red cells 1 Flashcards
what is anaemia
reduction in red cells or their Hb content
what are the causes of anaemia
blood loss
increased destruction
lack of production
defective production
what substances are required for red cell production
iron, copper, cobalt, manganese
B12, folic acid, thiamine, vit B6, C, E
amino acids
erythropoietin, GM-CSF, androgens, thyroxine
production of RBC
pluripotent stem cell under the influence or erythropoeitin then develop into RBC
eject nucleus just before leaving bone marrow
reticulocyte is the step just before a mature RBC
where does RBC breakdown occur
reticuloendothelial system
- macrophages in spleen, liver, lymph nodes, lungs etc
what is the normal life span of a RBC
120 days
what are RBC recycled into
globin –> amino acids –> reutilised
haem
- iron recycled into haemoglobin
- haam –> biliverdin –> bilirubin –> bound to albumin in plasma
bilirubin from RBC breakdown before it gets to liver - unconjugated
what is an erythrocyte
what is it made up of
mature RBC
membrane
enzymes
haemoglobin
where can genetic defects in congenital anaemia occur
what do they cause
prevalence
defects in cell membrane, metabolic pathways, Hb
most reduce RBC survival, result in haemolysis
carrier states are often silent, prevalence varies geographically
red cell membrane
skeletal proteins are reponsible for maintaining red cell shape and deformability - spectrin and ankyrin
defects can lead to increased red cell destruction
what is the commonest inherited membrane disorder
hereditary spherocytosis
what condition is this
hereditary spherocytosis
instead of biconcave shape, defect in skeletal protein leads to loss in structure and cells are sphere shaped
hereditary spherocytosis - dominant or recessive
most common forms are autosomal dominant
strong FHx
hereditary spherocytosis - protein defects
defects in 5 different structural proteins
ankyrin alpha spectrin beta spectrin band 3 protein 4.2
all lead to spherocytes
what happens to the cells in hereditary spherocytosis as a result of their changed shape
red cells are spherical
recognised by the body as foreign
removed from circulation by RE system (extravascular - broken down outside the blood vessels)
clinical presentation of hereditary spherocytosis
anaemia - red cells aren’t lasting as long
jaundice (neonatal)
splenomegaly - working more than normal
pigment gallstones - bilirubin in plasma is increased so more likely to crystallise in gallbladder
can be an incidental finding w/ very mild symptoms
treatment of hereditary spherocytosis
folic acid - increased requirements
tranfusion
splenectomy - if anaemia very severe; reduces red cell destruction
3 other rare membrane disordes
hereditary elliptocytosis
hereditary pyropoikilocytosis
south east asian ovalocytosis
what condition is this
hereditary elliptocytosis
less severe than spherocytosis but similar symptoms
what condition is this
hereditary pyropoikilocytosis
combination of different proteins involved
can become severley anaemic
how does south east asian ovalocytosis present
strange, large looking oval red cells
mild clinical picture
what is the function of glycolysis
provides energy
pathway interacts with the pentose phosphate shunt
what is the function of the pentose phosphate shunt
protects from oxidative damage
important link between pentose phosphate shunt and glycolytic pathway
glycose 6 - phosphate dehydrogenase
key to red cell survival
where can enzyme deficiencies occur
glucose 6 phosphate dehydrogenase - affects both pathways
pyruvate kinase - rarer, only affects glycolytic pathway
function of G6PD
protects red cell proteins (Hb) from oxidative damage
produces NADPH - vital for reduction of glutathione
reduced glutathione scavenges and detoxifies reactive oxygen species
G6PD deficiency
- how common
- what happens to cells
- protection?
commonest disease causing enzymopathy in the world
- many genetic variants
cells vulnerable to oxidative damage
confers protection against malaria
- most common in malarial areas
inheritance of G6PD deficiency
X linked
- affects males
- female carriers
what condition is this
G6PD deficiency
blister cells - top (pooling of Hb)
bite cells
clinical presentation of G6PD deficiency
variable
variable degrees of anaemia
neonatal jaundice
splenomegaly
pigment gallstones
drug, broad/fava bean or infection (increases free oxygen species) precipitated jaundice and anaemia:
- intravascular haemolysis - toxins are in the circulation w/ cells
- haemoglobinuria
triggers to haemolysis in G6PD deficiency
infection
acute illness e.g. DKA
broad (fava) beans
drugs - lots
what drugs can trigger haemolysis in G6PD deficiency
- don’t need to know for exam
antimalarials - primaquine, pamaquine
sulphonamides and sulphones - salazopyrin, dapsone, septrin
antibacterials - nitrofurantoin
analgesics - aspirin
antihelminthics - B-naphthol
misc - vit K analogues, probenecid, methylene blue
pyruvate kinase deficiency
- effects on cells
reduced ATP
increased 2,3-DPG
cells rigid
clinical presentation of pyruvate kinase deficiency
very rare
variable severity:
anaemia
jaundice
gallstones
can lead to haemolysis
what is the structure of Hb
2 alpha chains
2 beta chains
4 associated heme molecules - iron surrounded by protoporphyrin ring
what is the function of Hb
oxygen binding and unloading
changes binding structure when doing this
Hb and gas exchange
O2 to tissues
CO2 to lungs
oxygen dissociation curve
what is the Bohr effect
HbF
shifts as a compensatory mechanism
Bohr effect:
- acidosis
- hyperthermia
- hypercapnia
HbF - higher O2 affinity than HbA
describe normal adult Hb
composed of haem molecule and 2 alpha chains (4 alpha genes, Chr 16), 2 beta genes (2 beta genes, Chr 11)
over the first 6 mths of life the gene expression changes, HbF levels drop
what are haemoglobinopathies
inherited abnormalities of Hb synthesis
reduced/absent globin chain production - thalassaemia (alpha, beta, delta, gamma)
mutations leading to structurally abnormal globin chain (HbS - sickle cell, HbC, HbD, HbE, HbO Arab…)
areas with high prevalence of haemoglobinopathies
can occur in any ethnic group
concentrated in areas where malaria is/was endemic
usually because being a carrier allows some level of protection against malaria
inheritance of haemoglobinopathies
nearly all are autosomal recessive
2 asymptomatic carriers - 1/4 chance of having affected child, 1/2 change of being carrier/trait
Hb structure in sickle cell disease
2 normal alpha chains 2 beta (sickle chains) - point mutation
when the cell goes through hypoxic tissues it becomes sickle shaped as the abnormal Hb polymerises - rigid polymers irreversibly form rigid shapes
what condition is this
sickle cell (HbSS)
pathophysiology of sickle cell
- Hb S polymerisation
- vaso-occlusion
- endothelial dysfunction
- sterile inflammation
inheritance of sickle cell disorder
autosomal recessive
one of the commonest inherited disorders worldwide
clinical presentation of sickle cell disease
- painful vaso-occlusive crises: bone
- chest crisis - hypoxia - more sickling - endless cycle
- stroke - SCD is one of the biggest causes of stroke in children
- increased infection risk - hyposplenism
- chronic haemolytic anaemia - gallstones, aplastic crisis
- sequestration crises - spleen, liver
what is an aplastic crisis
can occur when erythrovirus infects RBCs, switches of RBC production
Aplastic crisis is defined as a decrease in Hb of 3g/dl or more with reticulocytopenia, usually resulting from parvovirus B19 infection
management of sickle cell - painful crisis
severe pain - often requires opiates (should be given within 30mins of presentation, effective analgesia by 1hr), avoid pethidine
hydration
oxygen
consider abx
life long prophylaxis in sickle cell disease
due to lack of splenic function
vaccination
penicillin (and malarial) prophylaxis
folic acid - long term increased requirements
management of acute events in sickle cell diseae
hydration oxygenation prompt treatment of infection analgesia - opiates, NSAIDs blood transfusion if very anaemic
long term management for sickle cell disease
blood transfusion - mainstay of management
- episodic/chronic
- complications: alloimmunisation, iron overload
disease modifying drugs - hydroxycarbamide (increases HbF, works well for painful crises)
bone marrow transplantation
gene therapy
what is alloimmunisation
develop alloantibodies against tranfused blood
Hb structure in thalassaemias
reduced or absent globin chain production
mutations/deletions in alpha genes (alpha thalassaemia)
αα/αα
-α/αα = α+
–/αα = α0 - incompatible with life
in beta genes (beta thalassaemia)
chain imbalance - chronic haemolysis and anaemia
spectrum of clinical severity in thalassaemia
homozygous alpha zero thalassaemia - no alpha chains, hydrops fetalis (incompatible with life)
beta thalassaemia major (homozygous beta thalassaemia) - no beta chains, transfusion dependent anaemia
non-transfusion dependent thalassaemia - ‘intermedia’ - range of genotypes (HbE/beta thal, HbH disease)
thalassaemia minor (common) - carrier state, hypochromic microcytic red cell indices
features of beta thalassaemia major
severe anaemia
- present at 3-6m/o (switch between HbF and HbA)
- expansion of ineffective bone marrow
- bony deformities
- splenomegaly
- growth retardation
life expectancy untreated/w/ irregular transfusions - <10yrs
what condition is this
beta thalassaemia major
no normal looking RBCs
nucleated RBCs also present in circulation
what is seen here and what condition is it associated with
skeletal expansion in the skull
white line = normal boundary of skull
hair on end appearance due to bone marrow expansion
beta thalassaemia major
treatment for beta thalassaemia major - transfusion
chronic transfusion support - 4-6wkly
normal growth and development
BUT - be aware of iron overloading
death in 2nd-3rd decades due to heart/liver/endocrine failure if iron loading untreated
treatment for beta thalassaemia major - iron chelation therapy
s/c desferrioxamine infusions (desferal) oral deferasirox (exjade)
good adherence to chelation - life expectancy near normal
- requires regular monitoring
- ferritin and MRI scans
what can be a cure for beta thalassaemia major
bone marrow transplantation
rare defects in haem synthesis
defects in mitochondrial steps of haem synthesis –> sideroblastic anaemia
- ALA synthesis mutations
- hereditary
- acquired (most common) - form of myelodysplasia
defects in cytoplasmic steps result in porphyrias
