Inherited disorders of haemoglobin

Question 1

What is the main haemoglobin in adults?What is it made of?

Answer 1

Haemoglobin A2 alpha chains and 2 beta chains

Question 2

How many genes encode the alpha globin chain?How many genes encode the beta globin chain?Which chromosomes are they on?

Answer 2

2 genes on chromosome 16 encode the alpha globin chain1 gene on chromosme 11 encodes the the beta globin chain

Question 3

Why do haemoglobin disorders not present immediately in children?

Answer 3

Because neonates have a different variant of haemoglobin which is comprised of 2 alpha chains and 2 gamma chains. The change to ‘normal’ haemoglobin only occurs at 16 weeks.

Question 4

What is the difference between a qualitative and a quantitative haemoglobin disorder?

Answer 4

A qualitative disorder results from changes to the globin chain amino acid sequence, resulting in variant haemoglobins, e.g. sickle cell diseaseA quantitative disorder results froma complete or partial reduction of globin chain, e.g. thalassaemia

Question 5

What is the genetic basis for sickle cell disease?What do the terms HbSS and HbAS mean?

Answer 5

A genetic polymorphism results in substitution of the amino acid valine for glutamic acid at position 6 of the beta globin chain. S means sickle A means normal. HbSS, homozygotes- sickle cell disease * Both beta globin chains are abnormal- instead of making HbA, they make the variant haemoglobin HbS. HbAS. heterozygotes- sickle cell trait (carrier) * Only one of the beta globin genes is abnormal * Make both HbA and HbS

Question 6

What is the pathophysiology of SCD?

Answer 6

HbS has a propensity to polymerise when in the deoxyhaemoglobin state.Alters the structure of the red blood cells- appear like sickles on a blood film.Reduced deformability of red blood cells, resulting in veno-occlusion.Reduced life span of red cells because of haemolysis.

Question 7

Why do sufferers of sickle cell anaemia have a higher proportion of immature red cells?

Answer 7

Because the body reacts to the destruction of red blood cells by producing new ones but cannot keep up with demand. Therefore the bone marrow will kick out immature cells.

Question 8

What clinical features can shortened red cell lifespans produce?What potential downfalls can arise from a compensatory increase in red cell production?

Answer 8

Increased bilirubin, jaundice.Pigment gall stones.ReticulocytosisPotential for folate deficiency

Question 9

What is the acute presentation of SCD?

Answer 9

Painful vasocclusive crisesInfections * septicaemia, meningitis, UTI, osteomyelitis * Hyposplenism (functional asplenia/splenic atrophy), so at particular risk of pneumococcus, haemophilus and meingococcus (encapsulated organisms) * Acute chest syndrome * Stroke

Question 10

What are the management principles of sickle cell crises?

Answer 10

Analgesia

Fluids- oral preferred, careful fluid balance

Oxygen- monitor saturations

LMWH- increased risk of thromboembolic events

Question 11

What are the clinical features of acute sickle chest syndrome?How is it managed?

Answer 11

A form of acute lung injury distinct from pneumonia. Leading cause of death. High risk: inpatients with crisis, pregnancy, post-partum Tachypnoea, cough, chest pain, rib pain, hypoxia, fever Clinical or radiological evidence of consolidation, pulmonary infiltrates. Risk of recurrence O2, CPAP, ventilation + general support (fluids, physio) + transfusion

Question 12

What screening tools are used for sickle cell?

Answer 12

Children- Transcranial doppler to assess risk of strokeAdults- Echocardiography for pulmonary hypertension

Question 13

Why are sickle cell sufferers on hydroxycarbamide?

Answer 13

Hydroxycarbamide- pushing up production of HbF (2 alpha and 2 gamma). Can cause neutropoenia.

Question 14

What is the genetic basis and pathophysiology of alpha thalassaemia?

Answer 14

Reduction of alpha globin chain production * lack of HbA * relative excess of beta and gamma chains, form abnormal haemoglobins * B4= HbH * Y4= Hb Bart’s Autosomal recessive inheritance, various genetic defects Pathophysiology * Ineffective haematopoiesis and haemolysis due to unstable red cells cause anaemia.

Question 15

What are the genetic alpha compositions in: *

Normal *

Heterozygous a+ *

Homozygous a+ *

Heterozygous a0 *

Haemoglobin H disease *

Hb Barts hydrops

Answer 15

aa/aa

• a/aa
• a/-a

–/aa

–/-a

thal intermedia–/–

still birth

Question 16

What is the genetic basis for beta thalassaemia?

Answer 16

Reduction of B-chain globin chain production

B/B Normal

B/- Beta thalassaemia trait

• /- Homozygous beta thalassaemia major
• /B+ compound heterozygote

Beta thalassaemia intermedia

Question 17

What is the pathophysiology of beta thalassaemia?

Answer 17

Absent or severely reduced b chain productionRelative excess of alpha chainsExcess alpha chains are unstable and precipitate in red cell precursors, interfering with red cell maturationIneffective erythropoiesis and haemolysis lead to anaemia

Question 18

What is the presentation of beta thalassaemia major?

Answer 18

Healthy at birthProgressive anaemia as HbF reducesFailure to thriveCardiac failureExtramedullary heamopoiesisBony overgrowth especially of skullIdeally detected as part of antetnatal screening programme

Question 19

What are the requirements for blood transfusions?What are the hazards?

Answer 19

Starts around 6-9 monthsContinues 2-4 weekly for life (unless patients have bone marrow transplants)Reverses progressive anaemiaHazards of transfusion * Alloimmunisation * Haemolytic transfusion reactions * Transfusion associated infection * Iron overload

Question 20

What is iron overload? What is it associated with?

Answer 20

Major toxicity of chronic blood transfusion.Contributes to growth failure and cardiac/hepatic toxicity.Anterior pituitary iron deposition affects hypothalamo-pituitary axis * Hypogonadism * Hypoparathyroidism * Hypothyroidism Pancreatic damage

Question 21

How is cardiac disease managed in iron overload?

Answer 21

Associated with severe iron overloadWas universal by end of second decade prior to induction of iron chelation therapy, with deaths usually by the age of 15-20 years.Issues with sudden cardiac death and dysrhythmiaprevantable with iron chelation Assess cardiac iron using MRI t2

Question 22

What is desferrioxamine?

Answer 22

Subcutaneous infusions, 3-5 nights/week. Deferoxamine, sold under the brand name Desferal, is a medication that binds iron and aluminium. It is specifically used in iron overdose, hemochromatosis either due to multiple blood transfusions or an underlying genetic condition, and aluminium toxicity in people on dialysis.

Question 23

Who is bone marrow transplantation not offered to?

Answer 23

adults, it is only offered to children