8/7- Thalassemias and Hemoglobin Disorders Flashcards

1
Q

What is a hemoglobinopathy?

A

Mutations that affect the structure of beta or alpha chains

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2
Q

What are thalassemias?

A

Mutations that affect the balance of production of alpha and beta chains such that not enough alpha or beta chains exist

  • Imbalance of alpha and beta globins production
  • It’s the ratio that is important
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3
Q

Case)

  • 34 yo black man is referred for microcytic RBCs
  • Hx unremarkable and no family hx of anemia
  • CBC shows hematocrit of 39% with MCV of 79, low retic count
  • Microcytic RBCs with some hypochromia on smear
  • Ferritin is 120 ng/mL
  • Hemoglobin electrophoresis is normal

Which is the most likely diagnosis?

A. G6PD deficiency

B. Alpha thalassemia minor

C. Beta thalassemia minor

D. Sickle trait

E. Anemia of chronic disease

A

Which is the most likely diagnosis?

A. G6PD deficiency

B. Alpha thalassemia minor

C. Beta thalassemia minor

D. Sickle trait

E. Anemia of chronic disease

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4
Q

Most alpha thalassemias result from what kind of mutations?

A

Gene deletions

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5
Q

Most beta thalassemias result from what kind of mutations?

A

Point mutations (more than 400 known)

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6
Q

What is the typical beta/alpha ratio?

A

1.2 (?)

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7
Q

Damage in thalassemia is due to the chain in excess or scarcity?

A

Damage is done by globin chain that is in excess

  • alpha chain is incredibly unstable
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8
Q

Alpha thalassemias result from what?

  • Result?
  • Ratio?
  • Pathophysiology?
A
  • Most commonly from gene deletions resulting in decreased alpha chain production and excess beta chains
  • beta/alpha ratio is increased
  • Red cell membrane damage is due to excess beta chains which can associate das tretramers (B4 or hemoglobin H)
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9
Q

Beta thalassemias result from what?

  • Result?
  • Ratio?
  • Pathophysiology?
A
  • Most commonly from point mutations that affect mRNA production for beta chain synthesis
  • beta/alpha ratio is decreased (beta chain synthesis is decreased and there is an excess of alpha chains)
  • Alpha chains do not associate, but oxidize and precipitate and are very toxic to the RBC membrane (so unstable they do not form a tetramer recognizable on electrophoresis)
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10
Q

Epidemiology/geography of thalassemias?

A
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11
Q

Which thalassemia type presents earlier?

A

Alpha

  • Alpha Hb is switched to adult form early in life
  • Alpha thalassemia will be present at birth
  • Most severe alpha thalassemia results in hydrops fatalis (stillbirth)
  • Beta thalassemias don’t present until you attempt full expression of the beta chain somewhere between 6 mo of age and 1 yr
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12
Q

What is seen in alpha thalassemia (aa/a3.7)

A
  • Normal iron studies
  • Normal Hb electrophoresis
  • Trait is common in black Americans (30%)
  • Normal or borderline low Hb
  • Very mild: hypochromic microcytic
  • Silent carrier?
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13
Q

What is seen in alpha thalassemia (a3.7/a3.7)

A
  • Mild anemia
  • Microcytosis
  • 1-3% of black Americans
  • No need for genetic counseling
  • Pts are warned to check iron studies before accepting a diagnosis of iron deficiency
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14
Q

Case)

  • Pt from China
  • 60 yo woman presenting with pallor and microcytic anemia
  • Ferritin is 1000 ng
  • Hematocrit is 28%, MCV 65
  • Retics 4.2
A

Thalassemia

  • On PBS: see marked hypochromia and microcytosis with some tear drops and normal platelets
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15
Q

What is this?

A

Golf Ball RBCs (Weatherall)

  • Micro Heinz bodies of precipitated beta tetramer or Hemoglobin H
  • New methylene blue or crystal violet
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16
Q

Pathophysiology of Hemoglobin H disease?

A
  • Children at birth have tetramers of gamma, “Barts”
  • Within a few motnhs, they mostly have adult hemoglobin and the beta chain excess forms beta tetramers, or Hemoglobin H
17
Q

What happens when both chromosomes have gene deletions (no functioning alpha genes)?

A

Hydrops Fetalis- Stillborn

  • Development of the fetus is affected by the very high O2 affinity of tetramers of fetal gamma chains (Bart’s)
  • The placenta is huge
18
Q

Which produces more globin, alpha 1 or alpha 2?

A

Alpha 2 produces more globin than alpha 1

19
Q

Relative amounts of globin produced by genes? Certain mutation effects?

A
  • Just 1 functioning gene = HbH disease
  • No functioning genes = Hydrops featlis with Hb Bart’s
20
Q

What is Hemoglobin Constant Spring?

A
  • Stop codon mutation that results in a long globin that is unstable (hemoglobin being made but unstable)
  • Acts somewhat like a 2 gene mutation
21
Q

Another chart describing genotypes of alpha thalassemias

A
22
Q

Case)

  • 30 yo man presents with anemia with hematocrit of 30, Hb of 10, and MCV of 60
  • PBS show microcytosis and hypochromia and some basophilic stippling
  • Iron studies are normal
  • Greek ethnicity
  • Hemoglobin electrophoresis is normal except for increased A2 of 5.5%

Which of the following is the most likely diagnosis?

A. Sickle cell disease

B. Alpha thalassemia

C. Beta thalassemia minor

D. G6PD deficiency

A

Which of the following is the most likely diagnosis?

A. Sickle cell disease

B. Alpha thalassemia

C. Beta thalassemia minor?

D. G6PD deficiency

23
Q

What is this?

A

Beta thalassemia minor

  • Hematologically: microcytic hypochromic RBCs with a lot of targeting and some basophilic stippling
  • Cells are uniformly small so the red blood cell size distribution width (RDW) is normal
  • Iron deficiency is marked by the variability of iron available to the red blood cell so the cells are small, but more variable in size, the RDW is increased
24
Q

Genes behind beta thalassemia minor? major?

Chromosomes involved?

A

Minor: One normal beta gene on chromosome 11 and a thalassemic beta mutation on the other

Major: Two genes affected

25
Q

Again, what is the underlying mutation mechanism that typically results in beta thalassemias?

A

Typical beta thalassemic mutations affect mRNA splicing, or sometimes transcription initiation

26
Q

Cellular pathogenesis of beta thalassemia?

A
27
Q

What is this?

A

Beta Thalassemia Major

  • More extreme targeting, microcytosis
  • Marrow is greatly expanded and nucleated reds circulate (leak out from expanded marrow); increased after splenectomy
28
Q

Which of these is with splenectomy? without?

A

Left: pre-splenectomy

Right: post-splenectomy

29
Q

What is this showing?

A

Marrow expansion with extramedullary hematopoesis

  • Wads of hematopoeitic tissue hanging off the spine
30
Q

What is this showing?

A

Hair on end

  • Diploe is expanded
  • Can be seen in thal major and sometimes in other congenital hemolytic anemias such as sickle cell dz
31
Q

What is this showing?

A

Chipmunk facies characteristic in beta thal major

32
Q

What is this showing?

A

Extramedullary hematopoeisis causing massive splenomegaly (in beta thal major)

33
Q

Chronic transfusions result in what? Management?

A

Chronic transfusions produce iron overlaod; managed with iron chelation

  • If not compliant, iron overload results in cardiomopathy, liver problems, and diabetes
34
Q

What is this?

A

Iron stain in a heart of a pt with transfusional iron overload

35
Q

Overview of beta thalassemias

A

- βthal minor: microcytic, hypochromic anemia; hemoglobin electrophoresis reveals increased A2, sometimes F

- βthal major: alpha chain excess results in in-effective erythropoiesis, marrow expansion, myeloid metaplasia

- β thal major: transfusions, iron chelation

- β thal major: Role of BMT

36
Q

Examples of hemoglobinopathies?

A

- High Affinity Hemoglobins—Polycythemia

- Unstable hemoglobins—Heinz body hemolytic anemia

- M hemoglobins/Congenital Methemoglobinemia (enzymopathy)

- Sickle Cell Disease

37
Q

What is this showing? What is causing it?

A

Cyanosis here is really Met hemoglobin

  • Pts with M hemoglobin may be more slate colored
  • Cyanosis due to hypoxia may be bluer (observed when there is more than 5 g/dL of deoxyHb)
  • Cyanosis is seen when there is 1.5 gm/dL of methemoglobin