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SAM Module A Haematology > Leukocyte and clotting disorders > Flashcards

Leukocyte and clotting disorders Flashcards

1
Q

When does a left shift (increased neutrophils) occur?

A

When increased band cells are present, this
most commonly is associated with ACUTE INFLAMMATION
Occasionally occurs with other conditions
(immune‐mediated disease or bone marrow
disease)

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2
Q

What are the types of left shift?

A 
Regenerative Left Shift
– Increased band cells
– Neutrophilia
– +/‐ less mature myeloid cells
Degenerative Left Shift
– Increased band cells with prominence of less mature myeloid cells
– Neutropaenia or neutrophils WNL
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3
Q

Outline the life of neutrophils

A

Half‐life approximately 7.5 hours
• Live 24‐48 hours after emigration into tissues
• Dog – marrow reserve contains approx 5 day supply assuming normal rates of depletion
• Peripheral blood numbers in MARGINAL and CIRCULATING pools (MP = CP in dog; MP = 3xCP in cat)
• Approx 3‐5 days needed to influence numbers
in peripheral blood

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4
Q

What are the types of neutrophilic leukocytosis?

A
  • Physiologic
  • Corticosteroid‐induced
  • Inflammatory
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5
Q

What is physiologic leukocytosis?

A

Caused by fear, excitement or strenuous exercise
Result of mobilization of marginating pool (total neutrophil pool remains the same)
Mild, transient leukocytosis (10‐20 minutes)

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6
Q

What is corticosteroid induced leukocytosis?

A

Mild to moderate (usually does not exceed 35,000; occasionally higher)
Peak 6‐8 hours after single oral dose of prednisolone
Increased bone marrow release of neutrophils and decreased migration from circulation
Decreased adherence of neutrophils and shift form marginating to circulating pool

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7
Q

What toxic changes can be seen in leukocytes?

A 
Recognized primarily in neutrophils, but may occur in any leukocyte type
Occur during development in the bone marrow due to inflammation, infection and/or toxicity
COMMON
Doehle bodies (Esp cats)
Cytoplasmic basophilia
Cytoplasmic vacuolation
Toxic granulation
LESS COMMON
Hyposegmentation
Nuclear ring forms
Giant cells
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8
Q

How do you grade toxic changes?

A

DEGREE of involvement
TYPE of change
NUMBER of cells involved
Examples:
Few Dohle Bodies in many neutrophils or 1‐2 Doehle Bodies in 3‐5 neutrophils per hpf (40x)
Slight toxic granulation in moderate neutrophils
Or slight toxic granulation in 5‐10 neutrophils per hpf

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9
Q

What is a leukaemoid response?

AKA neutrophilic leukocytosis

A

50,000 neutrophils/ul in dogs and cats
Increased marrow granulopoiesis and extramedullary haematopoiesis (spleen and liver)
Most commonly seen with inflammation, infection or neoplasia
+/‐ left shift and/or less mature myeloid cells

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10
Q

What are the main conditions associated with a leukaemoid response?

A 
Pyometra
Hepatozoonosis
Haemolytic anaemia
Malignant neoplasms of non‐
haematolymphopoietic origin
G‐CSF therapy
Leukocyte adhesion defect
Myeloproliferative disease (chronic myeloid leukaemia)
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11
Q

What is Leukocyte Adhesion Defect

A

Reported in Irish Setters in 1975
Fatal immunodeficiency
Autosomal deficiency
Progressive neutrophilia with recurrent bacterial and mycotic infections
Deficiency of glycoproteins (B2‐integrins) on leukocyte surface needed for cell adherence and egress into tissues

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12
Q

What are the signs of leukocyte adhesion defect?

A

If survive puppyhood, history of gingivitis with gingival recession and tooth loss, respiratory isease, diarrhoea, failure to achieve expected growth and weight, oral ulcers
Neutrophilia (may exceed 40,000/ul, sometimes as much as 100,000/ul)
Genetic test available

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13
Q

What are the three types of neutropaenia?

A

Decreased or ineffective production
Overwhelming demand by the tissues
Shfit from circulating to marginal pool

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14
Q

What can cause decreased or ineffective neutrophil pool?

A 
Chemotherapy
Immunosuppressive drugs
Drug reactions
Viral infection
Myelofibrosis
Stem cell disease
Idiopathic aplasia/hypoplasia
Immune‐mediated neutropaenia
Myelophthesis
Myelodysplastic syndrome
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15
Q

What types of overwhelming tissue demand lead to neutrophilia?

A

Intense peracute to acute inflammatory conditions
Often associated with gram‐negative bacterial infection
Often involve large surface areas (peritonitis, pneumonia, pyometra)

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16
Q

What can cause Shift from the circulating to marginating neutrophil pool?

A

Endotoxaemia or anaphylactic shock

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17
Q

What are the specific conditions associated with neutropaenia?

A

Cyclic haematopoiesis (Grey collies, Border collies, sometimes other breeds)
Vitamin B12 malabsorption
Immune‐mediated neutropaenia
Border Collie neutropaenia (hypothesized migration problem)

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18
Q

What is cyclic haematopoeisis?

A

Disease of pluripotential haematopoietic stem cells
resulting in on/off production of blood cells
Autosomal recessive
Linked to diluted coat colour (Grey collie dogs), but
also seen in other breeds with or without colour dilution (Border collies)
Cyclic neutropaenia at 14‐21 day intervals. Other
cell types also cycle from WNL to above Reference interval.

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19
Q

What are the clinical signs of cyclic haematopoiesis?

A 
Gingivitis
Lymphadenopathy
Excessive bleeding
Pneumonia
Diarrhoea
Subcutaneous abscesses
Intermittent lameness
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20
Q

Aside from cell number changes, what are the other differences in animals with cyclic haematopoiesis?

A 
Other cyclic fluctuations in
Acute phase proteins
Corticotropins and cortisol
VWF
Qualitative function defects in platelets
Cutaneous mast cell deficiency
Altered sensitivity (decreased) to G‐CSF
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21
Q

Outline the condition of b12 malabsorption

A

Giant Schnauzers and Border Collies, also reported in cats
Absorption requires intrinsic factor and intestinal receptor (cubulin)
B12 is an essential cofactor for metabolism and nucleic acid synthesis
Results in nonregenerative anaemia with neutropaenia
and megaloblastosis of erythroid and myeloid precursors , macrocytic erythrocytes and hypersegmented neutrophils

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22
Q

What are the clinical signs of b12 malabsorption

A 
Failure to thrive (8‐12 weeks)
Inappetence
Death (often by 5‐6 months old)
\+/‐ elevated ALT and bile acid stimulation test,
hyperammonaemia (mimic PSS)
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23
Q

How do you diagnose B12 malabsorption?

A

Subnormal serum cobalamin (B12) levels ( 4 weeks )
Increased serum methylmalonic acid concentration
Increased serum homocysteine concentrations (later
development, not in cats)

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24
Q

Outline eosinophilia

A

Classic association with response to
Parasites
Allergies (skin, respiratory)
Associated with mast cells
Mucous membrane irritation
Some neoplasias (esp MCT and T‐cell lymphomas)
Some endocrine conditions (hypoadrenocorticism;
hyperthyroidism in the cat)
Primary a tissue‐dwelling leukocyte (rather than in
circulation)

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25
Q

When do you get eosinopaenia?

A

Corticosteroid‐mediated
Catecholamine‐mediated
May be undetected since many reference intervals include 0 (no eosinophils is within normal limits)

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26
Q

When does monocytosis occur?

A

Acute or chronic inflammation (bacterial, immune‐
mediated haemolytic anaemia, necrosis, osteomyelitis, pyogranulomatous disease)
Trauma
Rebound phenomenon
Neoplasia
Parasitic disease
Corticosteroid‐induced

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27
Q

What can cause lymphocytosis?

A

Chronic antigenic stimulation (fungal, bacterial, viral, protozoal infections)
Hypoadrenocorticism
Lymphoid neoplasia
Physiologic lymphocytosis (esp. cats, uncommon in dogs)

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28
Q

What can cause lymphopaenia?

A 
Corticosteroid‐mediated
Immunosuppression
Usually < 500 lymphocytes/ul
Lymphoma or generalized granulomatous disease
Immunosuppressive drugs
Loss of lymphocyte‐rich fluids (PLE, enteritis, chylothorax, chyloperitoneum)
Malignancy
Viral infections (usually acute stages)
29
Q

What can cause basophilia?

A

Drug‐induced (heparin, penicillin)
Hypersensitivity/inflammatory conditions
(respiratory, GI, certain fungal conditions)
Neoplasia (Basophilic leukaemia, disseminated
mast cell neoplasia, essential thrombocythaemia,
lymphomatoid granulomatosis, thymoma)
Parasitic disease (esp. Ancylostoma and Uncinaria,
Dirofilaria immitis, Dipetalonema reconditum and
Hepatozoan canis)

30
Q

What is leukaemia

A

Definition: Neoplastic proliferation of haemopoietic cells originating in the bone marrow.
Classify by
Cell type
Clinical course (acute, chronic)
Presence or absence of circulating neoplastic cells (‘aleukaemic’ leukaemia)
Some ‘confusing’ terminology in the literature
May have some morphologic ‘clues’ as to origin
Traditionally have used cytochemical stains for
further classification of cell type of origin, no can do:
Flow cytometry
PCR for clonality

31
Q

If you are concerned a leukocyte abnormalities is the primary problem, but it is mild to moderate, what should you do?

A

If mild or moderate abnormality with few or
no clinical signs, suggest retest in 3‐5 days to
determine if persistent
3. If persistent abnormality and no cause becomes apparent, consider
a. Bone marrow aspirate and core biopsy
b. Other investigations (radiography,
ultrasound, aspirates, biopsies, genetic testing)
4. Consider breed predispositions and problems

32
Q

What is primary haemostasis?

A

Results in formation of the primary platelet plug
Involves platelets, the blood vessel wall and von Willebrand factor.
Involves vascular contraction, platelet adhesion (mediated by VWF), platelet activation and platelet aggregation resulting formation of a platelet plug (stabilized by fibrin).
Platelets provide a phospholipid surface (this used to be called PF3) and receptors for the binding of coagulation factors for secondary haemostasis .

33
Q

What is secondary haemostasis?

A

Results in formation of the fibrin clot and maintaining
vasoconstriction.
This involves circulating coagulation factors which when activated, act as enzymes and cofactors (factors V and VIII), along with calcium and platelets, in a ‘coagulation cascade’ to form a fibrin clot.
Classically divided into Intrinsic, Extrinsic and Common
Pathways.

34
Q

Aside from the three main pathways, what are the other pathways in the coagulation cascade?

A

Also have
Alternate pathway (mediated by tissue factor‐
Factor VII complex)
and
Contact pathways (prekallikrein and kininogen‐ mediated) that may stimulate the Coagulation Cascade.

35
Q

Outline the properties of thrombin

A

Has both pro‐thrombotic and anti‐thrombotic properties
Prothrombotic activites include
Stimulation of platelet aggregation
Generation of fibrin from fibrinogen
Activates Factor V and Factor VIII
Activates Factor XIII (essential for cross‐linking of fibrin)
Generates thrombin‐activatable fibrinolytic inhibitor (TAFI)
Antithrombotic activities include
Binding to thrombomodulin on endothelial cells ‐ activates Protein C and Protein S, which inhibit activation of Factors V and VIII, limiting thrombin generation

36
Q

What are the important coagulation inhibitors?

A

Antithrombin III‐Heparin pathway
Neutralization of activated factors of the intrinsic
pathway

Thromobomodulin‐Protein C‐Protein S Pathway
Degradation of cofactors (VIIIa and Va)

Result: Only a LARGE procoagulant stimulus results in fibrin production sufficient to generate an obstructive thrombus

37
Q

What is anti thrombin 3

A

Accounts for approximately 80% of plasma thrombin‐inhibiting capacity
Binds to thrombin ‐‐‐‐ prevents conversion of fibrinogen to fibrin
Catalyzed by Heparin
May be lost with glomerulonephropathy

38
Q

What is tertiary haemostasis (fibrinolysis)

A

Process of clot dissolution (preventing unwanted or
unphysiologic thrombosis)
May be
PRIMARY (physiologic)
or
SECONDARY (due to medication or pathologic
disorders or other causes – such as infections or
tissue hypoxia)

39
Q

Outline the process of fibrinolysis

A

Plasminogen ‐‐‐‐‐ activated to Plasmin by intrinsic and extrinsic pathway factors (tissue plasminogen activator [tPA])‐‐‐‐‐‐ degrades fibrin and fibrinogen ‐‐‐‐‐ producing fibrinogen degradation products (FDPs, which include D‐ dimers)
FDPs themselves may be anti‐haemostatic

40
Q

What are the associated types of bleeding with primary haemostasis disorders?

A 
Petechiae
ecchymoses,
bruising
bleeding from gums with teething,
oozing following a wound or venipuncture,
Epistaxis
melaena,
haematuria, 
retinal haemorrhages.
Petechiation not seen with VWD
May have overlap with bleeding types associated with secondary haemostasis if condition is severe
41
Q

What are the associated types of bleeding with secondary haemostasis disorders?

A

Haematoma Formation,
bleeding into joints or other body cavities,
oozing following wounds or venipuncture
Ecchymoses and bruising also may occur.

42
Q

What types of disorders are primary haemostasis disorders

A 
Vascular wall problems
Connective tissue disorders
Thrombocytopaenia
Platelet Function
Defects
43
Q

What types of disorders are secondary haemostasis disorders?

A

Coagulation Factor Dysfunction or Deficiency

Coagulation Factor inhibitors

44
Q

Outline the activated clot time test

A

Typical Reference Intervals: Dog (60‐90 sec)
Cat (< 165 sec)
Checks for a Coagulation Factor Abnormality ; may be
prolonged with marked thrombocytopaenia
Less sensitive than APTT
Abnormal when one or more coagulation factors < 10%.
Requires platelet phospholipid source, diatomaceoous earth activator and incubation at 37 degrees C

45
Q

Outline the BMBT test

A

Typical Reference Interval: Dogs and Cats (< 3.3 min)
Evaluates Primary haemostasis (vasculitis, vascular wall
disorder, connective tissue disorder, thrombocytopaenia, platelet function defect)
Relatively insensitive (must have severe problem to be
prolonged)
May be slightly prolonged in sedated or anaesthetized animals compared to those without sedation or anaesthesia (Standardize your method and establish reference interval)

46
Q

Outline the Whole Blood Clotting Time

A

Typical Reference Interval: Dogs (3‐13 min)
Cats (< 8 min)
Assesses Secondary Haemostasis (intrinsic pathway);
prolonged with severe thrombocytopaenia.
Relatively insensitive.
Prolonged when one or more factors < 5%.
Influenced by volume of blood, haematocrit, tube
size and tube coating (use uncoated glass tubes).
Requires platelet phospholipid source

47
Q

Outline the vWF antigen assay

A

Typical Reference Interval: Dog (< 50% = affected; 70% ‐180% = WNL).
Cat –established by testing laboratory
Assesses Von Willebrand Factor levels (probability of
bleeding highest when < 20%)
ELISA has largely replaced rocket immunoelectrophoresis method as standard.
Do not test pregnant or in‐ heat bitches. Can test
puppies at 6‐8 weeks old.

48
Q

Outline VWB genetic testing

A

Only available for some breeds

49
Q

Outline thrombin clot time

A

Typical Reference Interval: Varies with laboratory and
instrument and reagents
Assesses Hypofibrinogenaemia or Dysfibrinogenaemia
(abnormal function), defective fibrin formation (inhibited by FDPs) or thrombin inhibitors (heparin)
Can be converted to fibrinogen concentration by comparison to a standard curve derived from purified fibrinogen. Not offered by some laboratories.

50
Q

Outline Activated Partial Thromoboplastic Time (APTT)

A

Secondary Haemostasis: Intrinsic and Common Pathways

Prolonged when one or more factors < 30%

51
Q

Outline Prothrombin Time (PT)

A

Secondary Haemostasis: Extrinsic and Common Pathways

Prolonged when one or more factors < 30%

52
Q

Outline Fibrin/Fibrinogen Degradation Products (FDPs)

A

Assesses Tertiary Haemostasis (Fibrinolysis). Often
elevated with DIC, internal haemorrhage, thrombosis
or thrombo‐embolism.

53
Q

Outline D Dimer testing

A 
Typical reference interval: May be semi‐quantitative
or quantitative, vary with test kit
Tertiary Haemostasis (Fibrinolysis); specific for
plasmin cleavage of cross‐ linked fibrin. Often elevated with DIC, internal haemorrhage, thrombosis or thrombo‐embolism.
Highest results appear to occur with thromboembolism
54
Q

Outline Antithrombin III testing

A

Typical Reference interval: Dogs: < 50% = decreased
ATIII; > 80% = Within expected limits.
Inhibition of Secondary Haemostasis . Often decreased with DIC, PLN, PLE, some drugs.
Test based on ability to inhibit thrombin or activated Factor X

55
Q

Outline thromboelastography

A

Recent increased interest in this method for evaluation of platelet function and detection of possible hypercoagulable states Requires immediate analysis
Most often conducted as patient‐side (inclinic) test at referral institutions
May be useful for prognosis in critical care and
internal medicine cases

56
Q

What are the types of haemophilia in domestic species?

A

Both sex‐linked recessive genes = males affected
Homozygous females rare (often die in utero)
Haemophilia A ‐ Factor XIII deficiency
Haemophilia B – Factor IX deficiency

57
Q

What genetic testing can you do for haemophilia?

A

Genetic Test for Haemophilia B available for
Lhasa Apso and Bull Terrier.
Other genetic test: Factor VII Deficiency ‐
associated with mild to moderate bleeding. Recessive gene. Airedale, Alaskan Klee Kai, Beagle, Giant Schnauzer, Scottish Deerhound.

58
Q

How does Haemophillia A testing work?

A

Factor VIII levels are reported as a percentage of activity compared to a known standard. Values of 60 ‐ 150% are considered to be within normal limits. Haemophilia A has been documented in a variety of
canine breeds.
Factor VIII assay result of <10% - Moderate to severe clinical bleeding is often present. There may be
spontaneous haemorrhage or associated with minimal trauma. These may include intra‐articular haemorrhage, bleeding into body cavities, excessive bleeding with teething and/or haematoma formation.
Factor VIII assay result of <20%
Clinical bleeding may be present with major trauma or surgery.

59
Q

How does testing occur with haemophilia A with carrier females?

A

• Carrier females usually do not have problems with clinical bleeding, even with trauma or surgery, but potential exists if levels are low and/or if other concurrent diseases are present.
• Carrier females have, on average 50% of the normal Factor VIII level, but levels from 25 ‐ 80% have been found in known female carriers. This represents some overlap with the expected reference interval in normal individuals.
• Production of nonaffected sons increases the
confidence of non‐ carrier status in a bitch.
• If a bitch which is the daughter of a known carrier
has a factor VIII level of >60% and has produced 2
sons which are not affected, there is a 95%
probability that she is not a carrier of the
Haemophilia A gene.
• The following table indicates probabilities of non‐carrier status associated with production of unaffected sons by bitches that are daughters of carriers

60
Q

What is DIC?

A

Recognized clinical syndrome in the dog, rarely diagnosed in the cat. May be pronounced fibrinolytic system in the dog with higher incidence of thrombotic disease in the cat
Complex thromboembolic disease that may manifest as bleeding, thrombosis and/or multiple organ/system failure.

61
Q

Which conditions are associated with DIC?

A 
Systemic Inflammatory Response Syndrome
Uncontrolled immune‐mediated cellular destruction
Burns or Trauma
Metabolic acidosis
Severe shock
Disseminated or vascular neoplasia
Hepatosplenic disease
Heartworm disease
Envenomation
62
Q

What occurs in per acute DIC?

A

No clinical signs
Accelerated coagulation, fibrinmolysis and consumption of anticoagulants occurring
PT, APTT and ACT may be WNL or shortened.
Platelet count may be beginning to decrease.
FDPs or D‐dimer not elevated.
Antithrombin III decreased (< 80%)

63
Q

What occurs in consumptive DIC?

A

Clinical signs occur. Often oozing from venipuncture sites or other types of haemorrhage.
PT Prolonged APTT and ACT within normal limits or prolonged.
Fibrinogen decreased, normal or elevated.
FDPs or D‐dime may or may not be increased.
Antithrombin III decreased.

64
Q

What occurs in chronic DIC?

A

PT, APTT and ACT within normal limits or prolonged.
Platelet count decreased.
Fibrinogen normal or low.
FDPs or D‐dimer may or may not be increased.
Antithrombin III may be within normal limits or decreased.

65
Q

How do you diagnose DIC?

A

Usually high support if three or more of the following associated with conditions predisposing to DIC:

  1. Prolonged PT, APTT and/or ACT
  2. Thrombocytopaenia
  3. Hypofibrinogenaemia (not be heat precipitation method)
  4. Elevated FDPs or D‐dimer
  5. Decreased ATIII

Look for deterioration of multiple organs/systems associated with intravascular coagulation and decreased blood flow. Have a high index of suspicion

66
Q

How does rodenticide toxicity work?

A

Due to anti‐Vitamin K activity (Vitamin K antagonism)
Factor activation requires post‐ribosomal carboxylation of glutamyl residues on Factors II, VII, IX and X.
Vit K required for synthesis of Proteins C and S (inhibitors of factors V and VIII)
Therefore, PT is first test to show elevation (typically
peaks at 36‐72 hours post‐ingestion). Once Vitamin K
factors depleted, both PT and APTT elevated.

67
Q

How do different anti-coagulant rodenticides work?

A

First generation Vitamin K antagonist rodenticides
(warfarin, pindone) – low toxicity in nontarget species;
require repeated ingestion; short biologic half‐life –
approx 14.5 hours.
Second generation Vitamin K antagonist rodenticides (4‐ hydroxy coumarins = bromadiolone and bradifacoum and indan‐1,3‐diones = Pindone and Diphacinone) – longer duration of action, more potent, rely on single dose for toxicity, biological half‐life dependent on plasma protein binding, so relay toxicosis possible.

68
Q

Which conditions lead to increased susceptibility to rodenticide toxicity?

A 
High lipid diet
Coccidiostat or Cephalosporin treatment
Corticosteroid treatment
Broad‐spectrum antibiotic treatment
Uraemia
Liver disease
DIC
Pancreatic insufficiency
Viral infection
GI disease
69
Q

How do you monitor rodenticide toxicity

A

Check PT and APTT for diagnosis
Recheck PT and APTT for normalization after 48 hours of Vitamin K therapy Recheck PT and APTT at 48‐72 hours following end of treatment course to determine if prolonged PT and APTT recurs ‐‐‐‐ resume treatment.
Potential adverse effect of Vit K therapy = Heinz
body anaemia (periodic check of FBC and blood
film evaluation recommended).

SAM Module A Haematology (9 decks)

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