Haematology 2

Question 1

genetics of sickle cell disease

Answer 1

HbS is a result of a point mutation in codon 6 of the Beta-globin chain

Change in the amino acid from glutamine to valine

Question 2

What are the different forms of Sickle cell disease

Answer 2

1. Sickle cell anaemia (HbSS): homozygous for HbS (no HbA)
2. HbSC disease: also no HbA (HbC is from another point mutation in the beta globin)
3. Sickle beta-thalassaemia: HbS from one parent, Beta-thalassaemia from the other. Similar to sickle cell anaemia
4. Sickle train: heterozygous. Carriers. Asymptomatic

Question 3

What is the effect of the HbS mutation?

Answer 3

HbS polymerises within RBCs forming rigid tubular spiral bodies - deform into sickle shaped RBC

Reduced lifespan.
May be trapped in microcirculation - vaso-occlusion and therefore ischaemia to organ/bone. Exacerbated by low oxygen tension, dehydration, cold

Question 4

General symptoms and signs of sickle cell disease (risks)

Answer 4

Moderate anaemia (Hb 6-10)
with clinically detectable jaundice from chronic haemolysis

Increased risk of infection from encapsulated organisms: Pneumococci and HiB.
Osteomyelitis from Salmonella

This is due to hyposplenism secondary to chronic sickling and microinfarction

Splenomegaly - common in young children

Question 5

Acute risks in sickle cell disease

Answer 5

Vaso-occlusive crises - PAINFUL

Hand-foot syndrome in late infancy (swelling and pain of fingers and/or feet)

Bones and limbs most common sites. Acute chest syndrome is the most serious type.
These crises may be precipitated by exposure to cold, hypoxia, dehydration, excessive exercise/stress or infection

Acute anaemia:
Haemolytic crises
Aplastic crises (parvovirus causes complete temporary cessation of red blood cell production)
Sequestration crises - Sudden splenic or hepatic enlargement, abdo pain and circulatory collapse from accumulation of sickled cells in spleen

Priapism - needs to be treated promptly with exchange infusion, as it may lead to fibrosis of corpora cavernosa and subsequent erectile impotence

Question 6

Long-term problems of sickle cell disease

Answer 6

Short stature and delayed puberty
Stroke and cognitive problems (1 in 10 have stroke, 2 in 10 have subtle damage)

Cardiac enlargement from chronic anaemia
Heart failure from uncorrected anaemia
Renal dysfunction
Pigment gallstones
Adenotonsillar hypertrophy - if it leads to nocturnal hypoxaemia it may cause vaso-occlusive crises

Question 7

Screening for Sickle cell disease?

Answer 7

Guthrie test (heel-prick) in first weeks of life

Early diagnosis allows penicillin prophylaxis instead of awaiting potentially severe infection

Prenatal diagnosis: Chorionic villus sampling at the end of first trimester if parents wish to have it

Question 8

Prognosis of sickle cell disease

Answer 8

Cause of premature death due to severe complications

50% of patients with HbSS die before the age of 40yrs

Mortality rate in childhood is 3% - usually from bacterial infection

Question 9

Prophylaxis for sickle cell disease

Answer 9

Increased susceptibility to encapsulated organisms (HiB, pneumococcus, meningococcus)

Daily oral penicillin throughout childhood

Once-daily oral folic acid because of increased demand for folic acid due to chronic haemolytic anaemia

Avoid exposure to cold, excessive stress/exercise, dehydration or hypoxia (eg drinks before sport, dress warmly eg. after swimming or when in winter)

Question 10

Treatment of painful crises in sickle cell disease

Answer 10

Oral or IV analgesia
Good hydration (oral or iv)
Oxygen if sats low

Exchange transfusion is indicated for acute chest syndrome, stroke and priapism

Question 11

Treatment of Chronic problems in sickle cell disease

Answer 11

Hydroxyurea (increases HbF) may be useful for children with recurrent hospital admissions for painful vaso-oclusive crises

Monitoring for side effects is required (especially WCC suppression)

1-5% are severely affected (stroke or unresponsive to hydroxyurea): Bone marrow transplant is the only cure. ONly with an HLA-identical sibling as a donor.. 90% cure rate, 5% mortality

Question 12

Ethnic prevalence of beta thalassaemias

Answer 12

Occur most often in people from the Indian subcontinent

Question 13

2 types of beta thalassaemia

Answer 13

Both have severe reduction in the production of beta-globin (and thus HbA)

Beta-thalassaemia major is the most severe form of the disease. HbA cannot be produced

Beta-thalassaemia intermedia is milder and variable severity (small amount of HbA and/or large amount of HbF could be produced)

Question 14

Clinical features of beta-thalassaemia

Answer 14

Severe anaemia (transfusion dependant) - from 3-6 months with jaundice

Failure to thrive/growth failure

Extramedullary haemopoiesis (prevented by regular blood transfusions) - hepatosplenomegaly and bone marrow expansion

Pallor
Jaundice
Bossing of skull
Maxillary overgrowth
Splenomegaly
Hepatomegaly

Question 15

Prenatal diagnosis of beta-thalassaemia

Answer 15

For heterozygous parents:
1 in 4 risk

DNA analysis of a chorionic villus sample
Genetic counselling to help parents make an informed decision about whether or not to continue pregnancy

Question 16

management of beta-thalassaemia

Answer 16

Fatal without regular blood transfusions

Lifelong monthly transfusion of RBC to maintain Hb above 10g/dl (for growth)

However, repeated blood transfusions cause chronic iron overload, which causes cardiac failure, liver cirrhosis, DM, infertility and growth failure.
Iron chelation with Sc desferrioxamine or oral iron chelator drug is needed from 2-3 yrs of age

Good compliance means they can live into 40s.
It is difficult, however and those who cannot have a high mortality in early adulthood from iron overload

Question 17

Complications of multiple transfusions

Answer 17

Iron deposition leading to:
Cardiomyopathy
Liver cirrhosis
Diabetes
Delayed growth and sexual maturation (pituitary)
Hyperpigmentation (skin)

Antibody formation in 10%:
Allo-antibodies to transfused RBCs, which makes finding compatible blood very difficult

Venous access is common problem.

Question 18

Definitive treatment of beta-thalassaemia

Answer 18

Majr bone marrow transplantation

Reserved for children with an HLA identical sibling (95% chance of success) - 5% mortality

Question 19

Lab values in beta thalassaemia trait

Answer 19

Heterozygotes are usually asymptomatic - but RBC are hypochromic and microcytic

Mild anaemia: reduction in MCV

Raised HbA2
Sometimes there is raised HbF

To distinguish from IDA, measure serum ferritin (low in IDA but not in beta-thalassaemia)

Question 20

How does the most severe form of alpha-thalassaemia (major) usually present? Management?

Answer 20

Deletion of all four alpha-globin genes

Mid-trimester with fetal hydrops (oedema and ascites) from fetal anaemia - always fatal in utero or within hours of delivery.

Only way to survive is monthly intra-uterine transfusions followed by lifelong transfusions

Question 21

Diagnosis of alpha thalassaemia

Answer 21

Hb electrophoresis
or
Hb high-performance liquid chromatography

Question 22

Symptoms of non-major alpha thalassaemia

Answer 22

3 alpha-globin gene deletions - mild-moderate anaemia. Sometimes transfusions required

2 deletions - usually asymptomatic and mild/no anaemia