Hemoglobinopathies And Thalassemia

Question 1

Normal RBC characteristics

Answer 1

Lack nuclei and filled with 4 hemoglobin molecules bound by a iron molecule for each heme group

Approximately 7.5 um in diameter and are biconcave

Question 2

Sickle cell anemia (HbS)

Answer 2

Hemoglobinopathies that leads to a change in glutamate - > valine residues
- leads to a point mutation of A -> T in amino acid at the 6th position

• most common familial hemolytic anemia especially among African Americans
  ( doesn’t get eliminated via natural selection since being a carrier for sickle cell protects against specific species of malaria that are common in Africa)

Question 3

Pathogenesis of sickle cell (HbS)

Answer 3

B-globin chains tend to associate into polymers while deoxygenated
- causes sickle, elongated shapes

if carrier, only 50% of RBCs are HbS, if homozygous, all are.

These sickle cells when first produced can be reversed with oxygen, however over time the damage done to the membrane skeleton via switching between normal and sickle cell forms causes irrreversible shapes
- damage caused by abnormal
Influxes of calcium and losses off potassium with each sickling episode

These irreversible shaped sickle cells get lodged in splenic cords and destroyed via macrophages
- extravascular anemia

Question 4

Two major pathological consequences in HbS

Answer 4

Moderate-severe hemolytic anemia (cells usually only last 20 days compared to the normal 120 days)
- severity is determined based on fracture of irreversible cells

Vasooculsive crisis: causes ischemic tissue damage and pain

• hand-foot
• acute chest
• stroke
• proliferative retinopathy

Question 5

Causes for anatomical chances in SC anemia

Answer 5

Severe chronic hemolytic anemia

Microvascular obstructions

Increased break down of heme to bilirubin

Question 6

Morphological symptoms of HbS

Answer 6

Moderate splenomegaly in children
- overtime becomes chronic splenic erythrostasis that produces an autosplenectomy

Prominent cheekbones
-caused by increased bone resorption

Extramedullay hematopoiesis in liver and spleen ( increase in progenitor cells)

Vascular congestion, thrombosis and infarction
- can be done to any organ

Hemosiderosis and pigmented gallstones (black/purple gallstones)

Question 7

Normal hematocrit in patients with HbS

Answer 7

18-30%

• there are no symptoms in HbS until 6 months, when HbF levels plummet and HbS rise*

Question 8

Thalassemias

Answer 8

Inherited disorders that cause mutation in either a/b globin genes
- causes a decrease in overall level one of the globin chains usually, and causes precipitate of the normal producing one

Autosomal codominant disorder

A-globin genes (two) are on chromosome 16

B-globin gene (only 1) are on chromosome 11

Question 9

B-thalassemia pathogenesis

Answer 9

Can be B0 (no beta globin chains are produced)
Or can be B+ (reduced B-globin chain production

Most common mutations lead to abnormal RNA splicing of B-globin genes
- can also affect promoter or coding regions but less common

Question 10

B-thalassemia minor/trait
Vs
B- thalassemia major

Answer 10

Minor/trait = Only one of the B-globin genes are affected
-Asymptomatic or mildly symptomatic

Major = both of the B-globin genes are affected (either 0/+)
- produces negative symptoms

Question 11

Why is iron overload possible in thalassemia patients

Answer 11

They have low hepcidin levels which is a negative regulator of iron absorption
- without it, body resorbs all iron

Caused by ineffective hematopoiesis which in turn lowers hepcidin levels which then increases absorption of the dietary iron

Question 12

Why are HbH and Hb Bart RBCs produced in a-thalassemia bad?

Answer 12

They have to high of affinity for oxygen so it wont release oxygen to the tissues
- look normal on microscopes

• produced in 3/4 gene issues*

Question 13

Morphology of B-minor and a-trait thalassemia

Answer 13

Target cells: increased surface are-to-volume ratio that has a central sark red spot that is an accumulation of cytoplasm

Hypochromic, regular shaped RBCs

Question 14

morphology of B-major thalassemia

Answer 14

Microcytosis, hypochromic cells that are variable in shapes and size

Still possess some nucleated normal red cells

Large numbers of hyperplastic reticulocytes

produces splenomegaly/ hepatomegaly and lymphadenopathy and skeletal deformities by expansion of red bone marrow

Question 15

Clinical features of B-major thalassemia

Answer 15

Increased splenomegaly, hepatomegaly, lymphadenopathy

Growth retardation and cachexia

Severe hemisiderosis (iron overload)
- must use cheleting agents

• fought with blood transfusion, iron chelators and hematopoietic stem cell transplants*

Usually kills in 30s due to secondary hemochromatosis induced cardiac damage if not treated

Question 16

Clinical features of B-minor and a-trait thalassemia

Answer 16

Usually asymptomatic with very mild hypochromic anemia symptoms

• normal life expectancy

Question 17

Diagnosis of thalassemias

Answer 17

Diagnosis is based on clinical background usually, however a Hb electrophoresis is the cardinal way to determine for sure.

B-trait = decreased HbA compared to normal

B-major = very low HbA and very high HbF

HbH (heterozygous) = prescence of HbH

Question 18

Principle features of extravacular hemolysis

Answer 18

Anemia, splenomegaly and jaundice

Question 19

Main treatment of sickle cell anemia

Answer 19

Hydroxyurea with prophylactic treatment with penicillin
- penicillin used to prevent pneumococcal infections

• approximately 50% of patients survive longer than 50 years of age*
• only curative agent is allogeneic bone marrow transplants*

Question 20

A-thalassemia pathogenesis

Answer 20

Instead of inheriting mutations of genes, a-globlin genes experience deletions in one of the 4 genes in chromosome 11. The severity is dependent on how many deletions occur

Question 21

Types of a-thalassemia

Answer 21

1/4 = silent
- asymptomatic

2/4 = trait

3/4 = HbH (b and y chained globins)
- forms hemoglobin that has super high affinity for oxygen which makes them ineffective at delivering it to tissues

4/4 = Bart (hydros fetalis)
- kills infants by forming even more HbH that is even more effective at binding oxygen and not letting go

Question 22

Treatment of B-thalassemia major

Answer 22

Minor/trait = not really any treatment

Major = iron chelators, treatment of secondary disorders and hematopoietic stem cell transplants when possible