5.1 Haemoglobinopathies And Haemolytic Anaemias Flashcards
1
Q
Defects at what 3 stages may cause anaemia?
A
During production in bone marrow ( Reduced or dysfunctional erythropoiesis, Abnormal Haem synthesis, Abnormal globin chain synthesis)
When red blood cells are travelling in the peripheral circulatory system ( Abnormal structure, Mechanical damage, Abnormal metabolism, excessive blood loss)
During removal of red blood cells (Increased removal by reticuloendothelial system)
2
Q
What are haemoglobinopathies?
A
Inherited disorders typically autosomal recessive that produce defects in the synthesis of globin chains.
3
Q
What condition results from a reduced or absent expression of normal globin chains?
A
Thalassaemias
4
Q
What are thalassaemias?
A
A condition resulting from globin gene mutations that reduce expression of specific individual globin proteins resulting in an imbalance in the composition of the haemoglobin tetramer
5
Q
What condition arises from abnormal globin chain variants with altered stability and/or function?
A
Sickle cell disease
6
Q
What is haemoglobin?
A
A large globular protein in red blood cells?
7
Q
What is the function of haemoglobin?
A
To bind to oxygen using its haem group, and transport it around the body.
8
Q
What is the structure of haemoglobin?
A
Haemoglobin is a tetramer of 4 globin polypeptide chains; 2 alpha (α) and two non-alpha chains (β, δ or γ). Each globin chain is complexed with an oxygen binding haem group.
9
Q
Why are different haemoglobins expressed during
development?
A
as an adaptive response to variations in oxygen requirements.
10
Q
what is the dominant form of haemoglobin before birth?
A
Fetal haemoglobin HbF
11
Q
What is the dominant form of haemoglobin after birth?
A
haemoglobin A HbA
12
Q
Where are the Haemoglobin A gene complexes located?
A
On chromosome 16.
13
Q
Where are the genes for bets, gamma and delta haemoglobins found?
A
Found together in a cluster on chromosome 11.
14
Q
How many haemoglobin A genes do humans have?
A
Humans have 4 α genes (2 on maternal chromosome and 2 on paternal chromosome)
15
Q
How many haemoglobin B genes do humans have?
A
2 HbB (1 on each chromosome)
16
Q
What causes thalassaemias?
A
Defects in this regulation of expression of globin genes
17
Q
What are the 2 types of thalassaemia?
A
Beta thalassaemia
Alpha thalassaemia
18
Q
Where is thalassaemia particularly prevalent?
A
South Asian, Mediterranean, Middle East, Far East.
19
Q
Why is it important to be aware of the ethnicity of your individual patients and patient population?
A
As some populations may be more prone to carry genetic abnormalities (thalassaemias) which need to be considered (for prenatal counselling)
20
Q
What is haemoglobin H disease?
A
Lack of function of 3 or 4 alpha globin genes leads to a condition called haemoglobin H disease , characterised by sever microcytosis, anaemia, haemolysis and splenomegaly.
21
Q
How many different types of alpha thalassaemia are there?
A
4.
Vary according to the number of alpha haemoglobin genes deleted.
22
Q
What occurs when 1 haemoglobin A gene is deleted?
A
Patient is a silent carrier. Asymptomatic.
23
Q
What happens if there are 2 haemoglobin A genes deleted?
A
Alpha-thalassemia trait. Patient has minimal or no anaemia.
Microcytosis and hypochromia in RBCs Resembles β-thalassemia minor
24
Q
What occurs when 3 haemoglobin A genes are deleted?
A
Haemoglobin H disease. Moderately sever symptoms of anaemia. Tetramers of β-globin (called HbH) form resulting in microcytic, hypochromic anaemia with target cells and Heinz bodies. Resembles β-thalassemia intermedia.
25
What occurs when all 4 haemoglobin A genes are deleted?
Hydroperoxyl fetalis. Severe symptoms of anaemia, usually resulting in intrauterine death.
All 4 α genes deleted. Excess γ-globin forms tetramers in foetus (called Hb Bart) that is unable to deliver oxygen to tissues.
26
How is beta thalassaemia usually caused?
Usually caused by gene mutation on chromosome 11 rather than deletion.
27
How many different types of beta thalassaemia are there?
3
Beta thalassaemia minor
Beta thalassaemia intermedia
Beta thalassaemia major.
28
What is beta thalassaemia minor?
Beta thalassaemia is heterozygous with 1 normal and one abnormal gene (βo (total absence) /β or β+ (reduction of globin production)/β).
Usually asymptomatic with a minor or β- mild anaemia (very microcytic and hypochromic rbcs) Resembles α-Thalassemia trait.
29
What is beta thalassaemia intermedia?
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)
Results in severe anaemia, but not enough to require regular transfusions. Resembles Haemoglobin H disease.
30
What is beta thalassaemia major?
Homozygous thalassaemia where both beta haemoglobin genes are abnormal.
Homozygous (βo/βo or β+/β+)
Severe transfusion-dependent anaemia. Problems manifest 6 to 9 months after birth as synthesis switches from HbF to HbA. Usually recognized in first year of birth.
31
What will a peripheral blood smear from patient with severe thalassaemia will typically show?
Hypochromic and microcytic red blood cells due to low haemoglobin.
Anisopoikilocytosis (variation in size and shape)
Target cells
Circulating nucleated red blood cells
Heinz bodies (unaffected globin chain form insoluble aggregates)
32
Why is thalassaemia also a form of haemolytic anaemia?
Thalassaemia results in insoluble aggregates of chain of the unaffected globin chain.
These haemoglobin aggregates get oxidised and result in:
• Premature death of erythroid precursors within bone marrow
leading to ineffective erythropoiesis
• Excessive destruction of mature red cells in spleen leading to shortened red blood cell survival.
33
What is a haemolytic anaemia?
A condition resulting in red blood cells being destroyed prematurely.
34
How does the body react to compensate for thalassaemia?
1. Extramedullary haemopoiesis occurs in 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 .
2. Stimulation of erythropoesis by reduced oxygen delivery which further contributes to the drive to make more defective red cells.
3. Excessive absorption of dietary iron due to ineffective haematopoiesis.
4. Repeated blood transfusions required to treat the anaemia
35
What are the clinical consequences of thalassaemia?
1. Iron overload
- caused by repeated blood transfusions and excessive dietary absorption
2. Anaemia
- ineffective erythropoiesis (fewer RBCs leave the bone marrow, RBcs are microcytic, hypochromic, Heinz bodies)
- haemolytic anaemia as defective RBC are destroyed in the spleen
3. Splenomegaly / Hepatomegaly
- extramedullary haemopoiesis stimulated by increase in erythropoietin to compensate for inefficient erythropoiesis
- splenomegaly as excess defective RBCs are destroyed.
4. Skeletal deformities
- due to bone marrow expansion due to extra medullary haematopoiesis and increase in erythropoietin
36
How is thalassaemia treated?
Red cell transfusion from childhood
iron chelation (delays iron overload)
folic acid to support erythropoiesis
immunisation against opportunistic infection
holistic care to pick up and manage complications
stem cell transplantation
pre-conception counselling for at risk couples and antenatal screening
37
how is sickle cell disease inherited?
autosomal recessive resulting from non conservative missense mutation in the beta globing gene.
38
how is the beta globing gene changed in sickle cell disease?
mutation of alanine base to a thymine base. GAG codon is then changed to GTG resulting in glutamic acid being substituted by valine at position 6
39
how is valine different from glutamic acid?
valine is uncharged, glutamic acid is charged. Valine in HbS is therefore more likely to polymerise at low oxygen tension
40
what are the symptoms experienced by a patient with heterozygous sickle cell anaemia?
mild asymptomatic anaemia, with symptoms of anaemia brought on in stress conditions such as high altitude
41
why can sickling syndromes vary in severity?
can be heterozygous (mild asymptomatic) or homozygous (severe sickling syndrome)
heterozygous sickle cell anaemia can also be co-inherited with other haemoglobinpathioes such as beta thalassaemia.
42
how is sickle cell disease inherited?
autosomal recessive mode of inheritance
43
Why is sickle cell disease common is West Africa?
as it confers protection against malaria. Was a form of natural selection as those without sickle cell were more likely to be infected with malaria
44
how does HbS compare to HbA?
HbS readily gives up oxygen in comparison to HbA. Has a lower affinity
45
how are sickle cells formed?
When HbS is in a low oxygen state. Deoxygenated HbS forms polymers that cause RBC to form sickle shaped cells
46
what happens to sickled RBCs?
Reversible: some sickled RBCs can reform normal HbS, but lose elasticity after repeated episode of sickling.mSuch damaged RBCs fail to return to normal biconcave shape even after increase in oxygen tension. \
Irreversible: irreversibly sickled cells are less deformable and can cause occlusions in small peripheral blood vessels.
47
when do occlusions happen in sickle cell disease?
in periphery blood vessels, occurs in cold environments that cause vasoconstriction.
48
How long before sickle cells are haemolysed?
20-30 days
49
What 3 crises experienced in sickle cell disease?
Vaso-occlusion crisis
Aplastic crisis
Haemolytic crisis
50
What is vast-occlusive crisis?
A common crisis of sickle cell disease. Occlusion of small capillaries. May lead to stroke, acute chest syndrome, chronic kidney disease, joint damage through vascular necrosis.
51
What is an aplastic crisi?
A crisis triggered by sickle cell disease. Often triggered by parvovirus. Bone marrow stops working, doesn’t produce enough RBCs.
52
What are the clinical consequences of sickle cell disease?
```
Retinopathy resulting in vision impairment
Splenicatrophy
Avascular necrosis
Acute chest syndrome
Stroke
Osteomyelitis
Skin ulcers
Kidney infarcts
Priaprism
Jaundice
Anaemia
```
53
What is priaprism?
An unwanted permanent erection
54
Why do patients with sickle cell anaemia have a reduced life expectancy?
As they are more likely to experience stroke, acute chest syndrome and multi-organ failure.
55
Why do patients with sickle cell disease experience anaemia?
As sickle cells have a shorter life expectancy than typical erythrocytes and are haemolysed after 20-30 days.
56
Why do patients with sickle cell experience jaundice and gall stones?
Due to increased bilirubin resulting from chronic haemolysis
57
How does splenic atrophy result from sickle cell disease?
Splenic atrophy due to splenic infarction with an associated susceptibility to infection by encapsulated bacteria such as streptococcus pneumonia and streptococcus meningitidus.
58
What are the treatments of priaprism?
Folic acid
Penicillin and vaccinations if hyposplenic
Hydroxycarbamide - increases HbF levels and has other effects.
Red cell exchange
59
Where can haemolysis of RBCs occur?
Blood vessels (intravascular haemolysis)
Spleen and wider RES ( extravascular haemolysis)
60
What is haemolytic anaemia?
Where rate of haemolysis exceeds capacity of marrow to compensate (~ 6 fold increase max) then the rate of destruction exceeds rate of production and anaemia develops.
61
How can haemolytic anaemia a be inherited?
```
Glycolysis defect (Pyruvate kinase deficiency)
Pentose phosphate pathway defect (G6PDH deficiency)
Membrane protein defect (hereditary spherocytosis)
Haemoglobin defect (sickle cell)
```
62
How can haemolytic anaemia be acquired?
Mechanical damage (microangiopathic anaemia)
Antibody damage ( autoimmune )
Oxidant damage ( exposure to chemicals or oxidants )
Heat damage ( severe burns )
Enzymatic damage (snake venom )
63
What are the key laboratory findings of haemolytic anaemia?
Raised reticulocytes
Raised bilirubin
Raised lactate dehydrogenase
64
What are clinical symptoms of haemolytic anaemia?
Jaundice
Pigment gallstones
Splenomegaly (due to overworking of the red pulp)
Massive sudden haemolysis (from incomparable blood transfusion) can cause cardiac arrest due to lack of oxygen delivery and hyperkalaemia due to release of intracellular contents.
65
What are the presenting symptoms of jaundice?
Yellow discolouration of the skin and sclera
Urine dark in colour due to conjugated bilirubin
66
What are the 3 inherited defects in the red cell membrane structure?
Hereditary spherocytosis
Hereditary eliptocytosis
Hereditary pyropoikilocytosis
67
What is hereditary spherocytosis?
An inherited autosomal dominant RBC membrane defect. Cells take on a spherical shape.
Ankyrin, spectrin, protein 4.2 or Band 3 defects disrupt membrane-cytoskeletal
interactions.
Cells less flexible and more easily damaged
68
What is hereditary eliptocytosis?
An inherited RBC membrane defect. Many cells elliptical rather than biconcave disc shape
Spectrin defect most common. Also defects in band 4.1, Band 3 and
glycophorin C proteins.
69
What is hereditary pyropoikilocytosis?
An inherited defect in the RBC membrane. Spectrin defect. Severe form of hereditary elliptocytosis. Abnormal sensitivity of red cells to heat. Similar morphology to that seen in thermal
burns.
70
What are microangiopathic haemolytic anaemias?
Anaemia resulting from mechanical damage acquired from cells getting forced through a narrow opening under high pressure.
71
How can RBCs acquire damage?
Microangiopathic haemolytic anaemia
Heat damage
Osmotic damage drowning in fresh water)
72
How do microangiopathic haemolytic anaemias damage cells?
1. Sheer stress as cells pass through defective heart valve (stenosis)
2. Cells snagging on fibrin strands in small vessels where increased activation of clotting cascade has occurred (DIC)
73
What is thrombotic thrombocytopenia purpura?
A syndrome where small thrombi form within the microvasculature.
74
What are schistocytes?
Fragments of RBC resulting from mechanical damage.The presence of schistocytes is a good indicator that some form of pathology is present.
75
What is an epitope?
The epitope is the part of an antigen molecule to which an antibody attaches itself.
76
What are autoimmune haemolytic anaemias?
Haemolytic anaemias caused by autoantibodies binding to red cell membrane proteins. Macrophages n spleen recognise antibody bound red blood cells as abnormal and removes them by phagocytosis. As spleen is overworked, splenomegaly occurs. Short red blood cell lifespan results in anaemia.
77
What causes auto immune haemolytic anaemias?
Can be due to:
Reaction from drugs such as cephalosporins.
Infections
Cancers of lymphoid system
78
How can autoimmune haemolytic anaemias be classified?
Classified as either “warm” (IgG) or “cold” (IgM) based on temperature antibodies react best at under laboratory conditions.
79
What is the direct Coombs test?
A test used to detect antibodies or complement bound to the surface of red blood cells. The patients red cells are mixed with anti-human globulin antibody.
80
What test is used to determine whether a patients haemolysis is immune related?
Direct Coombs test
81
What is pyruvate kinase deficiency?
An inherited metabolic disorder due to mutations in the PKLR gene. Results in pyruvate kinase deficiency.
82
why is pyruvate kinase deficiency a cause of haemolytic anaemias?
As red blood cells lack mitochondria, they rely on glycolysis for supply of ATP.. A deficiency in pyruvate kinase means glycolysis cannot be completed and the sodium potassium ATPase pump activity is inhibited. Cellular death occurs in these RBCs and results in haemolytic anaemia.
83
how is pyruvate kinase deficiency treated?
mild deficiency does not require treatment.
severe deficiency may require regular blood transfusion.
84
what is glucose-6-phosphate dehydrogenase deficiency?
an X-linked recessive inborn error of metabolism. G6PDH is the rate limiting enzyme in the pentose phosphate pathway. A deficiency in this pathway means that GSSG (oxidised glutathione) will not be adequately reduced to GH (reduced glutathione) and RBCs are more likely to experience oxidation damage.
85
why are patients with G6PDH deficiency likely to experience haemolytic anaemias?
as in states of oxidative stress such as infection or exposure to certain chemicals or medications, RBCs will not have adequate protection and are more likely to acquire oxidative damage. These damaged RBCs are phagocytosed in the spleen. Also results in jaundice.
86
what is the function of spectrin?
an actin cross linking and molecular scaffold protein that links the plasma membrane to the actin cytoskeleton
87
what is the function of ankyrin?
links the integral plasma membrane proteins to the underlying actin-spectrin cytoskeleton.
88
what is the function of band 3?
an integral membrane protein that facilitates chloride and bicarbonate exchange across the plasma membrane
physical linkage of the plasma membrane to the underlying cytoskeleton
89
what is the function of protein 4.2?
an ATP binding protein which may regulate the association of band 3 with ankyrin.
90
what are Howell-Jolly bodies?
a cytopthological finding of basophilic nuclear remnants (clusters of DNA) in circulating RBCs. Presence usually signifies a damaged or absent spleen.
