Anticoagulant Rodenticides



At the turn of the century, the rodenticides depended upon heavy metals such as arsenic, thallium and phosphorus along with red squill and strychnine.  This changed in the 1940s as investigators uncovered warfarin to be the cause of death in cattle who consumed sweet clover. The mechanism of its action was elucidated as impeding coagulation, which lead to hemorrhage as the cause of death. Warfarin was quickly adopted as the major rodenticide.  Rodent resistance to warfarin, however, became prevalent in the 1960s via autosomal dominant gene transmittance (1). Novel compounds were synthesized to combat rodent resistance, thereby creating a new class of anticoagulants- the superwarfarins, or long-acting anticoagulant rodenticides(LAAR) (2).

In 2007, the American Association of Poison Control Centers reported 12,839 exposures to anticoagulant compounds. Standard warfarin rodenticides accounted for < 3% of the total amount, leaving greater than 98% of exposures in the superwarfarin/LAAR group.  Thus, the emergence of these compounds as a source of exogenous coagulopathy in humans has become more evident in recent years.


Mechanism of Action

The oral anticoagulants can be divided into two groups, the 4-hydroxycoumarins and the indandiones (4). The most common of these include brodifacoum, difenacoum, and chlorphacinone.  Regardless of their classification, all anticoagulants work by inhibiting the generation of an active form of vitamin K1 via inhibition of vitamin K1 reductases.  Activation of clotting factors II, VII, IX, and X require the presence of vitamin K as a cofactor.  When vitamin K cannot be regenerated, clotting factors cannot be activated and a coagulopathy results involving both the extrinsic and intrinsic pathways (3).  The ratio of vitamin K1 2,3-epoxide to vitamin K1 is increased because the inactive compound cannot be reduced back to the active parent form.  This ratio has also been documented to be increased in human overdoses (5,6).

Graphic of mechanism of action of rodenticides


Studies in rats and rabbits demonstrate that the clinical effects of the LAAR at a cellular level relate to their being highly lipid soluble and highly concentrated in the liver.  Brodifacoum has been demonstrated to have zero-order kinetics following overdose (7).  Overall, these compounds are 100 times more potent than warfarin (8, 9, 10, 11). The typical warfarin-containing rodenticide contains approximately 0.025% active compound, whereas brodifacoum packages contain 0.005% (3).  The half-lives of the coagulation factors vary from 5 hours for factor VII to 60 hours for factor II, accounting for the delayed onset of anticoagulation clinically, which can vary from 24-36 hours after an overdose.  Finally, the elimination half-life of the LAAR is much prolonged when compared to warfarin.  Warfarins half-life averages 37 hours with a duration of action from 2-5 days (12), whereas the half-life of brodifacoum can be demonstrated to be as long as 156 hours in rats (10).  In human studies, the elimination half-life of brodifacoum is weeks to months (13, 14).

Clinical Presentation

Clinical effects are varied dependent upon many variables, the most important being the dose of the LAAR ingested.  Thus, it becomes crucial to distinguish between accidental and intentional exposures, as the former usually results in a smaller dose.  Acute exposure can present as vague symptoms involving the GI tract, such as nausea, vomiting, and abdominal pain (22).  Chronic exposures or overdoses present with bleeding from essentially any organ system, usually involving more than 1-2 systems simultaneously.  Epistaxis, hematuria, friable gums, petechiae, hematomas, compartment syndrome, hematemesis and melena, hemoptysis from alveolar hemorrhage, ecchymoses, and vaginal bleeding are possible presentations (5, 6, 13, 14, 16, 17, 30, 34, 35, 44-51).  To date, five deaths have been reported in the literature with the direct causes as follows: subdural bleeding (15, 19), subarachnoid hemorrhage (16), massive pulmonary hemorrhage (17), and vaginal bleeding (18).  It should be noted that the clinical signs of bleeding are usually delayed in comparison to the time of ingestion.

Differential Diagnosis

When a patient presents with a coagulopathy, other sources must be ruled out unless the history is obvious.  Decreased coagulation factors can result from congential deficiencies of coagulation factors (hemophilia, Von Wilebrands disease, etc), acquired liver dysfunction, and vitamin K deficiency from malnutrition.  In contrast, consumption of coagulation factors can be present in DIC, sepsis, snake evenomation, and hyperthermia.  Coagulation inhibitors must also be ruled out.  Finally, thrombocytopenia can cause bleeding (3). 

Laboratory Prolongation of the PT or INR (a PT ratio) is usually the first laboratory indication that a coagulopathy exists.  In severe cases, the PTT can also be prolonged, representing involvement of both the intrinsic and extrinsic coagulation systems.  Other sources of bleeding must be eliminated.  For example, in both DIC and evenomation fibrinogen will be decreased and fibrin split products increased (3).  Furthermore, coagulation inhibitors can be ruled out by mixing the patients plasma with normal plasma (6).  Measurement of the specific clotting factors clinches the diagnosis in that all four vitamin-K dependent factors will be decreased (II, VII, IX and X), while others will be normal (3).  The vitamin K1 2,3-epoxide/K1 ratio can also be measured, with a normal ration of 2-3 (6, 20).  Finally, the actual suspected rodenticide can be measured by a variety of assays: radioimmunoassay, enzyme-linked immunosorbent assay, and HPLC (3).



A review of the literature indicates no added benefit for home or health care facility decontamination for those patients with unintentional exposures (1, 21-25).  An AAPCC out-of-hospital management guideline for LAAR poisoning also recommends no gastric decontamination for small, unintentional ingestions (26).  However, limited number of adults, in whom LAAR overdose is more likely, were enrolled in these studies.  From the available data, it can be inferred that in patients who present with a recent history of ingesting a large amount of LAAR, gastric decontamination with a single dose of activated charcoal should be considered.

Reversal of coagulopathy

Symptomatic Anticoagulated Patient

If the amount of bleeding is severe, such as with intracerebral or GI hemorrhage, vaginal bleeding, or compartment syndrome, FFP is indicated to replace the deficit coagulation factors.  This can be given as needed to correct the PT and stop any clinical bleeding (3).  Simultaneously vitamin K1 therapy should be started, preferably by the subcutaneous route.  Intravenous vitamin K has been associated with anaphylactoid reactions and should be avoided (27, 28).  Dosages in the literature have ranged from 10-25 mg; the American College of Chest Physicians recommends the following (29):
serious bleeding: 10 mg
non-serious bleeding  INR 6-10: 0.5-1 mg
INR 10-20: 3-5 mg
INR > 20: 10 mg

Asymptomatic Anticoagulated Patient

If there is not active or life-threatening bleeding, but a prolonged PT, oral vitamin K1 administration is preferred.  A starting dose has been suggested as 100 mg divided TID-QID (3).  However, there are cases where >100 mg/d has been necessary to reverse a coagulopathy (30).  The half-life of vitamin K1 has been estimated as 6 hours based upon animal data (31).  In one study with a patient having an INR of 38, oral therapy was begun at 150 mg every 6 hours.  After 1 and days, the INR and PTT had returned to normal; the dose was presumed to be supertherapeutic with the assumption that oral vitamin K1 poses little toxicity (32).  No official recommendations based upon presenting INR have been postulated.  For now, the approach appears to involve titrating the dose as needed to correct the INR, with a gradual taper as time progresses (3). 

The endpoint of oral therapy is empirical.  Many case reports have continued treatment until the PT becomes normal (33, 13), with a follow-up INR 24-48 hours after discontinuation of therapy (3).  It has been hypothesized that the coagulation factor levels could be monitored until normal as an alternative to waiting for the INR to rise or clinical symptoms to develop (5); this has yet to be reported in the literature.  Finally, monitoring the vitamin K1 2,3-epoxide/vitamin K1 ratio may also prove to be of benefit (6) as INR and PTT values alone may be normal over a wide range of coagulation factor levels (5).

Asymptomatic Nonanticoagulated Patient

Acute doses of prophylactic vitamin K should not be given to a patient with a known or suspected ingestion of LAAR who is asymptomatic. Such treatment will render any future PT value (obtained if clinical symptoms develop) useless for an estimation of the amount of LAAR-induced coagulopathy.(26)  Furthermore, a life-threatening coagulopathy would develop gradually. Therefore, giving 1 or 2 doses of vitamin K will not assist in preventing this condition (4).



Patients with unintentional ingestion of less than 1 mg of LAAR active ingredient can be safely observed at home without laboratory monitoring (26).  In the unlikely event that an adult would unintentionally ingest of 1 mg or more LAAR, these patients should be evaluated for coagulopathy.  Asymptomatic individuals should be evaluated at 48-72 hours after exposure; symptomatic adults should be immediately evaluated (26).  Most of the adult presentations are that of suicide attempts (5, 16, 17, 30, 32, 33) or psychiatric disturbances (34, 35).  These patients, in addition to exposures where malicious intent or abuse is suspected, should also be referred to an emergency department (26).  Pregnant patients with unintentional ingestion of less that 1 mg of LAAR ingredient should be referred to their obstetrician or primary care provider as an anticoagulant therapy who accidentally ingest LAAR also should be referred to a health care facility for a baseline INR and a follow up IRN at 48-72 hours post ingestion (26).


Patients with unintentional ingestion of less that 1 mg of LAAR active ingredient can be safely observed at home without laboratory monitoring (26).  This includes practically all unintentional ingestions in children less than 6 years of age (see table 1).

The most serious complications resulted from possible chronic exposure versus acute accidental ingestion.  For example, in one case series bromodialone, used as a rat poison, was accessible to two children who had presumptive chronic ingestions until they presented symptomatically with a neck hematoma and hemarthosis (38).  Another case resulted in a calf hematoma and bilateral occipital hemorrhagic infarcts from brodifacoum pellets and rat droppings that contained the poison.  Although direct ingestion of these substances was never witnessed, it was inferred (42).  Finally, easy bruising and epistaxis had been noted in one child whose parents used brodifacoum rat poisoning in the home (43).  Thus, for children in whom a small amount of acute exposure to LAAR can be documented, the likelihood of clinical effects is rare. 

Table 1- Case series of children ingesting superwarfarins

AuthornTypeProlonged PT/INRTreatmentComplicationsRef
Katona (1986)8variable0/2nonenone36
Bennet (1987)25Brodifacoum/diphacinone0/16IpecacEpistaxis (1)3
Greeff (1987)2Bromodialone2/2Intubation,vit K1Neck hematoma (1), hemarthrosis (1)38
Sullivan (1989)82variable0/39Ipecac, ACnone21
Smolinske (1989)110variable8/110Dilution, ipecacVomiting (2), heme positive stool (3)22
Morrissey (1995)1790variable1/78Ipecacnone1
Chua (1998)8variable1/8Ipecac, vit K1none39
Shepherd (1998)10733Brodifacoum39/10733GI decontamination- not specifiedMinor bleeding (16)- not specified23
Wahl (1999)751variable0/64Ipecac, ACnone24
Ingels (2000)465variable2/243noneEpistaxis (2)25
Mullins (2000)542variable1/456Not specifiednone40

Jenny L. Thacker, M.D., Nov 2001, Minnesota Poison Control System, Hennepin County Medical Center.

Revised 11/09, Laurie Willhite, PharmD, CSPI


1. Morrissey, B., et al: Washingtons experience and recommendations re: anticoagulant rodenticides.  Vet Hum Toxicol 1995; 37: 362-363.
2. Hadler, M.R., et al: Novel 4-hydroxycoumarin anticoagulants active against resistant rats. Nature 1975; 253: 275.
3. Burkhart, K. K.: Anticoagulant rodenticides. Clinical Toxicology, 1st ed. WB Saunders, 02000; 848-853.
4. Hoffman, R.S.: Anticoagulants.  Goldfranks Toxicologic Emergencies, 6th ed. Appleton and Lange, 1996; 703-718.
5. Hoffman, R.S., et al: Evaluation of coagulation factor abnormalities in long-acting anticoagulation overdoses. J Toxicol Clin Toxicol 1988: 26: 233-248.
6. Ross, G.S., et al: An acquired hemorrhagic disorder from long-acting rodenticide ingestion. Arch Int Med 1992: 152: 410.
7. Bruno, G.R., et al: Elimination kinetics of brodifacoum and serum vitamin K1 concentrations in long-acting anticoagulant overdose. J Toxicol Clin Toxicol 1996; 34: 568.
8.  Leck, J.B., et al: A comparative study of the effects of warfarin and brodifacoum on the relationship between vitamin K1 metabolism and clotting factor activity in warfarin-susceptible and warfarin-resistant rats.  Biochem Pharmacol 1991; 30: 123-128.
9. Park, B.K., et al: A comparison of vitamin K antagonism by warfarin, difenacoum and brodifacoum in the rabbit.  Biochem Pharmacol 1982; 31: 3635-3639.
10. Bachmann, K.A., et al: Dispositional and pharmacodynaminc characteristics of brodifacoum in warfarin-sensitive rats. Pharmacology 1983; 27: 281-288.
11. Breckenridge, A., et al: A study of the relationship between the pharmacokinetics and pharmacodynamics of the 4-hydroxycoumarin anticoagulants warfarin, difenacoum and brodifacoum in the rabbit.  Br J Pharmacol 1985; 84: 81.
12. Benet, L.Z, et al: Design and optimization of dosage regiments: pharmacokinetic data.  Goodman and Gillmans The Pharmacologic Basis of Therapeutics.   1985; 1713. 
13. Hollinger, B.R., et al: Case management and plasma half-life in a case of brodifacoum poisoning.  Arch Int Med 1993; 153: 1925.
14. Weitzel, J.N., et al: Surreptitious ingestion of a long-acting vitamin K antagonist/rodenticide, brodifacoum.  Blood 1990; 76: 2555-2559.
15. Baseshore, L.M., et al: Death following ingestion of superwarfarin rodenticide: a case report. Vet Hum Toxicol 1987; 29: 459.
16. Kruse, J.A., et al: Fatal rodenticide poisoning with brodifacoum.  Ann of Emerg Med 1992; 21: 331-336.
17. Palmer, R.B, et al: Fatal brodifacoum rodenticide poisoning: autopsy and toxicologic findings.  J of Forensic Sci 1999; 44: 851-855.
18. Routh, C.R., et al: Superwarfarin ingestion and detection.  Am J of Hematol 1991; 36: 50.
19. Helmuth, R.A., et al: Fatal ingestion of a brodifacoum-containting rodenticide. Lab Med 1989; 20:25.
20. Brechtold, H., et al: Plasma vitamin K1-2,3 epoxidase diagnostic aid to detect surreptitious ingestion of oral anticoagulants.  Lancet 1983; 1: 596.
21. Sullivan, M.P., et al: Long-acting anticoagulant rodenticides: an evaluation of  88 cases.  Vet Hum Toxicol 1989; 31: 361.
22. Smolinske, S.C., et al: Superwarfarin poisoning in children: a prospective study. Pediatrics 1989; 84: 490-494.
23.  Shepherd, G., et al: Acute pediatric brodifacoum ingestions. Clinical Toxicology 1998; 36: 464.
24.  Wahl, M., et al: A retrospective review of triage criteria of accidental long-acting anticoagulant rodenticide ingestions in children. European Association of Poison Centres and Clinical Toxicologists (XIX International Congress) 1999; Abstract # 19.
25.  Ingels, M., et al: A prospective study of acute unintentional pediatric superwarfarin ingestions without decontamination. Clin Toxicol 2000; 38: 556.
26.  Caravati, EM, et al.  Long-acting anticoagulant rodenticide poisoning: an evidence bases consensus guideline for out-of-hospital management.  Clin Tox 2007; 45: 1-22.27 Rubia, J., et al: Anaphylactic shock and vitamin K1. Ann Int Med 1989; 110: 943.
27.  OReilly, R.A. et al: Intravenous vitamin K1 injection: dangerous prophylaxis. Arch Int Med 1995; 155: 2127.
28.  Becker, R.C., et al: Antithrombotic therapy: an abbreviated reference for clinicians. Arch Int Med 1995; 155: 149.
29.  Sheen, S.R., et al: Symptomatic brodifacoum ingestion requiring high dose phytonadione therapy. Vet Hum Toxicol 1992; 12: 309.
30. Park, B.K., et al: Plasma disposition of vitamin K1 in relation to anticoagulant poisoning. Br J Pharmacol 1984; 18: 655-662.
31. Bruno, G.R., et al: Long-acting anticoagulant overdose: brodifacoum kinetics and optimal vitamin K dosing. Ann Emerg Med 2000; 36: 262-267.
32. Jones, E.C., et al: Prolonged anticoagulation in rat poisoning. JAMA 1984; 252: 3005-3006.
33. Lipton, R.A. et al: Human ingestion of a superwarfarin rodenticide resulting in a prolonged anticoagulant effect. JAMA 1984: 252: 3004-3005.
34. Berry, R.G., et al: Surreptitious superwarfarin ingestion with brodifacoum. South Med J 2000; 93: 74-75.
35. Katona, et al: Anticoagulant rodenticide poisoning. Vet Hum Toxicol 1986; 28: 478.
36. Bennett, D.L., et al: Long-acting anticoagulant ingestion: a prospective study. Vet Hum Toxicol 1987; 29: 472.
37. Greeff, M.C., et al: Superwarfarin (bromodialone) poisoning in two children resulting in prolonged anticoagulation. Lancet 1987; 2: 1269.
38. Chua, et al: Superwarfarin poisoning. Arch Intern Med 1998; 158: 1929-1932.
39. Mullins, M.E., et al: Unintentional pediatric superwarfarin exposures: do we really need a prothrombin time? Pediatrics 2000; 105: 402-404.
40.  Babcock, J., et al: Rodenticide-induced coagulopathy in a young child. Am J Ped Hematol Oncol 1993; 15: 126.
41. Watts, R.G., et al: Accidental poisoning with a superwarfarin compund (brodifacoum) in a child. Pediatrics 1990; 86: 883-887.
42. Travis, S.F., et al: Spontaneous hemorrhage associated with accidental brodifacoum poisoning in a child. J Ped 1993; 122: 982-984.
43. Chow, E.Y., et al: A case of bromadiolone (superwarfarin) ingestion. Can Med Assoc J 1992; 147: 60-62.
44. Tecimer, C., et al: Surreptitious superwarfarin poisoning with brodifacoum. South Med J1997; 90: 1053-1055.
45.  Exner, D.V., et al: Superwarfarin ingestion. Can Med Assoc J 146: 34-35.
46. Morgan, B.W., et al: Spontaneous hemoperitoneum from brodifacoum overdose. Am L Emerg Med 1996; 14: 656-659.
47. Butcher, G.P, et al: Difenacoum poisoning as a cause of hematuria. Hum and Exp Toxicol 1992; 11: 553-554.
48. McCarthy, P.T., et al: Covert poisoning with difenacoum: clinical and toxicological observations. Hum and Exp Toxicol 1997; 16: 166-170.
49. Barnett, V.T., et al: Diffuse alveolar hemorrhage secondary to superwarfarin ingestion. Chest 1992; 102: 1301-1302.
50. Corke, P.J.: Superwarfarin (brodifacoum) poisoning. Aneaesth Intens Care 1997; 25: 707-709.


View full site