8/7- Thalassemias and Hemoglobin Disorders Flashcards
What is a hemoglobinopathy?
Mutations that affect the structure of beta or alpha chains
What are thalassemias?
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
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
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
Most alpha thalassemias result from what kind of mutations?
Gene deletions
Most beta thalassemias result from what kind of mutations?
Point mutations (more than 400 known)
What is the typical beta/alpha ratio?
1.2 (?)
Damage in thalassemia is due to the chain in excess or scarcity?
Damage is done by globin chain that is in excess
- alpha chain is incredibly unstable
Alpha thalassemias result from what?
- Result?
- Ratio?
- Pathophysiology?
- 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)
Beta thalassemias result from what?
- Result?
- Ratio?
- Pathophysiology?
- 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)
Epidemiology/geography of thalassemias?
Which thalassemia type presents earlier?
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
What is seen in alpha thalassemia (aa/a3.7)
- Normal iron studies
- Normal Hb electrophoresis
- Trait is common in black Americans (30%)
- Normal or borderline low Hb
- Very mild: hypochromic microcytic
- Silent carrier?
What is seen in alpha thalassemia (a3.7/a3.7)
- 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
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
Thalassemia
- On PBS: see marked hypochromia and microcytosis with some tear drops and normal platelets
What is this?
Golf Ball RBCs (Weatherall)
- Micro Heinz bodies of precipitated beta tetramer or Hemoglobin H
- New methylene blue or crystal violet
What happens when both chromosomes have gene deletions (no functioning alpha genes)?
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
Relative amounts of globin produced by genes? Certain mutation effects?
- Just 1 functioning gene = HbH disease
- No functioning genes = Hydrops featlis with Hb Bart’s
Another chart describing genotypes of alpha thalassemias
What is this?
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
Cellular pathogenesis of beta thalassemia?
What is this?
Beta Thalassemia Major
- More extreme targeting, microcytosis
- Marrow is greatly expanded and nucleated reds circulate (leak out from expanded marrow); increased after splenectomy
Which of these is with splenectomy? without?
Left: pre-splenectomy
Right: post-splenectomy
What is this showing?
Marrow expansion with extramedullary hematopoesis
- Wads of hematopoeitic tissue hanging off the spine
What is this showing?
Hair on end
- Diploe is expanded
- Can be seen in thal major and sometimes in other congenital hemolytic anemias such as sickle cell dz
What is this showing?
Chipmunk facies characteristic in beta thal major
What is this showing?
Extramedullary hematopoeisis causing massive splenomegaly (in beta thal major)
Chronic transfusions result in what? Management?
Chronic transfusions produce iron overlaod; managed with iron chelation
- If not compliant, iron overload results in cardiomopathy, liver problems, and diabetes
What is this?
Iron stain in a heart of a pt with transfusional iron overload
What is this showing? What is causing it?
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
