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Classifications

Harrison's Part

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Mappings

MONDO

MONDO:0029000 poisoning Not Yet Curated

MONDO has no chlorophacinone-, indanedione-, or rodenticide-specific poisoning term. MONDO:0029000 is the nearest ancestor concept and is recorded as a broad cross-reference only.

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Discussions and Knowledge Gaps

5

Does loss of gamma-carboxylation of the anticoagulant proteins C and S explain the thrombotic events reported in anticoagulant rodenticide poisoning?

KNOWLEDGE GAP protein_c_s_paradoxical_thrombosis

Attached to

pathophysiology#Impaired Gamma-Carboxylation of Vitamin K-Dependent Clotting Factors

Proteins C and S are vitamin K-dependent substrates of the same hepatic carboxylase as factors II, VII, IX and X, so a vitamin K antagonist depletes anticoagulant and procoagulant proteins together. Thrombotic events, including a fatal cerebral vein thrombosis reported as a suspected chlorophacinone poisoning, occur in this class and are difficult to reconcile with pure anticoagulation. No cited source here measures protein C or protein S activity in a chlorophacinone poisoning, so the mechanism is left as an open question rather than curated as a causal edge.

Show evidence (2 references)

PMID:16716547 SUPPORT DIRECT Human Clinical

"The authors report a case of suspicious chlorophacinone poisoning with a problematic diagnosis."

Reports a fatal thrombotic event in a chlorophacinone poisoning. The paper's own wording is "suspicious" with a "problematic diagnosis", so it is cited here as a case that raises the question, not as a settled attribution.

PMID:26239439 SUPPORT INDIRECT Human Clinical

"Long-acting anticoagulant rodenticide-induced paradoxical thrombosis and thrombotic complications accompanying hemostatic therapy have also been observed."

Confirms paradoxical thrombosis is observed across the class and separates it from thrombosis caused by haemostatic therapy. Marked indirect because it reports the observation without testing a mechanism.

Why does chlorophacinone-induced hypocoagulability persist after plasma chlorophacinone concentrations have fallen to low values?

KNOWLEDGE GAP persistence_after_plasma_clearance

Attached to

pathophysiology#Hepatic Accumulation and Prolonged Elimination

In a monitored human poisoning the hypocoagulability outlasted the measurable plasma concentration. The treating authors offered two candidate explanations, accumulation in target cells and an unidentified active metabolite, and distinguished neither. Which of the two operates determines whether plasma chlorophacinone concentration is a usable guide to stopping vitamin K therapy.

Proposed experiments

Paired hepatic and plasma chlorophacinone measurement with metabolite profiling

chlorophacinone_metabolite_vs_compartment

Measure chlorophacinone and its metabolites in plasma alongside INR through the resolution phase of human poisonings, with untargeted metabolite profiling, to determine whether a persisting parent compound compartment or an active metabolite accounts for the residual effect.

Show evidence (3 references)

PMID:23109180 SUPPORT INDIRECT Model Organism

"Extensive metabolism of chlorophacinone was also found, and was similar (in nature and proportion of metabolites) across strains (3 OH-metabolites identified)."

Three hydroxy-metabolites of chlorophacinone have been identified in rat, so the metabolite arm of this question is not that no metabolite is known but that none has been shown active in humans. Marked indirect because the work is in rat.

PMID:23109180 SUPPORT INDIRECT Model Organism

"Accumulation of chlorophacinone occurs from day 1 to day 4, and an equilibrium is reached, suggesting rapid elimination."

Cuts against the tissue-accumulation arm: hepatic chlorophacinone reaches a plateau within four days in rat, which the authors read as rapid elimination rather than indefinite retention. Marked indirect because the work is in rat and because the human coagulopathy is what needs explaining.

PMID:10216974 SUPPORT INDIRECT Human Clinical

"Chlorophacinone accumulation in target cells or existence of an unidentified metabolite may explain persistence of the hypocoagulability syndrome at low plasmatic concentrations of chlorophacinone."

States the unresolved alternative explanations directly.

Should chlorophacinone be curated as a first-generation anticoagulant rodenticide or as a long-acting anticoagulant rodenticide?

INTERPRETATION first_generation_versus_long_acting

Two authoritative sources place chlorophacinone in opposite groups, and both are right on their own terms. Watt and colleagues group it with the long-acting rodenticides on human duration of effect. Esther and colleagues list it with warfarin and coumatetralyl as first-generation, which is a statement about rodent potency and the number of feeds needed to kill a rat. "Generation" is a rodent-efficacy term and "long-acting" is a human-toxicology term, so chlorophacinone is first-generation by potency and long-acting by duration. The distinction matters clinically, because the first-generation label wrongly implies a warfarin-length course of treatment. This entry curates the human-toxicology reading and records the conflict rather than resolving it silently.

Show evidence (2 references)

PMID:16499407 SUPPORT DIRECT Other

"This group includes the second generation 4-hydroxycoumarins brodifacoum, bromadiolone, difenacoum, flocoumafen and the indanedione derivatives chlorophacinone and diphacinone."

Places chlorophacinone in the long-acting anticoagulant rodenticide group.

PMID:24781908 SUPPORT DIRECT Other

"Anticoagulants of the first generation (warfarin, chlorophacinone, coumatetralyl) as well as bromadiolone and difenacoum are not an option for the control of resistant Norway rats."

Places chlorophacinone in the first-generation group, in a rodent-control context.

Do indandione anticoagulants, chlorophacinone among them, uncouple oxidative phosphorylation, and does that contribute to human toxicity beyond the coagulopathy?

KNOWLEDGE GAP indandione_mitochondrial_uncoupling

Attached to

pathophysiology#Systemic Chlorophacinone Exposure

Toxicology reference texts repeatedly describe the indandiones as uncouplers of oxidative phosphorylation, a property the 4-hydroxycoumarins are said to lack, and attribute cardiopulmonary and neurologic injury in laboratory rodents to it. The claim is not curated here because no primary source for it could be located: PubMed queries pairing chlorophacinone, and separately indandione, diphacinone and pindone, with uncoupling, mitochondria and oxidative phosphorylation returned no records. The gap is recorded rather than the claim, because a widely repeated mechanism with no retrievable primary citation is worth flagging. Note that chlorophacinone does have a documented off-target activity, FXR antagonism, cited below; the absent evidence is for uncoupling in particular, not for off-target action in general.

Proposed experiments

Respirometry of isolated mitochondria exposed to chlorophacinone

chlorophacinone_mitochondrial_respirometry

Measure oxygen consumption, membrane potential and ATP synthesis in isolated hepatic and cardiac mitochondria across a chlorophacinone concentration range spanning those reached in human poisoning, against a 4-hydroxycoumarin comparator and a known uncoupler control, to establish whether the uncoupling property exists and at what concentration.

The cited evidence item records a different off-target mechanism rather than the uncoupling claim itself. No source is offered for uncoupling, because that is the point of the entry: attaching a reference that does not make the claim would defeat it.

Show evidence (1 reference)

PMID:27773686 SUPPORT INDIRECT In Vitro

"Our results showed that chlorophacinone and ivermectin had distinct modes of action (MOA) in modulating FXR-coregulator interactions and compound selectivity against the four aforementioned functionally-relevant nuclear receptors."

Chlorophacinone has a documented off-target activity, antagonism of the nuclear receptor FXR in a validated screen. It is cited here so this gap is not read as "chlorophacinone has no off-target activity"; what lacks a primary source is uncoupling specifically. Marked indirect because the assays are cell-based and the paper makes no claim about human poisoning.

Does the published argument against using cytochrome P450 inducers in long-acting anticoagulant rodenticide poisoning apply to chlorophacinone?

INTERPRETATION cyp_induction_transferability

Attached to

pathophysiology#Hepatic Accumulation and Prolonged Elimination

This entry curates phenobarbital enzyme induction as a reported adjunct. A published position argues against CYP inducers in this poisoning, but its reasoning is specific to brodifacoum, which the authors state does not undergo significant hepatic metabolism. Chlorophacinone does: three hydroxy-metabolites have been identified and metabolism is described as extensive in rat. The argument therefore does not obviously transfer, and the two chlorophacinone reports that used phenobarbital are uncontrolled single patients. Recorded as an open interpretation rather than settled either way, because the safety objection about sedating a bleeding patient stands regardless of the metabolism question.

Show evidence (3 references)

PMID:30689138 SUPPORT INDIRECT Other

"Therefore, we propose that CYP inducers should not be used to accelerate the clearance of brodifacoum from poisoned patients, but that alternative approaches such as reducing enterohepatic recirculation of brodifacoum, or using lipid emulsions to scavenge brodifacoum throughout the body, be considered."

States the position being weighed, in full: the authors do not simply reject enzyme induction, they redirect to interrupting enterohepatic recirculation or scavenging the drug. Marked indirect because it is a proposal about brodifacoum, not chlorophacinone.

PMID:30689138 SUPPORT INDIRECT Other

"unlike warfarin, brodifacoum does not undergo significant metabolism in the liver, nor have the effects of phenobarbital on vitamin K1 metabolism been previously determined"

Gives the premise on which that position rests, which is the premise that may not hold for chlorophacinone. Marked indirect for the same reason.

PMID:23109180 SUPPORT INDIRECT Model Organism

"Extensive metabolism of chlorophacinone was also found, and was similar (in nature and proportion of metabolites) across strains (3 OH-metabolites identified)."

Chlorophacinone, unlike brodifacoum, is extensively metabolised, which is why the argument may not transfer. Marked indirect because the work is in rat.

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Pathophysiology

9

Systemic Chlorophacinone Exposure

Chlorophacinone enters the body by ingestion of bait or concentrate. Inhalational and transcutaneous routes are documented for the anticoagulant rodenticides as a class; the cited source does not attribute either specifically to chlorophacinone. Ingested doses reported in human cases span roughly 100 mg to nearly 2 g, and plasma concentrations after a large deliberate ingestion reach the tens of mg/L.

Downstream

Vitamin K Epoxide Reductase Inhibition Absorbed chlorophacinone reaches the hepatocyte endoplasmic reticulum and binds the vitamin K epoxide reductase complex.

Hepatic Accumulation and Prolonged Elimination The absorbed compound partitions into liver, where it is retained far longer than plasma concentrations alone would suggest.

Show evidence (3 references)

PMID:10216974 SUPPORT DIRECT Human Clinical

"Comprehensive testing for abused and therapeutic drugs in blood confirmed chlorophacinone (maximum plasma level: 27.6 mg/L), an antivitamin K (AVK) rodenticide."

Documents measured systemic chlorophacinone exposure in a human poisoning and identifies the compound as a vitamin K antagonist.

PMID:10216974 SUPPORT DIRECT Human Clinical

"A 33-year-old man was admitted 8 hours after voluntary ingestion of 1875 mg of chlorophacinone (C'Operat 750 mL)."

Gives the ingested dose in a deliberate human chlorophacinone poisoning.

PMID:26239439 SUPPORT INDIRECT Human Clinical

"Inhalational, transcutaneous, and oral routes of exposure have been documented."

Establishes the routes of exposure for the long-acting anticoagulant rodenticide class. Marked indirect because the review reports routes for the class as a whole and does not attribute each route to chlorophacinone specifically.

Vitamin K Epoxide Reductase Inhibition

Chlorophacinone inhibits the vitamin K 2,3-epoxide reductase complex (VKORC1) in the hepatocyte endoplasmic reticulum. VKORC1 normally reduces vitamin K 2,3-epoxide back to vitamin K hydroquinone; blocking it halts the vitamin K cycle at the epoxide step.

hepatocyte CL:0000182

VKORC1 hgnc:23663

vitamin K epoxide reductase activity GO:0047057 ↓ DECREASED

Downstream

Depletion of the Reduced Vitamin K Pool With the epoxide reductase blocked, vitamin K 2,3-epoxide accumulates and the hydroquinone pool available as carboxylase cofactor falls.

Show evidence (4 references)

PMID:26239439 SUPPORT INDIRECT Other

"Long-acting anticoagulant rodenticides (LAARs) inhibit vitamin K epoxide reductase (VKOR)."

Names VKOR as the molecular target for the long-acting anticoagulant rodenticides. Marked indirect because the sentence is class-level and does not name chlorophacinone.

PMID:35970209 SUPPORT INDIRECT Computational

"Computational analysis of binding predictions found out that the brown rat S149I mutation predicted a high reduction of the binding affinity of chlorophacinone and brodifacoum ARs"

Chlorophacinone is modelled as a VKORC1 ligand whose binding is abolished by a VKORC1 active-site substitution, which is evidence that VKORC1 is its target. Marked indirect because the binding is predicted computationally, in rat VKORC1 rather than human.

PMID:31857739 SUPPORT INDIRECT Other

"The mechanism of action is by inhibition of vitamin K epoxide reductase, resulting in the inability of the body to recycle vitamin K."

States epoxide reductase inhibition and the resulting failure to recycle vitamin K. Marked indirect because the review covers the long-acting rodenticides as a class. Note also that the review frames the class as warfarin derivatives, which chlorophacinone is not: it is an indanedione, so the review's structural reasoning about bulky aromatic sidechains does not carry over even though the enzyme target does.

+ 1 more reference

Depletion of the Reduced Vitamin K Pool

The hepatic pool of reduced vitamin K (hydroquinone) is depleted because the epoxide formed at each carboxylation cycle cannot be recycled. Dietary vitamin K intake alone does not replace it at the rate the cycle consumes it, which is why exogenous vitamin K1 in gram-scale cumulative doses is the antidote.

vitamin K metabolic process GO:0042373 ↓ DECREASED

Downstream

Impaired Gamma-Carboxylation of Vitamin K-Dependent Clotting Factors Gamma-glutamyl carboxylase requires vitamin K hydroquinone as cofactor, so the depleted pool limits carboxylation directly.

Show evidence (1 reference)

PMID:3222685 SUPPORT DIRECT Human Clinical

"Under high dose vitamin K therapy the Quick was rapidly corrected but fell again on each vitamin K withdrawal."

Correction on exogenous vitamin K and relapse on its withdrawal is the clinical signature of a depleted, pharmacologically unreplenishable reduced vitamin K pool in a chlorophacinone-poisoned patient.

Impaired Gamma-Carboxylation of Vitamin K-Dependent Clotting Factors

Hepatic gamma-glutamyl carboxylase can no longer convert glutamate residues in the Gla domains of the vitamin K-dependent proteins to gamma-carboxyglutamate. The affected proteins are prothrombin (factor II) and factors VII, IX and X, together with the anticoagulant proteins C and S. Under-carboxylated Gla domains cannot chelate calcium and so cannot dock the factor onto anionic phospholipid membranes.

hepatocyte CL:0000182

GGCX hgnc:4247 F2 hgnc:3535 F7 hgnc:3544 F9 hgnc:3551 F10 hgnc:3528 PROC hgnc:9451 PROS1 hgnc:9456

peptidyl-glutamic acid carboxylation GO:0017187 ↓ DECREASED

Downstream

Functional Deficiency of Coagulation Factors II, VII, IX and X Under-carboxylated factors are secreted but cannot assemble on membranes, so measured factor activity falls.

Show evidence (1 reference)

PMID:16499407 SUPPORT INDIRECT Other

"Anticoagulant rodenticides inhibit vitamin K(1)-2,3 epoxide reductase and thus the synthesis of vitamin K and subsequently clotting factors II, VII, IX and X."

Identifies factors II, VII, IX and X as the affected proteins. Marked indirect because the abstract does not itself use the term gamma-carboxylation.

Functional Deficiency of Coagulation Factors II, VII, IX and X

Circulating activity of prothrombin and factors VII, IX and X falls. Because factor VII has the shortest half-life of the four, the prothrombin time and INR move first; the activated partial thromboplastin time follows as factors IX, X and II decline.

F2 hgnc:3535 F7 hgnc:3544 F9 hgnc:3551 F10 hgnc:3528

Downstream

Prolonged Coagulopathy Loss of the four factors disables both the extrinsic and the common coagulation pathway, giving a global clotting defect.

Show evidence (2 references)

PMID:3222685 SUPPORT DIRECT Human Clinical

"Prothrombin time (and vitamin K dependent factors VII and X) finally normalized only 7 weeks after chlorophacinone ingestion."

Reports factor VII and factor X activity as the quantities that were depressed and later normalized after chlorophacinone ingestion.

PMID:16499407 SUPPORT INDIRECT Other

"If active bleeding occurs, prothrombin complex concentrate (which contains factors II, VII, IX and X) 50 units/kg, or recombinant activated factor VII 1.2-4.8 mg or fresh frozen plasma 15 mL/kg (if no concentrate is available) and phytomenadione 10mg intravenously (100 microg/kg bodyweight for a..."

Replacing exactly factors II, VII, IX and X is the recommended haemostatic response, which corroborates that those four are the deficient proteins. Marked indirect because this is a therapeutic recommendation, not a direct measurement of factor levels.

Hepatic Accumulation and Prolonged Elimination

Chlorophacinone is lipid-soluble, accumulates in liver and undergoes enterohepatic recirculation, so its biological half-life is long and grows longer with larger ingested doses. This is the property that separates the long-acting rodenticides from warfarin clinically, and it is what makes the coagulopathy last weeks rather than days. Chlorophacinone is nevertheless shorter-acting than the second-generation compounds: the class treatment durations reported in reviews are driven by brodifacoum and should not be read as a chlorophacinone expectation.

Downstream

Prolonged Coagulopathy Because drug persists in liver after plasma levels fall, inhibition of the vitamin K cycle continues and the coagulopathy rebounds whenever vitamin K replacement stops.

Show evidence (3 references)

PMID:16499407 SUPPORT INDIRECT Other

"The greater potency and duration of action of long-acting anticoagulant rodenticides is attributed to their: (i) greater affinity for vitamin K(1)-2,3-epoxide reductase; (ii) ability to disrupt the vitamin K(1)-epoxide cycle at more than one point; (iii) hepatic accumulation; and (iv) unusually..."

Names hepatic accumulation, lipid solubility and enterohepatic circulation as the basis for the prolonged action of the long-acting group, to which the same review assigns chlorophacinone. Marked indirect because the sentence is about the class. Only clauses (iii) and (iv), hepatic accumulation and long biological half-life, are curated on this node. Clauses (i) and (ii), greater VKOR affinity and disruption of the cycle at more than one point, are deliberately not carried over: this entry also records that rodent-efficacy sources call chlorophacinone first-generation, which is a statement about lower potency, so a class-level affinity claim cannot be asserted for it here.

PMID:2769823 SUPPORT DIRECT Human Clinical

"The determination of half-lives was investigated and the results indicate that the greater the quantity absorbed, the longer the half-life."

Measures chlorophacinone half-life in three human poisonings and shows it lengthens with dose, the kinetic behaviour of a saturable accumulating compartment.

PMID:10216974 SUPPORT INDIRECT Human Clinical

"Chlorophacinone accumulation in target cells or existence of an unidentified metabolite may explain persistence of the hypocoagulability syndrome at low plasmatic concentrations of chlorophacinone."

Observes that the coagulopathy outlasts measurable plasma chlorophacinone. Marked indirect because the authors offer tissue accumulation as one of two candidate explanations rather than demonstrating it.

Prolonged Coagulopathy

The clotting defect is global, severe and long-lived. Prothrombin time, INR and activated partial thromboplastin time are grossly prolonged, often beyond the measurable range of the assay, and normalization can take weeks to months after a single large ingestion.

blood coagulation GO:0007596 ↓ DECREASED hemostasis GO:0007599 ↓ DECREASED

Downstream

Multicompartment Hemorrhage With thrombin generation crippled, haemostatic plugs cannot be stabilized, so bleeding occurs at mucosal surfaces, into soft tissue and into any internal organ.

Show evidence (2 references)

PMID:2769823 SUPPORT DIRECT Human Clinical

"The data collected in this study confirm the particularly prolonged anticoagulant effect of this compound and show that the knowledge of plasma concentrations may be very useful for clinicians"

Confirms the prolonged anticoagulant effect from serial measurements in three human chlorophacinone intoxications.

PMID:3222685 SUPPORT DIRECT Human Clinical

"Her Quick time at admission was less than 10% (Prothrombin time 79 sec., normal control 12 sec.)."

Quantifies the severity of the coagulopathy at presentation in a chlorophacinone poisoning.

Multicompartment Hemorrhage

Bleeding is characteristically multifocal rather than confined to one site. Mucocutaneous bleeding predominates, with haematuria the single most frequently reported manifestation, and haemorrhage into serous cavities, muscle and the central nervous system also occurs.

hemostasis GO:0007599 ↓ DECREASED

Animal models

Accidental chlorophacinone poisoning in calves Cattle recapitulates Reproduces the multicompartment haemorrhage of human chlorophacinone poisoning, with the same agent confirmed analytically in tissue.

Accidental chlorophacinone poisoning in lambs Sheep recapitulates Reproduces multicompartment haemorrhage with epistaxis as the presenting sign, in a second ruminant species and at liver concentrations roughly sixfold below the calf series.

Downstream

Hypovolemic Shock and Death Continued blood loss, or haemorrhage into a closed and unforgiving compartment such as the cranium, is what kills.

Show evidence (2 references)

PMID:40974629 SUPPORT INDIRECT Human Clinical

"Multi-organ hemorrhage was the predominant clinical manifestation, with hematuria being the most frequently reported symptom (n = 39)."

Establishes multi-organ haemorrhage as the dominant presentation across 88 human anticoagulant rodenticide poisonings, which is what this node claims. Marked indirect because the series pools rodenticides and does not report a chlorophacinone stratum.

PMID:35000500 SUPPORT INDIRECT Model Organism

"Each of the submitted calves had moderate-to-severe hemorrhage within various tissues and body cavities, including the thymus, subcutaneous region of the neck, mediastinum, lungs, pericardial sac, heart, spleen, perirenal fat, urinary bladder, and skeletal muscle, including the diaphragm."

A chlorophacinone-attributed, liver-residue-confirmed poisoning in which the anatomical distribution of the bleeding was documented at necropsy. Recorded as veterinary in vivo evidence supplementing, not replacing, the human case evidence for this node.

Hypovolemic Shock and Death

Death follows either exsanguinating blood loss with hypovolaemic shock or haemorrhage into the central nervous system. Intracranial haemorrhage is the most commonly reported cause of death in this class of poisoning.

Show evidence (2 references)

PMID:26239439 SUPPORT INDIRECT Human Clinical

"Deaths were most commonly associated with intracranial hemorrhage."

Identifies the leading fatal event across 174 reviewed cases. Marked indirect because the review reports the class and does not stratify by agent.

PMID:40974629 SUPPORT INDIRECT Human Clinical

"Six fatalities occurred and autopsy findings in three cases primarily indicated multi-organ hemorrhage and necrosis."

Reports fatalities and their autopsy correlate in a pooled anticoagulant rodenticide case series. Marked indirect for the same pooling reason.

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Pathograph

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Phenotypes

19

Blood 12

Prolonged Prothrombin Time HP:0008151

Show evidence (2 references)

PMID:3222685 SUPPORT DIRECT Human Clinical

"Her Quick time at admission was less than 10% (Prothrombin time 79 sec., normal control 12 sec.)."

A chlorophacinone-poisoned patient with a prothrombin time of 79 seconds against a 12-second control.

PMID:26239439 SUPPORT INDIRECT Human Clinical

"Most patients present with coagulation assay values beyond measurable limits."

Describes the typical magnitude of the derangement. Marked indirect because it is a class-level statement.

Prolonged Activated Partial Thromboplastin Time Prolonged partial thromboplastin time HP:0003645

Show evidence (1 reference)

PMID:40974629 SUPPORT INDIRECT Human Clinical

"Coagulation function tests revealed average values of aPTT, PT, and INR of aPTT: 110 (3.71 ∼ 212) s, PT: 100 (11.6 ∼ 300) s and INR: 9 (0.98 ∼ 38.2), respectively, all significantly exceeding normal ranges."

Reports aPTT prolongation alongside PT and INR across 88 anticoagulant rodenticide poisonings. Marked indirect because the series pools agents.

Reduced Factor VII Activity HP:0008169

Show evidence (1 reference)

PMID:3222685 SUPPORT DIRECT Human Clinical

"Prothrombin time (and vitamin K dependent factors VII and X) finally normalized only 7 weeks after chlorophacinone ingestion."

Factor VII activity was depressed and was tracked to normalization in a chlorophacinone poisoning.

Reduced Factor X Activity HP:0008321

Show evidence (1 reference)

PMID:3222685 SUPPORT DIRECT Human Clinical

"Prothrombin time (and vitamin K dependent factors VII and X) finally normalized only 7 weeks after chlorophacinone ingestion."

Factor X activity was depressed and was tracked to normalization in a chlorophacinone poisoning.

Epistaxis HP:0000421

Show evidence (1 reference)

PMID:16499407 SUPPORT INDIRECT Human Clinical

"Substantial ingestion produces epistaxis, gingival bleeding, widespread bruising, haematomas, haematuria with flank pain, menorrhagia, gastrointestinal bleeding, rectal bleeding and haemorrhage into any internal organ; anaemia may result."

Lists epistaxis among the bleeding manifestations of substantial anticoagulant rodenticide ingestion.

Gingival Bleeding HP:0000225

Show evidence (1 reference)

PMID:16499407 SUPPORT INDIRECT Human Clinical

"Substantial ingestion produces epistaxis, gingival bleeding, widespread bruising, haematomas, haematuria with flank pain, menorrhagia, gastrointestinal bleeding, rectal bleeding and haemorrhage into any internal organ; anaemia may result."

Lists gingival bleeding among the mucocutaneous manifestations.

Widespread Bruising Bruising susceptibility HP:0000978

Show evidence (1 reference)

PMID:16499407 SUPPORT INDIRECT Human Clinical

"Substantial ingestion produces epistaxis, gingival bleeding, widespread bruising, haematomas, haematuria with flank pain, menorrhagia, gastrointestinal bleeding, rectal bleeding and haemorrhage into any internal organ; anaemia may result."

Lists widespread bruising and haematomas among the manifestations.

Gastrointestinal Hemorrhage HP:0002239

Show evidence (1 reference)

PMID:16499407 SUPPORT INDIRECT Human Clinical

"Substantial ingestion produces epistaxis, gingival bleeding, widespread bruising, haematomas, haematuria with flank pain, menorrhagia, gastrointestinal bleeding, rectal bleeding and haemorrhage into any internal organ; anaemia may result."

Lists gastrointestinal and rectal bleeding among the manifestations.

Hematochezia HP:0002573

Show evidence (1 reference)

PMID:16499407 SUPPORT INDIRECT Human Clinical

"Substantial ingestion produces epistaxis, gingival bleeding, widespread bruising, haematomas, haematuria with flank pain, menorrhagia, gastrointestinal bleeding, rectal bleeding and haemorrhage into any internal organ; anaemia may result."

Lists rectal bleeding separately from gastrointestinal bleeding among the manifestations.

Intracranial Hemorrhage HP:0002170

Show evidence (1 reference)

PMID:26239439 SUPPORT INDIRECT Human Clinical

"Deaths were most commonly associated with intracranial hemorrhage."

Identifies intracranial haemorrhage as the leading fatal event across 174 reviewed cases. Marked indirect because the review is class-level.

Menorrhagia HP:0000132

Show evidence (1 reference)

PMID:16499407 SUPPORT INDIRECT Human Clinical

"Substantial ingestion produces epistaxis, gingival bleeding, widespread bruising, haematomas, haematuria with flank pain, menorrhagia, gastrointestinal bleeding, rectal bleeding and haemorrhage into any internal organ; anaemia may result."

Lists menorrhagia among the bleeding manifestations.

Anemia HP:0001903

Show evidence (1 reference)

PMID:16499407 SUPPORT INDIRECT Human Clinical

"Substantial ingestion produces epistaxis, gingival bleeding, widespread bruising, haematomas, haematuria with flank pain, menorrhagia, gastrointestinal bleeding, rectal bleeding and haemorrhage into any internal organ; anaemia may result."

States that anaemia may follow the blood loss.

Cardiovascular 1

Hypovolemic Shock HP:0031274

Show evidence (1 reference)

PMID:16499407 SUPPORT INDIRECT Human Clinical

"Severe blood loss may result in hypovolaemic shock, coma and death."

States hypovolaemic shock as a consequence of severe blood loss in anticoagulant rodenticide poisoning.

Digestive 2

Hemoperitoneum HP:0011854

Show evidence (1 reference)

PMID:16499407 SUPPORT INDIRECT Human Clinical

"Spontaneous haemoperitoneum has been described."

Reports spontaneous haemoperitoneum in anticoagulant rodenticide poisoning.

Nausea HP:0002018

Show evidence (1 reference)

PMID:10216974 SUPPORT DIRECT Human Clinical

"The examination revealed excitation and nausea, with a normal prothrombin index (PI)."

Reports nausea at presentation, eight hours after ingestion and before the prothrombin index had fallen.

Genitourinary 1

Hematuria HP:0000790

Show evidence (2 references)

PMID:40974629 SUPPORT INDIRECT Human Clinical

"Multi-organ hemorrhage was the predominant clinical manifestation, with hematuria being the most frequently reported symptom (n = 39)."

Establishes haematuria as the most frequently reported bleeding manifestation, in 39 of 88 pooled cases. No frequency band is curated from that proportion: the series is a synthesis of published case reports and so is enriched for severe and fatal presentations, and this entry's own epidemiology records that only about 2 per cent of reported exposures produce morbidity at all. The sources support a rank, not a rate. Marked indirect because the denominator covers anticoagulant rodenticides collectively rather than chlorophacinone alone.

PMID:26239439 SUPPORT INDIRECT Human Clinical

"The most frequently reported bleeding sites are mucocutaneous, with hematuria being the most common feature."

An independent review of 174 cases reaches the same ranking. Marked indirect because it gives a rank rather than a proportion, and is class-level.

Nervous System 1

Coma HP:0001259

Show evidence (1 reference)

PMID:16499407 SUPPORT INDIRECT Human Clinical

"Severe blood loss may result in hypovolaemic shock, coma and death."

Names coma as a terminal consequence of severe blood loss in anticoagulant rodenticide poisoning. Marked indirect because the sentence is class-level.

Constitutional 1

Flank Pain HP:0030157

Show evidence (1 reference)

PMID:16499407 SUPPORT INDIRECT Human Clinical

"Substantial ingestion produces epistaxis, gingival bleeding, widespread bruising, haematomas, haematuria with flank pain, menorrhagia, gastrointestinal bleeding, rectal bleeding and haemorrhage into any internal organ; anaemia may result."

Flank pain is reported accompanying haematuria.

Other 1

Acute Compartment Syndrome

Show evidence (1 reference)

PMID:32447894 SUPPORT INDIRECT Human Clinical

"The early manifestations of this patient were mainly coagulation dysfunction, and finally acute osteofascial compartment syndrome."

Reports compartment syndrome following anticoagulant rodenticide poisoning. Marked indirect because the case report names the agent only as an anticoagulant rodenticide, not as chlorophacinone. No phenotype term is bound: HPO has no compartment syndrome term.

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Medical Actions

3

High-Dose Prolonged Vitamin K1 (Phytomenadione)

Action: Pharmacotherapy NCIT:C15986

Agent: phylloquinone CHEBI:18067

Platform: Small molecule

Phytomenadione (vitamin K1) is the antidote. Supplying vitamin K from outside restores the carboxylase cofactor that the inhibited epoxide reductase can no longer regenerate, and the coagulation profile corrects within hours. Because chlorophacinone persists, the dose required is far above ordinary warfarin reversal doses and treatment must continue for weeks; withdrawal before the drug has cleared produces rebound coagulopathy.

Mechanism Target:

RESTORES Depletion of the Reduced Vitamin K Pool — Exogenous vitamin K1 replenishes the substrate for the carboxylase cofactor pool without requiring the inhibited epoxide reductase.

Show evidence (1 reference)

PMID:3222685 SUPPORT DIRECT Human Clinical

"Under high dose vitamin K therapy the Quick was rapidly corrected but fell again on each vitamin K withdrawal."

Correction on vitamin K and relapse off it, in a chlorophacinone poisoning, is a direct demonstration that vitamin K supply is the limiting quantity this treatment restores.

Show evidence (5 references)

PMID:3222685 SUPPORT DIRECT Human Clinical

"This case emphasizes the need for prolonged clinical and laboratory follow-up for rodenticide intoxications and for vitamin K administration for several weeks."

States the duration of vitamin K therapy required after chlorophacinone poisoning.

PMID:26239439 SUPPORT INDIRECT Human Clinical

"Treatment of acute hemorrhagic symptoms often required intravenous vitamin K1 in excess of 50 to 100 mg; chronic maintenance with 100 mg PO vitamin K1 daily was the most frequently used dose required to suppress coagulopathy."

Gives the dose magnitude actually used across reported cases. Marked indirect because the doses are pooled across long-acting anticoagulant rodenticides rather than reported for chlorophacinone alone.

PMID:26239439 SUPPORT INDIRECT Human Clinical

"Treatment courses averaged 168 days."

Quantifies treatment duration across the reviewed cases. Marked indirect for the same class-level reason, and the figure should not be read as a chlorophacinone expectation: the reviewed long-acting cases are dominated by brodifacoum, whose effect outlasts chlorophacinone's.

+ 2 more references

Coagulation Factor Replacement

Action: Pharmacotherapy NCIT:C15986

Agent: four-factor prothrombin complex concentrate NCIT:C208347

Platform: Protein replacement

For active bleeding, immediate replacement of the missing factors is given alongside vitamin K1, since vitamin K takes hours to restore carboxylation. Prothrombin complex concentrate is preferred because it contains exactly the four deficient factors; fresh frozen plasma is the fallback, and recombinant activated factor VII has also been used.

Mechanism Target:

BYPASSES Functional Deficiency of Coagulation Factors II, VII, IX and X — Transfused factor concentrate supplies fully carboxylated factors directly, bypassing the blocked hepatic carboxylation step.

Show evidence (1 reference)

PMID:16499407 SUPPORT INDIRECT Other

"If active bleeding occurs, prothrombin complex concentrate (which contains factors II, VII, IX and X) 50 units/kg, or recombinant activated factor VII 1.2-4.8 mg or fresh frozen plasma 15 mL/kg (if no concentrate is available) and phytomenadione 10mg intravenously (100 microg/kg bodyweight for a..."

Specifies replacement of precisely the four deficient factors as the treatment for active bleeding.

Show evidence (2 references)

PMID:26239439 SUPPORT INDIRECT Human Clinical

"Adjunctive hemostatic therapy with recombinant factor VIIa and prothrombin complex concentrate has been reported, and phenobarbital has been used to expedite LAAR metabolism."

Confirms the adjunctive haemostatic agents used in practice. Marked indirect because the review pools long-acting anticoagulant rodenticides.

PMID:31857739 SUPPORT INDIRECT Other

"Treatment for superwarfarin poisoning includes rapid correction of factor deficiencies with either 4-factor prothrombin complex concentrate or fresh frozen plasma in patients with active bleeding"

Names four-factor prothrombin complex concentrate ahead of fresh frozen plasma and confines factor replacement to patients who are bleeding. Marked indirect because the review speaks for the long-acting class.

Phenobarbital Enzyme Induction

Action: Pharmacotherapy NCIT:C15986

Agent: phenobarbital CHEBI:8069

Platform: Small molecule

Phenobarbital has been used to accelerate hepatic metabolism of chlorophacinone and shorten the coagulopathy. In one human case the apparent elimination half-life under phenobarbital was 3.27 days, shorter than in previously reported cases. This is an adjunct with limited evidence, not standard care.

Mechanism Target:

INHIBITS Hepatic Accumulation and Prolonged Elimination — Cytochrome P450 induction increases the rate at which chlorophacinone is cleared, shortening the period over which it can inhibit the vitamin K cycle.

Show evidence (1 reference)

PMID:2769823 SUPPORT DIRECT Human Clinical

"An increased elimination was noted when phenobarbital was administered."

Reports increased chlorophacinone elimination on phenobarbital. The observation is from a single uncontrolled case within a three-patient series, so it is weak evidence for a directly stated result.

Show evidence (1 reference)

PMID:10216974 SUPPORT DIRECT Human Clinical

"Under phenobarbital 200 mg/day, chlorophacinone exhibited an apparent elimination half-life (3.27 days) shorter than in previously reported cases."

Quantifies the half-life observed under phenobarbital against a historical comparison. The comparison is with previously reported cases rather than a control arm, so the effect size is not established.

🌍

Environmental Factors

1

Chlorophacinone rodenticide exposure

Exposure to chlorophacinone-containing rodenticide bait, concentrate or powder. Human exposure is most often unintentional and paediatric, but the cases that produce severe coagulopathy are typically deliberate ingestions of concentrate by adults. Occupational exposure is also reported.

Show evidence (4 references)

PMID:32645465 SUPPORT INDIRECT Model Organism

"Chlorophacinone was detected in milk on day 2 post-exposure and remained quantifiable for at least 7 days in milk of these 11 ewes."

Chlorophacinone transfers into the milk of exposed livestock, so a food-chain route to human exposure exists in principle. Marked indirect because the measurement is in sheep and the same paper concludes that dairy products after a one-week withdrawal pose low consumer risk; no human poisoning by this route is reported.

PMID:16499407 SUPPORT INDIRECT Human Clinical

"Most cases of anticoagulant rodenticide exposure involve young children and, as a consequence, the amounts ingested are almost invariably small."

Characterizes the dominant exposure population for anticoagulant rodenticides, of which chlorophacinone is one.

PMID:16499407 SUPPORT INDIRECT Human Clinical

"Occupational exposure has also been reported."

Records occupational exposure as an additional route for this class.

+ 1 more reference

Mechanism Target:

TRIGGERS Systemic Chlorophacinone Exposure — Ingestion of chlorophacinone bait or concentrate is the route by which the systemic chlorophacinone burden is established.

Show evidence (1 reference)

PMID:10216974 SUPPORT DIRECT Human Clinical

"A 33-year-old man was admitted 8 hours after voluntary ingestion of 1875 mg of chlorophacinone (C'Operat 750 mL)."

Ties ingestion of a named chlorophacinone product to the resulting systemic exposure in a human case.

🔬

Biochemical Markers

2

Plasma chlorophacinone concentration (PRESENT)

Show evidence (3 references)

PMID:10216974 SUPPORT DIRECT Human Clinical

"Comprehensive testing for abused and therapeutic drugs in blood confirmed chlorophacinone (maximum plasma level: 27.6 mg/L), an antivitamin K (AVK) rodenticide."

Reports a measured maximum plasma chlorophacinone concentration in a human poisoning.

PMID:2769823 SUPPORT DIRECT Human Clinical

"Plasma chlorophacinone determinations were performed in three cases of intoxication."

Establishes plasma chlorophacinone measurement as the analytical basis for confirming and following this poisoning.

PMID:1522713 SUPPORT DIRECT Human Clinical

"Application of this method to 20 intoxicated patients indicated that the risk of bleeding syndrome, which is always associated with this kind of intoxication, is no longer present when chlorophacinone levels drop to below 1 microgram/mL."

The largest chlorophacinone-specific human series available here, twenty poisoned patients, and the only source proposing a serum concentration below which bleeding risk has resolved.

International normalized ratio (PRESENT)

Show evidence (2 references)

PMID:16499407 SUPPORT INDIRECT Other

"In all other cases, the INR should be measured 36-48 hours post exposure."

States the recommended timing for INR measurement after anticoagulant rodenticide exposure, which is set by the delay before the coagulopathy declares itself.

PMID:40974629 SUPPORT INDIRECT Human Clinical

"Coagulation function tests revealed average values of aPTT, PT, and INR of aPTT: 110 (3.71 ∼ 212) s, PT: 100 (11.6 ∼ 300) s and INR: 9 (0.98 ∼ 38.2), respectively, all significantly exceeding normal ranges."

Gives the observed INR range across 88 pooled anticoagulant rodenticide poisonings. Marked indirect because the series does not stratify by agent.

🔬

Diagnosis

3

Delayed coagulation testing after exposure

The coagulopathy is not present at the moment of exposure. Prothrombin time and INR should be measured 36 to 48 hours after exposure, because an earlier normal result does not exclude poisoning. In a case series the median latency to presentation was four days.

In young children with the small unintentional ingestions that dominate reported exposures, routine INR measurement is considered unnecessary.

Show evidence (7 references)

PMID:16499407 SUPPORT INDIRECT Other

"There are now sufficient data in young children exposed to anticoagulant rodenticides to conclude that routine measurement of the international normalised ratio (INR) is unnecessary."

States that the small unintentional paediatric ingestions which dominate reported exposures do not need routine coagulation testing, the counterweight to the 36 to 48 hour rule above. Marked indirect because it is a recommendation for the class rather than a chlorophacinone finding.

PMID:17357377 SUPPORT INDIRECT Other

"Patients with unintentional ingestion of less than 1 mg of LAAR active ingredient can be safely observed at home without laboratory monitoring."

The consensus out-of-hospital guideline puts a dose threshold on that recommendation. Marked indirect because the guideline covers long-acting anticoagulant rodenticides collectively.

PMID:17357377 SUPPORT INDIRECT Other

"Patients with unintentional ingestion of 1 mg or more of active ingredient and are asymptomatic should be evaluated for coagulopathy at 48-72 hours after exposure (Grade B)."

Gives the graded recommendation and testing window above that threshold. Marked indirect for the same class-level reason.

+ 4 more references

Suspicion on unexplained prothrombin time prolongation

Where no exposure is reported, the poisoning is found by suspecting it. An unexplained prolonged prothrombin time is the trigger to send a rodenticide assay.

Show evidence (1 reference)

PMID:31857739 SUPPORT INDIRECT Other

"Superwarfarin poisoning should therefore be suspected in all patients with unexplained prolongation of prothrombin time, and can be confirmed by their detection in serum."

States the diagnostic posture for this class of poisoning when the history is absent. Marked indirect because the review addresses the long-acting rodenticides collectively.

Analytical confirmation of chlorophacinone

Chlorophacinone is identified and quantified in plasma or serum by HPLC or LC-MS/MS. Analytical confirmation is what distinguishes chlorophacinone poisoning from the other anticoagulant rodenticides and from warfarin, since the coagulation profile alone cannot.

Show evidence (2 references)

PMID:10216974 SUPPORT DIRECT Human Clinical

"A simple HPLC procedure for the determination of chlorophacinone in human plasma is reported for that purpose."

Describes the analytical method by which chlorophacinone is confirmed in human plasma.

PMID:39893780 SUPPORT INDIRECT Other

"The method was validated according to the FDA recommendations for all compounds, with an eight-min run time in human whole blood, the gold standard in toxicological forensic investigation."

Reports the validation result for a panel whose eighteen analytes include chlorophacinone, which is what allows the specific agent to be named rather than inferred. Marked indirect because performance is reported for all compounds together rather than for chlorophacinone alone.

📈

Progression

3

Latent

Duration: 0 to 24 hours after exposure

Coagulation is still normal. Non-specific symptoms such as nausea may occur. A normal coagulation panel drawn in this window excludes nothing.

Show evidence (1 reference)

PMID:10216974 SUPPORT DIRECT Human Clinical

"The examination revealed excitation and nausea, with a normal prothrombin index (PI)."

Eight hours after ingesting 1875 mg of chlorophacinone the prothrombin index was still normal, which fixes the latent phase.

Coagulopathy onset

Duration: about 1 to 4 days after exposure

Prothrombin time and INR rise as factor VII, the shortest-lived of the affected factors, is depleted. Bleeding may begin. The reported median latency to clinical presentation is four days.

Show evidence (1 reference)

PMID:40974629 SUPPORT INDIRECT Human Clinical

"The median latency period was 4 days (range: 1 ∼ 30)."

Gives the interval from exposure to presentation. Marked indirect because the series pools anticoagulant rodenticides.

Resolution with rebound

Duration: weeks to months

Under vitamin K1 the coagulation profile corrects and relapses on each withdrawal. Full normalization took seven weeks in the reported case. Relapse here is the expected course, not a complication.

Show evidence (1 reference)

PMID:3222685 SUPPORT DIRECT Human Clinical

"Prothrombin time (and vitamin K dependent factors VII and X) finally normalized only 7 weeks after chlorophacinone ingestion."

Fixes the duration of the resolution phase in a chlorophacinone poisoning.

🌍

Epidemiology

3

Registered field use in France

Chlorophacinone's share of human poisoning is small and country-dependent, because it tracks the compound's registration. In France it is one of only two anticoagulants registered for field use, so it appears there far more than in series from countries where the second-generation compounds dominate.

Show evidence (1 reference)

PMID:21171851 SUPPORT INDIRECT Human Clinical

"In wildlife, bromadiolone and chlorophacinone are by far the most important products, being the only ones registered for field use."

States chlorophacinone's registration position in France, which is why the human case literature clusters there.

Exposure circumstances and severity

Reported anticoagulant rodenticide exposures are dominated by young children and are mostly accidental and clinically trivial. The severe cases come from deliberate adult ingestion.

Show evidence (2 references)

PMID:21171851 SUPPORT INDIRECT Human Clinical

"Overall, the proportion of anticoagulant exposure reported to the Lyon poison control center appeared very limited and mostly occurred in young children, with no or very limited clinical severity."

Characterizes the exposure population and its severity in the French poison-centre data. Marked indirect because the figures cover anticoagulant rodenticides collectively.

PMID:21171851 SUPPORT INDIRECT Human Clinical

"There is no report of mortality in the human data, and less than 1% of all exposure cases in domestic animals were fatal."

Records the absence of deaths in four years of French human data, which is the counterweight to the severity of the published case reports. Marked indirect because agents are pooled.

Reported burden in the United States

United States poison-centre data for the long-acting anticoagulant rodenticides as a class give the order of magnitude of reported exposure. No chlorophacinone-specific incidence or prevalence figure exists.

These are reported exposures, not diagnosed cases of poisoning, and they cannot be separated by agent.

Show evidence (2 references)

PMID:26239439 SUPPORT INDIRECT Human Clinical

"In the United States, on average, there were 10413 exposures reported with 2750 patients treated annually."

Gives annual reported exposures and treated patients. Marked indirect because the figure covers the long-acting class, not chlorophacinone.

PMID:26239439 SUPPORT INDIRECT Human Clinical

"Fortunately, only 2% of all exposures result in morbidity or mortality."

Quantifies the proportion of reported exposures that matter clinically. Marked indirect for the same class-level reason.

🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from Chlorophacinone Poisoning:

Vitamin K-Dependent Coagulation Factor Deficiency MONDO:0015722

Overlapping Features Biallelic germline variants in VKORC1 or GGCX produce the same combined deficiency of the vitamin K-dependent factors by disabling the same two steps that chlorophacinone blocks pharmacologically.

Distinguishing Features

Germline VKORC1 or GGCX variants are present and the presentation is lifelong rather than following a single exposure.
No anticoagulant rodenticide is detectable on toxicological analysis.
Skeletal and other extra-haemostatic features of GGCX deficiency have no counterpart in an acute poisoning.

Warfarin or other coumarin anticoagulant

Overlapping Features Therapeutic warfarin, warfarin overdose, and the other coumarin oral anticoagulants produce the same vitamin K antagonist coagulopathy through the same enzyme.

Distinguishing Features

A drug history and a therapeutic indication are usually present.
Warfarin coagulopathy resolves within days of stopping the drug and responds to ordinary reversal doses of vitamin K, not to months of high-dose therapy.
Analytical confirmation separates the compounds.

Show evidence (1 reference)

PMID:26239439 SUPPORT INDIRECT Other

"Long-acting anticoagulant rodenticides have an extremely high affinity for VKOR compared with warfarin, characterized by rebound coagulopathy and bleeding after initial treatment and the need for high-dose, long-term therapy with vitamin K1."

Contrasts the rodenticide course with warfarin's, which is the distinguishing feature. Marked indirect because the review speaks for the long-acting class.

Liver failure

Overlapping Features Hepatic synthetic failure also depresses the vitamin K-dependent factors and prolongs the prothrombin time.

Distinguishing Features

Factor V is synthesized in the liver but is not vitamin K dependent, so it is reduced in liver failure and unaffected by a vitamin K antagonist. This factor V versus factor VII pattern is the standard discriminator; no source cited in this entry reports it, so it is recorded as clinical convention rather than curated as evidenced content.
Other markers of hepatic failure, such as bilirubin, albumin and transaminases, are deranged.
The coagulopathy of liver failure does not correct on high-dose vitamin K1 and does not rebound on its withdrawal.

Disseminated intravascular coagulation

Overlapping Features Consumptive coagulopathy also prolongs the prothrombin time and causes multi-site bleeding.

Distinguishing Features

Platelet count and fibrinogen are low and D-dimer is raised in disseminated intravascular coagulation; a vitamin K antagonist leaves the platelet count and fibrinogen untouched.
A precipitating illness such as sepsis, malignancy or obstetric catastrophe is present.
Recorded as clinical convention. No source cited in this entry reports these discriminating values.

Other anticoagulant rodenticide poisoning

Overlapping Features Brodifacoum, bromadiolone, difenacoum, difethialone, flocoumafen and coumatetralyl produce a clinically indistinguishable coagulopathy through the same target. In pooled case series brodifacoum and bromadiolone are the agents most often identified.

Distinguishing Features

Only analytical confirmation separates the agents; the coagulation profile does not.
The second-generation compounds persist far longer, so treatment courses run months rather than weeks.

Show evidence (1 reference)

PMID:40974629 SUPPORT INDIRECT Human Clinical

"About the types of rodenticides, a total of 38 cases reported 7 distinct types, with brodifacoum and bromadiolone being the most common"

Establishes that several agents in this class present the same way and that the commonest identified are not chlorophacinone. Marked indirect because the sentence is about agent distribution rather than about distinguishing them clinically.

🐁

Animal Models

2

Accidental chlorophacinone poisoning in calves

Fourteen crossbred calves ingested chlorophacinone powder present in their housing. Three were submitted for necropsy, with chlorophacinone confirmed in liver at 2.9 to 4.2 ppm. This is a naturally occurring, dose-uncontrolled veterinary poisoning rather than a designed experimental model, and it is recorded here because it couples a confirmed chlorophacinone tissue burden to a documented anatomical distribution of haemorrhage.

Species

Cattle

Genotype

wild type

Publication

PMID:35000500

Pathograph links

Multicompartment Hemorrhage recapitulates fidelity: moderate Reproduces the multicompartment haemorrhage of human chlorophacinone poisoning, with the same agent confirmed analytically in tissue.

Limitations: An uncontrolled accidental exposure in a ruminant, with no measured ingested dose, no coagulation assays reported, and no treatment arm. Bovine vitamin K handling and rumen microbial vitamin K synthesis differ from human, so the dose-response cannot be carried across.

Readouts

Chlorophacinone concentration in liver

Direction: INCREASED

Interpretation: Confirms that the haemorrhage occurred against a measured chlorophacinone tissue burden rather than a presumed exposure.

Show evidence (1 reference)

PMID:35000500 SUPPORT DIRECT Model Organism

"Significant concentrations of chlorophacinone were detected at 4.2, 3.6, and 2.9 ppm in liver."

Reports the measured hepatic chlorophacinone concentrations.

Show evidence (1 reference)

PMID:35000500 SUPPORT DIRECT Model Organism

"Acute hemorrhage and death occurred in fourteen 1.5-mo-old, crossbred calves following ingestion of the vitamin K antagonist chlorophacinone."

Attributes acute haemorrhage and death to chlorophacinone ingestion, which is what makes this exposure informative for the haemorrhage node.

Show evidence (1 reference)

PMID:35000500 SUPPORT DIRECT Model Organism

"Three calves were submitted to the Iowa State University Veterinary Diagnostic Laboratory for diagnostic evaluation following an abrupt increase in morbidity and mortality in a calf herd associated with epistaxis and widespread hemorrhage."

Establishes the exposure event and the animals examined, which is what this entry records as a naturally occurring chlorophacinone poisoning.

Accidental chlorophacinone poisoning in lambs

Eleven lambs reached old bait placed between the wall studs of their housing through a hole in the plywood. Two were necropsied, with chlorophacinone confirmed in liver at 0.58 and 0.50 ppm. A second species with a confirmed chlorophacinone tissue burden, and the source of the tempo: these animals died within one to two hours of the first sign.

Species

Sheep

Genotype

wild type

Publication

PMID:17037620

Pathograph links

Multicompartment Hemorrhage recapitulates fidelity: moderate Reproduces multicompartment haemorrhage with epistaxis as the presenting sign, in a second ruminant species and at liver concentrations roughly sixfold below the calf series.

Limitations: An uncontrolled accidental exposure with no measured ingested dose, no coagulation assays, and no treatment arm. The liver concentrations differ sixfold from the calf epizootic, and age, species and dose timing all differ, so no lethal threshold can be derived from the pair. The centrilobular hepatocellular necrosis reported at necropsy is most parsimoniously hypoxic in an exsanguinating animal and is deliberately not curated as chlorophacinone hepatotoxicity. Ovine vitamin K handling, including rumen microbial synthesis, differs from human.

Readouts

Time from first clinical sign to death

Direction: DECREASED

Interpretation: Records how fast the haemorrhagic phase can run once it declares itself in a heavily exposed animal.

Show evidence (1 reference)

PMID:17037620 SUPPORT DIRECT Model Organism

"Affected animals died within 1-2 hours from the onset of clinical signs."

Reports the interval measured in the affected lambs.

Show evidence (1 reference)

PMID:17037620 SUPPORT DIRECT Model Organism

"Eleven lambs, approximately 1-2 months of age, suddenly developed epistaxis, respiratory distress, and facial and cervical swelling."

Documents the presenting haemorrhagic syndrome attributed to chlorophacinone in this epizootic.

Show evidence (1 reference)

PMID:17037620 SUPPORT DIRECT Model Organism

"The anticoagulant chlorophacinone was detected in the livers at 0.58 ppm and 0.50 ppm (wet weight), respectively."

Confirms chlorophacinone analytically in the affected animals, which is what makes this exposure informative rather than presumptive.

{ }

Source YAML

click to show

name: Chlorophacinone Poisoning
creation_date: "2026-09-03T00:00:00Z"
category: Environmental
categories:
- Toxic Exposure Disorder
- Rodenticide Poisoning
- Acquired Coagulopathy
synonyms:
- chlorophacinone intoxication
- indanedione anticoagulant rodenticide poisoning
description: >-
  Chlorophacinone poisoning is an acquired, vitamin K-antagonist coagulopathy
  caused by ingestion of, or other exposure to, the indanedione anticoagulant
  rodenticide chlorophacinone. Chlorophacinone inhibits vitamin K 2,3-epoxide
  reductase, so the reduced vitamin K needed as cofactor for hepatic
  gamma-carboxylation is not regenerated and the vitamin K-dependent
  coagulation factors II, VII, IX and X are secreted in an
  under-carboxylated, functionally inactive form. The resulting coagulopathy
  presents after a latent interval with mucocutaneous and internal bleeding
  and, because chlorophacinone accumulates in liver and is eliminated slowly,
  it can persist for weeks to months and rebound whenever vitamin K
  replacement is withdrawn.
notes: >-
  MONDO has no term for chlorophacinone poisoning, for indanedione or
  anticoagulant rodenticide poisoning, or for rodenticide poisoning generally.
  The entry therefore carries no primary disease_term; the only mapping
  recorded is a broad cross-reference to MONDO:0029000 (poisoning), which
  deliberately does not retire the concept from the MONDO curation queue. A
  request for a specific MONDO term is the right follow-up. PIVKA-II is the
  mechanistically specific marker of vitamin K antagonism and is not curated
  as a phenotype here, because no source cited in this entry reports PIVKA-II
  measurement in chlorophacinone poisoning. No datasets are curated: no
  transcriptomic, proteomic, metabolomic or perturbation dataset for
  chlorophacinone exposure was found, only residue chemistry in wildlife and
  livestock tissue, which measures the compound rather than any host response.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0029000
      label: poisoning
    mapping_predicate: skos:broadMatch
    mapping_source: dismech
    mapping_justification: >-
      MONDO has no chlorophacinone-, indanedione-, or rodenticide-specific
      poisoning term. MONDO:0029000 is the nearest ancestor concept and is
      recorded as a broad cross-reference only.
classifications:
  harrisons_chapter:
  - classification_value: POISONING_ENVENOMATION
    evidence:
    - reference: PMID:16499407
      reference_title: "Anticoagulant rodenticides."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: OTHER
      snippet: "This group includes the second generation 4-hydroxycoumarins brodifacoum, bromadiolone, difenacoum, flocoumafen and the indanedione derivatives chlorophacinone and diphacinone."
      explanation: >-
        Places chlorophacinone within the anticoagulant rodenticides, a
        pesticide poisoning entity handled in the poisoning and overdose
        chapter rather than in a haematology chapter.
pathophysiology:
- name: Systemic Chlorophacinone Exposure
  biological_scale: ORGANISM
  description: >-
    Chlorophacinone enters the body by ingestion of bait or concentrate.
    Inhalational and transcutaneous routes are documented for the
    anticoagulant rodenticides as a class; the cited source does not attribute
    either specifically to chlorophacinone. Ingested doses reported in human
    cases span roughly 100 mg to nearly 2 g, and plasma concentrations after a
    large deliberate ingestion reach the tens of mg/L.
  chemical_entities:
  - preferred_term: chlorophacinone
    term:
      id: CHEBI:81796
      label: Chlorophacinone
  evidence:
  - reference: PMID:10216974
    reference_title: "Toxicological management of chlorophacinone poisoning."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Comprehensive testing for abused and therapeutic drugs in blood confirmed chlorophacinone (maximum plasma level: 27.6 mg/L), an antivitamin K (AVK) rodenticide."
    explanation: >-
      Documents measured systemic chlorophacinone exposure in a human
      poisoning and identifies the compound as a vitamin K antagonist.
  - reference: PMID:10216974
    reference_title: "Toxicological management of chlorophacinone poisoning."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 33-year-old man was admitted 8 hours after voluntary ingestion of 1875 mg of chlorophacinone (C'Operat 750 mL)."
    explanation: >-
      Gives the ingested dose in a deliberate human chlorophacinone poisoning.
  - reference: PMID:26239439
    reference_title: "Long-Acting Anticoagulant Rodenticide (Superwarfarin) Poisoning: A Review of Its Historical Development, Epidemiology, and Clinical Management."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Inhalational, transcutaneous, and oral routes of exposure have been documented."
    explanation: >-
      Establishes the routes of exposure for the long-acting anticoagulant
      rodenticide class. Marked indirect because the review reports routes for
      the class as a whole and does not attribute each route to
      chlorophacinone specifically.
  downstream:
  - target: Vitamin K Epoxide Reductase Inhibition
    causal_link_type: DIRECT
    description: >-
      Absorbed chlorophacinone reaches the hepatocyte endoplasmic reticulum
      and binds the vitamin K epoxide reductase complex.
    evidence:
    - reference: PMID:16499407
      reference_title: "Anticoagulant rodenticides."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: "Anticoagulant rodenticides inhibit vitamin K(1)-2,3 epoxide reductase and thus the synthesis of vitamin K and subsequently clotting factors II, VII, IX and X."
      explanation: >-
        States the pharmacological target of the anticoagulant rodenticides,
        the class to which the same review assigns chlorophacinone. Tagged
        OTHER because the sentence is a pharmacological assertion in a
        narrative review rather than a reported study result.
  - target: Hepatic Accumulation and Prolonged Elimination
    causal_link_type: DIRECT
    description: >-
      The absorbed compound partitions into liver, where it is retained far
      longer than plasma concentrations alone would suggest.
    evidence:
    - reference: PMID:2769823
      reference_title: "Chlorophacinone intoxication. A biological and toxicological study."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "The determination of half-lives was investigated and the results indicate that the greater the quantity absorbed, the longer the half-life."
      explanation: >-
        Links the absorbed chlorophacinone burden to the duration of its own
        elimination in human poisoning cases.
- name: Vitamin K Epoxide Reductase Inhibition
  biological_scale: MOLECULAR
  description: >-
    Chlorophacinone inhibits the vitamin K 2,3-epoxide reductase complex
    (VKORC1) in the hepatocyte endoplasmic reticulum. VKORC1 normally reduces
    vitamin K 2,3-epoxide back to vitamin K hydroquinone; blocking it halts
    the vitamin K cycle at the epoxide step.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  molecular_functions:
  - preferred_term: vitamin K epoxide reductase activity
    modifier: DECREASED
    term:
      id: GO:0047057
      label: vitamin-K-epoxide reductase (warfarin-sensitive) activity
  genes:
  - preferred_term: VKORC1
    term:
      id: hgnc:23663
      label: VKORC1
  evidence:
  - reference: PMID:26239439
    reference_title: "Long-Acting Anticoagulant Rodenticide (Superwarfarin) Poisoning: A Review of Its Historical Development, Epidemiology, and Clinical Management."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "Long-acting anticoagulant rodenticides (LAARs) inhibit vitamin K epoxide reductase (VKOR)."
    explanation: >-
      Names VKOR as the molecular target for the long-acting anticoagulant
      rodenticides. Marked indirect because the sentence is class-level and does not
      name chlorophacinone.
  - reference: PMID:35970209
    reference_title: "VKORC1 single nucleotide polymorphisms in rodents in Spain."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: COMPUTATIONAL
    snippet: "Computational analysis of binding predictions found out that the brown rat S149I mutation predicted a high reduction of the binding affinity of chlorophacinone and brodifacoum ARs"
    explanation: >-
      Chlorophacinone is modelled as a VKORC1 ligand whose binding is
      abolished by a VKORC1 active-site substitution, which is evidence that
      VKORC1 is its target. Marked indirect because the binding is predicted
      computationally, in rat VKORC1 rather than human.
  - reference: PMID:31857739
    reference_title: "Superwarfarin (Long-Acting Anticoagulant Rodenticides) Poisoning: from Pathophysiology to Laboratory-Guided Clinical Management."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "The mechanism of action is by inhibition of vitamin K epoxide reductase, resulting in the inability of the body to recycle vitamin K."
    explanation: >-
      States epoxide reductase inhibition and the resulting failure to recycle
      vitamin K. Marked indirect because the review covers the long-acting
      rodenticides as a class. Note also that the review frames the class as
      warfarin derivatives, which chlorophacinone is not: it is an indanedione,
      so the review's structural reasoning about bulky aromatic sidechains does
      not carry over even though the enzyme target does.
  - reference: PMID:24781908
    reference_title: "[Rodenticide resistance and consequences]."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Polymorphisms in the vitamin K epoxide reductase complex subunit 1 (VKORC1) gene and respective substitutions of amino acids in the VKOR enzyme are the major cause for rodenticide resistance."
    explanation: >-
      Rodenticide resistance maps to VKORC1 coding changes, which is genetic
      corroboration that VKORC1 is the drug target. Marked indirect on two
      steps: the quoted sentence says "rodenticide" rather than naming
      chlorophacinone, and it concerns rodent resistance genetics rather than
      human poisoning.
  downstream:
  - target: Depletion of the Reduced Vitamin K Pool
    causal_link_type: DIRECT
    description: >-
      With the epoxide reductase blocked, vitamin K 2,3-epoxide accumulates
      and the hydroquinone pool available as carboxylase cofactor falls.
    evidence:
    - reference: PMID:16499407
      reference_title: "Anticoagulant rodenticides."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: "Anticoagulant rodenticides inhibit vitamin K(1)-2,3 epoxide reductase and thus the synthesis of vitamin K and subsequently clotting factors II, VII, IX and X."
      explanation: >-
        States that epoxide reductase inhibition curtails vitamin K supply,
        which is this edge.
- name: Depletion of the Reduced Vitamin K Pool
  biological_scale: MOLECULAR
  description: >-
    The hepatic pool of reduced vitamin K (hydroquinone) is depleted because
    the epoxide formed at each carboxylation cycle cannot be recycled. Dietary
    vitamin K intake alone does not replace it at the rate the cycle consumes
    it, which is why exogenous vitamin K1 in gram-scale cumulative doses is
    the antidote.
  biological_processes:
  - preferred_term: vitamin K metabolic process
    modifier: DECREASED
    term:
      id: GO:0042373
      label: vitamin K metabolic process
  chemical_entities:
  - preferred_term: phylloquinone
    term:
      id: CHEBI:18067
      label: phylloquinone
  evidence:
  - reference: PMID:3222685
    reference_title: "[Prolonged anticoagulation following chlorophacinone poisoning]."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Under high dose vitamin K therapy the Quick was rapidly corrected but fell again on each vitamin K withdrawal."
    explanation: >-
      Correction on exogenous vitamin K and relapse on its withdrawal is the
      clinical signature of a depleted, pharmacologically unreplenishable
      reduced vitamin K pool in a chlorophacinone-poisoned patient.
  downstream:
  - target: Impaired Gamma-Carboxylation of Vitamin K-Dependent Clotting Factors
    causal_link_type: DIRECT
    description: >-
      Gamma-glutamyl carboxylase requires vitamin K hydroquinone as cofactor,
      so the depleted pool limits carboxylation directly.
    evidence:
    - reference: PMID:16499407
      reference_title: "Anticoagulant rodenticides."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: "Anticoagulant rodenticides inhibit vitamin K(1)-2,3 epoxide reductase and thus the synthesis of vitamin K and subsequently clotting factors II, VII, IX and X."
      explanation: >-
        The review couples loss of vitamin K to loss of the four factors.
        Marked indirect because the abstract states the consequence for the
        factors without naming gamma-carboxylation as the intervening step.
- name: Impaired Gamma-Carboxylation of Vitamin K-Dependent Clotting Factors
  biological_scale: CELLULAR
  description: >-
    Hepatic gamma-glutamyl carboxylase can no longer convert glutamate
    residues in the Gla domains of the vitamin K-dependent proteins to
    gamma-carboxyglutamate. The affected proteins are prothrombin (factor II)
    and factors VII, IX and X, together with the anticoagulant proteins C and
    S. Under-carboxylated Gla domains cannot chelate calcium and so cannot
    dock the factor onto anionic phospholipid membranes.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: peptidyl-glutamic acid carboxylation
    modifier: DECREASED
    term:
      id: GO:0017187
      label: peptidyl-glutamic acid carboxylation
  genes:
  - preferred_term: GGCX
    term:
      id: hgnc:4247
      label: GGCX
  - preferred_term: F2
    term:
      id: hgnc:3535
      label: F2
  - preferred_term: F7
    term:
      id: hgnc:3544
      label: F7
  - preferred_term: F9
    term:
      id: hgnc:3551
      label: F9
  - preferred_term: F10
    term:
      id: hgnc:3528
      label: F10
  - preferred_term: PROC
    term:
      id: hgnc:9451
      label: PROC
  - preferred_term: PROS1
    term:
      id: hgnc:9456
      label: PROS1
  notes: >-
    Proteins C and S are listed as substrates of the same carboxylase and are
    lost alongside the procoagulant factors. Their loss is the accepted
    explanation offered for the paradoxical thrombotic events reported in this
    class of poisoning, but no cited reference here demonstrates that
    mechanism, so it is recorded as a hypothesis in `discussions` rather than
    as a curated causal edge.
  evidence:
  - reference: PMID:16499407
    reference_title: "Anticoagulant rodenticides."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "Anticoagulant rodenticides inhibit vitamin K(1)-2,3 epoxide reductase and thus the synthesis of vitamin K and subsequently clotting factors II, VII, IX and X."
    explanation: >-
      Identifies factors II, VII, IX and X as the affected proteins. Marked indirect
      because the abstract does not itself use the term gamma-carboxylation.
  downstream:
  - target: Functional Deficiency of Coagulation Factors II, VII, IX and X
    causal_link_type: DIRECT
    description: >-
      Under-carboxylated factors are secreted but cannot assemble on
      membranes, so measured factor activity falls.
    evidence:
    - reference: PMID:3222685
      reference_title: "[Prolonged anticoagulation following chlorophacinone poisoning]."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Prothrombin time (and vitamin K dependent factors VII and X) finally normalized only 7 weeks after chlorophacinone ingestion."
      explanation: >-
        Directly measures loss of vitamin K-dependent factor activity, and its
        recovery, in a chlorophacinone-poisoned patient.
- name: Functional Deficiency of Coagulation Factors II, VII, IX and X
  biological_scale: MOLECULAR
  description: >-
    Circulating activity of prothrombin and factors VII, IX and X falls.
    Because factor VII has the shortest half-life of the four, the prothrombin
    time and INR move first; the activated partial thromboplastin time follows
    as factors IX, X and II decline.
  notes: >-
    The order in which the four factors fall, and the resulting fact that the
    prothrombin time moves before the activated partial thromboplastin time,
    follows from their differing plasma half-lives. That is standard
    coagulation physiology and is not demonstrated in any source cited in this
    entry, which report the depressed factor activities without measuring the
    sequence. The ordering is stated because it explains the delayed onset and
    the assay pattern, not because a cited paper establishes it.
  genes:
  - preferred_term: F2
    term:
      id: hgnc:3535
      label: F2
  - preferred_term: F7
    term:
      id: hgnc:3544
      label: F7
  - preferred_term: F9
    term:
      id: hgnc:3551
      label: F9
  - preferred_term: F10
    term:
      id: hgnc:3528
      label: F10
  evidence:
  - reference: PMID:3222685
    reference_title: "[Prolonged anticoagulation following chlorophacinone poisoning]."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prothrombin time (and vitamin K dependent factors VII and X) finally normalized only 7 weeks after chlorophacinone ingestion."
    explanation: >-
      Reports factor VII and factor X activity as the quantities that were
      depressed and later normalized after chlorophacinone ingestion.
  - reference: PMID:16499407
    reference_title: "Anticoagulant rodenticides."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "If active bleeding occurs, prothrombin complex concentrate (which contains factors II, VII, IX and X) 50 units/kg, or recombinant activated factor VII 1.2-4.8 mg or fresh frozen plasma 15 mL/kg (if no concentrate is available) and phytomenadione 10mg intravenously (100 microg/kg bodyweight for a child) should be given."
    explanation: >-
      Replacing exactly factors II, VII, IX and X is the recommended
      haemostatic response, which corroborates that those four are the
      deficient proteins. Marked indirect because this is a therapeutic
      recommendation, not a direct measurement of factor levels.
  downstream:
  - target: Prolonged Coagulopathy
    causal_link_type: DIRECT
    description: >-
      Loss of the four factors disables both the extrinsic and the common
      coagulation pathway, giving a global clotting defect.
    evidence:
    - reference: PMID:40974629
      reference_title: "A retrospective analysis of 88 anticoagulant rodenticide poisoning cases: Characteristics and forensic implications."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Coagulation function tests revealed average values of aPTT, PT, and INR of aPTT: 110 (3.71 ∼ 212) s, PT: 100 (11.6 ∼ 300) s and INR: 9 (0.98 ∼ 38.2), respectively, all significantly exceeding normal ranges."
      explanation: >-
        Both PT and aPTT are grossly prolonged, which is the expected pattern
        when the shared factors of the extrinsic and common pathways are lost.
        Marked indirect because the case series covers anticoagulant
        rodenticides collectively and reports no chlorophacinone stratum.
- name: Hepatic Accumulation and Prolonged Elimination
  biological_scale: ORGANISM
  description: >-
    Chlorophacinone is lipid-soluble, accumulates in liver and undergoes
    enterohepatic recirculation, so its biological half-life is long and grows
    longer with larger ingested doses. This is the property that separates the
    long-acting rodenticides from warfarin clinically, and it is what makes
    the coagulopathy last weeks rather than days. Chlorophacinone is
    nevertheless shorter-acting than the second-generation compounds: the
    class treatment durations reported in reviews are driven by brodifacoum
    and should not be read as a chlorophacinone expectation.
  notes: >-
    Because enterohepatic recirculation is part of what sustains this node,
    interrupting it is a plausible therapeutic target. A bile sequestrant,
    cholestyramine, cut mortality from 67 per cent to 11 per cent in a rabbit
    model of brodifacoum poisoning (PMID:29897553). That is a different
    compound in a different species, and no chlorophacinone data exist, so no
    treatment is curated from it. Recorded because the node names the mechanism
    the intervention would act on.
  chemical_entities:
  - preferred_term: chlorophacinone
    term:
      id: CHEBI:81796
      label: Chlorophacinone
  evidence:
  - reference: PMID:16499407
    reference_title: "Anticoagulant rodenticides."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "The greater potency and duration of action of long-acting anticoagulant rodenticides is attributed to their: (i) greater affinity for vitamin K(1)-2,3-epoxide reductase; (ii) ability to disrupt the vitamin K(1)-epoxide cycle at more than one point; (iii) hepatic accumulation; and (iv) unusually long biological half-lives due to high lipid solubility and enterohepatic circulation."
    explanation: >-
      Names hepatic accumulation, lipid solubility and enterohepatic
      circulation as the basis for the prolonged action of the long-acting
      group, to which the same review assigns chlorophacinone. Marked indirect
      because the sentence is about the class. Only clauses (iii) and (iv),
      hepatic accumulation and long biological half-life, are curated on this
      node. Clauses (i) and (ii), greater VKOR affinity and disruption of the
      cycle at more than one point, are deliberately not carried over: this
      entry also records that rodent-efficacy sources call chlorophacinone
      first-generation, which is a statement about lower potency, so a
      class-level affinity claim cannot be asserted for it here.
  - reference: PMID:2769823
    reference_title: "Chlorophacinone intoxication. A biological and toxicological study."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The determination of half-lives was investigated and the results indicate that the greater the quantity absorbed, the longer the half-life."
    explanation: >-
      Measures chlorophacinone half-life in three human poisonings and shows
      it lengthens with dose, the kinetic behaviour of a saturable
      accumulating compartment.
  - reference: PMID:10216974
    reference_title: "Toxicological management of chlorophacinone poisoning."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chlorophacinone accumulation in target cells or existence of an unidentified metabolite may explain persistence of the hypocoagulability syndrome at low plasmatic concentrations of chlorophacinone."
    explanation: >-
      Observes that the coagulopathy outlasts measurable plasma
      chlorophacinone. Marked indirect because the authors offer tissue accumulation
      as one of two candidate explanations rather than demonstrating it.
  downstream:
  - target: Prolonged Coagulopathy
    causal_link_type: DIRECT
    description: >-
      Because drug persists in liver after plasma levels fall, inhibition of
      the vitamin K cycle continues and the coagulopathy rebounds whenever
      vitamin K replacement stops.
    evidence:
    - reference: PMID:26239439
      reference_title: "Long-Acting Anticoagulant Rodenticide (Superwarfarin) Poisoning: A Review of Its Historical Development, Epidemiology, and Clinical Management."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: "Long-acting anticoagulant rodenticides have an extremely high affinity for VKOR compared with warfarin, characterized by rebound coagulopathy and bleeding after initial treatment and the need for high-dose, long-term therapy with vitamin K1."
      explanation: >-
        Links the persistent drug-target interaction to rebound coagulopathy
        and to the need for prolonged vitamin K1. Marked indirect because the
        review speaks for the class and does not report a chlorophacinone
        stratum.
- name: Prolonged Coagulopathy
  biological_scale: ORGANISM
  description: >-
    The clotting defect is global, severe and long-lived. Prothrombin time,
    INR and activated partial thromboplastin time are grossly prolonged, often
    beyond the measurable range of the assay, and normalization can take weeks
    to months after a single large ingestion.
  biological_processes:
  - preferred_term: blood coagulation
    modifier: DECREASED
    term:
      id: GO:0007596
      label: blood coagulation
  - preferred_term: hemostasis
    modifier: DECREASED
    term:
      id: GO:0007599
      label: hemostasis
  evidence:
  - reference: PMID:2769823
    reference_title: "Chlorophacinone intoxication. A biological and toxicological study."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The data collected in this study confirm the particularly prolonged anticoagulant effect of this compound and show that the knowledge of plasma concentrations may be very useful for clinicians"
    explanation: >-
      Confirms the prolonged anticoagulant effect from serial measurements in
      three human chlorophacinone intoxications.
  - reference: PMID:3222685
    reference_title: "[Prolonged anticoagulation following chlorophacinone poisoning]."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her Quick time at admission was less than 10% (Prothrombin time 79 sec., normal control 12 sec.)."
    explanation: >-
      Quantifies the severity of the coagulopathy at presentation in a
      chlorophacinone poisoning.
  downstream:
  - target: Multicompartment Hemorrhage
    causal_link_type: DIRECT
    description: >-
      With thrombin generation crippled, haemostatic plugs cannot be
      stabilized, so bleeding occurs at mucosal surfaces, into soft tissue and
      into any internal organ.
    evidence:
    - reference: PMID:16499407
      reference_title: "Anticoagulant rodenticides."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Substantial ingestion produces epistaxis, gingival bleeding, widespread bruising, haematomas, haematuria with flank pain, menorrhagia, gastrointestinal bleeding, rectal bleeding and haemorrhage into any internal organ; anaemia may result."
      explanation: >-
        Enumerates the bleeding manifestations that follow substantial
        anticoagulant rodenticide ingestion.
- name: Multicompartment Hemorrhage
  biological_scale: ORGANISM
  description: >-
    Bleeding is characteristically multifocal rather than confined to one
    site. Mucocutaneous bleeding predominates, with haematuria the single most
    frequently reported manifestation, and haemorrhage into serous cavities,
    muscle and the central nervous system also occurs.
  biological_processes:
  - preferred_term: hemostasis
    modifier: DECREASED
    term:
      id: GO:0007599
      label: hemostasis
  evidence:
  - reference: PMID:40974629
    reference_title: "A retrospective analysis of 88 anticoagulant rodenticide poisoning cases: Characteristics and forensic implications."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Multi-organ hemorrhage was the predominant clinical manifestation, with hematuria being the most frequently reported symptom (n = 39)."
    explanation: >-
      Establishes multi-organ haemorrhage as the dominant presentation across
      88 human anticoagulant rodenticide poisonings, which is what this node
      claims. Marked indirect because the series pools rodenticides and does
      not report a chlorophacinone stratum.
  - reference: PMID:35000500
    reference_title: "Acute hemorrhage and death in calves following chlorophacinone exposure."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Each of the submitted calves had moderate-to-severe hemorrhage within various tissues and body cavities, including the thymus, subcutaneous region of the neck, mediastinum, lungs, pericardial sac, heart, spleen, perirenal fat, urinary bladder, and skeletal muscle, including the diaphragm."
    explanation: >-
      A chlorophacinone-attributed, liver-residue-confirmed poisoning in which
      the anatomical distribution of the bleeding was documented at necropsy.
      Recorded as veterinary in vivo evidence supplementing, not replacing,
      the human case evidence for this node.
  downstream:
  - target: Hypovolemic Shock and Death
    causal_link_type: DIRECT
    description: >-
      Continued blood loss, or haemorrhage into a closed and unforgiving
      compartment such as the cranium, is what kills.
    evidence:
    - reference: PMID:16499407
      reference_title: "Anticoagulant rodenticides."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Severe blood loss may result in hypovolaemic shock, coma and death."
      explanation: >-
        States the fatal pathway from haemorrhage in anticoagulant rodenticide
        poisoning.
- name: Hypovolemic Shock and Death
  biological_scale: ORGANISM
  description: >-
    Death follows either exsanguinating blood loss with hypovolaemic shock or
    haemorrhage into the central nervous system. Intracranial haemorrhage is
    the most commonly reported cause of death in this class of poisoning.
  evidence:
  - reference: PMID:26239439
    reference_title: "Long-Acting Anticoagulant Rodenticide (Superwarfarin) Poisoning: A Review of Its Historical Development, Epidemiology, and Clinical Management."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deaths were most commonly associated with intracranial hemorrhage."
    explanation: >-
      Identifies the leading fatal event across 174 reviewed cases. Marked indirect
      because the review reports the class and does not stratify by agent.
  - reference: PMID:40974629
    reference_title: "A retrospective analysis of 88 anticoagulant rodenticide poisoning cases: Characteristics and forensic implications."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Six fatalities occurred and autopsy findings in three cases primarily indicated multi-organ hemorrhage and necrosis."
    explanation: >-
      Reports fatalities and their autopsy correlate in a pooled anticoagulant
      rodenticide case series. Marked indirect for the same pooling reason.
phenotypes:
- category: Laboratory
  name: Prolonged Prothrombin Time
  description: >-
    Prothrombin time and INR are prolonged, usually first and most markedly,
    because factor VII has the shortest half-life of the affected factors.
    Values frequently exceed the measurable range of the assay.
  phenotype_term:
    preferred_term: Prolonged prothrombin time
    term:
      id: HP:0008151
      label: Prolonged prothrombin time
  diagnostic: true
  evidence:
  - reference: PMID:3222685
    reference_title: "[Prolonged anticoagulation following chlorophacinone poisoning]."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her Quick time at admission was less than 10% (Prothrombin time 79 sec., normal control 12 sec.)."
    explanation: >-
      A chlorophacinone-poisoned patient with a prothrombin time of 79 seconds
      against a 12-second control.
  - reference: PMID:26239439
    reference_title: "Long-Acting Anticoagulant Rodenticide (Superwarfarin) Poisoning: A Review of Its Historical Development, Epidemiology, and Clinical Management."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients present with coagulation assay values beyond measurable limits."
    explanation: >-
      Describes the typical magnitude of the derangement. Marked indirect because it
      is a class-level statement.
- category: Laboratory
  name: Prolonged Activated Partial Thromboplastin Time
  description: >-
    The activated partial thromboplastin time is also prolonged, reflecting
    loss of factors IX, X and II from the intrinsic and common pathways.
  phenotype_term:
    preferred_term: Prolonged partial thromboplastin time
    term:
      id: HP:0003645
      label: Prolonged partial thromboplastin time
  evidence:
  - reference: PMID:40974629
    reference_title: "A retrospective analysis of 88 anticoagulant rodenticide poisoning cases: Characteristics and forensic implications."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Coagulation function tests revealed average values of aPTT, PT, and INR of aPTT: 110 (3.71 ∼ 212) s, PT: 100 (11.6 ∼ 300) s and INR: 9 (0.98 ∼ 38.2), respectively, all significantly exceeding normal ranges."
    explanation: >-
      Reports aPTT prolongation alongside PT and INR across 88 anticoagulant
      rodenticide poisonings. Marked indirect because the series pools agents.
- category: Laboratory
  name: Reduced Factor VII Activity
  phenotype_term:
    preferred_term: Reduced factor VII activity
    term:
      id: HP:0008169
      label: Reduced factor VII activity
  description: >-
    Factor VII activity falls earliest because its plasma half-life is the
    shortest of the vitamin K-dependent procoagulant factors.
  evidence:
  - reference: PMID:3222685
    reference_title: "[Prolonged anticoagulation following chlorophacinone poisoning]."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prothrombin time (and vitamin K dependent factors VII and X) finally normalized only 7 weeks after chlorophacinone ingestion."
    explanation: >-
      Factor VII activity was depressed and was tracked to normalization in a
      chlorophacinone poisoning.
- category: Laboratory
  name: Reduced Factor X Activity
  phenotype_term:
    preferred_term: Reduced factor X activity
    term:
      id: HP:0008321
      label: Reduced factor X activity
  evidence:
  - reference: PMID:3222685
    reference_title: "[Prolonged anticoagulation following chlorophacinone poisoning]."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prothrombin time (and vitamin K dependent factors VII and X) finally normalized only 7 weeks after chlorophacinone ingestion."
    explanation: >-
      Factor X activity was depressed and was tracked to normalization in a
      chlorophacinone poisoning.
- category: Hematologic
  name: Hematuria
  description: >-
    Blood in the urine, frequently with flank pain from clot passage. This is
    the single most commonly reported bleeding manifestation of anticoagulant
    rodenticide poisoning.
  phenotype_term:
    preferred_term: Hematuria
    term:
      id: HP:0000790
      label: Hematuria
  evidence:
  - reference: PMID:40974629
    reference_title: "A retrospective analysis of 88 anticoagulant rodenticide poisoning cases: Characteristics and forensic implications."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Multi-organ hemorrhage was the predominant clinical manifestation, with hematuria being the most frequently reported symptom (n = 39)."
    explanation: >-
      Establishes haematuria as the most frequently reported bleeding
      manifestation, in 39 of 88 pooled cases. No frequency band is curated
      from that proportion: the series is a synthesis of published case
      reports and so is enriched for severe and fatal presentations, and this
      entry's own epidemiology records that only about 2 per cent of reported
      exposures produce morbidity at all. The sources support a rank, not a
      rate. Marked indirect because the denominator covers anticoagulant
      rodenticides collectively rather than chlorophacinone alone.
  - reference: PMID:26239439
    reference_title: "Long-Acting Anticoagulant Rodenticide (Superwarfarin) Poisoning: A Review of Its Historical Development, Epidemiology, and Clinical Management."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most frequently reported bleeding sites are mucocutaneous, with hematuria being the most common feature."
    explanation: >-
      An independent review of 174 cases reaches the same ranking. Marked indirect
      because it gives a rank rather than a proportion, and is class-level.
- category: Hematologic
  name: Epistaxis
  phenotype_term:
    preferred_term: Epistaxis
    term:
      id: HP:0000421
      label: Epistaxis
  evidence:
  - reference: PMID:16499407
    reference_title: "Anticoagulant rodenticides."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Substantial ingestion produces epistaxis, gingival bleeding, widespread bruising, haematomas, haematuria with flank pain, menorrhagia, gastrointestinal bleeding, rectal bleeding and haemorrhage into any internal organ; anaemia may result."
    explanation: >-
      Lists epistaxis among the bleeding manifestations of substantial
      anticoagulant rodenticide ingestion.
- category: Hematologic
  name: Gingival Bleeding
  phenotype_term:
    preferred_term: Gingival bleeding
    term:
      id: HP:0000225
      label: Gingival bleeding
  evidence:
  - reference: PMID:16499407
    reference_title: "Anticoagulant rodenticides."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Substantial ingestion produces epistaxis, gingival bleeding, widespread bruising, haematomas, haematuria with flank pain, menorrhagia, gastrointestinal bleeding, rectal bleeding and haemorrhage into any internal organ; anaemia may result."
    explanation: >-
      Lists gingival bleeding among the mucocutaneous manifestations.
- category: Hematologic
  name: Widespread Bruising
  phenotype_term:
    preferred_term: Bruising susceptibility
    term:
      id: HP:0000978
      label: Bruising susceptibility
  evidence:
  - reference: PMID:16499407
    reference_title: "Anticoagulant rodenticides."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Substantial ingestion produces epistaxis, gingival bleeding, widespread bruising, haematomas, haematuria with flank pain, menorrhagia, gastrointestinal bleeding, rectal bleeding and haemorrhage into any internal organ; anaemia may result."
    explanation: >-
      Lists widespread bruising and haematomas among the manifestations.
- category: Gastrointestinal
  name: Gastrointestinal Hemorrhage
  phenotype_term:
    preferred_term: Gastrointestinal hemorrhage
    term:
      id: HP:0002239
      label: Gastrointestinal hemorrhage
  evidence:
  - reference: PMID:16499407
    reference_title: "Anticoagulant rodenticides."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Substantial ingestion produces epistaxis, gingival bleeding, widespread bruising, haematomas, haematuria with flank pain, menorrhagia, gastrointestinal bleeding, rectal bleeding and haemorrhage into any internal organ; anaemia may result."
    explanation: >-
      Lists gastrointestinal and rectal bleeding among the manifestations.
- category: Gastrointestinal
  name: Hematochezia
  phenotype_term:
    preferred_term: Hematochezia
    term:
      id: HP:0002573
      label: Hematochezia
  evidence:
  - reference: PMID:16499407
    reference_title: "Anticoagulant rodenticides."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Substantial ingestion produces epistaxis, gingival bleeding, widespread bruising, haematomas, haematuria with flank pain, menorrhagia, gastrointestinal bleeding, rectal bleeding and haemorrhage into any internal organ; anaemia may result."
    explanation: >-
      Lists rectal bleeding separately from gastrointestinal bleeding among the
      manifestations.
- category: Neurologic
  name: Intracranial Hemorrhage
  description: >-
    Bleeding into the cranial vault, including intracerebral and intracerebellar
    haemorrhage. This is the manifestation most often responsible for death.
  phenotype_term:
    preferred_term: Intracranial hemorrhage
    term:
      id: HP:0002170
      label: Intracranial hemorrhage
  severity: SEVERE
  evidence:
  - reference: PMID:26239439
    reference_title: "Long-Acting Anticoagulant Rodenticide (Superwarfarin) Poisoning: A Review of Its Historical Development, Epidemiology, and Clinical Management."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deaths were most commonly associated with intracranial hemorrhage."
    explanation: >-
      Identifies intracranial haemorrhage as the leading fatal event across
      174 reviewed cases. Marked indirect because the review is class-level.
- category: Hematologic
  name: Hemoperitoneum
  phenotype_term:
    preferred_term: Hemoperitoneum
    term:
      id: HP:0011854
      label: Hemoperitoneum
  evidence:
  - reference: PMID:16499407
    reference_title: "Anticoagulant rodenticides."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spontaneous haemoperitoneum has been described."
    explanation: >-
      Reports spontaneous haemoperitoneum in anticoagulant rodenticide
      poisoning.
- category: Genitourinary
  name: Menorrhagia
  phenotype_term:
    preferred_term: Menorrhagia
    term:
      id: HP:0000132
      label: Menorrhagia
  evidence:
  - reference: PMID:16499407
    reference_title: "Anticoagulant rodenticides."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Substantial ingestion produces epistaxis, gingival bleeding, widespread bruising, haematomas, haematuria with flank pain, menorrhagia, gastrointestinal bleeding, rectal bleeding and haemorrhage into any internal organ; anaemia may result."
    explanation: >-
      Lists menorrhagia among the bleeding manifestations.
- category: Genitourinary
  name: Flank Pain
  phenotype_term:
    preferred_term: Flank pain
    term:
      id: HP:0030157
      label: Flank pain
  evidence:
  - reference: PMID:16499407
    reference_title: "Anticoagulant rodenticides."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Substantial ingestion produces epistaxis, gingival bleeding, widespread bruising, haematomas, haematuria with flank pain, menorrhagia, gastrointestinal bleeding, rectal bleeding and haemorrhage into any internal organ; anaemia may result."
    explanation: >-
      Flank pain is reported accompanying haematuria.
- category: Hematologic
  name: Anemia
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:16499407
    reference_title: "Anticoagulant rodenticides."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Substantial ingestion produces epistaxis, gingival bleeding, widespread bruising, haematomas, haematuria with flank pain, menorrhagia, gastrointestinal bleeding, rectal bleeding and haemorrhage into any internal organ; anaemia may result."
    explanation: >-
      States that anaemia may follow the blood loss.
- category: Cardiovascular
  name: Hypovolemic Shock
  phenotype_term:
    preferred_term: Hypovolemic shock
    term:
      id: HP:0031274
      label: Hypovolemic shock
  severity: SEVERE
  evidence:
  - reference: PMID:16499407
    reference_title: "Anticoagulant rodenticides."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severe blood loss may result in hypovolaemic shock, coma and death."
    explanation: >-
      States hypovolaemic shock as a consequence of severe blood loss in
      anticoagulant rodenticide poisoning.
- category: Gastrointestinal
  name: Nausea
  description: >-
    Nausea with agitation was recorded in the early, pre-coagulopathic phase of
    a large deliberate chlorophacinone ingestion.
  phenotype_term:
    preferred_term: Nausea
    term:
      id: HP:0002018
      label: Nausea
  evidence:
  - reference: PMID:10216974
    reference_title: "Toxicological management of chlorophacinone poisoning."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The examination revealed excitation and nausea, with a normal prothrombin index (PI)."
    explanation: >-
      Reports nausea at presentation, eight hours after ingestion and before
      the prothrombin index had fallen.
- category: Neurologic
  name: Coma
  phenotype_term:
    preferred_term: Coma
    term:
      id: HP:0001259
      label: Coma
  severity: SEVERE
  evidence:
  - reference: PMID:16499407
    reference_title: "Anticoagulant rodenticides."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severe blood loss may result in hypovolaemic shock, coma and death."
    explanation: >-
      Names coma as a terminal consequence of severe blood loss in
      anticoagulant rodenticide poisoning. Marked indirect because the sentence
      is class-level.
- category: Musculoskeletal
  name: Acute Compartment Syndrome
  description: >-
    Bleeding into a closed fascial compartment can raise compartment pressure
    enough to cause ischaemic injury to the muscle and nerve within it. This is
    a surgically actionable complication that does not follow from haemorrhage
    and hypovolaemia alone, and diagnosis was delayed five days in the reported
    case.
  evidence:
  - reference: PMID:32447894
    reference_title: "[A case of acute osteofascial compartment syndrome caused by rodenticide poisoning]."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The early manifestations of this patient were mainly coagulation dysfunction, and finally acute osteofascial compartment syndrome."
    explanation: >-
      Reports compartment syndrome following anticoagulant rodenticide
      poisoning. Marked indirect because the case report names the agent only
      as an anticoagulant rodenticide, not as chlorophacinone. No phenotype
      term is bound: HPO has no compartment syndrome term.
biochemical:
- name: Plasma chlorophacinone concentration
  presence: PRESENT
  evidence:
  - reference: PMID:10216974
    reference_title: "Toxicological management of chlorophacinone poisoning."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Comprehensive testing for abused and therapeutic drugs in blood confirmed chlorophacinone (maximum plasma level: 27.6 mg/L), an antivitamin K (AVK) rodenticide."
    explanation: >-
      Reports a measured maximum plasma chlorophacinone concentration in a
      human poisoning.
  - reference: PMID:2769823
    reference_title: "Chlorophacinone intoxication. A biological and toxicological study."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Plasma chlorophacinone determinations were performed in three cases of intoxication."
    explanation: >-
      Establishes plasma chlorophacinone measurement as the analytical basis
      for confirming and following this poisoning.
  - reference: PMID:1522713
    reference_title: "Rapid high-performance liquid chromatographic assay of chlorophacinone in human serum."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Application of this method to 20 intoxicated patients indicated that the risk of bleeding syndrome, which is always associated with this kind of intoxication, is no longer present when chlorophacinone levels drop to below 1 microgram/mL."
    explanation: >-
      The largest chlorophacinone-specific human series available here, twenty
      poisoned patients, and the only source proposing a serum concentration
      below which bleeding risk has resolved.
  notes: >-
    Quantification of chlorophacinone in plasma or serum confirms the agent and
    tracks the exposure. It is measured by HPLC or LC-MS/MS. Concentrations
    after large deliberate ingestion reach tens of mg/L. A plasma concentration
    in the reference range does not exclude ongoing poisoning: in the cited
    case the hypocoagulability persisted while chlorophacinone levels were low.
- name: International normalized ratio
  presence: PRESENT
  notes: >-
    The INR is the practical bedside measure of the coagulopathy and the
    quantity used to decide when and how long to give vitamin K1. In a
    poisoning that is not already bleeding, guidance is to measure it 36 to 48
    hours after exposure, since an INR drawn earlier can still be normal.
  evidence:
  - reference: PMID:16499407
    reference_title: "Anticoagulant rodenticides."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "In all other cases, the INR should be measured 36-48 hours post exposure."
    explanation: >-
      States the recommended timing for INR measurement after anticoagulant
      rodenticide exposure, which is set by the delay before the coagulopathy
      declares itself.
  - reference: PMID:40974629
    reference_title: "A retrospective analysis of 88 anticoagulant rodenticide poisoning cases: Characteristics and forensic implications."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Coagulation function tests revealed average values of aPTT, PT, and INR of aPTT: 110 (3.71 ∼ 212) s, PT: 100 (11.6 ∼ 300) s and INR: 9 (0.98 ∼ 38.2), respectively, all significantly exceeding normal ranges."
    explanation: >-
      Gives the observed INR range across 88 pooled anticoagulant rodenticide
      poisonings. Marked indirect because the series does not stratify by
      agent.
environmental:
- name: Chlorophacinone rodenticide exposure
  description: >-
    Exposure to chlorophacinone-containing rodenticide bait, concentrate or
    powder. Human exposure is most often unintentional and paediatric, but the
    cases that produce severe coagulopathy are typically deliberate ingestions
    of concentrate by adults. Occupational exposure is also reported.
  effect: TRIGGERS
  exposure_term:
    preferred_term: exposure to anticoagulant rodenticide
    term:
      id: ECTO:9002177
      label: exposure to anticoagulant rodenticide
    qualifiers:
    - predicate:
        preferred_term: has input
        term:
          id: RO:0002233
          label: has input
      value:
        preferred_term: chlorophacinone
        term:
          id: CHEBI:81796
          label: Chlorophacinone
  evidence:
  - reference: PMID:32645465
    reference_title: "Accidental chlorophacinone exposure of lactating ewes: Clinical follow-up and human health dietary implications."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Chlorophacinone was detected in milk on day 2 post-exposure and remained quantifiable for at least 7 days in milk of these 11 ewes."
    explanation: >-
      Chlorophacinone transfers into the milk of exposed livestock, so a
      food-chain route to human exposure exists in principle. Marked indirect
      because the measurement is in sheep and the same paper concludes that
      dairy products after a one-week withdrawal pose low consumer risk; no
      human poisoning by this route is reported.
  - reference: PMID:16499407
    reference_title: "Anticoagulant rodenticides."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most cases of anticoagulant rodenticide exposure involve young children and, as a consequence, the amounts ingested are almost invariably small."
    explanation: >-
      Characterizes the dominant exposure population for anticoagulant
      rodenticides, of which chlorophacinone is one.
  - reference: PMID:16499407
    reference_title: "Anticoagulant rodenticides."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Occupational exposure has also been reported."
    explanation: >-
      Records occupational exposure as an additional route for this class.
  - reference: PMID:40974629
    reference_title: "A retrospective analysis of 88 anticoagulant rodenticide poisoning cases: Characteristics and forensic implications."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 88 poisoning cases were identified, comprising 52 cases of accidental poisoning, 31 cases of suicidal poisoning, 3 cases of unknown poisoning and 2 cases of homicide."
    explanation: >-
      Gives the distribution of intent across reported anticoagulant
      rodenticide poisonings. Marked indirect because agents are pooled.
  influences_mechanisms:
  - target: Systemic Chlorophacinone Exposure
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Ingestion of chlorophacinone bait or concentrate is the route by which
      the systemic chlorophacinone burden is established.
    evidence:
    - reference: PMID:10216974
      reference_title: "Toxicological management of chlorophacinone poisoning."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "A 33-year-old man was admitted 8 hours after voluntary ingestion of 1875 mg of chlorophacinone (C'Operat 750 mL)."
      explanation: >-
        Ties ingestion of a named chlorophacinone product to the resulting
        systemic exposure in a human case.
treatments:
- name: High-Dose Prolonged Vitamin K1 (Phytomenadione)
  description: >-
    Phytomenadione (vitamin K1) is the antidote. Supplying vitamin K from
    outside restores the carboxylase cofactor that the inhibited epoxide
    reductase can no longer regenerate, and the coagulation profile corrects
    within hours. Because chlorophacinone persists, the dose required is far
    above ordinary warfarin reversal doses and treatment must continue for
    weeks; withdrawal before the drug has cleared produces rebound
    coagulopathy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: phylloquinone
      term:
        id: CHEBI:18067
        label: phylloquinone
  target_mechanisms:
  - target: Depletion of the Reduced Vitamin K Pool
    treatment_effect: RESTORES
    description: >-
      Exogenous vitamin K1 replenishes the substrate for the carboxylase
      cofactor pool without requiring the inhibited epoxide reductase.
    evidence:
    - reference: PMID:3222685
      reference_title: "[Prolonged anticoagulation following chlorophacinone poisoning]."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Under high dose vitamin K therapy the Quick was rapidly corrected but fell again on each vitamin K withdrawal."
      explanation: >-
        Correction on vitamin K and relapse off it, in a chlorophacinone
        poisoning, is a direct demonstration that vitamin K supply is the
        limiting quantity this treatment restores.
  evidence:
  - reference: PMID:3222685
    reference_title: "[Prolonged anticoagulation following chlorophacinone poisoning]."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case emphasizes the need for prolonged clinical and laboratory follow-up for rodenticide intoxications and for vitamin K administration for several weeks."
    explanation: >-
      States the duration of vitamin K therapy required after chlorophacinone
      poisoning.
  - reference: PMID:26239439
    reference_title: "Long-Acting Anticoagulant Rodenticide (Superwarfarin) Poisoning: A Review of Its Historical Development, Epidemiology, and Clinical Management."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of acute hemorrhagic symptoms often required intravenous vitamin K1 in excess of 50 to 100 mg; chronic maintenance with 100 mg PO vitamin K1 daily was the most frequently used dose required to suppress coagulopathy."
    explanation: >-
      Gives the dose magnitude actually used across reported cases. Marked indirect
      because the doses are pooled across long-acting anticoagulant
      rodenticides rather than reported for chlorophacinone alone.
  - reference: PMID:26239439
    reference_title: "Long-Acting Anticoagulant Rodenticide (Superwarfarin) Poisoning: A Review of Its Historical Development, Epidemiology, and Clinical Management."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment courses averaged 168 days."
    explanation: >-
      Quantifies treatment duration across the reviewed cases. Marked indirect
      for the same class-level reason, and the figure should not be read as a
      chlorophacinone expectation: the reviewed long-acting cases are dominated
      by brodifacoum, whose effect outlasts chlorophacinone's.
  - reference: PMID:31857739
    reference_title: "Superwarfarin (Long-Acting Anticoagulant Rodenticides) Poisoning: from Pathophysiology to Laboratory-Guided Clinical Management."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "Treatment for superwarfarin poisoning includes rapid correction of factor deficiencies with either 4-factor prothrombin complex concentrate or fresh frozen plasma in patients with active bleeding, and high dose vitamin K therapy given multiple times per day for a prolonged period of weeks to months."
    explanation: >-
      Gives the dosing frequency and the duration of high-dose vitamin K.
      Marked indirect because the review speaks for the long-acting class.
  - reference: PMID:16499407
    reference_title: "Anticoagulant rodenticides."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "If there is no active bleeding and the INR is < or =4.0, no treatment is required; if the INR is > or =4.0 phytomenadione 10mg should be administered intravenously."
    explanation: >-
      Gives the INR threshold at which vitamin K is started in a patient who
      is not bleeding, which is the decision this treatment turns on.
- name: Coagulation Factor Replacement
  description: >-
    For active bleeding, immediate replacement of the missing factors is given
    alongside vitamin K1, since vitamin K takes hours to restore carboxylation.
    Prothrombin complex concentrate is preferred because it contains exactly
    the four deficient factors; fresh frozen plasma is the fallback, and
    recombinant activated factor VII has also been used.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: four-factor prothrombin complex concentrate
      term:
        id: NCIT:C208347
        label: Four-factor Prothrombin Complex Concentrate
  target_mechanisms:
  - target: Functional Deficiency of Coagulation Factors II, VII, IX and X
    treatment_effect: BYPASSES
    description: >-
      Transfused factor concentrate supplies fully carboxylated factors
      directly, bypassing the blocked hepatic carboxylation step.
    evidence:
    - reference: PMID:16499407
      reference_title: "Anticoagulant rodenticides."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: "If active bleeding occurs, prothrombin complex concentrate (which contains factors II, VII, IX and X) 50 units/kg, or recombinant activated factor VII 1.2-4.8 mg or fresh frozen plasma 15 mL/kg (if no concentrate is available) and phytomenadione 10mg intravenously (100 microg/kg bodyweight for a child) should be given."
      explanation: >-
        Specifies replacement of precisely the four deficient factors as the
        treatment for active bleeding.
  evidence:
  - reference: PMID:26239439
    reference_title: "Long-Acting Anticoagulant Rodenticide (Superwarfarin) Poisoning: A Review of Its Historical Development, Epidemiology, and Clinical Management."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Adjunctive hemostatic therapy with recombinant factor VIIa and prothrombin complex concentrate has been reported, and phenobarbital has been used to expedite LAAR metabolism."
    explanation: >-
      Confirms the adjunctive haemostatic agents used in practice. Marked indirect
      because the review pools long-acting anticoagulant rodenticides.
  - reference: PMID:31857739
    reference_title: "Superwarfarin (Long-Acting Anticoagulant Rodenticides) Poisoning: from Pathophysiology to Laboratory-Guided Clinical Management."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "Treatment for superwarfarin poisoning includes rapid correction of factor deficiencies with either 4-factor prothrombin complex concentrate or fresh frozen plasma in patients with active bleeding"
    explanation: >-
      Names four-factor prothrombin complex concentrate ahead of fresh frozen
      plasma and confines factor replacement to patients who are bleeding.
      Marked indirect because the review speaks for the long-acting class.
  notes: >-
    Thrombotic complications accompanying haemostatic therapy have been
    reported in this class of poisoning, so factor replacement is reserved for
    active bleeding rather than used to correct a number. Only four-factor
    prothrombin complex concentrate is bound as a therapeutic_agent.
    Recombinant activated factor VII and fresh frozen plasma, both named in
    the same recommendation, are not: no suitable term was resolved for
    either.
- name: Phenobarbital Enzyme Induction
  description: >-
    Phenobarbital has been used to accelerate hepatic metabolism of
    chlorophacinone and shorten the coagulopathy. In one human case the
    apparent elimination half-life under phenobarbital was 3.27 days, shorter
    than in previously reported cases. This is an adjunct with limited
    evidence, not standard care.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: phenobarbital
      term:
        id: CHEBI:8069
        label: phenobarbital
  target_mechanisms:
  - target: Hepatic Accumulation and Prolonged Elimination
    treatment_effect: INHIBITS
    description: >-
      Cytochrome P450 induction increases the rate at which chlorophacinone is
      cleared, shortening the period over which it can inhibit the vitamin K
      cycle.
    evidence:
    - reference: PMID:2769823
      reference_title: "Chlorophacinone intoxication. A biological and toxicological study."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "An increased elimination was noted when phenobarbital was administered."
      explanation: >-
        Reports increased chlorophacinone elimination on phenobarbital. The
        observation is from a single uncontrolled case within a three-patient
        series, so it is weak evidence for a directly stated result.
  evidence:
  - reference: PMID:10216974
    reference_title: "Toxicological management of chlorophacinone poisoning."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Under phenobarbital 200 mg/day, chlorophacinone exhibited an apparent elimination half-life (3.27 days) shorter than in previously reported cases."
    explanation: >-
      Quantifies the half-life observed under phenobarbital against a
      historical comparison. The comparison is with previously
      reported cases rather than a control arm, so the effect size is not
      established.
  notes: >-
    Recorded because it is the specific adjunct repeatedly tried in
    chlorophacinone poisoning, not because the evidence is strong. Both
    supporting reports are uncontrolled single-patient observations with
    historical comparators.
diagnosis:
- name: Delayed coagulation testing after exposure
  description: >-
    The coagulopathy is not present at the moment of exposure. Prothrombin
    time and INR should be measured 36 to 48 hours after exposure, because an
    earlier normal result does not exclude poisoning. In a case series the
    median latency to presentation was four days.
  evidence:
  - reference: PMID:16499407
    reference_title: "Anticoagulant rodenticides."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "There are now sufficient data in young children exposed to anticoagulant rodenticides to conclude that routine measurement of the international normalised ratio (INR) is unnecessary."
    explanation: >-
      States that the small unintentional paediatric ingestions which dominate
      reported exposures do not need routine coagulation testing, the
      counterweight to the 36 to 48 hour rule above. Marked indirect because it
      is a recommendation for the class rather than a chlorophacinone finding.
  - reference: PMID:17357377
    reference_title: "Long-acting anticoagulant rodenticide poisoning: an evidence-based consensus guideline for out-of-hospital management."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "Patients with unintentional ingestion of less than 1 mg of LAAR active ingredient can be safely observed at home without laboratory monitoring."
    explanation: >-
      The consensus out-of-hospital guideline puts a dose threshold on that
      recommendation. Marked indirect because the guideline covers long-acting
      anticoagulant rodenticides collectively.
  - reference: PMID:17357377
    reference_title: "Long-acting anticoagulant rodenticide poisoning: an evidence-based consensus guideline for out-of-hospital management."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "Patients with unintentional ingestion of 1 mg or more of active ingredient and are asymptomatic should be evaluated for coagulopathy at 48-72 hours after exposure (Grade B)."
    explanation: >-
      Gives the graded recommendation and testing window above that threshold.
      Marked indirect for the same class-level reason.
  - reference: PMID:2729812
    reference_title: "[Prolonged hypocoagulability following the ingestion of anticoagulant raticides]."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The duration of the abnormalities is unpredictable; the prothrombin time should therefore be checked 48 hours after stopping Vitamin K therapy to detect any recurrence."
    explanation: >-
      Names the test that catches the rebound this entry models: a prothrombin
      time 48 hours after vitamin K is stopped. Marked indirect because the
      eleven-patient Paris series pools chlorophacinone with bromadiolone and
      warfarin.
  - reference: PMID:2729812
    reference_title: "[Prolonged hypocoagulability following the ingestion of anticoagulant raticides]."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The absence of early clinical signs probably explains the number of late admissions."
    explanation: >-
      Attributes late presentation to the silent latent phase. Marked indirect
      because the series pools three anticoagulants.
  - reference: PMID:16499407
    reference_title: "Anticoagulant rodenticides."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "In all other cases, the INR should be measured 36-48 hours post exposure."
    explanation: >-
      States the recommended timing of coagulation testing after exposure.
  - reference: PMID:40974629
    reference_title: "A retrospective analysis of 88 anticoagulant rodenticide poisoning cases: Characteristics and forensic implications."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The median latency period was 4 days (range: 1 ∼ 30)."
    explanation: >-
      Quantifies the delay between exposure and clinical presentation.
      Marked indirect because the series pools anticoagulant rodenticides.
  notes: >-
    In young children with the small unintentional ingestions that dominate
    reported exposures, routine INR measurement is considered unnecessary.
- name: Suspicion on unexplained prothrombin time prolongation
  description: >-
    Where no exposure is reported, the poisoning is found by suspecting it.
    An unexplained prolonged prothrombin time is the trigger to send a
    rodenticide assay.
  evidence:
  - reference: PMID:31857739
    reference_title: "Superwarfarin (Long-Acting Anticoagulant Rodenticides) Poisoning: from Pathophysiology to Laboratory-Guided Clinical Management."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "Superwarfarin poisoning should therefore be suspected in all patients with unexplained prolongation of prothrombin time, and can be confirmed by their detection in serum."
    explanation: >-
      States the diagnostic posture for this class of poisoning when the
      history is absent. Marked indirect because the review addresses the
      long-acting rodenticides collectively.
- name: Analytical confirmation of chlorophacinone
  description: >-
    Chlorophacinone is identified and quantified in plasma or serum by HPLC or
    LC-MS/MS. Analytical confirmation is what distinguishes chlorophacinone
    poisoning from the other anticoagulant rodenticides and from warfarin,
    since the coagulation profile alone cannot.
  evidence:
  - reference: PMID:10216974
    reference_title: "Toxicological management of chlorophacinone poisoning."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "A simple HPLC procedure for the determination of chlorophacinone in human plasma is reported for that purpose."
    explanation: >-
      Describes the analytical method by which chlorophacinone is confirmed in
      human plasma.
  - reference: PMID:39893780
    reference_title: "Simultaneous quantification of eighteen therapeutic oral anticoagulants, rodenticides, and antiplatelet agents by LC-MS/MS and its application in post-mortem forensic cases."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "The method was validated according to the FDA recommendations for all compounds, with an eight-min run time in human whole blood, the gold standard in toxicological forensic investigation."
    explanation: >-
      Reports the validation result for a panel whose eighteen analytes
      include chlorophacinone, which is what allows the specific agent to be
      named rather than inferred. Marked indirect because performance is
      reported for all compounds together rather than for chlorophacinone
      alone.
progression:
- phase: Latent
  duration: 0 to 24 hours after exposure
  notes: >-
    Coagulation is still normal. Non-specific symptoms such as nausea may
    occur. A normal coagulation panel drawn in this window excludes nothing.
  evidence:
  - reference: PMID:10216974
    reference_title: "Toxicological management of chlorophacinone poisoning."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The examination revealed excitation and nausea, with a normal prothrombin index (PI)."
    explanation: >-
      Eight hours after ingesting 1875 mg of chlorophacinone the prothrombin
      index was still normal, which fixes the latent phase.
- phase: Coagulopathy onset
  duration: about 1 to 4 days after exposure
  notes: >-
    Prothrombin time and INR rise as factor VII, the shortest-lived of the
    affected factors, is depleted. Bleeding may begin. The reported median
    latency to clinical presentation is four days.
  evidence:
  - reference: PMID:40974629
    reference_title: "A retrospective analysis of 88 anticoagulant rodenticide poisoning cases: Characteristics and forensic implications."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The median latency period was 4 days (range: 1 ∼ 30)."
    explanation: >-
      Gives the interval from exposure to presentation. Marked indirect because
      the series pools anticoagulant rodenticides.
- phase: Resolution with rebound
  duration: weeks to months
  notes: >-
    Under vitamin K1 the coagulation profile corrects and relapses on each
    withdrawal. Full normalization took seven weeks in the reported case.
    Relapse here is the expected course, not a complication.
  evidence:
  - reference: PMID:3222685
    reference_title: "[Prolonged anticoagulation following chlorophacinone poisoning]."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prothrombin time (and vitamin K dependent factors VII and X) finally normalized only 7 weeks after chlorophacinone ingestion."
    explanation: >-
      Fixes the duration of the resolution phase in a chlorophacinone
      poisoning.
epidemiology:
- name: Registered field use in France
  description: >-
    Chlorophacinone's share of human poisoning is small and country-dependent,
    because it tracks the compound's registration. In France it is one of only
    two anticoagulants registered for field use, so it appears there far more
    than in series from countries where the second-generation compounds
    dominate.
  evidence:
  - reference: PMID:21171851
    reference_title: "Prevalence of anticoagulant rodenticide poisoning in humans and animals in France and substances involved."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "In wildlife, bromadiolone and chlorophacinone are by far the most important products, being the only ones registered for field use."
    explanation: >-
      States chlorophacinone's registration position in France, which is why
      the human case literature clusters there.
- name: Exposure circumstances and severity
  description: >-
    Reported anticoagulant rodenticide exposures are dominated by young
    children and are mostly accidental and clinically trivial. The severe cases
    come from deliberate adult ingestion.
  evidence:
  - reference: PMID:21171851
    reference_title: "Prevalence of anticoagulant rodenticide poisoning in humans and animals in France and substances involved."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, the proportion of anticoagulant exposure reported to the Lyon poison control center appeared very limited and mostly occurred in young children, with no or very limited clinical severity."
    explanation: >-
      Characterizes the exposure population and its severity in the French
      poison-centre data. Marked indirect because the figures cover
      anticoagulant rodenticides collectively.
  - reference: PMID:21171851
    reference_title: "Prevalence of anticoagulant rodenticide poisoning in humans and animals in France and substances involved."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is no report of mortality in the human data, and less than 1% of all exposure cases in domestic animals were fatal."
    explanation: >-
      Records the absence of deaths in four years of French human data, which
      is the counterweight to the severity of the published case reports.
      Marked indirect because agents are pooled.
- name: Reported burden in the United States
  description: >-
    United States poison-centre data for the long-acting anticoagulant
    rodenticides as a class give the order of magnitude of reported exposure.
    No chlorophacinone-specific incidence or prevalence figure exists.
  evidence:
  - reference: PMID:26239439
    reference_title: "Long-Acting Anticoagulant Rodenticide (Superwarfarin) Poisoning: A Review of Its Historical Development, Epidemiology, and Clinical Management."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the United States, on average, there were 10413 exposures reported with 2750 patients treated annually."
    explanation: >-
      Gives annual reported exposures and treated patients. Marked indirect
      because the figure covers the long-acting class, not chlorophacinone.
  - reference: PMID:26239439
    reference_title: "Long-Acting Anticoagulant Rodenticide (Superwarfarin) Poisoning: A Review of Its Historical Development, Epidemiology, and Clinical Management."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fortunately, only 2% of all exposures result in morbidity or mortality."
    explanation: >-
      Quantifies the proportion of reported exposures that matter clinically.
      Marked indirect for the same class-level reason.
  notes: >-
    These are reported exposures, not diagnosed cases of poisoning, and they
    cannot be separated by agent.
differential_diagnoses:
- name: Vitamin K-Dependent Coagulation Factor Deficiency
  disease_term:
    preferred_term: congenital vitamin K-dependent coagulation factors deficiency
    term:
      id: MONDO:0015722
      label: congenital vitamin K-dependent coagulation factors deficiency
  description: >-
    Biallelic germline variants in VKORC1 or GGCX produce the same combined
    deficiency of the vitamin K-dependent factors by disabling the same two
    steps that chlorophacinone blocks pharmacologically.
  distinguishing_features:
  - Germline VKORC1 or GGCX variants are present and the presentation is lifelong rather than following a single exposure.
  - No anticoagulant rodenticide is detectable on toxicological analysis.
  - Skeletal and other extra-haemostatic features of GGCX deficiency have no counterpart in an acute poisoning.
  notes: >-
    The genetic counterpart of the acquired lesion here, so an unexplained
    combined deficiency of the vitamin K-dependent factors should be worked up
    against both.
- name: Warfarin or other coumarin anticoagulant
  description: >-
    Therapeutic warfarin, warfarin overdose, and the other coumarin oral
    anticoagulants produce the same vitamin K antagonist coagulopathy through
    the same enzyme.
  distinguishing_features:
  - A drug history and a therapeutic indication are usually present.
  - Warfarin coagulopathy resolves within days of stopping the drug and responds to ordinary reversal doses of vitamin K, not to months of high-dose therapy.
  - Analytical confirmation separates the compounds.
  evidence:
  - reference: PMID:26239439
    reference_title: "Long-Acting Anticoagulant Rodenticide (Superwarfarin) Poisoning: A Review of Its Historical Development, Epidemiology, and Clinical Management."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "Long-acting anticoagulant rodenticides have an extremely high affinity for VKOR compared with warfarin, characterized by rebound coagulopathy and bleeding after initial treatment and the need for high-dose, long-term therapy with vitamin K1."
    explanation: >-
      Contrasts the rodenticide course with warfarin's, which is the
      distinguishing feature. Marked indirect because the review speaks for the
      long-acting class.
- name: Liver failure
  description: >-
    Hepatic synthetic failure also depresses the vitamin K-dependent factors
    and prolongs the prothrombin time.
  distinguishing_features:
  - Factor V is synthesized in the liver but is not vitamin K dependent, so it is reduced in liver failure and unaffected by a vitamin K antagonist. This factor V versus factor VII pattern is the standard discriminator; no source cited in this entry reports it, so it is recorded as clinical convention rather than curated as evidenced content.
  - Other markers of hepatic failure, such as bilirubin, albumin and transaminases, are deranged.
  - The coagulopathy of liver failure does not correct on high-dose vitamin K1 and does not rebound on its withdrawal.
- name: Disseminated intravascular coagulation
  description: >-
    Consumptive coagulopathy also prolongs the prothrombin time and causes
    multi-site bleeding.
  distinguishing_features:
  - Platelet count and fibrinogen are low and D-dimer is raised in disseminated intravascular coagulation; a vitamin K antagonist leaves the platelet count and fibrinogen untouched.
  - A precipitating illness such as sepsis, malignancy or obstetric catastrophe is present.
  - Recorded as clinical convention. No source cited in this entry reports these discriminating values.
- name: Other anticoagulant rodenticide poisoning
  description: >-
    Brodifacoum, bromadiolone, difenacoum, difethialone, flocoumafen and
    coumatetralyl produce a clinically indistinguishable coagulopathy through
    the same target. In pooled case series brodifacoum and bromadiolone are the
    agents most often identified.
  distinguishing_features:
  - Only analytical confirmation separates the agents; the coagulation profile does not.
  - The second-generation compounds persist far longer, so treatment courses run months rather than weeks.
  evidence:
  - reference: PMID:40974629
    reference_title: "A retrospective analysis of 88 anticoagulant rodenticide poisoning cases: Characteristics and forensic implications."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "About the types of rodenticides, a total of 38 cases reported 7 distinct types, with brodifacoum and bromadiolone being the most common"
    explanation: >-
      Establishes that several agents in this class present the same way and
      that the commonest identified are not chlorophacinone. Marked indirect
      because the sentence is about agent distribution rather than about
      distinguishing them clinically.
animal_models:
- name: Accidental chlorophacinone poisoning in calves
  species: Cattle
  genotype: wild type
  description: >-
    Fourteen crossbred calves ingested chlorophacinone powder present in their
    housing. Three were submitted for necropsy, with chlorophacinone confirmed
    in liver at 2.9 to 4.2 ppm. This is a naturally occurring, dose-uncontrolled
    veterinary poisoning rather than a designed experimental model, and it is
    recorded here because it couples a confirmed chlorophacinone tissue burden
    to a documented anatomical distribution of haemorrhage.
  publication: PMID:35000500
  evidence:
  - reference: PMID:35000500
    reference_title: "Acute hemorrhage and death in calves following chlorophacinone exposure."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Three calves were submitted to the Iowa State University Veterinary Diagnostic Laboratory for diagnostic evaluation following an abrupt increase in morbidity and mortality in a calf herd associated with epistaxis and widespread hemorrhage."
    explanation: >-
      Establishes the exposure event and the animals examined, which is what
      this entry records as a naturally occurring chlorophacinone poisoning.
  modeled_mechanisms:
  - target: Multicompartment Hemorrhage
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the multicompartment haemorrhage of human chlorophacinone
      poisoning, with the same agent confirmed analytically in tissue.
    limitations: >-
      An uncontrolled accidental exposure in a ruminant, with no measured
      ingested dose, no coagulation assays reported, and no treatment arm.
      Bovine vitamin K handling and rumen microbial vitamin K synthesis differ
      from human, so the dose-response cannot be carried across.
    readouts:
    - name: Chlorophacinone concentration in liver
      target: Multicompartment Hemorrhage
      direction: INCREASED
      interpretation: >-
        Confirms that the haemorrhage occurred against a measured
        chlorophacinone tissue burden rather than a presumed exposure.
      evidence:
      - reference: PMID:35000500
        reference_title: "Acute hemorrhage and death in calves following chlorophacinone exposure."
        supports: SUPPORT
        directness: DIRECT
        evidence_source: MODEL_ORGANISM
        snippet: "Significant concentrations of chlorophacinone were detected at 4.2, 3.6, and 2.9 ppm in liver."
        explanation: >-
          Reports the measured hepatic chlorophacinone concentrations.
    evidence:
    - reference: PMID:35000500
      reference_title: "Acute hemorrhage and death in calves following chlorophacinone exposure."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Acute hemorrhage and death occurred in fourteen 1.5-mo-old, crossbred calves following ingestion of the vitamin K antagonist chlorophacinone."
      explanation: >-
        Attributes acute haemorrhage and death to chlorophacinone ingestion,
        which is what makes this exposure informative for the haemorrhage node.
- name: Accidental chlorophacinone poisoning in lambs
  species: Sheep
  genotype: wild type
  description: >-
    Eleven lambs reached old bait placed between the wall studs of their
    housing through a hole in the plywood. Two were necropsied, with
    chlorophacinone confirmed in liver at 0.58 and 0.50 ppm. A second species
    with a confirmed chlorophacinone tissue burden, and the source of the
    tempo: these animals died within one to two hours of the first sign.
  publication: PMID:17037620
  evidence:
  - reference: PMID:17037620
    reference_title: "Chlorophacinone exposure causing an epizootic of acute fatal hemorrhage in lambs."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "The anticoagulant chlorophacinone was detected in the livers at 0.58 ppm and 0.50 ppm (wet weight), respectively."
    explanation: >-
      Confirms chlorophacinone analytically in the affected animals, which is
      what makes this exposure informative rather than presumptive.
  modeled_mechanisms:
  - target: Multicompartment Hemorrhage
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces multicompartment haemorrhage with epistaxis as the presenting
      sign, in a second ruminant species and at liver concentrations roughly
      sixfold below the calf series.
    limitations: >-
      An uncontrolled accidental exposure with no measured ingested dose, no
      coagulation assays, and no treatment arm. The liver concentrations differ
      sixfold from the calf epizootic, and age, species and dose timing all
      differ, so no lethal threshold can be derived from the pair. The
      centrilobular hepatocellular necrosis reported at necropsy is most
      parsimoniously hypoxic in an exsanguinating animal and is deliberately
      not curated as chlorophacinone hepatotoxicity. Ovine vitamin K handling,
      including rumen microbial synthesis, differs from human.
    readouts:
    - name: Time from first clinical sign to death
      target: Multicompartment Hemorrhage
      direction: DECREASED
      interpretation: >-
        Records how fast the haemorrhagic phase can run once it declares
        itself in a heavily exposed animal.
      evidence:
      - reference: PMID:17037620
        reference_title: "Chlorophacinone exposure causing an epizootic of acute fatal hemorrhage in lambs."
        supports: SUPPORT
        directness: DIRECT
        evidence_source: MODEL_ORGANISM
        snippet: "Affected animals died within 1-2 hours from the onset of clinical signs."
        explanation: >-
          Reports the interval measured in the affected lambs.
    evidence:
    - reference: PMID:17037620
      reference_title: "Chlorophacinone exposure causing an epizootic of acute fatal hemorrhage in lambs."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Eleven lambs, approximately 1-2 months of age, suddenly developed epistaxis, respiratory distress, and facial and cervical swelling."
      explanation: >-
        Documents the presenting haemorrhagic syndrome attributed to
        chlorophacinone in this epizootic.
discussions:
- discussion_id: protein_c_s_paradoxical_thrombosis
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does loss of gamma-carboxylation of the anticoagulant proteins C and S
    explain the thrombotic events reported in anticoagulant rodenticide
    poisoning?
  attaches_to:
  - "pathophysiology#Impaired Gamma-Carboxylation of Vitamin K-Dependent Clotting Factors"
  rationale: >-
    Proteins C and S are vitamin K-dependent substrates of the same hepatic
    carboxylase as factors II, VII, IX and X, so a vitamin K antagonist
    depletes anticoagulant and procoagulant proteins together. Thrombotic
    events, including a fatal cerebral vein thrombosis reported as a suspected
    chlorophacinone poisoning, occur in this class and are difficult to
    reconcile with pure anticoagulation. No cited source here measures protein
    C or protein S activity in a chlorophacinone poisoning, so the mechanism
    is left as an open question rather than curated as a causal edge.
  evidence:
  - reference: PMID:16716547
    reference_title: "Lethal paradoxical cerebral vein thrombosis due to suspicious anticoagulant rodenticide intoxication with chlorophacinone."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The authors report a case of suspicious chlorophacinone poisoning with a problematic diagnosis."
    explanation: >-
      Reports a fatal thrombotic event in a chlorophacinone poisoning. The
      paper's own wording is "suspicious" with a "problematic diagnosis", so
      it is cited here as a case that raises the question, not as a settled
      attribution.
  - reference: PMID:26239439
    reference_title: "Long-Acting Anticoagulant Rodenticide (Superwarfarin) Poisoning: A Review of Its Historical Development, Epidemiology, and Clinical Management."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Long-acting anticoagulant rodenticide-induced paradoxical thrombosis and thrombotic complications accompanying hemostatic therapy have also been observed."
    explanation: >-
      Confirms paradoxical thrombosis is observed across the class and
      separates it from thrombosis caused by haemostatic therapy. Marked indirect
      because it reports the observation without testing a mechanism.
- discussion_id: persistence_after_plasma_clearance
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why does chlorophacinone-induced hypocoagulability persist after plasma
    chlorophacinone concentrations have fallen to low values?
  attaches_to:
  - "pathophysiology#Hepatic Accumulation and Prolonged Elimination"
  rationale: >-
    In a monitored human poisoning the hypocoagulability outlasted the
    measurable plasma concentration. The treating authors offered two
    candidate explanations, accumulation in target cells and an unidentified
    active metabolite, and distinguished neither. Which of the two operates
    determines whether plasma chlorophacinone concentration is a usable guide
    to stopping vitamin K therapy.
  proposed_experiments:
  - experiment_id: chlorophacinone_metabolite_vs_compartment
    name: Paired hepatic and plasma chlorophacinone measurement with metabolite profiling
    description: >-
      Measure chlorophacinone and its metabolites in plasma alongside INR
      through the resolution phase of human poisonings, with untargeted
      metabolite profiling, to determine whether a persisting parent compound
      compartment or an active metabolite accounts for the residual effect.
  evidence:
  - reference: PMID:23109180
    reference_title: "Bioaccumulation of chlorophacinone in strains of rats resistant to anticoagulants."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Extensive metabolism of chlorophacinone was also found, and was similar (in nature and proportion of metabolites) across strains (3 OH-metabolites identified)."
    explanation: >-
      Three hydroxy-metabolites of chlorophacinone have been identified in rat,
      so the metabolite arm of this question is not that no metabolite is known
      but that none has been shown active in humans. Marked indirect because
      the work is in rat.
  - reference: PMID:23109180
    reference_title: "Bioaccumulation of chlorophacinone in strains of rats resistant to anticoagulants."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Accumulation of chlorophacinone occurs from day 1 to day 4, and an equilibrium is reached, suggesting rapid elimination."
    explanation: >-
      Cuts against the tissue-accumulation arm: hepatic chlorophacinone reaches
      a plateau within four days in rat, which the authors read as rapid
      elimination rather than indefinite retention. Marked indirect because the
      work is in rat and because the human coagulopathy is what needs
      explaining.
  - reference: PMID:10216974
    reference_title: "Toxicological management of chlorophacinone poisoning."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chlorophacinone accumulation in target cells or existence of an unidentified metabolite may explain persistence of the hypocoagulability syndrome at low plasmatic concentrations of chlorophacinone."
    explanation: >-
      States the unresolved alternative explanations directly.
- discussion_id: first_generation_versus_long_acting
  kind: INTERPRETATION
  prompt: >-
    Should chlorophacinone be curated as a first-generation anticoagulant
    rodenticide or as a long-acting anticoagulant rodenticide?
  rationale: >-
    Two authoritative sources place chlorophacinone in opposite groups, and
    both are right on their own terms. Watt and colleagues group it with the
    long-acting rodenticides on human duration of effect. Esther and
    colleagues list it with warfarin and coumatetralyl as first-generation,
    which is a statement about rodent potency and the number of feeds needed
    to kill a rat. "Generation" is a rodent-efficacy term and "long-acting" is
    a human-toxicology term, so chlorophacinone is first-generation by potency
    and long-acting by duration. The distinction matters clinically, because
    the first-generation label wrongly implies a warfarin-length course of
    treatment. This entry curates the human-toxicology reading and records the
    conflict rather than resolving it silently.
  evidence:
  - reference: PMID:16499407
    reference_title: "Anticoagulant rodenticides."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    snippet: "This group includes the second generation 4-hydroxycoumarins brodifacoum, bromadiolone, difenacoum, flocoumafen and the indanedione derivatives chlorophacinone and diphacinone."
    explanation: >-
      Places chlorophacinone in the long-acting anticoagulant rodenticide
      group.
  - reference: PMID:24781908
    reference_title: "[Rodenticide resistance and consequences]."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    snippet: "Anticoagulants of the first generation (warfarin, chlorophacinone, coumatetralyl) as well as bromadiolone and difenacoum are not an option for the control of resistant Norway rats."
    explanation: >-
      Places chlorophacinone in the first-generation group, in a
      rodent-control context.
- discussion_id: indandione_mitochondrial_uncoupling
  kind: KNOWLEDGE_GAP
  prompt: >-
    Do indandione anticoagulants, chlorophacinone among them, uncouple
    oxidative phosphorylation, and does that contribute to human toxicity
    beyond the coagulopathy?
  attaches_to:
  - "pathophysiology#Systemic Chlorophacinone Exposure"
  rationale: >-
    Toxicology reference texts repeatedly describe the indandiones as
    uncouplers of oxidative phosphorylation, a property the 4-hydroxycoumarins
    are said to lack, and attribute cardiopulmonary and neurologic injury in
    laboratory rodents to it. The claim is not curated here because no primary
    source for it could be located: PubMed queries pairing chlorophacinone,
    and separately indandione, diphacinone and pindone, with uncoupling,
    mitochondria and oxidative phosphorylation returned no records. The gap is
    recorded rather than the claim, because a widely repeated mechanism with
    no retrievable primary citation is worth flagging. Note that
    chlorophacinone does have a documented off-target activity, FXR
    antagonism, cited below; the absent evidence is for uncoupling in
    particular, not for off-target action in general.
  proposed_experiments:
  - experiment_id: chlorophacinone_mitochondrial_respirometry
    name: Respirometry of isolated mitochondria exposed to chlorophacinone
    description: >-
      Measure oxygen consumption, membrane potential and ATP synthesis in
      isolated hepatic and cardiac mitochondria across a chlorophacinone
      concentration range spanning those reached in human poisoning, against a
      4-hydroxycoumarin comparator and a known uncoupler control, to establish
      whether the uncoupling property exists and at what concentration.
  evidence:
  - reference: PMID:27773686
    reference_title: "Differential modulation of FXR activity by chlorophacinone and ivermectin analogs."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "Our results showed that chlorophacinone and ivermectin had distinct modes of action (MOA) in modulating FXR-coregulator interactions and compound selectivity against the four aforementioned functionally-relevant nuclear receptors."
    explanation: >-
      Chlorophacinone has a documented off-target activity, antagonism of the
      nuclear receptor FXR in a validated screen. It is cited here so this gap
      is not read as "chlorophacinone has no off-target activity"; what lacks a
      primary source is uncoupling specifically. Marked indirect because the
      assays are cell-based and the paper makes no claim about human poisoning.
  notes: >-
    The cited evidence item records a different off-target mechanism rather
    than the uncoupling claim itself. No source is offered for uncoupling,
    because that is the point of the entry: attaching a reference that does
    not make the claim would defeat it.
- discussion_id: cyp_induction_transferability
  kind: INTERPRETATION
  prompt: >-
    Does the published argument against using cytochrome P450 inducers in
    long-acting anticoagulant rodenticide poisoning apply to chlorophacinone?
  attaches_to:
  - "pathophysiology#Hepatic Accumulation and Prolonged Elimination"
  rationale: >-
    This entry curates phenobarbital enzyme induction as a reported adjunct.
    A published position argues against CYP inducers in this poisoning, but its
    reasoning is specific to brodifacoum, which the authors state does not
    undergo significant hepatic metabolism. Chlorophacinone does: three
    hydroxy-metabolites have been identified and metabolism is described as
    extensive in rat. The argument therefore does not obviously transfer, and
    the two chlorophacinone reports that used phenobarbital are uncontrolled
    single patients. Recorded as an open interpretation rather than settled
    either way, because the safety objection about sedating a bleeding patient
    stands regardless of the metabolism question.
  evidence:
  - reference: PMID:30689138
    reference_title: "Should Cytochrome P450 Inducers be Used to Accelerate Clearance of Brodifacoum from Poisoned Patients?"
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "Therefore, we propose that CYP inducers should not be used to accelerate the clearance of brodifacoum from poisoned patients, but that alternative approaches such as reducing enterohepatic recirculation of brodifacoum, or using lipid emulsions to scavenge brodifacoum throughout the body, be considered."
    explanation: >-
      States the position being weighed, in full: the authors do not simply
      reject enzyme induction, they redirect to interrupting enterohepatic
      recirculation or scavenging the drug. Marked indirect because it is a
      proposal about brodifacoum, not chlorophacinone.
  - reference: PMID:30689138
    reference_title: "Should Cytochrome P450 Inducers be Used to Accelerate Clearance of Brodifacoum from Poisoned Patients?"
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "unlike warfarin, brodifacoum does not undergo significant metabolism in the liver, nor have the effects of phenobarbital on vitamin K1 metabolism been previously determined"
    explanation: >-
      Gives the premise on which that position rests, which is the premise that
      may not hold for chlorophacinone. Marked indirect for the same reason.
  - reference: PMID:23109180
    reference_title: "Bioaccumulation of chlorophacinone in strains of rats resistant to anticoagulants."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Extensive metabolism of chlorophacinone was also found, and was similar (in nature and proportion of metabolites) across strains (3 OH-metabolites identified)."
    explanation: >-
      Chlorophacinone, unlike brodifacoum, is extensively metabolised, which is
      why the argument may not transfer. Marked indirect because the work is in
      rat.
references:
- reference: PMID:16499407
  title: "Anticoagulant rodenticides."
- reference: PMID:26239439
  title: "Long-Acting Anticoagulant Rodenticide (Superwarfarin) Poisoning: A Review of Its Historical Development, Epidemiology, and Clinical Management."
- reference: PMID:10216974
  title: "Toxicological management of chlorophacinone poisoning."
- reference: PMID:2769823
  title: "Chlorophacinone intoxication. A biological and toxicological study."
- reference: PMID:3222685
  title: "[Prolonged anticoagulation following chlorophacinone poisoning]."
- reference: PMID:16716547
  title: "Lethal paradoxical cerebral vein thrombosis due to suspicious anticoagulant rodenticide intoxication with chlorophacinone."
- reference: PMID:35000500
  title: "Acute hemorrhage and death in calves following chlorophacinone exposure."
- reference: PMID:40974629
  title: "A retrospective analysis of 88 anticoagulant rodenticide poisoning cases: Characteristics and forensic implications."
- reference: PMID:24781908
  title: "[Rodenticide resistance and consequences]."
- reference: PMID:35970209
  title: "VKORC1 single nucleotide polymorphisms in rodents in Spain."
- reference: PMID:21171851
  title: "Prevalence of anticoagulant rodenticide poisoning in humans and animals in France and substances involved."
- reference: PMID:39893780
  title: "Simultaneous quantification of eighteen therapeutic oral anticoagulants, rodenticides, and antiplatelet agents by LC-MS/MS and its application in post-mortem forensic cases."
- reference: PMID:31857739
  title: "Superwarfarin (Long-Acting Anticoagulant Rodenticides) Poisoning: from Pathophysiology to Laboratory-Guided Clinical Management."
- reference: PMID:17357377
  title: "Long-acting anticoagulant rodenticide poisoning: an evidence-based consensus guideline for out-of-hospital management."
- reference: PMID:2729812
  title: "[Prolonged hypocoagulability following the ingestion of anticoagulant raticides]."
- reference: PMID:1522713
  title: "Rapid high-performance liquid chromatographic assay of chlorophacinone in human serum."
- reference: PMID:23109180
  title: "Bioaccumulation of chlorophacinone in strains of rats resistant to anticoagulants."
- reference: PMID:30689138
  title: "Should Cytochrome P450 Inducers be Used to Accelerate Clearance of Brodifacoum from Poisoned Patients?"
- reference: PMID:32447894
  title: "[A case of acute osteofascial compartment syndrome caused by rodenticide poisoning]."
- reference: PMID:27773686
  title: "Differential modulation of FXR activity by chlorophacinone and ivermectin analogs."
- reference: PMID:17037620
  title: "Chlorophacinone exposure causing an epizootic of acute fatal hemorrhage in lambs."
- reference: PMID:32645465
  title: "Accidental chlorophacinone exposure of lactating ewes: Clinical follow-up and human health dietary implications."
- reference: PMID:29897553
  title: "The Bile Sequestrant Cholestyramine Increases Survival in a Rabbit Model of Brodifacoum Poisoning."

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References & Deep Research