Aop:187

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This is a legacy representation of this AOP. Please see the current version here:

https://aopwiki.org/aops/187


AOP Title

Anticoagulant rodenticide inhibition of vitamin K epoxide reductase resulting coagulopathy and hemorrhage
Short name: VKOR inhibition resulting in coagulopathy

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Status

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This AOP page was last modified on 12/11/2016.

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Abstract

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Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality
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 Strong
Reduced ability to generate ATP, Uncoupling of oxidative phosphorylation
Impairment of post-translational modification (carboxylation) of osteocalcin, Anticoagulant rodenticide interferes with carboxylation of Gla proteins in bone Moderate

Key Events

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

Adverse Outcome

Adverse Outcome
Population trajectory, Impaired recruitment

Relationships Among Key Events and the Adverse Outcome

Event Description Triggers Weight of Evidence Quantitative Understanding
Depletion from blood of fully functional carboxylated clotting factors, Hemostasis Directly Leads to Failure of secondary hemostasis , Under carboxylated clotting factors will not assemble on cell surfaces to form clot Strong Strong
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 Directly Leads to Under carboxylation of clotting factors (e.g., des-gamma-carboxy prothrombin) , Failure in gamma-glutamyl carboxylation of clotting factors II, VII, IX and X Strong Strong
Under carboxylation of clotting factors (e.g., des-gamma-carboxy prothrombin) , Failure in gamma-glutamyl carboxylation of clotting factors II, VII, IX and X Indirectly Leads to Depletion from blood of fully functional carboxylated clotting factors, Hemostasis Strong Strong
Failure of secondary hemostasis , Under carboxylated clotting factors will not assemble on cell surfaces to form clot Directly Leads to Unresolved blood loss (hemorrhage), Failure in vascular repair mechanisms Strong Strong
Unresolved blood loss (hemorrhage), Failure in vascular repair mechanisms Directly Leads to Impaired oxygen delivery and nutrient delivery to tissue, impaired carbon dioxide and waste product removal, Blood loss and development of anemia Strong Strong
Acidosis, hypovolemic shock and organ dysfunction, Reduced fitness or even mortality Indirectly Leads to Population trajectory, Impaired recruitment Weak Weak
Impaired oxygen delivery and nutrient delivery to tissue, impaired carbon dioxide and waste product removal, Blood loss and development of anemia Indirectly Leads to Acidosis, hypovolemic shock and organ dysfunction, Reduced fitness or even mortality Moderate Strong

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Life Stage Applicability

Life Stage Evidence Links
all life stages Strong

Taxonomic Applicability

Name Scientific Name Evidence Links
humans Homo sapiens Strong NCBI
Rodentia spp. Rodentia sp. Strong NCBI
birds Moderate
mammals Strong

Sex Applicability

Sex Evidence Links
Male
Female

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Overall Assessment of the AOP

Domain of Applicability

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

Molecular Initiating Event Summary, Key Event Summary
Provide an overall assessment of the essentiality for the key events in the AOP. Support calls for individual key events can be included in the molecular initiating event, key event, and adverse outcome tables above.

Weight of Evidence Summary

Summary Table
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Quantitative Considerations

Summary Table
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Considerations for Potential Applications of the AOP (optional)

References