0327 - Red Cell Disorders I

Question 1

What is anaemia?

Answer 1

A reduction in haemoglobin due to quantitative or qualitative impairment in red cell production (including those causing premature cell lysis).

Question 2

What are the clinical features of haemolytic anaemia?

Answer 2

Pallor
Jaundice
Splenomegaly
Gallstones (bilirubin)

Question 3

What are some DDX’s for haemolytic anaemia?

Answer 3

Thalassaemia
Sickle Cell Anaemia
Hereditary Spherocytosis

Question 4

What are the laboratory features of haemolytic anaemia?

RBC/Film, WBC, Platelets, Bilirubin, LDH, Haptoglobin

Answer 4

RBC changes - could be spherocytes, poikilocytes, polychromasia, reticulocytosis
WBC and platelets often normal
Raised bilirubin
Raised LDH (released by lysis)
Low haptoglobin (binds free Hb, so all taken up)

Question 5

What is the difference between a thalassaemia and a haemoglobinopathy?

Answer 5

Thalassaemia - imbalance in globin chains (e.g. beta thalassaemia)
Haemoglobinopathy - structural abnormality in the globin molecule due to point mutations (e.g. Sickle cell disease)

Question 6

What is the difference between foetal and adult Hb?

Answer 6

Foetal - alpha and gamma strands (2 of each)
Adult - Alpha and Beta strands (2 of each), with around 3% A2 (alpha and delta strands - 2 of each), which is increased in beta thalassaemia.

Question 7

Which chromosomes code for alpha and beta haemoglobins?

Answer 7

Alpha - Chromosome 16 (2 places, 4 sites total)

Beta - Chromosome 11 (1 place, 2 sites total)

Question 8

How does Hb change over foetal gestation?

Answer 8

Hb ramps up to 6 weeks, where around 50% will be alpha, most of rest gamma.
Gamma drops off rapidly at birth, with beta rising significantly from 36 weeks.

Question 9

How can you test for Haemoglobin qualities and haemoglobinopathies?

Answer 9

High Pressure Liquid Chromatography. Formerly used electrophoresis.
Can also do a DNA study if you know the change you’re looking for.

Question 10

Provide a brief overview of the pathophysiology of beta thalassaemia major.

Answer 10

Autosomal Recessive - Decreased or no synthesis of beta chain prevents formation of normal Hb tetramere.
Free alpha chains form unstable aggregates, leading to cell membrane damage, loss of K+, and impaired DNA synthesis.
This causes destruction of RBC precursors within marrow, and haemolysis in spleen, leading to anaemia.
Severe enough anaemia leads to extramedullary erythropoiesis (compensation), and skeletal abnormalities in children.
Also leads to excess absorption of iron, which, together with repeated blood transfusions, causes severe iron overload (can now be treated with chelation).

Question 11

What are the three main problems associated with beta thalassaemia major?

Answer 11

Ineffective erythropoisis
Anaemia
Iron overload leading to organ damage.

Question 12

What are the clinical features of beta thalassaemia major?

Answer 12

Severe anaemia
Ineffective and extramedullary erythro/haemopoisis
Enlarged liver and spleen
Expansion of flat bones, with spontaneous fractures
Iron overload (biggest problem, now treated with chelation)
Reduced growth, endocrinopathy, delayed puberty

Question 13

What are the laboratory features of beta thalassaemia major?

Blood film, Marrow, Hb HPLC

Answer 13

Anaemia
Hypochromic cells, target cells, Nucleated RBCs
Marrow - red cell hyperplasia, increased iron
Most Hb is HbF

Question 14

What is alpha thalassaemia? How can it vary in severity?

Answer 14

Genetic disease characterised by the deletion of any or all of the four normally present alpha-globin chains.
Defect in 1-2 genes - Hypochromic, microcytic blood film, no clinical significance except for genetic counselling.
Defect in 3 genes - HbH disease (tetramers of B-Hb), Thalassaemia intermedia
Defect in 4 genes - Hydrops foetalis.

Question 15

What is sickle cell anaemia?

Answer 15

Commonest severe structural Hb variant. A disease in which abnormal HbS polymerises when deoxygenated. This forms sickle-shaped cells, which live around 20 days, cannot easily travel through capillaries, and adhere to endothelium, causing infarctions (the main problem). Particularly get trapped in spleen.

Question 16

What is the pathophysiology of sickle cell disease?

Answer 16

Valine is substituted by glutamic acid in the 6th position of the beta globin chain, due to a single base pair change, converting it from HbA to HbS. When deoxygenated, HbS polymerises, causing RBCs to become a stiff sickle-shape, which can get trapped and slow or occlude blood flow.

Question 17

What are the clinical features of sickle cell anaemia?

Answer 17

Chronic haemolytic anaemia (jaundice, hyperbilirubinaemia, gallstones)
Vaso-occlusive crises, including pain and micro-infarctions (main problem).
Increased susceptibility to infections.

Question 18

What is hereditary spherocytosis (including pathophysiology and Mendelian inheritence)?

Answer 18

Disorder of the RBC membrane that renders cells spheroidal, less deformable, and vulnerable to splenic sequestration and destruction by macrophages. Believed to be caused by a deficiency of spectrin leading to loss of some cell membrane and spherification.
Autosomal dominant in ⅔ cases, but with unique mutations for each family. Onset at any age.

Question 19

What is the treatment for hereditary spherocytosis?

Answer 19

Often not required. Splenectomy in severe cases.
Cholecystectomy for stones.
Folic Acid (essential for erythropoiesis)

Question 20

What are the clinical features of hereditary spherocytosis?

Answer 20

Same as for all haemolytic anaemia
Pallor
Jaundice
Splenomegaly
Gallstones
Leg ulcers
Aplastic Crises.

Question 21

How do you diagnose hereditary spherocytosis?

Answer 21

Anaemia with spherocytosis
Blood Film (small, dark cells)
Flow cytometry for specific membrane defects

Question 22

What is G6PD Deficiency?

Answer 22

A genetic deficiency in G6PD leaves the RBC unable to reduce NADP to NADPH, and vulnerable to oxidative stress and premature lysis due to lower levels of reduced glutathione (important antioxidant). Particularly vulnerable to trigger exposures (foods, drugs etc) that may decompensate the G6PD.
X-linked.