Haematology, Coagulation, Hemolymphatics Flashcards
1
Q
What is the mechanism of action for n-acetylcysteine in methemoglobinemia?
A
reduces NAPQ1 which means Fe2+ wont oxidase into Fe3+
2
Q
what is the mechanism of action for methylene blue in methemoglobinemia?
A
Increased reduction of MetHb by NADPH dehydrogenas. works as an electron shuttle (NADPH becomes NADP, methylene blue becomes leukomethylene blue and HbFe3+ becomes HbFe2+)
3
Q
Why is methylene blue as methaemoglobin treatment a higher risk in cats than dogs?
A
Cats have higher number of sulfate groups and less effective splenic mononuclear system. risks are heinz body anemia and the reconversion of Hb to MHb
(NAPQ1 oxidases haemoglobin (Fe2+ -> Fe3+) (Fe and sulfhydryl) forming methaemoglobin ie more sulfhydryl to form methemoglobin)
4
Q
Name 4 antioxidants
A
Superoxide dismutase, catalase, glutathione peroxidase, glutathione, CYB5R
5
Q
How is hemoglobin broken down?
A
- Degraded by macrophages into globin (protein part) and heme
- Globin degraded into amino acids and re-used in bone marrow
- Heme degraded into porphyrine and then Fe, biliverdin and CO (carbon monoxide)
- Fe transported into bone marrow by transferrin and re-used or to transported to liver for storage as ferritin
- Biliverdin -> bilirubin
- CO -> carboxyhaemoglobin and exhaled
6
Q
Name three ways CO2 is transported in the blood
A
- Dissolved in solution
- Buffered with water as carbonic acid (70% of CO2 formed in tissue is transported this way)
- Bound to protein, particularly haemoglobin (carbamin hemoglobin)
7
Q
How does tPA viscoelastic monitoring improve the diagnosis of fibrinolysis?
A
tPA should cause fibrinolysis. If doesn’t respond to tPA its because there are increased levels of PAI. Increased levels of PAI could indicate prone to thrombosis/hypofibrinolysis
8
Q
What laboratory test is gold standard for Glanzmann thrombasthenia and anti-thrombocyte therapy?
A
Light transmission aggregometry
9
Q
Give two examples of a LMWH
A
Daltaparin, enoxaparin
10
Q
Name 2 direct thrombin inhibitors (DIT) and what could be a reason they could possible work better than heparin and antithrombin
A
Desirudin, lepirudin, dapigatran
heparin and AT have trouble binding to heparin site on thrombin when thrombin is fibrin bound. Doesn’t require AT as cofacotor
11
Q
Name a vitamin K epoxide reductase inhibitor
A
warfarin
12
Q
Name 2 anti Xa activity drugs
A
Rivaroxan, apixaban, edoxaban, fondparinux
13
Q
What is the most common factor deficiency in cats and what are the clinical signs?
A
XII, no clinical signs but prolonged APTT
14
Q
What laboratory test can be used to test for fibrinogen concentration?
A
Clauss test
15
Q
What is the pathogenesis of acute traumatic coagulopathy?
A
Endogenous coagulopathy immediate (minutes) after trauma. Severe tissue injury , shock induced hypoperfusion, systemic inflammation and endothelial damage, catecholamine release-> hypocoagulability and hyperfibrinolysis. - Caused by endothelial cell activation, glycocalyx dysfunction, PLT dysfunction, increased tPA, activation protein C. lead eventually to fibrinolysis shutdown
16
Q
In Goggs et al 2018, 3 or more abnormal laboratory values where predictive of non-survival to hospital discharge for dogs with DIC. Name 2 laboratory values that were increased and 2 that were decreased
A
- Increased PT, APTT, d-dimer
- Decreased Antithrombin, fibrinogen, PLT
17
Q
Name 4 conditions that are at high risk of causing DIC
A
- Prolonged hypotension
- SIRS
- Disturbed blood flow to major organ
- Major tissue trauma
18
Q
Define DIC according to ISTH
A
ISTH definition: DIC is an acquired syndrome characterized by the intravascular activation of coagulation with loss of localization arising from different causes. It can originate from and cause damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction.
19
Q
Incidence of ATE in HCM cats?
A
35%
20
Q
What type of thrombus is most common in IMHA
A
PTE (venous)
21
Q
What is Virchows triad
A
- Endothelial dysfunction
- Altered blood flow, blood stasis
- Hypercoagulability
22
Q
What is another name for factor XII deficiency (inherited disorder)
A
Hageman deficiency
23
Q
What is hypoproconvertinemia?
A
Inherited factor VII deficiency
24
Q
Name 4 reasons for acquired intrinsic platelet dysfunction
A
- PLT inhibitors
- Uraemia
- Synthetic colloids
- Myeloproliferative disease
- Pit viper envenomation
- DIC
- Trauma-induced coagulopathy
25
Name 4 inherited intrinsic platelet dysfunctions
- Glanzmann thrombasthenia
- Chediak-higashi syndrome
- Selective ADP deficiency
- Cyclic haematopoiesis
- Procoagulant expression disorders (Scott syndrome)
26
Give 3 examples of topical hemostatic products and 1 hemostatic dressing.
- Gelatin foams
- Oxidized cellulose
- Collagen-based matrices
- Topical thrombin
Dressings
- Kaolin-impregnated gauze
- Chitin or chitosan
27
How does recombinant factor VII work? In what conditions can it be considered?
Initiates coagulation by increasing interaction between VII and TF. Also has bypass effect where it binds directly to phospholipid membrane of activated PLT. Haemophilia A in dogs
28
What receptor does desmopressin act on and what does in do in coagulation?
V2 receptor. Endothelial release of VIII and vWf
29
List 3 thrombolytics
- Streptokinase
- Urokinase
- tPA (tissue plasmingen activator)
- aplteplase
- reteplase
30
List 3 ways alpha 2-antiplasmin inhibits fibrinolysis?
- Occupy lysin bindings site so free plasmin cant bind
- Form complexes with active plasmin and neutralises its action
- Prevents absorption of plasminogen onto fibrin clot
- Cross links fibrin and enhances its resistance to plasmin
31
What are the 3 main inhibitors of fibrinolysis and which is most relevant?
- PAI (plasminogen activator inhibitor). Most relevant. Stops tPA
- alpha2 antiplasmin (a2ap)
- TAFI (thrombin activatable fibrin inhibitor). Bind lysin
32
List 6 activities of thrombin (factor II) and if they are anti- or procoagulant
Procoagulant
- Removes peptide from fibrinogen forming fibrin monomer
- Activated XIII (fibrin crosslinking)
- Accelerates actions of VIII, IX, X, XI, XII?
- Activates TAFI (thrombin activatable fibrinolysis inhibitor)
- Binds to PAR receptor on PLT and cause PLT aggregation (granula release, integrin activation etc)
- Positive feedback on prothrombin
- Stimulates microparticles
- Vasoconstrictor
anticoagulant
- Activates tissue plasminogen activator (tPA)
- Binds to thrombomodulin and activated protein C
- Activated prostacyclin
- Releases histamine (vasodilator)
33
How does protein C inhibit coagulation?
Thrombin binds to thrombomodulin -> activates protein C -> activate protein S -> binds factor V and VIII
34
Which two factors does antithrombin mostly inhibit?
Factor II (thrombin) and X. lesser extent IX, VII-TF complex
35
What are the 3 most important anticoagulation proteins?
- Antithrombin
- Protein C
- Tissue factor pathway inhibitor (TFPI)
- (less important heparan, thrombomodulin, alpha 1 protease inhibitor, alpha 2 macroglobulin)
36
How does microparticles contribute to coagulation?
Contains cell surface proteins that contribute to coagulation. Which protein will depend on what cell the membrane surrounding vesicles comes from. Ex p selectin from PLT, TF from monocytes. Stimulated by cytokines, thrombin, shear stress, hypoxia.
37
What drug inhibit the aIIbB3 receptor?
abcixmab
38
What are alternative names for factor I, II, III and factor IV in the coagulation cascade?
I fibrinogen (Ia fibrin)
II prothrombin (IIa thrombin)
III tissue factor, tissue thromboplastin
IV calcium ion
39
Is aspirin or clopidogrel superior in preventing reoccurrence of ATE in cats?
Aspirin 49%, clopidogrel 75% + > x 2 median time until recurrence
40
What receptor does clopidogrel bind to? give two examples of how plt aggregation is affected by clopidogrel
Irreversible binding to P2Y12 receptor, blocking ADP
- Decreased release of granula -> decreased activation fibrinogen receptors (a2bB3)
- Reduced release of serotonin
- Thromboxane A2 production possible affected by clopidogrel
41
What receptor does thrombin bind to on the PLT?
PAR
42
What happens in canine-scott disease and what breed is affected?
PS (phospatidyleserine) doesn’t get flipped out and impairment to produce microvesicles
German shepherd, eskimo spitz, basset
43
Describe the 3 different types of vWf disease and give an example of a breed affected for each type
1 quantitative – all multimers present but at low conc. Dobermann. Airdale terrier
2 qualitative – lacking large mutlimers and low conc. German short hair pointer
3 absolute lack. Dutch kookier, Scottish terrier, Shetland sheepdog
44
Give 4 functions of thromboxane
- Granule release
- Conformation shape change
- PS exposure (phospatidylserine)
- Increased a2bB3
- Increased TXa production
45
With receptor is absent in Glanzmann thrombasthenia ? And what does in normally bind? What breed?
- a2bB3 (in high shear stress, also binds vWf)
- fibrinogen
- otterhounds, great pyrenes, DSH
46
Which receptor is absent in Bernard Soulier disease? And what does in normally bind? What breeds?
- GP 1b-IX-V
- vWf (also binds thrombin, thrombospodin, P selectin)
- cocker spaniel
47
Name 4 different PLT receptor families and give one example of a receptor in each family.
- Leucine rich receptors
o GP 1b IX V
- Immunoglobulin superfamily receptors
o GP VI
- G protein linked receptors
o P2Y receptor
o PAR receptors
- Intergrin receptor
o a2bB3
- prostaglandin family receptors
o thromboxane
o prostacyclin
o serotonin
o epinephrine
48
What is inside-out signalling in PLT activation?
- The process of activation of integrin receptors αIIbβ3 by upstream signal, induced by agonist stimulation of other cell surface receptors
(Induces conformational changes on the extracellular domains of the receptors that enhance the affinity for ligands)
- Can be initiated by GPVI and GP-Ib-IX-V
(Increase phospholipase C -> IP3 and DAG -> increase in intracellular Ca)
49
What is outside-in signaling in PLT aggregation?
- Conformational change in the extracellular domains of αIIbβ3 following activation -> interaction with fibrinogen and vWF
- Ligand binding by αIIbβ3 mediates platelet aggregation and triggers functional events through “outside-in” signals
o Cytoskeletal rearrangement
o Granule secretion
o Procoagulant surface expression
o Clot retraction
50
During activation phase of the primary hemostasis, name 3 events?
- Fibrinogen receptor activation
- Membrane flipping
- Shape change
- Granule release (secretion)
51
Name 2 PLT dense granula and 2 PLT alpha granula content
Dense: ADP, ATP, 5-HT, histamine, Ca, Mg, P
Alpha: P selectin, fibrinogen, fibronectin, thrombospodin, PAI, vWf
52
During adhesion phase of primary haemostasis, name 1 receptors used in direct and
1 in indirect adhesion. Why do we call it indirect?
Direct: GP VI
Indirect: GPib IX V. via vWf
53
What is the name of the integrin fibrinogen receptor?
αIIbβ3
54
Name 3 inhibitory mechanism for initiation of primary haemostasis
- Endothelial release of prostacyclin
- Endothelial release of ADPase
- NO release by glycocalyx at sites of high velocity
- Negatively charged endothelial cell surface (glycosaminoglycans, proteoglycans via anchoring of heparan sulphate)
- Physical barrier of endothelial call
- Tissue factor pathway inhibitor (TFPI) on cell surface – decreased interaction of TF and VII
- Thrombomodulin binds thrombin and protein C inactivated Va, VIIIa
- tPA
55
Name 5 adverse reactions to HIIVIG?
- Acute hypersensitivity
o Fever, dyspnoea, urticaria, convulsions, diarrhea, vomiting, tachycardia, hypotension, facial swelling
- Thromboembolism
- Kidney failure
- Hypotension
- pseudohypoNa
- aseptic meningits
- fluid overload
- type III hypersensitivity reaction
56
How does HIVIG change prognosis in ITP?
Shorten time to recovery, shorten complete resolution time, shorten hospitalization time.
NO difference in mortality, cost or pRBC transfusions
57
Give 4 functions (mechanism of action) of HIVIG
- Blockage Fc receptors by Ig G (inhibits phagocytosis, prevent immune complex interaction, arrest antibody dependant cellular toxicity)
- Elimination pathogenic autoantibodies (donor antibodies bind to abnormal host antibodies and stimulate removal
- Modulation cytokine synthesis (fewer IL2, IFNy, TNFa)
- Inhibition of complement (blocks C3 and C4 Iin classical pathway)
- mediation Fas-Fas ligand
58
What is glucorticoid potency and mineralcorticoid effect of:
cortisol
hydrocortisone
prednisone
dexamethasone
fludrocortisone
deoxycorticosterone
aldosterone
gc p. mceffect
cortisol 1 1
hydrocortisone 1 0.8
prednisone 3.5-4 0.8
dexamethasone 30 0
fludrocortisone 10 125-200
deoxycorticosterone 0 20
aldosterone 0 200-100
59
Give 8 examples of anti-inflammatory glucocorticoid effects
- Anti-inflammatory effects
o Suppression of proinflammatory cytokines and chemokines
o Decreased expression of endothelial cellular adhesion molecules
o Diminished inflammatory enzyme activity (COX)
o Suppression of T cell proliferation
o Inhibition of mononuclear phagocytosis and chemotaxis
o Apoptosis of activated lymphocytes
o Induction of anti-inflammatory cytokines (IL10)
o Stabilization lysosomal membranes
- Hematopoietic effects
- Metabolic effects
- Endocrine effects
- Neurological and muscular effects
- Renal effects
- Misc effects
Summary: synthesis of hormone and cytokine receptors, and other proteins involved in gluconeogenesis, protein catabolism, lipolysis, immune response, h2o balance
60
Describe the arachidonic acid cascade
Cell membrane phospholipids – arachidonic acid – COX (cyclooxygenase) OR LOX (lipoxygenase)
COX go onto prostaglandin. Prostaglandin go onto prostacyclin, thromboxane and other prostaglandin
LOX go onto leukotrienes
61
How much of cortisol is protein bound?
90-95% (40% to transcortin, 50% to albumin, 5-10% is free)
62
What is the half life of cortisol and how is it metabolised?
Half life 1.5 h. metabolised in liver to glucuronic acid and sulphated. Excreted in bile and also urine
63
What is the rate limiting step in steroid production in the adrenal?
Pregnenolone
(ACTH -> adenyl cyclase -> cAMP -> intracellular enzyme incl protein kinase A -> converts cholesterol to pregnenolone (rate limiting step)
64
Which antithrombotic does IMHA consensus from ACVIM and Curative guidelines say to use as first choice in IMHA?
Unfractioned heparin (+/- antiplatelet clopidogrel)
65
What infection has intermediate to high evidence to cause IMHA in dog and is immunosuppressant needed?
Piroplasms (Babesia Gibsoni). No, just treat infection
66
What drugs can maybe cause IMHA in dogs? which drug in cats?
Dogs cefazedone, cefalosporin
Cats propylthiouracil (antithyroid)
67
Why can there be hypertension and vasoconstriction in IMHA?
Haemoglobin (especially free) scavenge nitic oxide NO.
68
For definite diagnosis of IMHA, what Is needed?
anemia
2 or more signs of immunmediated destruction
- Spherocytes (dogs only)
- Positive agglutination test without washing
- Positive direct coombs test OR flow cytometry OR Agglutination persisting with washing
AND 1 or more signs of haemolysis
- hyperbilirubinemia, significant bilirubinuria, or icterus without functional hepatic disease, posthepatic cholestasis or sepsis
- hemoglobinemia
- Hemoglobinuria
- Erythrocyte ghost
69
How does IMHA cause haemolysis via the immune system, give 3 ways
- Complement system
o Via C3b opsonization and phagocytosis by neutrophils and macrophages
o Membrane attack complex via C5b6789 (created pores in RBC membrane that are permeable to ions causing osmotic rupture and lysis)
- Antibody dependant cell-mediated cytotoxicity (ADCC)
o NK cell activated via Fc receptor
70
% IMHA that are classified as idiopathic? What is the mortality for IMHA?
60-75% idiopathic. 50% mortality
71
Name 3 breeds that get pyruvate kinase deficiency
Basenji, Beagle, Poodle, Toy eskimo, daschund, chihuahua, pug etc
72
What is a howell-jolly body?
fragment of nucleus which has not extruded during normal RBC maturation. Stains purple as contains DNA. If very frequent might indicate dyserythropoeisis
73
What is poikilocytosis?
Altered cell shape
74
Does spherocytes have a higher specificity or sensitivity for IMHA?
Sensitivity 63%, specificity 95% ie if you have them, you have IMHA, if you don’t have them, you could still have IMHA
75
How do you calculate the oxygen extraction rate and what is it normally?
VO2/DO2
25%
76
How do you calculate haematocrit?
RBC x MCV/10
77
Give 5 reasons for erythrocytosis
- Dehydration - relative form
- Splenic contraction – relative form
- Hypoxemia, Cardiovascular disease, Pulmonary disease
- Renal disease
- Extramedullary neoplasia (polycythaemia vera)
78
Describe the structure of haemoglobin (include chains, haem moiety, and Fe state)
4 hemegroups and 4 polypeptide chains (globins: alpha 1, alpha 2, beta 1, beta 2).
Each hemegroup composed of a porphyrin ring attached to an iron atom Fe2+ (ferrous state)
Each iron atom can bind to one O2
79
How does feline haemoglobin differ from canine haemoglobin? What does this make it susceptible to, and what is the clinical significance of this?
Dogs have 2-4 sulfhydryl groups, cats have 8. This affects the cooperative property. Also makes cats more prone to oxidative damage (and has more Heinz bodies naturally) but also means tolerate anaemia better.
NAPQ1 oxidases haemoglobin (Fe2+ -> Fe3+) (Fe and sulfhydryl) forming methaemoglobin ie more sulfhydryl to form methemoglobin
80
What is Hufner’s constant?
1.34
1,34=oxygen binding capacity of haemoglobin: 1,34 ml per gram hemoglobin
CaO2 = blood O2 content, carriage of O2 in the blood = (1.34 x Hb x SaO2) + (0.003 x PaO2)
81
What is meant by cooperativity? (in hemoglobin)
When not bonded deoxyhaemoglobin stays in tense state. When the first O2 molecule binds the oxyhaemoglobin shifts to a relaxed state (conformation change of the monomer). This state makes it easier for additional O2 molecules to bind to the other heme groups (cooperative property).
As a molecule of oxygen binds to haem, it pulls the Fe2+ ion closer towards the plane of the protoporphyrin ring, slightly flattening the ring and so changing its shape. This small movement within the centre of the globin chain is transmitted to the surface of the molecule. Ionic interactions holding the four globin chains together are distracted and, as they re-form in a different position, the quaternary structure is altered, which increases the oxygen binding affinity of the other globin chains.
82
Explain the R and T states of haemoglobin
The T-state is the deoxy form of hemoglobin (meaning that it lacks an oxygen species) and is also known as "deoxyhemoglobin”. In the T state the crevice where the heme molecule is located is small, making it more difficult for the oxygen to get access.
The R-state is the fully oxygenated form: "oxyhemoglobin." Due to confirmation change (cooperative change) the crevice is enlarged and oxygen can get easier access.
83
Draw and label the oxyhaemoglobin dissociation curve
Spo2 on y axel. Po2 on x axel. S shaped (from 90/60 a more step drop)
84
List 4 factors that decrease the oxygen affinity of haemoglobin. What effect will these factors have on the P50, and on the shift of the oxyhaemoglobin dissociation curve?
Decreased affinity = more offloading, shift curve to the right, increased p50
Increased affinity= less offloading, shift curve to the left, decreased p50
Decreased affinity: Low O2, high pCO2, increased H conc (acidosis), increased temp, increased 2,3 diphosphateglycerate conc (2,3 DPG)
Increased affinity: (Shifting O2 curve to the left, Increased affinity / less offloading:
- Methemoglobinemia, carboxyhaemoglobin, metabolic alkalosis (bicarbonate administration), (some haemoglobin substitutes like oxyglobin))
85
What is 2-3 DPG? What physiological/pathophysiological conditions increase its production? What happens to 2-3 DPG during storage of packed red blood cells, and what effect does this have on oxygen carriage in the recipient?
2,3 diphosphate glycerate (2,3 DPG), anionic organic phosphate. Produced in glycolysis: binds to hemoglobin and decreases affinity for oxygen, increased offloading
chronic anaemia or hypoxia: increased 2,3-diphosphoglycerate (2,3-DPG). This increases oxygen dissociation (more offloading, right shift) and thereby increases DO2. In cats chloride is major effector molecule. Cats have different haemoglobin structure, more sulfhydryl groups and tolerate chronic anaemia better.
Acidosis: reduced 2,3-DPG.
Stored blood: reduced 2,3-DPG
2,3-diphosphoglycerate is made in the RBC and haemoglobin uses it to control oxygen transfer from the red blood cells to the tissue, ie the reduced levels cause a left shift of the oxyhaemoglobin dissociation curve and there is less oxygen offloading to the tissue
86
What is the Haldane effect?
Haldane and Bohr effects – used to describe changes in the affinity of oxygen for hemoglobin
- Both Haldane and Bohr effects are the same features of the same phenomenon
- Haldane effect is what happens to pH and CO2 binding because of oxygen
- Bohr effect is what happens to oxygen binding because of CO2 and lower pH.
Haldane effect
The Haldane effect is a physicochemical phenomenon which describes the increased capacity of blood to carry CO2 under conditions of decreased haemoglobin oxygen saturation -> The less O2 saturation (deoxygenation of blood), the more Co2 can be taken up by haemoglobin,
Enhanced affinity for deoxyhaemoglobin for protons enhances synthesis of HCO3 and subsequently increases the capacity of deoxygenated blood for CO2
Oxygen toxicity: O2 therapy increases oxygenated Hb and reduced the capacity to bind CO2
87
What is the Bohr effect?
The Bohr effect describes how carbon dioxide and H+ affect the affinity of hemoglobin for oxygen.
(The Haldane effect describes how oxygen concentrations determine the affinity of hemoglobin's for carbon dioxide).
Oxygen (O2) competitively and reversibly binds to hemoglobin, with certain changes within the environment altering the affinity in which this relationship occurs.
Oxygen affinity for hemoglobin decreases in the presence of CO2 -> increase in pH lead to less oxygen affinity and facilitated release of O2 into tissue (right shift of dissociation curve)
88
How does fetal haemoglobin differ structurally from adult haemoglobin, and what effect does this have on the oxyhaemoglobin dissociation curve?
2 alpha and 2 gamma subunits (adults have 2 alpha and 2 beta subunits). Binds oxygen more strongly than adult, enables transfer of oxygen from mum (in placenta when offloading occurs in mum). Reduces offloading in the tissue (left shift of dissociations curve)
89
How does anaemia affect the oxyhaemoglobin dissociation curve?
chronic anaemia: due to increased 2,3-diphosphoglycerate (2,3-DPG) there is increased oxygen dissociation (more offloading, right shift) and thereby increases DO2.
In cats chloride is major effector molecule. Cats have different haemoglobin structure, more sulfhydryl groups and tolerate chronic anaemia better.
90
Anaemic patients with severe hypoxaemia may not show clinical evidence of cyanosis. Why?
Cyanosis=Presence of deoxygenated haemoglobin in the observed tissue
5 g/dl (PCV 15%) of deoxygenated haemoglobin need to be present before cyanosis is seen.
g/dl x 3 = PCV.
91
How does carboxyhaemoglobinaemia affect the oxyhaemoglobin dissociation curve?
Increased affinity, less offloading, shifts it to the left.
Has 240 times the affinity to hemoglobin that of 02.
92
What is methaemoglobin?
Formed by reversible oxidation of heme iron to the ferric state (Fe3+)- cannot carry O2 as Fe3+ cannot bind it.
(NAPQ1 oxidases haemoglobin (Fe2+ -> Fe3+) (Fe and sulfhydryl) forming methaemoglobin ie more sulfhydryl to form methemoglobin)
93
List some common toxins that cause methaemoglobinaemia
acetaminophen toxicity
nitroglycerin, nitroprusside
topical benzocaine formulations (local anaesthetic)
phenazopyridine (urinary tract analgesic)
nitrites
nitrates
hydroxycarbamide
skunk musk
daspone,
Metoclopramide
sulfonamider
94
How does methaemoglobin contribute to the formation of Heinz bodies?
Oxidative damage sulfhydryl groups cause conformational change in globin chains that results in precipitation of denatured globin. The globin and metabolised metHb clumb into Heinz bodies.
Methemoglobin a step in the destruction of the hemoglobin, Heinz bodies are inclusions in the red blood cells composed of denaturated hemoglobin (globin chains)
95
Describe the effect on pulse oximeter readings of 1) carboxyhaemoglobin and 2) methaemoglobin.
Pulse oximeter: uses photoplethysmography: calculates O2 saturation based on different light absorption spectra for oxygenated (940 nm) and deoxygenated haemoglobin (660 nm)
Carboxyhemoglobin: absorbs infrared light similarly to oxygenated haemoglobin and produces falsely high SpO2 readings.
Methemoglobin: absorbs both wavelengths (660 and 940 nm) of light equally well. In the presence of metHb (if more than 30%) the pulse oximeter defaults to a value of 85%, reading high or low depending on the patient's actual saturation level.
96
What is cooximetry?
co-oximetry: measures oxyHb, deoxyHb, COHb, MetHb. Uses several wavelengths, doesn’t required pulsative flow, some blood gas machines
97
How does haemoglobin contribute to carbon dioxide carriage in the blood?
Carbon dioxide is transported in the blood in three ways: (i) dissolved in solution; (ii) buffered with water as carbonic acid; (iii) bound to proteins, particularly haemoglobin.
Carbon dioxide combines rapidly to the terminal uncharged amino groups (R-NH2) to form carbamino compounds: R-NH2 + CO2 -> RNH - CO2 + Hþ
The amount of carbon dioxide held in blood in the carbamino form is small but it accounts a third of the difference between venous and arterial carbon dioxide content.
Reduced (deoxyhemoglobin) haemoglobin is 3.5 times more effective in combining with carbon dioxide than oxyhaemoglobin. Carbon dioxide combines readily with haemoglobin to form a carbamino bond at a lower partial pressure than oxygen, but haemoglobin carries less than a quarter of the amount of carbon dioxide compared with oxygen. By contrast, foetal haemoglobin, owing to the replacement of the b-chain with g-chains, combines with oxygen at a lower partial pressure. Carbon monoxide has a greater affinity for haemoglobin and so displaces oxygen
Hemoglobin can carry 4 carbon dioxide molecules
When carbon dioxide binds to hemoglobin, a molecule called carbaminohemoglobin is formed. Binding of carbon dioxide to hemoglobin is reversible. Therefore, when it reaches the lungs, the carbon dioxide can freely dissociate from the hemoglobin and be expelled from the body
In pulmonary capillary blood, the red blood cell releases carbon dioxide and the haemoglobin affinity for oxygen is increased. The oxygenated haemoglobin binds fewer hydrogen ions making it more acidic but the fall in PCO2, and the shift in chloride and bicarbonate ions, makes the red blood cell less acidic.
Haemoglobin forms carbamino compounds with carbon dioxide and buffers hydrogen ions within the erythrocyte, so facilitating the carriage of carbon dioxide in blood
98
How does lead affect hemoglobin?
Lead inhibits enzymes in the hemoglobin synthesis -> higher concentration of heme precursors. Can cause photosensitivity
99
What is the mechanism for anaemia in inflammatory disease?
inflammatory cytokines supress erythropoiesis, epo release, and response to epo, and upregulate hepcidin
100
What is hepcidin?
Enzyme that inhibit iron absorption from intestines and iron release from macrophages via binding to ferroportin
101
What breeds are associated with macrocytic normochromic anemia
Miniature and toy puddles
102
What breeds are associated with microcytic hypochromic/normochromic?
Shar-pei, Siberian husky
103
What are non breed related causes of microcytic hypo/normochromic?
o Iron deficiency, PSS
Why in iron deficiency?
Less iron (protoporphyrin IX + iron form heme) means less haemoglobin. Less haemoglobin means less inhibition of mitosis. More mitosis means smaller RBC
104
What is the definition of a Non-immunologic transfusion reaction according to TRACS?
An adverse reaction to transfusion of blood or blood component caused by physical or chemical changes to the blood cells or product, contamination, or secondary to the volume infused
105
At what PCV is anemia likely to cause a murmur?
murmur due to anaemia PCV 18-20%. often left sided, soft or musical tone
106
At what serum bilirubin is icterus visible?
icterus if serum bilirubin is > 2 mg/dl. Pigmenturia shows earlier.
107
What is the most common feature of toxicity in neutrophils?
Foamy basophilia of the cytoplasm. Döhle bodies (intracytoplasmic basophilia precipitated of RNA), giant neutrophils, abbernat nuclear changes such as ring forms also represent toxic change
108
Are döhle bodies always significant for toxicity?
Yes in dogs, no in cats. In cats can be seen in healthy animals
109
How does a reactive lymphocyte look?
Larger than normal, with increased amounts of basophilic cytoplasm and large nuclei containing fine granular chromatin
110
What diseases/pathology does anemia, with high nucleated red cells without polychromasia?
Possible lead toxicity in dogs. FeLV infection in cats
111
What organ disease is acantocytes linked to?
Liver disease
112
What characterized iron deficiency on a blood smear?
small red blod cells with increased areas of central pallor, more fragile so more schizocytes.
113
What organs can be affected when you see dacocyts on a blood smear and the px has non reg anemia?
Myelofibrosis or renal disease (glomerulonephritis)
114
Diseases of what organ may predispose animals to aluminum toxicosis?
Kidney disease
115
What is the ideal chelator for cooper toxicosis?
C-penicillamine. Will increase intestinal elimination of cooper
116
Which erythrocyte change has been well-described in occurring with lead toxicity?
Rubricytosis with basophilic stipling
117
Which organ is primarily affected in dogs with manganese toxicosis?
Liver
118
When is therapeutic drug monitoring recommend in IMHA (ACVIM consensus)?
- poor response to tx
- possible interaction between drugs
- emerging secondary infection
119
PLT activation can sometimes be seen in IMHA, what is the mechanism behind?
Secondary to pathological tissue factor-mediated thrombin generation, rather than a primary event
120
What are lymphoblasts?
Larger lymphocytes with proportionally more cytoplasm and organelles than small lymphocytes. They are active cells that have been recently stimulated by antigen and are participating in ta current immune response. Ex cells within lymphoid follicular germinal centres.
121
What are plasma cells?
Late stage of development of B lymphocytes. Can secrete immunoglobulins in high concentration. Have a distinct nucleus with condensation of chromatin referred to as clock face or bicycle wheel. The round nucleus is located to one side of the cell
122
What are HES (high endothelial venules)?
Modified cuboidal endothelial cells that protrude into the vessel (HES). These cells contain vascular addressins for lymphocyte homing receptors to attach to, so the lymphocytes can enter vessel via diapedesis.
123
What are the two primary factors that determine lymph flow?
- Interstital pressure
- Lymphatic pump
124
Clopidogrel works on which PLT receptor?
ADP, adenosine diphosphate receptor (antagonist).
125
What are Weibel-palade bodies?
Weibel-Palade bodies are small storage granules located in endothelial cells comprising the intima of the heart and blood vessels. They are found in arteries, capillaries, veins, and the endocardium, but notably not in the lymphatic vessels. These bodies function to store two principal molecules, P-selectin and Von Willebrand factor. vWf released after endothelial injury has resulted in the exposure of subendothelial collagen
126
What is the lifespan of a thrombocyte in dogs and in cats?
6 days -/+ 1 day. Same for both
127
Unfractionated heparin and low molecular weight heparin primarily act on which factors?
Unfractioned heparin acts with antithrombin on factors IIa and Xa. LMWH acts on Xa
128
Which factors are in the prothrombinase complex?
Va and Xa
129
Which factors are in the tenase complex?
IXa, VIIIa, Ca
130
What are white and red clots?
Arterial: high shear, PLTs held together by fibrin strands. White clots
Venous: low shear, fibrin and red blood cells. Red clots
131
How long is the half life of coagulation factor VII?
6.2 h
132
Why does warfarin have both a pro and anti-coagulation effect?
Warfarin inhibits the activity of vitamin K epoxide reductase. Vit K epoxide reductase is required to reduce vitamin K epoxide back to active form (hydroquinone active reduced vitamin k) necessary for coagulation formation. Vit K is also required to produce protein C and S. factors II, VII, IX, X are procoag but protein C and S are anticoag.
133
What % of dogs with hemangiosarcoma also has right atrium hemangiosarcoma?
25% in one study, 9% in other
134
How much of the blood volume can be pooled in the spleen?
30%
135
What it the most common agent in bacterial joint arthritis?
Gram positive aerobs (I think this is non-surgical joint infections)
136
What is an L-form bacteria?
Mutant bacterium that has lost its cell wall. Can be seen in joint infections (subcutaneous abscesses with associated polyarthritis)
137
Traumatic hemoperitoneum has been reported to occur in what % of dogs suffering blunt trauma?
23%
138
What are the three most common reasons for pulmonary hypertension in the dog?
Left sided CHF, heartworm/parasites, chronic lower airway disease
Not common: idiopathic, TPE, shunts
139
Which of the following pulmonary lobar arteries are most likely to be enlarged in dogs with pulmonary hypertension?
A. Right pulmonary lobar arteries
B. Left pulmonary lobar arteries
C. Cranial pulmonary lobar arteries
D. Caudal pulmonary lobar arteries
caudal pulmonary lobar arteries
140
What is the most commonly reported cause of an asymmetrically distributed right sided unstructured interstitial pulmonary pattern associated with non-cardiogenic pulmonary edema?
A. Airway obstruction
B. Electrocution
C. Seizures
D. Systemic inflammatory response syndrome
airway obstruction
141
How does glucocorticoids immunosuppress?
Glucocorticoids bind an intracytoplasmic receptor. The drug–receptor complex moves to the nucleus to associate with DNA, leading to gene activation. has effect by stabilization of cell membranes in granulocytes, mast cells, macrophages -> inhibits production of infl mediators and cytokines like IL1, IL6, TNFa. Prednisolone can decrease blood lymphocyte numbers and the concentration of serum IgG, IgM and IgA in normal dogs.
142
Why are cats steroid resistant?
Cats are relatively ‘steroid resistant’ compared with dogs, as they may have a lower expression of glucocorticoid receptors within tissue cells. Steroids cause decreased blood lymphocyte number but not decreased IgG or IgA concentrations. IL10 gene transcription increases.
143
How does azathioprine work?
How does azathioprine work?
Azathioprine is a prodrug that gets metabolised in liver to active metabolite 6-mercaptopurine. 6-MP gets incorporated into S phase of cell cycle where it inhibits purine synthesis. And thereby dna and rna. thereby decreases T-cell function and B cell function.
6-MP is further metabolised by tiopurine methyltransferase (TPMT) and xanthine oxidase to inactive metabolites
144
Why are cats sensitive to azathioprine?
Cats have extra bone marrow sensitive and an get profound neutropenia, pancytopenia due to deficiency in thiopurine methyltransferase (TPMT) (aka active metabolite 6-mercaptopurine doesn’t get metabolised into inactive metabolites)
145
How does chlorambucil work and what other drug has similar action?
Cyclophosphamide
Alkylate DNA and act in non cell cycle specific manner. Acts on lymphocytes
146
How does cyclosporine work?
Ciclosporin inhibits T-cell activation via blocking cytokine (particularly IL-2) gene transcription.
More details: binds to cytoplasmic receptor cytophilin which inhibits enzyme calcineurin. Calcineurin has a role in cytokine gene transcription, where by binding to NF-AT induces transcription of especially interleukin 2 -> inhibition of cytokines (IL2 etc) involved in regulation of T-cell activation and proliferation -> blocks T helper cell production. indirect suppression of B cell response
147
How does intravenous humane immunoglobulins work in imha and imtp?
Intravenous immunoglobulin therapy (mostly IgG) may be effective in IMHA/IMTP by blocking macrophage Fc receptors and in other immune mediated diseases by binding to lymphocyte surface molecules and inhibiting the function of these cells.
