Haemoglobinopathies Flashcards by Joanne McEwan

structure of haemoglobin?

tetramer made of 2 alpha globin like chains and 2 beta globin like chains
one haem group attached to each globin chain

How well did you know this?

Not at all

Perfectly

what do globin chains do?

keep haem soluble and protect haem from oxidation

How well did you know this?

Not at all

Perfectly

what are the major forms of Hb?

HbA (2 alpha chains and 2 beta chains)
HbA2 (2 alpha and 2 delta chains)
HbF (2 alpha and 2 gamma chains)

How well did you know this?

Not at all

Perfectly

which Hb is the major form present in adults?

HbA = 97%
HbA2 = 2.5%
HbF = 0-0.5%

How well did you know this?

Not at all

Perfectly

genetic control of globin chain production?

alpha like genes = chromosome 16 (2 alpha genes per chromosome, 4 per cell)
beta-like genes are on chromosome 11 (one beta gene per chromosome, 2 per cell)
expression of globin genes changes during embryonic life and childhood

How well did you know this?

Not at all

Perfectly

when does amount of Hb reach adult levels? clinical implication of this?

6-12 months of age

beta chain problems wont manifest until then

How well did you know this?

Not at all

Perfectly

what are haemoglobinopathies?

hereditary conditions affecting globin chain synthesis

mutations behave as autosomal recessive disorders

How well did you know this?

Not at all

Perfectly

2 main groups of haemoglobinopathies?

thalassaemias (decreased rate of globin chain synthesis)

structural haemoglobin variants (normal production of abnormal globin chain - cariant Hb such as HbS)

How well did you know this?

Not at all

Perfectly

what is thalassaemia and what are the types?

reduced globin chain synthesis resulting in impaired haemoglobin production

alpha thalassaemia (alpha chains affected)
beta thalassaemia (beta chains affected)

How well did you know this?

Not at all

Perfectly

consequences of thalassaemia?

inadequate Hb production leading to microcytic hypochromatic anaemia
if severe can lead to: unbalanced accumulation of globin chains (toxic to cell), haemolysis and ineffective erythropoiesis

How well did you know this?

Not at all

Perfectly

where is thalassaemia most common?

malaria endemic areas

How well did you know this?

Not at all

Perfectly

how does alpha thalassaemia occur?

depletion of one alpha or both alpha genes from chromosome 16
results in reduced (alpha+) or absent (alpha0) alpha chain synthesis from that chromosome
all types of Hb are affected as all types have alpha chains

How well did you know this?

Not at all

Perfectly

classifications of alpha thalassaemia?

based on number of alpha genes
unaffected = 4 normal alpha genes
alpha thalassaemia trait = 1 or 2 alpha genes missing
HbH disease = only one alpha gene left
Hb Barts hydrops fetalis = no functional alpha genes

How well did you know this?

Not at all

Perfectly

describe alpha thalassaemia trait?

1 or 2 alpha genes missing
asymptomatic carrier
no treatment needed
causes microcytic hypochromatic red cells with mild anaemia
low iron but normal ferritin

How well did you know this?

Not at all

Perfectly

what is HbH disease?

more severe form of alpha thalassaemia with only 1 working alpha gene per cell
anaemia with very low MCV and MCH

How well did you know this?

Not at all

Perfectly

how is HbH inherited?

…

How well did you know this?

Not at all

Perfectly

what causes HbH disease?

excess beta chains form tetramers (beta4) called HbH

red cell inclusions of HbH can be seen with special stains

How well did you know this?

Not at all

Perfectly

how might HbH present?

jaundice

splenomegaly

How well did you know this?

Not at all

Perfectly

what is Hb Barts Hydrops Foetalis syndrome?

most severe form of alpha thalassaemia
no alpha genes inherited from either parent
minimal/no alpha chain production (therefore HbF and HbA cant be made)
no alpha chains to bind to so tetramers of Hb barts (gamma4) and HbH (beta4) produced

How well did you know this?

Not at all

Perfectly

clinical features of Hb Barts Hydrops Foetalis syndrome?

profound anaemia
cardiac failure
growth retardation
severe hepatosplenomegaly 
skeletal and cardio abnormalities 
almost all die in utero

How well did you know this?

Not at all

Perfectly

blood film in Hb barts hydrops foetalis syndrome?

numerous nucleated RBCs in peripheral blood

How well did you know this?

Not at all

Perfectly

what causes beta thalassaemia?

disorder of beta chain synthesis usually caused by point mutations
reduced (Beta+) or absent (Beta0) beta chain production depending on mutation
only beta chains affected so only HbA affected

How well did you know this?

Not at all

Perfectly

classification of beta thalassaemia?

based on clinical severity
beta thalassaemia trait
beta thalassaemia intermedia
beta thalassaemia major

what is beta thalassaemia trait?

Beta+/beta or beta0/beta

asymptomatic, no/mild anaemia, low MCV/MCH, raised HbA2 is diagnostic

what is beta thalassaemia intermedia?

beta+/beta+ or Beta0/beta+ | moderate severity requiring occasional transfusion (similar phenotype to HbH disease)

what is beta thalassaemia major?

beta0/beta0 | severe, lifelong transfusion dependency

clinical features of beta thalassaemia major?

presents aged 6-24 months (as HbF falls) pallor and failure to thrive extramedullary haematopoiesis causing hepatosplenomegaly, skeletal changes and organ damage

Hb analysis in beta thalassaemia major?

mainly HbF | no HbA

complications of extramedullary haematopoiesis?

cord compression

how is beta thalassaemia major managed?

regular transfusion programme to maintain Hb at 95-105g/L (suppresses ineffective erythropoiesis, inhibits over-absorption of iron) bone marrow transplant may be an option if carried out before complications develop

main cause of mortality in treated beta thalassaemia major?

iron overload

conseqences of iron overload?

``` endocrine dysfunction (impaired growth and puberty development, diabetes, osteoporosis) cardiac disease (cardiomyopathy, arrhythmias) liver disease (cirrhosis, hepatocellular cancer) ```

how is iron overload managed?

cant do venesection as already anaemic | iron chelating drugs (e.g desferrioxamine) bind to iron which is then excreted

why does iron overload occur in treatment of beta thalassaemia major?

250mg of iron per unit of packed red cells | chronic anaemia drives increased iron absorption so a lot of the iron is absorbed

other complications of transfusion?

viral infection alloantibodies (hard to crossmatch) transfusion reactions increased risk of sepsis (bacteria like iron)

pathophysiology of sickle cell disease?

point mutation in codon 6 of the beta globin gene that substitutes glutamine to valine producing betaS this alters the structure of the resulting Hb > HbS HbS polymerises if exposed to low oxygen levels for a prolonged period polymerised HbS distorts the RBC, damaging the RBC membrane

describe sickle cell trait

one normal, one abnormal beta gene (beta/betaS) asymptomatic carrier state with few clinical features as HbS level is too low to polymerise can happen in severe hypoxia (e.g altitude) normal blood film

Hb components in sickle cell trait?

mainly HbA (<50% HbS)

describe sickle cell anaemia?

two abnormal beta genes (betaS/betaS) | episodes of tissue infarction due to vascular occlusion (sickle crisis)

clinical features of sickle cell anaemia?

symptoms depend in site and severity of infarction in sickle crisus pain may be severely severe chronic haemolysis (short RBC lifespan) sequestration of sickled RBCs in liver and spleen hyposplenism due to repeated splenic infarcts

other sickling disorders (sickle cell disease)

compound heterozygosity for HbS and another beta chain mutation, e.g - HbS/Beta thalassaemia - HbSC disease (milder but increased risk of thrombosis)

what is sickle crisis?

sickle vaso-occlusion resulting in tissue ischaemia and pain

what can precipitate a sickle crisis?

``` hypoxia dehydration infection cold exposure stress/fatigue ```

how is a sickle crisis managed?

``` opiate analgesia hydration rest oxygen antibiotics if infection present red cell exchange transfusion (alternating venesection and transfusion) in severe crisis (e.g lung crisis or stroke) ```

how are sickle disorders managed long term?

hyposplenism (reduce risk of infection) via prophylactic penicillin and pneumococcus/meningococcus/haemophilus vaccination folic acid supplementation (increased RBC turnover so increased demand) hydroxycarbamide can reduce severity of disease by inducing HbF production regular transfusion in selected cases

how is haemoglobinopathy diagnosed?

bloods (FBC, Hb, RBCs) blood film ethnic origin high performance liquid chromatography (HPLC) or electrophoresis to quantify haemoglobins present

what does HPLC show in haemoglobinopathy?

``` abnormal haemoglobins (e.g HbS) raised HbA2 = diagnostic of beta thalassaemia trait ```

HPLC in normal patient?

HbA >80% HbF <1% HbA2 1.5-3.5%

commonest monogenic disorders worldwide?

haemoglobinopathies

inheritance of haemoglobinopathies?

AR | carriers unaffected

general definition of thalassaemias?

decreased rate of globin chain synthesis

when should thalassaemia be suspected?

microcytic hypochromic anaemia with normal ferritin

how is beta thalassaemia trait diagnosed?

raised HbA2

main structural haemoglobin problem?

sickle cell anaemia

what causes sickle cell anaemia?

point specific mutation in beta globin gene | causes HbS to polymerise and distort RBC shape and cause vaso-occlusion

why is lifelong penicillin and vaccinations needed in sickle cell anaemia?

hyposplenism