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Haematology Lectures > L.9 Red Cell Membrane Disorders > Flashcards

L.9 Red Cell Membrane Disorders Flashcards

1
Q

What is the composition of the red cell membrane?

A

Approx. 50% Protein, 40% Lipid, 10% Carbohydrate

This trilaminar structure is essential for membrane function.

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2
Q

What are the components of the outer hydrophilic region of the red cell membrane?

A

Glycolipid, glycoprotein, and protein

These components play roles in cell recognition and signaling.

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3
Q

What is found in the central hydrophobic layer of the red cell membrane?

A

Protein, cholesterol, and phospholipid

Cholesterol adds rigidity to the membrane.

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4
Q

What is the function of the inner hydrophilic layer of the red cell membrane?

A

Functions as an internal cytoskeletal scaffold

This layer supports the membrane structure and shape.

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5
Q

What are the four main proteins in the red cell membrane’s cytoskeleton?

A

Spectrin, actin, protein 4.1, and ankyrin

These proteins are crucial for maintaining the biconcave shape of red blood cells.

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6
Q

What is the role of the membrane cytoskeleton?

A

Maintains the normal biconcave shape of the red cell

The shape is important for its function in the circulatory system.

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7
Q

Describe the flexibility and elasticity of the RBC membrane.

A

Capable of responding to fluid force and stress

This property allows RBCs to navigate through narrow capillaries.

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8
Q

How much can a normal 8mM RBC deform to pass through a 3mM blood vessel lumen?

A

Can deform significantly, increasing length by 250%

This deformation is crucial for microvasculature transit.

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9
Q

What is the biconcave disc shape of RBCs beneficial for?

A

Maximizes surface area ratio to volume/size

This shape enhances gas exchange efficiency.

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10
Q

What substances are RBCs freely permeable to?

A

H2O, anions, chloride (Cl-), and bicarbonate (HCO3-)

This permeability is essential for proper cell function.

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11
Q

What is the relative permeability of RBCs to cations?

A

Relatively impermeable to Na+ and K+

This selectivity is important for maintaining cell volume and potential.

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12
Q

What regulates the Na+/K+ concentration gradient in RBCs?

A

Sodium potassium pump

This energy-requiring system is crucial for cell homeostasis.

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13
Q

What happens if Na+/K+ regulation breaks down in RBCs?

A

Sodium leaks into the cell, bringing water with it, causing rupture

This can lead to cell lysis and loss of function.

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14
Q

What is the function of the Ca++ ATP-ase pump in RBCs?

A

Actively pumps Ca++ from the interior of the cell

This helps maintain calcium homeostasis within the cell.

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15
Q

What does the sodium potassium pump bind first?

A

3 intracellular Na+ ions

This is the initial step in the pump’s mechanism, utilizing ATP.

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16
Q

What happens to ATP during the operation of the sodium potassium pump?

A

ATP is hydrolysed, leading to phosphorylation of the pump

This phosphorylation occurs at a highly conserved aspartate residue.

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17
Q

What effect does phosphorylation have on the sodium potassium pump?

A

It causes a conformational change that exposes Na+ ions to the outside

The phosphorylated form has a low affinity for sodium ions.

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18
Q

How many extracellular K+ ions does the pump bind after releasing Na+ ions?

A

2 extracellular K+ ions

This step leads to the dephosphorylation of the pump.

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19
Q

What is the role of ATP after the sodium potassium pump binds K+ ions?

A

ATP binds again and the pump reorients to release potassium ions inside the cell

This resets the pump for the next cycle.

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20
Q

What is the major component of the red cell cytoskeleton?

A

Spectrin

Spectrin consists of two intercooled non-identical filamentous subunits that form heterodimers.

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21
Q

What structure do spectrin dimers form?

A

Tetramers

The head of each chain/dimer pair binds with the opposite subunit head of another dimer.

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22
Q

What do the tails of spectrin tetramers bind to?

A

A protein cluster of short Actin microfilaments

This binding is enhanced by the protein 4.1.

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23
Q

What function does the protein 4.2 serve in the red cell membrane?

A

It forms a two-dimensional web secured to the lipid bilayer by Ankyrin

This web structure is important for maintaining membrane integrity.

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24
Q

What is the role of Ankyrin in red blood cells?

A

Anchors Spectrin to the cytoplasmic domain of the anion transporter

This attachment is crucial for the stability of the RBC membrane.

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25
What are the components of Spectrin?
a and b chains ## Footnote These chains are the principal structural elements of the RBC membrane.
26
What is the function of Adducin protein?
Promotes the association of spectrin with F actin ## Footnote This association is important for maintaining the cytoskeleton structure.
27
What is Band 3 in the context of red blood cells?
The major transmembrane protein involved in chloride-bicarbonate exchange ## Footnote It contains binding sites for ankyrin, band 4.1, band 4.2, and glycolytic enzymes.
28
What percentage of RBC mass does Band 4.1 constitute?
5% ## Footnote It promotes the affinity of spectrin to actin and links the skeleton to the membrane.
29
What is the association of Band 4.2 with other proteins?
Associates with Band 3 ## Footnote A deficiency of this protein is linked to haemolytic anaemia.
30
What results from the absence or abnormality of red cell membrane proteins or lipids?
Defective deformability and premature destruction of the red cell (haemolytic anaemia) ## Footnote This leads to anaemia when the rate of destruction exceeds marrow production of RBCs.
31
What is the normal RBC survival time?
110 - 120 days
32
Name two inherited red cell membrane defects.
* Hereditary Spherocytosis (HS) * Hereditary Elliptocytosis (HE)
33
What is the classical shape of red blood cells in Hereditary Spherocytosis?
Spherical shape
34
What is the prevalence of Hereditary Spherocytosis among Northern Europeans?
1 in 2,000 - 5,000
35
How is Hereditary Spherocytosis inherited?
Autosomal dominant manner (20% spontaneous mutation)
36
What family history is often present in individuals with Hereditary Spherocytosis?
* Anaemia * Jaundice * Splenectomy * Known HS
37
At what age do individuals with Hereditary Spherocytosis typically present symptoms?
Any age; often more severely affected individuals present earlier
38
What are some clinical findings in Hereditary Spherocytosis?
* Fatigue from severe anaemia * Jaundice * Family history * Pallor * Splenomegaly
39
What happens to spherocytes in the spleen?
They get trapped, engulfed, and destroyed by splenic macrophages
40
How long is the survival time of spherocytes compared to normal RBCs?
20 days
41
What can compensate for the degree of haemolysis in some cases of Hereditary Spherocytosis?
Increased production of RBCs in the bone marrow
42
What is a common management for severe anaemia in Hereditary Spherocytosis?
Blood transfusions
43
What results from a deficiency in spectrin, ankyrin, or band 3?
Uncoupling in the vertical interactions of the lipid bilayer skeleton and loss of membrane microvesicles
44
What causes the separation of the spectrin-phospholipid bilayer in RBC membranes?
Defects in vertical stabilisation of the phospholipid bilayer
45
What happens to older red blood cells as a result of lipid loss?
They become microspherocytes
46
What aggravates the spherocytic change in Hereditary Spherocytosis?
Repeated passage through the spleen
47
What are the characteristics of mild hereditary spherocytosis?
Normal Hb, little or no splenomegaly, haemolytic episode triggered by infection, autosomal dominant in 20-30% of cases. ## Footnote Mild disease may not show significant symptoms until triggered by an infection.
48
What are the symptoms of moderate hereditary spherocytosis?
Mild to moderate anaemia, moderate splenomegaly, episodes of jaundice, increased occurrence of gallstones, autosomal dominant in 60 to 75% of cases. ## Footnote Moderate disease presents more pronounced symptoms compared to mild disease.
49
What defines severe hereditary spherocytosis?
Chronic jaundice, enlarged spleen, serious haemolytic anaemia needing transfusion, autosomal recessive in 5% of cases. ## Footnote Severe disease often requires medical intervention due to the severity of symptoms.
50
What can trigger an aplastic crisis in hereditary spherocytosis patients?
Infection with parvovirus B19. ## Footnote This virus attacks erythroid precursors in the bone marrow, leading to a temporary absence of erythropoiesis.
51
What are the laboratory findings in hereditary spherocytosis?
Hb value between 30 and 60 g/L, increased reticulocyte count (not always), normal or reduced MCV, increased MCHC, increased plasma bilirubin, characteristic small spherocytes on blood film. ## Footnote Spherocytes lack a central area of pallor and appear densely haemoglobinised.
52
What is a characteristic finding on the blood film for hereditary spherocytosis?
Small spherocyte that lacks a central area of pallor and appears densely haemoglobinised. ## Footnote This finding is also observed in autoimmune hemolytic anemia (AIHA).
53
What does a negative direct antiglobulin test indicate in the context of hereditary spherocytosis?
It excludes spherocytosis due to an autoantibody. ## Footnote This test helps differentiate hereditary spherocytosis from autoimmune causes.
54
Fill in the blank: Patients with hereditary spherocytosis may be asymptomatic until they contract _______.
parvovirus B19 infection. ## Footnote This infection can lead to an acute crisis in otherwise asymptomatic individuals.
55
What is the typical presentation during an aplastic crisis caused by parvovirus B19?
Rapidly progressive anaemia, acute onset of marked pallor, lethargy, and fever. ## Footnote These symptoms arise due to the absence of erythropoiesis.
56
What is the reticulocyte count during the recovery phase from an aplastic crisis?
Increased reticulocyte count. ## Footnote Following recovery, permanent immunity usually results.
57
What does EMA bind to in Hereditary Spherocytosis (HS)?
EMA binds to band 3 protein, lysine 430 ## Footnote This accounts for 80% of the fluorescence produced in the test.
58
What is the reported sensitivity and specificity of the EMA test for HS?
Sensitivity: 92.7%, Specificity: 99.1% ## Footnote May be abnormal in other red-cell disorders, particularly congenital dyserythropoietic anaemia type II (CDA-II).
59
When are additional tests indicated in a typical case of HS?
When: * Clinical phenotype is more severe than expected * Red-cell abnormalities are more severe than seen in one known affected parent * Splenectomy is considered and morphology is atypical ## Footnote Important to exclude rare forms of red-cell disorder where splenectomy is contraindicated.
60
What is the value of splenectomy in congenital dyserythropoietic anaemia type II (CDA-II)?
Of little value in CDA-II ## Footnote CDA-II may be confused with HS.
61
What does SDS-PAGE analyze in atypical cases of HS?
Red-cell membrane content and establishes which membrane protein is deficient ## Footnote Demonstrates protein bands for spectrin, ankyrin, band 3, and protein 4.2.
62
What does the osmotic fragility test (OF) measure?
Increased sensitivity of spherocytes to lysis in a gradient of sodium chloride concentrations ## Footnote Compared with normal red cells.
63
How does incubation at 37°C for 24 hours affect the osmotic fragility test?
Improves sensitivity ## Footnote Test is not specific, showing increased OF in any condition with spherocytes.
64
Why is the osmotic fragility test no longer recommended?
Time-consuming and may give false negative results in infants and mild cases ## Footnote About 20% of mild HS cases missed by this test.
65
What is the treatment for symptomatic moderate or severe HS?
Splenectomy ## Footnote Howell jolly bodies may be seen on blood film.
66
What effect does splenectomy have on erythrocyte cytoskeletal abnormalities?
Does not alter cytoskeletal abnormalities ## Footnote Eliminates the primary location of haemolysis.
67
What is the current consensus regarding splenectomy in mild HS?
Discouraged due to risks of immunocompromise outweighing haemolytic complications ## Footnote In moderate or severe HS, the risk-benefit ratio is inverted.
68
What benefits does splenectomy provide in patients with moderate or severe HS?
Substantially diminishes haemolysis and incidence of pigment gallstones ## Footnote This makes the procedure more favorable in these cases.
69
What type of disorder is Hereditary Elliptocytosis?
Rare, autosomal dominant disorder ## Footnote Hereditary Elliptocytosis (HE) is characterized by the presence of discoidal elliptocytes in the blood.
70
What is the estimated prevalence of elliptocytosis in northern European heritage?
About 1 in every 2,500 people ## Footnote The true incidence is unknown as many patients are asymptomatic.
71
What leads to defective spectrin dimer formation in Hereditary Elliptocytosis?
Mutations in a or b spectrin ## Footnote These mutations are the most common cause of HE.
72
What proteins can be deficient or dysfunctional in Hereditary Elliptocytosis?
Protein 4.1 or band 3 ## Footnote These proteins are crucial for maintaining erythrocyte membrane integrity.
73
How does the severity of haemolysis relate to spectrin deficiency in HE?
Severity of haemolysis depends on the degree of spectrin deficiency ## Footnote The percentage of elliptocytes present also reflects the severity of HE.
74
What is the classification of Hereditary Elliptocytosis based on erythrocyte morphology?
Common HE, Spherocytic HE, Southeast Asian ovalocytosis ## Footnote Each classification presents with different shapes and severities of RBCs.
75
What characterizes Common HE?
Variable haemolysis – elliptocytic shaped RBCs ## Footnote This form shows a range of symptoms and severity.
76
What characterizes Spherocytic HE?
Haemolytic – spherocytes and fat elliptocytes ## Footnote This form typically presents with more severe symptoms.
77
What characterizes Southeast Asian ovalocytosis?
Mild/absent haemolysis – roundish elliptocytes that are also stomatocytic ## Footnote This variant generally has less severe symptoms.
78
What effect do HE RBCs have on Na+ permeability?
HE RBCs are abnormally permeable to Na+ ## Footnote This increased permeability demands more ATP for cation pump activity.
79
What laboratory findings are commonly observed in patients with HE?
90% show no overt signs of haemolysis ## Footnote Although RC survival can be decreased, haemolysis is usually mild and well compensated for by the bone marrow.
80
What does a blood film show for a positive diagnosis of HE?
25-90% elliptocytes present with positive family history ## Footnote Diagnosis relies heavily on the percentage of elliptocytes observed.
81
What is the characteristic shape of oval cells in HE?
Long diameter > 2 times the short diameter ## Footnote This morphological feature helps in diagnosing HE.
82
What happens to reticulocytes and bilirubin levels in HE?
Increased reticulocytes and bilirubin ## Footnote These increases are indicative of RBC turnover and destruction.
83
What is the effect of splenectomy on RBC damage in HE?
May decrease the rate of RBC damage ## Footnote Surgical removal of the spleen can help manage symptoms.
84
What is the typical percentage of elliptical-shaped RBCs in mild cases of HE?
Fewer than 15% ## Footnote In mild cases, elliptocytosis is often harmless.
85
What crises can some individuals with HE experience?
RBCs rupture, leading to anaemia, jaundice, and gallstones ## Footnote These crises may be triggered by viral infections.
86
What is usually higher than 120g/l in patients with HE?
Hb levels ## Footnote This level is typically maintained in asymptomatic cases.
87
What does a negative direct antiglobulin test indicate in HE?
No autoimmune hemolysis ## Footnote This finding helps differentiate HE from other hemolytic anemias.
88
What are the reticulocyte levels in the haemolytic variants of HE?
Elevated to as high as 20% ## Footnote This indicates increased RBC turnover in severe cases.
89
What additional cell types are usually evident in haemolytic HE variants?
Microelliptocytes, poikilocytes, schistocytes, spherocytes ## Footnote These cell types reflect the severity of the disorder.
90
What does bone marrow examination show in HE?
Erythroid hyperplasia with normal maturation ## Footnote This finding indicates a compensatory response to increased RBC destruction.
91
What is Paroxysmal Nocturnal Haemoglobinuria (PNH)?
A rare, acquired haematopoietic stem cell defect occurring at 2-6 cases per million ## Footnote PNH is characterized by somatic mutation of the PIG-A gene leading to GPI-anchor deficiency.
92
What causes the deficiency in GPI-anchor in PNH?
Somatic mutation of the PIG-A gene ## Footnote This mutation prevents the assembly of the GPI-anchor.
93
Which blood cells are affected by PNH?
RBCs, WBCs, and platelets ## Footnote WBCs are not functionally impaired despite being affected.
94
How are RBCs affected in PNH?
RBCs are vulnerable to complement-mediated lysis ## Footnote This vulnerability is due to the deficiency of complement regulatory proteins.
95
What is the gold standard for diagnosing PNH?
Flow cytometry ## Footnote It tests for the absence of ≥2 GPI-anchored proteins on RBCs, monocytes, and granulocytes.
96
Name key markers tested by flow cytometry for PNH.
CD55, CD59, CD14, CD16, CD24, CD66b ## Footnote These markers help identify the absence of GPI-anchored proteins.
97
What does the FLAER assay detect?
PNH clones in all blood cell types ## Footnote FLAER binds specifically to the GPI-anchor.
98
What is the sensitivity of the FLAER assay?
Can detect as low as 0.5% clone size ## Footnote This makes it one of the most specific and sensitive methods for diagnosing PNH.
99
What is the role of fluorescein-labelled proaerolysin (FLAER) in PNH diagnosis?
Detects PNH cells to a level of 0.5% ## Footnote It binds to RBCs via GPI anchor and initiates haemolysis in its natural form.
100
What is the significance of the lack of FLAER binding in granulocytes?
It is sufficient for the diagnosis of PNH ## Footnote This is because FLAER specifically binds the GPI anchor.
101
What happens due to GPI-anchor deficiency in PNH?
Loss of complement regulatory proteins: CD55 (DAF) and CD59 (MIRL) ## Footnote This leads to increased lysis of RBCs by complement.
102
What syndromes are associated with PNH?
Bone marrow failure syndromes like Aplastic Anaemia and Myelodysplastic Syndrome ## Footnote These conditions are often seen in patients with PNH.
103
What is the treatment for PNH?
Eculizumab ## Footnote Eculizumab is a monoclonal antibody that inhibits complement activation.

Haematology Lectures (14 decks)

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