3. Hemoglobinopathies and Thalassemias

Hemoglobinopathy

a hereditary disorder in which a structural abnormality results from an alteration of the DNA genetic code for one or more globin chains

HbA has what chains?

2 alpha and 2 beta

HbA2 has what chains?

2 alpha and 2 delta

HbF has what chains?

2 alpha and 2 gamma

Most common adult hemoglobin is…

HbA

Gene mutations commonly affect the … chain of adult hemoglobin A

beta

Will an individual with one normal globin gene and one mutant gene have the trait or the disease?

The trait

Will an individual with both mutant globin genes (with both parents having the mutation) have the trait or the disease?

The disease

Is the disease or trait symptomatic?

Disease

Sickle cell anemia is most commonly found in person of … ancestry

African

Sickle Cell anemia occurs from a mutation in the 6th nucleotide position of the beta chain. This changes glutamic acid to…

Valine 

Production of Hemoglobin S from the hemoglobin mutation results in the production of…

sickled RBCs

In sickle cell anemia, when the hemoglobin molecules picks up the oxygen in the lungs (oxyhemoglobin). What shape does the RBC have?

Normal discoid shape

In sickle cell anemia, when the hemoglobin molecules release oxygen into the tissues (deoxyhemoglobin). What shape does the RBC have?

The sickle shape

What causes the characteristic sickle shape in sickle cell anemia after oxygen is released?

The hemoglobin chains become sticky and coil into long rods that distort the cell

Do sickle cells go back to their normal shape after picking up oxygen again?

yes - tis a cycle

In sickle cell anemia, the flexibility of the RBCs decreases and will eventually not be able to return to normal shape. This decreases the lifespan and premature death leading to…

hemolytic anemia

The sickled cells cause

blockages i.e. no oxygen

Sickle cell crises occur no more than …

6 a year

Acidosis, hypoxia, dehydration, infection, fever, exposure to extreme cold, and excessive exercise

These factors can trigger a what?

Sickle Cell crisis

What has this blood picture?

• normochromic, normocytic anemia

• elevated RDW

• Retics and NRBCs

• Poikilocytosis

Sickle cell anemia

What is another name for sickled cells?

drepanocytes

Screening for sickle cell anemia is from the

Sickledex solubility test where HgbS forms a cloudy solution

What is the confirmation test for Hgb S?

Hemoglobin electrophoresis

Electrophoresis

process that causes movement of particles in an electric field, resulting in bands that separate toward one end or the other 

Major component of hgb in normal RBC

Hgb A1

Minor component of hgb in normal RBC (~2-3% total)

Hgb A2

Major hemoglobin in fetus, minimal in adults

Hgb F

Abnormal form of hemoglobin associated with sickle cell disease

Hgb S

A hemoglobin variant, resulting in mild to severe hemolytic anemia

Hgb C

Purpose of hemoglobin electrophoresis

To separate and identify different types of hemoglobin based on charge

At alkaline (pH ~8.6), which hgb moves the fastest toward positive end?

Hgb A

Why is acid electrophoresis sometimes used in addition to alkaline?

To confirm results, because some hemoglobins migrate together at alkaline pH

The treatment of sickle cell anemia is hydroxyurea. This induces … production which blocks the interactions between the deoxygenated hemoglobin S molecules

fetal hemoglobin

The hydroxyurea gene therapy blocks the transcription factor …, that represses fetal hemoglobin expression

BCL11A

The sickle cell TRAIT appears to offer protection to … 

Malaria

Why people are people with the sickle cell trait more protected against malaria?

Malaria parasites utilize the oxygen in cells. The parasites affect the oxygen in cell, causing them to sickle and become subsequently phagocytized in spleen.

Is this for the sickle disease or trait?

• no drepanocytes

• normal pb smears, maybe some targets

• solubility test +

• Electrophoresis

  • HbA - 50-65%

  • HgbS - 35-45%

  • HgF - normal

  • HgbA2 - normal

Trait

Hemoglobin C disease occurs from a mutation in the 6th nucleotide position of the beta chain. This changes glutamic acid to…

lysine

Hemoglobin C disease results in

decreased solubility for deoxygenated hemoglobin leading to washington monument shaped crystals

Deformed cells from hemoglobin C are removed by spleen leading to

mild to moderate hemolytic anemia

What has this blood pictures?

• normochromic, normocytic anemia

• target cells and hgb C crystals

• Reticulocytosis

Hemoglobin C

Definitive diagnosis for Hemoglobin C is from…

hemoglobin electrophoresis

Is treatment for Hemoglobin C necessary?

nope

Hemoglobin SC is shown in lab on electrophoresis when both … and … are present

Hgb S, Hgb C

Hemoglobin E disease occurs from a mutation in the 26th nucleotide position of the beta chain. This changes glutamic acid to…

Lysine

What has this blood picture?

• hypochromic microcytic anemia

• microcytes and target cells

• electrophoresis definitive

Hemoglobin E

What is Thalassemia also known as?

Cooley’s Anemia

What is Thalassemia?

inherited disorders of hemoglobin synthesis that produce reduced amounts of normal hemoglobin and reduces blood oxygen capacity

Beta thalassemia and alpha thalassemia affects

beta and alpha chain synthesis, respectively

What disorder is it when beta globin chain production is extremely low?

Beta thalassemias

When beta globin chain production is extremely low, less … will be produced

Hemoglobin A

3 categories of beta thalassemias are…

minor, major, intermedia

These clinical symptoms are indicative of…

• chronic anemia

• splenomegaly

• Bone malformations- due to chronic anemia, teh bm expands to compensate deformities

Beta thalassemias

What has this blood picture?

• mild asymptomatic hemolytic anemia

• Hypochromic, microcytic 

• Target cells, elliptocytosis, basophilic stippling

Beta thalassemia minor

This beta thalassemia has severe anemia and is detected at early age as the gamma and beta switch places due to its severity

Major

Why does beta thal. major cause iron overload?

Because of increased iron absorption (from suppressed hepcidin due to ineffective erythropoiesis) and repeated blood transfusions

What hormone is abnormally low in beta thal major, leading to xs iron absorption?

Hepcidin

Body has no physiological way to excrete large amounts of

Iron

In beta thal major, what type of drug is given to reduce iron accumulation?

Chelating drugs (like desferrioxamine)

What has this blood picture?

• severe hemolytic anemia (3-4 hgb)

• extremely hypochromic, microcytic

  • marked poikilocytosis

Beta Thalassemia major

What is life expectancy of someone with Beta thalassemia major?

Teen to 40s

Treatment for Beta thal major?

Regular blood transfusions

what disorder is it when alpha chain synthesis is extremely reduced?

Alpha thalassemia

3 categories of Alpha thalassemias are…

minor, HbH disease, and hydrops fetalis (homozygous alpha thalassemia)

Excess unpaired beta chain in Alpha thalassemia will form hemoglobin H AKA…

Hgb H disease

Hydrops fetalis is when…

no alpha chains are being produced

The Hydrops Fetalis disease is…

incompatible with life