Hemoglobinopathies

Question 1

Types of hemoglobin

Answer 1

A: α2β2

A2: α2δ2

F: α2γ2

Question 2

β Thalassemia

Answer 2

For whatever reason, beta chain production is down relative to alpha. Thus, you end up with an excess of alpha chains, which are usually degraded in thalassemia trait, but can aggregate and cause apoptosis in homozygotes.

Less hemoglobin A is produced overall, hence the cells are microcytic and have a higher proportion of A2 and F.

Question 3

Which chromosomes are each of the globin genes on?

Answer 3

Alpha is on 16

All the others are on 11

Question 4

An α thalassemia trait individual has ___ α genes.

Answer 4

An α thalassemia trait individual has 2 α genes.

People with 3 get along without any symptoms as silent carriers.

Question 5

Hb H disease

Answer 5

When a patient has only one α chain.

Results in a substantial β chain excess that precipitates β tetramers. These are insoluble and will quickly cause apoptosis of erythroid precursors, resulting in a hemolytic anemia. Surviving cells will be microcytic and may be targeted.

Question 6

α Thalassemia major

Answer 6

Aka hydrops fetalis

No α chains. Most common in individuals of Asian ancestry.

γ chain tetramers form, but are incapable of releasing oxygen.

These individuals usually succumb to death before or shortly after birth. Generalized edema is a consequence of tissue hypoxia.

Question 7

What causes Hb S to aggregate?

Answer 7

βs has a Glu ⇒ Val mutation. This valine is exposed to the aqueous environment when Hb S is deoxygenated.

But, under certain low pH, low temperature, high concentration, or prolonged temporal conditions, these valines are prone to aggregation with one another.

Question 8

Irreversibly sickled cells

Answer 8

Small percentage of red cells in a sickle cell patient that are sickled at baseline, regardless of temperature, pH, or oxygenation. These are the ones we see on blood smear

Question 9

Which organs are inherently at risk for sickle cell crisis and why?

Answer 9

The spleen, marrow, and venous sinusoids of the corpus cavernosa. These are particularly at risk because they have slow circulation.

The brain, because it is a site of high risk for proliferative vasculopathy, which in turn slows local circulation.

Question 10

In all hemoglobinopathies, there may be ____ at the stage of erythroid precursors.

Answer 10

In all hemoglobinopathies, there may be apoptosis at the stage of erythroid precursors.

Thus, any of them can potentially result in jaundice or scleral icertus.

Question 11

Most diseases resulting in ineffective erythropoiesis will also result in ___ as a complication.

Answer 11

Most diseases resulting in ineffective erythropoiesis will also result in iron overload as a complication.

Develops because of the combined effects of enhanced absorption of iron from the gastrointestinal tract and red cell transfusions

Question 12

Side effects of high levels of EPO and high erythroid progenitor proliferation

Answer 12

• Extramedullary hematopoiesis
• Expansion of erythroid marrow into the peripheral skeleton leads to osteopenia

Question 13

Answer 13

β Thalassemia blood smear

Note the microcytosis, target cells, and red cell stippling (aka punctate basophilia, granular red cells)

Question 14

Clinical presentaiton of β Thalassemia Major

Answer 14

• Presents at very young age, <1st year of life
• Hepatosplenomegaly (extramedullary hematopoiesis and splenic clearance)
• Iron overload
• Fair-skinned patients often have a light bronze appearance, due to a combination of pallor, icterus, and enhanced skin pigmentation
• deformities of the frontal bones and/or maxillary bones (“chipmunk face”)
• malocclusion of the jaw
• Widespread osteopoenia

Question 15

Following splenectomy, β thalassemia patients have a marked expansion of ___ in blood.

Answer 15

Following splenectomy, β thalassemia patients have a marked expansion of nucleated erythroid precursors in blood.

Question 16

The antenatal diagnosis of homozygous or compound heterozygous β-thalassemia can be made by analysis of fetal DNA obtained by ____.

Answer 16

The antenatal diagnosis of homozygous or compound heterozygous β-thalassemia can be made by analysis of fetal DNA obtained by chorionic villus biopsy

Question 17

Skeletal deformities in β thalassemia patients may be prevented by ___.

Answer 17

Skeletal deformities in β thalassemia patients may be prevented by staying on top of blood transfusions.

Think about it: The skeletal deformities are a manifestation of widespread hematopoiesis, which is the result of high EPO due to hypoxia in the kidney. Giving frequent transfusions keeps the kidney oxygenated, decreasing EPO and preventing widespread/extramedullary hematopoiesis.

Unfortunately, this also presdisposes to iron overload

Question 18

Why do many β thalassemia patients benefit from splenectomy?

Answer 18

It improves survival of endogenous red cells and therefore reduces the transfusion requirement. Thus, it also helps ward off iron overload.

However, splenectomies have been associated with an increased risk of deep venous thrombosis and pulmonary embolus as patients get older.

Question 19

β-Thalassemia Intermedia

Answer 19

Still homozygous, but many have β⁺-thalassemia alleles which still produce some functional β. They may also have a coinherited α-thalassemia, which actually makes clinical presentation better by reducing the imbalance!

Patients with β-thalassemia intermedia by definition are not transfusion dependent.

Question 20

β^E or E/β Thalassemia

Answer 20

The β^E mutation is a single base substitution at the boundary between exon 1 and intron 1, leading to impaired splicing and therefore lowered β-globin expression. Accordingly, Hb E produces a phenotype resembling a very mild form of β+-thalassemia.

Question 21

α-thalassemia, β-thalassemia, and sickle cell mutation all confer resistance to. . .

Answer 21

Plasmodium falciparum

This explains why hemoglobinopathies are so prevalent. Malaria has had an enormous impact on our evolutionary history.

Question 22

Answer 22

Hemoglobin H disease, aka triple Hb α deletion

Note small red cells with prominent pale target cells and considerable variation in red cell size.

Question 23

Answer 23

Hydrops fetalis, aka α-Thalassemia Major

This film shows small, often misshaped, red cells and nucleated erythroid precursors with varying degrees of maturation.

Star-candy appearance

Question 24

Answer 24

Sickle Cell

Question 25

Rarely sickle cell trait individuals sustain ___

Answer 25

Rarely sickle cell trait individuals sustain splenic infarction, stroke, or sudden death following strenuous military or athletic training, particularly at high altitude

Question 26

Of all places in the human body, ____ is particularly susceptible to sickle cell infarction.

Answer 26

Of all places in the human body, the renal medulla is particularly susceptible to sickle cell infarction.

Question 27

___ inhibits the polymerization of Hb S

Answer 27

Hb F inhibits the polymerization of Hb S

Not only because it can’t itself polymerize, but because it cannot be induced into a Hb S polymer

Question 28

The rate at which polymerization and sickling occur depends primarily on ___ and ___.

Answer 28

The rate at which polymerization and sickling occur depends primarily on extent of deoxygenation and concentration of Hb S.

Question 29

Effects of sickling on the sickled red cell itself

Answer 29

Causes membrane damage that may lead to intracellular calcium leakage.

The increased calcium activates an outward directed potassium channel, leading to loss of both potassium and water. As SS red cells become progressively dehydrated, the increasing intracellular hemoglobin concentration greatly lowers the delay time, thereby enhancing sickling.

This is how a red cell becomes irreversibly sickled

Question 30

The most important variable affecting the clinical severity of sickle cell disease is ___.

Answer 30

The most important variable affecting the clinical severity of sickle cell disease is the level of Hb F.

Question 31

Ways of diagnosing Sickle Cell

Answer 31

• Genotype
• Electrophoresis (S has its own band)
• Precipitation properties (Hb S can be induced to precipitate much more easily than A, A2, or F)

Question 32

Clinical picture for Sickle Cell

Answer 32

• Anemia
• Vaso-occlusion (sickle cell crisis)
• Acute chest syndrome (vaso-occlusive crisis of the lungs), most common cause of death for individuals of all ages with SS
• Chronic multiorgan complications from vaso-occlusive events
• Frequent dermal ulcerations (caused by a mix of factors)
• Sickle cell retinopathy​ (leading cause of mono-ocular blindness)
  *

Question 33

Therapy for sickle cell patients

Answer 33

• Hydroxyurea to increase Hb F
• Have low threshold for antibiotics for sickle cell patients, as infections are frequent
• Stem cell transplant
• Splenectomy may be necessary in many patients in order to prevent autosplenectomy and sepsis from spleen necrosis

Question 34

How do you tell alpha thalassemia trait and beta thalassemia trait apart without genetic testing?

Answer 34

Alpha thalassemia trait has normal HbA2, while it is elevated in beta thalassemia trait.

Question 35

How do blood smears change when you remove the spleen from thalassemia patients?

Answer 35

• Increased nucleated erythroid precursors
• Increased Howley-Jolly bodies (nuclear remnants)
• Increased targetoid cells

Question 36

Definition of acute chest syndrome

Answer 36

The combination of:

1. Fever
2. Any respiratory symptom
3. New pulmonary infiltrate on CXR

Question 37

Viruses which may cause aplastic crisis (acute suppression of bone marrow, especially erythroid cells)

Answer 37

• Parvovirus (this one specifically attacks erythroid precursors)
• EBV (this and below suppress all marrow cells)
• CMV