Haemoglobinopathies Flashcards by Veronica Haughey

What is haemoglobin?

Tetramer made up of 2 alpha-like globin and 2 beta-like globin chains

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How many haem groups attach to each globin chain?

One haem group per chain = 4 per haemoglobin molecule

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What are the major forms of haemoglobin?

HbA = major form present in adults, 2 alpha and 2 beta chains 
HbA2 = 2 alpha and 2 delta chains 
HbF = 2 alpha and 2 gamma chains

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Where are alpha like genes located?

Chromosome 16 = two alpha genes per chromosome so 4 per cell

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Where are beta like genes located?

Chromosome 11 = one beta gene per chromosome so 2 per cell

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Is the expression of globin genes constant throughout life?

No = changes during embryonic life and childhood

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What are haemoglobinopathies?

Autosomal recessive hereditary conditions affecting globin chain synthesis

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What are the two main groups of haemoglobinopathies?

Thalassaemias and structural haemoglobin variants

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What occurs in structural haemoglobin variants?

Normal production of abnormal globin chain causing variant haemoglobin

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Are haemoglobinopathies common?

Relatively = most common monogenic disorders and major cause of morbidity worldwide

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What occurs in thalassaemias?

Reduced globin chain synthesis resulting in impaired haemoglobin production

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What are the type of thalassaemias?

Alpha = affects alpha chains
Beta = affects beta chains

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What is the consequence of thalassaemias?

Inadequate Hb production causing microcytic hypochromatic anaemia

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What can occur if thalassaemias are severe?

Unbalanced accumulation of globin chain

Haemolysis and ineffective erythropoiesis

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What areas are thalassaemias more common in?

Areas with endemic malaria

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How many alpha genes do unaffected alpha thalassaemia sufferers have?

4 normal alpha genes

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What causes alpha thalassaemia?

Deletion of one a+ or both a0 alpha genes from chromosome 16 = causes reduced a+ or absent a0 alpha chain synthesis from that gene

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What types of haemoglobin can be affected by alpha thalassaemia?

HbA, HbA2 and HbF

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How is alpha thalassaemia classified?

By the number of alpha genes

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What are the different classes of alpha thalassaemia?

Unaffected = 4 normal alpha genes
Alpha thalassaemia trait = one or two alpha genes absent
HbH disease = only one alpha gene left
Hb Barts hydrops foetalis = no functional alpha genes

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What kind of state is alpha thalassaemia state?

Asymptomatic thalassaemia trait = no treatment needed

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What are the features of alpha thalassaemia trait?

Microcytic and hypochromatic red cells with mild anaemia

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How is alpha thalassaemia distinguished from iron deficiency?

Ferritin is normal in alpha thalassaemia

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What is HbH disease?

More severe form of alpha thalassaemia = only one working alpha gene per cell

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What are the features of HbH disease?

Anaemia with very low MCV and MCH Excess beta chains form tetramers called HbH Causes jaundice and splenomegaly

What can be seen on stains of patients with HbH disease?

Red cell inclusions of HbH can be seen with special stains

Where is HbH disease common?

SE Asia

How can HbH disease be treated?

May need transfusion

What is Hb Barts hydrops foetalis?

Severest form of alpha thalassaemia = no alpha genes inherited from either parent

What are the consequences of Hb Barts hydrops foetalis?

Minimal or no alpha chain production so HbF and HbA can't be made = tetramers Hb Barts and HbH produced as no alpha chains to bind

Why is there antenatal screening for Hb Barts hydrops foetalis when both parents are from SE Asia?

Possible risk of developing disease as a0 thalassaemia trait is prevalent in this area

What are the features of Hb Barts hydrops foetalis?

Profound anaemia, cardiac failure, growth retardation, severe hepatosplenomegaly, skeletal and CV abnormalities

What is the prognosis of Hb Barts hydrops foetalis?

Poor = most die in utero

What kind of mutations tend to cause beta thalassaemias?

Point mutations = causes reduced (b+) or absent (b0) beta chain production depending on mutation

What type of haemoglobin is affected by beta thalassaemia?

HbA

How are beta thalassaemias classed?

By severity

What are the different classes of beta thalassaemia?

Beta thalassaemia trait = b+/b or b0/b Beta thalassaemia intermedia = b+/b+ or b+/b0 Beta thalassaemia major = b0/b0

What are the severity of the different beta thalassaemias?

Beta thalassaemia trait = asymptomatic, no/mild anaemia Beta thalassaemia intermedia = moderate severity Beta thalassaemia major = severe

What are the features of beta thalassaemia trait?

Low MCV and MCH | Raised HbA2 is diagnostic

What types of beta thalassaemia need transfusion?

Beta thalassaemia intermedia = may need occasional transfusion Beta thalassaemia major = lifelong transfusion dependency

When does beta thalassaemia major present?

Age 6-24 months = presents as Hbf falls

How does beta thalassaemia major present?

Pallor and failure to thrive

What occurs in beta thalassaemia major?

Extramedullary haematopoiesis = causes hepatosplenomegaly, skeletal changes, organ damage and spinal compression

What does haemoglobin analysis of beta thalassaemia major show?

Mainly HbF and no HbA

How is beta thalassaemia major treated?

Regular transfusions to maintain Hb at 95-105g/l | Bone marrow transfusion = only if carried out before complications develop

What are the benefits of transfusion in beta thalassaemia major?

Suppresses ineffective erythropoiesis Inhibits over-absorption of iron Allows for normal growth and development

What is a potential complication of transfusions to treat beta thalassaemia major?

Iron overload

What are the consequences of iron overload?

Endocrine dysfunction = impaired growth and pubertal development, diabetes, osteoporosis Cardiac disease = cardiomyopathy, arrhythmias Liver disease = cirrhosis, hepatocellular cancer

How much iron is there per unit of packed red cells?

250mg

What affect does chronic anaemia have on iron metabolism?

Drives increased iron absorption

Why is venesection not feasible as a treatment for iron overload?

Patient already anaemic

How is iron overload treated?

Iron chelating drugs (e.g desferrioxamine) = bind to iron which is then excreted

What are some complications of iron overload related to transfusion?

Viral infection (HIV, Hep B/C), alloantibodies, transfusion reactions

Why are patients with iron overload more at risk of infections?

Bacteria like iron

What causes sicking disorders?

Point mutations in codon 6 of beta globin gene that substitutes glutamine to valine producing bS

What effect does the production of bS have on haemoglobin?

Alters the structure causing the formation of HbS

What happens to HbS when it is exposed to low oxygen levels for a prolonged period?

HbS polymerises distorting the red cell and damaging the cell membrane

What causes sickle cell trait?

One normal and one abnormal b gene

What are the features of sickle cell trait?

Asymptomatic carrier state = few clinical features as HbS level too low to polymerise Normal blood film = mainly HbA with <50% HbS

What causes sickle cell anaemia?

Two abnormal b genes

What effect does sickle cell anaemia have on red cells?

HbS >80% with no HbA | Chronic haemolysis causes shortened red cell lifespan

Why does hyposlenism occur in sickle cell anaemia?

Sickled red cells sequestered in liver and spleen causing repeated splenic infarcts

What are the episodes of tissue infarction due to vascular occlusion causing severe pain?

Sickle crisis

What causes sickle cell disease?

Compound heterozygosity for HbS and another b chain mutation like beta thalassaemia or HbSC disease

What are the features of HbSC disease?

Milder than sickle cell disease but increased risk of thrombosis

What causes sickle crisis?

Sickle vaso-occlusion causing tissue ischaemia and pain

What are the precipitants of sickle crisis?

Hypoxia, dehydration, infection, cold exposure, stress/fatigue

How is sickle crisis treated?

Opiate analgesia and hydration plus rest and oxygen Antibiotics if evidence of infection Red cell exchange transfusion in severe crisis

What is the long term management of sickle cell disease?

Prophylactic penicillin and vaccination Folic acid supplementation Hydroxycarbamide Regular transfusion in some to prevent stroke

Why do patients with sickle cell disease need prophylactic antibiotics?

To reduce risk of infection due to hyposplenism | Vaccinate against pneumococcus, meningococcus and haemophilus

Why do sickle cell patients need folic acid supplementation?

Increased cell turnover so increased demand

How does hydroxycarbamide reduce sickle cell disease severity?

Induces HbF production

How are haemoglobinopathies diagnosed?

FBC = Hb, red cell indices Blood film and ethnic origin High performance liquid chromatography or electrophoresis = identifies abnormal haemoglobins

What would high performance liquid chromatography of beta thalassaemia trait show?

Raised HbA2 is diagnostic

How are haemoglobinopathies screened for antenatally?

Family origin questionnaire and FBC | Further testing if from high risk area or abnormal red cell indices