249 - Thalassemia Flashcards
What defines thalassemia major vs. intermedia?
- Major: ≥8 transfusions in the last 12 months
- Intermedia: <8 transfusions in the last 12 months
Genotype does not accurately affect phenotype; classify operationally instead of genetically
Composition of hemoglobin Bart:
gamma-globin tetramer
- Formed during gestation due to deficient functional alpha-globin*
- Hb Bart decreases quickly after birth -> beta tetramers form instead (HbH)*
- Complete alpha-globin deficiency (0 working copies) usually results in hydrops fetalis, but if there is 1 working copy of alpha globin, then has HbH disease*
Composition of fetal hemoglobin:
2 alpha chains, 2 gamma chains
Higher O2 affinity than adult hemoglobin
What kind of anemia is present in beta-thalassemia?
Microcytic anemia despite hypercellular marrow
too much alpha chain for the decreased amount of beta chain –> extra alpha chain forms hemichromes and inclusion bodies –> apoptosis
What types of hemoglobin will be present in beta-thalassemia during…
- Newborn screening:
- Post-neonatal testing:
- Newborn screening:
- HbF only
- HbF only
- Post-neonatal testing:
- HbF
- More HbA2 than normal (two alpha globins + two delta globins)
What is the significance of Hemoglobin E?
(Severe phenotype?)
Point mutation in beta-globin splice site
- Homozygous HbE
- Benign clinical course; alpha/beta interface less stable under oxidative stress
- BUT: heterozygous for HbE and beta-thalassemia
- -> Severe phenotype
Is acute hemolysis more prominent in alpha-thalassemia or beta-thalassemia?
Alpha-thalassemia
On which chromosome is the beta-globin locus found?
Chromosome 11
List 4 treatments for thalassemia
- Transfusions
- Iron chelation - too much iron can develop b/c of the transfusions
- Splenectomy
- Bone marrow/stem cell transplant
Must manage both anemia and iron overload
What causes chronic hemolysis in beta-thalassemia?
Unpaired alpha-globin forms hemichromes and inclusion bodies in RBCs that induce apoptosis
Composition of normal adult hemoglobin:
2 alph achains, 2 beta chains
- Mutation in beta chain -> more production of HbA2 or HbF*
- (HbF is functional, HbA2 is not)*
Composition of hemoglobin H:
Beta-globin tetramer
- Only 1 working copy of alpha-globin (alpha-thalassemia)*
- -> HbH disease, where 1 working copy results in some normal hemoglobin (HbA, with 2 alpha, 2 beta) and some HbH (4 beta)*
What are the two primary mechanisms for anemia in thalassemia?
-
Ineffective erythropoiesis
- Reduced or absent beta globin –> can’t make the cells correctly
- -> unpaired alpha-globin, immature RBCs
-
Chronic hemolysis
- Unpaired alpha-globin forms hemichromes that induce RBC apoptosis
- -> sequestered in the spleen
For thalassemias, what testing is used for:
- Newborn screening (2):
- Postnatal testing (2):
- Newborn screening:
- High Performance Liquid Chromatography (HPLC)
- Hemoglobin electrophoresis
- Postnatal testing:
- CBC
- Hemoglobin electrophoresis
What is the consequence of globin chain imbalance within the cell?
The extra chains form hemichromes which induce RBC apoptosis
Which complications of thalassemia can be mitigated by transfusions? (5)
- Facial deformity
- Hypersplenism
- Anemia
- Pathological fractures
- Premature closure of the lower femoral epiphysis
What types of hemoglobin will be present in alpha-thalassemia during…
- Newborn screening:
- Post-neonatal testing:
- Newborn screening:
- Hb Bart’s (gamma tetramers)
- Post-neonatal testing
- HbH (beta tetramers)
What causes hepatosplenomegaly in thalassemia?
Globin chain imbalance, extra chains form hemichromes
- > Tags RBCs for apoptosis
- > Sequestered in spleen
Also exramedullary hematopoiesis -> hepatosplenomegaly
