The red blood cell and what can go wrong Flashcards
What do RBCs need to function?
efficient production (synthesis)
pliable (get through small vessels)
haemoglobin on which to carry oxygen
enzymes for metabolism
removal of defective cells
Define + describe erythropoiesis
RBC synthesis
in bone marrow
develop from common stem cell progenitor
What is the sequence from stem cell to mature RBC
stem cell –> erythroblast –> nucleated RBC –> reticulocyte –> mature RBCs
What are the requirements for erythropoiesis?
normal stem cell
normal maturation
healthy bone marrow microenvironment
growth factors (erythropoietin, GM-CSF)
essential components (iron, folate, vit B12, amino acids)
What is the shape of RBCs?
biconcave
Describe the structure of haemoglobin
tetramer –> 2 pairs globin chains (2 alpha, 2 beta)
haem molecule bound to each globin
iron within centre of haem
Describe haemoglobin production
3 phases = embryonic, foetal, adult
alpha chains:
- chromosome 16
- alpha in all Hb from foetal to adult
beta-like chains:
- beta in HbA adult
- gamma in HbF foetal
- delta in HbA2 in v low levels from week 30 gestation
- chromosome 11
What is the lifespan of a RBC and how are old RBCs removed?
120 days
old RBCs removed by macrophages –> found in spleen, liver and bone marrow
Define anaemia
reduced grams of Hb/L blood
below the age/sex adjusted normal range
What can cause anaemia?
too few RBCs
too little haemoglobin
an abnormally low haematocrit
Define haematocrit
ratio RBC:plasma
reduced if decreased RBCs or increased plasma
Anaemia symptoms
acute onset = symptoms more marked
chronic onset = less severe symptoms, time for body to compensate
fatigue + weakness
dyspnoea (breathlessness)
tachycardia (palpitations)
muscle cramps
angina/heart failure
Anaemia signs
pallor
tachypnoea
tachycardia
hypotension
What is MCV?
mean corpuscular volume
low MCV = microcytic
normal MCV = normocytic
high MCV = macrocytic
List causes of microcytic anaemia
iron deficiency
thalassaemia
anaemia of chronic disease
lead poisoning (rare)
sideroblastic anaemia (rare)
List causes of normocytic anaemia
anaemia of chronic disease
acute blood loss
chronic renal failure
mixed B12/folate + iron deficiency
bone marrow disorders
List causes of macrocytic anaemia
B12 or folate deficiency
liver disease
drugs (including alcohol)
reticulocytosis (haemolysis)
hypothyroidism
myelodysplasia
pregnancy
How else (other than MCV) can anaemia be classified?
decreased RBC production or increased RBC destruction or loss
Reduced red cell production causes
defective stem cells
defective maturation
unhealthy microenvironment
absence of stimulation by growth factors
lack of components for RBC formation
Reduced RBC production lab findings
usually normocytic and normochromic (unless deficiency B12, iron or folate)
reticulocytes not raised
Describe anaemia of chronic disease
ineffective iron utilisation due to raised hepcidin
mild to moderate (rarely <90g/L)
normochromic + normocytic (sometimes microcytic)
chronic inflammation (eg. RA, IBD)
chronic infection (eg. pneumonia, TB)
malignant disease
Define haemolysis
premature breakdown of RBCs (<120 days)
increased RBC destruction
Haemolysis signs
jaundice
dark urine
gallstones (RBC pigment)
Haemolysis blood results
anaemia (normocytic or macrocytic (reticulocytosis))
increased reticulocyte count
increased bilirubin
increased LDH
decreased haptoglobin
What are the 2 overarching causes of haemolysis?
intrinsic (abnormality within cell)
extrinsic (abnormality outside cell)
3 intrinsic haemolysis causes
membrane
metabolism (enzymes)
haemoglobin
Describe membrane abnormalities that cause haemolysis
Inherited:
- hereditary spherocytosis
- hereditary elliptocytosis
- hereditary stomatocytosis
consequences = RBC more easily damaged, macrophage removal, shortened RBC life
autosomal dominant
cause of prolonged neonatal jaundice
mild anaemia
fluctuant jaundice
gallstones
aplastic crises precipitated by Parvovirus (B19)
RBC membrane defects lab findings
anaemia (usually mild)
reticulocytosis
increased bilirubin
increased LDH
blood film = abnormally shaped RBC
direct antibody test negative
RBC membrane defects treatment
folic acid
splenectomy
Describe enzyme defects that cause haemolysis
inherited G6PD deficiency = most common
inability of RBC to protect itself from oxidative stress by glutathione production
X-linked recessive
African/Mediterranean descent >
acute episodes of haemolysis following oxidative stress (eg. drugs, infections, moth balls, Fava beans)
Define haemoglobinopathy
disorder of haemoglobin synthesis
Describe haemoglobin production
alpha globin chains made from foetus onwards
- 4 genes, 2 each chromosome
pair with beta-like globin chains
- 2 genes, 1 each chromosome
gamma (alpha 2, gamma 2) in foetus decline at birth, very low by 6 mo, HbF
beta (alpha 2, beta 2) from roughly 30 weeks gestation, HbA
delta (alpha 2, delta 2) very low levels from 30 weeks, HbA2
Describe thalassaemia
reduced globin chain synthesis
common in Asia, Africa + south Mediterranean
reduced/no alpha/beta chains produced
Consequences of thalassaemia
chain imbalance
excess alpha/beta chains precipitate
precipitated chains damage RBC membrane
damaged cells destroyed prematurely by macrophages
Describe thalassaemia classification
alpha thalassaemia = too few alpha chains
beta thalassaemia = too few beta chains
thalassaemia major = no alpha/beta chains
thalassaemia trait = reduced alpha/beta chains, no transfusions required
thalassaemia intermedia = intermediate clinical picture
Describe the clinical aspect of beta thalassaemia major
severe anaemia from 3-6 mo
hepatosplenomegaly
expansion of bone marrow
detected by newborn screening programme
Describe the clinical aspect of alpha thalassaemia major
fatal in utero (hydrops fetalis)
often alpha gene deletions
HbH disease = born with 1/4 alpha genes
variable phenotype
Describe the clinical aspect of thalassaemia trait
1 beta gene normal
mild microcytic anaemia
‘carrier’ can pass gene to child
asymptomatic
2 x beta thalassaemia trait procreate = 1/4 chance offspring will have beta thalassaemia major
increased % Hb = HbA2 (2 alpha, 2 delta)
What is Alpha-0 thalassaemia?
2 genes deleted from same chromosome
risk of alpha thalassaemia major in offspring
What is Alpha+ thalassaemia?
2 genes deleted from different chromosomes
risk of alpha thalassaemia major in offspring not present
How is thalassaemia/thalassaemia trait diagnosed?
hypochromic microcytic anaemia (exclude Fe deficiency)
Hb electrophoresis or HPLC (high performance liquid chromatography)
- beta thalassaemia trait = increased HbA2
- beta thalassaemia major = absence HbA
- cannot pick up alpha trait
genetic analysis required for alpha thalassaemia diagnosis
Thalassaemia management
major:
- lifelong transfusions (keep Hb >100g/L) [iron overload = iron chelators remove iron excess)
- splenectomy (reduce blood requirements)
- allogenic bone marrow transplant (success >80%)
trait:
- avoid iron unless Fe deficient
- genetic counselling
Describe sickle cell anaemia
abnormal globin chain structure
point mutation leads to single amino acid substitution (valine –> glutamate at position 6beta chain –> forms HbS)
HbS forms crystals when exposed to low oxygen levels –> causes ‘sickling’ of RBCs
homozygous = disease
heterozygous = trait
Sickle cell anaemia presentation
chronic haemolytic anaemia from 3-6mo (when HbF–>HbA)
rate of haemolysis may increase during crisis
Hb~60-90g/L (anaemia symptoms mild)
elongated red cells with pointy ends
Describe sickle cell trait
1 gene affected
benign condition
no/mild anaemia
normal RBC appearance
HbS = 25-45% total Hb
care taken during anaesthesia + high altitudes –> extreme low oxygen can cause sickling
genetic counselling
Describe blood vessel occlusion in sickle cell disease
sickle cells can cause tissue infarction by blocking blood vessels due to shape + ‘stickiness’
Sickle cell disease complications
occlude vessels:
- pain (especially bones)
- organ damage
- splenic infarction from age 2 (autosplenectomy)
- organ engorgement with blood (sequestration –> spleen, liver)
Sickle cell disease lab findings
blood film:
- sickle cells
- target cells
- nucleated red cells
- Howell-Jolly bodies (splenic atrophy)
sickle solubility screen positive
(HbS less soluble when oxygen levels low)
Hb electrophoresis/HPLC shows HbS, no HbA, variable amounts HbF)
Sickle cell management
prophylactic:
- avoid precipitating factors
- folic acid
- pneumococcal vaccine, regular oral penicillin
- hydroxycarbamide
crises:
- analgesia (opiates)
- rest
- rehydration
- oxygen +/- antibiotics
- blood transfusion/exchange transfusion (severe/chest crises)
stem cell transplantation
List 4 extrinsic causes of haemolysis
antibody attack
mechanical trauma
infections
chemical + physical agents
Describe how antibody attack causes haemolysis
antibodies primed to only attack foreign cells
autoimmunity = antibodies attack own cells
antibodies attacking RBC = autoimmune haemolytic anaemia (AIHA)
Describe how antibody attack causes haemolysis
antibodies primed to only attack foreign cells
autoimmunity = antibodies attack own cells
antibodies attacking RBC = autoimmune haemolytic anaemia (AIHA)SE
Describe autoimmune haemolytic anaemia (AIHA) testing
direct antiglobulin test (Coombs)
anti-human Ig added, if antibody on red cells, agglutination will occur due to crosslinking
warm = antibody reacts with RBC at 37 degrees celsius (IgG)
cold = antibody reacts with RBC < 37 degrees celsius (IgM)
Describe warm AIHA
antibody reacts with RBC at 37 degrees celsius (IgG)
idiopathic or secondary to:
- autoimmune conditions
- disordered immune system (CLL, low grade lymphoma)
- drugs (RBC membrane complex –> penicillin)(Ab against RBC membrane –> methyldopa)
Describe cold AIHA
antibody reacts with RBC < 37 degrees celsius (IgM)
idiopathic or secondary to:
- lymphoma
- infections (mycoplasma pneumonia, EBV)
- paroxysmal cold haemoglobinuria (rare, syphilis)
AIHA lab findings
Haemolysis:
- anaemia
- reticulocytosis
- increased LDH
- increased unconjugated bilirubin
+ve DAT (Coombs)
blood film = spherocytes (IgG), agglutination (IgM)
AIHA management
remove/treat underlying cause
keep patient warm if IgM (cold-reacting)
folic acid
transfusion
immune suppression (warm = corticosteroids, cold+warm = rituximab)
splenectomy for resistant cases (less helpful if IgM)
What infection can cause haemolysis?
malaria
Name 5 microangiopathic haemolytic anaemia causes?
DIC (disseminated intravascular coagulation)
TTP (thrombotic thrombocytopenic purpura)
HUS = haemolytic uremic syndrome
faulty mechanical heart valves
march haemoglobinuria
What chemicals/physical agents can cause haemolysis?
drugs (dapsone)
copper (wilson’s disease)
lead
burns
snake + spider bites
What is PNH?
paroxysmal nocturnal haemoglobinuria
- small print cause of intravascular haemolysis
- rare
- acquired defect marrow stem cells
- defect in anchorage of surface proteins because of absence of glycosyl phosphatidyllinositol (GP)
- RBC rendered sensitive to lysis by complement
Define haemoglobinopathy
An inherited condition in which haemoglobin does not function properly as there are mutations in haemoglobin
