Haemoglobin Anaemia And Haemoglobinopathies

Question 1

Give a an overview of what can lead to anaemia

Answer 1

 Lack of iron leads to anaemia
◦ Iron deficiency
◦ Anaemia of chronic disease (functional lack of iron)
 Deficiency in building blocks for DNA synthesis
lead to anaemia
◦ Vit B12
◦ Folate
 Mutations in the genes that encode the globin
proteins can lead to anaemia
◦ Thalassaemia
◦ Sickle cell disease

Question 2

How can anaemia result from problems with Hb synthesis?

Answer 2

Thalassaemia: reduced rate of synthesis of normal α- OR ß- globin chains (the α- and ß- thalassaemias)
Sickle cell disease: synthesis of an abnormal haemoglobin

Question 3

What is thalassaemia

Answer 3

 Heterogeneous group of genetic disorders with varied expression
worldwide – prevalence in S Asian, Mediterranean, Middle East (beta) and Far East (alpha)
 Importance in UK practice to be aware of ethnicity of your individual
patients and patient population (eg for prenatal counselling)

Question 4

What are the problems with Hb and RBCs in thalassaemia?

Answer 4

 Low level of intracellular haemoglobin accounts for hypochromic
microcytic red cells
 The relative excess of the other globin chain (eg insoluble aggregates
of alpha chains in ß-thal) contributes to the defective nature of the
red cell
 Most of the maturing erythroblasts are destroyed within the bone
marrow and there is excessive destruction of mature red cells in the
spleen
 So… as well as defective Hb production this is a form of haemolytic
anaemia also as the red cells are destroyed

Question 5

What are teh different states in alpha thalassaemia?

Answer 5

Silent carrier state
○ Deletion of a single α-globin gene.
○ It is asymptomatic, without anaemia.
- if 2 people with single alphas deletion have a child the child may have thalassaemia

α-Thalassemia trait
○ Deletion of two α-globin genes.
○ It may affect both genes of one chromosome or one gene of each chromosome
○ There is minimal or no anaemia and no physical signs; clinical findings are identical to
those of β-thalassemia minor (microcytosis and hypochromia).

Hemoglobin H (HbH) disease
○ Deletion of three α-globin genes.
○ Tetramers of β-globin, called HbH, are formed
○ There is moderately severe anaemia, resembling β-thalassemia intermedia (microcytic,
hypochromic anaemia with target cells and Heinz bodies in the blood film).
- transfusion dependency

Hydrops fetalis
○ Deletion of all four α-globin genes
○ In the foetus, excess of γ-globin chains form tetramers (Hb Bart) that are unable to
deliver the oxygen to tissues. Usually intrauterine death - not viable for life
- gamma globin chains

Question 6

What is β-Thalassaemia major

Answer 6

β-Thalassaemia major
○ Severe transfusion-dependent anaemia that first becomes manifest 6 to 9
months after birth as synthesis switches from HbF to HbA
○ Homozygous
○ Either type βo or β (βo/βo or β/β)

Question 7

What is β-Thalassaemia minor or β-thalassemia trait

Answer 7

β-Thalassaemia minor or β-thalassemia trait
○ Usually asymptomatic with a mild anemia
○ Heterozygous
○ One normal gene (βo/β or β/β)

Question 8

What is β-Thalassaemia intermedia

Answer 8

β-Thalassaemia intermedia
○ Severe anaemia, but not enough so to require regular blood transfusions
○ Genetically heterogeneous
○ Mild variants of homozygous β-thalassemia
○ Severe variants of heterozygous (βo/β or β/β)
○ Some double heterozygosity for the βo or β genes (βo/β)

Question 9

What are some problems with RBCs in thalassaemia?

Answer 9

Target red cells, small/pale cells, nucleated RBCs

Question 10

What are the consequences of thalassaemia

Answer 10

 Extramedullary haemopoiesis is an attempt to compensate but results in splenomegaly, hepatomegaly and expansion of haemopoiesis into the bone cortex ..this impairs growth and causes classical skeletal abnormalities
- stimulates erythropoietin - feedback loop working but
 Reduced oxygen delivery leads to stimulation of EPO which further
contributes to the drive to make more defective red cells
 Iron overload is major cause of premature death and occurs due to:
◦ Excessive absorption of dietary iron due to ineffective
haematopoiesis
◦ Repeated blood transfusions required to treat the anaemia
- body unable to excrete iron
 Reduced Life expectancy

Question 11

What causes sickle cell disease?

Answer 11

 Inheritance of the sickle ß-globin chain
 A point mutation causes substitution of valine for glutamic acid in
position 6 in the ß-chain
 HbSS = homozygous sickle cell anaemia, is most common cause of
severe sickling syndrome
 HbS can also be co-inherited with another abnormal Hb eg HbC
(HbSC ) or ß-thal (HbS ß-thal) to cause a sickling disorder
 HbS carrier state causes a mild asymptomatic anaemia and is found in up to 30% of W African people as it confers protection against malaria
- many types of Hb - common to get S from one parent and C from another

Question 12

What us sickle cell disease?

Answer 12

 Symptoms of anaemia usually mild ie the anaemia is well tolerated as HbS readily gives up Oxygen in comparison to HbA
Normally not a problem to have sickle cell
but if blood in periphery - polymers of detox HbS - red cells forma c sickle
these are less deformable and stick in vessels
 Problems come in low oxygen state when the deoxygenated HbS forms polymers and the red cells form a sickle shape
 Irreversibly sickled red cells are less deformable and can cause occlusion in small blood vessels – ‘sticky’

Question 13

What problems can result from sickle cell disease?

Answer 13

• Stroke - small clots in brain
• Retiopathy due to small thrombosis in eyes

Lung:

• Pneumonia
• infarcts
• acute chest syndrome

Kidney:

• decreased concentrating ability
• infarcts

Spleen:

• repeated infarction
• leading to atrophy
• Pigment gallstones
• avascular necrosis of femoral head
• osteomyelitis (infection of the bone)
• painful chest and bone
• skin ulcers

Iron overload

• Heart
• Liver

Question 14

What are 3 types of sickle cell crises

Answer 14

The clinical pattern of disease is very variable between individuals

Crises, 3 types:
1. Vaso-occlusive
Painful bone crises Organ – chest, spleen
2. Aplastic (often triggered by parvovirus infection)
3. Haemolytic

End organ damage
as a result of chronic or acute thromboses or oxygen deprivation

Question 15

What are the consequences of sickle cell anaemia

Answer 15

 Reduced Life expectancy – though improving in UK, life
expectancy with HbSS now 67 years. Commonest causes of death in UK: Stroke, Multi-organ failure, acute chest
syndrome
 Acute and chronic pain problems
 Stroke, cognitive and neurological problems, kidney failure, priapism (sustained painful erection)

Question 16

What is haemolytic anaemia

Answer 16

 Results from the abnormal breakdown of red blood cells (= haemolysis) :
◦ within blood vessels (intravascular haemolysis)
◦ or in the spleen or wider RES (extravascular haemolysis)
 Red cells normal lifespan ~120 days
 The bone marrow can compensate for a decrease in lifespan by increasing red cell production but has capacity to increase by around 6 x so if rate of destruction exceeds this anaemia develops
- if rate o destruction is greater than rate of production - anaemia

Question 17

What does haemolytic anaemia result in?

Answer 17

◦ Symptoms of anaemia – severity worse if Hb v low or if an acute fall in
Hb rather than in chronic disease
◦ Accumulation of bilirubin leading to jaundice and associated risk of
complications such as pigment gallstones.
◦ Overworking of the red pulp leading to splenomegaly
◦ Massive sudden haemolysis (as can happen in an incompatible blood
transfusion) can cause cardiac arrest due to:
 Lack of oxygen delivery to tissues
 Hyperkalaemia as a result of release of intracellular contents

Question 18

What are 2 causes of haemolytic anaemia and wha do they cause?

Answer 18

Inherited (defective gene)

• Glycolysis defect - pyruvate kinase deficiency limited ATP production
• Pentose-P pathway - G6PDH deficiency leads to oxidative damage
• Membrane protein e.g. herediatary spherocytosis
• Haemoglobin defect e.g. sickle cell

Acquired

• Mechanical damage - microangiopathic anaemia
• Antibody damage - autoimmune haemolytic anaemia
• Oxidant damage - exposure to chemicals or oxidants
• Heat damage e.g. severe burns
• Enzymatic damage e.g. snake venom

Question 19

What are acquired defects to red blood cells

Answer 19

Mechanical damage to red cells
 Heart valves
 Vasculitis
 MAHA (microangiopathies)
 DIC – disseminated intravascular
coagulopathy
◦ Heat damage
 Burns
◦ Osmotic change
 Drowning

Question 20

What is autoimmune haemolytic anaemia? What are the 2 types and the causes?

Answer 20

 In this condition autoantibodies (an Immunoglobulin protein
produced by own B lymphocytes) bind to the red cell membrane
proteins
 Broadly classified as
◦ warm autoimmune haemolytic anaemia (IgG, maximally active at 370C)
◦ cold autoimmune haemolytic anaemia (IgM, maximally active at 40C)
 Causes can be infections (eg chest infections in children causing the cold form) or cancers of the lymphoid system (eg B cell lymphoma)
 The spleen recognises the red cell as ‘abnormal’ and removes it .. So
reducing the life span

Question 21

What are key laboratory features of haemolytic anaemis?

Answer 21

 increased reticulocytes (as the marrow tries to compensate)
 raised bilirubin (breakdown of Haem)
 raised LDH (red cells rich in this enzyme)