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)
sequestration crisis
- sudden massive pooling of RBCs in an organ (usually spleen, sometimes liver) => severe anemia
- usually only occurs in children under 5 y/o (prior to autoinfarction of spleen
- treated with very cautious transfusion
hyperhemolysis
- episodes of accelerated rates of hemolysis
- maybe be triggered by VOE or by delayed hemolytic transfusion reactions
SCA symptoms
- priapism in males
- pregnancy complications: low birth weight infants, higher risk of maternal death
SCA treatment
Supportive:
- pain management
- simple or exchange transfusions
- infection prevention (vaccines, penicillin)
Disease modifying:
- hydroxyurea (increases Hb F)
- allogeneic stem cell transplant
Hb AS
- B/B^S
- sickle cell trait
- inheritance of a single Hb S allele
- generally asymptomatic = there is enough Hb A in the cells to prevent sickling, normal lifespan
= blood film usually normal, sometimes mild microcytosis and a few target cells - renal pathology, hematuria, acceleration of other renal diseases (PKD)
- higher risk of sudden death (especially related to intense exercise)
- higher risk of UTI (esp in pregnant females)
- associated with renal medullary carcinoma
Sickle solubility test
- Hb S present? quick test!
- add blood to reagent and look for turbidity
> detergent (lyse RBCs)
> reducing agent 2+ to 3+; deoxygenates the Hb - deoxy-Hb S polymerizes and precipitates out (sample becomes turbid)
- not 100% specific to HbS; other Hbs can be positive
- false positives = lipemia, excess blood to reagents
Hb C
- beta globin pt mutation
> HBB:c.19G>A
> B6 Glu>Lys - second Hb variant to be described after Hb S
Hb CC
- homozygous for Hb B^C mutations
- HbC forms crystals inside RBCs -> impaired deformability
=> K+ loss -> water loss -> dehydrated RBCs -> spherocytes, increase MCHC
= shortened RBC lifespan (40 days) - mild to moderate splenomegaly (usually no splenic autoinfarction)
- chronic hemolysis => cholelithiasis
Lab features of Hb CC
- mild to moderate hemolytic anemia (Hb 100-110 g/L)
- mild microcytosis (MCV 70-75 fL)
- reticulocytosis
- often elevated MCHC
- mildly elevated bilirubin
Hb CC blood film
- HbC crystals
- targets
- microspherocytes
- polychromasia
sickle cell disease
- Hb SX
=> X is other beta variant that interacts with Hb S and promotes sickling - most common is Hb SC disease
- can also have coinheritance of thalassemias with Hb S
> Hb S/B0
> Hb SS with alpha thal
Lab features of Hb SC disease
- Hb <80 g/L
- MCV around 70 fL
- RDW increased
- mildly increased reticulocyte count
- mild neutrophilia and monocytosis
- SC poikilocytes
- boat shaped cells (classic sickle cells less common)
- occasional Hb C crystals
- target cells
Hb E
- beta chain variant; B26 Glu>Lys
- abnormal alt splicing between exon 1 and intron 1
- decreased transcription of functional mRNA
- quantitative and qualitative defect
- B thal-like syndrome
- HB EE = mild microcytic anemia w target cells, asymptomatic
- HbAW = asymptomatic
- HB E/B 0 = can be severe, similar to B thal major
Hb D
- various Hb D variants have similar electrophoretic migration
- heterozygous is asymptomatic; homo = mild microcytic anemia; Hb S/D-Punjab = sickling disorder
- Hb D-Iran is not clinically significant and does not interact with Hb S; clinically like Hb S trait
Hb M
- a, B, gamma variants
- mutations cause increased tendency towards oxidation to methemoglobin (usually His>Tyr in heme pocket
=> usually results in pseudocyanosis (lavender-blue or slate grey) - some also have low O2 affinity and cause a degree of true cyanosis (purplish-blue)
