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Internal Medicine (Me) > 2 - Haemolytic Anaemias > Flashcards

2 - Haemolytic Anaemias Flashcards

1
Q

Classification of Haemolytic Anaemias

A

Intracorpuscular
Inherited - haemoglobinopathies, enzymopathies, membrane-cytoskeletal defects, channelopathies
Acquired - PNH

Extracorpuscular
Inherited - familial HUS
Acquired - microangiopathic (mechanical) destruction, toxic agents, drugs, infection, autoimmune

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2
Q

Clinical Features in Haemolytic Anaemia

A

Examination
- Jaundice and urine discolouration
- Pallor
- Splenomegaly (preferential site of haemolysis)
- Hepatomegaly
- Frontal bossing (in severe congenital case - overactivity of bone marrow)

Laboratory
- Anaemia with reticulocytosis
- Increased MCV/MCH (from reticulocytes)
- Hyperbilirubinaemia
- Raised LDH - can go up to 10x normal
- Reduced or absent haptoglobin

Initial tests to send:
FBC, reticulocytes, PBF, LDH, haptoglobin, total and direct bilirubin, LFT, Coombs

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3
Q

Pathophysiology of Haemolytic Anaemia

A
  1. Natural differentiation and maturation of RBC predisposes to limited repair response
    - RBC loss of cell organelles, biosynthetic abilities, extrusion of nucleus in exchange of accumulation of haemoglobin in cytoplasm for oxygen transportation
    - Curtailed metabolism response: no backup anaerobic glycolysis, no protein making cpacity for replacement, enzymes degrade and not replaced
    > metabolic failure leads to structural damage to membrane or failure of cation pump -> reduced RBC lifespan
  2. Band 3 molecule exposure
    - As RBC ages, increased band 3 moecule exposure on cell surface creates antigenic site to anti-band 3 IgG Ab
    - Opsonisation of senescent RBC and signaling for phagocytosis by macrophages
    > Process accelerated in HA
  3. Increased requirement for erythropoietic factors such as folic acid
  4. Increased bilirubin production -> gallstone
  5. Hyperstimulation of spleen
    - Hypersplenism -> neutropenia, thrombocytopenia
  6. Iron consequences
    A. Intravascular HA - haemoglobinuria -> iron loss
    B. Extravascular HA -> iron overload
    - Increased erythropoiesis suppresses hepcidin, causing increased iron absorption
    - Repeated blood transfusion increases iron load
    > Secondary haemochromatosis and complications
    (liver cirrhosis, heart failure)
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4
Q

How does HA becomes decompensated?

A

Compensation
- increased destruction -> compensatory increased in EPO and RBC output from bone marrow

Decompensation
- Increased/depleted erythropoiesis factor use
> Pregnancy, folate deficiency
> Kidney failure -> inadequate EPO production
- Intercurrent illness depressed erythropoiesis
> Acute infection, most significant parvovirus B19

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5
Q

What are the three essential components of RBC?

A
  1. Haemoglobin
  2. Membrane-cytoskeleton complex
  3. Metabolic process
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6
Q

What are the functions of membrane-cytoskeleton complex?

A
  1. Envelope for RBC cytoplasm
  2. Maintains normal RBC shape
  3. Cross membrane transplant of electrolytes and metabolites
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7
Q

What are the disease morphologies of membrane-cytoskeleton complex defect?

A
  1. Hereditary spherocytosis (HS)
  2. Hereditary elliptocytosis (HE)
  3. Stomatocytosis (usually channelopathies)
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8
Q

What is membrane-cytoskeleton complex?

A

Lipid bilayer incorporating phospholipids and cholesterol, spanned by proteins extending both extracellular and cytoplasmic domains

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9
Q

What is hereditary spherocytosis (HS) ?

A

Inherited abnormality spherical RBC (spherocytes) susceptible to lysis in hypotonic media
May be autosomal dominant or recessive

Prevalence: 1 in 2000-5000 in European ancestry

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10
Q

What are the genes associated with hereditary spherocytosis?

A

SPTA1 - chromosome 1q22-23 -> alpha-spectrin
SPTB - chromosome 14q23-24 -> beta-spectrin
ANK1 - chromosome 8p11 -> Ankyrin (majority)
SLC4A1 - chromosome 17q21 -> Band 3 (25%)
EPB42 - chromosome 15q15-21 -> Band 4.2 (3%)

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11
Q

What are the reasons for family history negative HS?

A
  1. De novo mutation - occurs in germ cell or early after zygote formation
  2. Recessive form of HS
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12
Q

What is the definition of haemolytic anaemia?
Rate of RBC _____ exceed the capacity of ____ resulting in ___

A

Rate of RBC destruction exceed the capacity of bone marrow production resulting in anaemia

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13
Q

What are the main signs of haemolytic anaemia? (4)

A
  1. Jaundice
  2. Urine discolouration
  3. Hepato/splenomegaly
  4. Skeletal deformity
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14
Q

Describe the spectrum of clinical severity of HS

A

Broad - mild to severe (depending on molecular lesions, degree of autosomal involvement, intercurrent conditions)

Mild - young adults or later in life
Severe - infancy -> severe anaemia

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15
Q

Diagnostic FBC/PBF morphology of HS (MCHC and RDW)

A

FBC
Anaemia - normocytic
MCHC > 34
RDW > 14%
Normal or slight decreased MCV

PBF - spherocytes

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16
Q

Confirmatory testing for HS

A

Osmotic fragility test
Acid glycerol lysist est
EMA-binding test
SDS-gel electrophoresis of membrane proteins
Molecular studies for mutation of genes

17
Q

Treatment for HS

A

Supportive
No definitive treatment yet
Selection criteria for splenectomy

18
Q

When should splenectomy be offered in HS?

A

Severe - age 4-6 years
Moderate - puberty
Mild - avoid

Consider partial splenectomy in certain cases
Preparations for splenectomy

19
Q

What are the pre-operative preparations for splenectomy in HS?

A
  1. Discussion on outcomes of splenectomy
  2. Vaccination - encapsulated bacteria (Neisseria meningitidis, streptococcus pneumoniae)
  3. +/- penicillin prophylaxis post-splenectomy
20
Q

What is hereditary elliptocytosis (HE) ?

A

Abnormally shaped elliptical RBC (elliptocytes)
No correlation between morphology and severity

Prevalence: 1 in 2000-4000

21
Q

What are the genes associated with hereditary elliptocytosis (HE)?

What is the significance of SLC4A1?

A

SPTA1 - chromosome 1q22-23 -> alpha-spectrin (65%)
SPTB - chromosome 14q23-24 -> beta-spectrin (30%)
SLC4A1 - chromosome 17q21 -> Band 3 (25%)
EPB41 - chromosome 1p33-34 -> Band 4.1 (5%)

SLC4A1 gene - South East Asia ovalocytosis
- Polymorphism up to 5-7% in SEA (Malaysia, Papua, Indonesia, Philippines) from malaria selection
> Asymptomatic in heterozygotes
> Lethal in homozygotes

22
Q

What HE gene condition is associated with most severe HA?

A

Biallelic mutations resulting in pyropoikilocytosis (HPP)
- Instability of cytoskeleton protein network due to decreased tetramerisation of spectrin dimers
- red cell volume marked decreased (MCV 50-60)
- bizarre poikilocytes on PBF
- may often benefit from splenectomy

Internal Medicine (Me) (27 decks)

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