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Flashcards in U2-Robbins-C14: RBC & Bleeding Disorders Deck (54)
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1

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

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

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

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

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

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

□ (A) Abnormalities in production of platelets by megakaryocytes

□ (B) Suppression of pluripotent stem cells

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

□ (D) Excessive loss of platelets in menstrual blood

□ (E) Defective platelet-endothelial interactions

(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

2

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

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

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

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

□ (A) IgE

□ (B) Complement C3b

□ (C) Histamine

□ (D) IgG

□ (E) Fibronectin

(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.

3

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

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

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

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

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

reported?

□ (A) Immunoassay for plasma von Willebrand factor

□ (B) Platelet count

□ (C) Prothrombin time

□ (D) Fibrin split products

□ (E) Platelet aggregation

(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.

4

A 25-year-old woman has a 3-year history of arthralgias. Physical examination shows no joint deformity, but she appears

pale. Laboratory studies show total RBC count of 4.7 million/mm3, hemoglobin of 12.5 g/dL, hematocrit of 37.1%, platelet

count of 217,000/mm3, and WBC count of 5890/mm3. The peripheral blood smear shows hypochromic and microcytic

RBCs. Total serum iron and ferritin levels are normal. Hemoglobin electrophoresis shows an elevated hemoglobin A2 level

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

Robbins & Cotran Review of Pathology Pg. 272

□ (A) Autoimmune hemolytic anemia

□ (B) β-Thalassemia minor

□ (C) Infection with Plasmodium vivax

□ (D) Anemia of chronic disease

□ (E) Iron deficiency anemia

(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.

5

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

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

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

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

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

these findings?

□ (A) Glucose-6-phosphate dehydrogenase

□ (B) Membrane cytoskeletal protein

□ (C) α-Globin chain

□ (D) Heme

□ (E) β-Globin chain

□ (F) Carbonic anhydrase

(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.

6

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

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

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

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

□ (A) Pernicious anemia

□ (B) Gastrointestinal blood loss

□ (C) Aplastic anemia

□ (D) β-Thalassemia major

□ (E) Warm autoimmune hemolytic anemia

(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.

7

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

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

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

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

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

□ (A) Macronodular cirrhosis

□ (B) Chronic renal failure

□ (C) Meningococcemia

□ (D) Vitamin C deficiency

□ (E) Metastatic carcinoma

(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.

8

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

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

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

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

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

following is the most likely mechanism for his anemia?

□ (A) Binding of IgM to red blood cells

□ (B) Chemotherapeutic bone marrow toxicity

□ (C) Cytomegalovirus hepatitis

□ (D) Dietary folate deficiency

□ (E) Metastases to colon

(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.

9

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

very pale. She has a history of chronic anemia, and spherocytes are observed on a peripheral blood smear. Her

hematocrit, which normally ranges from 35% to 38%, is now 28%, and the reticulocyte count is very low. The serum

bilirubin level is 0.9 mg/dL. Which of the following events is most likely to have occurred in this patient?

□ (A) Development of anti-RBC antibodies

□ (B) Disseminated intravascular coagulation

□ (C) Accelerated extravascular hemolysis in the spleen

□ (D) Reduced erythropoiesis from parvovirus infection

□ (E) Superimposed iron deficiency

(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.

10

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

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

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

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

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

examination of his peripheral blood smear?

□ (A) Howell-Jolly bodies

□ (B) Teardrop cells

□ (C) Macro-ovalocytes

□ (D) Schistocytes

□ (E) Target cells

(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.

11

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

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

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

patient?

□ (A) Infectious mononucleosis

□ (B) Mycoplasma pneumoniae infection

□ (C) Hereditary spherocytosis

□ (D) Escherichia coli septicemia

□ (E) Systemic lupus erythematosus

(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.

12

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

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

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

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

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

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

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

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

□ (A) You might need allogeneic bone marrow transplantation

□ (B) Expect increasing difficulty with joint mobility

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

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

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

(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.

13

A 12-year-old boy has a history of episodes of severe abdominal and back pain since early childhood. On physical

examination, he is afebrile, and there is no organomegaly. Laboratory studies show hemoglobin of 11.2 g/dL, platelet

count of 194,000/mm3, and WBC count of 9020/mm3. The peripheral blood smear shows occasional sickled cells,

nucleated RBCs, and Howell-Jolly bodies. Hemoglobin electrophoresis shows 1% hemoglobin A2, 6% hemoglobin F, and

93% hemoglobin S. Hydroxyurea therapy is found to be beneficial in this patient. Which of the following is the most likely

basis for its therapeutic efficacy?

□ (A) Increase in production of hemoglobin F

□ (B) Increase in production of hemoglobin A

□ (C) Decrease in overall globin synthesis

□ (D) Stimulation of erythrocyte production

□ (E) Increase in oxygen affinity of hemoglobin

(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.

14

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

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

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

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

underlying condition causing this patient's findings?

□ (A) Occult malignancy

□ (B) Autoimmune hemolytic anemia

□ (C) β-Thalassemia major

□ (D) Chronic alcoholism

□ (E) Vitamin B12 deficiency

□ (F) Hemophilia A

(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.

15

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

passes dark reddish brown urine. He is surprised by this because he has been healthy all his life and has had no major

illnesses. On physical examination, he is afebrile, and there are no remarkable findings. CBC shows a mild normocytic

anemia, but the peripheral blood smear shows precipitates of denatured globin (Heinz bodies) with supravital staining and

scattered “bite cells” in the population of RBCs. Which of the following is the most likely diagnosis?

□ (A) α-Thalassemia

□ (B) Sickle cell trait

□ (C) Glucose-6-phosphate dehydrogenase deficiency

□ (D) Autoimmune hemolytic anemia

□ (E) β-Thalassemia minor

□ (F) RBC membrane abnormality

(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

16

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

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

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

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

□ (A) Iron deficiency anemia

□ (B) Aplastic anemia

□ (C) Anemia of chronic disease

□ (D) Microangiopathic hemolytic anemia

□ (E) Megaloblastic anemia

□ (F) Thalassemia minor

(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.

17

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

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

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

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

□ (A) Cryptococcus neoformans

□ (B) Borrelia burgdorferi

□ (C) Treponema pallidum

□ (D) Plasmodium falciparum

□ (E) Clostridium perfringens

□ (F) Trypanosoma gambiense

□ (G) Schistosoma haematobium

(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

18

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

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

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

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

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

be most useful in determining the cause of her condition?

□ (A) Exposure to drugs

□ (B) Dietary history

□ (C) Recent bacterial infection

□ (D) Menstrual history

□ (E) Family history of anemias

(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.

19

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

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

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

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

□ (A) A1

□ (B) A2

□ (C) C

□ (D) E

□ (E) F

(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

20

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

organomegaly. He has several ecchymoses of the skin on the lower extremities. Laboratory studies show hemoglobin,

13.1 g/dL; hematocrit, 39.3%; platelet count, 287,600/mm3; WBC count, 6830/mm3; prothrombin time, 13 seconds; partial

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

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

ensue?

□ (A) Splenomegaly

□ (B) Conjunctival petechiae

□ (C) Hemolysis

□ (D) Hemochromatosis

□ (E) Hemarthroses

(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.

21

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

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

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

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

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

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

diathesis?

□ (A) Increased vascular fragility

□ (B) Toxic injury to the endothelium

□ (C) Reduced production of platelets

□ (D) Increased consumption of clotting factors and platelets

□ (E) Defects in platelet adhesion and aggregation

(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.

22

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

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

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

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

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

□ (A) β-Thalassemia major

□ (B) Disseminated intravascular coagulation

□ (C) Hereditary spherocytosis

□ (D) Idiopathic thrombocytopenic purpura

□ (E) Paroxysmal nocturnal hemoglobinuria

□ (F) Thrombotic thrombocytopenic purpura

□ (G) Warm autoimmune hemolytic anemia

(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.

23

A 30-year-old, previously healthy man passes dark brown urine several days after starting the prophylactic antimalarial

drug primaquine. On physical examination, he appears pale and is afebrile. There is no organomegaly. Laboratory studies

show that his serum haptoglobin level is decreased. Which of the following is the most likely explanation of these findings?

□ (A) Mechanical fragmentation of RBCs

□ (B) Increased susceptibility to lysis by complement

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

□ (D) Impaired globin synthesis

□ (E) Hemolysis of antibody-coated cells

□ (F) Oxidative injury to hemoglobin

□ (G) Reduced deformability of the RBC membrane

(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.

24

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

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

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

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

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

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

□ (A) Disseminated intravascular coagulation

□ (B) Hemophilia B

□ (C) Idiopathic thrombocytopenic purpura

□ (D) Metastatic breast carcinoma

□ (E) Thrombotic thrombocytopenic purpura

□ (F) Vitamin K deficiency

□ (G) Von Willebrand disease

(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.

25

A 12-year-old boy experienced sudden onset of severe abdominal pain and cramping accompanied by chest pain,

nonproductive cough, and fever. On physical examination, his temperature is 39°C, pulse is 110/min, respirations are

22/min, and blood pressure is 80/50 mm Hg. He has diffuse abdominal tenderness, but no masses or organomegaly.

Laboratory studies show a hematocrit of 18%. The peripheral blood smear is shown in the figure. A chest x-ray shows

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

□ (A) Intravascular hemolysis

□ (B) Chronic hypoxia of the pulmonary parenchyma

□ (C) Increased RBC adhesion to endothelium

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

□ (E) Formation of autoantibodies to alveolar basement membrane

(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.

26

A clinical study of patients who inherit mutations that reduce the level of spectrin in the RBC membrane cytoskeleton

shows an increased prevalence of chronic anemia with splenomegaly. For many patients, it is observed that splenectomy

reduces the severity of anemia. This beneficial effect of splenectomy is most likely related to which of the following

processes?

□ (A) Increase in synthesis of spectrin in RBCs

□ (B) Increase in deformability of RBCs

□ (C) Decrease in opsonization of RBCs

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

□ (E) Decrease in production of reactive oxygen species

(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.

27

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

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

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

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

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

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

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

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

□ (A) Hemolytic anemia

□ (B) Aplastic anemia

□ (C) Chronic blood loss

□ (D) Vitamin B12 deficiency

□ (E) Anemia of chronic disease

□ (F) Bone marrow metastases

(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

28

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

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

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

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

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

likely responsible for the low hematocrit?

□ (A) Warm autoimmune hemolytic anemia

□ (B) Paroxysmal nocturnal hemoglobinuria

□ (C) Microangiopathic hemolytic anemia

□ (D) β-Thalassemia major

□ (E) Aplastic anemia

(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

29

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

Causative organisms that have been cultured include Streptococcus pneumoniae and Haemophilus influenzae. On

physical examination, the child has no organomegaly and no deformities. Laboratory studies show hemoglobin of 9.2 g/dL,

hematocrit of 27.8%, platelet count of 372,000/mm3, and WBC count of 10,300/mm3. A hemoglobin electrophoresis shows

1% hemoglobin A2, 7% hemoglobin F, and 92% hemoglobin S. Which of the following is the most likely cause of the

repeated infections in this child?

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

□ (B) Reduced synthesis of immunoglobulins

□ (C) Impaired neutrophil production

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

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

(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.

30

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

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

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

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

following morphologic findings in RBCs in the peripheral blood?

□ (A) Reticulocytosis

□ (B) Leukoerythroblastosis

□ (C) Basophilic stippling

□ (D) Hypochromia

□ (E) Schistocytes

(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