Practice Questions

1. A 13-year-old boy has the sudden onset of severe abdominal pain and cramping accompanied
by chest pain, nonproductive cough, and fever. On physical examination, his temperature is
39 C, pulse is 110/min, respirations are 22/min, and blood pressure is 80/50 mm Hg. He has
diffuse abdominal tenderness, but no masses or organomegaly. Laboratory studies show a
hematocrit of 18%. The peripheral blood smear is shown in the figure. A chest radiograph
shows bilateral pulmonary infiltrates. Which of the following is the most likely mechanism
for initiation of his pulmonary problems?
1. Chronic hypoxia of the pulmonary parenchyma
2. Defects in the alternative pathway of complement activation
3. Extensive RBC adhesion to endothelium
4. Formation of autoantibodies to alveolar basement membrane
5. Intravascular antibody-induced hemolysis2.

The crescent-shaped RBCs (sickled RBCs) are characteristic of hemoglobin SS. This
disease is most common in individuals of African and eastern Arabian descent. The sickled
RBCs are susceptible to hemolysis (mainly vascular, in the spleen), but they also can cause
microvascular occlusions anywhere in the body, most commonly bone, lungs, liver, and
brain, leading to ischemia and severe pain. Vascular occlusions in the lungs are often
accompanied by infection and lead to acute chest syndrome. Abdominal pain and back
pain are common and severe, requiring prompt and effective analgesia. The cell
membranes of reversibly sickled cells are abnormally sticky, and they adhere to capillary
endothelium, especially in lungs. Vasoconstriction is caused by depletion of NO by free
hemoglobin. Adhesion of RBCs to endothelium retards blood flow, creates hypoxia, and
precipitates local sickling and vascular occlusion. Chronic tissue hypoxia does occur in
sickle cell anemia, but it produces insidious impairment of function in organs such as heart,
kidneys, and lungs. Defects in the alternative pathway of complement activation predispose
to infection with encapsulated bacteria, such as Haemophilus influenzae and Streptococcus
pneumoniae. Autoantibodies to alveolar basement membrane can be part of Goodpasture

syndrome, which also affects kidneys. The most severe intravascular hemolysis occurs with
major transfusion reactions.
2. An 18-year-old woman from Copenhagen, Denmark, has had malaise and a low-grade fever
for the past week, along with arthralgias. On physical examination, she appears very pale,
except for a bright red malar facial rash. She has a history of chronic anemia, and spherocytes
are observed on a peripheral blood smear. Her hematocrit, which normally ranges from 35%
to 38%, is now 28%, and the reticulocyte count is very low. The serum bilirubin level is 0.9
mg/dL. Which of the following events is most likely to have occurred in this patient?
1. Accelerated extravascular hemolysis in the spleen
2. Development of anti-RBC antibodies
3. Disseminated intravascular coagulation
4. Reduced erythropoiesis from parvovirus infection
5. Superimposed dietary iron deficiency
Patients with hereditary spherocytosis may have an aplastic crisis precipitated by a
parvovirus infection. In adults who do not have a defect in normal RBC production, such
as hereditary spherocytosis or sickle cell anemia, or who are not immunosuppressed,
parvovirus infection is self-limited and often goes unnoticed. When there is an underlying
RBC production defect, then RBC production is shut down by parvovirus, and there is no
reticulocytosis. Disseminated intravascular coagulation gives rise to thrombocytopenia,
bleeding, and the appearance of fragmented RBCs in the blood smear. Reticulocytosis
would be prominent with hemolysis and with RBC antibodies. Iron deficiency does not
occur in hemolytic anemias because the iron that is released from hemolyzed cells is reused.
3. A clinical study of patients who inherit mutations that reduce the level of ankyrin, the
principal binding site for spectrin, in the RBC membrane cytoskeleton shows an increased
prevalence of chronic anemia with splenomegaly. For many patients, it is observed that
splenectomy reduces the severity of anemia. This beneficial effect of splenectomy is most
likely related to which of the following processes?
1. Decrease in opsonization of RBCs and lysis in spleen
2. Decrease in production of reactive oxygen species by splenic macrophages
3. Decrease in splenic RBC sequestration and lysis
4. Increase in deformability of RBCs within splenic sinusoids
5. Increase in splenic storage of iron
In patients with hereditary spherocytosis, spheroidal cells are trapped and destroyed in the
spleen because the abnormal RBCs have reduced deformability. Splenectomy is beneficial
because the spherocytes are no longer detained by the spleen. Splenectomy has no effect on
the synthesis of spectrin or RBC deformability; the RBCs in spherocytosis are not killed by
opsonization. In warm antibody hemolytic anemias, opsonized RBCs are removed by the
spleen. Reactive oxygen species do not play a role in anemias. Iron is not the rate-limiting
step to RBC production when the iron can be recycled within the body.
4. A 3-year-old boy from Sicily has a poor appetite and is underweight for his age and height.
Physical examination shows hepatosplenomegaly. The hemoglobin concentration is 6 g/dL,

and the peripheral blood smear shows severely hypochromic and microcytic RBCs. The total
serum iron level is normal, and the reticulocyte count is 10%. A radiograph of the skull
shows maxillofacial deformities and expanded marrow spaces. Which of the following is the
most likely cause of this childs illness?
1. Imbalance in -globin and -globin chain production
2. Increased fragility of erythrocyte membranes
3. Reduced synthesis of hemoglobin F
4. Relative deficiency of vitamin B12
5. Sequestration of iron in reticuloendothelial cells
This patient of Mediterranean descent has -thalassemia major. In this condition, there is a
severe reduction in the synthesis of -globin chains without impairment of -globin
synthesis. The free, unpaired -globin chains form aggregates that precipitate within
normoblasts and cause them to undergo apoptosis. The death of RBC precursors in the
bone marrow is called ineffective erythropoiesis. Not only does this cause anemia, but it
also increases the absorption of dietary iron, giving rise to iron overload, which results in
hemochromatosis with infiltrative cardiomyopathy, hepatic cirrhosis, and bronze
diabetes from pancreatic islet dysfunction. The severe anemia triggers erythropoietin
synthesis, which expands the erythropoietic marrow. The marrow expansion encroaches on
the bones, causing maxillofacial deformities. Extramedullary hematopoiesis causes
hepatosplenomegaly. In comparison, the hemolytic anemia is mild in -thalassemia minor,
and there is very little ineffective erythropoiesis. Hemochromatosis is particularly
detrimental to the liver and heart. Patients with chronic anemia may require RBC
transfusions, which adds even more iron to body stores. The other listed options do not lead
to a marked expansion of hematopoiesis.
5. A 10-year-old child has experienced multiple episodes of pneumonia and meningitis with
septicemia since infancy. Causative organisms include Streptococcus pneumoniae and
Haemophilus influenzae. On physical examination, the child has no organomegaly and no
deformities. Laboratory studies show hemoglobin of 9.2 g/dL, hematocrit of 27.8%, platelet
count of 372,000/mm3, and WBC count of 10,300/mm3. A hemoglobin electrophoresis shows
1% hemoglobin A2, 7% hemoglobin F, and 92% hemoglobin S. Which of the following is the
most likely cause of the repeated infections in this child?
1. Absent endothelial cell expression of adhesion molecules
2. Diminished hepatic synthesis of complement proteins
3. Impaired neutrophil production
4. Loss of normal splenic function
5. Reduced synthesis of immunoglobulins
In sickle cell anemia, the cumulative ischemic damage to the spleen results in
autosplenectomy, leaving behind a small fibrotic remnant of this organ. The impaired
splenic function and resultant inability to clear bacteria from the bloodstream can occur
early in childhood, leading to risk for infection with encapsulated bacterial organisms.
Immunodeficiency results from lack of splenic function, not from lack of immunoglobulins.
Endothelium can be damaged with sickling, and adhesion between endothelial cells and
RBCs is increased in sickle cell anemia. Complement proteins are part of innate immune

responses in acute inflammation. There is no impairment in production or function of

neutrophils.
6. A 32-year-old woman from Hanoi, Vietnam, gives birth at 34 weeks gestation to a markedly
hydropic stillborn male infant. Autopsy findings include hepatosplenomegaly and
cardiomegaly, serous effusions in all body cavities, and generalized hydrops. No congenital
anomalies are noted. There is marked extramedullary hematopoiesis in visceral organs.
Which of the following hemoglobins is most likely predominant on hemoglobin
electrophoresis of the fetal RBCs?
1. Hemoglobin A1
2. Hemoglobin A2
3. Hemoglobin Barts
4. Hemoglobin E
5. Hemoglobin F
6. Hemoglobin H
The infant had -thalassemia major, which is most likely to occur in individuals of
Southeast Asian ancestry, each of whose parents could have two abnormal -globin genes
on chromosome 16. A complete lack of -globin chains precludes formation of hemoglobins
A1, A2, and F. Only a tetramer of chains (Barts hemoglobin) can be made, leading to
severe fetal anemia. Inheritance of three abnormal -globin chains leads to hemoglobin H
disease, with tetramers of chains; survival to adulthood is possible. Hemoglobin E disease
produces mild hemolytic anemias.
7. A 17-year-old girl has had a history of fatigue and weakness for her entire life. She has not
undergone puberty. On physical examination, secondary sex characteristics are not well
developed. She has hepatosplenomegaly. CBC shows hemoglobin of 9.1 g/dL, hematocrit of
26.7%, MCV of 66 m3, platelet count of 89,000/mm3, and WBC count of 3670/mm3. The
appearance of the peripheral blood smear is shown in the figure. Additional laboratory
findings include serum glucose of 144 mg/dL, TSH of 6.2 mU/mL, and ferritin of 679
ng/mL. A mutation in a gene encoding for which of the following is most likely to be present
in this girl?
1. Ankyrin
Good Question
2. -Globin
3. G6PD
4. HFE
5. NADPH oxidase
This patient has -thalassemia, probably of at least intermediate severity. There is
decreased -globin chain formation, with increased hemoglobin A2 and F to compensate.
There is ineffective erythropoiesis and increased erythropoietin to drive increased iron
absorption, leading to iron overload. Chronic anemia requiring transfusion therapy
exacerbates hemochromatosis. Iron deposited in endocrine tissues can lead to gonadal,
pituitary, thyroid, islet cell, and adrenal failure. Secondary hypersplenism can result from
the splenomegaly, with sequestration of platelets and leukocytes. The abnormal ankyrin
gene leads to hereditary spherocytosis and a mild hemolytic anemia with splenomegaly, but

not to iron overload. In glucose-6-phosphate dehydrogenase deficiency, sensitivity to

oxidizing agents causes a hemolytic anemia, but this usually is not ongoing. The HFE gene
is abnormal in hereditary hemochromatosis, leading to iron overload, but onset of the
disease occurs in middle age. Mutations involving NADPH oxidase lead to
immunodeficiency in chronic granulomatous disease.

8. A 12-year-old boy has a history of episodes of severe abdominal, chest, and back pain since
early childhood. On physical examination, he is afebrile, and there is no organomegaly.
Laboratory studies show hemoglobin of 11.2 g/dL, platelet count of 194,000/mm3, and WBC
count of 9020/mm3. The peripheral blood smear shows occasional sickled cells, nucleated
RBCs, and Howell-Jolly bodies. Hemoglobin electrophoresis shows 1% hemoglobin A2, 6%
hemoglobin F, and 93% hemoglobin S. Hydroxyurea therapy is found to be beneficial in this
patient. An increase in which of the following is the most likely basis for its therapeutic
efficacy?
1. Erythrocyte production
2. Overall globin chain synthesis
3. Oxygen affinity of hemoglobin
4. Production of hemoglobin A
5. Production of hemoglobin F
Children and adults with sickle cell anemia may benefit from hydroxyurea therapy, which
can increase the concentration of hemoglobin F in RBCs, which interferes with the
polymerization of hemoglobin S. However, the therapeutic response to hydroxyurea often
precedes the increase in hemoglobin F levels. Hydroxyurea also has an anti-inflammatory
effect, increases the mean RBC volume, and can be oxidized by heme groups to produce
nitric oxide that promotes vasodilation. Because hemoglobin F levels remain high through
the first 5 to 6 months of life, patients with sickle cell anemia typically do not manifest the
disease during infancy. Because both -globin chains are affected, no hemoglobin A1 is
produced, and A2 levels are never high. Globin synthesis overall is not going to increase,
and globin synthesis must be balanced to produce normal hemoglobin. The hemolysis
associated with sickling promotes erythropoiesis, but the concentration of hemoglobin S is

not changed. Hydroxyurea does not significantly shift the oxygen dissociation curve or
change the oxygen affinity of the various hemoglobins.
9. A 25-year-old woman has a 3-year history of arthralgias. Physical examination shows no
joint deformity, but she appears pale. Laboratory studies show total RBC count of 4.7
million/mm3, hemoglobin of 12.5 g/dL, hematocrit of 37.1%, platelet count of 217,000/mm3,
and WBC count of 5890/mm3. The peripheral blood smear shows hypochromic and
microcytic RBCs. Total serum iron and ferritin levels are normal. Hemoglobin
electrophoresis shows 93% hemoglobin A1 with elevated hemoglobin A2 level of 5.8% and
hemoglobin F level of 1.2%. What is the most likely diagnosis?
1. Anemia of chronic disease
2. Autoimmune hemolytic anemia
3. -Thalassemia minor
4. Infection with Plasmodium vivax
5. Iron deficiency anemia
Although -thalassemia minor and iron deficiency anemia are both characterized by
hypochromic and microcytic RBCs, there is no increase in hemoglobin A2 in iron
deficiency states. A normal serum ferritin level also excludes iron deficiency. In contrast to
-thalassemia major, there is usually a mild anemia without major organ dysfunction with
-thalassemia minor. Diseases that produce hemolysis and increase erythropoiesis (e.g.,
autoimmune hemolytic anemia, malaria) do not alter the composition of -globin chain
production. Anemia of chronic disease may mimic iron deficiency and thalassemia minor
with respect to hypochromia and microcytosis; however, anemia of chronic disease is
associated with an increase in the serum concentration of ferritin.
10. A 23-year-old African-American man passes dark reddish brown urine 3 days after taking an
anti-inflammatory medication that includes phenacetin. He is surprised, because he has been
healthy all his life and has had no major illnesses. On physical examination, he is afebrile,
and there are no remarkable findings. CBC shows a mild normocytic anemia, but the
peripheral blood smear shows precipitates of denatured globin (Heinz bodies) with supravital
staining and scattered bite cells in the population of RBCs. Which of the following is the
most likely diagnosis?
1. -Thalassemia minor
2. -Thalassemia minor
3. Glucose-6-phosphate dehydrogenase deficiency
4. Sickle cell trait
5. Abnormal ankyrin in RBC cytoskeletal membrane
6. Warm antibody autoimmune hemolytic anemia
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked disorder that affects
about 10% of African-American males. The lack of this enzyme subjects hemoglobin to
damage by oxidants, including drugs such as primaquine, sulfonamides, nitrofurantoin,
phenacetin, and aspirin (in large doses). Infection can also cause oxidative damage to
hemoglobin. Heinz bodies are denatured hemoglobin, and they damage the RBC
membrane, giving rise to intravascular hemolysis. The bite cells result from the attempts

of overeager splenic macrophages to pluck out the Heinz bodies, adding an element of
extravascular hemolysis. Heterozygotes with -thalassemia (1 or 2 abnormal genes out of 4
total -globin genes) have no major problems, but in cases of -thalassemia major,
perinatal death is the rule. Likewise, -thalassemia minor and sickle cell trait are
conditions usually with no major problems and no relation to drug usage. RBC membrane
abnormalities, such as hereditary spherocytosis (caused by abnormal spectrin), typically
produce a mild anemia without significant hemolysis, and there is no drug sensitivity. Some
autoimmune hemolytic anemias can be drug related, but the hemolysis is predominantly
extravascular.
11. Since childhood, a 30-year-old man has been easily fatigued with minimal exercise.
Laboratory studies show hypochromic microcytic anemia. Hemoglobin electrophoresis
reveals decreased Hgb A1 with increased Hgb A2 and Hgb F. His serum ferritin is markedly
increased. Which of the following mutations is most likely to be present in the -globin gene
of this man?
1. New stop codon
2. Single base insertion, with frameshift
3. Splice site
4. Three-base deletion
5. Trinucleotide repeat
This is one mechanism for + thalassemia. Because the introns are usually involved, the
flanking exons remain, and some normal splicing can occur, so that some -globin chain
synthesis can occur, but not sufficient for adequate hemoglobin production. The other
listed mutations lead to a block in translation, with no functional -globin chain synthesis,
typical for 0 thalassemia.
12. A 16-year-old boy notes passage of dark urine. He has a history of multiple bacterial
infections and venous thromboses for the past 10 years, including portal vein thrombosis in
the previous year. On physical examination, his right leg is swollen and tender. CBC shows
hemoglobin, 9.8 g/dL; hematocrit, 29.9%; MCV, 92 m3; platelet count, 150,000/mm3; and
WBC count, 3800/mm3 with 24% segmented neutrophils, 1% bands, 64% lymphocytes, 10%
monocytes, and 1% eosinophils. He has a reticulocytosis, and his serum haptoglobin level is
very low. A mutation affecting which of the following gene products is most likely to give
rise to this clinical condition?
1. -Globin chain
2. Factor V
3. Glucose-6-phosphate dehydrogenase
4. Phosphatidylinositol glycan A (PIGA)
5. Prothrombin G20210A
6. Spectrin
Paroxysmal nocturnal hemoglobinuria (PNH) is a disorder that results from an acquired
stem cell membrane defect produced by a PIGA gene mutation that prevents the
membrane expression of certain proteins that require a glycolipid anchor. These include
proteins that protect cells from lysis by spontaneously activated complement. As a result,

RBCs, granulocytes, and platelets are exquisitely sensitive to the lytic activity of
complement. The RBC lysis is intravascular, so patients can have hemoglobinuria (dark
urine). Defects in platelet function are believed to be responsible for venous thrombosis.
Recurrent infections can be caused by impaired leukocyte functions. Patients with PNH
may develop acute leukemia or aplastic anemia as complications. Mutations in the -globin
chain can give rise to hemoglobinopathies such as sickle cell anemia. Patients with factor V
(Leiden) and prothrombin G20210A mutations can present with thromboses, but there is
no anemia or leukopenia. Patients with glucose-6-phosphate dehydrogenase (G6PD)
deficiency have an episodic course from exposure to agents such as drugs that induce
hemolysis. Spectrin mutations give rise to hereditary spherocytosis.
13. A 30-year-old, previously healthy man from Lagos, Nigeria, passes dark brown urine 2 days
after starting the prophylactic antimalarial drug primaquine. On physical examination, he
appears pale and is afebrile. There is no organomegaly. Laboratory studies show that his
serum haptoglobin level is decreased. Which of the following is the most likely explanation
of these findings?
1. Antibody-mediated hemolysis
2. Impaired DNA synthesis
3. Impaired globin chain synthesis
4. Increased susceptibility to complement-induced lysis
5. Mechanical fragmentation of RBCs as a result of vascular narrowing
6. Oxidative injury to hemoglobin
7. Reduced deformability of RBC membrane
Glucose-6-phosphate dehydrogenase (G6PD) deficiency predisposes the hemoglobin in
RBCs to oxidative injury from drugs such as primaquine, and can induce hemolysis.
Oxidant injury to hemoglobin produces inclusion of denatured hemoglobin within RBCs.
The inclusions damage the cell membrane directly, giving rise to intravascular hemolysis.
These damaged RBCs have reduced membrane deformability, and they are removed from
the circulation by the spleen. The remaining mechanisms listed are not directly drug
dependent. Hemolytic anemias with antibody coating RBCs can occur with autoimmune
diseases, prior transfusion, and erythroblastosis fetalis. Impaired RBC nuclear maturation
occurs as a result of vitamin B12 or folate deficiency. Impaired globin synthesis occurs in
thalassemias. Complement lysis is enhanced in paroxysmal nocturnal hemoglobinuria,
which results from mutations in the PIGA gene. Mechanical fragmentation of RBCs is
typical of microangiopathic hemolytic anemias, such as disseminated intravascular
coagulation. Reduced RBC membrane deformability is seen in patients with abnormalities
in cytoskeletal proteins, such as spectrin; the latter causes hereditary spherocytosis.