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Hematology > Week 3 > Flashcards

Week 3 Flashcards

Hemoglobinopathies & Thalassemias, Structural & Quantitative Defects in Hemoglobin

1
Q

What are the main components of hemoglobin?

A

Hemoglobin consists of 4 heme molecules and 4 globin chains.

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2
Q

How many different types of globin chains are there?

A

There are 7 different types of globin chains.

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3
Q

How does globin chain production change?

A

Globin chain production changes with age, specifically during the embryonic, fetal, newborn, and adult stages.

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4
Q

How many amino acids are in the alpha globin chain?

A

The alpha globin chain consists of 141 amino acids.

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5
Q

How many amino acids are in the beta globin chain?

A

The beta globin chain consists of 146 amino acids.

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6
Q

How many amino acids are in the gamma globin chain?

A

The gamma globin chain consists of 146 amino acids.

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7
Q

How many amino acids are in the delta globin chain?

A

The delta globin chain consists of 146 amino acids.

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8
Q

What is known about the epsilon and theta globin chains?

A

The number of amino acids in the epsilon and theta globin chains is unknown.

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9
Q

How many amino acids are in the zeta globin chain?

A

The zeta globin chain consists of 141 amino acids.

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10
Q

Which genes are located on Chromosome 16 in hemoglobin genetics?

A

Chromosome 16 contains 2 alpha (α) genes and 1 zeta (ζ) gene.

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11
Q

Which genes are located on Chromosome 11 in hemoglobin genetics?

A

Chromosome 11 contains 1 beta (β), delta (δ), epsilon (ε), and 2 gamma (γ) genes.

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12
Q

Which mRNA is translated more efficiently, β-globin or α-globin?

A

β-globin mRNA is translated more efficiently than α-globin.

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13
Q

What is the result of the translation efficiency of β-globin and α-globin mRNA?

A

Approximately equal amounts of each globin chain are produced.

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14
Q

What happens to α-globin chains in early red blood cells (RBCs)?

A

Some excess α-globin chains are produced in early RBCs.

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15
Q

Which chromosomes contain the genes for β-globin and α-globin?

A

β-globin genes are on Chromosome 11, and α-globin genes are on Chromosome 16.

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16
Q

What happens to α and non-α chains as they come off the ribosomes?

A

They each bind one heme molecule and pair off.

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17
Q

What is formed when an α chain and a non-α chain bind a heme molecule and pair off?

A

An α, non-α dimer is formed.

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18
Q

What happens to the α, non-α dimer during hemoglobin assembly?

A

Each dimer combines with another dimer to form a tetramer hemoglobin (Hgb) molecule.

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19
Q

What is the final structure of hemoglobin?

A

A tetramer, consisting of two α chains and two non-α chains, each bound to a heme molecule.

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20
Q

What are the primary sites of blood cell production during fetal development?

A

Yolk sac, liver, spleen, and bone marrow.

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21
Q

How does the location of hematopoiesis change from intrauterine life to infancy?

A

Blood production starts in the yolk sac, shifts to the liver and spleen during fetal development, and then transitions to the bone marrow by birth.

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22
Q

What non-α globin chains are produced during early intrauterine life?

A

Zeta (ζ) and epsilon (ε) globin chains.

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23
Q

What is the main globin chain produced during fetal development?

A

Gamma (γ) globin chain.

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24
Q

When does the switch from fetal hemoglobin (Hb F) to adult hemoglobin (Hb A) occur?

A

The switch from Hb F (with γ-globin) to Hb A (with β-globin) occurs after birth, during infancy.

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25
Q

How does the production of β-globin and γ-globin change after birth?

A

After birth, β-globin production increases, while γ-globin production decreases.

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26
Q

What is the composition of adult hemoglobin A (HbA)?

A

Hemoglobin A is composed of 2 alpha (α2) and 2 beta (β2) chains.

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27
Q

What percentage of normal adult hemoglobin is composed of hemoglobin A (HbA)?

A

More than 95% of adult hemoglobin is HbA.

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28
Q

What is the composition of hemoglobin A2 (HbA2)?

A

Hemoglobin A2 is composed of 2 alpha (α2) and 2 delta (δ2) chains.

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29
Q

What percentage of normal adult hemoglobin is composed of hemoglobin A2 (HbA2)?

A

Less than 3.5% of adult hemoglobin is HbA2.

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30
Q

What is the composition of fetal hemoglobin (HbF)?

A

Fetal hemoglobin is composed of 2 alpha (α2) and 2 gamma (γ2) chains.

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31
Q

What percentage of normal adult hemoglobin is composed of fetal hemoglobin (HbF)?

A

1-2% of adult hemoglobin is HbF.

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32
Q

What are hemoglobinopathies?

A

Hemoglobinopathies are disorders caused by gene mutations in the globin genes.

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33
Q

What are the two types of changes that can occur in hemoglobinopathies?

A

The two types of changes are qualitative or structural changes and quantitative changes.

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34
Q

What is a qualitative or structural change in hemoglobinopathies?

A

A qualitative or structural change involves an alteration in the structure of the globin protein, often leading to abnormal hemoglobin (e.g., sickle cell disease).

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35
Q

What is a quantitative change in hemoglobinopathies?

A

A quantitative change involves an abnormal amount of globin chain production, such as decreased or absent production (e.g., thalassemia).

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36
Q

What is a point mutation in genetic mutations?

A

A point mutation is a change in one nucleotide, which can affect protein coding or regulatory sequences.

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37
Q

What effect does a deletion or insertion mutation have on a gene?

A

A deletion or insertion mutation causes a frameshift due to the loss or addition of a nucleotide.

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38
Q

What are chain extensions in genetic mutations?

A

Chain extensions occur when there is a mutation in the stop codon, allowing translation to continue, resulting in longer than normal globin chains.

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39
Q

What happens in gene fusion mutations?

A

In gene fusion mutations, two normal genes break between nucleotides, switch positions, and anneal to the opposite gene.

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40
Q

What is the relationship between the number of genes mutated and the severity of a genetic defect?

A

The more genes that are mutated, the greater the severity of the genetic defect.

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41
Q

What does it mean to be homozygous for a genetic mutation?

A

Homozygous means that genes from both parents are affected, often resulting in a more severe form of the disease.

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42
Q

What does it mean to be heterozygous for a genetic mutation?

A

Heterozygous means that only one gene is affected while the other gene is normal, often resulting in a trait rather than a disease.

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43
Q

What is another scenario that can occur in heterozygous mutations?

A

One gene may have one type of mutation, and the other gene may have a different mutation, leading to variability in the trait or disease.

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44
Q

How do genetic mutations affect hemoglobin?

A

Changes to the globin chain can affect the structure and likely the function of hemoglobin.

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45
Q

What are some possible outcomes of genetic mutations in hemoglobin?

A

Some forms of mutated hemoglobin can function normally, others cannot, and some degrade easily, leading to unstable hemoglobin.

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46
Q

What is an example of how mutations affect hemoglobin function?

A

Mutations can result in hemoglobin with different oxygen affinity or unstable hemoglobin that degrades easily.

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47
Q

What factors influence the impact of a mutation on hemoglobin function?

A

The impact depends on the chemical nature of the substituted amino acid, the location of the mutation, and zygosity.

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48
Q

Are all hemoglobin variants clinically significant?

A

No, many variants are clinically insignificant because they do not produce any physiological effect.

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49
Q

What causes the formation of Hemoglobin S (HbS)?

A

Hemoglobin S is caused by a point mutation in the β-globin gene.

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50
Q

What specific mutation occurs in Hemoglobin S?

A

The mutation changes the 6th amino acid in the β-globin chain from glutamic acid to valine.

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51
Q

What is the result of the mutation in Hemoglobin S?

A

Valine replaces glutamic acid at the 6th position, leading to the formation of Hemoglobin S (HbS).

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52
Q

How is Hemoglobin S represented?

A

Hemoglobin S can be represented as α2β2^S, α2β2^6Glu-Val, or α2β2^6Val.

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53
Q

What is the inheritance pattern of β – hemoglobin variants?

A

β – hemoglobin variants are inherited in an autosomal codominant manner, with one gene inherited from each parent.

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54
Q

How does a person inherit sickle cell disease (SCD)?

A

A person with sickle cell disease inherits the sickle gene from both parents.

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55
Q

What does it mean to have sickle trait (SCT)?

A

Individuals with sickle trait have inherited the sickle gene from one parent and a normal hemoglobin gene from the other parent.

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56
Q

What are the genetic combinations for sickle cell disease and sickle trait?

A

Sickle Cell Disease (SCD): SS (sickle gene from both parents)
Sickle Trait (SCT): AS (sickle gene from one parent and normal gene from the other)

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57
Q

What is the percentage of Hemoglobin A (Hb A) in individuals with sickle trait (SCT)?

A

60%

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58
Q

What is the percentage of Hemoglobin S (Hb S) in individuals with sickle trait (SCT)?

A

40%

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59
Q

What is the percentage of Hemoglobin A₂ (Hb A₂) in individuals with sickle trait (SCT)?

A

Normal - Slightly Increased (N - SI)

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60
Q

What is the percentage of Hemoglobin F (Hb F) in individuals with sickle trait (SCT)?

A

Normal (N)

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61
Q

What is the percentage of Hemoglobin A (Hb A) in individuals with sickle cell disease (SCD)?

A

0%

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62
Q

What is the percentage of Hemoglobin S (Hb S) in individuals with sickle cell disease (SCD)?

A

More than 80%

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63
Q

What is the percentage of Hemoglobin A₂ (Hb A₂) in individuals with sickle cell disease (SCD)?

A

2-5% (Normal - Slightly Increased)

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64
Q

What is the percentage of Hemoglobin F (Hb F) in individuals with sickle cell disease (SCD)?

A

1-20%

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65
Q

What is the key amino acid substitution in Hemoglobin S that affects molecular interaction?

A

Valine replaces glutamic acid, leading to altered interactions in hemoglobin molecules.

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66
Q

How does Hemoglobin S behave when oxygenated?

A

When oxygenated, Hemoglobin S does not form a hydrophobic pocket, so it remains soluble.

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67
Q

How does Hemoglobin S behave when deoxygenated?

A

When deoxygenated, a hydrophobic pocket forms, allowing valine from adjacent Hb S molecules to bind, causing polymer formation and making hemoglobin less soluble.

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68
Q

What happens to the shape of red blood cells as a result of Hemoglobin S polymerization?

A

The polymerization of Hemoglobin S causes red blood cells to become sickle-shaped.

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69
Q

Why does valine seek a hydrophobic niche in Hemoglobin S?

A

Valine is hydrophobic, so it looks for a hydrophobic environment to hide in when deoxygenated, leading to polymer formation.

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70
Q

At what oxygen saturation level does sickling occur in sickle cell disease (SS)?

A

Sickling occurs when oxygen saturation falls below 85%.

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71
Q

At what oxygen saturation level does sickling occur in sickle trait (AS)?

A

Sickling occurs when oxygen saturation falls below 40%.

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72
Q

What happens to blood flow as polymers form during sickling?

A

Blood becomes thick, slowing blood flow and promoting a hypoxic environment, which in turn promotes more sickling.

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73
Q

What are the two forms of sickle cells?

A
  1. Reversible sickle cells – These start off normal, but as conditions become anoxic, RBCs become sickle-shaped. They can travel into microvasculature as normal-shaped cells but later become distorted and cause vaso-occlusion.
  2. Irreversible sickle cells – These do not change shape regardless of oxygen tension and are removed by the spleen due to their abnormal shape.
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74
Q

How does cellular hydration affect sickling?

A

During polymerization, the movement of ions causes water to efflux from the cell, increasing the Hb S concentration, which further promotes polymerization and sickling.

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75
Q

How do symptoms of sickle cell disease (SCD) vary?

A

Symptoms can range from no symptoms to lethal outcomes.

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76
Q

Why are patients with sickle cell disease (SCD) generally fine up to the first 6 months of life?

A

Hemoglobin F (Hb F) compensates during the first 6 months of life, preventing symptoms.

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77
Q

What happens as mutant β chains replace normal γ chains in patients with SCD?

A

Hemoglobin S (Hb S) levels rise, leading to progressive hemolytic anemia.

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78
Q

What is a hallmark clinical feature of sickle cell disease (SCD)?

A

Vaso-occlusive crises (VOC) are a hallmark of SCD.

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79
Q

What happens during a vaso-occlusive crisis (VOC) in sickle cell disease?

A

Reversible sickle cells change shape, lose deformability, and occlude small capillaries and postcapillary venules, leading to blockage of blood flow.

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80
Q

What are some common causes of vaso-occlusion in sickle cell disease?

A

Acidosis, hypoxia, dehydration, infection, fever, and extreme cold.

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81
Q

What are the clinical manifestations of vaso-occlusion in bones in SCD?

A

Pain, hand-foot dactylitis, and osteomyelitis.

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82
Q

What are the clinical manifestations of vaso-occlusion in the lungs in SCD?

A

Pneumonia and acute chest syndrome.

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83
Q

What liver-related clinical features are seen in sickle cell disease?

A

Hepatomegaly and jaundice.

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84
Q

What spleen-related clinical features are seen in SCD?

A

Sequestration splenomegaly and autosplenectomy.

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85
Q

What clinical features are associated with the penis in SCD?

A

Priapism.

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86
Q

What eye-related clinical feature is seen in SCD?

A

Retinal hemorrhage.

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87
Q

What is a common urinary tract manifestation of vaso-occlusion in SCD?

A

Renal papillary necrosis.

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88
Q

What are some bacterial infections commonly seen in sickle cell disease?

A

Sepsis, pneumonia, and osteomyelitis.

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89
Q

What hematologic defects are associated with SCD?

A

Chronic hemolytic anemia, megaloblastic episodes, and aplastic episodes.

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90
Q

What cardiac defects are seen in SCD?

A

Enlarged heart and heart murmurs.

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91
Q

What other clinical features are associated with SCD?

A

Stunted growth and high-risk pregnancy.

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92
Q

What is a crucial component of managing sickle cell disease (SCD) to prevent dehydration?

A

Hydration.

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93
Q

What types of environments should individuals with SCD avoid?

A

Low oxygen environments, including strenuous exercise, high altitudes, small planes, and surgery with anesthesia.

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94
Q

What treatment is used to increase Hemoglobin F (Hb F) in SCD patients?

A

Hydroxyurea.

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95
Q

What are two important preventive measures for SCD patients?

A

Prophylactic antibiotics and up-to-date immunizations.

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96
Q

What is a key aspect of managing pain in sickle cell disease (SCD)?

A

Pain management.

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97
Q

What is the treatment approach for conditions resulting from vaso-occlusive crises (VOC) in SCD?

A

Treatment of specific conditions that result from VOC.

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98
Q

What is the purpose of blood exchange transfusion in SCD treatment?

A

To replace sickled red blood cells with normal red blood cells.

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99
Q

What is a treatment strategy for patients with iron overload due to transfusions?

A

Transfusions with iron chelation therapy.

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100
Q

What advanced treatment option is available for curing SCD?

A

Bone marrow/stem cell transplantation.

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101
Q

What emerging therapy holds potential for treating sickle cell disease?

A

Gene therapy.

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102
Q

What is sickle cell trait (SCT)?

A

A benign, heterozygous condition where the individual has one normal hemoglobin gene (A) and one sickle gene (S), resulting in Hb AS.

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103
Q

Are individuals with sickle cell trait usually symptomatic?

A

No, individuals with SCT are usually asymptomatic unless exposed to extremely hypoxic conditions.

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104
Q

Under what conditions can individuals with SCT experience systemic sickling and vascular occlusion?

A

Systemic sickling and vascular occlusion can occur in extremely hypoxic conditions, especially in the spleen and brain.

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105
Q

What is the most consistent abnormality seen in SCT patients?

A

Kidney impairment due to diminished perfusion to the kidneys.

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106
Q

What is the mutation involved in Hemoglobin C (Hb C)?

A

A point mutation in the β-globin gene, where lysine replaces glutamic acid at the 6th amino acid position of the β-globin chain.

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107
Q

What is the consequence of the amino acid substitution in Hemoglobin C?

A

The substitution results in short, thick Hb C crystals, even in the oxygenated state, with minimal disruption to the RBC shape.

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108
Q

How does Hemoglobin C affect the red blood cells (RBCs)?

A

There is less splenic sequestration and hemolysis compared to other hemoglobinopathies due to minimal RBC shape disruption.

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109
Q

How does Hemoglobin CC (Hb CC) manifest in patients?

A

Hb CC manifests in mild disease.

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110
Q

How does Hemoglobin AC (Hb AC) affect individuals?

A

Hb AC is asymptomatic.

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111
Q

What is the recommended management for Hemoglobin C conditions?

A

Usually, no specific treatment is required, but genetic counseling is recommended.

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112
Q

What is the genetic notation for Hemoglobin C?

A

Hemoglobin C can be denoted as α₂β₂^C or α₂β₂^6Glu-Lys.

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113
Q

What is the percentage of Hemoglobin A (Hb A) in individuals with Hemoglobin C trait?

A

60%

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114
Q

What is the percentage of Hemoglobin C (Hb C) in individuals with Hemoglobin C trait?

A

30%

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115
Q

What is the percentage of Hemoglobin A₂ (Hb A₂) and Hemoglobin F (Hb F) in Hemoglobin C trait?

A

Hb A₂: Normal to slightly increased (N - SI)
Hb F: Normal to slightly increased (N - SI)

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116
Q

What is the percentage of Hemoglobin A (Hb A) in individuals with Hemoglobin C disease?

A

0%

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117
Q

What is the percentage of Hemoglobin C (Hb C) in individuals with Hemoglobin C disease?

A

More than 90%

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118
Q

What is the percentage of Hemoglobin A₂ (Hb A₂) and Hemoglobin F (Hb F) in Hemoglobin C disease?

A

Hb A₂: 2%
Hb F: Less than 7%

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119
Q

What is the inheritance pattern of Hemoglobin C?

A

Hemoglobin C has a similar inheritance pattern as Hemoglobin S.

With one parent carrying the gene, 50% will have the AC trait, 50% will be normal.

With both parents carrying the gene, 25% will be normal, 50% will have AC trait, and 25% will have Hb CC.

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120
Q

What mutation occurs in Hemoglobin E (Hb E)?

A

A point mutation in the β-globin gene, resulting in a change at the 26th amino acid position.

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121
Q

What substitution takes place in Hemoglobin E?

A

Lysine replaces glutamic acid at the 26th position of the β-globin chain.

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122
Q

How does Hemoglobin E differ from Hemoglobin C in terms of substitution?

A

Both involve the same substitution (lysine replacing glutamic acid), but at different positions on the β-globin chain.

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123
Q

Does Hemoglobin E cause polymerization of the hemoglobin molecule?

A

No, it does not cause polymerization, but rather results in reduced production of Hemoglobin E.

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124
Q

What is the clinical manifestation of Hemoglobin E disease (Hb EE)?

A

Hb EE manifests as a mild anemia.

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125
Q

What are the symptoms of Hemoglobin E trait (Hb E trait)?

A

Hb E trait is typically asymptomatic.

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126
Q

Is therapy required for individuals with Hemoglobin E?

A

No specific therapy is required, but genetic counseling is recommended.

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127
Q

What is the genetic notation for Hemoglobin E?

A

Hemoglobin E is denoted as α₂β₂^E or α₂β₂^26Glu-Lys.

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128
Q

What is the percentage of Hemoglobin A (Hb A) in individuals with Hemoglobin E trait?

A

60-70%

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129
Q

What is the percentage of Hemoglobin E (Hb E) in individuals with Hemoglobin E trait?

A

30-40%

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130
Q

What are the percentages of Hemoglobin A₂ (Hb A₂) and Hemoglobin F (Hb F) in Hemoglobin E trait?

A

Both are typically within normal to slightly increased ranges (N - SI).

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131
Q

What is the percentage of Hemoglobin A (Hb A) in individuals with Hemoglobin E disease?

A

0%

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132
Q

What is the percentage of Hemoglobin E (Hb E) in individuals with Hemoglobin E disease?

A

More than 90%

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133
Q

What are the percentages of Hemoglobin A₂ (Hb A₂) and Hemoglobin F (Hb F) in Hemoglobin E disease?

A

Hb A₂: 2%
Hb F: Less than 7%

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134
Q

What is the inheritance pattern of Hemoglobin E?

A

Hemoglobin E has a similar inheritance pattern to Hemoglobin S and Hemoglobin C.

With one parent carrying the gene, 50% will have the AE trait, and 50% will be normal.

With both parents carrying the gene, 25% will be normal, 50% will have AE trait, and 25% will have Hb EE.

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135
Q

What are the two amino acid substitutions in Hemoglobin C-Harlem?

A

6th position: Valine replaces glutamic acid.
73rd position: Aspartic acid replaces asparagine.

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136
Q

How do patients with Hemoglobin C-Harlem typically present?

A

Patients are usually asymptomatic.

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137
Q

What is unique about Hemoglobin C-Harlem compared to other hemoglobinopathies?

A

It involves a double substitution on the β-globin chain.

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138
Q

What type of inheritance pattern does Hemoglobin SC exhibit?

A

Hemoglobin SC exhibits compound heterozygosity, where Hb S is inherited from one parent and Hb C from the other parent.

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139
Q

What percentage of Hemoglobin A (Hb A) is produced in individuals with Hemoglobin SC disease?

A

0% (No Hemoglobin A is produced).

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140
Q

What are the hemoglobin percentages in Hemoglobin SC disease?

A

Hb S: 45%
Hb C: 45%
Hb A₂: 2-4%
Hb F: 1%

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141
Q

How does Hemoglobin SC disease compare to sickle cell disease (SCD) in terms of severity?

A

Hemoglobin SC disease is usually milder than SCD, but it can still cause vaso-occlusive complications.

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142
Q

What symptoms are commonly seen in patients with Hemoglobin SC disease?

A

Patients exhibit moderate hemolytic anemia, splenomegaly, retinopathy, and respiratory tract infections.

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143
Q

What complications can occur in Hemoglobin SC disease despite its milder nature compared to SCD?

A

Vaso-occlusive complications, though they are less frequent and damaging compared to those in SCD.

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144
Q

What is unstable hemoglobin?

A

Unstable hemoglobin is caused by genetic mutations to the globin genes that create hemoglobin products which precipitate in vivo, producing Heinz bodies and causing hemolytic anemia.

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145
Q

What are Heinz bodies, and how are they related to unstable hemoglobin?

A

Heinz bodies are precipitated hemoglobin products found in red blood cells, caused by unstable hemoglobin, which leads to hemolytic anemia.

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146
Q

Do all unstable hemoglobins have clinical significance?

A

Most unstable hemoglobins have no clinical significance, although some may have altered oxygen affinity and cause hemolytic anemia.

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147
Q

What are the possible causes of hemoglobin instability due to amino acid substitutions?

A
  1. Substitution of a charged for an uncharged amino acid inside the molecule.
  2. Substitution of a polar for a nonpolar amino acid in the hydrophobic heme pocket.
  3. Substitution of an amino acid at the intersubunit contact point.
  4. Replacement of an amino acid with proline in a specific α helix section of the chain.
  5. Deletion or elongation of the chain.
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148
Q

When is unstable hemoglobin typically detected, and what are the key clinical findings?

A

It is typically detected in early childhood with hemolytic anemia (HA) accompanied by jaundice and splenomegaly.

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149
Q

What factors can worsen the condition of unstable hemoglobin?

A

The condition worsens with fever or ingestion of oxidant drugs.

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150
Q

How does unstable hemoglobin lead to immune activation in red blood cells (RBCs)?

A

Precipitated hemoglobin clusters RBC antigens, leading to the attachment of immunoglobulins and macrophage activation.

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151
Q

What is the consequence of Heinz bodies getting trapped in the spleen?

A

Heinz bodies getting trapped in the spleen result in shortened RBC survival.

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152
Q

What is the primary treatment for unstable hemoglobin?

A

Supportive treatment, with patients cautioned to avoid oxidant drugs. In severe cases, splenectomy may be required.

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153
Q

What is a common lab finding in patients with unstable hemoglobin regarding RBC morphology?

A

RBC morphology can vary from normal to slightly hypochromic.

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154
Q

What are the prominent lab findings seen in unstable hemoglobin on a blood smear?

A

Prominent basophilic stippling, increased polychromasia (4-20% reticulocytes), and Heinz bodies on a supravital stain.

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155
Q

What test is used to confirm the presence of unstable hemoglobin, and what is the result?

A

The isopropanol precipitation test shows flocculent precipitation if unstable hemoglobin is present.

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156
Q

What is a common finding in the complete blood count (CBC) of a patient with sickle cell disease?

A

Moderate leukocytosis with neutrophilia and a mild shift toward immature granulocytes.

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157
Q

What is usually present in the CBC of patients with sickle cell disease regarding platelets?

A

Thrombocytosis (increased platelet count).

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158
Q

How is red cell distribution width (RDW) affected in sickle cell disease?

A

RDW is increased.

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159
Q

What bone marrow finding is commonly associated with sickle cell disease?

A

Erythroid hyperplasia.

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160
Q

What are the biochemical findings in patients with sickle cell disease?

A

Elevated levels of indirect and total bilirubin.

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161
Q

What type of anemia is typically seen in sickle cell disease (SCD) on peripheral blood smear?

A

Normocytic normochromic (N/N) anemia.

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162
Q

What are the key features of polychromasia in sickle cell disease (SCD) on PBS?

A

Moderate to marked polychromasia, indicating increased reticulocyte production.

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163
Q

What are the hallmark cells seen in sickle cell disease on a PBS?

A

The presence of sickle cells and target cells is the hallmark of SCD.

164
Q

What additional RBC abnormalities can be seen in sickle cell disease on PBS?

A

Marked poikilocytosis, anisocytosis, normal RBCs, nRBCs, few spherocytes, basophilic stippling, Pappenheimer bodies, and Howell-Jolly (HJ) bodies.

165
Q

What is the typical reticulocyte count range in patients with sickle cell disease?

A

10-25%.

166
Q

What is the typical RBC morphology seen on a peripheral blood smear in sickle cell trait (SCT)?

A

Normal RBC morphology, with the exception of a few target cells.

167
Q

Are there any abnormalities in the leukocytes and thrombocytes in sickle cell trait (SCT)?

A

No, leukocytes and thrombocytes appear normal.

168
Q

What type of anemia is typically seen in Hemoglobin C (Hb C) on peripheral blood smear?

A

Normocytic normochromic (N/N) anemia.

169
Q

What is a notable RBC feature seen in Hemoglobin C on a PBS?

A

Marked increase in target cells.

170
Q

What is the level of polychromasia and reticulocytes in Hemoglobin C patients?

A

Increased polychromasia, with reticulocytes at 2-3%.

171
Q

What type of crystals may be seen in RBCs of Hemoglobin C patients, and what are they called?

A

Bar-shaped crystals, often referred to as ‘bar of gold’, which are polymers of Hemoglobin C.

172
Q

What other notable RBC shape might be observed in Hemoglobin C patients?

A

Folded cells, which resemble an ‘envelope’ form.

173
Q

Are nucleated RBCs (nRBCs) present in the peripheral blood smear of Hemoglobin C patients?

A

nRBCs may be present.

174
Q

What are the key findings on a peripheral blood smear (PBS) in Hemoglobin E (Hb E)?

A

Some to many microcytes
Few to many target cells
Normal reticulocyte count

175
Q

What type of anemia is typically seen in Hemoglobin SC (Hb SC) on peripheral blood smear?

A

Normocytic normochromic (N/N) anemia.

176
Q

What is a notable feature of RBC production in Hemoglobin SC on a PBS?

A

Increased polychromasia, indicating elevated reticulocyte production.

177
Q

What types of abnormal cells can be seen in Hemoglobin SC on a PBS?

A

Few sickle cells, target cells, and folded cells.

178
Q

What type of crystals can be found inside RBCs in Hemoglobin SC, and what are they called?

A

Intraerythrocytic blunt-ended crystals, often referred to as ‘mitten cells’ or ‘hand in glove’ cells.

179
Q

What is the principle behind the Sickle Solubility Test for Hb S?

A

Hb S is less soluble than Hb A when deoxygenated and precipitates, making it detectable in a buffered salt solution.

180
Q

What agents are used in the Sickle Solubility Test?

A

Lysing agent (saponin): Releases hemoglobin from RBCs.

Reducing agent (sodium dithionite): Reduces iron, preventing it from binding to oxygen.

181
Q

How is the result of the Sickle Solubility Test interpreted?

A

Positive (contains Hb S): Turbid solution where lines are not visible.

Negative (non-sickling hemoglobin): Clear solution where lines are visible.

182
Q

What can cause a false positive result in the Sickle Solubility Test?

A

Hyperlipidemia.
Rare hemoglobinopathies like Hb C-Harlem.
Too much blood added.

183
Q

What can cause a false negative result in the Sickle Solubility Test?

A

Infant under 6 months of age.
Low hematocrit.

184
Q

What sample is used in the Sickling Test for Hb S?

A

Fresh whole blood (WB) on a microscope slide.

185
Q

What reducing agent is used in the Sickling Test for Hb S?

A

Sodium metabisulphite (2%).

186
Q

How is the Sickling Test prepared and performed?

A
  1. Add 1 drop of whole blood on a slide.
  2. Add 2 drops of 2% sodium metabisulphite.
  3. Mix and seal the slide to prevent oxygen from entering.
  4. Observe for sickling after 15-30 minutes.
187
Q

Why do the red cells sickle in the Sickling Test?

A

Due to reduced oxygen tension caused by the sodium metabisulphite.

188
Q

What type of result will Hb C-Harlem show in the Sickling Test?

A

Negative result, as Hb C-Harlem does not sickle in this test.

189
Q

How are results for newborns with Hb S affected by the Sickling Test?

A

Newborns with less than 10% Hb S are weakly positive and can be easily missed, as they mostly have Hb F.

190
Q

What are the three levels of positivity in the Sickling Test for Hb S?

A

Strong positive
Moderate positive
Weak positive

191
Q

What screening tests are used for sickle cell anemia?

A

Sickling and Solubility tests.

192
Q

Can Sickling and Solubility tests distinguish between sickle cell trait (AS) and sickle cell disease (SS)?

A

No, these tests do not distinguish between the trait (AS) and the disease (SS).

193
Q

What is the principle behind hemoglobin electrophoresis?

A

Hemoglobin electrophoresis separates hemoglobin molecules in an electric field based on differences in total molecular charge.

194
Q

How do amino acid sequences affect hemoglobin movement in electrophoresis?

A

Different amino acid sequences result in different charges in both normal and mutated hemoglobins, which affect their movement through the electric field.

195
Q

What environment is used for hemoglobin electrophoresis, and what does it show?

A

It is done in an alkaline environment, producing mobility patterns that identify both variant and normal hemoglobins.

196
Q

Why might a second gel in an acidic environment be needed in hemoglobin electrophoresis?

A

Some hemoglobins have the same charge and similar mobility patterns, so an acidic environment helps to distinguish them more clearly.

197
Q

What is the pH of the screening run in hemoglobin electrophoresis, and what does it separate?

A

The screening run is done at an alkaline pH of 8.4 and separates hemoglobins A, F, S, and C.

198
Q

What challenge exists when identifying Hemoglobin C in electrophoresis?

A

Hb C runs with normal Hb A2, so if the band appears to be less than 10%, it is likely A2. However, Hb C trait has around 40% Hb C.

199
Q

What pH is used in cellulose acetate hemoglobin electrophoresis for screening?

A

Alkaline pH of 8.4.

200
Q

Which hemoglobins run together in alkaline electrophoresis?

A

Hemoglobin C, Harlem, E, and O run together with A₂.
Hemoglobin D and G run with Hemoglobin S.

201
Q

How can Hemoglobin D and G be differentiated from Hemoglobin S?

A

Hemoglobin D and G show a negative result in the Sickle Solubility and Sickling Tests, whereas Hemoglobin S does not.

202
Q

What are some limitations of alkaline hemoglobin electrophoresis?

A

Some hemoglobins (e.g., C Harlem, E, O, D, G) co-migrate with other hemoglobins like C, A₂, or S, requiring further testing to distinguish them.

203
Q

What is the pH used for Cellulose Acetate Hemoglobin Electrophoresis?

A

pH 8.4 (Alkaline Electrophoresis)

204
Q

What hemoglobins are tested in Cellulose Acetate Electrophoresis at pH 8.4?

A

Normal, Sickle Trait, Hemoglobin D Trait, SC Disease, SE Disease, Normal Cord Blood, C-Harlem Trait, Control

205
Q

Which hemoglobins co-migrate at pH 8.4 in Cellulose Acetate Electrophoresis?

A

Hemoglobin A2, C, E, O migrate together. Hemoglobin S, D, G migrate together.

206
Q

What is the pH used for Citrate Agar Hemoglobin Electrophoresis?

A

pH 6.0-6.2 (Acid Electrophoresis)

207
Q

What is the purpose of using Acid pH Electrophoresis (Citrate Agar)?

A

To separate hemoglobins C from A2 & E, O as well as S from D & G.

208
Q

Why is Alkaline Electrophoresis performed first in Hemoglobin Electrophoresis?

A

Alkaline electrophoresis is usually sufficient to diagnose conditions like SS (Sickle Cell Disease), AS (Sickle Cell Trait), and Thalassemia.

209
Q

In Acid pH (Citrate Agar) Electrophoresis, which hemoglobins co-migrate?

A

Hemoglobin A, D, G, E, and O migrate together at Acid pH.

210
Q

What principle does HPLC use for the separation and identification of hemoglobins?

A

HPLC separates and identifies hemoglobins based on varying ionic strength.

211
Q

How do hemoglobins interact with the column in HPLC?

A

Hemoglobins bind to a cation exchange column, and a buffer is injected to elute the hemoglobins at a predictable retention time.

212
Q

What does the retention time in HPLC indicate?

A

The retention time at which each hemoglobin comes off the column identifies the specific hemoglobin.

213
Q

How is the quantity of hemoglobin measured in HPLC?

A

The area under the peak in the HPLC output quantifies the fraction of hemoglobin present.

214
Q

What are the benefits of using HPLC for hemoglobin analysis?

A

HPLC is automated, user-friendly, and can confirm hemoglobin variants.

215
Q

What is the primary cause of the clinical manifestations in thalassemia?

A

Reduced or absent production of a particular globin chain.

216
Q

What results from the unequal production of α- or β-globin chains in thalassemia?

A

An imbalance in the production of α- or β-globin chains causes clinical manifestations in thalassemia.

217
Q

Which is more significant in causing the pathophysiology of thalassemia: reduced globin chain production or the α/β-globin chain imbalance?

A

The α/β-globin chain imbalance is more significant in causing the pathophysiology of thalassemia.

218
Q

What happens to the production of hemoglobin A (HbA) in β-Thalassemia?

A

There is a decrease in HbA production due to a β-globin gene mutation, leading to an excess of α-globin chains.

219
Q

What forms as a result of excess α-globin in β-Thalassemia?

A

Excess α-globin precipitates and forms inclusion bodies in RBC precursors, causing membrane damage and abnormal metabolism.

220
Q

What are the three main consequences of reduced HbA production in β-Thalassemia?

A
  1. Decreased hemoglobin per cell (hypochromia)
  2. Massive increase in immature RBC production
  3. Shortened RBC survival.
221
Q

What causes ineffective erythropoiesis in β-Thalassemia?

A

Massive death of RBC precursors in the bone marrow leads to ineffective erythropoiesis, with only a few abnormal RBCs surviving.

222
Q

What role does the spleen play in the pathology of β-Thalassemia?

A

The spleen sequesters abnormal RBCs, contributing to splenomegaly and hypersplenism.

223
Q

What are some systemic effects of tissue hypoxia caused by profound anemia in β-Thalassemia?

A

Tissue hypoxia leads to increased erythropoietin production, massive expansion of bone marrow, bony deformities, and increased gastrointestinal iron absorption.

224
Q

What are the complications of repeated blood transfusions in β-Thalassemia?

A

Transfusions can lead to iron overload and parenchymal iron deposition (hemachromatosis), causing damage to organs such as the liver, heart, and endocrine system.

225
Q

What are the complications of hypersplenism in β-Thalassemia?

A

Hypersplenism leads to increased hemoglobin catabolism, causing increased bilirubin levels and symptoms like jaundice, gallstones, and leg ulcers.

226
Q

What are the effects of iron overload in β-Thalassemia patients receiving frequent transfusions?

A

Iron overload leads to conditions such as cirrhosis, endocrine dysfunction, and cardiomyopathy.

227
Q

What does a skull radiograph typically show in β-Thalassemia?

A

The skull radiograph shows a “hair on end” appearance, which is a sign of severe bone marrow expansion.

228
Q

What bone-related abnormalities are seen in β-Thalassemia?

A

Severe osteoporosis, pseudofractures, thinning of the cortex, and bowing of the femur are common bone abnormalities in β-Thalassemia.

229
Q

What facial deformities are seen in untreated or inadequately treated β-Thalassemia patients?

A

Facial deformities include a small head, epicanthal folds, flat midface, smooth philtrum, thin upper lip, underdeveloped jaw, small eye openings, and a low nasal bridge.

230
Q

What causes the “hair on end” appearance in skull radiographs of β-Thalassemia patients?

A

The “hair on end” appearance is caused by excessive bone marrow activity due to chronic anemia, leading to marrow expansion.

231
Q

What skeletal deformities can occur in β-Thalassemia patients aside from cranial changes?

A

Aside from cranial changes, patients may experience bowing of the femur and other long bones due to marrow expansion and weakened bones.

232
Q

When do symptoms of β-Thalassemia typically begin to appear?

A

Symptoms of β-Thalassemia usually begin between 6–24 months of age, though individuals are typically asymptomatic during fetal life.

233
Q

What happens in α-Thalassemia due to a decrease in α-globin chains?

A

A decrease in α chains results in the accumulation of γ chains in the fetus and newborn, and β chains after 6 months of age.

234
Q

What stable tetramers form due to the accumulation of γ and β chains in α-Thalassemia?

A

Both γ and β chains are able to form stable tetramers, such as Hemoglobin H (Hgb H) from β chains.

235
Q

What is the result of tetramer formation in α-Thalassemia?

A

These tetramers precipitate in mature RBCs, forming inclusion bodies that are recognized and removed by splenic macrophages, leading to anemia.

236
Q

How does the accumulation of β-globin chains affect RBCs in α-Thalassemia?

A

Accumulation of β-globin chains results in the formation of β chain precipitates, which leads to the destruction of abnormal RBCs by the spleen.

237
Q

What hemoglobin forms from excess γ chains in α-Thalassemia, and when does it occur?

A

Excess γ chains form Hb Bart’s (γ₄) during fetal life and at birth.

238
Q

What is a key characteristic of Hb Bart’s (γ₄) in terms of oxygen affinity?

A

Hb Bart’s has a very high oxygen affinity, which leads to poor or no release of oxygen to tissues.

239
Q

What hemoglobin forms from excess β chains in α-Thalassemia, and when does it occur?

A

Excess β chains form Hb H (β₄), beginning a few weeks after birth and continuing throughout life.

240
Q

What is a vulnerability of Hb H (β₄) in α-Thalassemia?

A

Hb H is vulnerable to oxidation, leading to the formation of denatured hemoglobin bodies that precipitate out in RBCs.

241
Q

How does α-Thalassemia differ from β-Thalassemia in terms of its effects on different stages of life?

A

Unlike β-Thalassemia, α-Thalassemia affects the fetus and newborns due to the formation of pathological hemoglobins like Hb Bart’s and Hb H.

242
Q

What are the four categories of β-Thalassemia?

A

The four categories of β-Thalassemia are:

  1. β-Thalassemia silent carrier (heterozygous state)
  2. β-Thalassemia minor (heterozygous state)
  3. β-Thalassemia major (homozygous or compound heterozygous state)
  4. β-Thalassemia intermedia
243
Q

What is the genetic state of a β-Thalassemia silent carrier?

A

β-Thalassemia silent carrier is in the heterozygous state.

244
Q

What is the genetic state of β-Thalassemia minor?

A

β-Thalassemia minor is in the heterozygous state.

245
Q

What is the genetic state of β-Thalassemia major?

A

β-Thalassemia major is in the homozygous or compound heterozygous state.

246
Q

What is β-Thalassemia intermedia?

A

β-Thalassemia intermedia is a category that falls between β-Thalassemia minor and major in terms of severity.

247
Q

What is the genotype of a silent carrier of β-Thalassemia?

A

The genotype of a silent carrier of β-Thalassemia is βsilent/β.

248
Q

What are the hemoglobin levels (HbA, HbA2, HbF) in a silent carrier of β-Thalassemia?

A

In a silent carrier of β-Thalassemia:

HbA: Normal
HbA2: Normal
HbF: Normal

249
Q

What are the hematologic characteristics of a silent carrier of β-Thalassemia?

A

Silent carriers are asymptomatic and have normal hematologic parameters.

250
Q

What can result from a βsilent/β+ genotype?

A

A βsilent/β+ genotype can result in β-Thalassemia intermedia.

251
Q

What is the clinical outcome of a βsilent/βsilent genotype?

A

A βsilent/βsilent genotype results in a silent carrier state with no symptoms.

252
Q

What does the combination of βsilent and β° (β silent/β°) lead to in β-Thalassemia?

A

The combination of βsilent/β° leads to β-Thalassemia intermedia.

253
Q

What does a β°/β genotype represent in terms of β-Thalassemia?

A

A β°/β genotype represents β-Thalassemia minor.

254
Q

What are the possible genotypes for β-Thalassemia Minor?

A

The genotypes for β-Thalassemia Minor include:

β⁺/β
β⁰/β
δβ⁰/β

255
Q

How does hemoglobin A (HbA), hemoglobin A2 (HbA2), and hemoglobin F (HbF) levels change in β-Thalassemia Minor?

A

HbA: Decreased
HbA2: Increased
HbF: Normal to slightly increased (5-20%)

256
Q

What are the CBC findings in β-Thalassemia Minor?

A

Hemoglobin: Men – 110-150 g/L, Women – 100-130 g/L
RBC: Within reference interval or slightly elevated
MCV: Less than 75 fL
MCH: Less than 26 pg

257
Q

What are the reticulocyte levels in β-Thalassemia Minor?

A

Reticulocytes are within reference intervals or slightly increased.

258
Q

What peripheral blood smear (PBS) findings are typical in β-Thalassemia Minor?

A

PBS findings include:
Microcytic, hypochromic red blood cells
Target cells, elliptocytes, teardrop cells
Basophilic stippling

259
Q

What are the bone marrow findings in β-Thalassemia Minor?

A

Mild to moderate erythroid hyperplasia is typically seen in the bone marrow.

260
Q

What is the genotype for β Thalassemia Major?

A

The genotypes for β Thalassemia Major are: β⁺/β⁺, β⁺/β⁰, β⁰/β⁰.

261
Q

What are the hemoglobin levels in patients with β Thalassemia Major?

A

Hemoglobin levels are typically less than 70 g/L.

262
Q

How are RBC counts in β Thalassemia Major typically affected?

A

RBC counts are often within the reference interval or slightly elevated.

263
Q

What are the MCV and MCH values in β Thalassemia Major?

A

MCV: 50-70 fL, MCH: 12-20 pg.

264
Q

What are the chemistry results associated with β Thalassemia Major?

A

Serum haptoglobin is reduced or absent, and serum lactate dehydrogenase (LDH) is markedly elevated.

265
Q

How are reticulocytes affected in β Thalassemia Major?

A

Reticulocytes are mildly to moderately elevated.

266
Q

What findings are present in the peripheral blood smear (PBS) of β Thalassemia Major patients?

A

The PBS shows marked microcytosis and hypochromia, polychromasia, nucleated RBCs, target cells, teardrop cells, elliptocytes, RBC fragments, and inclusions such as basophilic stippling, Howell-Jolly bodies, and Pappenheimer bodies.

267
Q

What bone marrow changes are observed in β Thalassemia Major?

A

There is marked erythroid hyperplasia in the bone marrow.

268
Q

What hemoglobin types are seen in β Thalassemia Major for β⁺/β⁺ genotype?

A

Hb A is significantly decreased, Hb A₂ is variable, and Hb F is elevated.

269
Q

What hemoglobin types are seen in β Thalassemia Major for β⁺/β⁰ genotype?

A

Hb A is decreased, Hb A₂ is variable, and Hb F is elevated.

270
Q

What hemoglobin types are seen in β Thalassemia Major for β⁰/β⁰ genotype?

A

Hb A is absent, Hb A₂ is variable, and Hb F is elevated.

271
Q

What are the characteristic RBC findings on the peripheral blood smear (PBS) in β Thalassemia Major?

A

Marked microcytosis and hypochromia.

272
Q

What does polychromasia and nucleated RBCs (nRBCs) on the PBS indicate in β Thalassemia Major?

A

Ineffective but increased production of RBCs due to elevated erythropoietin (EPO).

273
Q

What does the presence of target cells, teardrop cells, elliptocytes, and RBC fragments suggest in β Thalassemia Major?

A

Increased destruction of RBCs in the bone marrow and spleen.

274
Q

Which RBC inclusions are commonly seen on the PBS in β Thalassemia Major?

A

Basophilic stippling, Howell-Jolly bodies (HJ), and Pappenheimer bodies.

275
Q

What is the cause of the decreased hemoglobin (Hb) production in β Thalassemia Major as seen on the PBS?

A

Ineffective erythropoiesis leads to decreased Hb production.

276
Q

What are the main types of poikilocytes seen on the PBS in β Thalassemia Major?

A

Target cells, teardrop cells, elliptocytes, and RBC fragments.

277
Q

Why is there increased erythropoietin (EPO) production in β Thalassemia Major?

A

Due to ineffective erythropoiesis and anemia, there is a compensatory increase in EPO to stimulate RBC production.

278
Q

What are the conventional therapies for β Thalassemia Major?

A

Conventional therapies include iron chelation with drugs like Deferoxamine, Deferiprone, and Deferasirox.

279
Q

What role does iron chelation therapy play in the treatment of β Thalassemia Major?

A

Iron chelation is used to reduce excess iron buildup due to frequent blood transfusions.

280
Q

What is the purpose of pharmaceutical induction of γ-globin in β Thalassemia Major?

A

The purpose is to stimulate the production of γ-globin, which can compensate for the defective β-globin, reducing the severity of the disease.

281
Q

Name some pharmaceutical agents used to induce γ-globin production in β Thalassemia Major.

A

Hydroxyurea, 5-azacytidine, and Decitabine are used to induce γ-globin production.

282
Q

What epigenetic regulation strategies are used in β Thalassemia Major treatment?

A

SCFAD (Butyrate) and transcription factor inhibitors, such as BCL11A and KLF1/C-MYB, are used to regulate γ-globin expression through epigenetic changes.

283
Q

What advanced therapies are available for β Thalassemia Major?

A

Advanced therapies include gene and cell therapy, which involves transduction of autologous hematopoietic stem cells (HSCs) with β or γ-globin vectors.

284
Q

How does gene and cell therapy work in β Thalassemia Major?

A

Gene and cell therapy involves introducing corrected genes into the patient’s stem cells, followed by freezing, release testing, and reintroduction into the body after conditioning with a myeloablative or immunosuppressive regimen.

285
Q

What is allogeneic hematopoietic stem cell (HSC) transplantation, and how is it used in β Thalassemia Major?

A

Allogeneic HSC transplantation is a curative approach where hematopoietic stem cells from a donor (either matched/unmatched, related/unrelated) are transplanted into the patient.

286
Q

What conditioning regimen is necessary before gene or HSC therapy in β Thalassemia Major?

A

A myeloablative or immunosuppressive regimen is necessary to prepare the body for the introduction of gene-corrected or donor stem cells.

287
Q

What is GVHD prophylaxis, and why is it important in β Thalassemia Major treatment?

A

GVHD prophylaxis (Graft-Versus-Host Disease) is crucial in allogeneic HSC transplantation to prevent the donor immune cells from attacking the recipient’s body.

288
Q

What is β Thalassemia Intermedia?

A

It is a form of Non-Transfusion-Dependent Thalassemia characterized by mild to moderate anemia and microcytic, hypochromic red blood cells.

289
Q

What genotypes are associated with β Thalassemia Intermedia?

A

βsilent/βsilent
β+/βsilent or β0/βsilent

290
Q

How are hemoglobin levels affected in β Thalassemia Intermedia?

A

Hb A: Decreased
Hb A2: Increased
Hb F: Increased

291
Q

What are the common lab findings in β Thalassemia Intermedia?

A

Hemoglobin: 70 - 100 g/L
RBC: Within reference interval or slightly elevated
MCV: 50 - 80 fL
MCH: 16 - 24 pg
Platelet and neutrophil counts: Low

292
Q

What is a potential complication for patients with β Thalassemia Intermedia?

A

Patients may develop iron overload, and they must be monitored for this condition after the age of 10.

293
Q

What is the Hgb A percentage in β Thalassemia Major?

A

Approximately 0% (Hgb A is only produced if a β+ mutation is present and ranges from 10% to 30%).

294
Q

What is the Hgb A2 percentage in β Thalassemia Major?

A

2-5%.

295
Q

What is the Hgb F percentage in β Thalassemia Major?

A

92-95%.

296
Q

What is the Hgb A percentage in β Thalassemia Intermedia?

A

5-35%.

297
Q

What is the Hgb A2 percentage in β Thalassemia Intermedia?

A

2-5%.

298
Q

What is the Hgb F percentage in β Thalassemia Intermedia?

A

60-95%.

299
Q

What is the Hgb A percentage in β Thalassemia Minor?

A

92-95%.

300
Q

What is the Hgb A2 percentage in β Thalassemia Minor?

A

3.5-7%

301
Q

What is the Hgb F percentage in β Thalassemia Minor?

A

1-5%

302
Q

How does RBC count differ between β Thalassemia Minor and IDA?

A

β Thalassemia Minor: Elevated RBC
IDA: Normal or slightly decreased RBC

303
Q

How does MCV differ between β Thalassemia Minor and IDA?

A

β Thalassemia Minor: Greatly decreased MCV with mildly decreased Hb
IDA: Normal or decreased MCV proportional to Hb decrease

304
Q

How does Hb change in β Thalassemia Minor compared to IDA?

A

β Thalassemia Minor: Chronic, steady decrease in Hb
IDA: Increasingly severe decrease in Hb

305
Q

What are the peripheral blood smear (PBS) findings in β Thalassemia Minor vs. IDA?

A

β Thalassemia Minor: Marked hypochromia/microcytosis, target cells, teardrop cells, increased polychromasia, basophilic stippling

IDA: Moderate to marked hypochromia/microcytosis, pencil cells, target cells, normal polychromasia

306
Q

How do serum iron levels compare between β Thalassemia Minor and IDA?

A

β Thalassemia Minor: Normal or increased serum iron
IDA: Decreased serum iron

307
Q

How does serum ferritin compare between β Thalassemia Minor and IDA?

A

β Thalassemia Minor: Normal or increased serum ferritin
IDA: Decreased serum ferritin

308
Q

How does TIBC (Total Iron-Binding Capacity) differ in β Thalassemia Minor vs. IDA?

A

β Thalassemia Minor: Normal or decreased TIBC
IDA: Increased TIBC

309
Q

How do reticulocyte levels compare between β Thalassemia Minor and IDA?

A

β Thalassemia Minor: Approximately 5%
IDA: Normal reticulocyte levels

310
Q

What special tests are used to differentiate β Thalassemia Minor from IDA?

A

β Thalassemia Minor: Elevated Hb A2 levels
IDA: Normal Hb A2 levels

311
Q

Why should iron deficiency be ruled out before evaluating Hb A2 levels for β Thalassemia Minor?

A

Low iron levels in β Thalassemia Minor patients can reduce Hb A2 levels, so iron stores should be replenished before testing for Hb A2.

312
Q

What are the four clinical syndromes of α-thalassemia?

A

Silent carrier state
α-thalassemia minor
Hb H disease
Hb Bart hydrops fetalis syndrome

313
Q

What determines the severity of α-thalassemia syndromes?

A

The number of genes affected and the amount of α chains produced.

314
Q

What is the silent carrier state in α-thalassemia?

A

A condition where one α-globin gene is deleted, but there are no clinical symptoms, and α chain production is near normal.

315
Q

What is α-thalassemia minor?

A

A condition where two α-globin genes are deleted, leading to mild anemia but generally asymptomatic.

316
Q

What is Hb H disease in α-thalassemia?

A

A condition where three α-globin genes are deleted, resulting in moderate to severe anemia and the production of Hb H (β4 tetramers).

317
Q

What is Hb Bart hydrops fetalis syndrome?

A

The most severe form of α-thalassemia where all four α-globin genes are deleted, leading to no α chain production, severe anemia, and typically fetal death.

318
Q

What is the genetic designation for normal α genes in α-thalassemia?

A

αα/αα (No gene deletions, normal α chain production).

319
Q

What is the genetic designation for the silent carrier state in α-thalassemia?

A

-α/αα (One gene deletion).

320
Q

What is the genetic designation for α-thalassemia minor with a heterozygous deletion?

A
  • -/αα (Two gene deletions, one from each chromosome).
321
Q

What is the genetic designation for α-thalassemia minor with a homozygous deletion?

A

-α/-α (Two gene deletions, one from each copy of the gene on both chromosomes).

322
Q

What is the genetic designation for Hb H disease (α-thalassemia intermedia)?

A
  • -/-α (Three gene deletions).
323
Q

What is the genetic designation for Hydrops fetalis (α-thalassemia major)?

A
  • -/- - (Four gene deletions, leading to no α chain production).
324
Q

What is the Hb A level in the silent carrier of α-thalassemia?

A

Normal (N).

325
Q

What is the Hb Bart percentage in newborns with the silent carrier of α-thalassemia?

A

1-2%

326
Q

Is Hb H present in adults with the silent carrier of α-thalassemia?

A

No, Hb H is absent (0%).

327
Q

What is the effect of one α-globin gene deletion in the silent carrier state?

A

There is a slight decrease in α chain production, but the α/β chain ratio remains nearly normal.

328
Q

Are there any hematologic abnormalities present in the silent carrier of α-thalassemia?

A

No, there are no hematologic abnormalities present.

329
Q

What causes α-thalassemia minor?

A

The deletion of two α-globin genes.

330
Q

What are the two forms of α-thalassemia minor?

A

Homozygous α⁺ (-α/-α)
Heterozygous α⁰ (–/αα)

331
Q

What are the Hb A levels in α-thalassemia minor (trait)?

A

Slightly decreased.

332
Q

What are the Hb Bart levels in newborns with α-thalassemia minor?

A

5-15%.

333
Q

Is Hb H present in adults with α-thalassemia minor?

A

No, Hb H is absent (0%).

334
Q

What is the clinical presentation of α-thalassemia minor?

A

It is asymptomatic and characterized by mild microcytic anemia with MCV < 80 fL and MCH < 27 pg.

335
Q

What causes Hemoglobin H (Hb H) disease?

A

The deletion of three α-globin genes, leaving only one α-globin gene to produce α chains (–/-α).

336
Q

What is the characteristic feature of Hb H disease at the molecular level?

A

Accumulation of unpaired β chains forming tetramers of Hb H in adults.

337
Q

What are the CBC findings in Hb H disease?

A

Hemoglobin levels between 70-100 g/L.

338
Q

What is the reticulocyte count in Hb H disease?

A

3-10%.

339
Q

What are the peripheral blood smear (PBS) findings in Hb H disease?

A

Microcytic, hypochromic red cells
Marked poikilocytosis, including target cells, bizarre shapes, and basophilic stippling
Hb H bodies seen in a supravital stain, appearing as “golf-ball” like structures

340
Q

What is observed in the bone marrow in Hb H disease?

A

Mild to moderate erythroid hyperplasia.

341
Q

What is the genotype for Hb H disease?

A

–/-α.

342
Q

What are the Hb A levels in Hb H disease?

A

Decreased.

343
Q

What are the Hb Bart levels in newborns with Hb H disease?

A

10-40%.

344
Q

What are the Hb H levels in adults with Hb H disease?

A

1-40%, with remaining Hb A and small amounts of Hb A2 and Hb Bart.

345
Q

How are Hb H bodies visualized?

A

Hb H bodies are visualized using a supravital stain.

346
Q

What do Hb H inclusions look like?

A

They appear as small, multiple, irregularly shaped greenish-blue bodies that are uniformly distributed throughout the red blood cell (RBC).

347
Q

What distinctive pattern do Hb H inclusions create on the RBC surface?

A

The inclusions create a pitted pattern on the RBC surface, similar to the pattern of a golf ball.

348
Q

How do Heinz bodies differ from Hb H bodies in appearance?

A

Heinz bodies are larger, fewer in number, and most often appear attached to the inner membrane of the RBC.

349
Q

What stain is used to visualize Heinz bodies?

A

Heinz bodies, like Hb H bodies, are best visualized using a supravital stain.

350
Q

Do most patients with Hemoglobin H disease require treatment?

A

No, most patients with Hemoglobin H disease require no treatment.

351
Q

When might a transfusion be required for patients with Hemoglobin H disease?

A

Transfusions may be required during hemolytic episodes.

352
Q

What should be promptly treated in patients with Hemoglobin H disease?

A

Infections should be treated promptly.

353
Q

What types of drugs should be avoided in Hemoglobin H disease?

A

Oxidant drugs should be avoided.

354
Q

What complication may develop in patients with Hemoglobin H disease, and how should it be managed?

A

Patients may develop iron overload, so their iron status should be monitored.

355
Q

What is absent in Hb Bart Hydrops Fetalis Syndrome?

A

All α-globin chains are absent.

356
Q

What is the predominant hemoglobin in Hb Bart Hydrops Fetalis Syndrome, and what is its significance?

A

Hb Bart (γ4) is the predominant hemoglobin, which has a very high oxygen affinity and will not release oxygen to tissues.

357
Q

How is the fetus able to survive until the third trimester in Hb Bart Hydrops Fetalis Syndrome?

A

The fetus survives because of Hb Portland (ζ2γ2), but it cannot support development beyond the third trimester.

358
Q

What happens to the fetus in Hb Bart Hydrops Fetalis Syndrome as it progresses?

A

The fetus becomes anoxic and is delivered prematurely as a stillborn with cardiac failure and severe edema (hydrops fetalis).

359
Q

What are the Hb A levels in Hb Bart Hydrops Fetalis Syndrome?

A

0 (no Hb A is produced).

360
Q

What are the Hb Bart levels in newborns with Hb Bart Hydrops Fetalis Syndrome?

A

80-90%, with the remainder being Hb Portland.

361
Q

What are the Hb H levels in adults with Hb Bart Hydrops Fetalis Syndrome?

A

Not applicable (NA) since the condition leads to stillbirth.

362
Q

What is the hemoglobin range in Hb Bart Hydrops Fetalis Syndrome?

A

Hemoglobin is between 30-80 g/L.

363
Q

How are reticulocyte levels affected in Hb Bart Hydrops Fetalis Syndrome?

A

Reticulocyte levels are increased.

364
Q

What are the peripheral blood smear (PBS) findings in Hb Bart Hydrops Fetalis Syndrome?

A

Marked microcytic and hypochromic red blood cells with numerous nucleated red blood cells (nRBCs).

365
Q

What is observed in the bone marrow of patients with Hb Bart Hydrops Fetalis Syndrome?

A

Marked erythroid hyperplasia

366
Q

What is the primary treatment for Hb Bart Hydrops Fetalis Syndrome to avoid death in utero or shortly after birth?

A

Aggressive transfusion therapy, including intrauterine transfusions.

367
Q

What is the prognosis if a neonate with Hb Bart Hydrops Fetalis Syndrome survives?

A

Lifelong transfusions are required.

368
Q

What are the hemoglobin levels in a normal individual for HbA, Hb Bart (in newborn), and HbH (in adults)?

A

HbA: 95-98%
Hb Bart: 0%
HbH: 0%

369
Q

What is the genotype and Hb Bart level in newborns for a silent carrier of α-thalassemia?

A

Genotype: -α/αα
Hb Bart: 1-2%

370
Q

What are the HbA and HbH levels for a silent carrier of α-thalassemia?

A

HbA: 95-98%
HbH: 0%

371
Q

What are the genotypes for α-thalassemia minor, and what are the Hb Bart levels in newborns?

A

Genotypes: –/αα or -α/-α
Hb Bart: 5-15%

372
Q

What are the HbA and HbH levels in adults with α-thalassemia minor?

A

HbA: 85-95%
HbH: <1%

373
Q

What is the genotype and Hb Bart level in newborns for HbH disease (α thalassemia intermedia)?

A

Genotype: –/-α
Hb Bart: 10-40%

374
Q

What are the HbA and HbH levels in adults with HbH disease?

A

HbA: Decreased
HbH: 1-40%

375
Q

What is the genotype and Hb Bart level in newborns with α-thalassemia major (hydrops fetalis)?

A

Genotype: –/–
Hb Bart: 80-90% (with 5-20% Hb Portland)

376
Q

What are the HbA and HbH levels in adults with α-thalassemia major?

A

HbA: 0%
HbH: 0-20%

377
Q

What are the possible offspring genotypes if both parents have one heterozygous α-thalassemia minor and one homozygous α-thalassemia minor?

A

–/– (Hydrops fetalis)
–/-α (Hb H disease)
-α/-α (α-thalassemia minor)
-α/αα (Silent carrier)

378
Q

What is the risk of having a child with Hb H disease if one parent has homozygous α-thalassemia minor (-α/-α) and the other has heterozygous α-thalassemia minor (-α/αα)?

A

There is a 50% chance of the child having Hb H disease (–/-α).

379
Q

What are the possible offspring genotypes if both parents have heterozygous α-thalassemia minor (-α/αα)?

A

–/– (Hydrops fetalis)
–/-α (Hb H disease)
-α/αα (Silent carrier)
αα/αα (Normal)

380
Q

If both parents have α-thalassemia minor (-α/-α), what is the risk of having a child with Hb H disease?

A

There is a 25% chance of the child having Hb H disease (–/-α).

381
Q

What determines the severity of clinical disease in Hemoglobin S – Thalassemia (Sickle-Thalassemia)?

A

The severity depends on how much Hb A is produced.

382
Q

How can individuals with Sickle-Thalassemia be distinguished from those with sickle cell anemia?

A

They can be distinguished by the presence of microcytes on the peripheral blood smear (PBS) and increased levels of Hb A2.

383
Q

What happens when a β⁺ or βsilent gene is inherited in Sickle-Thalassemia?

A

Hb A levels are present but less than the Hb S level, and splenomegaly is present alongside microcytes and increased Hb A2.

384
Q

What are the hemoglobin levels in Hb S – β⁺ thalassemia?

A

Hb A: Decreased
Hb A2: Increased
Hb F: Normal to increased
Hb S: Greater than Hb A

385
Q

What are the hemoglobin levels in Hb S – β⁰ thalassemia?

A

Hb A: Absent
Hb A2: Increased
Hb F: Normal to increased
Hb S: Present

386
Q

What RBC morphology is seen in Sickle-Thalassemia?

A

Microcytes, sickle cells, and target cells.

387
Q

What are the clinical manifestations of Sickle-Thalassemia?

A

They range from mild to severe anemia with recurrent vaso-occlusive episodes.

388
Q

What is the treatment for Sickle-Thalassemia?

A

Treatment ranges from no treatment to transfusion support and pain control.

389
Q

What physical findings suggest thalassemia?

A

Pallor (due to anemia)
Jaundice (due to hemolysis)
Splenomegaly (due to sequestration of abnormal RBCs and extramedullary erythropoiesis)
Skeletal deformities (due to expansion of the bone marrow cavities)

390
Q

What laboratory methods are used to diagnose thalassemia in a CBC?

A

RBC count: Normal to increased
Hb, HCT, MCV, MCH, MCHC: Decreased
RDW: Normal to increased

391
Q

What findings are expected in a peripheral blood smear (PBS) for thalassemia?

A

Microcytic, hypochromic RBCs with target cells
Elliptocytes
Increased polychromasia
Nucleated RBCs (nRBCs)
Basophilic stippling, Howell-Jolly bodies, and Pappenheimer bodies

392
Q

What is the reticulocyte count in thalassemia?

A

Normal to increased.

393
Q

What does supravital staining reveal in Hemoglobin H (Hb H) disease?

A

Many RBCs positive for Hb H inclusions in Hb H disease
Few RBCs positive for Hb H inclusions in α-thalassemia minor
Rare RBCs positive for Hb H inclusions in the silent carrier of α-thalassemia

394
Q

What are the biochemical findings in thalassemia?

A

Increased unconjugated bilirubin
Increased lactate dehydrogenase (LDH)
Decreased haptoglobin

395
Q

What is the purpose of hemoglobin electrophoresis (alkaline pH) in thalassemia diagnosis?

A

It is used to identify common and fast-moving hemoglobins by scanning a gel subjected to electrical current to visualize hemoglobin bands. Each hemoglobin band is reported as a percentage of total hemoglobin.

396
Q

What is a limitation of hemoglobin electrophoresis for quantifying Hb A2 and Hb F?

A

Fast-moving hemoglobins may run off the gel or have poor resolution, making it difficult to accurately quantify Hb A2 and Hb F, so confirmation is needed.

397
Q

How does High-Performance Liquid Chromatography (HPLC) work for thalassemia diagnosis?

A

Various hemoglobin types elute from a cation-exchange column at specific known times (retention time), visualized as peaks on a chromatogram. The area under each peak quantifies the hemoglobin fraction.

398
Q

Why is HPLC suited for β-thalassemia screening?

A

HPLC can accurately and quickly quantify Hb A, Hb A2, and Hb F, making it ideal for β-thalassemia screening.

399
Q

What role does molecular genetic testing play in thalassemia diagnosis?

A

Molecular genetic testing is required to detect specific mutations in globin genes and definitively identify the type of thalassemia.

400
Q

What does a normal hemoglobin electrophoresis result show?

A

Bands for Hb A, Hb F, and Hb A2.

401
Q

What does an abnormal hemoglobin electrophoresis result show in thalassemia?

A

The presence of additional bands for variant hemoglobins, such as Hb Bart’s or Hb H, which move quickly and may run off the gel.

402
Q

Why do fast-moving hemoglobins like Hb Bart’s or Hb H have poor resolution in electrophoresis?

A

They move quickly to the edges of the gel, leading to poor resolution or running off the gel.

403
Q

What is the hemoglobin distribution in a newborn?

A

Hb A: 20-30%
Hb F: 65-90%
Hb A2: < 1.0%

404
Q

What is the hemoglobin distribution in β-thalassemia intermedia?

A

Hb A: 5-35%
Hb F: 60-95%
Hb A2: 2-5%

405
Q

Why is it important to consider the patient’s age when diagnosing thalassemia?

A

A newborn’s hemoglobin distribution (with high Hb F and low Hb A) can resemble the hemoglobin distribution in β-thalassemia intermedia, making it important to differentiate based on age.

406
Q

How does hemoglobin distribution change as a baby grows older?

A

In older babies, the percentage of Hb A increases, and Hb F decreases, but in patients with β-thalassemia intermedia, Hb F remains high, and Hb A remains low, leading to a similar appearance.

407
Q

Why can a newborn’s hemoglobin distribution look similar to that of a patient with β-thalassemia intermedia?

A

Both can have elevated levels of Hb F and low levels of Hb A, so it is essential to consider patient age when interpreting results.

Hematology (6 decks)

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