HAEMOGLOBINOPATHIES Flashcards
what is the structure of HbA
2 alpha globin like chains
2 beta globin like chains
one haem
what is the structure of HbA2
2 alpha globin
2 delta globin
what its he structure of HbF
2 alpha globin
2 gamma globin
which type of Hb is present in the greatest quantities
HbA
how many alpha globin producing genes are there present in each cell
4
on which chromosome are the alpha globin genes located
chromosome 16
how many beta globin producing genes are there in each cell
2
on which chromosome are the beta globin genes located
chromosome 11
how are the different genes for Hb production arranged on the chromosome
they are arranged in order of expression
eg embryonic Hb, then fetal, then adult
what are the two main groups of haemoglobinopathies
thalassaemias
structural Hb variants
how do thalassaemias affect Hb production
decreased rate of normal globin chain synthesis
how do structural Hb variants affect Hb production
normal production of structurally abnormal globin chains
what type of anaemia does Thalassaemia cause
microcytic hypochromic anaemia due to inadequate Hb production
what are the complications of unbalanced accumulation of globin chains in Thalassaemia
ineffective erythropoiesis and haemolysis
where are thalassaemias most commonly found geographically
Mediterranean coast, Southern Asia, North African coast, subsaharan Africa
which types of Hb are affected by alpha thal
HbA
HbA2
HbF
what is the normal genotype of individuals unaffected by alpha thatl
(aa/aa)
how do mutations affect the genotype of patients with alpha thal
a+ (-a) (deletion of one alpha gene)
a0 (–) (deletion of both alpha genes)
what are the potential genotypes in alpha thal trait
one or two genes missing (out of four)
a+/a (-a/aa)
a0/a (–/aa)
a+/a+ (-a/-a)
what is HbH disease (and genotype)
only one alpha gene is left
a0/a+ (–/-a)
what is Hb Parts hydrops fetalis (and genotype)
no functional alpha genes
a0/a0 (–/–)
what is the presentation of alpha tha trait
normal asymptomatic
microcytic, hypo chromic red cells with mild anaemia
how can you distinguish alpha thal trait from iron deficiency anaemia
ferritin will be normal
how does HbH disease present
anaemia with very low MCV and MCH
what are HbH molecules and why are they formed
tetramers of excess beta chains which are unable to carry oxygen
produced in severe alpha that due to lack of alpha chains
what are clinical features of HbH disease
moderate anaemia to transfusion dependent
splenomegaly due to extramdeullary haematopoiesis
jaundice
in which populations is HbH disease most prevalent
SE asia
Middle East
mediterranean
what is the management of severe HbH disease
splenectomy +/- transfusion
what is the severest form of alpha thal
Hb barts hydrops fetalis
which types of Hb make up the majority of Hb at birth in hydrops fetalis
Hb barts (gamma tetramer) and HbH (beta tetramer)
why is there increased production of Hb parts and HbH in hydrops fetalis
there are no alpha genes inherited from either parent so alpha globin can’t be made
clinical features of hydrops fetalis
severe anaemia cardiac failure growth retardation severe hepatosplenomegaly skeletal and cardiovascular abnormalities
which types of Hb are affected in beta thal
HbA (a2b2)
what is the genotype of beta thal trait
B+/B or B0/B
what are the clinical features of beta thal trait
asymptomatic
no/mild anaemia
low MCV/MCH
raised HbA2
what is the genotype of beta thal intermedia
B+/B+ or B0/B+
what are the clinical features of beta thal intermedia
moderate severity anaemia
what is the genotype of beta thal major
B0/B0
at what age does beta thal major present and why
presents at 6-24 months
HbF (a2g2) levels fall and the circulation begins to depend on HbA (a2b2) which can’t be produced
how does beta thal major present
pallor failure to thrive hepatosplenomegaly skeletal changes organ damage
what will Hb analysis show in beta thal major
mainly HbF
minimal HbA
what are complications of extramedullary haemotopiesis in beta thal major
frontal bossing
cord compression
how is beta thal major managed
regular transfusions to maintain Hb at 95-105 g/L
what is the purpose of regular transfusions in beta thal major, beyond correcting the Hb concentration
suppresses ineffective erythropoiesis
inhibits over-absorption of iron
what are consequences of iron overload
impaired growth and pubertal development diabetes osteoporosis cardiomypoathy arrhythmias cirrhosis hepatocellular cancer
how is iron overload managed in beta thal major
iron chelating drugs
how is iron bound to chelators excreted
in urine or stool
what are complications of transfusions in beta thal major
viral infection (HIV, Hep)
alloantibodies
transfusion reactions
why is there an increased risk of sepsis in an iron overloaded patient
bacteria like iron
what type of mutations leads to production of Bs in sickling disorders
point mutation in codon 6 of the beta globin genes that substitutes glutamine to valine
how is the structure of Hb altered in sickling disorders
HbA (a2B2) becomes HbS (a2Bs2)
how is HbS less effective than HbA
it polymerises if exposed to low oxygen levels for a prolonged period of time
this distorts the red cell and damages the membrane
what is the genotype in sickle cell trait
one normal gene, one abnormal
B/Bs
what are the clinical features of sickle cell trait (HbAS)
few features are HbS levels are too low to polymerise
may sickle in severe hypoxia eg high altitude, under anaesthesia
what features are present on a blood film in a patient with HbAS (sickle cell trait)
normal blood film
what is the genotype in sickle cell anaemia (HbSS)
two abnormal genes (Bs/Bs)
what types of Hb are present in HbSS
> 80% HbS
no HbA
clinical features of HbSS
episodes of tissue infarction due to vascular occlusion (sickle crisis)
chronic haemolysis
sequestration of sickled RBCs in liver and spleen
hyposlenism due to repeated infarcts
where are common sites of sickle crisis
digits
bone marrow
lung spleen
CNS
what is sickle cell disease cf sickle cell anaemia
presence of HbS mutation in the presence of another beta chain mutation
eg HbS/beta thal
what are triggers for sickle crisis
hypoxia dehydration infection cold exposure stress/fatigue
how are painful sickle crises treated
opiate analgesia hydration rest oxygen antibiotics if evidence of infection red cell exchange transfusion in severe crisis (eg chest crisis or stroke)
what is red cell exchange transfusion and how does it improve symptoms in HbSS
combination of venesection followed by transfusion
decreases concentration of HbS and improves tissue perfusion
what are long term effects of sickle cell anaemia
impaired growth
risk of end organ damage
what are examples of end organ damage in sickle cell anaemia
pulmonary HTN renal disease avascular necrosis leg ulcers stroke
what complication does hyposplenism cause and how is it managed
increased risk of infection
- prophylactic penicillin
- vaccination against pneumococcus, meningococcus, haemophilia
long term management of sickle cell anaemia
folic acid supplementation (increased RBC turnover)
hydroxycarbamide (induces HbF production)
regular transfusion to prevent stroke
how to investigate Hbopathy
FBC (Hb, red cell indices)
blood film
ethnic origin
high performance liquid chromatography or gel electrophoresis to quantify Hb present
presence of HbS is indicative of what type go Hbopathy
sickling disease
raised HbA2 is diagnostic of…
beta thal trait
