1what part of hemoglobin is altered in thalassemias
globin chain
2how are globin chains altered in thalassemias
little to no synthesis of one or more chains
3which form of thalassemia provides protection against malaria
alpha-thal
4where is the beta gene located and how many are there
chomosome 11; total of 2 (one from each parent)
5genotype for normal beta chain synthesis
betaeta
6where are the alpha genes located and how many are there
two on chromosome 16, total of 4 (2 from each parent)
7genotype for normal alpha chain synthesis
alpha alpha/alpha alpha
8what globin chains are affected in beta-thals
beta, delta, gamma, epsilon
9beta^0 thal
no beta chains are produced
10what kind of beta thal results in no Hgb A production
beta 0eta 0
11beta^+ thal
partial deficiency of beta chains
12beta^ silent
carries a mutation that has little to no effect
13delta beta^ 0
no delta or beta chains are made
14which beta thal results in no Hgb A or Hgb A2 production
homozygous delta beta^ 0
15delta beta^ lepore
delta and beta chains fuse to create Hgb lepore
16alpha ^+
used to indicate deletion of alpha 1 or 2
17alpha^ 0
indicates deletion of both alpha 1 or 2
18alpha^ T
nondeletional mutations
19how is mrna transcription affected in thalassemias
decreased or inhibited fully
20how do mrna processing errors affect globin chain production
chain production is altered or stopped
21what translation errors result from genetic defects that cause thalassemias
stop codon is added or removed, creating defective mrna
22how does rbc morphology change in thalassemias
little to no globin chains production creates microcytic, hypochromic rbcs
23how does an unequal produciton of paired chains affect rbc precursors
decreases precursor and mature rbc survival
24what determines clinical severity of thalassemias
alphaeta chain imbalance
25how do alpha chains affect rbc morphology in beta thalassemias
unpaired chains precipitate in precursors, forming inclusions
26what kind of erythropoiesis occurs in beta thals
- sufficient erythropoiesis
- effective erythropoiesis
- ineffective erythropoiesis
- insufficient erythropoiesis
27how does alpha chain precipitation in beta thals affect overall rbc wellbeing
causes oxidative stress and damages cell membranes
28defective precursors made in beta thals are _______ by _________ in the marrow
phagocytised, macrophages
29describe extravascular hemolysis in beta thals
cells are destroyed by macrophages in the spleen due to the presence of inclusions
30when do beta thal symptoms begin to manifest in children and why
6-24 months; early presence of Hgb F prevents them from showing up earlier
31what type of Hgb generally increases in beta thals when symptoms begin to manifest
Hgb A2
32globin chain production shifts to _____ and _____ in beta thals
delta, gamma
33what kind of hgb is insufficient in beta thal major
Hgb A2
34how does beta thal major result in bone deformities/increased risks of fractures
severe anemia triggers increased EPO production, causes extreme erythroid hyperplasia
35how do beta thals affect the appearance of a skull in an xray
"hair on end" appearance
36mechanism that causes jaundice in beta thals
unconjugated bilirubin increases
37what element accumulates in various organs in beta thals
iron
38what symptoms are seen in children suffering from iron accumulation
mental delays, absence of sexual maturity
39what symptoms are seen in adults suffering from iron accumulation
cardiomyopathy, liver damage, exocrine dysfunction
40what globin chains are overproduced in fetuses/newborns with beta thal
gamma chains
41how do gamma chains behave in beta thals/what kind of hgb do they form
form tatramers, forming hgb bart
42what form of hgb is produced when excess beta chains form tetramers
hgb H
43how do hgb bart and hgb h affect erythroid precursors/erythropoiesis
no damage, no ineffective erythropoiesis
44how does the body handle hgb h precipitates
removed by spleen as they age, results in mod. hermolytic anemia
45how does hypoxia occur in alpha thals
hgb h and bart have a high affinity for oxygen so it can't be delivered to tissues
46what alpha gene mutation results in the production of hgb bart
deletion of all 4; --/--
47how does hydrops fetalis arise in cases of alpha thal
tissue hypoxia causes heart failure, fluid accumulates
48clinical syndromes associated with heterozygous beta thal minor
some hemolytic anemia, microcytic, hypochromic
49clinical syndromes associated with homozygous or compound heterozygous beta thal major
severe hemolytic anemia, microcytic, hypochromic, dependent on transfusions
50clinical syndromes associated with beta thal intermedia
mild-mod hemolytic anemia, microcytic, hypochromic
51alternate classifications for transfusion dependent thal
- beta thal major
- severe hgb eeta thal
- alpha thal major
52alternate classifications for non transfusion dependent thal
- beta thal intermedia
- mild/mod hgb eeta thal
- alpha thal intermedia
- hgb h disease
53how is beta chain production affected in silent carriers of beta thal
mildly decreased
54beta^ silenteta
silent carrier of beta thal
55how are alpha:beta ratios affected in silent carriers of beta thal
ratios are near normal
56what kind of beta thal do beta silenteta silent patients have and what kinds of hgb are increased
mild beta thal intermedia; increased hgb f and a2
57most common genotypes for beta thal minor
beta0eta or beta+eta
58what kind of beta thal results when there is one normal and one abnormal gene
beta thal minor
59what kind of beta thal is associated with the following symptoms:
- mild, asymptomatic anemia
- normal or slightly elevated rbcetic count
- microcytic/hypochromic
- mcv <75 fL, mch <26
- poik, target cells, elliptocytes, basophilic stippling
- 92-95% hgb A, 3.5-5% hgb A2, 1-5% hgb F
- beta thal major
- beta thal intermedia
- beta thal minor
- silent carrier
60when is beta thal major typically diagnosed
when a child's hgb A doesn't rise as expected
61what kind of beta thal is associated with the following symptoms:
- hgb <7g/dL
- mcv 50-70 fL, mch 12-20 pg
- microcytic, hypochromic, aniso, poik, target cells, teardrops, elliptocytes
- inclusions: baso stippling, howell-jolly, pappenheimer
- beta thal major
- beta thal minor
- beta thal intermedia
- silent beta thal carrier
62hgb F/hgb A levels with beta 0eta 0 beta thal major
92-95% Hgb F, no hgb A
63What does HPFH stand for?
Hereditary persistence of fetal hemoglobin
64What do both HPFH and δβ0-thalassemia result in?
Increased hemoglobin F into adulthood
65What causes increased Hgb F in HPFH?
Deletion in the δβ region or mutations in gamma-globin genes
66What is the typical Hgb F percentage in heterozygous deletional HPFH?
10–35%
67What is the Hgb F percentage in homozygous HPFH?
100%
68What is the phenotype of heterozygous δβ0-thalassemia?
Beta-thalassemia minor phenotype
69What is the Hgb F level in heterozygous δβ0-thalassemia?
5–20%
70What is the phenotype of homozygous δβ0-thalassemia?
Beta-thalassemia intermedia
71What causes Hemoglobin Lepore thalassemia?
Fusion of delta and beta globin genes
72What Hgb Lepore percentage is found in heterozygotes?
5–15%
73What is the Hgb composition in homozygous Lepore thalassemia?
80% Hgb F and 20% Hgb Lepore
74What is the most common defect in alpha-thalassemia?
Large deletions
75Which gene's mutation causes more severe alpha-thalassemia?
Alpha-2 (α2) gene
76What does the α0 haplotype represent?
Deletion of both alpha-globin genes on one chromosome
77What is the designation for the most common α-thalassemia haplotype?
(- α)
78What is Constant Spring mutation?
Non-deletional mutation that replaces the stop codon
79What are the four clinical syndromes of alpha-thalassemia?
Silent carrier state, α-thalassemia minor, Hgb H disease, Hgb Bart hydrops fetalis
80What genotype is associated with the silent carrier state?
(- α/αα)
81What percentage of Hgb Bart is found in silent carriers at birth?
1–2%
82What causes α-thalassemia minor?
Deletion of two alpha-globin genes
83What is the MCV level in α-thalassemia minor?
< 80 fL
84What is the Hgb Bart percentage at birth in α-thalassemia minor?
5–15%
85What causes Hemoglobin H disease?
Deletion of three alpha-globin genes
86What hemoglobin forms in Hemoglobin H disease due to excess beta chains?
Hgb H
87What is the typical Hgb level in Hemoglobin H disease?
7–10 g/dL
88Which stain is used to detect Hgb H inclusions?
Supravital stain (new methylene blue)
89What are the two syndromes associated with Hgb H disease?
ATR-16 and ATRX syndromes
90What does ATR-16 involve?
Large deletion removing zeta, alpha, and other nearby genes
91What causes ATRX syndrome?
Mutations in the ATRX gene on the X chromosome
92What is the genotype for Hgb Bart hydrops fetalis syndrome?
(- -/- -)
93What hemoglobin is primarily produced in Hgb Bart syndrome?
Hgb Bart (gamma tetramers)
94Why can't Hgb Bart deliver oxygen effectively?
It has a high oxygen affinity
95What are key features in diagnosing thalassemia on a smear?
Microcytosis, hypochromia, target cells, poikilocytosis
96What test confirms the presence of Hgb H inclusions?
Supravital staining with new methylene blue
97What is often elevated in thalassemia patients due to hemolysis?
Unconjugated bilirubin and LDH
98Which tests are used to identify hemoglobin variants?
Electrophoresis and HPLC
99What is the most common type of anemia worldwide?
Iron deficiency anemia
100What is the main cause of sideroblastic anemia?
Inadequate production of protoporphyrin
101What are the three causes of iron unavailability for heme production?
Inadequate stores, impaired mobilization, or intrinsic RBC defect
102How much iron is lost daily from the body?
About 1 mg
103What happens during stage 1 of iron deficiency anemia?
Progressive loss of storage iron without lab abnormalities
104What are some defining features of stage 2 iron deficiency anemia?
Depletion of storage iron with normal serum iron and RBC production
105What are key lab findings in stage 3 of iron deficiency anemia?
Low H&H, microcytic hypochromic cells
106What are some symptoms of iron deficiency anemia?
Fatigue, weakness, shortness of breath, pallor
107Who is at high risk for iron deficiency anemia?
Menstruating women, growing children, pregnant and nursing mothers
108What is march hemoglobinuria?
Exercise-induced hemoglobinuria, common in runners and soldiers
109What lab test indirectly measures transferrin?
TIBC
110What stain is used to detect iron in bone marrow?
Prussian blue
111What is the first indicator of response to iron therapy?
Increased Hgb content in reticulocytes
112What causes anemia of chronic inflammation?
Impaired iron kinetics due to inflammation
113What does hepcidin do?
Regulates iron absorption and release; increased during inflammation
114What protein sequesters iron during infection?
Lactoferrin
115What cytokine effects are seen in anemia of chronic inflammation?
Impair erythroid progenitor proliferation and reduce EPO response
116What is the typical Hgb level in anemia of chronic inflammation?
8–10 g/dL
117What type of anemia is seen in anemia of chronic inflammation?
Normocytic, normochromic
118What causes sideroblastic anemia?
Defective protoporphyrin synthesis
119What type of cell is characteristic in bone marrow of sideroblastic anemia?
Ringed sideroblast
120What is a key lab finding in lead poisoning?
Basophilic stippling
121What is a major symptom of hereditary porphyrias?
Photosensitivity
122What is hereditary hemochromatosis?
Primary iron overload due to mutations in iron-regulatory proteins
123What causes secondary iron overload?
Chronic anemias and repeated transfusions
124What lab test is used to screen for iron overload?
Transferrin saturation and serum iron
125What treatment is used for hereditary hemochromatosis?
Therapeutic phlebotomy
126What is the treatment for transfusion-related iron overload?
Iron-chelating drugs
127What causes macrocytic anemia in defects of DNA metabolism?
Impaired DNA synthesis in rapidly dividing cells
128What are the two types of macrocytic anemia?
Megaloblastic and nonmegaloblastic
129What deficiencies cause megaloblastic anemia?
Vitamin B12 and folate
130What are characteristic cells in megaloblastic anemia?
Oval macrocytes and hypersegmented neutrophils
131What differentiates nonmegaloblastic anemia?
Macrocytes without oval shape or hypersegmentation
132What are some causes of nonmegaloblastic macrocytic anemia?
Liver disease, chronic alcoholism, bone marrow failure
133What is vitamin B12 a cofactor for?
Isomerization of methylmalonyl CoA and methyl transfer from 5-methyltetrahydrofolate
134What is the result of vitamin B12 deficiency?
Build-up of methylmalonic acid and homocysteine
135What is the function of folate?
Transfers methyl groups for amino acid and nucleotide metabolism
136What is the main form of folate in the body?
5-methyltetrahydrofolate
137What happens when DNA synthesis is impaired?
Uridine is incorporated, leading to DNA strand breaks and apoptosis
138What is nuclear-cytoplasmic asynchrony?
Nucleus appears immature compared to more mature cytoplasm
139What symptoms are common in megaloblastic anemia?
Fatigue, weakness, shortness of breath, glossitis
140How fast does vitamin B12 deficiency develop?
Takes years
141How fast does folate deficiency develop?
In a few months
142What are common causes of folate deficiency?
Poor diet, increased need, malabsorption, drugs
143What are common causes of vitamin B12 deficiency?
Dietary deficiency, malabsorption, pernicious anemia
144What is pernicious anemia?
Autoimmune destruction of intrinsic factor, preventing B12 absorption
145What are classic blood smear findings in megaloblastic anemia?
Oval macrocytes, hypersegmented neutrophils
146What test is used to measure folate or vitamin B12 levels?
Serum folate and serum vitamin B12 tests
147What lab result indicates ineffective erythropoiesis?
Increased LDH and indirect bilirubin
148What test detects methylmalonic acid levels?
Serum MMA test
149What causes neurological symptoms in B12 deficiency but not folate deficiency?
Methylmalonic acid buildup affects nerves
150What type of anemia is seen in B12 or folate deficiency?
Macrocytic anemia
151What is the definitive test for pernicious anemia?
Intrinsic factor antibody test
152What is bone marrow failure?
Reduction or cessation of blood cell production in one or more cell lines
153What condition is commonly seen with bone marrow failure?
Pancytopenia
154What are common causes of bone marrow failure?
Drugs, radiation, chemicals, viruses, autoimmune disorders, genetic mutations
155What is aplastic anemia?
Rare bone marrow failure with pancytopenia and hypocellular marrow
156Is aplastic anemia more often acquired or inherited?
Acquired (80–85%)
157What is the most common presenting symptom of aplastic anemia?
Pancytopenia
158What virus is commonly associated with secondary aplastic anemia?
Hepatitis viruses (including parvovirus B19)
159What is a hallmark lab finding in aplastic anemia?
Reticulocytopenia
160What is the cellularity of bone marrow in aplastic anemia?
Hypocellular with large areas of adipose
161What treatment options exist for aplastic anemia?
Stem cell transplant and immunosuppressive therapy
162What is Fanconi anemia?
Most common inherited bone marrow failure syndrome
163What gene is most commonly mutated in Fanconi anemia?
FANCA
164What physical findings are seen in Fanconi anemia?
Thumb malformations, short stature, café-au-lait spots
165What test confirms Fanconi anemia?
Chromosomal breakage test
166What is dyskeratosis congenita?
Telomere disorder with mucocutaneous features and bone marrow failure
167What are classic symptoms of dyskeratosis congenita?
Abnormal skin pigmentation, dystrophic nails, oral leukoplakia
168What lab finding is seen in dyskeratosis congenita?
Shortened telomeres
169What is Shwachman-Bodian-Diamond syndrome?
Inherited syndrome affecting ribosomal biogenesis and mitotic spindle activity
170What organ system is commonly affected in Shwachman-Bodian-Diamond syndrome?
Pancreas (exocrine insufficiency)
171What lab finding is typical in Shwachman-Bodian-Diamond syndrome?
Cytopenia with increased fetal hemoglobin
172What is pure red cell aplasia (PRCA)?
Anemia with reticulocytopenia affecting only erythroid cells
173What is Diamond-Blackfan anemia?
Inherited PRCA with macrocytic anemia and physical abnormalities
174What enzyme is elevated in Diamond-Blackfan anemia?
Erythrocyte adenosine deaminase
175What is congenital dyserythropoietic anemia (CDA)?
Inherited disorder with ineffective erythropoiesis and dysplastic erythroblasts
176What complication can develop in CDA due to hemolysis/ineffective erythropoiesis?
Iron overload
177What is myelophthisic anemia?
Anemia caused by infiltration of bone marrow with abnormal cells
178What are common findings in myelophthisic anemia?
Teardrop cells, NRBCs, immature myeloid cells
179What causes anemia in chronic kidney disease?
Inability to produce erythropoietin
180What type of anemia is seen in chronic kidney disease?
Normocytic, normochromic with burr cells