Thalassemias Flashcards
Sickle cell-beta0 thalassemia vs. sickle cell-beta+ thalassemia
- beta0 = complete absence of beta globin (so no Hb A production (which is a tetramer of A2B2))
- beta+ = reduced amounts of beta globin
Hgb electrophoresis pattern of hbg S-beta0 thalassemia
*similar to Hb SS so it is hard to differentiate Hb SS from Hb S-beta thal
- nearly all Hb S
- no Hb A present
Clinical feature of hbg S-beta0 thalassemia
- as severe phenotype as homozygous SCD (since no Hb A production)
Clinical feature of hbg S-beta+ thalassemia
- more mild since they still have some beta globin production
- milder course than HB s -beta0 but may still have life-threatening episodes of acute chest, pain crises
Lab features of hbg S-beta+ thalassemia
- anemia, microcytosis
- Hb A fraction (5-30%)
Hbg E clinical features
asymptomatic with minal anemia and microcytosis
Most common form of hemoglobin in humans and structure
- hemoglobin A, which consists of 2 alpha subunits and 2 beta subunits
- hemoglobin A2 accounts for only 1-3%
alpha thal pathophysiology
defective alpha globin gene production - typically deletional
constant spring anemia - 1) ethnicity more prevalent in 2) clinical features
nondeletional subtype of alpha thal (deletional is far more common)
- southeast Asian
3) significant anemia, frequently requiring transfusions
Hgb A makeup (dominant hemoglobin in adults)
2 alpha units, 2 beta units
Alpha thal sequelae
heart failure, arrhythmias
iron overload
VTE
leg ulcers
normal hgb electrophoresis
hgb a (95%)
hgb a2(2-3%)
hgb F (1-2%)
alpha thal silent carrier (alpha thal minima) 1) presentation 2) hgb electrophoresis pattern
1) microcytosis, otherwise normal
2) normal (only one alpha gene missing)
alpha thal trait 1) presentation 2) hgb electrophoresis
1) mild microcytosis (deletion of 2 alpha genes).
*Looks like iron deficiency given low MCV
2) normal electrophoresis (need genetic testing)
hemoglobin H disease 1) physiology 1.5) clinical presentation 2) IHC stain that is positive 3) hgb electrophoresis
1) 3 alpha allele deletions, thus beta chain tetramers form (HbH)
1) variable, mild to moderate anemia, some transfusion dependent, others are not.
*They have intermittent anemia from infection, pregnancy, exposure to oxidant drugs.
2) Brilliant cresyl blue stain (stains inclusions)
*See photo online
3) hgb H peak (ranging 5-40%)
hemoglobin barts is
alpha thal major (hydrops fetalis)
*deletion of all 4 alpha genes so no synthesis of alpha chains and most hb is Hb barts (composed of gamma chains)
alpha thal major presentation
- typically death in utero, some survive with
- neurodevelopmental delays
- congenital anomalies
- growth delays
alpha thal major treatment
- iron chelation at age 1
- transfusions in utero and lifelong
- consideration of transplant
ATRX alpha thalassemia
X linked alpha thal associated with intellectual disability in young boys
Structure of hgb F
2 alpha chains, 2 gamma chains
Structure of hgb A2
2 alpha chains, 2 delta chains
Structure of hgb A1
2 alpha chains, 2 beta chains
beta thalassemia minor - 1) labs
1) microcytosis with mild or no anemia
beta thalassemia minor hgb electrophoresis
- mild increase in hgb A2 (, increase in delta chains in response to beta loss)
**SO remember HbA2>3.5%
beta thalassemia minor managment
observation
beta thalassemia major (b0b0) clinical features
- severe anemia seen in infancy
- iron overload from ineffective erythropoesis
- splenomegaly with functional asplenia
- osteoporosis
- hemolysis
beta thalassemia intermedia physiology
Either B+b0 or B+B+ (decrease in beta chain)
beta thalassemia major hgb electrophoresis
- no hgb A1 (can’t make beta chains)
*see alpha tetramers instead
transfusion dependent beta thalassemia management
luspatercept
hgb E 1) physiology 2) area with highest prevalence 3) homozygote presentation
1) point mutation leading to decrease in beta chain
2) Indian
3) minimal anemia with target cells
hgb lepore
- unequal recombination of beta and delta genes, resulting in stable globin
*has mobility of hgb S on electrophoresis so may look like sickle cell anemia on electrophoresis and looks like hgb A on acid electrophoresis
beta thalassemia minor physiology
B(normal)B+ or B(normal)B0
Alpha globin loci is located on what chromosome
16
Beta globin Loci is located on which chromosome
11
Hgb barts is composed of
gamma chains (alpha loss leads to increased gamma)
Other condition in which alpha thalassemia can develop
MDS
Transfusion target in transfusion dependent thalassemia
Hgb 9.5 (significantly reduced complications with higher transfusion threshold)
Most common endocrinopathy in thalassemia pts
Hypogonadotropic hypogonadism (Iron deposits in pituitary gland from iron overload)
Target ferritin in transfusion dependent thalassemia pts
Less than 1000
Deferoxamine SE’s
- hearing loss
- yersinia infection
- vision changes
- bone changes
Deferiprone SE’s
- neutropenia
- arthralgias
deferasirox SE’s
- AKI
- elevated liver enzymes
- GI bleeding
Luspatercept SE’s
- VTE
- HTN
- concern for worsening extramedullary hematopoietic masses (eg paraspinal masses)
Approved gene therapy for thalassemia
1) Betibeglogene autotemcel (beti-cel)
2) Exagamglogene autotemcel (exa-cel) - uses CRISPR
Contraindication to luspatercept in thalassemia
Paraspinal masses
Homozygous hemoglobin C clinical features
- mild hemolytic anemia
- gallstones
- splenomegaly
Hemoglobin M disorder clinical features
- asymptomatic cyanosis
- slate gray/brownish skin
*(hereditary methhemoglobinemia)
Hemoglobin M treatment
No treatment required
Abnormal MRI threshold for iron overload
T2 MRI <20 milliseconds
