Hemoglobinopathies Flashcards
hemoglobin structural variants are most often caused by …
point mutations in one of the globin genes
- usually single pt mutations => single AA substitution
- changes in AA sequence can alter the charge of the protein and change folding
T or F. There can only be point mutations for hemoglobin structural variants
F, there can also be insertions, deletions, and fusions
T or F. As with thals, many hemoglobinopathies are common in malaria endemic areas
T!
- confer protection from severe malarial infections
Why do delta and gamma variants in hemoglobin have little clinical impact in adults?
low expression
- even if they would otherwise be pathologic
Hemoglobin structural variants depends on …
mutation and zygosity
- homozygous: disease
- heterozygous: trait
lab techniques for Hb evaluation
- CBC
- blood film
- Hb electrophoresis
- molecular genetic testing (fragment analysis or sequencing)
most common and most clinically relevant structural variant
Hb S
these homozygotes have sickle cell anemia
Hb SS, beta^S/beta^S
beta globin point mutation
HbS
- HBB:c.20A>T
- B6 Glu>Val (E6V) which means 6th AA in beta globin protein is valine instead of glutamate
HbS results in a hemoglobin variant with _________ solubility
decreased
- precipitates and polymerizes when in deoxygenated form
- polymerization results in elongated RBCs = ‘sickle cells’
rate and extent of Hb S polymerization is dependent on several factors
- high intracell Hb conctn
- presence of other Hb variants (some are protective against sickling while others promote it)
- blood O2 saturation (polymerization occurs with deoxy-Hb S and is reversible in the oxygenated state
- low pH
- low temp
- 2,3- BPG (bisphosphoglyceric acids) levels
Hb SS
- sickle cell anemia
- autosomal recessive inheritance
- homozygosity for Hb S mutations leads to clinical symptoms
- clinically heterogeneous, multifactorial pathophysiology
> chronic inflammatory state with acute exacerbations
Hb SS clinical presentations
- vasoocclusive episodes (VOE)
- aplastic crisis
- sequestration crisis
- hyperhemolysis
Vasoocclusive episodes (VOE)
- acute exacerbations of underlying chronic pain
- most common manifestation, can occur anywhere in the body, in any tissue (often extremities, back, chest)
- vasooclusion -> tissue hypoxia -> pain
- precipitated by dehydration, infection, cold weather or idiopathic
- can be a med emergency (acute chest syndrome)
aplastic crisis
- marked reduction in RBC production, severe anemia
- often triggered by infection (parvovirus B19 most common)
