Haemaglobinopathies Flashcards
what is the structure of haemoglobin
tetramer made up of 2 alpha globin chains and 2 beta globin chains
there is one haem group attached to each globin chain = 4 haem groups in total
what are the major forms of haemoglobin
HbA (2 alpha, 2 beta chains)
HbA2 (2 alpha, 2 delta chains)
HbF (2 alpha and 2 gamma)
what form of haemoglobin is the most common
HbA
What chromosomes are alpha like genes on
chromosome 16
how many alpha genes are there per chromosome
2
i.e. 4 per cell
what chromosome are beta like genes on
chromosome 11
how many beta genes are there per chromosome
1
i.e. 2 per cell
does the expression of globin genes stay the same throughout life?
NO
changes during embryonic life + childhood
what are haemoglobinopathies
hereditary conditions affecting globin chain synthesis
how are haemoglobinopathies inherited
autosomal recessive
what are the two main groups of haemoglobinopathies
- Thalassaemias: decreased rate of globin chain synthesis
2. Structural haemoglobin variants: normal production of a structurally abnormal chain
what is thalassaemia
reduced globin chain synthesis resulting in impaired haemoglobin production
2 forms of thalassaemia
alpha thalassaemia – alpha chains affected
beta thalassaemia – beta chains affected
what type of anaemia is seen in thalassaemia
microcytic hypochromatic
what does wrong in thalassaemia
inadequate Hb production – microcytic hypo chromatic anaemia
Unbalanced accumulation of globin chains – ineffective erythropoiesis and haemolysis
what happens in alpha thalassaemia
mutations affecting alpha globin chain synthesis – reduced or absent synthesis of alpha chains
Results from a deletion of one or both alpha genes from chromosome 16
why does alpha thalassaemia present more severely
alpha chains are present in all forms of Hb
therefore HbA, HbA2 and HbF are all affected
what are the genotypes of alpha thalassaemia
Unaffected individuals have 4 normal alpha genes (aa/aa)
Alpha thalassaemia trait: one or 2 missing (-a/aa), (–/aa) or
(-a/-a)
HbH disease: only one alpha gene left (–/-a)
Hb Barts Hydrops fetalis: no functional genes (–/–)
features of alpha thalassaemia trait
usually (–/aa) or (-a/-a)
Asymptomatic
Microcytic hypochromatic red cells with mild anaemia
what can alpha thalassaemia trait be mistaken for and how can you tell the difference
iron deficiency anaemia (low ferritin)
in trait ferritin is normal, RBC count is high
what is HbH disease
severe form of alpha thalassaemia
only one alpha gene per cell |(–/-a)
chain production <30% of normal
blood results seen in HbH disease
anaemia with very low MCV and MCH (mean corpuscular haemoglobin)
why is it called HbH disease
excess beta chains form tetramers called HbH which cannot carry oxygen
red cell inclusions of HbH can be seen with special stains
symptoms of HbH disease
from mild anaemia to transfusion dependant
splenomegaly due to extramedullarly haematopoiesis
jaundice due to haemolysis and ineffective erythropoiesis
where is HbH disease most prevalent
South east Asia, Middle East and the mediterranean
treatment of severe HbH disease
splenectomy +/- transfusion
what is the most severe form of alpha thalassaemia
Hb Bart’s hydrops fetalis
what happens in Hb Bart’s hydrops fetalis syndrome
no alpha genes inherited from either parent (–/–)
minimal or no alpha chain production – HbA can’t be made
what form of Hb is the majority at birth in Hb Barts hypos fetalis syndrome
Hb Barts (y4) HbH(B4)
symptoms of Hb Barts Hydrops Fetalis
severe anaemia cardiac failure, oedema growth retardation severe hepatosplenomegaly skeletal and cardiovascular abnormalities most foetuses die in utero
what is beta thalassaemia
disorder of beta chain synthesis
reduced or absent beta chain production
only affects beta chains and so HbA (2 alpha, 2 beta) is the only form of Hb affected
what causes beta thalassaemia
usually a point mutation
what are the 3 forms of beta thalassaemia
beta thalassaemia trait
beta thalassaemia intermedia
beta thalassaemia major
what are the features of beta thalassaemia trait
asymptomatic
No/mild anaemia
low MCV/MCH
raised HbA2
features of beta thalassaemia intermedia
moderate severity requiring occasional transaction
features of beta thalassaemia major
severe, lifelong transfusion dependency
presentation of beta thalassaemia major
presents aged 6-24 months pallor, failure to thrive extra medullary haematopoiesis causing: - hepatosplenomegaly - skeletal changes - organ damage
lab features of beta thalassaemia major
severe anaemia
reticulocytosis
very low MCV/MCH
film: microcytosis, hypochromia, anisopoikilocytosis and target cells
complication of extramedullarly haematopoiesis
cord compression
management of beta thalassaemia major
regular transfusion programme
- to main Hb 95-105 g/l
- suppress ineffective erythropoiesis
- inhibit over-absorption of iron
main side effect of treatment of beta thalassaemia major
Iron overload from transfusion- main cause of mortality
consequences of iron overload
endocrine dysfunction: impaired growth/pubertal development, diabetes, osteoporosis
cardiac disease: arrhythmia/cardiomyopathy
Liver disease: cirrhosis, hepatocellular cancer
management of iron overload
desferrioxamine - iron chelating drug
how does desferrioxamine work
chelators bind to iron, complexes form and are excreted in urine/stool
pathophysiology behind iron overload
chronic anaemia drives increased iron absorption
what does iron overload make you more susceptible to
bacterial infections
what makes it hard to cross match blood in thalassaemia patients
formation of alloantibodies- formed against an antigen that is not present in their own blood
how is the diagnosis of thalassaemia made
Exclude iron deficiency
Blood film: hypochromia, target cells, anisopoikilocytosis
HPLC: raised HbA2 diagnostic of a beta thalassaemia trait (as there is no beta chains present in this form of Hb)
Genetic testing needed to see which form of alpha thalassaemia trait it is
pathophysiology of sickle cell disorders
point mutation in codon 6 of the beta globin gene that substitutes glutamine to valine
This alters the structure of the resulting Hb – HbS
HbS polymerises if exposed to low oxygen levels for a long period of time
This distorts the red cell, damaging the red cell membrane
what is the mutation in sickle cell disorders
codon 6 of the beta globin gene
what amino acid is changed in sickle cell disorders
glutamine to valine
what are the two forms of sickle cell disorders
sickle trait- HbAS
sickle cell anaemia - HbSS
features of sickle trait
one normal beta gene, one abnormal beta gene
asymptomatic
symptoms of sickle cell trait
few clinical features as HbS level is too low to polymerise
may sickle in severe hypoxia i.e. high altitude, under anaesthesia
features of sickle cell anaemia
two abnormal beta genes
autosomal recessive
HbS > 80% no HbA
what is a sickle crisis
episodes of tissue infarction due to vascular occlusion
symptoms of sickle cell crisis
Symptoms depend on site and severity:
Digits, bone marrow, lung, spleen, CNS often affected
pain may be extremely severe
Chronic haemolysis
Hyposplenism due to repeated splenic infarcts
what is sickle cell disease
heterozygosity for HbS and another beta chain mutation
e.g. sickle + beta thalassaemia
precipitants of a sickle cell crisis
hypoxia dehydration- makes HbS more likely to polymerise Infection Cold exposure stress/fatigue
treatment of sickle cell crisis
opiate analgesia hydration rest oxygen antibiotics if infection
in severe crisis (e.g. chest/neurological symptoms)- red cell exchange transfusion
how do you do a transfusion in a severe sickle crisis
venesection - transfuse and repeat
longterm effects of sickle cell anaemia
impaired growth risk of end organ damage: - pulmonary hypertension - renal disease - avascular necrosis - leg ulcers - stroke
long term treatment of sickle cell anaemia
splenectomy
folic acid supplementation
hydroxycarbamide
what would a patient need if they had a splenectomy
prophylactic penicillin
vaccination against pneumococcus, meningococcus, haemophilus
why do sickle cell anaemia patients need folic acid supplementation
increased RBC turnover causes increased demand
how does hydroxycarbamide work
reduces severity of disease by inducing HbF production
what does HPLC stand for and what does it do
high performance liquid chromatography: quantities haemoglobin present
what is raised HbA2 on HPLC diagnostic of
beta thalassaemia trait
