5. Case study 1
• A 15-year-old African-American female presents to the emergency
room with complaints of bilateral thigh and hip pain.
• The pain has been present for 1 day and is steadily increasing in
severity.
• Acetaminophen and ibuprofen have not relieved her symptoms.
• She denies any recent trauma or excessive exercise.
• She does report feeling fatigued and has been having burning
urination along with urinating frequently.
6. Case study 1
• She reports having similar pain episodes in the past, sometimes
requiring hospitalization.
• On examination, she is afebrile (without fever) and in no acute
distress.
• No one in her family has similar episodes.
• Her conjunctiva and mucosal membranes are slightly pale in
coloration.
• She has nonspecific bilateral anterior thigh pain with no abnormalities
appreciated. The remainder of her examination is completely normal.
7. Case study 1
• Her white blood cell count is elevated at 17,000/mm3 and her hemoglobin
(Hb) level is decreased at 7.1 g/dL.
• The urinalysis demonstrated an abnormal number of numerous bacteria.
• Based on blood smear report and the clinical features, the patient has
been diagnosed with sickle cell disease.
8. Question
The molecular event triggering this disease is which of the following?
A. A loss of quaternary structure of the hemoglobin molecule
B. An increase in oxygen binding to hemoglobin
C.A gain of ionic interactions, stabilizing the “T” form of hemoglobin
D. An increase in hydrophobic interactions between deoxyhemoglobin
molecules
E. An alteration in hemoglobin secondary structure leading to loss of the
“α” helix
11. Biochemical
defect
Inheritance Clinical
Manifestations
Diagnosis Treatment
• Point
mutation,
• glutamic acid
at the
• 6 th position in
β globin chain
is replaced by
Valine
• Autosomal recessive
• Heterozygotes have
one normal and one
sickle cell gene.
• The red blood cells of
these individuals
contain both HbS and
HbA.
• These individuals
have sickle cell trait.
• Usually do not show
the clinical symptoms
and can have a normal
life span.
1) Painful crisis
2) Chronic hemolytic
anemia
3) Organ damage
4) Impaired growth
and development
5) Increase
susceptibility to
infections
6) Chronic skin ulcers
7) Painless
hematuria may be
there
8) Neurological
complications
1) Peripheral blood
film –Normocytic
normochromic,
target cells, presence
of sickled cells is
confirmatory.
2) Positive test for
sickling
3) Bone marrow is
hyperplastic
4) Hemoglobin
electrophoresis
confirms the
diagnosis
A) Supportive treatment-
1) Adequate hydration
2) Antibiotics
3) Analgesics
4) Supplementation
with iron and folic acid
5) Oxygen administration
during attack
6)Blood transfusion
B) Antisickling agents-
1) Hydroxyurea
2) Recombinant
Erythropoietin
C) Permanent cure
1) Bone marrow
transplant
2) Gene therapy
Sickle cell disease
12. Case study-2
• A 26-week-old baby was brought to pediatric clinic because of increasing
lethargy and cyanosis.
• The infant had been in good health at birth, and the mother attempted
breastfeeding.
• Since the mother’s milk flow had ceased, the family physician had
recommended formula feeding.
• The child was unwell since then.
13. Case study-2
• The blood sample was collected and a positive test for methemoglobin
was obtained.
• A diagnosis of methemoglobinemia was made.
• The baby was treated for two days.
• At the time of discharge child was alert and there was no cyanosis. The
child was discharged with instructions to the mother concerning formula
prepared with distilled water.
• What is the cause for methemoglobinemia?
• What type of treatment was given to the baby?
14. 1) By exposure to oxidant
drugs
2) Exposure to chemicals
and poisons like- Chlorates,
Acetanilide, nitrites,
nitrobenzene, antipyrin,
phenacetin, sulfonamide
drugs
3) Familial
Methemoglobinemia-
deficiency of met
hemoglobin reductase
enzyme
Autosomal recessive in
familial
Methemoglobinemia
a) At concentrations of 3-15%- a
slight discoloration (e.g.- pale, gray,
blue) of the skin may be present.
b) At fractions of 15-20%- the patient
may be relatively asymptomatic, but
cyanosis is likely to be present.
c) At fractions of 25-50%-headache,
dyspnea, lightheadedness, syncope,
weakness, confusion, palpitations
and chest pain
d) At fractions of 50-70%-
i) Cardiovascular- abnormal cardiac
rhythms
ii) CNS- altered mental status,
delirium, seizures, coma
iii) Metabolic- Profound acidosis
1) Clinical cyanosis in the
presence of normal arterial
oxygen tensions is highly
suggestive of
Methemoglobinemia
("saturation gap").
2) The diagnosis of
methemoglobinemia is
confirmed by direct
measurement of
methemoglobin by a
multiple wavelength co-
oximeter.
1)Administration of
supplemental oxygen
2) Removal of the offending
oxidizing agent
3) Methylene blue is the
first-line antidotal agent.
4) Hyperbaric oxygen
therapy or packed RBC
exchange transfusions are
alternatives
Methemoglobinemia
15. Case study 3
• A 24-year-old patient was admitted to hospital suffering with fever for 10
days and had a history of intermittent jaundice for the past 4–5 years.
• His physical examination showed mild hemolytic facies and a palpable
spleen.
• On admission his hemoglobin was 8.4 gm/dl, MCV 76.6 fl, MCH 19.5 pg
with an abnormal platelet distribution.
16. Case study-3
• The peripheral smear showed presence of microcytes, elliptocytes and
tear drop cells.
• A diagnosis of Alpha thalassemia was made.
• What is the underlying defect in alpha thalassemia ?
17.
18. Gene
deletion
Autosomal recessive 1) Silent carrier state- Single gene
defect- no hematological
abnormality
2) α Thalassemia trait- Two gene
deletion-Microcytic hypochromic
type of red blood cells, no
significant hemolysis
3) Hb-H disease- Three gene
deletion- The affected individuals
have moderate to severe lifelong
hemolytic anemia, modest
degrees of ineffective
erythropoiesis, splenomegaly, and
variable bony changes.
4) Hydrops fetalis- 4 gene
deletion- No stable Hb tetramer,
most severe form, incompatible
with life
1) Hb –low
2) MCV and MCHC- low
depending upon the
defect
3) The peripheral blood
smear shows severe
anisopoikilocytosis,
severe hypochromia,
and nucleated red
blood cells.
4) Hb electrophoresis
confirms the diagnosis
Symptomatic
1) Iron
supplementation is to
be avoided
2) Folate
supplementation is
recommended
3) A blood transfusion
is to be administered
only if necessary
4) Rarely, allogeneic
stem cell
transplantation
Alpha Thalassemia
19. Question
The major abnormal form of hemoglobin that accumulates in a fetus with
the severe form of Alpha-thalassemia (hydrops fetalis) is composed of:
A A tetramer containing 2 –δ subunits and 2 β -subunits (δ2β2)
B A tetramer of 4 gamma-subunits (ϒ4)
C A tetramer of 4 beta-subunits (β4)
D A tetramer of 4 alpha-subunits (α4)
21. Case study-4
• An 8-year-old child has been brought to his pediatrician by his parents
after they noticed that he felt very fatigued.
• They also noted that his abdomen seemed to be enlarged.
• Examination reveals an enlarged spleen.
• Further history reveals that the child been given vitamins and iron
supplements over the last few months.
• Laboratory tests show a microcytic anemia and elevated iron levels in
tissues.
22. Question
Which of the following conditions is most consistent with the findings
in this patient?
A. Aplastic anemia
B. Sickle cell anemia
C. Pernicious anemia
D. Thalassemia major
E. Thalassemia minor
24. Point or frame shift
mutation causing
premature
termination of the
beta globin chain
Autosomal recessive
1) Beta Thalassemia minor- also called Beta
Thalassemia trait- Mild anemia, splenomegaly,
mild icterus, no significant manifestations.
2) Beta Thalassemia major- also called Cooley’s
anemia.
a) Severe anemia
b) Marked wasting, malnourished appearance
c) Slow growth and development
d) Typical skin color- mixture of icterus, pallor
and increased melanin deposition
e) Skeletal deformities- "Chipmunk Facies"
f) Cardiomegaly with signs of C.H.F.
g) Marked hepatomegaly and splenomegaly
1) β -thalassemia minor- modest
anemia, peripheral blood smear is
mildly abnormal, with hypochromia,
microcytosis, and target cells.
Hb electrophoresis confirms the
diagnosis.
2) β -thalassemia major- severe
anemia, and without transfusion the
hematocrit may fall to less than 10%.
The peripheral blood smear shows
severe poikilocytosis, hypochromia,
microcytosis, target cells, basophilic
stippling, and nucleated red blood cells.
Little or no hemoglobin A is present.
Variable amounts of hemoglobin A2 are
seen, and the major hemoglobin
present is hemoglobin F.
2) Bone marrow examination to rule
out other causes of anemia.
3)Skeletal changes can be observed
1) β -thalassemia minor-
no treatment is
recommended
2) β -thalassemia major-
a) blood transfusions
b) Desferal- chelation
therapy
c) Additionally,
splenectomy (removal of the
spleen), bone marrow
transplants are being
proposed as possible
treatments for thalassemia.
d) Gene reactivation-by
using butyrate and
hydroxyurea.
e) Gene replacement
therapy
Beta Thalassemia
26. Question
Severe β-thalassemia may not become clinically apparent until a child is
several months old because:
A Elevated hemoglobin A2 compensates for the missing β -globin genes.
B The oxygen needs of a newborn are minimal.
C Overexpression of zeta-globin (zeta) compensates for the missing b-
chain.
D The gamma to beta-globin switch is not complete until several
months after birth.
E The alpha-globin genes don't turn on until several months after birth.
27. Answer
• D The gamma to beta-globin switch is not complete until several
months after birth.
38. MCQ-6
• True regarding human Hb:
• α like globin genes are on chromosome 16
• β like globin genes are on chromosome 11
• LCR controlling α globin gene is modulated by ATRX
• All of the above
40. MCQ-7
The characteristic of sickle cell syndromes:
• Microvascular vasoocclusion
• Premature RBC destruction
• Stiff RBC membrane
• All of the above