Hemoglobin Disorders (Thalassemia and Sickle Cell) Flashcards
How many Beta globin genes are present on each chromosome?
one
What chromosome is the Beta globin gene located on
chromosome 11
What genotypes are considered to be B-thalassemia major?
Bo/Bo or B+/B+
What genotypes are considered to be B-thalassemia minor?
B/Bo or B/B+
Main sign of B-thalassemia minor
mild microcytic anemia
Thus, you’ll have decreased hepcidin and increased ferroportin to increase duodenal absorption
What is Fetal Hemoglobin’s structure (HgF)
Alpha2/Gamma2
What is Hemoglobin A2’s stucture
Alpha2/Delta2
What is Hemoglobin H’s structure
tetramer of betaglobin
Normally, when you’re born what happens to your alpha chain, beta chain, and gamma chain levels
alpha chain levels increase slightly but remains relatively constant compared to fetal levels
beta chain levels (initially 0) increase dramatically, and your gamma chain levels decrease
How many alpha globulin genes are on each chromosome?
2
What chromosome is the alpha globulin gene located on?
chromosome 16
Genetic Mechanism causing Alpha Thalassemias
gene deletions
Genetic Mechanism causing Beta Thalassemias
gene point mutations
If one of the 4 alpha genes is deleted, what condition do you have?
Alpha Thalassemia silent carrier or Alpha Thalaseemia Trait 1 (-a/aa) but you won’t have anemia because you do have a functional alpha globulin
If two of the 4 alpha genes is deleted, what condition do you have
Alpha Thalassemia trait 2 (–/aa) or (-a/-a), in 3% in African Americans
note. you will have some Hb Bart’s in this case
If three of the 4 alpha genes are deleted, what condition do you have?
Hemoglobin H Disease (a beta tetramer aka HgH)
If 4 of the 4 alpha genes are deleted, what condition do you have
Hydrops Fetalis (from gamma tetramer aka HbBart’s)
Microscopic Findings in both Thalassemia’s
target cells
microcytic rbc’s
Pathogenesis of Beta Thalassemia Major
you have massive erythroid hyperplasia (overactive bone marrow pushing out immature cells) that just can’t mature before they die
point mutations on both alleles of beta globulin means decreased beta globulin production.
The subsequent accumulation of unpaired Alpha globulins causes a bunch of bad things. These unpaired globulins–>alpha “hemichromes” or clumps–>inclusion bodies–>mess with cytoskeleton, flip membrane so inner proteins like phosphatidylserine are on the outside. leads to:
Thrombotic tendencies
Membrane damage
Autoimmune hemolysis
Ineffective erythropoesis
Why is there Iron Overload in Severe Thalassemia?
overactive bone marrow from ineffective erythropoesis reduces hepcidin levels, so you have increased ferroportin, and thus increased serum iron.
you also get excess iron in severe thalassemia when you require chronic blood transfusions (so you should give the blood transfusion with an iron chelator
Iron overload–>cirrhosis–>liver cancer
Pathogenesis of Alpha Thalassemia (specfically 3 alpha’s missing)
deletion of alpha genes–>unpaired beta’s form tetramers (HgH), but also these beta hemochromes–>heinz bodies and precipitate out, which leads to hemolysis too
note, you see hemolysis and ineffective erythropoesis, but WAY more hemolysis in peripheral blood, red blood cells can actually develop to maturity before lysing.
Clinical Findings of Beta Thalassemia Major
- Expanded facial features, because of expanded bones
- Expanded bone marrow–>osteoporosis
- Splayed teeth from expanded mandible and maxillary
- hepatosplenegomy
- skin ulcers (seen in a lot of hemolytic anemias)
Clinical Impact of Iron Load in B-Thalassemia Major?
organ damage to... Liver Heart Pancreas Thyroid Pituitary gland Other endocrine organs
Why do you not want to do phlebotomy to correct iron overload in Beta Thalassemia Major (you do it in Hemochromatosis)
Because in B-Thalassemia, you’re anemic…you DO NOT want to take out MORE blood cells from the body!
CBC indicators of thalasemia
anemia, microcytic conditions, but normal levels of everything else
How do you confirm alpha thalasemia with lab test?
you essentially have to first rule out beta thalasemia with a hemoglobin electrophoresis (bc beta thalasemia has elevated HgA2 and HgF) NO iron deficiency
next, you can do PCR for a common mutation (Weir didn’t specify which one)
also in the US you’re more likely to see this condition in African Americans
How do you confirm suspicion of beta thalasemia?
anemia but no iron deficiency.
hemoglobin electrophoresis checking for elevated HgA2 and HgF
Both thalassemia’s are microcytic anemias. What lab value differentiates it from other microcytic anemias?
normal (or elevated) iron levels, normal levels of transferrin and ferritin, may have reduced hepcidin IF IRON OVERLOAD, but the MAIN THING:
MCV««70!
Treatment option for Beta Thalassemia Major
iron chelating (bc of iron overload)
chronic blood transfusions from a young age
treat osteoporosis
treat hypogonadism and other endocrine probz
Are allogenic bone marrow transplants successful for thalasemia?
In young people yea!
Which has a higher affinity for oxygen, HbA or HbH and Hb Bart’s? What’s the implication of this?
HbH and Hb Bart’s have a higher affinity for oxygen.
This is bad because they won’t dump the oxygen into tissues like normal hemoglobin
You get hypoxiaaa
Do you get iron overload?
Not usually…so you don’t get all the endocrine and organ problems as you do in beta thalassemia major
Microcytic indication of Alpha Thalasemia that WONT be in Beta Thalassemia?
inclusion bodies of HgH (beta globin tetramers) in mature red cells (“golf ball cells” in peripheral blood
Genetic cause for Sickle Cell Trait or Disease
point mutation on the 6th amino acid for B globulin, causing glutamic acid to change into valine
(to have the disease you need point mutation in both chromosomes)
8% African Americans have the gene
Pathogenesis of Sickle Cell Disease
mutated betahemoglobin molecules come together to form polymers, altering skeletal shape of the red blood cells. So they plug shit up and cause ischemic damage
Plus, when you have infarctions of bones and other tissues, it is not just due to the clogging of vessels by sickled cells…it is also the resultant inflammatory damage by the white cells and the released nitric oxide (causing vascular spasm)
Clinical Findings of Sickle Cells Disease
“Hand-foot syndrome” : Dactylitis in children–>epiphyseal infarction, leading to shortened digits
Acute Chest Syndrome: due to fat embolization from the infarcted bone, can clog up pulmonary vessels, causing alveolar edema–>respiratory distress
Skin necrosis and ulceration
On an agar gel, what hemoglobin types would each of the following have a positive result for? Beta Thal. Sickle Cell Disease Sickle Cell Trait Hemoglobin C Normal
Beta thalassemia: elevation of A2 Sickle Cell :all S Sickle Cell Trait: elevated A and S (more A than S) Hb C: A and C Normal: A
Clinical Presentation of S/Beta-thal 0?
You would have sickle cell anemia with increased hemoglobin A2 and hemoglobin F levels
Sickle Cell Disease Therapy
Aggressively Hydrate
Transfuse in certain life threatening situations
(Severe anemia, hepatic crisis, acute chest syndrome, priapism, prophylactic transfusions in children with strokes)
Pain control
Oxygen if hypoxic
What do you have to be worried about with chronic transfusions in sickle cell patients
They run an increased risk of developing antibodies to minor antigens in donor blood
Mechanism of Action of Hydroxyurea treatment for Sickle Cell Anemia
Preventative treatment
Inhibits ribonucleotide reductase
It increases fetal hemoglobin and decreases white cells, this is for patients with recurrent crises, so you markedly diminish the crises by decreasing likelihood of flareups
