Thalassemias and Hemoglobinopathies Flashcards
Describe the % of total globin synthesis for alpha globin from conception to 50 yo.
Rises to max during fetal development and remains at max until end of life.
Describe the % of total globin synthesis for gamma globin from conception to 50 yo.
Rises to max during fetal development and drops at birth to minimum levels until end of life.
Describe the % of total globin synthesis for beta globin from conception to 50 yo.
Remains at minimum levels during fetal development. Rises rapidly at birth and remains at max until end of life.
Where does erythropoiesis predominate during fetal development?
Early: yolk sac
Early-late: liver, spleen
Late: bone marrow
Where does erythropoiesis predominate during post natal development?
Bone marrow
alpha globin genes are located on which chromosome?
16
beta globin genes are located on which chromosome?
11
Describe the hemoglobin proteins during embryonic development.
zeta2, epsilon2 (Hb Gower 1)
alpha2, epsilon2 (Hb Gower 2)
zeta2, gamma2 (Hb Portland)
Describe the hemoglobin proteins during fetal development.
alpha2, gamma2 (HbF)
Describe the hemoglobin proteins during adult development.
alpha2, beta2 (HbA)
alpha2, delta2 (HbA2)
“chipmunk facies” are typical of what thalassemia?
Beta Thalassemia major
Why do you have anemia in thalassemia?
Ineffective erythropoiesis –> apoptosis
Mechanical & immune removal of misshapen RBCs –> hemolysis
A mutation/deletion in chromosome 11 may lead to which thalassemia?
Beta
A mutation/deletion in chromosome 16 may lead to which thalassemia?
Alpha
Pts with Beta thalassemia major REQUIRE this treatment:
blood transfusions
Howell-Jolly bodies would be present following this treatment for Beta thalassemia or hereditary spherocytosis:
What do they represent?
Splenectomy; accumulation of RBCs with remnant nuclei that would normally have been bitten off by macrophages in the spleen.
Basophilic stippling can occur in pts from this region of the world with B-thalassemia, but less commonly in other populations with this disorder.
Mediterranean
What is a key microscopic finding that can distinguish Beta-thalassemia from Fe deficiency?
basophilic stippling (although not always present in B-thal pts)
What is RDW?
Red blood cell distribution width (RDW or RCDW) is a measure of the variation of red blood cell (RBC) volume that is reported as part of a standard complete blood count. Usually red blood cells are a standard size of about 6-8 μm in diameter.
Why is there Fe overload in thalassemia?
Transfusion Fe
Increased Fe absorption due to:
Ineffective erythropoiesis
- decreased hepcidin = more absorption, release
Fe taken up into liver, heart, & endocrine cells
Why does thalassemia cause endocrine and bone disease?
hypogonadism
Pituitary insufficiency
Osteopenia due to bone marrow expansion (crew cut), endocrine dysfunction, Fe chelators
Beta thalassemia causes an excess of which globin?
Alpha
excess alpha globin in B-thal results in 4 things that cause anemia. List/describe them.
1) Ineffective erythropoiesis due to inclusion bodies
2) Immune removal due to inclusion bodies and complement activation
3) Mechanical removal due to membrane damage, fragmentation, ^ rigidity, decreased deformability
4) Hypercoagulability due to membrane damage and phosphatidylserine relocation from cytoplasmic leaflet to EC leaflet.
What diagnostic techniques are needed to Dx thalassemia?
Family Hx
CBC
blood smear
physical exam
*Observation of elevated HbA2 or HbF for B-thal
*Observation of disproportionately elevated RBC count compared to Hb. Very low MCV with normal ferritin for A-thal
PCR for known mutation
Restriction Fragment Length Polymorphism Analysis for unknown mutation
List the supportive therapies for thalassemia.
Leukoreduction and viral testing for repeated transfusions
Drugs for Fe overload (Deferoxamine, Deferiprone, Deferasirox)
Hormone replacement for endocrinopathies
Osteoclast replacement and Vit. D for osteoporosis
List the curative therapies for thalassemia.
Hematopoietic stem-cell transplantation
Experimental therapies such as erythropoietin, HbF modifiers (such as hydroxyurea, butyrate) and antioxidant therapy.
Have allogenic cellular transplants for thalassemia proven to cure the disease?
yes, in up to 90% of cases. (up to 13% mortality in some cases)
What is Hb Bart?
an alpha-thalassemia resulting from an absence of both alpha globins (4 alleles missing from parents). Results in 4 gamma globins. Fetus dies in utero or soon after birth (hydrops fetalis)
Does HbH have a high or low O2 affinity
Very high
What is HbH?
3 alpha alleles missing from parents. Severe anemia. Unstable hemoglobin present in blood: Hemoglobin H (tetrameric β chains). Very high O2 affinity, can’t unload O2 at peripheral tissues. Results in hepatosplenomegaly.
Describe alpha-thal when 2 alpha alleles are missing.
The condition is called alpha thalassemia minor. Two α genes permit nearly normal production of red blood cells, but there is a mild microcytic hypochromic anemia. The disease in this form can be mistaken for iron deficiency anemia and treated inappropriately with iron.
Alpha thalassemia minor can exist in two forms:
alpha-thal-1 (αα/--), associated with Asians, involves cis deletion of both alpha genes on the same chromosome; alpha-thal-2 (α-/α-), associated with Africans, involves trans deletion of alpha genes on different (homologous) chromosomes
Describe alpha-thal when 1 alpha allele is missing.
This is known as alpha thalassemia minima and with this type there is minimal effect on hemoglobin synthesis. Three α-globin genes are enough to permit normal hemoglobin production, and there are no clinical symptoms. They have been called silent carriers. They may have a slightly reduced mean corpuscular volume and mean corpuscular hemoglobin.
Does Hb Bart’s have high or low O2 affinity?
Very high
What causes splenomegaly in HbH?
Precipitation of beta globin tetramers as red cells age results in decreased RBC deformability. Can’t make it through sinusoids of spleen, get jammed up, cause splenomegaly.
What percentage of African Americans carry the sickle cell trait?
8%
what fraction of African Americans are homozygous for the sickle cell trait?
1/625 homozygous
What in regions of the world does sickle cell anemia predominate?
Mediterranean, Saudi Arabia, India, (Africa?) < not on list
What is the AA substitution in sickle cell anemia?
Valine (hydrophilic) sub’d for Glutamate (hydrophobic)
What does the AA substitution in sickle cell anemia cause?
A deoxygenated RBC will cause HbS to polymerize, causing the RBC to assume a sickle shape morphology.
Describe a bone pathology associated with sickle cell amenia.
epiphyseal infarcts leading to shortening and flattening of long bones. symptom: dactylitis
If your pt has sickle cell disease, they must try to avoid:
infection, fever, dehydration, hypoxemia, & acidosis
Under what conditions would you transfuse a sickle cell pt?
Life threatening conditions such as:
severe anemia, hepatic crisis, acute chest syndrome, priapism (persistent erection)
stroke prophylaxis in children with strokes
If a sickle cell pt is hypoxic, what do you do?
Administer oxygen!
If a sickle cell pt is in severe pain, what do you do?
treat the pain! possibly with narcotics
What is going on in HbC disease?
Glutamate replaced with lysine. Results in polymerization similar to HbS (sickle cell) but not as bad
Which presents with worse symptoms, HbS or HbSC?
HbS. HbSC has milder symptoms because the pt is only heterozygous for sickle cell disease. Fewer sickled cells, fewer crises. Will see target cells, irregularly contracted cells (sickleish cells), and spherocytes in HbSC.
