1
Q
why might anaemia develop
A
1) Problems with blood cell formation in bone marrow
2) Problem with peripheral blood cells
3) Removal of RBC
2
Q
1) Problems with blood cell formation in bone marrow
A
- Reduced or dysfunctional erythropoiesis
- Abnormal haem synthesis
- Abnormal globin chain synthesis
3
Q
2) Problem with peripheral blood cells
A
- Abnormal structure
- Mechanical damage
- Abnormal metabolism
- Excessive bleeding
4
Q
3) Removal of RBC
A
Increased removal by reticuloendothelial system
5
Q
differ Hb expressed during
A
development as ana daptive resposnse to variation in oxygen requirments
6
Q
embryonic forms
A
- HbF= main form before birth
- hbA commnces before birth and steadily increases to become dominant after birth
7
Q
major Hb types in adults
A
usually 2alpha and 2 beta
8
Q
Structure of haemoglobin
A
Haemoglobin (Hb) is a globular protein composed of four protein chains (tetramer).
These four chains are made up of 2α paired with 2 other chain types
Attached to each of globin chain is an iron (Fe2+) ion which allows for oxygen bonding.
9
Q
A
10
Q
HbA
A
2α/2β
11
Q
HbA2
A
2α/2ẟ
12
Q
HbF
A
2α/2γ
13
Q
what are haemoglobinopathies
A
- are genetic disorders (usually autosomal recessive) that alter the structure of haemoglobin.
- This may result:
- in deformed structures
- reduced production of particular globin chains – called thalassaemias
- This results in reduced oxygen carrying capacity of the blood, and produces symptoms of anaemia
14
Q
reduced or absent expression of structurally normal chain
A
thalassaemia
15
Q
abnormality of the chains themselves
A
sickle cell
16
Q
how many alpha globin genes
A
- 2 on maternal chromosomes 16
- 2 on paternal chromosome 16
17
Q
how many B globin genes
A
2- 1 one ach chromsosome 11
18
Q
the globin gene clusters
A
19
Q
Thalassaemia
A
Thalassaemias are autosomal recessive, inherited diseases resulting from the reduced rate of synthesis of normal α- or β- globin chains.
20
Q
Blood smear for thalassaemia
A
This results in a lower level of intracellular haemoglobin which causes hypochromic, microcytic red cells seen in patients with thalassaemia.
- Anisopoikilocytosis with frequent target cells (arrow) and circulating nucleated red blood (arrow head) cells and heinz bodies
- RBC are not usually nucleated- high production
21
Q
hyperspenism and thalassaemia
A
In a patient with thalassaemia, the spleen breaks down abnormal RBCs and the iron from the cells is retained rather than being reused.
This excess iron causes hypersplenism, causing the spleen to break down more RBC and lowering haemoglobin levels even further – a splenectomy (removal of the spleen) is frequently performed.
22
Q
thalassaemia is most prevalent in
A
- South Asian
- Mediterranean
- Middle east (beta thal)
- Far eat (alpha thal)
23
Q
Alpha chains
A
Humans have 4 alpha-globin genes
- 2 found on maternal chromosome 16
- 2 found on paternal chromosome 16
24
Q
Alpha-Thalassaemia
A
α-thalassaemias are caused by mutations (usually deletions) in the HBA1 and/or HBA2 genes on chromosome 16. The increased deletion of α chains means there are an excess of β chains in adults, and γ chains in foetuses. This means the patient is unable to form the normal globular proteins in the pattern of 2α and 2 other. The relative excess of these other chains leads to defective red cells, which are destroyed in large numbers by the spleen – this causes haemolytic anaemia.
25
how many types of alpha thalassaemia
**Four types of disease- depending on how many alpha-globin genes deleted**
*The more alpha-globin genes deleted- the more serious the death*
26
alpha-thalassaemia: silent carrer state
* 1 alpha-globin gene deleted
* carrier of the disease with **no symptoms**
27
Alpha-thalassaemia trait
* two alpha-globin genes deleted
* minimal or no anaemia
* microcytosis and hypochromia in RBC
28
alpha- Thalassaemia- Haemoglobin H (HbH) disease
* 3 alpha-globin genes deleted
* modearley sevre
* tetramers of B globin (called HbH) form resulting in microcytic, hypochromic anaemia with target cells and heinzx bodies
29
alpha-thalassaemia- Hydrop fetalis
* 4 alpha-globin genes deleted
* severe
* results in intrauterine death
* excess Y-globin forms tertramers inf oetus (Hb Bart) that is unable to deliver oxygen to tissues (too high an affinity- cant release to tissue)
30
Beta-Thalassaemia
Beta thalassaemias are caused by mutations in the HBB gene on chromosome 11.
The body’s inability to construct β chains leads to the underproduction of HbA – which is the most prominent haemoglobin variant in the body.
This, similarly to α-thalassaemia, leads to microcytic anaemia.
31
Beta-thalassaemia is usually caused by a
mutation rather than deletion
32
B0
denotes total abscence of broduction of B-globin chains
33
B+
denotes reduction of Beta-globin production
34
how many types of Beta- Thalassaemia
3
## Footnote
Thalassaemia Minor
Thalassaemia Intermediate
Thalassaemia Major
35
Thalassaemia Minor
* Heterogenous with 1 nromal and one abnormal gene **(B0/B or B+/B)**
* This is the form of β-thalassaemia where only one of the alleles in chromosome 11 has a mutation, this patient is a carrier.
* The patient doesn't exhibit severe symptoms, but will have mild microcytic anaemia.
* Patients are often monitored without treatment (unnecessary transfusions may result in iron overload, leading to transfusion haemosiderosis causing damage to the liver, heart and endocrine glands).
36
Thalassaemia Intermedia
* In patients with beta thalassaemia intermedia, anaemia is present (symptoms range from mild to severe) but individuals are not transfusion dependent.
* seevre anameia
* Resembles HbH disease
* Patients are clinically heterogeneous.
37
Thalassaemia Major
* Also known as Cooley’s anaemia, this is the form where both alleles in chromosome 11 have mutations (homozygous recessive).
* B0/B0 or B+/B+
* Due to the massively reduced ability to produce HbA, the patient has severe microcytic and hypochromic anaemia and is transfusion and chelation (to treat iron overload) dependent.
* Patients may have abnormal skull bones due to excessive extramedullary haemopoiesis in an attempt to keep up with haemolysis.
* Hepatosplenomegaly is also present as a result.
38
consequences of thalassaemia
* **Extramedullary hemopoiesis** occurs in attempt to compensate but results in splenomegaly, hepatomegaly and expansion of hemopoiesis into the bone cortex (should usually be the bone marrow)- impairs growth and causes classical skeletal abnormalities
39
Reduced oxygen delivery leads to stimulation of
of EPO which further contributes to the drive to make more defective red cells
40
increased production of defective red cell leads to increased destruction by the RES
* This causes **iron overload** – major causes of premature death
* Excessive absorption of dietary iron to ineffective haematopoiesis
* Repeated blood transfusion required to treat the anaemia
41
treatment of thalassaemia
* Red cell transfusion from childhood
* Iron chelation (delay iron overload)
* Folic acid supports erythropoiesis
* Immunisation
* Holistic care
* Cardiology
* Endocrine
* Psychological
* Ophthalmology to manage complications
* Stem cell transplantation in some
* At higher risk of infections- immune boosting drugs
* Stem cell transplantation in some – replace the defective red cell production
* Pre-conception counselling for at risk couples and antenatal screening
42
sickle cell disease is
an autosomal recessive disease due to point mutations in beta globin genes
43
44
normal red blood cell vs sickle cell
Normally red blood cells have a biconcave shape and are flexible, meaning they can easily move through blood vessels.
However, in sickle cells disease, when deoxygenated the defective haemoglobin S (HbS - haemoglobin specific to sickle cell disease) polymerises causing deformation of the cell, losing its biconcave structure and becoming ‘sickle’ (or crescent moon) shaped. This irregular shape causes the sickle cells to become stuck in blood vessels, impairing the flow of blood to certain areas of the body. Furthermore, the cells are quite fragile so easily break down or are removed by the spleen, leading to a haemolytic anaemia.
45
in a carrier state of anaemia
* In carrier state mild asymptomatic anaemia
* 1 in 4 risk of passing on with a recessive partner
46
homozygous HbSS
* Very severe sickling syndrome
47
where is sickle cell disease prominant
***In W Africa 30% are carriers- confers protection against malaria***
48
what causes sickling of RBC
* Problems come in **low oxygen** state as deoxygenated HbS forms **polymers** that cause red cells form a **sickle shape**
* Irreversibly sickled red are cells **less deformable** and can cause **occlusion** in small blood vessels – ‘sticky’
49
Signs and symptoms of sickle cell disease
usually begin in early childhood and are caused by the sickle shape of RBC. The premature breakdown of the cells leads to anaemia (which can cause dyspnoea, fatigue and tachycardia) and if severe enough, pre-hepatic jaundice.
50
If sickle cells get stuck in blood vessels this can lead to
vaso-occlusive crises (which are very painful), as tissues and organs are deprived of oxygen and become ischaemic.
One of the most severe complications of sickle cell anaemia is acute chest syndrome, which is a serious condition and is also exquisitely painful.
51
3 different types of crises
vasococclusive
aplastic
haemolytic
52
vaso-occlusive
* Painful bone crises
* Organs can get blocked- chest (sickle chest syndrome), spleen (spleen can swell)
53
aplastic
often triggered by parvovirus (slapped cheek syndrome)
54
haemolytic
lots of cells destroyed
55
sickle cell crises cause damage to
end organs- result of acute thromboses and hypoxia
* Retinopathy
* Splenic atrophy
* Reduce immune system
* Due to splenic occlusion
* Avascular necrosis
* Acute chest syndrome
* Stroke
* Osteomyelitis
* Skin ulcers
* Kidney infarcts
* Priaprism
* Reduces life expectancy
56
**Treatments of sickle cell**
* Folic acid
* Penicillin and vaccinations as he hyposplenic
* Hydroxycarbadmide- increase HbF levels and other effects
* Red cell exchange
57
normal lifespan of an RBC is
120
58
Abnormal breakdown of RBC (haemolytic anaemia) reduces the lifespan and can occur in
* Blood vessels (intravascular haemolysis)
* Spleen and wider RES (extravascular haemolysis)
59
how does the bone marrow respond to haemolytic anaemia
* Bone marrow can compensate by increasing production but only up to a point
* If haemolysis exceed capacity of marrow to compensate then the rate of destruction exceeds rate of production and anaemia develops
60
haemolytic anaemia can be
inherited or acquired
61
haemolytic anaemia: inherited
* glycolysis defect
* pentose-P phosphate dmaage
* memrbane protein (hereditary spheorcytosis)
* Haemoglobin defect e.g. sickle cell or Thalassaemia
62
haemolytic anaemia: acquired
* mechanical damage (microangiopathic anaemia)
* Antibody damage
* oxdiant damage
* heat damage e.g. severe burns
* enzymatic damage e.g. snake venom
63
64
**Key lab findings in haemolytic anaemia**
* Raised reticulocytes
* Raid bilirubin (breakdown of haem)
* Raised LDH (lactose dehydrogenase) (red cells rich in this enzyme)
65
complications relaed to hameoltic anaemia
* Breakdown of RBC- **accumulation of bilirubin** leading to **jaundice** and associated risk of complications such as pigment **gallstones**
* **Overworking of red pulp leading to splenomegaly**
* Increased breakdown of blood cells
* **Massive sudden haemolysi**s e.g. from incompatible blood transfusion can cause cardiac arrest due to lack of oxygen delivery to tissues and hyperkalaemia due to release of intracellular contents
66
**Inherited defects in RBC membrane structure**
hereditary spherocytosis
hereditary elliptocytosis
hereditary pyropoikilocytosis
67
hereditary spherocytosis
* many RBC take spherical shape
* ankryrin, spectrin, protein 4.2 or Band 3 defecrs disrupt membrane-cytoskeletal itneractions
* cell less flexible and more easily damaged
68
hereditary elliptocytosis
* many cells ellipitcal shape
* spectirn defect most common
69
hereditary pyropoikilocytosis
* spectrin defect
* sevre form of hereditary elliptocytosis
* abnormal sensitivity of red cells to ehat
* similar morphology that seen in thermal burns
70
example of acquired damage
* Microangiopathic haemolytic anaemias result from mechanical damage (**MAHA)**
* Heat damage from severe burns
* Osmotic damage (drowning in freshwater)
71
Microangiopathic haemolytic anaemias result from mechanical damage
* Shear stress as cells pass through defective heart valves (e.g. in aortic valve stenosis- cells get damaged when forced through narrowed opening under high pressure)
* Cells snagging on fibrin strands in small vessels where increased activation of clotting cascade has occurred (disseminated intravascular coagulation)
72
shcistocytes
fragments resulting from mechanical damage- presence is an indicator of some form of pathology
73
**Autoimmune haemolytic anaemias**
* Caused by autoantibodies binding to red cell membrane
* Can result from infections (e.g. chest infections in children) or cancers of lymphoid system
* Classified as either warm (IgG) or cold (IgM) based on temp antibodies react best at under lab conditions
* Spleen recognised antibody bound cells as abnormal and removes them
* Red cell lifespan reduced resulting in anaemia
Haemotology
flashcards
Decks in class (12)
# Cards
-
Haemopoiesis and Bone marrow76
-
Full blood count57
-
Blood films41
-
Anaemia introduction38
-
Classification of Anaemia31
-
Anaemia: symptoms and treatment17
-
Macrocytic anaemia and vitamin B12 and folate38
-
Microcytic anaemia and Iron metabolism57
-
Haemoglobinopathies73
-
When haematopoiesis goes wrong43
-
Haematology in systemic disease37
-
The Spleen27
