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Hemolytic Anemias II
Terms in this set (56)
Describe the pathology in hereditary spherocytosis.
Intrinsic RBC membrane defect (cytoskeletal proteins) > membrane instability > spheroidal shape > decreased deformability > increase splenic trapping > macrophage erythrophagocytosis > premature extravascular hemolysis within spleen
List 3 characteristics features of hereditary spherocytosis.
(2) hemolytic anemia (HA)
(3) splenomegaly - splenectomy relieves the HA in severe cases
What are the modes of transmission of hereditary spherocytosis? What is their prevalence and degree of anemia?
(1) AD - most common - 75% of cases - variable degree of anemia
(2) AR - less common - more severe anemia - can be homozygous or compound heterozygous (two different AR mutations at the same locus)
List 2 protein complexes in the RBC membrane that, when lost, result in spherocytosis. How do they contribute to membrane stability?
(1) Actin - spectrin - 4.1 complex: helps maintain structural strength and stability
(2) Spectrin - ankyrin - band 3 complex: stabilizes the phospholipid bilayer
(1)Mutations in genes coding for which proteins are most likely to give rise to hereditary spherocytosis?
(2)What type of mutations are they?
(1) ankyrin, band 3, spectrin, or band 4.2
(2) framshift or nonsense
What are Howell-Jolly bodies? When do you see them?
Basophilic nuclear remnants in circulating erythrocytes. During maturation in the bone marrow late erythroblasts normally expel their nuclei, but in some cases a small portion of DNA remains. Its presence usually signifies a damaged or absent spleen.
What 4 clinical features are seen in hereditary spherocytosis? Do what degree?
Varying degrees of
(4) marrow hyperplasia
How many forms of hereditary spherocytosis are there? What are their prevalences?
(1) mild | 20-30%
(2) moderate | 60-70%
(3) mild/moderate | 10%
(4) severe | 3-5%
If a patient has an infection with Parvovirus B19 and is also suffering from a hemolytic anemia such as hereditary spherocytosis, what can result?
aplastic crisis - sudden decreases in RBC production aka reticulocytopenia followed by rubella-like rash
Between AD and AR hereditary spherocytosis, which is more likely to result in clinical complications? Such as?
-neonatal jaundice (rare)
What does G6PD do? Why is it significant?
Catalyzes 1st step in pentose phosphate pathway:
G6P + NADP --> 6-phosphogluconate + NADPH
It is significant because it provides the RBC with NADPH which is its only source of reducing potential to resist oxidant stress (like from H2O2) that leads to hemolysis
What is the mode of transmission for G6PD deficiency? How many mutations have been discovered?
What are the four most common G6PD deficiency variants?
(1) What is the G6PD activity in GdB variant G6PD deficiency? (2) What population is it most commonly found in?
(1) Normal activity - declines slowly with aging RBC - sustains GSH levels throughout RBC lifespan
(2) All world populations
What is the G6PD activity in GdA variant G6PD deficiency?What population is it most commonly found in?
(1) Normal activity
What is the G6PD activity in GdA- variant G6PD deficiency?What population is it most commonly found in?
(1) Normal activity in reticulocytes but enzyme is unstable - activity half-life is only 13 days > mature RBCs only have 10-60% enzyme activity
What is the G6PD activity in GdMed variant G6PD deficiency?What population is it most commonly found in?
(1) Enzyme is very unstable - 8 day half-life - reticulocytes have reduced activity - mature RBCs have activity <10%
(2) iran, iraq, india, pakistan, Greece, Sardinia
(1) What are Heinz bodies?
(2) What do you use to stain for them?
(1) Inclusions within red blood cells composed of denatured hemoglobin that can result from oxidative stress in G6PD deficiency.
(2) methyl crystal violet
What is the most common enzyme abnormality worldwide? What percent of the world's population carries this abnormality?
G6PD deficiency (result of gene mutation)
10% of the world's population
What disease can G6PD protect against? Why is this significant?
Malaria. There is a geographic distribution of the G6PD deficiency that mirrors malaria.
If G6PD deficiency is so common, why are there not as many clinically significant cases?
Most variants have a compensated hemolysis and show no signs of anemia in the steady. Anemia only occurs under severe oxidative stress to RBCs.
(1) According to the WHO, how many classes of G6PD deficiency are there?
(2) Which is the most severe?
(3) What class do GdMed fall under?
(4) What class do GdA- fall under?
(2) Class I is the worst
(3) Class II
(4) Class III
__1__ (food) can elicit a hemolytic crisis in __2__ (G6PD def variant).
(1) fava beans
__1__, __2__, and __3__ (drugs) can elicit a hemolytic crisis in __4__ (G6PD def variants).
(1) anti-malarials (primaquine, quinine, etc.)
(4) GdA- and GdMed
What 4 notable viral or bacterial infections can cause hemolysis?
(2) Influenza A
(4) typhoid fever
What is favism? Prevalent in which region?
Sudden onset of acute hemolysis within 1-2 days of eating fav beans. Common in the mediterranean.
(1) Which G6PD deficiency is common in the US?
(2) Among which race and gender?
(3) When do hemolytic episodes happen?
(2) black males
(3) 2-3 days after ingesting oxidant drug
What is a bite cell?
An abnormally shaped red blood cell with one or more semicircular portions removed from the cell margin resulting from the removal of denatured hemoglobin by macrophages in the spleen. Glucose-6-phosphate dehydrogenase deficiency, in which uncontrolled oxidative stress causes hemoglobin to denature and form Heinz bodies, is a common disorder that leads to the formation of bite cells.
What blood work is done to diagnose hemolytic anemia? What should you see in the blood work?
Decreased - haptoglobin
Increased - lactate dehydrogenase
Increased - bilirubin (indirect)
Increased - reticulocytes
+ Heinz bodies
What should be given to infants with prolonged neonatal jaundice due to G6PD deficiency?
(1) What is the second most common enzyme deficiency affecting RBCs?
(2) What does this enzyme catalyze?
(1) pyruvate kinase deficiency
(2) Phosphoenolpyruvate (PEP) + ADP >> Pyruvate + ATP
List 2 reasons why the pyruvate kinase reaction is so important to RBCs?
From glucose, it is responsible for producing 2 ATP's which:
(1) Is a significant energy source for RBCs.
(2) plays a major role is maintaining the cation gradient in the RBCs, thus protecting the cell from premature death
Describe how a RBC dies with a pyruvate kinase deficiency.
Deficient ATP synthesis > membrane damage, loss of intracellular K and water > cellular dehydration > cell contraction and crenation forming echinocytes (aka Burr cells:pictured) > extravascular hemolysis
How is pyruvate kinase deficiency managed?
For mild or moderate cases - supportive care
For severe cases - may benefit from splenectomy
Transfusions are sometimes used as well.
Describe the structure of a hemoglobin molecule.
- Consists of globin protein - tetramer of 4 folded polypeptides. - Each globin chain has a heme group in its center.
- One pair of globin chains designated alpha chains
- One pair of globin chains designated non-alpha chains
Describe a hemoglobin production timeline.
A = epsilon chain
B = alpha chain
C = gamma chain
D = beta chain
E = delta chain
(1) Which chains makes up Hb A?
(2) Hb A2?
(3) Hb F?
(1) alpha-2 | beta-2 (aka 2 alpha globins & 2 beta globins)
(2) alpha-2 | delta-2
(3) alpha-2 | gamma-2
(1) What precentage of Hb A, A2, and F is normally found in newborns?
(1) A - 25% | A2 - <1% | F - 75%
(2) A - 97% | A2 - 2-3% | F - <1%
What is the lifespan of Hb molecule? What happens after that?
120 days. The iron is recycle and used elsewhere. The porphyrin rings degraded to bilirubin and excreted by the liver.
(1) Which chromosome contains genes that encode alpha globin molecules?
(2) and non-alpha globin molecules?
(1) chromosome 16
(2) chromosome 11
(1) Between both chromosomes, how many alpha genes are present?
(2) Are they identical?
(3) What percentage of alpha globin production is each gene responsible for?
(1) There are 4 copies of the alpha globin gene.
(2) Each chromosome contains an alpha 1 gene and alpha 2 gene. The alpha 1's on each chromosome are identical to each other, as are the alpha 2's, making up 2 pairs of identical alpha globin genes termed the alpha1 pair and alpha2 pair.
(3) Each of the 4 genes encodes 25% of production. One alpha 1 and one alpha 2 come together to make an alpha globin, so between 2 chromosomes, 2 alpha globin molecules are formed.
(1) How many beta globin genes exists between each pair of chromosomes?
(2) How many delta globin genes exists between each pair of chromosomes?
(1) 2 - each beta gene codes for 1 beta globin molecule
(2) 2 - each delta gene codes for 1 delta globin molecule
(3) 4 - one gamma G gene and one gamma A gene produce 2 parts of one gamma globin molecule, so between 2 chromosomes, 2 gamma globin molecules are formed.
Normally, 2 beta globin genes express almost precisely the amount of globin protein as the alpha globin genes, allowing for globin production balance. If the globin gene production is unbalanced, what disease occurs?
What are the 2 mechanisms that hemoglobinopathies can occur?
Genetic defects leading to...
(1) quantitative abnormality in Hb synthesis = thalassemia
(2) structurally abnormal Hb
What are the most common structural Hb variants? Which ones leads to premature hemolysis? How?
(1) HbS > altered globin structure > abnormal polymerization > decreased RBC deformity > decreased RBC survival
(3) HbC > altered globin structure > abnormal crystallization > decreased RBC deformity > decreased RBC survival
(1) What is the mutation that causes HbS?
(2) What is the mutation that causes HbC?
(3) What is the mutation that causes HbC?
(1) GLU > VAL @ position 6 of beta globin chain
(2) GLU > LYS @ position 6 of beta globin chain
(3) GLU > LYS @ position 26 of beta globin chain
(1) What is the 3rd most common structural hemoglobinopathy?
(2) What population is it common in?
(3) What is the typical manifestation?
(2) SE asian decent
(3) Mild hemolytic anemia withOUT splenomegaly
Explain what can occur n a hemoglobinopathy in which abnormal Hb has an increased affinity for O2. Give an example disease.
Decreased O2 delivery to tissues > EPO stimulates erythropoiesis (even though there is no anemia) > increased Hb concentration + increased Hematocrit.
e.g. Hb Chesapeake
Explain what can occur n a hemoglobinopathy in which abnormal Hb has a decreased affinity for O2.
Decreased levels of oxygenated Hb and increased levels of deoxygenated Hb > cyanosis
e.g. Hb Seattle
List 4 ways in which Hb can be functionally abnormal. (What are the 4 classification of functionally abnormal Hb?)
(1) Aggregation (polymerization/Crystallization)
(2) Unstable Hb
(4) Oxygen affinity change
Explain the issue in methemoglobin.
Heme contains ferric iron (3+) vs. the normal ferrous iron (2+) and cannot bind O2 > increase deoxygenated Hb > cyanosis.
Explain the issue in unstable hemoglobin.
Unstable Hb is aka Heinz Body Anemia.
Precipitates of unstable Hb form inclusions in internal aspect of RBC membrane > decreased RBC deformability > shortened RBC survival
List the commonly used tests used to diagnose hemoglobinopathy.
(1) CBC with morphology
(2) Hb electrophoresis - cellulose acetate pH8.4 or citrate agar pH6
(4) Isoelectric focusing
(5) Solubility tests
(6) quantitation: Hb F, Hb Barts
(7) Heinz body stain (tests for unstable Hb)
(8) Gene analysis
Describe a cellulose acetate gel ph8.4 for various Hb variants.
Not sure what to make of this image, but she had it in the packet...
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