2 - Haemolytic Anaemias Flashcards
Classification of Haemolytic Anaemias
Intracorpuscular
Inherited - haemoglobinopathies, enzymopathies, membrane-cytoskeletal defects, channelopathies
Acquired - PNH
Extracorpuscular
Inherited - familial HUS
Acquired - microangiopathic (mechanical) destruction, toxic agents, drugs, infection, autoimmune
Clinical Features in Haemolytic Anaemia
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
Pathophysiology of Haemolytic Anaemia
- 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 - 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 - Increased requirement for erythropoietic factors such as folic acid
- Increased bilirubin production -> gallstone
- Hyperstimulation of spleen
- Hypersplenism -> neutropenia, thrombocytopenia - 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)
How does HA becomes decompensated?
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
What are the three essential components of RBC?
- Haemoglobin
- Membrane-cytoskeleton complex
- Metabolic process
What are the functions of membrane-cytoskeleton complex?
- Envelope for RBC cytoplasm
- Maintains normal RBC shape
- Cross membrane transplant of electrolytes and metabolites
What are the disease morphologies of membrane-cytoskeleton complex defect?
- Hereditary spherocytosis (HS)
- Hereditary elliptocytosis (HE)
- Stomatocytosis (usually channelopathies)
What is membrane-cytoskeleton complex?
Lipid bilayer incorporating phospholipids and cholesterol, spanned by proteins extending both extracellular and cytoplasmic domains
What is hereditary spherocytosis (HS) ?
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
What are the genes associated with hereditary spherocytosis?
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%)
What are the reasons for family history negative HS?
- De novo mutation - occurs in germ cell or early after zygote formation
- Recessive form of HS
What is the definition of haemolytic anaemia?
Rate of RBC _____ exceed the capacity of ____ resulting in ___
Rate of RBC destruction exceed the capacity of bone marrow production resulting in anaemia
What are the main signs of haemolytic anaemia? (4)
- Jaundice
- Urine discolouration
- Hepato/splenomegaly
- Skeletal deformity
Describe the spectrum of clinical severity of HS
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
Diagnostic FBC/PBF morphology of HS (MCHC and RDW)
FBC
Anaemia - normocytic
MCHC > 34
RDW > 14%
Normal or slight decreased MCV
PBF - spherocytes
Confirmatory testing for HS
Osmotic fragility test
Acid glycerol lysist est
EMA-binding test
SDS-gel electrophoresis of membrane proteins
Molecular studies for mutation of genes
Treatment for HS
Supportive
No definitive treatment yet
Selection criteria for splenectomy
When should splenectomy be offered in HS?
Severe - age 4-6 years
Moderate - puberty
Mild - avoid
Consider partial splenectomy in certain cases
Preparations for splenectomy
What are the pre-operative preparations for splenectomy in HS?
- Discussion on outcomes of splenectomy
- Vaccination - encapsulated bacteria (Neisseria meningitidis, streptococcus pneumoniae)
- +/- penicillin prophylaxis post-splenectomy
What is hereditary elliptocytosis (HE) ?
Abnormally shaped elliptical RBC (elliptocytes)
No correlation between morphology and severity
Prevalence: 1 in 2000-4000
What are the genes associated with hereditary elliptocytosis (HE)?
What is the significance of SLC4A1?
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
What HE gene condition is associated with most severe HA?
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
