Haematology and immune mediated disease Flashcards
1
Q
What is the difference between petechiae and ecchymoses?
A
Petechiae - <3mm, capillary bleeding
Ecchymoses - larger, small arteriole bleeding
2
Q
Causes of thrombocytopenia
A
Increased destruction, consumption, sequestration
Reduced production
3
Q
Coagulation abnormalities in DIC
A
Initially hypercoagulable, progresses to consumptive coagulopathy
4
Q
Causes of increased platelet consumption
A
DIC
5
Q
Causes of platelet sequestration
A
Hepatomegaly, splenomegaly, hypotension, hypothermia, endotoxaemia
6
Q
Name some inherited thrombopathias and the breed association
A
Glanzmann’s - Great Pyrenees/Otter Hounds
Thrombopathia of Bassett Hounds and Spitz
Delta storage pool deficiency - American Cocker Spaniel
7
Q
Causes of acquired thrombopathias
A
Infectious - rickettsial
Hepatic disease/uraemia
Neoplasia
Drugs - aspirin/clopidogrel, carprofen, hydroxylethyl starch solutions, omega-3 FA (in vitro only)
8
Q
Likely cause of surface bleeding in patient with normal platelet number and function
A
Vascular disorder
9
Q
Vascular disorders
A
Primary immune-mediated
Secondary to medications, infections, neoplasia
10
Q
Normal BMBT (dogs and cats)
A
<4 mins (dogs)
<2 mins (cats)
11
Q
Clinical signs of primary haemostat disorder
A
Petechiation, ecchymoses, mucosal bleeding, ocular haemorrhage, haematoma formation
12
Q
Calculation for manual platelet count
A
Platelets/hpf x 15-20
13
Q
What haematology findings are suggestive of increased platelet production?
A
Increased MPV, PDW, reticulated platelets
14
Q
What is the general pathogenesis of most immune-mediated haematological diseases (Th-1/Th-2)
A
Th-2 (antibody-mediated)
15
Q
What are the mechanisms through which immunosuppressive medication act to reduce immune-mediated disease?
A
1 - reduced production of antibody by lymphocytes
2 - suppressing clearance of opsonised cells by macrophages or complement
16
Q
Which antibody class is most associated with IMHA? What is it's half-life?
A
IgG
7 days
17
Q
How can platelet function be assessed?
A
Impedance whole blood aggregometry
Plasma-based light transmission aggregometry
Platelet function analysed (PFA-100)
18
Q
Which PFA cartridge has the highest sensitivity for canine platelets?
A
Collagen/ADP
19
Q
What is assessed by platelet aggregation?
A
Platelet number
Platelet function
vWF
20
Q
Which pathway and factors are assessed by PT?
A
Extrinsic
FVII, X, V, II, I
21
Q
What does an elevated PT with a normal aPTT indicate?
A
FVII deficiency
22
Q
What pathways and factors are assessed by aPTT?
A
Contact pathway, intrinsic pathway, common pathway
Prekallikrein, FXII, FXI, FVIII, FIX, FX, FV, FII, FI
23
Q
Which factors do not affect aPTT?
A
FVII and FXIII
24
Q
Are PT/aPTT affected by heparin?
A
PT - no
aPTT - yes
25
What is a common clinically irrelevant incidental finding on coagulation testing in cats
Factor XII deficiency (prolonged aPTT, normal PT)
26
What conditions are associated with an elevated aPTT but normal PT?
Haemophilia (A, B, C), heparin, FXII def
27
What conditions are associated with elevated PT and aPTT?
Rodenticide toxicity, liver disease, DIC, hypo-/dysfibrinogenaemia
28
What is tested by the ACT?
All factors but VII and XIII
29
What are FDPs?
| What does an elevation suggest?
Created when plasmin lyses fibrinogen, fibrin monomers, insoluble fibrin, cross-linked fibrin
Plasmin activity
30
What are D-dimers?
What does their elevation indicate?
What is their half life?
Form of FDP generated from cross-linked fibrin
Thrombin generation, fibrin formation, cross linking by FXIIIs and plasmin activity
Short half life (5h) - indicate recent fibrinolysis
31
How does altered PCV affect TEG analysis?
Higher hct - hypo coagulable tracing
| Lower hct - hyper coagulable tracing
32
What is assessed by a calibrated automated thrombogram (CAT)?
The ability to generate thrombin in real time in-vitro in response to a specific stimulus
Used with platelet-poor or platelet-rich plasma
33
Virchow's triad
Vascular stasis
Increased coagulability
Disruption or activation of vascular endothelium
34
By how much does a clotting factor need to be reduced to elevate PT/aPTT
30-50%
35
List acquired hyper coagulable states
```
IMHA
Cardiac disease (HCM, endocarditis, dirofilaria)
PLE
PLN
Neoplasia
Endocrine dz (HAC, hypoT, DM)
Prednisolone
Inflammation/Sepsis
```
36
List acquired hypo coagulable states
Vit K deficiency - rodenticide
Hepatic failure
DIC
Factor VIII and IX inhibitory antibodies as consequence of multiple transfusions in haemophilia
37
Vit K dependent coagulation factors?
II, VII, IX, X
| Protein C+S
38
How to anticoagulant rodenticides cause bleeding?
Inhibit vitK epoxide reductase - reduced vita essential for carboxylation of glutamic acid residues on coagulation factors
39
How soon after rodenticide ingestion is bleeding typically observed?
2-5 days
40
What can be measured to indicate rodenticide ingestion?
PIVKA - elevates within 12 hours of ingestion
41
What is the primary mediator of DIC?
Tissue factor
42
What are the risk factors for DIC development?
Prolonged hypotension
SIRS
Disturbed blood flow to major organ
Major tissue trauma
43
What has been associated with Increased mortality in dogs with DIC?
High D-dimer, low antithrombin, hypo coagulable TEG trace
44
Are the following indicated in DIC;
- Heparin
- Plasma
Heparin - no
| Plasma - if active bleeding
45
Labile clotting factors?
V and VIII
46
```
Scott syndrome
Breed
Inheritance
Signs
Cause
Test
```
GSD
Autosomal recessive
Epistaxis, soft tissue haemorrhage, surgical haemorrhage
Defect in procoagulant activity on platelet surface
Prothrombin consumption assay
47
```
Haemophilia - factor deficiency?
Signs
Test
Grading
Prognosis
```
```
A - VIII
B - IX
Prolonged bleeding, haematoma formation, mucosal bleeding, haemarthrosis
Prolonged aPTT/ACT, normal PT
Measurement of factor activity
Mild - 6-20%
Moderate - 2-5%
Severe - <2%
Variable
```
48
Where does erythropoiesis occur in:
a) The foetus
b) Normal Adult
c) Anaemic adult
a) BM and liver
b) BM
c) BM, liver and spleen (EMH)
49
How long does it take for red blood cells to mature and be released from the bone marrow?
5-7 days
50
Describe cat's reticulocytes
Aggregate reticulocytes develop into punctate reticulocytes, then remain in circulation for 2-3 weeks
51
How is the corrected reticulocyte count calculated? When is it useful?
CRC = (reticulocyte count x hct)/normal hct
RC normally expressed as % of circulating RBCs, may falsely elevate in anaemia
52
How long does it take for reticulocytosis to develop after haemorrhage/haemolysis?
2-5 days
53
Ddx for erythrocyte destruction
Non-immune haemolytic anaemia (intoxication, infection, red cell fragmentation syndrome, hereditary, hypophosphataemia (C))
Haemophagocytic anaemia
IMHA (associative/non-associative)
54
What is the mechanism of hypophosphataemia causing haemolysis?
Inhibition of ATP production
| Leads to decreased membrane stability, increased osmotic fragility, susceptibility to oxidative stress and haemolysis
55
Name 3 infections associated with haemolysis
Babesia
Haemoplasmosis
Feline cytauxzoonosis
56
Name 3 red cell fragmentation syndromes
Microangiopathic haemolytic anaemia - HSA, other neoplasia, CHF, glomerulonephritis, myelofibrosis
Haemolytic uraemia syndrome - renal arterial/arteriolar endothelial lesions induce local thrombi
DIC
57
What are the hereditary haemolytic anaemias? What are their mechanisms?
Pyruvate kinase deficiency and phosphofructokinase deficiency - impaired erythrocyte energy metabolism
Stomatocytosis - genetic membrane disorder
58
```
Pyruvate kinase deficiency
Species
Inheritance
Clinical presentation
Age at diagnosis
```
Dogs and cats
Autosomal recessive
Varying degree of regenerative anaemia. Progressive iron overload => haemosiderosis and liver fibrosis.
Dogs (not cats) develop progressive myelofibrosis and sclerosis
Dogs young, cats old
59
Phosphofructokinase deficiency
Species
Inheritance
Clinical presentation
Dogs only
Autosomal recessive
Some have no clinical signs, most have persistent haemolytic anaemia exacerbated by sporadic haemolytic crises secondary to exercise-induced hyperventilation alkalaemia
60
Haemophagocytic anaemia
Breed predispositions
Bernese Mountain Dog, Rottweiler, Golden Retriever, Flat Coat
61
Haemophagocytic anaemia
Pathogenesis
Sub-group of histiocytic sarcoma derived from macrophages. Demonstrate infiltrative growth in liver, spleen, lung and BM
62
Haemophagocytic anaemia
Clinical signs
Vague
Most have hepatosplenomegaly
Moderate-severe anaemia with abundant reticulocytosis
63
Haemophagocytic anaemia
Diagnosis
Demonstration of histiocytes containing RBCs or haemosiderin deposits
Immunophenotyping CD11/CD18
64
Haemophagocytic anaemia
Prognosis
MST 4 weeks
65
When does feline alloimmune haemolysis occur?
When type A/AB cat receives type B colostrum
66
What genetic mutation has been associated with polycythaemia vera in humans and dogs?
JAK2
67
What other haematological abnormality is described in cats with primary polycythaemia?
Thrombocytosis
68
What are the pathways for erythrocytosis?
Renal hypoxia => hypoxia inducible factor => erythropoietin (cortical fibroblasts)
Thyroid hormone => increased proliferation of erythroid progenitor cells
=> increased hypoxia induced EPO production
Glucocorticoids - synergise with HIF - form burst forming units - erythroid cells capable of self renewal
Growth factor - directly stimulates erythropoiesis
69
Which 2 endocrine conditions are associated with erythrocytosis?
Hyperthyroidism
| Hyperadrenocorticism
70
What are the ddx for erythrocytosis
Physiological
Primary
Secondary - physiologically appropriate
(R=>L shunt, PDA, TOF, pulmonary disease)
- physiologically inappropriate (renal hypoxia/aberrant EPO production)
71
What are the clinical signs of erythrocytosis?
Hypervolaemia - ocular - engorged retinal vessels, uveitis, retinal detachment, glaucoma
- engorged mucous membranes
Hyperviscosity - CNS - weakness, ataxia, seizures
Haemorrhage
PUPD
V/D
72
What ABG findings are consistent with a physiologically appropriate secondary erythrocytosis?
Arterial O2 sat <92%
73
What medical treatments have been described for primary erythrocytosis?
Hydroxyurea
Chlorambucil (humans only)
Radiophosphorus
74
What are the possible complications with phlebotomy?
Iron deficiency
| Hypoproteinaemia => oedema
75
What are the three components of primary haemostats?
Platelets
VWF
Vessel wall
76
Describe platelet development
Megakaryocyte precursor cells form platelet-specific organelles and surface proteins
Develop large pseudopodia, stretch to form pro-platelet processes
Platelet organelles move to end of pro platelet
Branch and constrict - beaded appearance
Proplatelets break away from megakaryocyte and fragment into platelets
77
What is the lifespan of a platelet in the circulation?
6-10 days
78
Describe platelet activation
Triggered by injury to vessel
| Platelets transform into adhesive spiny spheres - recognise and bind sub endothelial matrix
79
What are coated platelets?
Subset of collagen and thrombin-activated platelets
Scramble phosphatidylserine from inner membrane to outer - release PS micro-particles - act as scaffold for tens assembly
80
What substances antagonise platelet receptors and dampen platelet reactivity?
Prostacyclin, PGE2, PGD2
81
What is the most abundant platelet integrin receptor? What is it's function
Alpha-IIb-beta-3 complex (GPIIb/IIIa)
| Activation-dependent receptor for fibrinogen, fibronetin, vWF
82
What autoantibody target has been identified in fogs with ITP?
GPIIb/IIIa
83
Which drugs have been implicated in development of ITP?
Sulphonamides, cephalosporins
84
What infectious agents have been implicated in 2ndry ITP?
Anaplasma phagocytophilum, Babesia sp, Ehrlichia Canis, Leptospira sp, Leishmania infantum
85
What conditions have been associated with platelet-bound antibodies in dogs?
Lymphoma, HSA, histolytic sarcoma
| Chronic hepatitis, pancreatitis, SIRS
86
What are the mechanisms by which neoplasia causes thrombocytopenia?
Consumption (bleeding/DIC), sequestration, myelopthisis, platelet bound antibodies
87
How can a diagnosis of ITP be further supported? What are the limitations of the test?
Flow cytometric assay for platelet-bound antibody
Sensitive but not specific
Increase in stored samples
88
For which agent is there evidence as a sole agent in ITP?
MMF
89
What are the recognised types of vWD?
| What are their characteristics?
Type I - low VWF concentration, full array of multimers, mild-moderate bleeding
Type II - variable reduction in VWF concentration, absence of high molecular weight multimers, moderate-severe bleeding
Type III - complete absence of VWF - severe bleeding
90
Which breeds are associated with type I VWD?
BMD, Corgi ,Coton de Tulear, Doberman, Dutch Partridge dog, German Pinscher, Goldendoodle, Irish Setter, Kerry Blue Terrier, Manchester Terrier, Papillon, Poodle, Stabyhound, WHWT
91
Which breeds are associated with type II VWD?
GSHP, GWHP
92
Which breeds are associated with type III VWD?
Dutch Kooiker, Scottish Terrier, Shetland Sheepdog
93
What laboratory assessments of VWF are available?
VWF:Ag (ELISA)
DNA testing
Qualitative assay - WWF:collagen-blinding assay
94
How is VWF:Ag interpreted?
| What factors can alter it?
```
Normal - 70-180%
Boderline - 50-69%
Abnormal - 0-49%
Decrease - haemolysis
Increase - ill - inflammatory/septic, pregnancy
```
95
What are the modes of inheritance for VWD
Type I - autosomal dominant or recessive
Type II - autosomal recessive
Type III - autosomal recessive
96
How are qualitative VWF assays (CBA) interpreted?
```
Used to diagnose type II VWD
Assesses binding to collagen type I/III - dependent on high molecular weight multimers
Reported as ratio of VWF:CBA to VWF:Ag
1 = normal
2 = Type II VWD
```
97
When should VWD be treated?
Type II and III - bleeding inevitable
Type I - phenotype variable
Aim to control spontaneous/trauma-related bleeding
98
What are the treatment options for VWD?
Desmopressin - 30 mins before surgery or SID
Blood component - FWB, FFP, CRYO
Cryo ideal - 1 unit/10kg, ever 8-12 hours
99
What is the half life of plasma VWF?
12 hours
100
What is the evidence for DDAVP use in dogs with Type I VWD? Effect on VWF:Ag?
Raises plasma VWF concentration from 10 => 17%
Improved haemostat function (PFA-100)
Shortened BMBT
101
What are the risks of DDAVP treatment of VWF, particularly at high doses?
Water retention and hyponatraemia
Tachyphylaxis
Failure to stimulate VWF release from Weibel-palade bodies with repeat administration
102
What has been associated with acquired VWD in dogs?
MMVD and sub aortic stenosis (CKCS)
Following tetrastarch bolus
Angiostrongylus (case report)
103
What type of VWD has been reported in cats?
Type III
104
List some hereditary platelet dysfunctions
Glanzmann thrombasthenia
Calcium-diacylglycerol guanine exchange factor thombopathia (Basset thrombopathia)
Platelet procoagulant deficiency (Scott syndrome)
105
What tests are available for the diagnosis of Scott syndrome?
Flow cytometry
| DNA testing
106
What acquired platelet dysfunctions have been recognised in dogs?
Uraemia, hepatobiliary disease, paraproteinaemia
107
What anti-platelet medications are available and what are their mechanisms?
Aspirin - irreversible cyclooxygenase inhibitor
| Clopidogrel - P2Y12 ADP receptor antagonist
108
What congenital WBC disorders are described in dogs/cats?
```
Chediak-Higashi Syndrome
Pelger-Huet Anomaly
LAD
Trapped neutrophil syndrome
Pyruvate kinase deficiency
X-linked SCI
Autosomal recessive SCI
Cyclic haematopoiesis of grey collies
Common variable immunodeficiency
Lysosomal storage disease
```
109
What secondary WBC disorders are described?
```
Immune-mediated neutropaenia
Primary MDS
Secondary MDS
Secondary dysmyelopoiesis
Myeloproliferative disease
Myelopthisis
Myelotoxicosis
Viral - parvo/distemper/FeLV/FIV/FIP
Rickettsial/fungal
```
110
What are the causes of immune-mediated neutropaenia?
Primary
Secondary - tick-borne
- drugs (phb, cephalosporins)
111
How is primary immune-mediated neutropenia diagnosed?
Exclude other causes - overwhelming demand, reduced production (haemic neoplasia), drug-induced, sequestration (splenomegaly)
Flow cytometry (anti-neutrophil ABs) described
Rapid response to immunosuppression
112
What are the features of MDS?
Non-regen anaemia or multiple cytopaenias
Normal/hypercellular BM
BM - increased immature precursors, increased dysplastic cells, megaloblasts and erythroid precursors
Blast cells <30% nucleated cells
Lack of increased myeloid cells
