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2.2 Haematology > Red Cell Membrane Disorders > Flashcards

Red Cell Membrane Disorders Flashcards

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1
Q

Write about the structure of the red cell membrane
(5)

A

The membrane is semi-permeable

There is a submembranous filamentous protein meshwork that is attached to the inner surface of the RC membrane, called the membrane cytoskeleton

The four main proteins in this cytoskeleton are spectrin, actin, protein 4.1 and ankyrin

The cytoskeleton is important for maintaining the normal biconcave shape of the cell

The cholesterol content adds rigidity and reflects the plasma concentration

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2
Q

What are the four main proteins in the cytoskeleton

A

Spectrin
Actin
Protein 4.1
Ankyrin

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3
Q

What is the point of the cytoskeleton

A

Important for maintaining the normal biconcave shape of the red cell

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4
Q

What is the point of cholesterol

A

Adds rigidity to cell

Cholesterol content of the membrane also reflects the plasma concentration

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5
Q

Describe the chemical structure of the red cell
(4)

A

Composed of a trilaminar structure consisting of approximately 50% protein, 40% lipid and 10% carbohydrate

The outer hydrophilic region consists of glycolipid, glycoprotein and protein

The central hydrophilic layer contains protein and functions as an internal cytoskeletal scaffold

Proteins are integral and internal to the membrane

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6
Q

What are some characteristics of the red cell membrane?
(7)

A

Flexible and elastic and is capable of responding to fluid force and stress

The inner membrane composition is responsible for deformability

A normal 8uM rbc can deform to pass through a 3uM blood vessel lumen

The rbc can deform so that its length increases by 250% whereas an increase in surface area of only 3-4% is likely to lead to cell lysis

Biconcave disk shape allows the cell to have a maximum surface area ration to its volume/size

This maximises the transfer of gases in and out of the cell

It also gives the RBC its deformability, which allows the RBC to transverse the microvasculature

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7
Q

List the characteristics of the red cell membrane, in your own words
(4)

A

Flexible and elastic to respond to fluid force and stress

Ability to deform - stretch out its length to fit through vasculature

Biconcave shape for maximum surface area for gas diffusion

Biconcave shape to also aid deformability

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8
Q

Write about the permeability of the red cell

A

Freely permeable to H2O anions, chloride Cl- and bicarbonate HCO2-

Exchange occurs through exchange channels formed by integral proteins

Relatively permeable to cations such as Na+ and K+

Control of Na+ and K+ concentration gradient controls the red cell volume and water homeostasis

This Na+/K+ gradient is controlled by an energy requiring system known as the sodium potassium pump

This system is found in the plasma membrane of virtually every human cell and is common to all cellular life. It helps maintain cell potential and regulate cellular volume

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9
Q

What anions is the red blood cell freely permeable to?

A

H2O
Chloride (Cl-)
Bicarbonate (HCO2-)

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10
Q

Where does rbc exchange for anions occur?

A

Through exchange channels formed by integral proteins

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11
Q

What cations is the red blood cell relatively impermeable to

A

Na+
K+

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12
Q

Why is control of the Na+ and K+ concentration in red blood cells important?

A

Na+ and K+ concentration gradient controls the red cell volume and water homeostasis

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13
Q

What controls red cell Na+/K+ concentration

A

Controlled by an energy requiring system known as the sodium potassium pump

This mechanism is found on all human cells

It maintains cell potential and regulates cell volume

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14
Q

How do red cells maintain their cell potential

A

In order to maintain cell potential they must keep a low concentration of sodium ions and high levels of potassium ions within the cell (intracellular)

Outside the cells there are high concentrations of sodium and low concentrations of potassium, so diffusion occurs through ion channels in the plasma membrane

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15
Q

What happens if the Na+/k+ regulation breaks down

A

Sodium will leak into the cell and bring H2O with it causing the cell to rupture

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16
Q

How is Ca++ regulated by the red blood cell

A

Ca++ is actively pumped from the interior of the cell, by a Ca++ ATP-ase pump

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17
Q

Write about the sodium potassium pump
(5)

A

The pump, with bound ATP, bind 3 intracellular Na+ ions

ATP is hydrolysed, leading to phosphorylation of the pump at a highly conserved aspartate residue and the subsequent release of ADP

A conformational change in the pump exposes the Na+ ions to the outside

The phosphorylated form of the pump has a low affinity for sodium ions, so they are released

The pump binds 2 extracellular K+ ions, leading to the dephosphorylation of the pump

ATP binds, and the pump reorients to release potassium ions inside the cell so the pump is ready to go again

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18
Q

What happens when the sodium potassium pump hydrolyses ATP
(4)

A

This causes the phosphorylation of the pump at a highly conserved aspartate residue

This causes a subsequent release of ADP

There is also a conformational change in the pump which exposes the Na+ ions to the outside

The phosphorylated form of the pump has a low affinity for sodium ions so they are released

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19
Q

How does the pump become dephosphorylated?

A

The pump binds 2 extracellular K+ ions

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20
Q

What happens when the NA/K pump is dephosphorylated?

A

ATP binds, and the pump reorients to release potassium ions inside the cell so the pump is ready to go again

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21
Q

What is spectrin

A

The major component of the red cell cytoskeleton

It consists of two intercoiled non-identical filamentous subunits, which form heterodimers

The head of each chain/dimer pair bind with the opposite subunit head of another dimer and form a tetramer

The tails of spectrin tetramers bind to a protein cluster of short actin microfilaments

This binding is enhanced by protein 4.1

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22
Q

What does protein 4.1 do

A

Enhances the binding between the tails of spectrin tetramers to a protein cluster of short actin microfilaments

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23
Q

What does protein 4.2 do

A

The protein forms a two dimensional web that is secured to the overlying lipid bilayer by means of ankyrin

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24
Q

What does ankyrin do

A

It anchors spectrin to the cytoplasmic domain of the anion transporter

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25
What is the function of spectrin? (3)
Composed of alpha and beta chains Principle structural element of the cell membrane Plays a major role in cytoskeleton membrane organisation
26
What is the function of ankyrin
Involved in the attachment of the lipid bilayer
27
What is the function of adducin
Promotes the association of spectrin with F actin
28
What is the function of band 3
Its a major transmembrane protein and integral protein Responsible for chloride bicarbonate exchange Contains binding sites for ankyrin, band 4.1, 4.2 and glycolytic enzymes
29
What is the function of band 4.1
Consists of 5% of the rbc mass Promotes affinity of spectrin to actin Promotes the linkage of the skeleton to the membrane
30
What is the function of band 4.2
Associates with band 3 Deficiency of this protein is associated with haemolytic anaemia
31
What is a red cell membrane disorder
Absence/abnormality of the membrane proteins or lipids or defective protein interactions resulting in deformability and premature destruction of the red cell (haemolytic anaemia)
32
What causes anaemia
When the rate of destruction exceeds the capacity of the marrow to produce RBCs
33
What is normal RBC survival time
110-120 days
34
What are the two main red cell membrane defects
Hereditary spherocytosis (HS) Hereditary elliptocytosis (HE)
35
What is hereditary spherocytosis (6)
Membrane defect whereby the cell takes on the classical spherical shape Autosomal dominant inheritance 20% spontaneous mutation Presentation may be at any age but the more severely affected tend to present early in life Clinical severity ranges from no symptoms to fatigue to severe anaemia and jaundice Can be an accidental finding in those with no symptoms
36
What are the main symptoms of HS
Anaemia Jaundice Splenectomy
37
Comment on the prevalence of HS
Most common hereditary haemolytic anaemia among Northern Europeans Affects 1/2000-5000 Northern European Found in most ethnic groups
38
Write about the pathology of hereditary spherocytosis (4)
Spherocytes are less deformable Spherocytes get trapped, engulfed and destroyed by splenic macrophages leading to reduced lifespan of rbc (20 days) The quantitative deficiency of spectrin will relate to the degree of haemolysis and clinical severity In some cases the degree of haemolysis will be compensated by the increased production of rbcs
39
Write about the clinical finding of HS (6)
Anaemia Family history Mild jaundice Pallor Splenomegaly Haemoglobin fluctuates 10% of anaemia cases will have severe low haemoglobin and require blood transfusions
40
What causes hereditary spherocytosis and how does this happen
A deficiency in spectrin, ankyrin or band 3 These deficiencies cause uncoupling in the vertical interactions of the lipid bilayer skeleton and the loss of membrane microvesicles
41
What does defects in vertical stabilisation of the phospholipid bilayer do? (4)
This causes separation of the spectrin-phospholipid bilayer This causes a loss of lipid Loss of lipid results in a reduction of surface area and thus cases the older cells to become microspherocytes Repeated passage through the spleen aggravates the spherocytic change
42
Write about ankyrin-1 deficiency in HS (3)
Mild to moderate severity Seen in 50-67% of patients Dominant and recessive inheritance
43
Write about band 3 deficiency in HS
Mild to moderate severity Seen in 15-20% of patients Mostly dominant inheritance
44
Write about B spectrin deficiency in HS
Mild to moderate severity Seen in 15-20 % of patients Dominant inheritance
45
Write about alpha spectrin deficiency in HS
Severe disease seen in less than 5% of patients Recessive inheritance
46
Write about protein 4.2 deficiency in HS
Mild to moderate severity Less than 5% HS Recessive inheritance
47
What deficiencies can cause HS
Ankyrin-1 Band 3 B Spectrin A spectrin Protein 4.2
48
Write about the relationship between parvovirus B19 and HS (4)
Patients may be asymptomatic until they contract parvovirus B19 infection with resultant aplastic crisis Virus directly attacks erythroid precursors in the bone marrow and results in erythroid aplasia for about 10 days Rapidly progressive anaemia during this period of absent erythropoiesis and typically present with acute onset of marked pallor, lethargy and fever This infection may unmask hitherto undiagnosed HS in a family
49
How does a neonate present with HS
Hydrops fetalis (rare) Neonatal anaemia (rare) Neonatal jaundice
50
How does a young child present with HS
Severe haemolytic anaemia
51
How does a child present with HS? (4)
Anaemia Jaundice Parvovirus infection Incidental finding on blood count
52
How does an adult present with HS (4)
Parvovirus infection Incidental finding on blood count Extra-medullary haemopoiesis Anaemia unmasked by pregnancy
53
What are the four characteristics of mild HS
Normal Hb Little or no splenomegaly Haemolytic episode triggered by infection 20-30% of cases, autosomal dominant
54
What are the five characteristics of Moderate HS
Mild to moderate anaemia Moderate splenomegaly Episodes of jaundice Increased occurrence of gallstones 60 to 75% of cases are autosomal dominant
55
What are the four characteristics of severe HS
Chronic jaundice Enlarged spleen Serious haemolytic anaemia needing transfusion 5% of cases, autosomal recessive
56
What are the main laboratory findings of HS (6)
Hb between 30 and 60g/L Increased reticulocyte count (not always) Normal or reduced MCV Increased MCHC Increased plasma bilirubin Characteristic finding in HS is the small spherocyte on blood film which lacks a central area of pallor and appears densely haemoglobinised
57
When might you see increased reticulocytes in HS?
During the recovery phase Following recovery from an aplastic crisis Permanent immunity usually results
58
What do we need to rule out in order to diagnose hereditary spherocytosis
Autoantibodies Eosin 5-malemimide (EMA) Autoimmune haemolytic anaemia (AIHA) Haemolysis caused by irregular maternal igG antibodies
59
How do we rule out autoantibodies
Direct antiglobulin test -> needs to be negative to rule out
60
How do we rule out EMA
Flow cytometry
61
What does EMA stand for
Eosin 5-maleimide
62
How do we test for EMA? (3)
EMA binds to band 3 protein, lysine 430 This accounts for 80% of the fluorescence produced in flow cytometry The Rhesus complex is often bound however in HS positive patients, both of these proteins are often decreased fur to gene mutations
63
Explain in your own words how we carry out EMA testing in Hereditary Spherocytosis
Flow cytometry for EMA binding Healthy patient has a mean fluorescence intensity (MFI) of 523 while HS patient has a MFI of 442 There is less EMA binding in HS patient due to mutations in the band 3 protein, lysine 430 and Rhesus complex (less expression) This test may also be abnormal in other red-cell disorders such as CDA-II
64
What is CDA-II
Congenital dyserythropoietic anaemia type II
65
When is additional testing used in HS? (3)
When the clinical phenotype is more severe than expected from the red cell appearances The red-cell abnormalities are more sever than seen in the one known affected parent Splenectomy is considered and the morphology is atypical
66
What additional testing may be carried out for abnormal cases of HS
Quantitative protein analysis by SDS-PAGE may be undertaken in these atypical cases Osmotic fragility test -> confirmatory test
67
What is quantitative protein analysis by SDS -PAGE
Analysis of red-cell membrane content Establishes which membrane protein is deficient by demonstrating protein bands for spectrin, ankyrin, band 3 and protein 4.2
68
What is the osmotic fragility test
Test to measure the increased sensitivity of spherocytes to lysis in a gradient of sodium chloride concentrations compared with normal red cells
69
Why is the osmotic fragility test not carried out anymore
Although the sensitivity is improved by incubating the blood at 37 degree for 24 hours, this test is not specific, showing increased OF in any condition in which there are spherocytes present Time consuming and may give false negative results in infants and in mild cases. About 20% of cases of mild HS are missed by this test, so no longer recommended
70
How is HS treated
Splenectomy is the treatment for symptomatic moderate or sever HS, this eliminates the primary location of haemolysis
71
Why is splenectomy discouraged (2)
Discouraged in mild because the risks associated with the resultant immunocompromise outweigh the risk of haemolytic complications In patients with moderate to severe HS the risk-benefit ratio is inverted because splenectomy substantially diminishes haemolysis and the incidence of pigment gallstones
72
What is Hereditary Elliptocytosis
Rare, autosomal dominant disorder HE presents with discoidal elliptocytes Elliptocytosis affects about 1 in every 2,500 people Mutations in alpha or B spectrin most common which leads to defective spectrin dimer formation Deficiency or dysfunction of protein 4.1 or band 3 Severity of haemolysis depends on the degree of spectrin deficiency The % of eliptocytes present reflects HE severity
73
What causes HE
Mutations in alpha or B spectrin most common which leads to defective spectrin dimer formation Deficiency or dysfunction of protein 4.1 or band 3
74
What are the three main types of eliptocytosis
Common HE Spherocytic HE Southeast Asian ovalocytosis
75
What is common HE
Minimal to severe haemolysis Eliptocytes
76
What is spherocytic HE
Haemolysis present Spherocytes and fat elliptocytes
77
What is southeast asian ovalocytosis
Mild or absent haemolysis Roundish elliptocytes that are also stomatocytic
78
When is there haemolysis in HE
Severly dysfunctional proteins cause membrane fragmentation (haemolysis)
79
What is notable about the permeability of HE
The cells are abnormally permeable to Na+ which demands an increase in ATP to run cation pump and maintain osmotic equilibrium
80
What are the laboratory findings of HE (5)
90% have no signs of haemolysis RC survival can be decreased Haemolysis is very mild or compensated for by the BM Increased reticulocytes and bilirubin Surgery to remove the spleen may decrease the rate of RBC damage
81
How is HE diagnosed
Diagnosis depends on % of eliptocytes Positive diagnosis if 25-90% eliptocytes present with positive family history Oval cells with long diameter > 2 times the short diameter
82
Comment on the severity of HE
Its frequently harmless In mild cases, fewer than 15% of RBCs are elliptical shaped Some people may have crises in which the RBCs rupture, especially if they have a viral infection - can develop anaemia, jaundice and gallstones
83
What are the laboratory findings of HE
If asymptomatic, only symptom might by elliptocytes Hb levels higher than 120 g/L Negative DAT Reticulocytes elevated up to 4% If haemolytic Hb between 90 and 100 g/L Reticulocytes elevated to as high as 20% Bone marrow shows erythroid hyperplasia with normal maturation Microelliptocytes, poikilocytes, schistocytes, spherocytes evident
84
Write about PNH (6)
Paroxysmal Nocturnal Haemoglobinuria Rare, acquired haematopoietic stem cell defect Somatic mutation of the PIG-A gene Prevents assembly of the GPI-anchor protein and results in partial or complete deficiency of glycosylphosphatidylinositol (GPI) Deficiency seen in both WBC and RBC but WBC not affected by the GPI-deficiency RBC vulnerable to complement-mediated lysis
85
How is PNH characterised
Continuous destruction of PNH RBCs Often occurs in bone marrow failures
86
How is PNH characterised
Continuous destruction of PNH RBCs Often occurs in bone marrow failures
87
Write about the diagnosis of PNH
Delays in diagnosis range from 1 to 10 years Diagnosis often delayed or missed due to variable clinical manifestations e.g. lack of classical signs or changing appearance and symptoms of the disorder over time Increased mortality due to thromboembolism, severe marrow failure, small risk of clonal evolution to MDS/leukaemia
88
What can PNH cause
Chronic haemolytic anaemia with episodic crises -> due to complement-mediated intravascular haemolysis Propensity to thromboembolisms -> often at unusual sites e.g. cerebral, hepatic, splenic veins Bone marrow failure -> cytopenia and possible overlap with AA
89
What are the symptoms of PNH
Haemoglobulinuria Anaemia Fatigue Abdominal pain Thrombocytopenia Dysphagia Dyspnoea
90
What are the clinical signs of PHN
Acute renal failure CKD Stroke Cardiac dysfunction Pulmonary hypotension Hepatic failure DVT
91
How is PNH diagnosed (3)
Flow cytometry using GPI linked antibodies CD55, CD59, CD14, CD16, CD24, CD66b and more recently FLAER At least 2 GPI linked antibodies must be absent for the diagnosis Cells are analysed to detect PNH clones
92
Explain what cause PNH
Lack of expression of two GPI-anchored proteins involved in the regulation of complement renders PNH erythrocytes susceptible to complement-mediated lysis
93
How is PNH treated
Eculizumab A humanised monoclonal antibody directed against the terminal complement protein C5 Has resulted in dramatic improvement of survival and reduction in complications
94
What does FLAER stand for
Fluorescein-labelled proaerolysin
95
How is FLAER used in diagnosing PNH
Aerolysin is a bacterial toxin which binds to RBCs via GPI anchor and initiates haemolysis We can modify this aerolysin into a nonhaemolytic form of fluorescently labelled molecule to detect PNH cells This is the most specific test for PNH, as FLAER binds the GPI anchor specifically Lack of FLAER binding is sufficient for diagnosis of PNH
96
What are some requirements for PHN testing
Need to evaluate more than one cell line for deficiency Request quantitative results using gold standard testing: high-sensitivity analysis > 0.1% Request reports that provide clone sizes on all cell lines tested Ensure that more than one reagent agaisnt GPI anchor has been used Use FLAER
97
What happens in PNH
Lack of complement inhibitors (CD55 and CD59) on red blood cells Red blood cells become susceptible to complement attack
98
What are the main symptoms of PHN
Fatigue Bone marrow failure Thrombosis Anaemia Haemoglobinuria Smooth muscle dystonia: dysphagia, abdominal pain, male ED

2.2 Haematology (38 decks)

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