U2-Robbins-C14: RBC & Bleeding Disorders

Question 1

For the past 6 months, a 35-year-old woman has experienced an excessively heavy menstrual flow each month. She

also has noticed increasing numbers of pinpoint hemorrhages on her lower extremities in the past month. Physical

examination shows no organomegaly or lymphadenopathy. CBC shows hemoglobin of 14.2 g/dL, hematocrit of 42.5%,

MCV of 91 μm3, platelet count of 19,000/mm3, and WBC count of 6950/mm3. On admission to the hospital, she has melena

and is given a transfusion of platelets, but her platelet count does not increase. An emergency splenectomy is performed,

and her platelet count increases. Which of the following describes the most likely basis for her bleeding tendency?

□ (A) Abnormalities in production of platelets by megakaryocytes

□ (B) Suppression of pluripotent stem cells

□ (C) Destruction of antibody-coated platelets by the spleen

□ (D) Excessive loss of platelets in menstrual blood

□ (E) Defective platelet-endothelial interactions

Answer 1

(C) This patient’s bleeding tendency is caused by a low platelet count. She most likely has idiopathic thrombocytopenic

purpura (ITP), in which platelets are destroyed in the spleen after being coated with antibodies to platelet membrane

glycoproteins IIb-IIIa or Ib-IX affecting both the patient’s platelets and the transfused platelets. Because the spleen is the

source of the antibody and the site of destruction, splenectomy can be beneficial. There is no defect in the production of

platelets. Suppression of pluripotent stem cells gives rise to aplastic anemia, which is accompanied by pancytopenia.

Platelet functions are normal in ITP. Chronic blood loss would not lead to thrombocytopenia when normal bone marrow

function is present. Abnormal platelet-endothelial interactions are more likely to cause thrombosis

Question 2

A 22-year-old woman has experienced malaise and a sore throat for 2 weeks. Her fingers turn white on exposure to cold.

On physical examination, she has a temperature of 37.8°C, and the pharynx is erythematous. Laboratory findings include a

positive Monospot test result. Direct and indirect Coombs test results are positive at 4°C, although not at 37°C. Which of

the following substances on the surfaces of the RBCs most likely accounts for these findings?

□ (A) IgE

□ (B) Complement C3b

□ (C) Histamine

□ (D) IgG

□ (E) Fibronectin

Answer 2

(B) This patient has cold agglutinin disease, with antibody (usually IgM) coating RBCs. The IgM antibodies bind to the

RBCs at low temperature and fix complement; however, complement is not lytic at this temperature. With an increase in

temperature, the IgM is dissociated from the cell, leaving behind C3b. Most of the hemolysis occurs extravascularly in the

cells of the mononuclear phagocyte system, such as Kupffer cells in the liver, because the coating of complement C3b

acts as an opsonin. Raynaud phenomenon occurs in exposed, colder areas of the body, such as the fingers and toes. The

patient probably has an elevated cold agglutinin titer. IgE is present in allergic conditions, and histamine is released in type

I hypersensitivity reactions. IgG is typically involved in warm antibody hemolytic anemia, which is chronic and is not

triggered by cold. Fibronectin is an adhesive cell surface glycoprotein that aids in tissue healing.

Question 3

A 45-year-old woman has experienced malaise with nausea and vomiting for 3 months. On physical examination, she

has scleral icterus and a yellowish hue to her skin. She has difficulty remembering three objects after 3 minutes. There are

no neurologic deficits. Laboratory studies show a positive serologic test result for hepatitis C, a serum ALT of 310 U/L,

AST of 275 U/L, total bilirubin of 7.6 mg/dL, direct bilirubin of 5.8 mg/dL, alkaline phosphatase of 75 U/L, and ammonia of

55 μmol/L. An abnormal result of which of the following laboratory studies of hemostatic function is most likely to be

reported?

□ (A) Immunoassay for plasma von Willebrand factor

□ (B) Platelet count

□ (C) Prothrombin time

□ (D) Fibrin split products

□ (E) Platelet aggregation

Answer 3

(C) This patient has hepatitis C with severe hepatocyte damage. Many of the clotting factors that are instrumental in the

in vitro measurement of the extrinsic pathway of coagulation, as measured by the prothrombin time, are synthesized in the

liver. Von Willebrand factor is produced by endothelial cells, not hepatocytes. The platelet count is not affected directly by

liver disease. Increased fibrin split products suggest a consumptive coagulopathy, such as disseminated intravascular

coagulation. Platelet aggregation is a measure of platelet function, which is not significantly affected by liver disease.

Question 4

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 an elevated hemoglobin A2 level

of about 5.8%. What is the most likely diagnosis?

Robbins & Cotran Review of Pathology Pg. 272

□ (A) Autoimmune hemolytic anemia

□ (B) β-Thalassemia minor

□ (C) Infection with Plasmodium vivax

□ (D) Anemia of chronic disease

□ (E) Iron deficiency anemia

Answer 4

(B) Although β-thalassemia minor and iron deficiency anemia are 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 β-thalassemia major, there is usually a mild anemia without major organ dysfunction. Diseases that produce

hemolysis and increase erythropoiesis (e.g., autoimmune hemolytic anemia, malaria) do not alter the composition of β-

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.

Question 5

A 30-year-old woman has had a constant feeling of lethargy since childhood. On physical examination, she is afebrile

and has a pulse of 80/min, respirations of 15/min, and blood pressure of 110/70 mm Hg. The spleen tip is palpable, but

there is no abdominal pain or tenderness. Laboratory studies show hemoglobin of 11.7 g/dL, platelet count of

159,000/mm3, and WBC count of 5390/mm3. The peripheral blood smear shows spherocytosis. The circulating RBCs

show an increased osmotic fragility. An inherited abnormality in which of the following RBC components best accounts for

these findings?

□ (A) Glucose-6-phosphate dehydrogenase

□ (B) Membrane cytoskeletal protein

□ (C) α-Globin chain

□ (D) Heme

□ (E) β-Globin chain

□ (F) Carbonic anhydrase

Answer 5

(B) Spectrin and related proteins (e.g., protein 4.1, ankyrin) are cytoskeletal proteins that are important in maintaining

the RBC shape. Hereditary spherocytosis is a condition in which a mutation affects one of several membrane cytoskeletal

proteins, such as ankyrin (most common) and band 4.2, which binds spectrin to the transmembrane ion transporter, band

3, and protein 4.1, which binds the “tail” of spectrin to another transmembrane protein, glycophorin A. Cells with such

mutant proteins are less deformable. The abnormal RBCs seem to lack central pallor on a peripheral blood smear, and

they are sequestered and destroyed in the spleen. Glucose-6-phosphate dehydrogenase deficiency is an X-linked

condition that most commonly affects black males. Thalassemias with abnormal α-globin or β-globin chains are associated

with hypochromic microcytic anemias. Iron deficiency affects the heme portion of hemoglobin, leading to hypochromia and

to microcytosis. Carbonic anhydrase in RBCs helps to maintain buffering capacity.

Question 6

A 69-year-old, previously healthy woman has been feeling increasingly tired and weak for 4 months. On physical

examination, she is afebrile. There is no hepatosplenomegaly or lymphadenopathy. Laboratory studies show hemoglobin

of 9.3 g/dL, platelet count of 250,600/mm3, and WBC count of 6820/mm3. The appearance of the peripheral blood smear is

shown in the figure. Which of the following conditions should be suspected as the most likely cause of these findings?

□ (A) Pernicious anemia

□ (B) Gastrointestinal blood loss

□ (C) Aplastic anemia

□ (D) β-Thalassemia major

□ (E) Warm autoimmune hemolytic anemia

Answer 6

(B) The RBCs display hypochromia and microcytosis, consistent with iron deficiency. The most common cause of this in

elderly patients is chronic blood loss that originates from a gastrointestinal source (e.g., carcinoma, ulcer disease). At age

69, this patient is not menstruating, and vaginal bleeding is likely to be noticed as a “red flag” for a gynecologic

malignancy. Pernicious anemia from vitamin B12 deficiency would result in a macrocytic anemia. The RBCs are generally

normocytic in patients with aplastic anemia. Microcytosis may accompany thalassemias, but the patient would be unlikely

to live to the age of 69 years with β-thalassemia major. Autoimmune hemolytic anemias usually produce a normocytic

anemia, or the MCV can be slightly elevated, with a brisk reticulocytosis.

Question 7

A 76-year-old woman notices that small, pinpoint-to-blotchy areas of superficial hemorrhage have appeared on her gums

and on the skin of her arms and legs over the past 3 weeks. On physical examination, she is afebrile and has no

organomegaly. Laboratory studies show a normal prothrombin time and partial thromboplastin time. CBC shows

hemoglobin of 12.7 g/dL, hematocrit of 37.2%, MCV of 80 μm3, platelet count of 276,000/mm3, and WBC count of

5600/mm3. Platelet function studies and fibrinogen level are normal, and no fibrin split products are detectable. Which of the following conditions best explains these findings?

□ (A) Macronodular cirrhosis

□ (B) Chronic renal failure

□ (C) Meningococcemia

□ (D) Vitamin C deficiency

□ (E) Metastatic carcinoma

Answer 7

(D) Platelet number and function in this case are normal, and there is no detectable abnormality in the extrinsic or

intrinsic pathways of coagulation as measured by the prothrombin time or partial thromboplastin time. Petechiae and

ecchymoses can result from increased vascular fragility, a consequence of nutritional deficiency (e.g., vitamin C), infection

(e.g., meningococcemia), and vasculitic diseases. Liver disease would affect the prothrombin time. Chronic renal failure

may depress platelet function. Meningococcemia is an acute illness. Metastatic disease does not directly affect

hemostasis, although extensive marrow metastases could diminish platelet production.

Question 8

A 65-year-old man diagnosed with follicular non-Hodgkin’s lymphoma is treated with chemotherapy. He develops fever

and cough. On examination, there are bilateral pulmonary rales. A chest radiograph shows diffuse interstitial infiltrates. A

shell vial assay of sputum is positive for cytomegalovirus. He develops scleral icterus. Laboratory studies show

hemoglobin, 10.3 g/dL; hematocrit, 41.3%; MCV, 101 μm3; WBC count, 7600/mm3; and platelet count, 205,000/mm3. His

serum total bilirubin is 6 mg/dL, direct bilirubin is 0.8 mg/dL, and LDH is 1020 U/L. Coombs’s test is positive. Which of the

following is the most likely mechanism for his anemia?

□ (A) Binding of IgM to red blood cells

□ (B) Chemotherapeutic bone marrow toxicity

□ (C) Cytomegalovirus hepatitis

□ (D) Dietary folate deficiency

□ (E) Metastases to colon

Answer 8

(A) The findings point to Coombs-positive immune hemolytic anemia. Cold agglutinin immunohemolytic anemia can be

seen with lymphoid neoplasms and infections such as Mycoplasma, Epstein-Barr virus, HIV, influenza virus, and

cytomegalovirus. IgM binds to RBCs at cooler peripheral body regions, then fixes complement. At warmer central regions,

the antibody is eluted, but the complement marks the RBCs for extravascular destruction in the spleen, and there is

minimal intravascular hemolysis. The increased RBC turnover increases the MCV and the bilirubin, which is mainly

indirect. Chemotherapy can suppress bone marrow production, but more likely all cell lines, and without an immune
component. This patient has CMV infection, but hepatitis would likely increase direct and indirect bilirubin, and not account

for anemia. Folate deficiency could account for macrocytosis, but not a positive Coombs test. Non-Hodgkin lymphomas do

not often involve colon, but this might account for gastrointestinal bleeding with features of iron deficiency and

microcytosis.

Question 9

A 29-year-old woman has had malaise and a low-grade fever for the past week. On physical examination, she appears

very pale. 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?

□ (A) Development of anti-RBC antibodies

□ (B) Disseminated intravascular coagulation

□ (C) Accelerated extravascular hemolysis in the spleen

□ (D) Reduced erythropoiesis from parvovirus infection

□ (E) Superimposed iron deficiency

Answer 9

(D) This patient has 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 RBC production is shut down by parvovirus, 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 RBC antibodies. Iron deficiency does not

occur in hemolytic anemias because the iron that is released from hemolyzed cells is reused.

Question 10

A 60-year-old man has developed widespread ecchymoses over the skin in the past month. His medical history

includes a diagnosis of mucinous adenocarcinoma of the rectum. On physical examination, he appears cachectic and pale.

An abdominal CT scan shows multiple hepatic masses. Laboratory studies show prothrombin time of 30 seconds, partial

thromboplastin time of 55 seconds, platelet count of 15,200/mm3, and fibrinogen level of 75 mg/dL, and fibrin split product

levels (D dimer) that are very elevated. Which of the following morphologic findings is most likely to be present on

examination of his peripheral blood smear?

□ (A) Howell-Jolly bodies

□ (B) Teardrop cells

□ (C) Macro-ovalocytes

□ (D) Schistocytes

□ (E) Target cells

Answer 10

(D) This is an example of disseminated intravascular coagulation (DIC) with associated microangiopathic hemolytic

anemia. The DIC developed in the setting of a mucin-secreting adenocarcinoma. Howell-Jolly bodies are small, round

inclusions in RBCs that appear when the spleen is absent. Teardrop cells are most characteristic of myelofibrosis and

other infiltrative disorders of the marrow. Macro-ovalocytes are seen in megaloblastic anemias, such as vitamin B12

deficiency. Target cells appear in hemoglobin C disease or severe liver disease.

Question 11

A 30-year-old woman reports becoming increasingly tired for the past 5 months. On physical examination, she is

afebrile and has mild splenomegaly. Laboratory studies show a hemoglobin concentration of 11.8 g/dL and hematocrit of 35.1%. The peripheral blood smear shows spherocytes and rare nucleated RBCs. Direct and indirect Coombs test results

are positive at 37°C, although not at 4°C. Which of the following underlying diseases is most likely to be diagnosed in this

patient?

□ (A) Infectious mononucleosis

□ (B) Mycoplasma pneumoniae infection

□ (C) Hereditary spherocytosis

□ (D) Escherichia coli septicemia

□ (E) Systemic lupus erythematosus

Answer 11

(E) This patient has a warm autoimmune hemolytic anemia secondary to systemic lupus erythematosus (SLE). A

positive Coombs test result indicates the presence of anti-RBC antibodies in the serum and on the RBC surface. Most

cases of warm autoimmune hemolytic anemia are idiopathic, but one fourth occur in individuals with an identifiable

autoimmune disease, such as SLE. Some are caused by drugs such as α-methyldopa. The immunoglobulin coating the

RBCs acts as an opsonin to promote splenic phagocytosis. Nucleated RBCs can be seen in active hemolysis because the

marrow compensates by releasing immature RBCs. Infections such as mononucleosis and Mycoplasma are associated

with cold autoimmune hemolytic anemia (with an elevated cold agglutinin titer). The increased RBC destruction in

hereditary spherocytosis is extravascular and not immune mediated. Septicemia is more likely to lead to a

microangiopathic hemolytic anemia.

Question 12

A 23-year-old woman has had a history of bleeding problems all of her life, primarily heavy menstruation and bleeding

gums. A sister and an uncle also have bleeding problems. Physical examination shows several bruises ranging in color

from red to blue to purple on her arms and legs. There is no organomegaly, and no deformities are noted. Laboratory

studies show hemoglobin, 9.5 g/dL; hematocrit, 28.2%; platelet count, 229,300/mm3; WBC count, 7185/mm3; prothrombin

time, 12 seconds; and partial thromboplastin time, 38 seconds. A 1 : 1 dilution of the patient’s plasma with normal pooled

plasma corrects the partial thromboplastin time. Ristocetin-dependent platelet aggregation in patient plasma is markedly

reduced. Factor VIII activity is 30% (reference range 50% to 150%). Which of the following responses should the physician

use when advising the patient of potential consequences of this disease?

□ (A) You might need allogeneic bone marrow transplantation

□ (B) Expect increasing difficulty with joint mobility

□ (C) Anticoagulation is needed to prevent deep venous thrombosis

□ (D) You could experience excessive bleeding after oral surgery

□ (E) A splenectomy might be necessary to control the disease

Answer 12

(D) An inherited bleeding disorder with normal platelet count and prolonged bleeding time suggests von Willebrand

disease, confirmed by the ristocetin-dependent bioassay for von Willebrand factor (vWF). Von Willebrand disease is a

common bleeding disorder, with an estimated frequency of 1%. In most cases, it is inherited as an autosomal dominant

trait. In these cases, a reduction in the quantity of vWF impairs platelet adhesion to damaged vessel walls, and hemostasis

is compromised. Because vWF acts as a carrier for factor VIII, the level of this procoagulant protein (needed for the

intrinsic pathway) is diminished, as in this case. The levels of factor VIII rarely are reduced enough, however, to be

clinically significant. Prolonged partial thromboplastin time corrected by normal plasma is a reflection of factor VIII

deficiency. Because the disease is not a disorder of stem cells, transplantation is not helpful. Joint hemorrhages are a

feature of hemophilia A and B, not von Willebrand disease. Patients with von Willebrand disease are not prone to

thrombosis, as are individuals with factor V (Leiden) mutation or other inherited disorders of anticoagulation. Splenectomy

is useful in cases of idiopathic thrombocytopenic purpura, but the platelets are not consumed in von Willebrand disease.

Question 13

A 12-year-old boy has a history of episodes of severe abdominal 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. Which of the following is the most likely

basis for its therapeutic efficacy?

□ (A) Increase in production of hemoglobin F

□ (B) Increase in production of hemoglobin A

□ (C) Decrease in overall globin synthesis

□ (D) Stimulation of erythrocyte production

□ (E) Increase in oxygen affinity of hemoglobin

Answer 13

(A) 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 antiinflammatory

effect, increases the mean RBC volume, and can be oxidized by heme groups to produce nitric oxide.

Robbins & Cotran Review of Pathology Pg. 289

Because hemoglobin F levels are high for the first 5 to 6 months of life, patients with sickle cell anemia do not manifest the

disease during this period. Because both β-globin chains are affected, no hemoglobin A1 is produced. Globin synthesis

decreases with the thalassemias. The hemolysis associated with sickling promotes erythropoiesis, but the concentration of

hemoglobin S is not changed. Hydroxyurea does not shift the oxygen dissociation curve or change the oxygen affinity of

the various hemoglobins.

Question 14

A 73-year-old man has been healthy all his life. He takes no medications and has had no major illnesses or surgeries.

For the past year, he has become increasingly tired and listless, and he appears pale. Physical examination shows no

hepatosplenomegaly and no deformities. CBC shows hemoglobin, 9.7 g/dL; hematocrit, 29.9%; MCV, 69.7 mm3; RBC

count, 4.28 million/mm3; platelet count, 331,000/mm3; and WBC count, 5500/mm3. Which of the following is the most likely

underlying condition causing this patient’s findings?

□ (A) Occult malignancy

□ (B) Autoimmune hemolytic anemia

□ (C) β-Thalassemia major

□ (D) Chronic alcoholism

□ (E) Vitamin B12 deficiency

□ (F) Hemophilia A

Answer 14

(A) This patient has a microcytic anemia, which is typical of iron deficiency. Iron deficiency is the most common form of

anemia worldwide. The lack of iron impairs heme synthesis. The marrow response is to “downsize” the RBCs, resulting in

a microcytic and hypochromic anemia. At this patient’s age, bleeding from an occult malignancy should be strongly

suspected as the cause of iron deficiency. An autoimmune hemolytic anemia would appear as a normocytic anemia or as a

slightly increased MCV with pronounced reticulocytosis. Thalassemias may result in a microcytosis, but β-thalassemia

major causes severe anemia soon after birth, and survival to age 73 years is unlikely. Macrocytosis would accompany a

history of chronic alcoholism, probably because of poor diet and folate deficiency. Vitamin B12 deficiency also results in a

macrocytic anemia. By this patient’s age, hemophilia A would result in joint problems; because the bleeding is mainly into

soft tissues without blood loss, the iron is recycled.

Question 15

Three days after taking an anti-inflammatory medication that includes phenacetin, a 23-year-old African-American man

passes dark reddish brown urine. He is surprised by this 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?

□ (A) α-Thalassemia

□ (B) Sickle cell trait

□ (C) Glucose-6-phosphate dehydrogenase deficiency

□ (D) Autoimmune hemolytic anemia

□ (E) β-Thalassemia minor

□ (F) RBC membrane abnormality

Answer 15

(C) Glucose-6-phosphate dehydrogenase 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 also can cause oxidative damage to

hemoglobin. Heinz bodies 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 α-thalassemia have no major problems, but in cases of α-thalassemia major, perinatal

death is the rule. Likewise, β-thalassemia minor and sickle cell trait are conditions with no major problems and no relation

to drug usage. Some autoimmune hemolytic anemias can be drug related, but the hemolysis is predominantly

extravascular. 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

Question 16

A 50-year-old man has experienced chronic fatigue and weight loss for the past 3 months. There are no remarkable

findings on physical examination. Laboratory studies show hemoglobin, 11.2 g/dL; hematocrit, 33.3%; MCV, 91 μm3;

platelet count, 240,000/mm3; WBC count, 7550/mm3; serum iron 80 μg/dL; total iron-binding capacity, 145 μg/dL; and

serum ferritin, 565 ng/mL. The ANA test result is positive. Which of the following is the most likely diagnosis?

□ (A) Iron deficiency anemia

□ (B) Aplastic anemia

□ (C) Anemia of chronic disease

□ (D) Microangiopathic hemolytic anemia

□ (E) Megaloblastic anemia

□ (F) Thalassemia minor

Answer 16

(C) The increased ferritin concentration and reduced total iron-binding capacity are typical of anemia of chronic

disease, such as an autoimmune disease. Increased levels of cytokines such as interleukin-6 promote sequestration of

storage iron, with poor use for erythropoiesis. Secretion of erythropoietin by the kidney is impaired. Various underlying

diseases, including cancer, collagen vascular diseases, and chronic infections, can produce this pattern of anemia. Iron

deficiency would produce a microcytic anemia, with a low serum ferritin level. Aplastic anemia is unlikely because the

platelet count and WBC count are normal. Microangiopathic hemolytic anemias are caused by serious acute conditions

such as disseminated intravascular coagulation; these patients have thrombocytopenia caused by widespread thrombosis.

Megaloblastic anemias are macrocytic without an increase in iron stores. Thalassemia minor is uncommon and is not

associated with a positive ANA test result.

Question 17

In an epidemiologic study of anemias, the findings show that there is an increased prevalence of anemia in individuals

of West African ancestry. By hemoglobin electrophoresis, a subset of individuals of this ancestry are found to have

increased hemoglobin S levels. The distribution of infectious illnesses is correlated with the prevalence of hemoglobin S in

this population. Which of the following infectious agents is most likely to account for these observations?

□ (A) Cryptococcus neoformans

□ (B) Borrelia burgdorferi

□ (C) Treponema pallidum

□ (D) Plasmodium falciparum

□ (E) Clostridium perfringens

□ (F) Trypanosoma gambiense

□ (G) Schistosoma haematobium

Answer 17

(D) Throughout human history, malaria has been the driving force for increasing the gene frequency of hemoglobin S.

Individuals who are heterozygous for hemoglobin S have the sickle cell trait. They are resistant to malaria because the

parasites grow poorly or die at low oxygen concentrations, perhaps because of low potassium levels caused by potassium

efflux from RBCs on hemoglobin sickling. The malarial parasite cannot complete its life cycle. Clostridium neoformans can

cause granulomatous disease in immunocompromised individuals. Borrelia burgdorferi is the spirochete that causes Lyme

disease. Treponema pallidum is the infectious agent causing syphilis. Clostridium perfringens may produce gas gangrene

after soft-tissue injuries. Trypanosoma gambiense infection causes sleeping sickness. Schistosoma haematobium

infection leads to hematuria and iron deficiency anemia

Question 18

A 41-year-old woman sees her physician because of a 2-week history of multiple ecchymoses on her extremities after

only minor trauma. She also reports feeling extremely weak. Over the previous 24 hours, she has developed a severe

cough productive of yellowish sputum. On physical examination, her temperature is 38.4°C, and she has diffuse crackles on all lung fields. Laboratory studies show hemoglobin, 7.2 g/dL; hematocrit, 21.4%; MCV, 88 μm3; platelet count,

35,000/mm3; and WBC count, 1400/mm3 with 20% segmented neutrophils, 1% bands, 66% lymphocytes, and 13%

monocytes. The reticulocyte count is 0.1%. Given these laboratory findings, which of the following historical findings would

be most useful in determining the cause of her condition?

□ (A) Exposure to drugs

□ (B) Dietary history

□ (C) Recent bacterial infection

□ (D) Menstrual history

□ (E) Family history of anemias

Answer 18

(A) The pancytopenia and absence of a reticulocytosis strongly suggest bone marrow failure. Aplastic anemia has no

apparent cause in half of all cases. In other cases, drugs and toxins may be identified; drugs such as chemotherapeutic

agents are best known for this effect. A preceding viral infection may be identified in some cases, but bacterial infections

rarely cause aplastic anemias. Individuals with pancytopenia are subject to bleeding disorders because of the low platelet

Robbins & Cotran Review of Pathology Pg. 290

count and to infections because of the low WBC count. Dietary history would not be helpful because this patient’s clinical

and laboratory picture is not characteristic of iron deficiency or vitamin B12 deficiency. Menstrual history would be relevant

if the patient had hypochromic microcytic anemia. The only known familial cause of aplastic anemia (Fanconi anemia) is

rare.

Question 19

A clinical study of patients with hemoglobinopathies reveals that some of these patients developed episodes of acute

chest, back, and abdominal pain; recurrent infections with Streptococcus pneumoniae; and chronic anemia as children

and adults. They experienced none of these problems as infants, however. The presence of which of the following types

of hemoglobin during infancy most likely provided protection from complications of their hemoglobinopathy?

□ (A) A1

□ (B) A2

□ (C) C

□ (D) E

□ (E) F

Answer 19

(E) These patients have sickle cell disease with hemoglobin S. During infancy, the amount of fetal hemoglobin being

produced is sufficient to prevent most complications of the disease, such as vaso-occlusive crises and infections. After

infancy, the amount of hemoglobin F declines, but drugs such as hydroxyurea can induce increased production of

hemoglobin F. Hemoglobin A1 is the normal adult hemoglobin that is absent with homozygous sickle cell anemia.

Hemoglobin A2 is not produced in sufficient quantities to ameliorate the effects of hemoglobinopathies. Hemoglobins C and

E when homozygous produce anemia much milder than hemoglobin S disease, and when heterozygous help ameliorate

hemoglobin S, but there is no differential production of hemoglobin C or E in infancy

Question 20

A 5-year-old boy has had a history of easy bruising and blood in his urine since infancy. Physical examination shows no

organomegaly. He has several ecchymoses of the skin on the lower extremities. Laboratory studies show hemoglobin,
13. 1 g/dL; hematocrit, 39.3%; platelet count, 287,600/mm3; WBC count, 6830/mm3; prothrombin time, 13 seconds; partial

thromboplastin time, 54 seconds; and less than 1% factor VIII activity measured in plasma. If he does not receive

transfusions of recombinant factor VIII concentrate, which of the following manifestations of this illness is most likely to

ensue?

□ (A) Splenomegaly

□ (B) Conjunctival petechiae

□ (C) Hemolysis

□ (D) Hemochromatosis

□ (E) Hemarthroses

Answer 20

(E) The severity of hemophilia A depends on the amount of factor VIII activity. With less than 1% activity, there is

severe disease, and joint hemorrhages are common, leading to severe joint deformity and ankylosis. Mild (1% to 5%) and

moderate (5% to 75%) activity is often asymptomatic except in severe trauma. The bleeding tendency is not associated

with splenomegaly. Petechiae, seen in patients with thrombocytopenia, are not a feature of hemophilia. Factor VIII

deficiency does not affect the life span of RBCs. Because individuals with factor VIII deficiency do not depend on RBC

transfusions, iron overload is not a usual consequence.

Question 21

A 23-year-old woman in her 25th week of pregnancy has felt no fetal movement for the past 3 days. Three weeks later,

she still has not given birth and suddenly develops dyspnea with cyanosis. On physical examination, her temperature is

36.9°C, pulse is 102/min, respirations are 21/min, and blood pressure is 80/40 mm Hg. She has large ecchymoses over

the skin of her entire body. A stool sample is positive for occult blood. Laboratory studies show an elevated prothrombin

time and partial thromboplastin time. The platelet count is decreased, plasma fibrinogen is markedly decreased, and fibrin

split products are detected. A blood culture is negative. Which of the following is the most likely cause of the bleeding

diathesis?

□ (A) Increased vascular fragility

□ (B) Toxic injury to the endothelium

□ (C) Reduced production of platelets

□ (D) Increased consumption of clotting factors and platelets

□ (E) Defects in platelet adhesion and aggregation

Answer 21

(D) The presence of thrombocytopenia, increased prothrombin and partial thromboplastin times, and fibrin split

products, and the low fibrinogen concentration all suggest disseminated intravascular coagulation (DIC), which was most

likely caused by a retained dead fetus, an obstetric complication that can lead to DIC through release of thromboplastins

from the fetus. This release causes widespread microvascular thrombosis and consumes clotting factors and platelets.

There is no damage to the vascular endothelium or vascular wall. Platelet production is normal, but platelets are

consumed by widespread thrombosis of small vessels. There is no defect in platelet function.

Question 22

A 54-year-old woman sees her physician because of sudden onset of headaches and photophobia. This condition has

been worsening for the past 2 days. On physical examination, she has a temperature of 38°C and is disoriented. CBC

shows hemoglobin of 11.2 g/dL, hematocrit of 33.7%, MCV of 94 μm3, platelet count of 32,000/mm3, and WBC count of

9900/mm3. The peripheral blood smear shows schistocytes. The serum urea nitrogen level is 38 mg/dL, and the creatinine

level is 3.9 mg/dL. Which of the following is the most likely diagnosis?

□ (A) β-Thalassemia major

□ (B) Disseminated intravascular coagulation

□ (C) Hereditary spherocytosis

□ (D) Idiopathic thrombocytopenic purpura

□ (E) Paroxysmal nocturnal hemoglobinuria

□ (F) Thrombotic thrombocytopenic purpura

□ (G) Warm autoimmune hemolytic anemia

Answer 22

(F) The diagnosis of thrombotic thrombocytopenic purpura (TTP) is based on finding a classic pentad: transient

neurologic problems, fever, thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. The diagnosis

is confirmed by demonstration of von Willebrand factor monomers in the serum. These abnormalities are produced by

small platelet-fibrin thrombi in small vessels in multiple organs. The heart, brain, and kidney often are severely affected. Of

the other choices, only disseminated intravascular coagulation is a microangiopathic hemolytic anemia, but the pentad of

TTP is missing.

Question 23

A 30-year-old, previously healthy man passes dark brown urine several 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?

□ (A) Mechanical fragmentation of RBCs

□ (B) Increased susceptibility to lysis by complement

□ (C) Nuclear maturation defects resulting from impaired DNA synthesis

□ (D) Impaired globin synthesis

□ (E) Hemolysis of antibody-coated cells

□ (F) Oxidative injury to hemoglobin

□ (G) Reduced deformability of the RBC membrane

Answer 23

(F) This patient has glucose-6-phosphate dehydrogenase deficiency. A drug that leads to oxidative injury to the RBCs,

such as primaquine, 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 cells have

reduced membrane deformability, and they are removed from the circulation by the spleen. The remaining mechanisms

listed are not directly drug dependent. Mechanical fragmentation of RBCs is typical of microangiopathic hemolytic

anemias, such as disseminated intravascular coagulation. Complement lysis is enhanced in paroxysmal nocturnal

hemoglobinuria, which results from mutations in the PIGA gene. Impaired RBC nuclear maturation occurs as a result of

vitamin B12 or folate deficiency. Impaired globin synthesis occurs in thalassemias. Hemolytic anemias with antibody coating

RBCs can occur with autoimmune diseases, prior transfusion, and erythroblastosis fetalis. Reduced RBC membrane

deformability is seen in patients with abnormalities in cytoskeletal proteins, such as spectrin; the latter causes hereditary

spherocytosis.

Question 24

A 42-year-old woman has had nosebleeds, easy bruising, and increased bleeding with her menstrual periods for the

past 4 months. On physical examination, her temperature is 37°C, pulse is 88/min, respirations are 18/min, and blood

pressure is 90/60 mm Hg. She has scattered petechiae over the distal extremities. There is no organomegaly. Laboratory

studies show hemoglobin of 12.3 g/dL, hematocrit of 37%, platelet count of 21,500/mm3, and WBC count of 7370/mm3. A

bone marrow biopsy specimen shows a marked increase in megakaryocytes. The prothrombin and partial thromboplastin

times are within the reference range. What is the most likely diagnosis?

□ (A) Disseminated intravascular coagulation

□ (B) Hemophilia B

□ (C) Idiopathic thrombocytopenic purpura

□ (D) Metastatic breast carcinoma

□ (E) Thrombotic thrombocytopenic purpura

□ (F) Vitamin K deficiency

□ (G) Von Willebrand disease

Answer 24

(C) Reduced numbers of platelets can result from decreased production or increased destruction. Marrow examination

in this case shows numerous megakaryocytes, which excludes decreased production. Accelerated destruction can be caused by hypersplenism, but there is no splenomegaly in this case. Peripheral platelet destruction is often

immunologically mediated and can result from well-known autoimmune diseases such as systemic lupus erythematosus, or

it can be idiopathic. When all known causes of thrombocytopenia are excluded, a diagnosis of idiopathic (immune)

thrombocytopenic purpura (ITP) can be made. This patient seems to have no other symptoms or signs and has no history

of drug intake or infections that can cause thrombocytopenia. ITP is most likely. Thrombotic thrombocytopenic purpura

(TTP) is another entity to be considered, but TTP produces a microangiopathic hemolytic anemia (MAHA) that typically is

associated with fever, neurologic symptoms, and renal failure. Disseminated intravascular coagulation is another form of

MAHA. Hemophilia B, similar to hemophilia A, leads to soft-tissue bleeding, and the partial thromboplastin time is

prolonged, but the platelet count is normal. Metastases can act as a space-occupying lesion in the marrow to reduce

hematopoiesis, but this is unlikely to be selective with megakaryocytes, and in this case, there is a megakaryocytic

hyperplasia. Vitamin K deficiency prolongs the prothrombin time initially and the partial thromboplastin time if severe, but

does not affect platelets. In von Willebrand disease, bleeding is due to abnormal platelet adhesion, but platelet numbers

are normal.

Question 25

A 12-year-old boy experienced 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 x-ray shows

bilateral pulmonary infiltrates. Which of the following is the most likely mechanism for initiation of his pulmonary problems?

□ (A) Intravascular hemolysis

□ (B) Chronic hypoxia of the pulmonary parenchyma

□ (C) Increased RBC adhesion to endothelium

□ (D) Defects in the alternative pathway of complement activation

□ (E) Formation of autoantibodies to alveolar basement membrane

Answer 25

(C) 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 the “acute chest syndrome.” 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.

Question 26

A clinical study of patients who inherit mutations that reduce the level of 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?

□ (A) Increase in synthesis of spectrin in RBCs

□ (B) Increase in deformability of RBCs

□ (C) Decrease in opsonization of RBCs

□ (D) Decrease in trapping of RBCs in the spleen

□ (E) Decrease in production of reactive oxygen species

Answer 26

(D) 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 as a result; 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.

Question 27

A 39-year-old woman sees her physician because she has experienced abdominal pain and intermittent low-volume

diarrhea for the past 3 months. On physical examination, she is afebrile. A stool sample is positive for occult blood. A

colonoscopy is performed, and biopsy specimens from the terminal ileum and colon show microscopic findings consistent

with Crohn’s disease. Because she has failed to respond to medical therapy, surgery is warranted, and part of the colon

and terminal ileum are removed. She is transfused with 2 U of packed RBCs during surgery. Several weeks later, she

appears healthy, but complains of easy fatigability. On investigation, CBC findings show hemoglobin of 10.6 g/dL,

hematocrit of 31.6%, RBC count of 2.69 million/μL, MCV of 118 μm3, platelet count of 378,000/mm3, and WBC count of

9800/mm3. The reticulocyte count is 0.3%. Which of the following is most likely to produce these findings?

□ (A) Hemolytic anemia

□ (B) Aplastic anemia

□ (C) Chronic blood loss

□ (D) Vitamin B12 deficiency

□ (E) Anemia of chronic disease

□ (F) Bone marrow metastases

Answer 27

(D) The high MCV indicates a marked macrocytosis, greater than would be accounted for by a reticulocytosis alone.

The two best-known causes for such an anemia (also known as megaloblastic anemia when characteristic megaloblastic

precursors are seen in the bone marrow) are vitamin B12 and folate deficiency. Because vitamin B12 is absorbed in the

terminal ileum, its removal can cause vitamin B12 deficiency. Hemolytic anemia is unlikely several weeks after blood

transfusion. Chronic blood loss and iron deficiency produce a microcytic pattern of anemia, as does dietary iron deficiency.

Anemia of chronic disease is generally a normocytic anemia. Inflammatory bowel diseases (e.g., Crohn disease) increase

the risk of malignancy, but myelophthisic anemias (from space-occupying lesions of the marrow) are usually normocytic to

mildly macrocytic (from reticulocytosis

Question 28

A 45-year-old man has a 3-day history of flank pain and fever. On physical examination, his temperature is 37.9°C.

There is right costovertebral angle tenderness. Laboratory studies include a urine culture that is positive for Escherichia coli. The WBC count is 13,310/mm3. Two days later, he becomes hypotensive, and a blood culture is positive for E. coli.

He requires increasing pressor support to maintain blood pressure. He develops a guaiac-positive stool and ecchymoses

of the skin. CBC shows hemoglobin of 9.2 g/dL, hematocrit of 28.1%, and platelet count of 70,000/mm3. Increased

amounts of fibrin split products are identified in the blood (elevated D dimer). Which of the following conditions is most

likely responsible for the low hematocrit?

□ (A) Warm autoimmune hemolytic anemia

□ (B) Paroxysmal nocturnal hemoglobinuria

□ (C) Microangiopathic hemolytic anemia

□ (D) β-Thalassemia major

□ (E) Aplastic anemia

Answer 28

(C) This patient has disseminated intravascular coagulation, which can result from gram-negative septicemia. This is a

form of microangiopathic hemolytic anemia, in which there is deposition of fibrin strands in small vessels. The RBCs are

damaged during passage between these strands. Coagulation factors and platelets are consumed, which does not occur

with other forms of hemolytic anemia. Paroxysmal nocturnal hemoglobinuria and the hemolytic anemias do not typically

cause a consumptive coagulopathy. Thalassemias produce chronic anemia with ineffective erythropoiesis; there also is an

extravascular hemolytic component without the complication of bleeding. Aplastic anemia refers to the loss of marrow stem

cell activity and is associated with anemia, leukopenia, and thrombocytopenia. Aplastic anemia can follow infections, most

often viral, but rarely bacterial

Question 29

A 10-year-old child has experienced multiple episodes of pneumonia and meningitis with septicemia since infancy.

Causative organisms that have been cultured 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?

□ (A) Loss of normal splenic function from recurrent ischemic injury

□ (B) Reduced synthesis of immunoglobulins

□ (C) Impaired neutrophil production

□ (D) Reduced synthesis of complement proteins by the liver

□ (E) Reduced expression of adhesion molecules on endothelial cells

Answer 29

(A) In sickle cell anemia, the cumulative 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 infection with encapsulated bacterial organisms. Immunodeficiency results from

lack of splenic function, not from lack of immunoglobulins. There is no impairment in production or function of neutrophils.

C-reactive protein is a marker of acute inflammation, and it does not help clear bacteria. Adhesion between endothelial

cells and RBCs is increased in sickle cell anemia.

Question 30

A healthy 19-year-old woman suffered blunt abdominal trauma in a motor vehicle accident. On admission to the

hospital, her initial hematocrit was 33%, but over the next hour, it decreased to 28%. A paracentesis yielded

serosanguineous fluid. She was taken to surgery, where a liver laceration was repaired, and 1 L of bloody fluid was

removed from the peritoneal cavity. She remained stable. A CBC performed 3 days later is most likely to show which of the

following morphologic findings in RBCs in the peripheral blood?

□ (A) Reticulocytosis

□ (B) Leukoerythroblastosis

□ (C) Basophilic stippling

□ (D) Hypochromia

□ (E) Schistocytes

Answer 30

(A) The acute blood loss, in this case probably intraperitoneal hemorrhage, results in a reticulocytosis from marrow

stimulation by anemia. Leukoerythroblastosis is typical of a myelophthisic process in the marrow. Basophilic stippling of

RBCs suggests a marrow injury, such as with a drug or toxin. Hypochromic RBCs occur in iron deficiency and

thalassemias, both associated with reduced hemoglobin synthesis. Acute blood loss does not give rise to iron deficiency.

Schistocytes suggest a microangiopathic hemolytic anemia, which can accompany shock or sepsis

Question 31

A 32-year-old woman from Saigon, 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 findings is most likely to be present on hemoglobin electrophoresis of the fetal RBCs?

□ (A) Hemoglobin A1

□ (B) Hemoglobin A2

□ (C) Hemoglobin Bart’s

□ (D) Hemoglobin C

Robbins & Cotran Review of Pathology Pg. 280

□ (E) Hemoglobin E

□ (F) Hemoglobin F

□ (G) Hemoglobin H

□ (H) Hemoglobin S

Answer 31

(C) The infant had α-thalassemia major, which is most likely to be occur in individuals of Southeast Asian ancestry,

each of whose parents could have two abnormal α-globin genes on chromosome 16. A complete lack of α-globin chains

precludes formation of hemoglobins A1, A2, and F. Only a tetramer of γ chains (Bart’s hemoglobin) can be made, leading to

severe fetal anemia. Inheritance of three abnormal α-globin chains leads to hemoglobin H disease, with tetramers of β

chains; survival to adulthood is possible. Individuals with hemoglobin S usually are asymptomatic in infancy because of

hemoglobin F production. Hemoglobins C and E produce mild hemolytic anemias.

Question 32

A 17-year-old boy reports passage of dark urine to his physician. 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 μm3; 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?

□ (A) Spectrin

□ (B) Glucose-6-phosphate dehydrogenase

□ (C) Phosphatidylinositol glycan A (PIGA)

□ (D) β-Globin chain

□ (E) Factor V

□ (F) Prothrombin G20210A

Answer 32

(C) This patient has paroxysmal nocturnal hemoglobinuria, a disorder that results from an acquired myeloid stem cell

membrane defect produced by a mutation in the PIGA gene. A mutation in this gene 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; 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 paroxysmal nocturnal hemoglobinuria also may have acute leukemia or aplastic anemia as
complications. Spectrin mutations give rise to hereditary spherocytosis. Patients with glucose-6-phosphate dehydrogenase

deficiency have an episodic course from exposure to agents such as drugs that induce hemolysis. Mutations in the β-

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

Question 33

A 32-year-old man has reported easy fatigability since childhood. On physical examination, he is normally developed

and is afebrile. Laboratory studies show hemoglobin of 8.8 g/dL, hematocrit of 26.3%, platelet count of 199,000/mm3, and

WBC count of 5350/mm3. α-Globin inclusions are present in erythroblasts and erythrocytes, leading to increased

phagocytosis by cells of the mononuclear phagocyte system. Hemoglobin electrophoresis shows hemoglobin A2 of 6%,

hemoglobin F of 1%, and hemoglobin A1 of 93%. The serum ferritin level is 3090 ng/mL. Which of the following is the most

likely diagnosis?

□ (A) Autoimmune hemolytic anemia

□ (B) Glucose-6-phosphate dehydrogenase deficiency

□ (C) Megaloblastic anemia

□ (D) β-Thalassemia

□ (E) Sickle cell anemia

□ (F) Paroxysmal nocturnal hemoglobinuria

Answer 33

(D) The reduced β-globin synthesis results in a relative excess of α-globin chains that precipitate in RBCs and their

precursors. These precipitates make the cells more susceptible to damage and removal. This intramedullary loss of RBC

precursors is termed ineffective erythropoiesis. It acts as a trigger for greater dietary absorption of iron by unknown

mechanisms. Hemolysis of RBCs in the periphery (e.g., spleen, liver) releases iron that can be reused for hemoglobin
synthesis. Hemolysis can occur in glucose-6-phosphate dehydrogenase deficiency with oxidative injury to RBCs,

particularly in ingestion of certain drugs. In megaloblastic anemias, there is enough iron but not enough vitamin B12 or

folate. In sickle cell anemia, the β-globin chains are abnormal, leading to sickling of RBCs, which are destroyed in the

spleen; however, there is no ineffective erythropoiesis. Complement lysis is enhanced in paroxysmal nocturnal

hemoglobinuria, which results from mutations in the PIGA gene. Patients with this disorder have a history of infections.

Question 34

A 13-year-old child has a history of easy bruising. At age 10 years, he experienced hemorrhaging around the pharynx

that produced acute airway obstruction. On physical examination, he has marked reduction in joint mobility of the ankles,

knees, and elbows. Family history indicates that other male relatives have similar bleeding problems. Laboratory studies

show hemoglobin, 13.1 g/dL; hematocrit, 39.2%; platelet count, 228,000/mm3; WBC count, 5950/mm3; prothrombin time,

13 seconds; and partial thromboplastin time, 52 seconds. A 1 : 1 dilution of the patient’s plasma with normal pooled plasma

does not correct the partial thromboplastin time. Which of the following is the most likely diagnosis?

□ (A) Antiphospholipid syndrome

□ (B) Factor V mutation

□ (C) Disseminated intravascular coagulation

□ (D) Hemophilia A with a factor VIII inhibitor

□ (E) Idiopathic thrombocytopenic purpura

□ (F) Von Willebrand disease

□ (G) Vitamin K deficiency

Answer 34

(D) The patient’s history is typical of hemophilia A caused by decreased factor VIII activity or factor VIII deficiency. The

affected patient is male and has male relatives who are affected (X-linked transmission), and there is history of bleeding,

especially into joints. The partial thromboplastin time (PTT) is prolonged because factor VIII is required for the intrinsic

pathway; the prothrombin time (PT) is normal because the extrinsic pathway does not depend on factor VIII function. The

inability to correct PTT by mixing with normal plasma is important. If the patient had a deficiency of factor VIII only, the

addition of normal plasma, a source of factor VIII, would have corrected the PTT. Failure to correct PTT by normal plasma

indicates the presence of an inhibitor in the patient’s serum. About 15% of patients with hemophilia eventually develop an

inhibitor to factor VIII. The antiphospholipid syndrome has similar PT and PTT findings because an inhibitor is present, but

these patients have thromboses and bleeding, typically in adulthood, and without a family history. The factor V (Leiden) mutation leads to recurrent thromboses. Disseminated intravascular coagulation is an acute condition resulting from an

underlying disease that triggers the coagulation mechanisms, and typically the platelets are consumed. Idiopathic

thrombocytopenic purpura results from an autoimmune condition with thrombocytopenia leading to bleeding. In von

Willebrand disease, the platelet count, PT, and PTT all are normal—the problem is decreased platelet adherence from

decreased von Willebrand factor. Vitamin K deficiency leads to an abnormal PT.

Question 35

A 16-year-old girl has a history of easy bruising and hemorrhages. Since menarche at the age of 14 years, she has had

menometrorrhagia. On physical examination, she displays joint deformity and has decreased mobility of the ankles, knees,

and wrists. Laboratory studies show hemoglobin, 11.8 g/dL; hematocrit, 35.1%; platelet count, 267,000/mm3; WBC count,

5960/mm3; prothrombin time, 13 seconds; and partial thromboplastin time, 60 seconds. A 1 : 1 dilution of the patient’s

plasma with normal pooled plasma corrects the partial thromboplastin time. Which of the following is the most likely

diagnosis?

□ (A) Antiphospholipid syndrome

□ (B) Disseminated intravascular coagulation

□ (C) Hemophilia A

□ (D) Idiopathic thrombocytopenic purpura

□ (E) Thrombotic thrombocytopenic purpura

□ (F) Vitamin K deficiency

□ (G) Von Willebrand disease

Answer 35

(C) The history in this case is similar to that in question 34; however, the partial thromboplastin time (PTT) is corrected

by normal pooled plasma. The patient has hemophilia A caused either by decreased factor VIII activity or by factor VIII

deficiency, and inhibitors of factor VIII are absent from the patient’s serum. How is this possible in a female patient? Xinactivation

(“unfavorable lyonization”) can explain this phenomenon and could explain why female carriers of hemophilia A

or B have a tendency to bleed. (“When you have eliminated the impossible, that which remains, however improbable, must

be the truth,” said Sherlock Holmes in The Sign of Four.) An in vitro mixing study of patient and pooled plasma such as

this usually corrects an abnormality caused by a deficiency of a procoagulant factor, but if there is a coagulation inhibitor

in the patient’s plasma, the clotting test would show an abnormal result. The mixing study excludes the antiphospholipid

syndrome. Disseminated intravascular coagulation is an acute problem with consumption of platelets and coagulation

factors, making the prothrombin time (PT) and PTT prolonged. Idiopathic thrombocytopenic purpura is characterized by

the presence of antiplatelet antibodies and thrombocytopenia. Thrombotic thrombocytopenic purpura is a microangiopathic

hemolytic anemia characterized by renal failure and central nervous system abnormalities. Vitamin K deficiency should

prolong the PT. Von Willebrand disease is caused by decreased platelet adhesion and has features resembling

thrombocytopenia

Question 36

A 22-year-old woman has experienced febrile episodes over the past 2 weeks. On physical examination, her

temperature is 37.5°C, pulse is 82/min, respirations are 18/min, and blood pressure is 105/65 mm Hg. Laboratory studies

show hemoglobin of 10.8 g/dL, hematocrit of 32.5%, platelet count of 245,700/mm3, and WBC count of 8320/mm3. The

serum haptoglobin level is decreased, but direct and indirect Coombs test results are negative. The reticulocyte count is

increased. The prothrombin time is 12 seconds, and the partial thromboplastin time is 31 seconds. The patient is observed

over the next week and found to have temperature spikes to 39.1°C, with shaking chills every 48 hours. Infection with

which of the following organisms is most likely to cause this patient’s illness?

□ (A) Aspergillus niger

□ (B) Babesia microti

□ (C) Dirofilaria

□ (D) Escherichia coli

□ (E) Plasmodium vivax

□ (F) Wuchereria bancrofti

Answer 36

(E) This patient has benign tertian malaria. The bite of the Anopheles mosquito introduces sporozoites, which travel to

the liver to reproduce. The resulting merozoites are released into the bloodstream and infect RBCs. Asexual reproduction

within the RBCs yields trophozoites, and periodic hemolysis with release of the parasites produces the characteristic

clinical findings. Aspergillus organisms invade blood vessels and cause thrombosis, but hemolysis of RBCs is

inconsequential. Babesiosis is far less common than malaria, is endemic to the northeastern United States, and does not

produce episodic fevers. Dirofilaria is the heartworm found in dogs, which rarely infects humans and does not cause

hemolysis. Similar to other gram-negative bacteria, Escherichia coli can release lipopolysaccharide, which causes severe

sepsis and possible disseminated intravascular coagulation, a microangiopathic hemolytic anemia. Wuchereria bancrofti is

a nematode that prefers to live in lymphatics

Question 37

A 62-year-old man goes to the emergency department in an obvious state of inebriation. He is well known there

because this scenario has been repeated many times over the years. On physical examination, he is afebrile. The spleen

tip is palpable, and the liver edge is firm. Laboratory studies show hemoglobin of 8.2 g/dL, hematocrit of 25.1%, MCV of

107 μm3, platelet count of 135,000/mm3, and WBC count of 3920/mm3. The peripheral blood smear shows prominent

anisocytosis and macrocytosis. Polychromatophilic RBCs are difficult to find. A few of the neutrophils show six to seven

nuclear lobes. Which of the following is the most likely explanation of these findings?

□ (A) Mechanical fragmentation of RBCs

□ (B) Increased susceptibility to lysis by complement

□ (C) Nuclear maturation defects resulting from impaired DNA synthesis

□ (D) Hemolysis of antibody-coated cells

□ (E) Reduced deformability of the RBC membrane

□ (F) Production of abnormal hemoglobin

(G) Imbalance in synthesis of α-globin and β-globin chains

Answer 37

(C) This patient has chronic alcoholism and folate deficiency, giving rise to megaloblastic anemia. Folic acid and

vitamin B12 act as coenzymes in the DNA synthetic pathway. A deficiency of either impairs the normal process of nuclear

maturation. The nuclei remain large and primitive looking, giving rise to megaloblasts. The mature RBCs also are larger

than normal (macrocytes). The nuclear maturation defect affects all rapidly dividing cells in the body, including other

hematopoietic lineages. Patients can have thrombocytopenia and leukopenia, often because of secondary hypersplenism

(alcoholic cirrhosis, leading to splenomegaly). Neutrophils often show defective segmentation, manifested by extra nuclear

lobes. Polychromatophilic RBCs represent reticulocytes, and their number is reduced because of the failure of marrow to

produce adequate numbers of RBCs despite anemia. Mechanical fragmentation of RBCs is typical of microangiopathic

hemolytic anemias, such as disseminated intravascular coagulation. Complement lysis is enhanced in paroxysmal

nocturnal hemoglobinuria, which results from mutations in the PIGA gene. Hemolytic anemias, in which antibody coats

RBCs, can occur in autoimmune diseases, prior transfusion, and erythroblastosis fetalis. Reduced RBC membrane

deformability is seen in patients with abnormalities of cytoskeletal proteins, such as spectrin; the latter causes hereditary

spherocytosis. Hemoglobinopathies can produce a mild macrocytosis because more reticulocytes are released. An

imbalance in α-globin and β-globin chain synthesis, seen in thalassemias, leads to microcytosis of RBCs.

Question 38

A 3-year-old boy of Italian ancestry is brought to the physician because he 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 an expanded marrow space. Which

of the following is the most likely principal cause of this child’s illness?

□ (A) Reduced synthesis of hemoglobin F

□ (B) Imbalance in production of α-globin and β-globin chains

□ (C) Sequestration of iron in reticuloendothelial cells

□ (D) Increased fragility of erythrocyte membrane

□ (E) Relative deficiency of vitamin B12

Answer 38

(B) This patient, of Mediterranean descent, has β-thalassemia major. In this condition, there is a severe reduction in

the synthesis of β-globin chains without impairment of α-globin synthesis. The free, unpaired α-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 β-

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

Question 39

A 28-year-old, previously healthy man has noted increasing fatigue for the past 6 months and formation of bruises after

minimal trauma. Over the past 2 days, he has developed a cough. On physical examination, his temperature is 38.9°C,

and he has diffuse rales in both lungs. He has no hepatosplenomegaly and no lymphadenopathy. Laboratory findings

include a sputum culture positive for Streptococcus pneumoniae, hemoglobin of 7.2 g/dL, hematocrit of 21.7%, platelet

count of 23,400/mm3, WBC count of 1310/mm3, prothrombin time of 13 seconds, partial thromboplastin time of 28 seconds,

and total bilirubin of 1 mg/dL. The ANA test result is negative. What is the most likely explanation of these findings?

□ (A) Hemolysis of antibody-coated cells

□ (B) Hypersplenism

□ (C) Increased susceptibility to lysis by complement

□ (D) Metastatic adenocarcinoma

□ (E) Nuclear maturation defects resulting from impaired DNA synthesis

□ (F) Stem cell defect

□ (G) Varicella-zoster virus infection

Answer 39

(F) This patient has aplastic anemia with marked pancytopenia. Many cases are idiopathic, although some can follow

toxic exposures to chemotherapy drugs or to chemicals, such as benzene. Some cases may follow viral hepatitis

infections. An intrinsic defect in stem cells, or T lymphocyte suppression of stem cells, can play a role in the development

of aplastic anemia. Hemolysis is unlikely because the bilirubin is normal, and there is no history of an autoimmune disease.

Sequestration of peripheral blood cells in an enlarged spleen could account for mild pancytopenia, but in this case the

spleen is not enlarged. An increased susceptibility to complement lysis occurs in paroxysmal nocturnal hemoglobinuria as

a result of mutations in the PIGA gene. It is unlikely that the patient has metastatic disease at this age, with no prior illness;

metastases are more likely to produce a leukoerythroblastic peripheral blood appearance. Nuclear maturation defects are

typical of megaloblastic anemias. Chickenpox (varicella-zoster virus infection) is unlikely to produce aplastic anemia; the

virus becomes latent in neuronal ganglia.

Question 40

A 55-year-old, otherwise healthy man has experienced minor fatigue on exertion for the past 9 months. He has no

significant previous medical or surgical history. On physical examination, there are no remarkable findings. Laboratory

studies show hemoglobin of 11.7 g/dL, hematocrit of 34.8%, MCV of 73 μm3, platelet count of 315,000/mm3, and WBC

count of 8035/mm3. Which of the following is the most sensitive and cost-effective test that the physician should order to

help to determine the cause of these findings?

□ (A) Serum iron

□ (B) Serum transferrin

□ (C) Serum haptoglobin

□ (D) Bone marrow biopsy

□ (E) Serum ferritin

□ (F) Hemoglobin electrophoresis

Answer 40

(E) This patient has a microcytic anemia, so iron deficiency anemia must be considered. The ferritin concentration is a

measure of storage iron because it is derived from the total body storage pool in the liver, spleen, and marrow. About 80%

of functional body iron is contained in hemoglobin; the remainder is in muscle myoglobin. Transferrin, a serum transport

protein for iron, usually has about 33% iron saturation. Individuals with severe liver disease can have an elevated serum

ferritin level because of its release from liver stores. The serum iron concentration or transferrin level by itself gives no

indication of iron stores because in anemia of chronic disease, the patient’s iron level can be normal to low, and the

transferrin levels also can be normal to low, but iron stores are increased. The serum haptoglobin level is decreased with

intravascular hemolysis, but the anemia is normocytic because the iron can be recycled. A bone marrow biopsy specimen

provides a good indication of iron stores because the iron stain of the marrow shows hemosiderin in macrophages, but

such a biopsy is an expensive procedure. Some patients with hemoglobinopathies, such as β-thalassemias, also can have

a microcytic anemia, but this is far less common than iron deficiency

Question 41

A clinical study is performed involving adult patients diagnosed with microangiopathic hemolytic anemia. The patients

did not have diarrhea. The patients had schistocytes present on peripheral blood smears. Some of these patients were

found to have a deficiency of a metalloproteinase known as ADAMTS-13. Which of the following conditions were these

ADAMTS-13-deficient patients most likely to have?

□ (A) Disseminated intravascular coagulopathy (DIC)

□ (B) Hemolytic-uremic syndrome (HUS)

□ (C) Heparin-induced thrombocytopenia (HIT)

□ (D) Idiopathic thrombocytopenic purpura (ITP)

□ (E) Systemic lupus erythematosus (SLE)

□ (F) Thrombotic thrombocytopenic purpura (TTP)

Answer 41

(F) A deficiency of ADAMTS-13, from an acquired antibody to this metalloproteinase or a genetic mutation in the

encoding gene, can lead to accumulation of large von Willebrand multimers that promote platelet microaggregate

formation, resulting in TTP marked by microangiopathic hemolytic anemia, fever, neurologic changes, thrombocytopenia,

and renal failure. DIC results from conditions that promote consumption of coagulation factors, not a metalloproteinase

deficiency. HUS is very similar to TTP, but is more likely related to a preceding infectious gastroenteritis with diarrhea. HIT

occurs in about 5% of individuals receiving heparin, and the most serious complication is widespread arterial and venous

thrombosis. ITP is mainly complicated by bleeding from thrombocytopenia. SLE can be associated with autoimmune

mediated cytopenias.

Question 42

A 78-year-old man complains of worsening malaise and fatigue over the past 5 months. On physical examination, he is

afebrile and normotensive. The spleen tip is palpable. A CBC shows hemoglobin, 10.6 g/dL; hematocrit, 29.8%; MCV,

92 μm3; platelet count, 95,000/mm3; and WBC count, 4900/mm3 with 67% segmented neutrophils, 4% bands, 2%

metamyelocytes, 22% lymphocytes, 5% monocytes, and 3 nucleated RBCs per 100 WBCs. The peripheral blood smear

shows occasional teardrop cells. An examination of the bone marrow biopsy specimen and smear is most likely to show

which of the following findings?

□ (A) Marrow packed with myeloblasts

□ (B) Marrow fibrosis with reduced hematopoiesis

□ (C) Replacement of marrow by fat

□ (D) Presence of numerous megaloblasts

□ (E) Marked normoblastic erythroid hyperplasia

Answer 42

(B) Teardrop RBCs are indicative of a myelophthisic disorder (i.e., something filling the bone marrow, such as fibrous

thrombotic thrombocytopenic purpura connective tissue). The leukoerythroblastosis, including immature RBCs and WBCs,

is most indicative of myelofibrosis. Splenomegaly also is typically seen in myelofibrosis. A leukoerythroblastic picture also

can be seen in patients with infections and metastases involving the marrow. Marrow packed with myeloblasts is typical of

acute myeloid leukemia. In this condition, the peripheral blood also would show myeloblasts and failure of myeloid

maturation. Replacement of marrow by fat occurs in aplastic anemia, which is characterized by pancytopenia. The

presence of megaloblasts in the marrow indicates folate or vitamin B12 deficiency—both cause macrocytic anemia.

Hyperplasia of normoblasts occurs in hemolytic anemias. Leukoerythroblastosis is not seen in hemolytic anemias.

Question 43

A clinical study is performed to assess outcomes in patients who have macrocytic anemias. A comparison of laboratory

testing strategies shows that the best strategy includes testing for vitamin B12 (cobalamin) and folate. What is the most

important reason for ordering these tests simultaneously?

□ (A) Both nutrients are absorbed similarly

□ (B) Therapy for one deficiency also treats the other

□ (C) The peripheral blood smear appears the same for both deficiencies

□ (D) Aplastic anemia can result from lack of either nutrient

□ (E) Neurologic injury must be avoided

Answer 43

(E) Although folate and vitamin B12 deficiency give rise to a macrocytic anemia, a deficiency of vitamin B12 also can

result in demyelination of the posterior and lateral columns of the spinal cord. The anemia caused by vitamin B12

deficiency can be ameliorated by increased administration of folate; this masks the potential neurologic injury by improving the anemia. Treating vitamin B12 deficiency does not improve the anemia caused by folate deficiency, however. Folate has

no cofactor for absorption, but vitamin B12 must be complexed to intrinsic factor and secreted by gastric parietal cells, and

then the complex must be absorbed in the terminal ileum, so diseases such as atrophic gastritis and Crohn’s disease can

affect vitamin B12 absorption more than folate. The peripheral smear could appear the same and offer

Question 44

A 26-year-old woman has experienced chronic fatigue since early childhood. She also has had episodes of severe pain

in the abdomen, back, and legs. On physical examination, there is no organomegaly. Laboratory studies show hemoglobin,

8.9 g/dL; hematocrit, 26.9%; platelet count, 300,100/mm3; and WBC count, 5560/mm3. Hemoglobin electrophoresis shows

1% hemoglobin A2, 6% hemoglobin F, and 93% hemoglobin S. Which of the following is this patient most likely to develop

as a complication of the underlying disease?

□ (A) Micronodular cirrhosis

□ (B) Chronic atrophic gastritis

□ (C) Pigment gallstones

□ (D) High rate of stillbirths

□ (E) Esophageal web

Answer 44

(C) The hemolysis that accompanies sickle cell anemia results in an increased indirect hyperbilirubinemia, which

favors the development of gallstones containing bilirubin pigment. Cirrhosis can occur because of hemochromatosis in β-

thalassemia major. Chronic atrophic gastritis leads to loss of parietal cells, and the resulting vitamin B12 malabsorption

causes pernicious anemia. Stillbirths suggest thalassemia major. Esophageal webs occur rarely in the setting of chronic

iron deficiency anemia.

Question 45

A 9-year-old boy has developed prominent bruises on his extremities over the past week. On physical examination, he

has ecchymoses and petechiae on his arms and legs. Laboratory studies show hemoglobin, 13.8 g/dL; hematocrit, 41.9%;

MCV, 93 μm3; platelet count, 22,300/mm3; and WBC count, 7720/mm3. He had respiratory syncytial virus pneumonia 3

weeks ago. His condition improves with corticosteroid therapy. Which of the following abnormalities is most likely to cause his hemorrhagic diathesis?

□ (A) Antiplatelet antibodies

□ (B) Bone marrow aplasia

□ (C) Glycoprotein IIb/IIIa dysfunction

□ (D) Vitamin C deficiency

□ (E) Von Willebrand factor metalloproteinase deficiency

Answer 45

(A) Acute immune thrombocytopenic purpura (ITP) and chronic ITP are caused by antiplatelet autoantibodies, but the

acute form is typically seen in children after a viral disease. If the bone marrow were aplastic, all cell lines should be

reduced. Glycoprotein IIb/IIIa dysfunction/deficiency can be seen with Glanzmann thrombasthenia and chronic ITP. Scurvy

owing to vitamin C deficiency leads to increased capillary fragility with ecchymoses, but not to thrombocytopenia. Von

Willebrand factor metalloproteinase deficiency is a feature of thrombotic thrombocytopenic purpura

Question 46

A 77-year-old man has experienced increasing malaise and a 6-kg weight loss over the past year. He has noted more

severe and constant back pain for the past 3 months. On physical examination, his temperature is 38.7°C. His prostate is

firm and irregular when palpated on digital rectal examination. There is no organomegaly. A stool sample is negative for

occult blood. Laboratory studies include a urine culture positive for Escherichia coli, serum glucose of 70 mg/dL,

creatinine of 1.1 mg/dL, total bilirubin of 1 mg/dL, alkaline phosphatase of 293 U/L, calcium of 10.3 mg/dL, phosphorus of

2.6 mg/dL, and PSA of 25 ng/mL. CBC shows hemoglobin, 9.1 g/dL; hematocrit, 27.3%; MCV, 94 μm3; platelet count,

55,600/mm3; and WBC count, 3570/mm3 with 18% segmented neutrophils, 7% bands, 2% metamyelocytes, 1%

myelocytes, 61% lymphocytes, 11% monocytes, and 3 nucleated RBCs per 100 WBCs. What is the most likely diagnosis?

□ (A) Anemia of chronic disease

□ (B) Aplastic anemia

□ (C) Hemolytic anemia

□ (D) Megaloblastic anemia

□ (E) Myelophthisic anemia

□ (F) Thalassemia

Answer 46

(E) This patient has findings most suggestive of prostatic adenocarcinoma that has metastasized to the bone. High

alkaline phosphatase, hypercalcemia, and a leukoerythroblastic pattern in the peripheral blood (immature WBCs and

RBCs) are a consequence of the tumor acting as a space-occupying lesion. Myelophthisic anemias also may be caused

by infections. The anemia of chronic disease is mild. Aplastic anemias are unlikely to include leukoerythroblastosis.

Hemolytic anemia should be accompanied by an increase in bilirubin and no abnormalities in calcium metabolism. The

MCV in this case is not in the megaloblastic range. Thalassemias can lead to ineffective erythropoiesis, but not to

pancytopenia

Question 47

Soon after crossing the finish line in a 10-km race, a 31-year-old man collapses. On physical examination, his

temperature is 40.1°C, pulse is 101/min, respirations are 22/min, and blood pressure is 85/50 mm Hg. He is not perspiring,

and his skin shows tenting. Laboratory studies show Na+, 155 mmol/L; K+, 4.6 mmol/L; Cl−, 106 mmol/L; CO2, 27 mmol/L;

glucose, 68 mg/dL; creatinine, 1.8 mg/dL; hemoglobin, 20.1 g/dL; hematocrit, 60.3%; platelet count, 230,400/mm3; and

WBC count, 6830/mm3. What is the most likely diagnosis?

□ (A) Erythroleukemia

□ (B) Chronic obstructive pulmonary disease

□ (C) Diabetes insipidus

□ (D) Hemoconcentration

□ (E) Increased erythropoietin levels

□ (F) Polycythemia vera

Answer 47

(D) This man has heat stroke caused by hyperthermia and loss of perspiration from dehydration, which is producing

hemoconcentration with a relative polycythemia (note the elevated serum sodium level). Erythroleukemia is quite rare, and

patients with this disorder are too ill to run a race. Chronic obstructive pulmonary disease is a cause of secondary

polycythemia from chronic hypoxemia, but it does not produce hemoconcentration. Diabetes insipidus can result from a

lack of antidiuretic hormone release, which leads to free water loss and dehydration, but not to hyperthermia. Increased

erythropoietin levels are seen in secondary polycythemias, including those associated with chronic hypoxemia (high

altitude or lung disease) and those associated with neoplasms secreting erythropoietin (renal cell carcinoma).

Polycythemia vera is a form of myeloproliferative disorder, in which erythropoietin levels are low, and there is no

dehydration

Question 48

During the past 6 months, a 60-year-old man has noticed a malar skin rash that is made worse by sun exposure. He

also has had arthralgias and myalgias. On physical examination, he is afebrile and has a pulse of 100/min, respirations of

20/min, and blood pressure of 100/60 mm Hg. There is erythema of skin over the bridge of the nose. No organomegaly is

noted. Laboratory findings include positive serologic test results for ANA and double-stranded DNA, hemoglobin of
8. 1 g/dL, hematocrit of 24.4%, platelet count of 87,000/mm3, and WBC count of 3950/mm3. The peripheral blood smear

shows nucleated RBCs. A dipstick urinalysis is positive for blood, but there are no WBCs, RBCs, or casts seen on

microscopic examination of the urine. Which of the following serum laboratory findings is most likely to be present?

□ (A) Elevated D dimer

□ (B) Negative Coombs antiglobulin test

□ (C) Decreased iron

□ (D) Elevated prostate-specific antigen

□ (E) Diminished haptoglobin

Answer 48

(E) Haptoglobin is a serum protein that binds to free hemoglobin. Ordinarily, circulating hemoglobin is contained within

RBCs, but hemolysis can release free hemoglobin. The haptoglobin is used up as the amount of free hemoglobin

increases. An elevated D dimer level suggests a microangiopathic hemolytic anemia. Systemic lupus erythematosus is an

autoimmune disease that can result in hemolysis by means of autoantibodies directed at RBCs, and the Coombs test

result is often positive. Decreased iron can cause a hypochromic, microcytic anemia, but with hemolysis, the RBCs are

recycled, and the iron is not lost. Prostatic adenocarcinoma could produce leukoerythroblastosis if widely metastatic to

bone, but not hemolysis

Question 49

A 45-year-old woman has experienced worsening arthritis of her hands and feet for the past 15 years. On physical

examination, there are marked deformities of the hands and feet, with ulnar deviation of the hands and swan-neck

deformities of the fingers. Laboratory studies show an elevated level of rheumatoid factor. CBC shows hemoglobin,

11.6 g/dL; hematocrit, 34.8%; MCV, 87 μm3; platelet count, 268,000/mm3; and WBC count, 6800/mm3. There is a normal

serum haptoglobin level, serum iron concentration of 20 μg/dL, total iron-binding capacity of 195 μg/dL, percent saturation

of 10.2, and serum ferritin concentration of 317 ng/mL. No fibrin split products are detected. The reticulocyte concentration

is 1.1%. What is the most likely mechanism underlying this patient’s hematologic abnormalities?

□ (A) Poor use of stored iron

□ (B) Space-occupying lesions in the bone marrow

□ (C) Mutation in the phosphatidylinositol glycan A (PIGA) gene

□ (D) Sequestration of red blood cells in splenic sinusoids

□ (E) Impaired synthesis of β-globin chains

□ (F) Warm antibodies against red blood cell membranes

Answer 49

(A) The iron concentration and iron-binding capacity are low; however, in contrast to the finding in anemia of iron

deficiency, the serum ferritin level is increased. This increase is typical of anemia of chronic disease. Underlying chronic

inflammatory or neoplastic diseases increase the secretion of cytokines such as interleukin-1, tumor necrosis factor, and

interferon-γ. These cytokines promote sequestration of iron in storage compartments and depress erythropoietin production. Metastases are space-occupying lesions (myelophthisic process) that can lead to leukoerythroblastosis, with

nucleated RBCs and immature WBCs appearing on the peripheral blood smear. Complement lysis is enhanced in

paroxysmal nocturnal hemoglobinuria, which results from mutations in the PIGA gene. Patients with this disorder have a

history of infections. Sequestration of RBCs in the spleen occur when RBC membranes are abnormal, as in hereditary

spherocytosis or sickle cell anemia, or RBCs are coated by antibodies, as in autoimmune hemolytic anemias. Impaired

synthesis of β-globin chains gives rise to β-thalassemias, also characterized by hemolysis. Warm auto-antibody hemolytic

anemias occur in several autoimmune diseases, such as systemic lupus erythematosus, but not in patients with

rheumatoid arthritis, as in this case. Normal serum haptoglobin rules out intravascular hemolysis; iron is recycled at a rapid

rate.

Question 50

An infant is born at 34 weeks’ gestation to a 28-year-old woman, G3, P2. At birth, the infant is observed to be markedly

hydropic and icteric. A cord blood sample is taken, and direct Coombs’ test result is positive for the infant’s RBCs. Which

of the following is the most likely diagnosis?

□ (A) Mechanical fragmentation of RBCs

□ (B) Nuclear maturation defects resulting from impaired DNA synthesis

□ (C) Impaired globin synthesis

□ (D) Hemolysis of antibody-coated cells

□ (E) Stem cell defect

□ (F) Oxidative injury to hemoglobin

□ (G) Reduced deformability of the RBC membrane

Answer 50

(D) The infant most likely has erythroblastosis fetalis because of the maternal antibodies coating the fetal cells. A fetalmaternal

hemorrhage in utero or at the time of delivery in a previous pregnancy (or with previous transfusion of

incompatible blood) can sensitize the mother, resulting in production of IgG antibodies. In subsequent pregnancies, these

antibodies (in contrast to the naturally occurring IgM antibodies) can cross the placenta to attach to fetal cells, leading to

hemolysis. In the past, most cases were caused by Rh incompatibility (e.g., Rh-negative mother, Rh-positive infant), but

the use of RhoGAM administered at birth to Rh-negative mothers has eliminated almost all such cases. Other, less

common blood group antigens can be involved in this process, however. The other conditions listed are not antibody

mediated. Mechanical fragmentation of RBCs is typical of microangiopathic hemolytic anemias, such as disseminated

intravascular coagulation, which is more typical of pregnant women with obstetric complications. Impaired RBC nuclear

maturation occurs as a result of vitamin B12 or folate deficiency. Impaired globin synthesis occurs in thalassemias. A stem

cell defect results in aplastic anemia and immunodeficiency. Oxidative injury to hemoglobin is typical of glucose-6-

phosphate dehydrogenase deficiency. Reduced RBC membrane deformability is seen in patients with abnormalities in

cytoskeletal proteins, such as spectrin; the latter causes hereditary spherocytosis.

Question 51

A 65-year-old man has experienced worsening fatigue for the past 5 months. On physical examination, he is afebrile

and has a pulse of 91/min, respirations of 18/min, and blood pressure of 105/60 mm Hg. There is no organomegaly. A

stool sample is positive for occult blood. Laboratory findings include hemoglobin of 5.9 g/dL, hematocrit of 17.3%, MCV of

96 μm3, platelet count of 250,000/mm3, and WBC count of 7800/mm3. The reticulocyte concentration is 3.9%. No fibrin

split products are detected, and direct and indirect Coombs’ test results are negative. A bone marrow biopsy specimen

shows marked erythroid hyperplasia. Which of the following conditions best explains these findings?

□ (A) Chronic blood loss

□ (B) Iron deficiency anemia

□ (C) Aplastic anemia

□ (D) Metastatic prostatic adenocarcinoma

□ (E) Autoimmune hemolytic anemia

Answer 51

(A) The marked reticulocytosis and marrow hyperplasia indicate that the marrow is responding to a decrease in RBCs.

The reticulocytes are larger RBCs that slightly increase the MCV. Iron deficiency impairs the ability of the marrow to mount

a significant and sustained reticulocytosis. Iron deficiency anemia is typically microcytic and hypochromic. An aplastic

marrow is very hypocellular and unable to respond to anemia; it is associated with pancytopenia. Infiltrative disorders,

such as metastases in the marrow, would impair the ability to mount a reticulocytosis of this degree. The normal Coombs

test results exclude an autoimmune hemolytic anemia

Question 52

A 21-year-old woman known to have a protein C deficiency develops recurrent pulmonary thromboembolism and is

placed on anticoagulant therapy. Two weeks after initiation of this therapy, she has a sudden change in mental status and experiences difficulty speaking and swallowing. A cerebral angiogram shows a distal left middle cerebral artery occlusion.

Laboratory studies show hemoglobin of 13 g/dL, platelet count of 65,400/mm3, WBC count of 5924/mm3, prothrombin time

of 12 seconds, and partial thromboplastin time of 51 seconds. The anticoagulant therapy is discontinued. Which of the

following pharmacologic agents used as an anticoagulant in this patient is most likely to have caused these findings?

□ (A) Acetylsalicylic acid (aspirin)

□ (B) Warfarin

□ (C) Heparin

□ (D) Tissue plasminogen activator

□ (E) Urokinase

Answer 52

(C) This patient has heparin-induced thrombocytopenia, which affects 3% to 5% of patients treated for 1 to 2 weeks

with unfractionated heparin. These patients form IgG antibodies to heparin–platelet factor 4 complexes that bind to Fc

receptors on the surface of platelets, causing platelet activation and, paradoxically, thrombosis. Aspirin has antiplatelet

effects that take days to occur, and bleeding (not thrombosis) is the major risk. Warfarin (Coumadin) was avoided in this

patient because of the protein C deficiency; typically, the patient is switched from heparin to warfarin. Warfarin therapy

prolongs the prothrombin time by interfering with vitamin K–dependent clotting factor synthesis in the liver. Tissue

plasminogen activator and urokinase are fibrinolytic agents, with the former used acutely to treat conditions such as

coronary thrombosis, although the latter also may be used for venous clot lysis.

Question 53

A 45-year-old woman has experienced episodes of blurred vision and headaches for the past 6 months. She has had

worsening confusion with paresthesias over the past 3 days. On physical examination, she has a temperature of 39.6°C,

pulse of 100/min, respiratory rate of 20/min, and blood pressure of 80/50 mm Hg. Petechial hemorrhages are noted over

her trunk and extremities. Laboratory findings include hemoglobin, 10.9 g/dL; hematocrit, 34%; MCV, 96/min3; platelet

count, 28,000/mm3; and WBC count, 8500/mm3. Fragmented RBCs are noted on her peripheral blood smear. Blood urea

nitrogen is 40 mg/dL, and serum creatinine is 3.1 mg/dL. Which of the following is the most likely underlying cause for her

findings?

□ (A) Defective ADP-induced platelet aggregation

□ (B) Presence of antibodies against von Willebrand’s factor metalloproteinase

□ (C) Formation of auto-antibodies to platelet glycoproteins IIb/IIIa and Ib-IX

□ (D) Circulating toxin that injures capillary endothelium

□ (E) Inappropriate release of thromboplastic substances into blood

□ (F) Decreased factor VIII activity

Answer 53

(B) The clinical features (neurologic abnormalities, fever, thrombocytopenia, microangiopathic hemolytic anemia, renal

failure) point to thrombotic thrombocytopenic purpura (TTP), in which there is an inherited or acquired deficiency of the

von Willebrand factor (vWF) metalloproteinase (ADAMTS-13) that normally cleaves very high molecular weight multimers

of vWF. The absence of ADAMTS-13 gives rise to large multimers of vWF that promote widespread platelet aggregation,

and the resulting microvascular occlusions in brain, kidney, and elsewhere produce organ dysfunction, thrombocytopenia,

microangiopathic hemolytic anemia (MAHA), and bleeding. Defective aggregation of platelets in the presence of ADP and

thrombin is a feature of a rare inherited disorder of platelets called Glanzmann thrombasthenia. Circulating toxins,

principally endotoxins elaborated by Enterobacteriaceae such as Escherichia coli are important in causing endothelial

injury in hemolytic-uremic syndrome (HUS). HUS has similar clinical findings to TTP, but has a different pathogenesis.

Release of thromboplastic substances from tumor cells or a retained dead fetus can lead to disseminated intravascular

coagulation with MAHA, but this patient has no source of thromboplastins. Decreased factor VIII activity is a feature of

hemophilia A, an X-linked disorder rare in women, characterized by bleeding into soft tissues, such as joints, and normal platelet number and function.

Question 54

A clinical study is performed using patients diagnosed with peptic ulcer disease, chronic blood loss, and hypochromic

microcytic anemia. Their serum ferritin levels average 5 to 7 μg/mL. The rate of duodenal iron absorption in this study

group is found to be much higher than in a normal control group. After treatment with omeprazole and clarithromycin, study

group patients have hematocrits of 40% to 42%, MCV of 82 to 85 μm3, and serum ferritin of less than 12 μg/mL. Measured

rates of iron absorption in the study group after therapy are now decreased to the range of the normal controls. Which of

the following substances derived from liver is most likely to have been increased in the study group patients before

therapy, returning to normal after therapy?

□ (A) Transferrin

□ (B) Hemosiderin

□ (C) Hepcidin

□ (D) Divalent metal transporter-1 (DMT-1)

□ (E) HLA-like transmembrane protein

Answer 54

(C) Iron absorption from the gut is tightly controlled. When body iron stores are adequate, absorption of dietary iron via

DMT-1 in the duodenum is retarded, and release of iron from storage pools is inhibited. When body iron stores decrease,

as with chronic blood loss, iron absorption increases. The liver-derived plasma peptide hepcidin has been found to be the

iron absorption regulator. Hepcidin levels increase when iron stores are high. Such fine control of iron absorption may fail,

as in patients with ineffective erythropoiesis (e.g., β-thalassemia) who continue to absorb iron despite excess storage iron.

Hepcidin levels are inappropriately low with both hereditary and acquired hemochromatosis. Transferrin transports iron

between plasma, iron stores, and developing erythroblasts. Hemosiderin is an aggregated form of ferritin that does not

circulate and is found only in tissues. DMT-1 is an iron transporter that moves nonheme iron from the gut lumen to

duodenal epithelium. Mutations in the HFE gene, which encodes an HLA-like transmembrane protein, lead to excessive

absorption of dietary iron and hemochromatosis.