U2-Robbins-C14: RBC & Bleeding Disorders Flashcards
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
(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
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
(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.
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
(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.
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
(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.
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
(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.
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
(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.
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
(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.
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
(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.
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
(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.
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
(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.
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
(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.
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
(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.
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
(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.
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
(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.
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
(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
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
(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.
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
(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
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
(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.
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
(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
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
(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.
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
(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.
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
(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.
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
(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.
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
(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.
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
(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.
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
(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.
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
(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
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
(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
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
(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.
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
(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
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
(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.
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
(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
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
(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.
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
(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.
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
(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
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
(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
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
(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.
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
(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
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
(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.
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
(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
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)
(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.
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
(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.
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
(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
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
(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.
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
(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
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
(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
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
(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
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
(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
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
(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.
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
(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.
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
(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
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
(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.
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
(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.
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
(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.
