Lecture 19 - Blood Toxicants Tutorial Flashcards
- Anticoagulant rodenticides come in what formulations?
- What color are these formulations?
- Pellets, grains, powders, bait bars, liquids
- Green, red, orange, yellow, etc
Not all rodenticides are?
anticoagulants
Examples: – Bromethalin, cholecalciferol, strychnine, zinc
phosphine, others
After anticoagulant rodenticide is ingested, it is absorbed, leading to __________ of vitamin K1 epoxide reductase. This leads to the __________ of the synthesis of Vitamin K-dependent clotting factors, which leads to the depletion of existing clotting factors. The patient will typically start to bleed ___-___ days post-exposure.
After anticoagulant rodenticide is ingested, it is absorbed, leading to inhibition of vitamin K1 epoxide reductase. This leads to the inhibition of the synthesis of Vitamin K-dependent clotting factors, which leads to the depletion of existing clotting factors. The patient will typically start to bleed 3-5 days post-exposure.
- Name the enzyme that converts inactive coagulation proteins to active coagulation proteins.
- Name the enzyme that converts inactive vitamin K into active vitamin K.
- Vitamin K-dependent carboxylase
- Vitamin K epoxide reductase & Vitamin K reductase.
ACRs inhibit the enzyme ___________ ___ _______ _________ and hence impair the recycling of Vitamin K.
ACRs inhibit Vitamin K epoxide reductase and hence impair the recycling of Vitamin K.
When this enzyme is inhibited, the oxidized Vitamin K epoxide can not be converted to _________, _________ form of Vitamin K. As a result, Vitamin K dependent clotting factors can not be _________.
ACRs only inhibit the synthesis of _____ clotting factors and do not effect ______ clotting factors already in circulation. This is why you only see clinical signs 3-5 days post-ingestion, because that is when pre-formed factors are depleted.
When this enzyme is inhibited, the oxidized Vitamin K epoxide can not be converted to reduced functional form of Vitamin K. As a result, Vitamin K dep, clotting factors can not be activated.
ACRs only inhibit the synthesis of new clotting factors and do not effect preformed clotting factors already in circulation. This is why you only see clinical signs 3-5 days post-ingestion, because that is when pre-formed factors are depleted.
What are the Types of anticoagulant rodenticides?
What are the Half-lives of common anticoagulant
rodenticides
Warfarin
Diphacinone
Brodifacoum
Bromadiolone
Important: it takes ~ ____ half-lives for the toxicant to be cleared from the body – this means ____ days or _____ for ____-acting ACRs
Important: it takes ~ 5 half-lives for the toxicant to be cleared from the body – this means 30 days or more for long-acting ACRs
LD50 tells us nothing about ____________ toxic dose (MTD). NO good information about ____ and _____ exists for ACRs.
LD50 tells us nothing about minimum toxic dose (MTD). NO good information about MTD and MLD exists for ACRs
In the absence of literature on MTD and MLD, some use a value based on “_____ __ ______”
– Assumes minimum lethal dose (MLD) is ___/10 of the LD50, and minimum toxic dose is ___/10 of the MLD
* Very unscientific, often ________ assumptions
In the absence of literature on MTD and MLD, some use a value based on “Rule of Tens”
– Assumes minimum lethal dose (MLD) is 1/10 of the LD50, and minimum toxic dose is 1/10 of the MLD
* Very unscientific, often INCORRECT assumptions
- DO NOT USE THE “RULE OF TENS”
– Death often determined by where _______ occurs - Animals have died after ingesting much _____ than 1/10 of the LD50
- Not much difference between ______ and _____ for ACRs
- DO NOT USE THE “RULE OF TENS”
– Death often determined by where bleeding occurs - Animals have died after ingesting much less than 1/10
of the LD50 - Not much difference between MTD and MLD for ACRs
What are the clinical signs?
- Delayed!
– Typically start ___ to ___ days post-ingestion
* Start after depletion of _______ active factors - Signs are associated with _______
– Signs can be _____ or _______
– Bleeding can occur _________ - ______ depend on where the bleeding is
occurring
– ______ or _______
– _______ in body
- Delayed!
– Typically start 3 to 5 days post-ingestion
* Start after depletion of circulating active factors - Signs are associated with bleeding
– Signs can be subtle or blatant
– Bleeding can occur anywhere - Signs depend on where the bleeding is
occurring
– Internal or external
– Location in body
Blood coagulation involves 2 pathways:
1. Intrinsic
2. Extrinsic
Operate independently and converge at common pathway, causing soluble plasma protein, fibrinogen, to be converted into insoluble fibrin polymer which stops the bleeding.
In each pathway, at least one factor depends on Vitamin K.
Extrinsic; pathway: factor 7
Intrinsic: fator 9
Common pathway: 2, 10
When vitamin k is deficient, the coagulation cascade is interrupted and formation of insoluble fibrin polymer does not occur.
Half lives: imp in understanding which of the clotting time is first to be prolonged.
first half life that is exceeded when exposed to aCR is factor 7, so extrinsic pathway is the first to be disrupted. this manifests as prolongation of one stage prothrombin time.
if exposure to ACR continues, factor 9 –> intrinsic pathway compromised. APTT is the second clotting time to be prolonged.
ACT is the last clotting time to be prolonged b/c you need to have 95% depletion of factor 10 and 2, both of which have long half lives.
Diagnostic tests contd.
* CBC
– May see anemia
* Mild to severe; regenerative
* But: don’t always see anemia!
– May see thrombocytopenia: platelets used up
– May see neutrophilia
– May see hypoproteinemia
* Radiography: helps to locate site of internal bleeding
* Ultrasound: helps to locate site of internal bleeding
* Thoracocentesis & abdominocentesis: help to identify
type/cause of effusion
- CBC
– May see _____- Mild to severe; __________
- But: don’t always see _______!
– May see ____________: platelets used up
– May see ________
– May see ______________- ___________: helps to locate site of internal bleeding
- ___________: helps to locate site of internal bleeding
- __________ & __________: help to identify type/cause of effusion
- Coagulation panels
– In-house analysis - 3?
– Local human hospitals
- Be sure to send sample from normal dog as well
- ACT (activated clotting time) test
– Vit K-dependent coagulation factors need to
be very severely _________ to see increase
- ACT (activated clotting time) test
- CBC
– May see anemia
* Mild to severe; regenerative
* But: don’t always see anemia!
– May see thrombocytopenia: platelets used up
– May see neutrophilia
– May see hypoproteinemia - Radiography: helps to locate site of internal bleeding
- Ultrasound: helps to locate site of internal bleeding
- Thoracocentesis & abdominocentesis: help to identify
type/cause of effusion - Coagulation panels
– In-house analysis - APTT, OSPT, ACT
– Local human hospitals
* Be sure to send sample from normal dog as well - ACT (activated clotting time) test
– Vit K-dependent coagulation factors need to
be very severely depleted to see increase
The goal of Tx is to activate __________ __________
Give antidote: _____ ______ ______ ____ to _____ these factors.
The goal of Tx is to activate coagulation factors.
Give antidote: oral active Vit K1 to activate these factors.
Vitamin K1
* Also called
phytonadione
Vitamin K1 comes in what forms?
- Oral capsules/tablets: 25 mg or 50 mg (double
strength) - Injectable: 10 mg/mL solution in 30 mL and 100 mL
vials - Human products: 5 mg tablets (oral); 2 mg/mL and 10 mg/mL (injectable emulsions) in 0.5 mL amps
Vitamin K1
* Give ________ – even the injectable form
– Good ______ bioavailability
– Do NOT give ___ or ____
* Anaphylaxis (___); hematomas (___); pain (____)
– Even avoid ____ whenever possible
* Allergic reactions
– Best to give with a _____ meal - Better absorption
Vitamin K1
* Give ORALLY – even the injectable form
– Good oral bioavailability
– Do NOT give IV or IM
* Anaphylaxis (IV); hematomas (IM); pain (IM)
– Even avoid SQ whenever possible
* Allergic reactions
– Best to give with a fatty meal - Better absorption
Vitamin K1 is NOT a __________ agent
– Does NOT stop _____ bleeding right away
Vitamin K1 is NOT a clotting agent
– Does NOT stop active bleeding right away
Vitamin K1
* How long to effect?
– 6 to 12 h? 12 to 48 h?
– Assume it will take ~ 24 h for K1 to start having
its effects
* In cases seen early, you do not expect to see
bleeding for another 24-48 h, so delay in vitamin
K1 effect is not a problem
Vitamin K1
* Adverse reactions?
– Few at therapeutic doses if given orally
Vitamin K1
* Duration of treatment
– Depends on type and half-life of AC: Must
treat until the ACR has been eliminated from
the body
* 4 weeks or longer for long-acting anticoagulants
* 10 days to 2 weeks for warfarin
Vitamin K1
- Decontaminate
– Why decontaminate if antidote is available?
* Lack of owner compliance in medicating patient
Vitamin K1
What if type of ACR is unknown?
– Either assume it is long-acting, or treat for 10
days, stop for a few days and then retest clotting
times
* It is recommend to treat as if long-acting
If exposure dose is very low and decontamination
appears successful, do you need to treat with
vitamin K1?
Or should you recheck clotting profile in 48-72 h?
- Especially a dilemma with very large dogs ($$$)
- Animal size (i.e., cost of treatment) may help decide
What about using multi-vitamin
supplements?
– Concentration of K1 not high enough
to be effective
What about vitamin K3?
– Don’t use it!
– Not active, takes time to become activated
– Many adverse effects have been reported:
* Renal failure
* Heinz body anemia
* Methemoglobinemia
* Even though cheaper, lack of efficacy and
increased risks far outweigh any cost benefit
What is immediately necessary with lung bleeds?
With lung bleeds, immediate transfusion
is absolutely necessary
– Need coagulation factors immediately
* Fresh frozen plasma, frozen plasma or fresh
whole blood
– Patient can die very quickly with lung bleeds
- Vitamin K1
– Dose and duration? - 1 month or more, high end of dose
- Supportive care
– O2, cage rest, monitor lungs & breathing
carefully
– If bleeding within chest cavity, may need to tap
What is the treatment plan for the scenario 3 patient?
What are the at home care instructions?
- IMPORTANT!
– Although “antidote” is vitamin K1, the most
important treatment in cases with ACTIVE
BLEEDING is BLOOD TRANSFUSION
– Provides active clotting factors IMMEDIATELY - Vitamin K1 does NOT provide immediate
active clotting factors
– Enables body to produce active clotting factors
– Takes ~24 h before new clotting factors ready - If NO active bleeding is occurring (e.g.,
early cases) treat with vitamin K1
– Perform decontamination if indicated
– Need to treat with vitamin K1 until the ACR is
eliminated completely
* It takes ~5 half-lives for complete elimination
- If ACTIVE bleeding is occurring, treat with
vitamin K1 AND a transfusion
– Transfusion is needed to stop active bleeding
* Clotting factors +/- RBCs
* Esp. with lung or CNS bleeds or severe anemia - Vitamin K1 allows production of new clotting
factors
– Remember, it takes ~24 h to start having effect.
– Treat until ACR is completely eliminated from
body - It is too late to decontaminate if clinical signs
are present
- Horses
– Most common cause of anticoagulant poisoning
is therapeutic warfarin
– Also can eat rat poisons placed in barn
– Note: factor 9 may be depleted before factor 7
in horses, so APTT may increase first
- Cattle
– Most common cause is moldy sweet clover
(dicoumarol)
