SM_251b: Thalassemia Flashcards
Thalassemias are ___
Thalassemias are inherited blood disorders cuased by mutations in beta globin that result in inability of body to produce globin
Globins are ____
Globins are key components of hemoglobin
- Inability to make globin causes anemia
HbF is ___
HbF is alpha2-gamma2

HbA is ____
HbA is alpha2-beta2

HbA2 is ___
HbA2 is alpha2-delta2

Describe normal erythropoesis
Normal erythropoesis: erythroid precursor cells proliferate and differentiate into mature RBCs
- Early stage: EPO -> commited progenitor cells divide / differentiate into proerythroblasts (EPO-dependent)
- Late stage: cells further mature through series of normoblast stages until enucleation -> rectic, mature RBCs (not EPO-dependent)
Beta thalassemia occurs due to mutations on ___
Beta thalassemia occurs due to mutations on beta globin locus

DNA mutations in beta thalassemia ___ predict phenotype
DNA mutations in beta thalassemia do NOT predict phenotype
- Suggests genetic modifiers affect disease severity
Beta thalassemia is defined ___
Beta thalassemia is defined operationally
- ≤ 8 transfusions in last 12 months: thalassemia major
- < 8 transfusions: thalassemia intermedia
Describe modifying genes in thalassemia
Modifying genes in thalassemia
- Innate ability to produce HbF
- Alpha globin genotype: alpha thalassemia reduces alpha globin excess, extra alpha globin genes enhance imbalance
- Genes that encode alpha globin chaperones or protect against hemolysis: alpha hemoglobin stabilizing protein, chaperone heat shock protein 70
Hemoglobin E disease is common in ____ populations and involves ____
Hemoglobin E disease is common in Southeast Asian populations and involves a single amino acid substitution caused by a point mutation in the beta globin gene
- Activates cryptic mRNA splice site, reduced beta globin production
- Homozygous Hb E is associated with relatively benign clinical course: microcytosis with mild/no anemia, weakened alpha/beta interface and less stable under oxidative stress
- Coinheritance of Hb E with beta thalassemia results in a condition with similar severity as beta thalassemia
Describe alpha thalassemia mutations and genotypes
Alpha thalassemia mutations and genotypes

Describe HbH disease
HbH disease
- Caused by mutation affecting 3/4 alpha genes
- Found in patients from Southeast Asia, Middle East, Mediterranean
- Most often results from deletional mutations
- Nondeletional: deletion of 2 genes from one allele with alpha thalassemia point mutations plus small insertion / deletion in one other alpha globin gene: more anemia, more symptomatic than deletional
Describe Hb Constant Spring
Hb Constant Spring
- Caused by nondeletional mutation in alpha2 gene
- High frequency among Southeast Asian
- Defect results in elongation of 3’ mRNA sequences and is unstable
- Homozygous HbCS clinical picture similar to HbH disease
- Co-inheritance with deletion of two other alpha genes results in moderate to severe condition: HbH / Constant Spring
Beta thalassemia involves ___ erythropoiesis
Beta thalassemia involves ineffective erythropoiesis
- Microcytic anemia despite hypercellular marrow
- Elevated endogenous EPO and relative EPO-resistance
- Extramedullary hematopoiesis and chronic hemolysis also contribute to phenotype

Describe pathophysiology of alpha thalassemia
Alpha thalassemia pathophysiology
- Excess gamma-globin during fetal development forms gamma-4 tetramers (Hb Bart): nonfunctional, decreases after birth
- Excess beta globin postnatally forms beta-4 tetramers (HbH): relatively unstable and nonfunction, intracellular RBC inclusion bodies
- Intracellular globin chains precipitate -> ineffective erythropoiesis -> membrane dysfunction and local oxidative damage
- Acute hemolysis is more prominent in alpha thalassemia and HbH disease compared to beta thalassemia
Methods for diagnosis of thalassemia are ____, ____, ____, and ____
Methods for diagnosis of thalassemia are high performance liquid chromatography, hemoglobin electrophoresis, DNA analysis, and CBC
High performance liquid chromatography allows for ___
High performance liquid chromatography allows for efficient reproductible separation of normal and common abnormal globin variants

Describe hemoglobin electrophoresis
Hemoglobin electrophoresis
- Separation of normal and most common abnormal globin variants
- Performed at both alkaline and acid pH
- Cannot quantify HbA2
- Test used for confirmatory testing for beta globin defects

Diagnostic criteria for thalassemia ___ beyond infancy
Diagnostic criteria for thalassemia change beyond infancy

Thalassemia peripheral blood smear involves ___ with marked ___ and ___
Thalassemia peripheral blood smear involves microcytic hypochromic anemia with marked anisocytosis and poikylocytosis
- RBC changes in thalassemia due to ineffective erythropoeisis and hemolysis

Describe clinical features of beta thalassemia
Beta thalassemia clinical features
- Poor growth
- Thal facies
- Jaundice, hyperpigmented skin
- Hepatosplenomegaly
- Endocrine dysfunction
- Cardiomyopathy
- Bony deformities, increased fracture risk
Optimal thalassemia care balances ___ with ___
Optimal thalassemia care balances appropriate transfusion support with adequate iron chelation
- Complications in thalassemia often result from an inability to do one or both
Describe clinical features of alpha thalassemia
Alpha thalassemia clinical features
- Usually results in fetal demise
- HbH hydrops fetalis: typically due to nondeletional mutation of alpha 2 globin gene plus deletion of both alpha genes from other allele
- Survival depends on intrauterine diagnosis and intervention
- Associated with neurocognitive deficits, limb abnormalities, and hepatomegaly with persistent fetal hematopoiesis in the liver


