Thalassemia Flashcards
(22 cards)
What is normal adult Hb made of / what would be a normal Hb electrophoresis result?
Hb A 95-98% : 2 alpha and 2 B globins
Hb A2 2-3% (<2.5%) : 2 alpha and 2 delta chains
Hb F 1-2% : 2 alpha and 2 gamma
Alpha and B globins are on which chromosome?
Chrosome 16 (alpha) and 11 (B globins)
What is the structure of hemoglobin?
Tetramere consisting of 2 pairs of globin chains
Heme (complex of ferrous iron) is linked to each globin monomer and reversibly bind 1 oxygen molecule
What is the pathophysiology of hemolytic anemia in hemoglobinopathies?
It results from decreased solubility and instability of Hb
Thalassemias is a quantitative or qualitative disorder of hemoglobin?
Quantitative : unbalanced production of alpha or beta globin that is structurally normal
vs qualitative : HbS, Hb Koln, HbM-Saskatoon, HbM-Iwate
What is the pathophysiology of alpha thal?
Mutation causing deletions of DNA on chromosome 16
You have 2 copies of the gene on each chromosome = 4 total
Mutation that decrease or cause the absence of the synthesis of 1 or more globin chains leading to unbalanced synthesis of individual alpha and beta subunits
What happens in case of imbalanced production of alpha and B globin chains?
Excess unpaired globin is unstable and precipitates within early RBC precursors in the bone marrow and oxidatively damages the cellular memrbane
If the imbalance is severe, most of the RBC precursors in the bone marrow are destroyed before they can be released into the circulation = ineffective erythropoiesis
How do you classify thalassemias?
Transfusion-dependent thalassemia (TDT)
Non transfusion dependent thalassemia (NTDT)
Where is B thalassemia prevalent?
Mediterranean region, middle east, india, pakistan, southeast asia
Less common in Africa
Rarely encountered in northern european white persons
What is the pathophysiology of B thalassemia?
Results from > 350 different mutations in the B globin gene complex of chromosome 11
You have 1 gene on each chromosome so 2 copies total
Leads to complete loss of globin synthesis (B0_ or decresed synthesis (B+)
What is the genotype of B thalassemia major and intermedia?
Can be caused by various genotypes:
- Homozygosity for 2 B0 allele : B0/B0
- Compound heterozygosity B0/B+ or severe HbE/B thall (TDT) or moderated HbE/B thall (NTDT)
What is the genotype of B thalassemia traits?
Generally heterowygious
- B / B0
- B / B+
But some patients who are homozygouns or compound heterozygous for 2 very mild B+ alleles may also have a B thalassemia minor phenotype
What is the definition of compound heterozygosity?
condition of having two or more heterogeneous recessive alleles at a particular locus that can cause genetic disease
Pathophysio of increased iron absorption in thalassemia ?
Ineffective erythropoiesis = decreased hepcidin = makes iron more available
Does neonates with B thalassemia trait have anemia?
Neonates dont’ have anemia or microcytosis
These develop with increasing age as the transition from HbF to HbA production progresses
What is the diagnosis on electrophoresis of B thalassemia ?
Trait beta thalassemie :
HbA2 levels are elevated to > 3.5% (usually 4 to 7%) and HbF levels may be mildly increased
Beta thalassemie transfusion dependante :
Variable elevation of HbA2
Persistant elevation of HbF after neonate period
HbA is absent in homozygous B0 thalassemia
HbA2 =2 alpha and 2 delta
HbF : 2 alpha and 2 gamma
In what timing does anemia occur in transfusion dependent B thalassemia ?
Symptoms are usually evident within the first 6 to 12 months of life as the HbF level begins to decline and severe anemia occurs with Hb < 70
Where is alpha thall endemic ?
Africa, Mediterranean region, Southeast Asia
To a lesser extent Middle East
What is the genotype and frequency of silent carrier state?
Genotype is −a/aa. (- means deletion)
Occurs in 1 in 3 African Americans
Called a+-thal
(vs a0-thal : - -/a a)
What is Hb Constant Spring ?
One example of nondeletional alpha thal, common in Southeast Asia, resulting from a mutation that affects termination of translation and results in abnorally elongated a chains
Alpha-thal : deletion in cis vs trans configuration and where is it prevalent ?
- /a a is more prevalent in Asian descent
- a/- a is more common in African or Mediterranean descent
Is there more ineffective erythropoiesis in alpha or beta thal?
In beta thal for sure
In alpha thal, excess B and gamma chains form tetramers that are more soluble than unpaired a-globins and form RBC inclusions slowly
Consequently, although a-thal is associated with a hemolytic anemia, it does not lead to significant ineffective erythropoiesis
