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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

Graphical Representation

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Authors

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Point of Contact

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Barnett Rattner   (email point of contact)

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 Do not cite Under Development 1.31 Included in OECD Work Plan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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diphacinone November 29, 2016 18:42
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3-[3-(4'-bromo[1,1'-biphenyl]-4-yl)-3-hydroxy-1-phenylpropyl]-4-hydroxy-2-benzopyrone November 29, 2016 18:42

Abstract

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Background (optional)

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Summary of the AOP

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Events: Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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Sequence Type Event ID Title Short name
1 MIE 1134 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
2 MIE 1138 Uncoupling of oxidative phosphorylation, Reduced ability to generate ATP Uncoupling of oxidative phosphorylation, Reduced ability to generate ATP
3 MIE 1169 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
4 KE 1122 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
5 KE 1130 Failure in vascular repair mechanisms, Unresolved blood loss (hemorrhage) Failure in vascular repair mechanisms, Unresolved blood loss (hemorrhage)
6 KE 1131 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
7 KE 1132 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
8 KE 1133 Hemostasis, Depletion from blood of fully functional carboxylated clotting factors Hemostasis, Depletion from blood of fully functional carboxylated clotting factors
9 KE 1135 Reduced fitness or even mortality, Acidosis, hypovolemic shock and organ dysfunction Reduced fitness or even mortality, Acidosis, hypovolemic shock and organ dysfunction
10 KE 1151 Osteoporosis and vascular calcification, Bone deterioration Osteoporosis and vascular calcification, Bone deterioration
11 AO 1136 Impaired recruitment , Population trajectory Impaired recruitment , Population trajectory

Relationships Between Two Key Events
(Including MIEs and AOs)

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Title Adjacency Evidence Quantitative Understanding
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 adjacent High High
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 adjacent High High
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) adjacent High High
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 adjacent High High
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 non-adjacent High High
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 non-adjacent Moderate High
Reduced fitness or even mortality, Acidosis, hypovolemic shock and organ dysfunction leads to Impaired recruitment , Population trajectory non-adjacent Low Low

Network View

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Stressors

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Life Stage Applicability

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Life stage Evidence
All life stages High

Taxonomic Applicability

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

Sex Applicability

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Sex Evidence
Male
Female

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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Evidence Assessment

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

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