Test 3: Thalassemias Flashcards
1
Q
 genetically diverse group of disorders (Which may appear clinically similar) That are caused by decrease or absent production of globein chains
* defect lies in the rate of synthesis of the chains
A
Thalassemias
2
Q
What is the difference between Hemoglobinopathies and thalassemias?
A
Hemoglobinopathies: Structural defect in glove and chain due to DNA mutation
Thalassemias: Defect lies in the RATE of synthesis
3
Q
Where are thalassemias typically prevalent? 
A
High frequency all around the Mediterranean, throughout Middle East, India, and southeast Asia
Thalassa= Greek for “sea”
How many areas, follows the same geographic distribution as malaria
4
Q
What is beta-gamma switch?
A
Gamma globin switches off, and beta globin switches on right before birth
5
Q
Epsilon and Zaida are ___________only.
A
Embryonic
6
Q
Globin chain that remains at constant levels starting in second trimester
A
Alpha globin
7
Q
Globin chain that turns on right before birth
A
Beta globin
8
Q
What is the exact nature of the molecular/cellular defect in thalassemia‘s?
A
Reduced or absent synthesis of one or more globin chains creating an imbalance of globin synthesis
9
Q
 what is the first consequence of thalassemias?
The second?
A
Reduced production of functional hemoglobin tetramers.
Increase production of abnormal hemoglobin tetramers form the leftover unpaired globin chains.
10
Q
Gamma4 =
A
Hgb Bart
11
Q
Beta4 =
A
Hgb H
12
Q
Alpha4 =
A
Too unstable to survive (Precipitates causing hemolytic anemia) 
13
Q
Alpha thalassemia = defect in…
A
Alpha chain synthesis rate
14
Q
Beta thalassemia = Defect in…
A
beta chain synthesis rate
15
Q
“Thal major” (for both alpha and beta) = 
A
Homozygous
16
Q
“Thal minor” (for both alpha and beta) =
A
Heterozygous
17
Q
A2 is made up of?
What are the proportions? 
A
Two alpha and two delta
Newborn: <0.5
Adult: 2.5
18
Q
What is A1 what up of?
What are the proportions?
A
Two alpha and two beta
Newborn: 20%
Adult: 97%
19
Q
What is fetal (F) hemoglobin made of?
What are the proportions?
A
Two alpha and two gamma
Newborn: 80%
Adult: <1%

20
Q
What is Gower II composed of?
A
Two alpha and two epsilon
Embryonic only 
21
Q
What is Gower I composed of? 
A
Two Zata and two epsilon
embryonic only
22
Q
What is Portland composed of?
A
Two zada and two gamma
embryonic only
23
Q
What is seen on peripheral smear‘s with Thalassemias? 
A
Micro, hypo RBCs, worse in beta thalassemia‘s
24
Q
Why are increased RBC counts seen with patients with thalassemias? 
A
To make up for chronic hypoxia, more RBCs but they are smaller which have less hemoglobin
(worse in beta thalassemia)
25
________-thalassemias have greater hemolytic anemia due to highly unstable tetramers. Increased RBC count with worse MCV and MHC.
Beta
26
In _______-thalassemia, defective chain production results in excess chain production in fetal in adult life. Involves a lack of hemoglobin synthesis and cells have a short lifespan and cannot carry oxygen effectively. 
Alpha
27
What determines the severity of alpha thalassemia? 
Genetic alterations cause one, two, three, or all four alpha genes
Severity ranges from only having one alpha gene deleted or suppressed to lethal with all four alpha genes deleted or suppressed
28
Two loci on chromosome ______ = Total of four alpha genes.
16
29
How is it denoted if one alpha gene is deleted?
(-a)
a+-Thal
30
How is it denoted if two alpha genes are deleted?
(- -)
a^0-Thal
31
With a decrease or absence of alpha chains, excess _____ and ______ chains accumulate to form tetramers.
Gamma, beta
-Hgb Bart (Gamma4)
-Hgb H (Beta4) 
32
Without alpha chains, hemoglobin _____ in fetus and hemoglobin ______ in infant are both affected, so symptoms of alpha thalassemia appear before birth and continue thereafter
F, A1
33
What is the worst case of alpha thalassemia?
Hgb Bart or Hydrops Fetalis (- -, - -) or Alpha-Thal major, Also known as homozygous alpha^0 Thalassemia
No alpha globin is produced, so Hgb Bart (Gamma4) is primary hemoglobin 
34
What is the prognosis for hemoglobin Bart (Hydrops fetalis)? 
Nonfunctional, so condition is lethal, infants usually grossly edematous due to onset of congestive heart failure early in gestation are commonly stillborn
35
Why does hemoglobin bart allow the fetus serve to survive until the third trimester? 
Due to hemoglobin Portland, and then dies of Anoxia
-Disease may trigger toxemia in mom during pregnancy and postpartum hemorrhage later
36
What does hemoglobin Bart (- -, - -) show on electrophoresis?
Alkaline hemoglobin electrophoresis shows 80% hemoglobin Bart, 20% hemoglobin Portland (Little or no hemoglobin H and no hemoglobin A1) 
37
How does a peripheral blood smear appear with hemoglobin Bart? 
The population is it commonly seen in?
Loaded with nRBC‘s
Southeast Agents, especially Filipinos
38
What are the five clinical Syndromes of alpha thalassemia?
1. Hemoglobin Bart (- -, - -)
2. Hemoglobin H disease (- -/-a)
3. Hemoglobin H- Constant Spring disease (- -/a^cs a)
4. Alpha-thalassemia minor (- -, aa or -a/-a)
5. a-Thal Silent Carrier (-a /aa)
39
Caused by deletion of three out of four alpha globin chain genes
-Occurs AFTER Beta gamma switch
-Huge decrease in alpha chain synthesis means RBC makes mostly beta4 tetramers, hemoglobin H has increased oxygen affinity (x10 that of Hgb A)
-Symptomatic but not fatal
Hemoglobin H disease (- -/ - a)
40
Hgb H =
Beta4
41
Hgb ____ tends to precipitate as greenish blue inclusions (Using brilliant cresyl blue supravital stain)  and older RBCs…. Triggering chronic hemolytic anemia.
H
(type of alpha thalassemia)
42
How can you tell hemoglobin H from Heinz bodies?
Human globin H inclusions tend to be quite numerous and scattered all over the cell
Heinz Body inclusions are fewer And located more on the periphery
43
Globin electrophoresis shows hemoglobin H, decreased ….
Hemoglobin A1 and A2, and N and hemoglobin F???
44
What morphology is typically seen with hemoglobin H disease (- -/ - a) ?
Target cells, micro, hypo
45
What is the prognosis of  hemoglobin H disease (- -/ - a) ?
Lifelong mild to moderate anemia (Due to instability of hemoglobin H and inability of bone marrow to compensate)
46
What is the treatment for hemoglobin H disease (- -/ - a) ?
No therapy except transfusion therapy and splenectomy
47
Why is Hgb H - Constant Spring Disease (- -/a CSa) also classified as a hemoglobinopathy?
Is also in an elongated hemoglobin due to alpha chain mutation
48
What is the cause of  Hgb H - Constant Spring Disease (- -/a CSa)?
One mutated and one normal alpha gene on one of the chromosome 16s
Plus 2 deleted alpha genes on the other chromosome 16th
* two normal beta chains, one normal alpha chain, and one abnormal alpha chain with 31 extra amino acids
49
How does  Hgb H - Constant Spring Disease (- -/a CSa) appear on alkaline electrophoresis? 
Shows hemoglobin H, A1, A2, and 1-3% hemoglobin Constant Spring 
50
how does Hgb H - Constant Spring Disease (- -/a CSa) morphology appear?
Targets and micro, hypo peripheral blood picture, and lack of treatment and prognosis all pretty much the same as in hemoglobin H disease
51
The peripheral blood picture of Hgb H - Constant Spring Disease (- -/a CSa) could be confused with a severe ….
Iron deficiency anemia
52
caused by two normal and two abnormal alpha genes
a-Thalassemia Minor (--/aa or - a/-a),
aka.
*a-Thal Trait
53
How does alkaline hemoglobin electrophoresis show for  a-Thalassemia Minor (--/aa or - a/- a)
Virtually normal
54
a-Thalassemia Minor (--/aa or - a/- a):
Very few hemoglobin H inclusions (So hemoglobin age rarely seen on electrophoresis, why?
Because patient has a few leftover beta chains 
55
What is the morphology And symptoms of a-Thalassemia Minor (--/aa or - a/- a)?
Decrease MCV and MCH, frequent Poilk with Target cells
No real clinical disease
56
Alpha thalassemia syndrome where three out of four A’s is OK 
-caused by only one gene deletion 
a-Thal Silent Carrier (- a /aa)
57
What is the morphology and lab findings of a-Thal Silent Carrier (- a /aa)?
Slightly decreased or normal MCV and MCH, looks slightly micro, hypo
58
how does a-Thal Silent Carrier (- a /aa) show on alkaline electrophoresis?
Normal. Benign condition
Genetic testing required for diagnosis
59
 what is the prevalence of a-Thal Silent Carrier (- a /aa)
30% prevalence in African-Americans
(H0 = Disease originated in north Africa) 
60
Beta thalassemia:
One locus on Chromosome _____ = Two beta genes 
11
Normal genotype is (beta/beta) 
61
What kind of anemia is beta thalassemia‘s? 
Hemolytic
62
In beta thalassemia, Without beta chains, access _____ chains will accumulate, however, they are too unstable to stay as tetramers, so they Precipitate instead and cause plasma membrane damage
Alpha
63
What are the lab findings in all beta thalassemia‘s?
-Increased RBC count (unlike alpha thalassemias)
-decreased MCV, MCH
-normal or slightly decreased MCHC
-increased hemoglobin F
64
Beta thalassemia when there is no beta chain production, thus no hemoglobin A1 (Similar in severity to SCD) 
B^0
65
Beta thalassemia where there is reduced beta chain production, decrease hemoglobin A1, with variable severity
B^+
66
In beta thalassemia multiple mutations are possible. They can be defects at every step in globin synthesis. Problem is usually _______ mutations not just the more simple scenario of gene deletions
Point
67
Beta thalassemia that is a severe anemia. Symptoms appear in first two years of life, with failure to thrive and skeletal abnormalities due to massive bone marrow expansion
Beta thalassemia major (aka Cooley’s anemia) 
68
What are the lab findings in Beta thalassemia major (aka Cooley’s anemia)?
Increased RBCs with decreased MCV and MCH****
69
What is the morphology seen in Beta thalassemia major (aka Cooley’s anemia)?
Marked basophilic stippling, target, teardrops, and nRBCs
70
What is shown on electrophoresis testing with Beta thalassemia major (aka Cooley’s anemia) ?
Increased hemoglobin F on alkaline electrophoresis, slightly increased hemoglobin A2, absent hemoglobin A
71
What is the treatment for Beta thalassemia major (aka Cooley’s anemia)?
Treated with regular transfusions (To prevent bone deformity) Consequent major cause of morbidity is iron overload so must follow with iron chelation therapy using *desferroxamine
-bone marrow transplant may be used
72
What is used for Fe chelation therapy?
Desferroxamine
73
Beta thalassemia:
Moderate anemia but normal growth in children
Beta-Thalassemia intermedia
74
What are the lab findings in Beta-Thalassemia intermedia?
Increased RBCs with decreased MCV and MCH
75
What is the morphology seen in Beta-Thalassemia intermedia?
-Some basophilic stippling and nRBCs
-moderate targets
76
What does alkaline electrophoresis show in Beta-Thalassemia intermedia?
Increased hemoglobin F, decrease hemoglobin A
77
How is Beta-Thalassemia intermedia treated?
With supportive care as needed. Few transfusions needed
78
Beta thalassemia with one normal beta gene, Mild or no anemia
Beta-Thalassemia Minor
79
What are the lab findings in Beta-Thalassemia Minor?
Increased RBCs with decreased MCV and MCH
80
What is the morphology seen in Beta-Thalassemia Minor?
Slight basophilic stippling and few targets
81
How is Beta-Thalassemia Minor differentiated from IDA? 
Red blood cell count is greater than you would expect for degree of micro, hypo
82
Beta thalassemia:
-B^SC/B = genotype
-No anemia and no treatment
-Very slight Peripheral smear changes
Thalassemia Silent Carrier
83
B^0 = _____ beta chains, so no _____
No, A1
84
B+ = ________ beta chains, _______A1
Some, some
85
What is hemoglobin S-Thal Disease? 
A hemoglobinopathy and a thalassemia in one
Can be… (S-beta-Thal) or (S-alpha-Thal)
-double heterozygotes
-distinguishable by electrophoresis, microcytosis, and splenomegaly
86
Hgb S-beta^0 Thal is like Hgb ____
SS
87
Hgb S-beta^+Thal is like Hgb ____
AS
88
Caused by decrease (delta-beta+) or absence (delta-beta^0) of both delta and beta chains
Both chains have a thalassemia***
Delta beta-thalassemia
89
What is the RBC morphology in Delta beta-thalassemia
Normal RBC morphology (Still micro, hypo) and variable anemia that is mild to moderate
Can have hepatosplenomegaly with bone changes
90
What is seen on electrophoresis in Delta beta-thalassemia 
Increased hemoglobin F, decreased hemoglobin A1, Variable hemoglobin A2
91
*REMEMBER*
Delta beta-thalassemia is what it’s bane implies: __________ Delta and beta chains
Decreased or absent 
92
-Alpha chain is OK, but beta chain is a delta-beta fusion
-caused by Delta-Beta chain fusion from unequal crossover‘s
* both a Hemoglobinopathy and a thalassemia
Hgb Lepore
93
 what is the prognosis for Hgb lepore?
Stable, normal function except for slightly increase oxygen affinity (Shift to the left)
Severity depends on whether other mutations are present in Delta-beta chains
94
-characterized by increase hemoglobin F in adults, but without clinical/hematology features of thalassemia (Even though it is just another thalassemia) 
Hereditary persistence of fetal hemoglobin (HPFH) 
95
-caused by deletion/inactivation of delta-beta gene complex, resulting in persistence of gamma chains
-less symptomatic than Delta-Beta thalassemia
Hereditary persistence of fetal hemoglobin (HPFH)
96
What is the prognosis for  Hereditary persistence of fetal hemoglobin (HPFH)?
No significant clinical abnormalities
97
What are the two sub populations of HPFH? 
-Homozygotes: 100% hemoglobin F with slightly micro, hypo cells
-Heterozygotes: 15 to 35% hemoglobin F on alkaline electrophoresis and near normal lab results
98
What are the laboratory tests used in diagnosing thalassemias?
1. *** Hemoglobin electrophoresis- At alkaline and acid pHs
2. Hemoglobin of quantification-Alkaline denaturation test (Accurate and precise)
3. Hemoglobin A2 quantification
4. Brilliant Cresyl Blue stain
5. Acid Elution test for Hgb F aka. Kleihauer-Betke (K-B) Slide Test
99
Ion exchange microchromatography
Hemoglobin A2 qualification
100
FEP/ZPP levels are
____________ in IDA
____________ in thalassemias
Increased
Normal
