intention/self-harm	49 (32.9%)	100 (67.1%)
Unintentional/malicious	0 (0%)	20 (100%)
Hypoalbuminemia			<0.001 ^c
Yes	14 (77.8%)	4 (22.2%)
No	35 (23.2%)	116 (76.8%)
eGFR			0.005 ^b
Abnormal	29 (20.6%)	43 (79.4%)
Normal	20 (40.3%)	77 (59.7%)
Elevated bilirubin			1^b
Yes	2 (33.3%)	4 (66.7%)
No	47 (28.8%)	116 (71.2%)
Elevated ALP level			0.1087^b
Yes	0	7 (100%)
No	49 (30.2%)	113 (69.8%)
Elevated ALT level			0.041^b
Yes	7 (58.3%)	5 (41.7%)
No	42 (26.8%)	115 (73.2%)
Paracetamol co-ingestion			0.018 ^c
Yes	6 (66.7%)	3 (33.3%)
No	43 (26.9%)	117 (73.1%)
Alcohol co-ingestion			0.233^b
Yes	10 (40.0%)	15 (60.0%)
No	39 (27.1%)	105 (72.9%)
History of liver disease			0.674^c
Yes	1 (14.3.0%)	6 (85.7%)
No	48 (29.6%)	114 (70.4%)
History of renal disease			0.628^c
Yes	2 (40.0%)	3 (60.0%)
No	47 (28.7%)	117 (71.3%)

INR: International Normalized Ratio; eGFR: estimated glomerular filtration rate; ALP: alkaline phosphatase; ALT: alanine aminotransferase.

Bold represents the significant p value.

By the Wilcoxon rank sum test.

By the chi-square test.

By the Fisher exact test.

Multivariate logistic regression

Out of the eight factors that were significantly associated with coagulopathy after anticogulant rodenticide ingestion in the univariate study, the following four factors had reached a statistical significance at 95% confidence in the multivariate logistic regression model: ingestion of more than one pack (p < 0.001; odd ratio (OR) = 19.8; 95% confidence interval (CI) = 6.78–65.7), ingestion of first-generation anticoagulant rodenticide (p = 0.006; OR = 5.2; 95% CI = 1.96–15.2), hypoalbuminemia (p < 0.001; OR = 22.4; 95% CI = 6.17–99.0) and elevated ALT level on presentation (p = 0.039; OR = 7.11; 95% CI = 1.58–33.1). The R square value of the final logistic regression model was 0.4 (Table 2). Paracetamol co-ingestion had a near significance (p = 0.067) in the multivariate study.

Table 2.

Multivariate logistic regression model—p-value, odd ratios and 95% CI.

Factors associated with coagulopathy after anticoagulant rodenticide ingestion	p-value	Odd ratio (95% CI)
Ingestion of more than one pack	<0.001	19.8 (6.78–65.7)
Ingestion of first-generation anticoagulant rodenticide	0.006	5.2 (1.96–15.2)
Hypoalbuminemia	<0.001	22.4 (6.17–99.0)
Elevated ALT level	0.039	7.11 (1.58–33.1)

CI: confidence interval; ALT: alanine aminotransferase.

Discussion

This is the largest local retrospective study in Hong Kong on the development of coagulopathy among patients who ingested rodenticide. Around 29% of patients (n = 49) developed coagulopathy. In this study, the most common anticoagulant rodenticide agents ingested were bromadiolone (n = 98), followed by brodifacoum (n = 23) and warfarin (n = 22). This was different from the previous local study,¹ in which warfarin was the most common agent. This could represent an increase in prevalence of second-generation anticoagulant rodenticide in the market.

Factors related to development of coagulopathy (INR ⩾1.3)

Although bleeding was uncommon after rodenticide ingestion, the development of coagulopathy (29%) was not. Around 25% of our patients eventually required vitamin K1 treatment. We had identified factors that were associated with coagulopathy after rodenticide ingestion, including ingestion of more than one pack, ingestion of first-generation anticoagulant, hypoalbuminemia, and elevated ALT level on presentation. This would help early identification of high-risk group that might need close monitoring of INR level and guide the usage of vitamin K1 treatment. This was the first local study that had identified hypoalbuminemia and elevated ALT level being significantly associated with coagulopathy after anticoagulant rodenticide ingestion.

Amount of ingestion

Ingestion of larger amount of anticoagulant leads to coagulopathy. In this study, ingestion of more than one pack was significantly associated with coagulopathy, which was consistent with the previous local study.¹

Formula of anticoagulant rodenticide

Ingestion of first-generation anticoagulant was significantly associated with coagulopathy, compared to second-generation anticoagulant. In humans, the lowest published toxic dose of brodifacoum was 0.12–0.172 mg/kg.¹⁰ One textbook listed the toxic dose of second-generation anticoagulant active ingredient as greater than 0.1 mg/kg.¹¹ In acute overdose of warfarin, the toxic dose was thought to be over 0.5 mg/kg.¹²

The concentration of second-generation anticoagulant in the rodenticide in this study was around 0.005%, whereas the concentration of warfarin in the rodenticide in the study was around 0.1%, which was 20 times higher. For an average sized adult weighted 70 kg, the toxic dose of brodifacoum would be around 8.4 mg, and 35 mg for warfarin. Based on the mean package weight of rodenticide found in Hong Kong (63.7 g, range = 42.5–100 g),¹ one pack of rodenticide with warfarin 0.1% contained around 63.7 mg of warfarin (range = 42.5–100 mg), whereas one pack of rodenticide with bromadiolone 0.005% or bromadiolone 0.005% only contained around 3.19 mg of active ingredients (range = 2.13–5 mg).

Ingestion of one pack of first-generation anticoagulant could reach the toxic dose while one pack of second-generation anticoagulant might not. The much higher concentration in first-generation anticoagulant rodenticide might explain its significant association with coagulopathy after ingestion.

Albumin level

Our data suggested that hypoalbuminemia on presentation was associated with coagulopathy after anticoagulant rodenticide ingestion. Anticoagulants in rodenticides are vitamin K antagonists, which are more than 90% albumin bound in circulation. Only free, unbound vitamin K antagonist is biologically active.¹³ Hypoalbuminemia increases the free fraction of vitamin K antagonist in plasma,¹⁴ and thus enhances its anticoagulation effect. There had been studies which showed significant association between hypoalbuminemia and coagulopathy after anticoagulant usage. In a Korean study⁷ on coagulopathy after brodifacoum exposure, lower albumin level was significantly associated with coagulopathy. An observational study of 402 patients in the United Kingdom¹⁵ had shown that for patients with non-valvular atrial fibrillation receiving anticoagulation therapy with warfarin, hypoalbuminemia was a significant predictor of all bleeding in patients aged <75 years. A prospective cohort study on 755 patients in Japan¹⁶ had shown that hypoalbuminemia increases the likelihood of supratherapeutic INR control and risk of major bleeding events in patients on warfarin for atrial fibrillation.

Alanine aminotransaminase

Alanine aminotransaminase (ALT) is a transaminase enzyme most commonly found in the liver, and can also be found in various body tissues such as kidney, heart and muscles. In this study, elevated ALT level on presentation was significantly associated with coagulopathy after anticoagulant rodenticide ingestion. Liver plays an important role in drug metabolism, protein and clotting factors synthesis,¹⁷ elevated ALT can be related to hepatocyte damages. Both first- and second-generation anticoagulants undergo hepatic p450 metabolism,^5,18
–21 and thus, the rodenticide metabolism might be affected in hepatocyte damages. A study on Asian patients on warfarin initiation therapy had shown that a high ALT level was significantly associated with a high INR level (INR ⩾4).²²

We took the results from the first liver and renal function test taken after rodenticide ingestion for analysis, as the liver and renal function status prior to anticoagulant rodenticide ingestion were not available in most patients due to the retrospective nature of this study. Among the poison co-ingested by patients, paracetamol and alcohol were the ones that might cause hepatocyte injuries. In our patients with elevated ALT level (n = 12), only two had paracetamol co-ingestion and none had alcohol co-ingestion, and in our patients with hypoalbuminemia (n = 18), none had paracetamol co-ingestion and only two had alcohol co-ingestion. Although whether the elevated ALT level and hypoalbuminemia were caused by anticoagulant rodenticide ingestion could not be statistically determined in this study, it is a logical deduction that they were likely due to anticoagulant rodenticide ingestion, and that these factors were associated with the development of coagulopathy based on our statistical analysis and the literature reviewed.

Co-ingestion

One hundred four patients had co-ingestion. The most common co-ingestion was alcohol, sleeping pills, and paracetamol. Patients who co-ingested paracetamol were significantly associated with coagulopathy after rodenticide ingestion in the univariate study (p = 0.018), and were close to significance in the multivariate regression model (p = 0.067).

There had been evidence proposed on interaction between warfarin and paracetamol. Five randomized control trials were performed,^23
–27 with four showing a significant increase in INR in patients with concomitant use of warfarin and paracetamol. This could be explained by the effect of paracetamol on the level of functional factor VII. Two of the randomized control trials^25,27 also found a significant reduction in functional clotting factors in patients with concomitant use of warfarin and paracetamol. A cohort study²⁸ had also shown that in patients with paracetamol poisoning, functional factor VII and factor IX were lowered.

A previous study²⁹ had found that the toxic metabolite from paracetamol overdose N-acetyl-para-benzoquinone imine (NAPQI) interferes with vitamin K-dependent gamma-carboxylase (VKD-carb) and vitamin K epoxide reductase (VKOR) activities. These two enzymes are involved in the vitamin K cycle and their inhibition affects the regeneration of vitamin K and subsequently interferes with the activation of vitamin K-dependent clotting factors.³⁰ The near significance of paracetamol co-ingestion in our multivariate regression study could be due to small sample size of patients.

Implication in clinical practice

Based on the findings in this study, we propose an updated management flowchart for patients with anticoagulant rodenticide ingestion (Figure 2). This helps to identify patients at higher risk of coagulopathy for closer monitoring, and reduce unnecessary hospital admissions and investigations in low risk cases.

Figure 2.

Management flowchart for patients with anticoagulant rodenticide ingestion.

Patients with coagulopathy after rodenticide ingestion

Forty-nine patients in this study developed coagulopathy after ingestion of rodenticide. Four patients developed bleeding symptoms, while 45 patients with deranged INR were asymptomatic. Comparing these two groups, patients who had bleeding symptoms had a significantly higher median first deranged INR level (3.95 vs 1.53, p = 0.024). The median peak INR level were higher in the bleeding group, but the difference was not significant (4 vs 2.1, p = 0.257).

Mortality was rare in this study where only two deaths were reported (1.67%). One was an 85-year-old female who ingested one pack of bromadiolone intentionally, and developed coagulopathy with a peak INR level of 2.1. She suffered from ST-elevation myocardial infarction and died 2 days after ingestion. Another death case was a 79-year-old male with terminal lung cancer who ingested one pack of bishydroxycoumarin intentionally. He developed coagulopathy with an INR level of 1.8 and complicated with development of hemothorax. He was given vitamin K1 treatment and INR level normalized afterwards. He died 4 days after ingestion, with his cause of death documented as terminal lung cancer.

Out of 49 patients with coagulopathy, 41 patients (83.7%) received vitamin K1 treatment and 8 patients (16.3%) did not. Further studies can be performed on topics related to vitamin K1 treatment, especially the relationship between albumin level, ALT level, and/or paracetamol co-ingestion and vitamin K1 dosage and duration.

Limitations

The unit of rodenticide ingested was not unanimous among the hospital records. Most were documented in terms of packs. Some were documented in grams, and were converted to number of packs in this study based on the mean package size of rodenticides available in Hong Kong.¹ This might cause discrepancy from the true ingested dose as the package weight might vary between different brands. In addition, there are currently no quantitative tests available for measurement of rodenticide level in urine or serum samples, causing difficulty in ascertaining the exact amount of rodenticide ingested.

Twelve patients in this study were given prophylactic vitamin K1 before the first INR result was available. This might lead to a false normal INR level. It is not advised to give vitamin K1 prophylactically after rodenticide ingestion until confirmation of coagulopathy,³¹ as it may affect the subsequent monitoring of INR trend and give a false reassurance if there is a “normal” clotting profile.

In 58 cases, the toxicology tests (urine, serum or both) were negative. This could be due to the fact that tests for rodenticide identification in serum or urine samples are only available in the Toxicology Reference Laboratory (TRL) in Princess Margaret Hospital. In this study, not all samples were tested in the TRL. Laboratory toxicological confirmation tests (urine or serum) were not performed in 35 cases (20.7%). The diagnosis of anticoagulant rodenticide poisoning of these patients was solely based on the clinical history by the patients or informants.

The retrospective nature of the study and relatively small sample size may limit the power of multivariate analysis. Further studies can be performed on the association of age and underlying medical disease with development of coagulopathy after anticoagulant rodenticide ingestion.

Conclusion

Ingestion of more than one pack and ingestion of first-generation anticoagulant rodenticides were significantly associated with development of coagulopathy after anticoagulant rodenticide ingestion. Patients who developed hypoalbuminemia or elevated ALT level as a result of anticoagulant rodenticide ingestion were also significantly associated with the development of coagulopathy.

Footnotes

Acknowledgements

The authors thank Dr Tse Man Li of the Hong Kong Poison and Information Centre for his intellectual support to this study.

Author contributions

Dr K.W.T. (MBChB) designed and conceptualized the study, collected and analyzed the data, and drafted and revised the manuscript for intellectual content. Dr C.K.C. (MBBS, FHKCEM, FHKAM (Emergency medicine)) designed and conceptualized the study, interpreted the data, and revised the manuscript for intellectual content. Dr S.L. (MBBS, FHKCEM, FHKAM (Emergency medicine)) designed and conceptualized the study, interpreted the data, and revised the manuscript for intellectual content. All the authors approved the article to be published. All the authors participated sufficiently in the work to take public responsibility for appropriate portions of the content. The authors alone are responsible for its contents and writing of the article.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Availability of data and materials

The data were retrieved from the HKPIC and Clinical Management System Database of HA.

Informed consent

Written informed consent was not required by research ethics committee as this is a retrospective study without patient intervention and no identifiable patient data have been included in the manuscript.

Ethical approval

The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by The Kowloon Central Cluster Ethics Committee of the Hospital Authority (reference no. KC/KE-20-01300/ER-3).

Human rights

There were no human right conflicts to declare.

ORCID iDs

Ka Wing Tam

Shan Liu

References

Othman

Chan

Lau

The epidemiology of household rodenticides poisoning in Hong Kong and its risk factors for developing coagulopathy. Hong Kong J Emerg Med 2014; 21(6): 339–345.

Dawson

Garthwaite

. Rodenticide usage by local authorities in Great Britain. In: Foreign Agents Registration Act and Department for Environment (eds) Pesticide usage survey report 185. York, 2001, pp. 4–5.

Gummin

Mowry

Spyker

, et al. 2018 annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 36th annual report (Erratum in: Clin Toxicol (Phila) 2019; 57(12): e1). Clin Toxicol (Phila) 2019; 57(12): 1220–1413.

Ansell

Hirsh

Poller

, et al. The pharmacology and management of the vitamin K antagonists: the seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy (Erratum in: Chest 2005; 127(1): 415–416). Chest 2004; 126(Suppl. 3): 204S–233S.

Watt

Proudfoot

Bradberry

, et al. Anticoagulant rodenticides. Toxicol Rev 2005; 24(4): 259–269.

Bruno

Howland

McMeeking

, et al. Long-acting anticoagulant overdose: brodifacoum kinetics and optimal vitamin K dosing. Ann Emerg Med 2000; 36(3): 262–267.

Lee

You

Moon

, et al. Evaluation of risk factors in patients with vitamin K-dependent coagulopathy presumed to be caused by exposure to brodifacoum. Korean J Intern Med 2014; 29(4): 498–508.

Levey

Coresh

Greene

, et al. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med 2006; 145: 247–254.

National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. Am J Kidney Dis 2002; 39(2, Suppl. 1): S1–S266.

10.

Patocka

Petroianu

Kuca

Toxic potential of superwarfarin: brodifacoum. Mil Med Sci Lett 2013; 82: 32–38.

11.

Metts

Jr Stewart

Jr.

Rodenticides. In: Haddad

Shannon

Winchester

(eds) Clinical management of poisoning and drug overdose. 3rd ed. Philadelphia, PA: W.B. Saunders, 1998, pp. 864–875.

12.

Bates

Mintz

Phytonadione therapy in a multiple-drug overdose involving warfarin. Pharmacotherapy 2000; 20: 1208–1215.

13.

Ufer

Comparative pharmacokinetics of vitamin K antagonists. Clin Pharmacokinet 2005; 44: 1227–1246.

14.

Tárnoky

AL.

Warfarin and albumin. Br Med J (Clin Res Ed) 1982; 285(6344): 812.

15.

Abdelhafiz

Myint

Tayek

, et al. Anemia, hypoalbuminemia, and renal impairment as predictors of bleeding complications in patients receiving anticoagulation therapy for nonvalvular atrial fibrillation: a secondary analysis. Clin Ther 2009; 31: 1534–1539.

16.

Kawai

Harada

Motoike

, et al. Impact of serum albumin levels on supratherapeutic PT-INR control and bleeding risk in atrial fibrillation patients on warfarin: a prospective cohort study. Int J Cardiol Heart Vasc 2019; 22: 111–116.

17.

Kalra

Yetiskul

Wehrle

, et al. Physiology, liver. In: StatPearls [internet]. Treasure Island, FL: StatPearls Publishing, 2020, https://www.ncbi.nlm.nih.gov/books/NBK535438/

18.

Yip

Anticoagulant rodenticides. In: Dart

Caravati

McGuigan

(eds) Medical toxicology. Philadelphia, PA: Lippincott Williams & Wilkins, 2004, p. 1497.

19.

Lai

Ewald

. Anticoagulants. In: Shannon

Borron

Burns

(eds) Haddad and Winchester’s clinical management of poisoning and drug overdose (Vol. 1051). Philadelphia, PA: Saunders, 2007, pp. 1053–1062.

20.

Vandenbroucke

Bousquet-Melou

De Backer

, et al. Pharmacokinetics of eight anticoagulant rodenticides in mice after single oral administration. J Vet Pharmacol Ther 2008; 31(5): 437–445.

21.

Berny

de Oliveira

Videmann

, et al. Assessment of ruminal degradation, oral bioavailability, and toxic effects of anticoagulant rodenticides in sheep. Am J Vet Res 2006; 67(2): 363–371.

22.

Ohara

Takahashi

Lee

, et al. Determinants of the over-anticoagulation response during warfarin initiation therapy in Asian patients based on population pharmacokinetic-pharmacodynamic analyses. PLoS ONE 2014; 9(8): e105891.

23.

Antlitz

Awalt

LF.

A double-blind study of acetaminophen used in conjunction with oral anticoagulant therapy. Curr Ther Res Clin Exp 1969; 11(6): 360–361.

24.

Mahé

Bertrand

Drouet

, et al. Paracetamol: a haemorrhagic risk factor in patients on warfarin. Br J Clin Pharmacol 2005; 59(3): 371–374.

25.

Mahé

Bertrand

Drouet

, et al. Interaction between paracetamol and warfarin in patients: a double-blind, placebo-controlled, randomized study. Haematologica 2006; 91(12): 1621–1627.

26.

Parra

Beckey

Stevens

GR.

The effect of acetaminophen on the international normalized ratio in patients stabilized on warfarin therapy. Pharmacotherapy 2007; 27(5): 675–683.

27.

Zhang

Bal-dit-Sollier

Drouet

, et al. Interaction between acetaminophen and warfarin in adults receiving long-term oral anticoagulants: a randomized controlled trial. Eur J Clin Pharmacol 2011; 67(3): 309–314.

28.

Whyte

Buckley

Reith

, et al. Acetaminophen causes an increased International Normalized Ratio by reducing functional factor VII. Ther Drug Monit 2000; 22(6): 742–748.

29.

Thijssen

Soute

Vervoort

, et al. Paracetamol (acetaminophen) warfarin interaction: NAPQI, the toxic metabolite of paracetamol, is an inhibitor of enzymes in the vitamin K cycle. Thromb Haemost 2004; 92(4): 797–802.

30.

Stafford

DW.

The vitamin K cycle. J Thromb Haemost 2005; 3: 1873–1878.

31.

Caravati

Erdman

Scharman

, et al. Long-acting anticoagulant rodenticide poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila) 2007; 45(1): 1–22.

Anticoagulant rodenticide ingestion: Who will develop coagulopathy?

Abstract

Introduction:

Methods:

Results:

Conclusion:

Keywords

Introduction

Method

Study design

Statistical analysis

Results

Statistical analysis: deranged INR group versus normal INR group

Univariate analysis

Multivariate logistic regression

Discussion

Factors related to development of coagulopathy (INR ⩾1.3)

Amount of ingestion

Formula of anticoagulant rodenticide

Albumin level

Alanine aminotransaminase

Co-ingestion

Implication in clinical practice

Patients with coagulopathy after rodenticide ingestion

Limitations

Conclusion

Footnotes

Acknowledgements

Author contributions

Declaration of conflicting interests

Funding

Availability of data and materials

Informed consent

Ethical approval

Human rights

ORCID iDs

References