API

Aop: 187

AOP Title

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Anticoagulant rodenticide inhibition of vitamin K epoxide reductase resulting coagulopathy and hemorrhage

Short name:

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VKOR inhibition resulting in coagulopathy

Authors

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Point of Contact

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Barnett Rattner

Contributors

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  • Barnett Rattner

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development 1.31 Included in OECD Work Plan


This AOP was last modified on December 03, 2016 16:37

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Revision dates for related pages

Page Revision Date/Time
Under carboxylated clotting factors will not assemble on cell surfaces to form clot, Failure of secondary hemostasis December 03, 2016 16:37
Failure in vascular repair mechanisms, Unresolved blood loss (hemorrhage) September 16, 2017 10:17
Failure in gamma-glutamyl carboxylation of clotting factors II, VII, IX and X, Under carboxylation of clotting factors (e.g., des-gamma-carboxy prothrombin) December 03, 2016 16:37
Blood loss and development of anemia, Impaired oxygen delivery and nutrient delivery to tissue, impaired carbon dioxide and waste product removal December 03, 2016 16:37
Hemostasis, Depletion from blood of fully functional carboxylated clotting factors December 03, 2016 16:37
Irreversible inhibition of hepatic VKOR by binding of AR at tyrosine 139, Failure to cycle vitamin K epoxide to vitamin K to form vitamin K hydroquinone December 03, 2016 16:37
Reduced fitness or even mortality, Acidosis, hypovolemic shock and organ dysfunction December 03, 2016 16:37
Impaired recruitment , Population trajectory December 03, 2016 16:37
Uncoupling of oxidative phosphorylation, Reduced ability to generate ATP September 16, 2017 10:17
Osteoporosis and vascular calcification, Bone deterioration December 03, 2016 16:37
Anticoagulant rodenticide interferes with carboxylation of Gla proteins in bone, Impairment of post-translational modification (carboxylation) of osteocalcin December 03, 2016 16:37
Failure in gamma-glutamyl carboxylation of clotting factors II, VII, IX and X, Under carbo leads to Hemostasis, Depletion from blood of fully functional carboxylated clotting factors December 03, 2016 16:38
Hemostasis, Depletion from blood of fully functional carboxylated clotting factors leads to Under carboxylated clotting factors will not assemble on cell surfaces to form clot, Failur December 03, 2016 16:38
Irreversible inhibition of hepatic VKOR by binding of AR at tyrosine 139, Failure to cycle leads to Failure in gamma-glutamyl carboxylation of clotting factors II, VII, IX and X, Under carbo December 03, 2016 16:38
Under carboxylated clotting factors will not assemble on cell surfaces to form clot, Failur leads to Failure in vascular repair mechanisms, Unresolved blood loss (hemorrhage) December 03, 2016 16:38
Failure in vascular repair mechanisms, Unresolved blood loss (hemorrhage) leads to Blood loss and development of anemia, Impaired oxygen delivery and nutrient delivery to tis December 03, 2016 16:38
Blood loss and development of anemia, Impaired oxygen delivery and nutrient delivery to tis leads to Reduced fitness or even mortality, Acidosis, hypovolemic shock and organ dysfunction December 03, 2016 16:38
Reduced fitness or even mortality, Acidosis, hypovolemic shock and organ dysfunction leads to Impaired recruitment , Population trajectory December 03, 2016 16:38
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Abstract

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Background (optional)

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Summary of the AOP

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Stressors

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Molecular Initiating Event

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Title Short name
Irreversible inhibition of hepatic VKOR by binding of AR at tyrosine 139, Failure to cycle vitamin K epoxide to vitamin K to form vitamin K hydroquinone Irreversible inhibition of hepatic VKOR by binding of AR at tyrosine 139, Failure to cycle
Uncoupling of oxidative phosphorylation, Reduced ability to generate ATP Uncoupling of oxidative phosphorylation, Reduced ability to generate ATP
Anticoagulant rodenticide interferes with carboxylation of Gla proteins in bone, Impairment of post-translational modification (carboxylation) of osteocalcin Anticoagulant rodenticide interferes with carboxylation of Gla proteins in bone, Impairment

Key Events

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Title Short name
Under carboxylated clotting factors will not assemble on cell surfaces to form clot, Failure of secondary hemostasis Under carboxylated clotting factors will not assemble on cell surfaces to form clot, Failur
Failure in vascular repair mechanisms, Unresolved blood loss (hemorrhage) Failure in vascular repair mechanisms, Unresolved blood loss (hemorrhage)
Failure in gamma-glutamyl carboxylation of clotting factors II, VII, IX and X, Under carboxylation of clotting factors (e.g., des-gamma-carboxy prothrombin) Failure in gamma-glutamyl carboxylation of clotting factors II, VII, IX and X, Under carbo
Blood loss and development of anemia, Impaired oxygen delivery and nutrient delivery to tissue, impaired carbon dioxide and waste product removal Blood loss and development of anemia, Impaired oxygen delivery and nutrient delivery to tis
Hemostasis, Depletion from blood of fully functional carboxylated clotting factors Hemostasis, Depletion from blood of fully functional carboxylated clotting factors
Reduced fitness or even mortality, Acidosis, hypovolemic shock and organ dysfunction Reduced fitness or even mortality, Acidosis, hypovolemic shock and organ dysfunction
Osteoporosis and vascular calcification, Bone deterioration Osteoporosis and vascular calcification, Bone deterioration

Adverse Outcome

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Title Short name
Impaired recruitment , Population trajectory Impaired recruitment , Population trajectory

Relationships Between Two Key Events (Including MIEs and AOs)

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Title Directness Evidence Quantitative Understanding
Failure in gamma-glutamyl carboxylation of clotting factors II, VII, IX and X, Under carbo leads to Hemostasis, Depletion from blood of fully functional carboxylated clotting factors Indirectly leads to Strong Strong
Hemostasis, Depletion from blood of fully functional carboxylated clotting factors leads to Under carboxylated clotting factors will not assemble on cell surfaces to form clot, Failur Directly leads to Strong Strong
Irreversible inhibition of hepatic VKOR by binding of AR at tyrosine 139, Failure to cycle leads to Failure in gamma-glutamyl carboxylation of clotting factors II, VII, IX and X, Under carbo Directly leads to Strong Strong
Under carboxylated clotting factors will not assemble on cell surfaces to form clot, Failur leads to Failure in vascular repair mechanisms, Unresolved blood loss (hemorrhage) Directly leads to Strong Strong
Failure in vascular repair mechanisms, Unresolved blood loss (hemorrhage) leads to Blood loss and development of anemia, Impaired oxygen delivery and nutrient delivery to tis Directly leads to Strong Strong
Blood loss and development of anemia, Impaired oxygen delivery and nutrient delivery to tis leads to Reduced fitness or even mortality, Acidosis, hypovolemic shock and organ dysfunction Indirectly leads to Moderate Strong
Reduced fitness or even mortality, Acidosis, hypovolemic shock and organ dysfunction leads to Impaired recruitment , Population trajectory Indirectly leads to Weak Weak

Network View

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Life Stage Applicability

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Life stage Evidence
All life stages Strong

Taxonomic Applicability

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Term Scientific Term Evidence Link
humans Homo sapiens Strong NCBI
Rodentia spp. Rodentia sp. Strong NCBI
birds Tachycineta bicolor Moderate NCBI
mammals mammals Strong NCBI

Sex Applicability

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Sex Evidence
Male
Female

Graphical Representation

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Click to download graphical representation template

Overall Assessment of the AOP

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Domain of Applicability

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Life Stage Applicability, Taxonomic Applicability, Sex Applicability
Elaborate on the domains of applicability listed in the summary section above. Specifically, provide the literature supporting, or excluding, certain domains. Female rodents are less sensitive to ARs than males Female humans are more sensitive ti ARs than males


Essentiality of the Key Events

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Weight of Evidence Summary

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Quantitative Considerations

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Considerations for Potential Applications of the AOP (optional)

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References

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