Lecture 17 - Hematoxicology I Flashcards
Blood cells have high _______ and _______ capacity (? cells/sec). They are vulnerable to ________ such as antimitotic agents.
proliferative, regenerative, 1-3 million, xenobiotics
The main clinical manifestations of hematotoxicosis are?
methemoglobinemia,
hemolysis, coagulation defects, and anemia
All US states except (3?) have vipers. These viper belong to which genera?
Hawaii (HI), Maine (ME), and Arkansas (AK)
Crotalus, Sistrurus, Agkistrodon
Vipers include?
Rattle snakes, pygmy rattle snakes, Massasauga,
water moccasins, cottonmouths, copperheads
Incidence: about ____ bites occur annually in cats and dogs in the US. 90% of venomous bites occur between ____ and _____ and 99% of the bites are due to pit vipers
150K, April, October
How do you ID a pit viper?
List the toxic principles of pit vipers.
List the victim variables Affecting the Severity of Envenomation.
1) Bite victim variables that alter the severity of the envenomation include species of the victim and the body mass. A large victim provides a large volume to dilute the venom resulting in less severe envenomation. In contrast the venom is much more concentrated in tissues of a small victim resulting a more severe envenomation syndrome.
2) The location of the bite also determines the severity of the envenomation. For example, a bite to the tongue is a lot worse than a bite to the limb because the swelling that ensues can block the airway resulting in death. Additionally, post-bite behavior such as excitability causes the venom to spread faster in the body and therefore it is recommended to keep the bite victim calm.
3) Another variable is the time it takes to get medical attention. The sooner the victim is taken to a veterinary hospital for primary medical attention the greater the likelihood of a favorable outcome.
4) The type of first aid applied affects the outcome of the envenomation. As you will see shortly, most of the first aid procedures for snakebite that you have heard about are not useful at all and make the envenomation worse.
5) Lastly, the concurrent use of medications such as NSAIDs may make the victim more susceptible to clotting defects and impair the victim’s immune response.
List the snake variable Affecting the Severity of Envenomation.
1) the species. The toxicity of pit viper venoms is highest in rattle snakes followed by
water moccasins and then copperheads.
2) the size or age of the snake can alter the severity of the envenomation. You may be
surprised to hear that young snakes are more dangerous than mature snakes. This
is because young snakes usually inject all the amount of venom they have while
mature snakes regulate the amount of venom they inject depending on the
situation.
3) the motivation of the snake is one of the most important factors that determines
the severity of the envenomation. Pit vipers control the amount of venom they
inject depending on the snake’s perception of the situation. The initial defensive
strikes usually do not deliver any venom to the bite recipient and they are referred
to as dry bites. In contrast offensive bites deliver a measured amount of venom
into the victim while agonal bites deliver the entire venom load and are therefore
the most dangerous.
4) The fourth variable is the degree of regeneration of the venom since last venom
use. Generally, it takes about 21 days to replenish expended venom.
5) Lastly, snake show increased aggression and produce more venom with
environmental warming
The envenomation syndrome reflects the complexity of the venom
The victim’s response to the venom components varies with the _______ of snake, the ________ of venom injected, and the __________ of the bite recipient
It may take _______ for all venom fractions to be cleared by the body
The envenomation syndrome reflects the complexity of the venom
The victim’s response to the venom components varies with the species of snake, the volume of venom injected, and the species of the bite recipient
It may take weeks for all venom fractions to be cleared by the body
Rattlesnake envenomation typically results in one
of three presentations:
1). Tissue destruction, coagulopathy & hypotension
○ This is the classic syndrome seen with diamondback rattlesnake
2). Neurotoxicosis: seen with Mojave rattlesnake
3). Combination of classic syndrome and neurotoxicosis
What is the MOT of a snake bite from a pit viper?
The primary purpose of the venom is to
__________ prey and ________ its tissues.
Enzymatic fraction/spreading factors break-
down _________ tissue –> ______ penetration
and _______ of toxins. These enzymes include: ?
Mycotoxins destroy _______ tissue
Coagulants/anticoagulants impair ______
Cardiotoxins ________ heart function
Cardiovascular toxins induce ____ pain, tissue ______ and ________
Neurotoxins inhibit or increase release of
___________
__________ polypeptides and lipids including killing factors potentiate the venom by up to 50x
Cardiovascular toxins induce local pain, tissue necrosis and hypotension
Neurotoxins inhibit or increase release of
neurotransmitters
Nonenzymatic polypeptides and lipids including killing factors potentiate the venom by up to 50x
What are the clinical signs of a snake bite from a pit viper?
Cats are more ________ than dogs but are brought to a vet in worse state
25% of the bites are ____ = no _______, no ______ signs
Severity depends on victim and snake ______, and post-bite ________
______ wounds, ______, severe _________,
__________, ________, ________ and
_________ of the skin may be observed
_______ vascular permeability –> regional
_________, _____ or _____ mucous membranes
_________, ________ respiration, _____, _________, __________
Muscle ________, ________, enlarged and painful regional ________ ____
See below
Snake bite - pit viper
How do you dx a snake vite from a pit viper?
List the first aid measures used to treat a snake bite from a pit viper.
What first aid measures should you avoid when treating a snake bite from a pit viper?
How do you treat a snake bite from a pit viper?
Early intravenous ________ administration
Aggressive intravenous ________ fluid therapy
Monitor _________ and _________ profile
Monitor diameter of _________
_________ administration
_________ to calm the patient; however, they have no effect upon pit viper venom, and they do not prevent ______ reaction to antivenom
When antivenom is not administered, pain is controlled with IV _______. _______ is peferred. Avoid _______ because it causes histamine release
No __________ due to risk of clotting anomalies
See below
What is a leading cause of death in cats and dogs?
Anticoagulant Rodenticides
List the most common type of rodenticides.
What is the MOT of anticoagulant rodenticide toxicity?
Age: _______ and __________ animals are more sensitive to ACRs.
High fat diet: Fats are digested to _______ ________ which displace ACRs from plasma ______ thus facilitating ACR distribution and increasing toxicity.
Prolonged use of oral ________ kills intestinal microbes that synthesize Vit ___ thus increasing toxicity of ACRs.
Hepatic disease: Impaired liver function _________ the synthesis of vit K- dependent clotting factors.
1972 is a mnemonic for vit K-dependent clotting factors.
Age: Young and geriatric animals are more sensitive to ACRs.
High fat diet: Fats are digested to fatty acids which displace ACRs from plasma albumin thus facilitating ACR distribution and increasing toxicity.
Prolonged use of oral antibiotics kills intestinal microbes that synthesize Vit
K1 thus increasing toxicity of ACRs.
Hepatic disease: Impaired liver function reduces the synthesis of vit K- dependent clotting factors.
The final step in the synthesis of vit K-dependent clotting factors take place in
the ______ and involves __________ of the inactive protein.
The reaction requires vitamin ____ as a co-factor and is catalyzed by vit K-dependent ___________. In the process vit K is oxidized to an inactive form known as vit K ________ and
in order to sustain the process of activating vit K-dependent clotting factors the inactive vit K epoxide has to be _________.
This reactivation involves 2 reactions: The first reaction is catalyzed by vit K epoxide _______ while the second reaction is catalyzed by vit K _________. Together, these reactions convert the __________ vit K epoxide back to the _____, _______ form of vit K (___________) which can then engage in the activation of coagulation factors. The ACRs impair the ecycling of vit K by inhibiting vit K ________ _______. When this enzyme is inhibited, the oxidized vit K epoxide cannot be converted to the ________ functional form of vit K and as a resulted vit K-dependent clotting factors cannot be __________.
Note that the ACRs inhibit only the _________ of new clotting factors and do not affect the _________ factors already in circulation.
Therefore, the clinical signs of ACR toxicosis start when the ________ factors are depleted which takes ?
The final step in the synthesis of vit K-dependent clotting factors take place in
the liver and involves carboxylation of the inactive protein.
The reaction requires vitamin K as a co-factor and is catalyzed by vit K-dependent carboxylase. In the process vit K is oxidized to an inactive form known as vit K epoxide and
in order to sustain the process of activating vit K-dependent clotting factors the inactive vit K epoxide has to be reactivated. This reactivation involves 2 reactions. The first reaction is catalyzed by vit K epoxide reductase while the second reaction is catalyzed by vit K reductase. Together, these reactions convert the inactive vit K epoxide back to the active reduced form of vit K (hydroquinone) which can then engage in the activation of coagulation factors. The ACRs impair the recycling of vit K by inhibiting vit K epoxide reductase. When this enzyme is inhibited the oxidized vit K epoxide cannot be converted to the reduced functional form of vit K and as a resulted vit K-dependent
clotting factors cannot be activated.
Note that the ACRs inhibit only the synthesis of new clotting factors and do not affect the preformed factors already in circulation.
Therefore, the clinical signs of ACR toxicosis start when the preformed factors are depleted which takes 3-5 days
What are the clinical signs of anticoagulant rodenticide toxicity?
How do you Dx anticoagulant rodenticide toxicity?
Blood coagulation basically involves 2 separate pathways that operate ____________.
These are the intrinsic pathway which a relatively _____ process lasting __-___ minutes (in vitro) and the extrinsic pathway which is a relatively _____ process and last __-___ sec following contact between ____ and ___ tissue.
The two pathways operate ________ and eventually converge at the ________ pathway ultimately causing the soluble plasma protein, __________, to be converted into the _________ polymer which stops the bleeding.
Within each of these pathways, at least one factor depends on vitamin K for its synthesis.
In the extrinsic pathway there is factor _____, in the intrinsic pathway there is factor ___ while in the common pathway there are factors ___ and ___.
When vitamin K is __________ the coagulation cascade is interrupted, and formation of the insoluble fibrin polymer does not occur.
Blood coagulation basically involves 2 separate pathways that operate simultaneously.
These are the intrinsic pathway which a relatively slow process lasting 5-15
minutes (in vitro) and the extrinsic pathway which is a relatively rapid process
and last 10-12 sec following contact between blood and damaged tissue.
The two pathways operate independently and eventually converge at the common pathway ultimately causing the soluble plasma protein, fibrinogen, to be converted into the insoluble polymer which stops the bleeding.
Within each of these pathways, at least one factor depends on vitamin K for its synthesis.
In the extrinsic pathway there is factor VII, in the intrinsic pathway there is factor IX while in the common pathway there are factors II and X.
When vitamin K is deficient the coagulation cascade is interrupted, and formation of the insoluble fibrin polymer does not occur.
The time it takes for a specific coagulation time to be prolonged during ACR toxicosis depends on the ____-____ of the vit-dependent clotting factor(s) associated with it.
Specifically, the coagulation time associated with the coagulation factor with the _________ half-life is the first to be prolonged.
You can see here that factor VII within the extrinsic pathway has the shortest half-life of ____ hours and it is followed by factor IX of the intrinsic pathway which has a half-life of ___ hours. Then we have factor X in the common pathway with a half-life of __ hrs and
lastly factor II also in the common pathway with a half-life of ____ hours. So clearly, because factor VII has the shortest half-life the ____ which is associated with this factor would be the first to be prolonged and it is therefore the most _______ test for ACR toxicosis.
However, you do not get to see clinical signs when only _____ is prolonged because coagulation is still supported by the _______ and _______ pathways for which the clotting factors would not have been depleted at this time. The second clotting time to be prolonged is the _____ which is associated with factor ____ of the intrinsic pathway.
Lastly, the least sensitive clotting time is the _____ because it is associated with clotting factors with the ________ half-lives.
In addition, the activities of factors IX, X, and II need to be very severely depleted (to <___% of normal) for the ACT to be prolonged.
Nonetheless, when ACT is prolonged, you are dealing with a very _______ case of ACR
toxicosis because there is hardly any vit K-dependent clotting factors in circulation
The time it takes for a specific coagulation time to be prolonged during ACR toxicosis depends on the half-life of the vit-dependent clotting factor(s) associated with it.
Specifically, the coagulation time associated with the coagulation factor with the shorted half-life is the first to be prolonged.
You can see here that factor VII within the extrinsic pathway has the shortest half-life of 6 hours and it is followed by factor IX of the intrinsic pathway which has a half-life of 25 hours.
Then we have factor X in the common pathway with a half-life of 40h and
lastly factor II also in the common pathway with a half-life of 65 hours. So clearly, because factor VII has the shortest half-life the OSPT (one stage prothrombin time, aka PT prothrombin time) which is associated with this factor would be the first to be prolonged and it is therefore the most sensitive test for ACR toxicosis.
However, you do not get to see clinical signs when only OSPT is prolonged because coagulation is still supported by the intrinsic and common pathways for which the clotting factors would not have been depleted at this time.
The second clotting time to be prolonged is the APPT (activated partial thromboplastin time) which associated with factor IX of the intrinsic pathway.
Lastly, the least sensitive clotting time is the ACT (activated coagulation time) because it is associated with clotting factors with the longest half-lives.
In addition, the activities of factors IX, X, and II need to be very severely depleted (to <5% of normal) for the ACT to be prolonged.
Nonetheless, when ACT is prolonged, you are dealing with a very severe case of ACR
toxicosis because there is hardly any vit K-dependent clotting factors in circulation
How do you treat anticoagulant rodenticide toxicity?
- Blood transfusion is particularly necessary when there is severe anemia or
when bleeding is occurring in the lungs or the brain. - Vit K1 is the antidote for ACR toxicosis.
The duration of vit K1 therapy depends on the type of ACR you are dealing with. - For first gen/short acting ACR Tx for 10-14 days. For second gen/long acting ACR Tx for up to 30 days.
- Antibiotics are indicated when there is effusion into the pleural or thoracic
cavity to minimize risk of bacterial infection. - Pleural tap and thoracic tap are done to drain the effusion/fluid that has accumulated in the pleural and thoracic cavity, respectively.
What are you DDx for anticoagulant rodenticide toxicity?
What plant is pictured below?
White and yellow sweet clovers are popular as fodder crop because they have
high nutritional value (comparable to alfalfa), and they are resistant to drought.
Describe the ADME of Melilotus spp. (White & Yellow Sweet Clovers) toxicity?
What are the clinical signs of Melilotus spp. (White & Yellow Sweet Clovers) toxicity?
List the nitrate accumulating plants.
What is the MOT of Nitrate-Nitrite toxicity?
Nitrate-nitrite toxicity
In the rumen, rumen microbes reduce nitrates to ammonia which they utilize to synthesize their protein.
This reduction takes place in two reactions where nitrate is initially reduced tom nitrite which is further reduced to ammonia. The problem is that the first reaction that involves reduction of nitrate to nitrite is fast while the second reaction involving reduction of nitrite to ammonia is slow. As a result, nitrites accumulate and are then absorbed into the bloodstreams where they oxidized Fe2+ of Hb to Fe3+ to form MetHb.
Under normal physiological states, there is always some oxidation of Hb to MetHb but the enzyme methemoglobin reductase effectively reduces the metHb back to Hb.
However, when there is excessive oxidation of Hb to MetHb this enzyme (methemoglobin reductase) can no longer effectively reduce metHb to Hb to sustain sufficient delivery of oxygen to animal tissues.
