Thalassemia Flashcards
1
Q
Hemoglobinopathies
A
- Abnormal Hb
- Reduced production rate of Hb
- Persistence of fetal Hb (harmless but offers ways to cure Hbopathies
2
Q
Prevention
A
-All serious Hbopathies are autosomal recessive and can be identified in parents before they have children
3
Q
Genetics and composition of Hb
A
- 4 different types of chains A, B, G (F) and D (A2)
- All of the genes for these chains are on chrom 11, except for A chain which is on chrom 16
- Both the A and G loci are duplicated
- Hb F (fetal) is A2G2 and is present in the second trimester (first trimester 3 different Hbs are present, some containing E and Z chains)
- HbF expressing cells are resistant to malaria entry, higher HbF levels means more selective advantage against malaria
- Hb A and A2 (A2D2) are present in the third trimester and the remainder of life, along with Hb F
- HbA is 97% of adult Hb, (HbF is .5% and HbA2 is 2.5%)
- HbF and HbA2 are much higher in HbE (unstable B chain) since HbA cannot exist (HbE homozygous recessive is milder b/c more HbF/A2 to compensate)
4
Q
Thalassemia
A
- Genetic disorder where there is an unbalance in the abundance/function of either the A or B chains of the glob in protein
- In A thalassemia there is reduced A chain content, leading to free B chains
- In B thalassemia there is reduced B chain content, leading to free A chains
- These defective Hb molecules precipitate on the RBC membrane, causing hemolysis via macrophage phagocytosis in spleen/liver (hemolytic anemia)
- Hb also precipitates on nuclear membrane causing apoptosis during retic development (ineffective production), presenting as heinz bodies (A4 form only B thal, or HbH only A thal)
5
Q
Pathophysiology of thalassemia
A
- Hemolysis and ineffective production lead to increased bili and LDH levels
- Increased retic counts (may be normal for the less severe cases, more elevated for the more severe cases) and anemia
- Splenomegaly and extramedullary hematopoiesis
- Erythroid hyperplasia
- Lab values depend on type of thalassemia
6
Q
B thalassemia
A
- Gene defects in the B chain, can be either s (subtle decrease in function), + (normal function but reduced amount), or o (no B chain made)
- Patients have excess of free A chains, which precipitate on cell membrane as heinz bodies
- 4 categories of B thalassemia: major, intermedia, minor, minima
- A person can be a carrier of the trait, where they have one defective (either Bs, B+, or Bo) form of the gene and one normal form
- Carriers of the trait are heterozygous and are either B thal minima or B thal minor
- Carriers of trait have 50/50 chance of donating the mutated form of the gene to offspring
- Children w/ B thal are initially normal due to high levels of HbF, symptoms present at 3 mo of age
- People with B thal can have increased HbA2 and HbF, the increase correlates w/ how severe the B thal is (highest increase in major)
7
Q
B thal minima and minor
A
- B thal minima is least severe form of heterozygous B thal: 1 normal gene and 1 Bs gene
- Have no real symptoms
- RBCs usually microcytic and some target cells apparent
- B thal minor is mild form of the disease (heterozygous or homozygous recessive w/ one Bs): one normal (or Bs) and one Bo or B+
- Characterized by minor anemia, low MCV and MCHC, microcystosis and hypochromia
- Retic may be slightly increased due to hemolysis
8
Q
B thal intermedia and major
A
- B thal intermedia is homozygous recessive, but the less severe form
- Patients will have B+/B+, Bo/B+, or Bs/Bo genotypes
- Characterized by moderate anemia, low MCV and MCHC, microcystosis and hypochromia
- Retic slightly increased due to hemolysis
- B thal major is homozygous recessive most severe form
- Patients will be Bo/Bo
- Characterized by severe anemia, low MCV and MCHC, microcystosis and hypochromia
- Retic will be increased due to hemolysis
- Babies will have crew-cut X rays of skull and hands
9
Q
Ranges for HbA2 and HbF in B thal
A
- In all cases both the HbA2 and HbF are elevated
- These are only elevated in B thal (in A thal there is increased amount of HbH)
- B thal minor: HbA2 is 4-6% and HbF is 1-5%
- B thal intermedia: HbA2 is 4-8% and HbF is 5-10%
- B thal major: HbA2 is 8-12% and HbF is 90%
10
Q
Complications of B thal major
A
- Inclusion bodies (heinz bodies or on nuclear membrane) leads to destruction of RBCs
- The resulting chronic anemia leads to high EPO and reduced hepcidin levels
- The perpetual state of this leads to overactive marrow and hypersplenism (extramedullary erythropoiesis)
- Over active marrow causes increased fractures, increased Gi absorption of Fe (amplified by reduced hepcidin, worsened by blot transfusions)
- Fe loading on heart, liver, endocrine organs
- Leads to more HbA2 and HbF
11
Q
Alpha thalassemia
A
- There are 4 alpha genes (2 from each parent) as opposed to 2 B genes
- Each A gene can be individually mutated, meaning there are 3 different forms of A thal (1, 2, or 3 A genes mutated)
- 4 mutated A genes is incompatible w/ life
- Leads to more HbH
12
Q
A thal minima and minor
A
- A thal minima (silent carrier) have only one mutated A gene and are asymptomatic
- They may have mild microcytosis and some HbH (B4, shifts O2 curve to left), but no anemia
- A thal minor patients have 2 mutated A genes, either in cis (both genes on the same chrom) or trans (one on each of the two chroms)
- Similar to B thal minor (microcystosis), but HbA2 level is normal
- Have frequent HbH bodies
- May have slight increased retic count
13
Q
A thal intermedia (HbH disease)
A
- Three mutated A genes, leaving only one functional A gene
- The patient has large amounts of HbH (20%), and their O2 curve shifted way to the left
- Leads to hemolytic anemia, erythroid hyperplasia and increased retic count
- However these patients are rarely transfusion dependent
14
Q
Rx of thal
A
- Transfusion therapy for those w/ severe conditions
- Transfusion increases risk of iron overload, place on Fe chelating agent to reduce this
- HSC transplant also an option
- Complications of thal: abnormal RBCs consume NO (esp in lungs) leading to vasoconstriction and pulmonary hypertension, also demineralization of bone, hyperplasia of upper lip, hypertrophy of liver and spleen
- Splenectomy may be required
- Gene therapy
