Questions for RBC and bleeding disorders

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 30-year-old woman complains of recent easy fatigability, bruising, and recurrent throat infections. Physical examination reveals numerous petechiae over her body and mouth. Abnormal laboratory findings include hemoglobin of 6 g/dL, WBC of 1,500/mL, and platelets of 20,000/mL. The bone marrow is hypocellular and displays increased fat. What is the appropriate diagnosis? (A) Aplastic anemia (B) Iron-deficiency anemia (C) Megaloblastic anemia (D) Myelofibrosis with myeloid metaplasia (E) Pure red cell aplasia

A: Aplastic anemia is a disorder of pluripotential stem cells that leads to bone marrow failure. The disorder features hypocellular bone marrow and pancytopenia (decreased circulating levels of all formed elements in the blood). Most cases are idiopathic. The bone marrow in aplastic anemia shows variably reduced cellularity, depending on the clinical stage of the disease. There is a decrease in the number of cells of myeloid, erythroid, and megakaryocytic lineages, with a relative increase in lymphocytes and plasma cells. As the cellularity decreases, there is a corresponding increase in bone marrow fat. Anemia, leukopenia (primarily granulocytopenia), and thrombocytopenia characterize aplastic anemia. Patients with aplastic anemia present with weakness, fatigue, infection, and bleeding. - Iron-deficiency anemia and megaloblastic anemia are not characterized by a hypoplastic bone marrow. - Myelofibrosis shows increased connective tissue. - Megakaryocytes and myeloid cells are not decreased in pure red cell aplasia

A patient with a history of chronic alcoholism presents with a macrocytic anemia and thrombocytopenia. Blood smear examination demonstrates numerous oval macrocytes and hypersegmented neutrophils. A Schilling test is normal. Which of the following is the most likely diagnosis? (A) Anemia of chronic disease (B) Folic acid defi ciency (C) G6PD defi ciency (D) Iron defi ciency anemia (E) Sickle cell anemia

B: Folic acid defi ciency. Folic acid defi ciency commonly occurs in alcoholics who have poor nutrition. Macrocytosis, hypersegmented neutrophils, and a normal Schilling test (vitamin B12 absorption) point to folic acid defi - ciency. Folic acid and vitamin B12 are required for synthesis of DNA, and defi ciency of either factor leads to megaloblas- tic transformation of hematopoietic cells. Macrocytosis and hypersegmented neutrophils are not features of the other choices.

A 67-year-old woman with a prosthetic aortic valve develops progressive anemia. Examination of a peripheral blood smear reveals reticulocytosis and schistocytes. What is the appropriate diagnosis? (A) Acanthocytosis (B) Henoch-Schönlein purpura (C) Idiopathic thrombocytopenic purpura (D) Macroangiopathic hemolytic anemia (E) Microangiopathic hemolytic anemia

D: Macroangiopathic hemolytic anemia most commonly results from direct erythrocyte trauma due to an abnormal vascular surface (e.g., prosthetic heart valve, synthetic vascular graft). Anemia is mild to moderate and is accompanied by an appropriate reticulocyte response. Blood smear examination reveals fragmented red blood cells (schistocytes) and polychromasia. E) Although microangiopathic hemolytic anemia results in morphologically-similar red blood cells, it reflects changes in small blood vessels.

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 14-year-old boy presents with acute onset of right flank pain, which developed after he helped his father paint the ceiling of his bedroom. Physical examination demonstrates an area of ecchymosis in the right flank that is tender to palpation. The patient has a lifelong history of easy bruising. His brother shows the same tendency. The serum level of clotting factor VIII is less than 2% of normal. Which of the following is the most likely underlying mechanism for bleeding tendency in this patient? (A) Circulating antibodies directed against factor VIII (B) Decreased hepatic synthesis of multiple coagulation factors (C) Deficiency of vitamin K (D) Genetic defect involving the factor VIII gene (E) Nonimmune peripheral consumption of coagulation proteins

D: Genetic defect involving the factor VIII gene. Hemophilia A is an X-linked recessive disorder of blood clotting that results in spontaneous bleeding, particularly into joints, muscles, and internal organs. Classic hemophilia results from mutations in the gene encoding factor VIII (hemophilia A). Hemophilia A is the most frequently encountered sex-linked inherited bleeding disorder (1 per 5,000 to 10,000 males). C and E) represent acquired disorders.

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 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 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.

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

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 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.

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 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 displays hypochromia and microcytosis RBC's. 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 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 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.

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 TIBC 145 μg/dL 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 results

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 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? X- inactivation ("unfavorable lyonization") can explain this phenomenon and could explain why female carriers of hemophilia A or B have a tendency to bleed. 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 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

(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 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.

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 (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 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 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 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 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 units 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 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 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 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.

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.

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.

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 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 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 offers no means for distinguishing these deficiencies. An aplastic anemia is unlikely to result from a nutritional deficiency.

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 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 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 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 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 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 60-year-old man presents with a 6-month history of increas- ing fatigue. Physical examination reveals marked pallor, and a CBC shows a macrocytic anemia. Which of the following is the most likely cause of anemia in this patient? (A) Alcoholism (B) Chronic disease (C) Iron defi ciency (D) Renal disease (E) Thalassemia

A: Alcoholism. Macrocytic anemia may be caused by impaired DNA synthesis due to a defi ciency of folic acid or vitamin B12. This results in abnormal nuclear development, which, in turn, leads to ineffective erythrocyte maturation and macrocytic anemia. Folic acid defi ciency is most commonly due to inadequate dietary intake, which often develops in patients with poorly balanced diets (e.g., alcoholics). often, excessive loss of iron. Women who have menorrhagia, especially those who consume restricted diets, are especially prone to iron defi ciency anemia. Iron stores of the body are reduced, as evidenced by reduced levels of serum ferritin (not increased ferritin, choice B) and low iron saturation (iron/total iron binding capacity). None of the other laboratory fi ndings would be expected in a patient with iron defi ciency anemia.

A 23-year-old, previously healthy man of Italian origin develops moderate to severe hemolytic anemia. The previ- ous evening he had celebrated a Saint's day with a feast of beans and pasta. Urinalysis shows free hemoglobin, and the direct Coombs test is negative. Supravital staining of the blood smear demonstrates numerous membrane-bound inclusions (Heinz bodies) within erythrocytes. Which of the following is the most likely diagnosis? (A) G6PD defi ciency (B) Paroxysmal nocturnal hemoglobinuria (C) Sickle cell anemia (D) β-Thalassemia minor (E) Warm antibody autoimmune hemolytic anemia

A: G6PD defi ciency. G6PD defi ciency is an X-linked disorder that causes a hemolytic anemia character- ized by abnormal sensitivity of red cells to oxidative stress. The highest prevalence is in Africa and the Mediterranean region. Because of the role of G6PD in recycling reduced glutathione, red cells defi cient in this enzyme are susceptible to oxidative stress, which, in this case, is fava bean ingestion (favism). In quiescent periods, the erythrocytes of G6PD defi ciency appear normal. However, during a hemolytic episode precipitated by oxidative stress, Heinz bodies can be demonstrated by suprav- ital staining. Full expression of G6PD defi ciency is seen only in males, with females being asymptomatic carriers. Heinz bodies are not characteristic of the other choices.

A 4-year-old boy develops severe bleeding into the knee joint. Laboratory studies show that serum levels of factor IX are reduced, but levels of factor VIII are normal. What is the appropriate diagnosis? (A) Hemophilia A (B) Hemophilia B (C) Henoch-Schönlein purpura (D) Idiopathic thrombocytopenic purpura (E) von Willebrand disease

B: Hemophilia B is an X-linked recessive disease caused by mutations in the gene encoding factor IX. It accounts for only 10% of all cases of hemophilia. One third of all cases represent new mutations. It is clinically indistinguishable from hemophilia A (factor VIII deficiency) In both forms of hemophilia, the partial thromboplastin time (PTT) is prolonged. Mixing of a patient's blood with that of a normal donor normalizes the PTT.

A 45-year-old chronic alcoholic man presents with mental confusion. The peripheral blood smear shows numerous spur cells. The morphologic abnormalities demonstrated in this blood smear are most likely associated with which of the following conditions? (A) Abnormal spectrin in red cell membranes (B) Chronic liver disease (C) Chronic renal failure (D) Microthrombi in capillaries (E) Vitamin B12 deficiency

B: Chronic liver disease. Acanthocytosis (shown in the photomicrograph) results from a defect within the lipid bilayer of the red cell membrane and features spiny projections of the surface, which may be associated with hemolysis. The most common cause of acanthocytosis (spur cells) is chronic liver disease, in which increased free cholesterol is deposited within the cell membrane. Abnormalities in the lipid membrane cause erythrocytes to become deformed and develop irregular spiny surface projections and centrally dense cytoplasm (acanthocytes or spur cells).

A 39-year-old woman presents with a 2-month history of upper abdominal pain, weakness, and fatigue. Physical exami- nation reveals marked pallor. Laboratory studies show micro- cytic, hypochromic anemia (hemoglobin = 8.5 g/dL) and mild thrombocytosis. Gastroscopy discloses a mucosal defect in the antrum measuring 1.5 cm in diameter. Which of the following best describes the pathogenesis of anemia in this patient? (A) Defective globin chain synthesis (B) Impaired heme synthesis (C) Poor utilization of iron stores (D) Synthesis of structurally abnormal hemoglobin mol- ecules (E) Toxic damage to bone marrow stem cells

B: Impaired heme synthesis. The presence of a peptic ulcer incriminates gastrointestinal bleeding as the cause of anemia. The resulting iron defi ciency interferes with heme synthesis and thus leads to impaired hemoglobin production and anemia. Defective globin chain synthesis (choice A) and synthesis of structurally abnormal hemoglobin molecules (choice D) are hemoglobinopathies. Poor utilization of iron stores (choice C) refl ects sideroblastic anemia and anemia of chronic disease.

An 18-year-old man is rushed to the emergency room in shock following a motor vehicle accident. He is transfused with 5 U of blood. Following the transfusion the patient complains of fever, nausea, vomiting, and chest pain. Laboratory data show elevated indirect serum bilirubin, decreased serum haptoglobin, and a positive Coombs test. Which of the following is the most likely diagnosis? (A) Autoimmune hemolytic anemia (B) Disseminated intravascular coagulation (C) Hemolytic transfusion reaction (D) Hemolytic uremic syndrome (E) Microangiopathic hemolysis

C) An immediate hemolytic transfusion reaction occurs when grossly incompatible blood is administered to patients with preformed alloantibodies, usually because of clerical errors. Massive hemolysis of the transfused blood may be associated with severe complications, including hypotension, renal failure, and even death. A) Not related to blood transfusions. B, D, and E) are not characterized by a positive Coombs test.

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 56-year-old man presents with a 2-week history of fatigue. The patient's past medical history is signifi cant for aortic and mitral valve replacement 5 months ago. A CBC shows mod- erate anemia with an increased reticulocyte count. Which of the following best explains the pathogenesis of anemia in this patient? (A) Complement-mediated hemolysis (B) Decreased blood fl ow (C) Direct red cell trauma (D) Sludging of erythrocytes (E) Thrombin activation

C: Direct red cell trauma. Red cell fragmenta- tion syndromes are disorders in which erythrocytes are sub- jected to mechanical disruption as they circulate in the blood (intravascular hemolysis). These disorders are classifi ed as either macroangiopathic (large vessels), as in this case, or microangio- pathic (capillaries), according to the site of hemolysis. Mechani- cal fragmentation of red cells is primarily due either to alteration of the endothelial surface of blood vessels or disturbances in blood fl ow patterns that lead to turbulence and increased shear stress. Macroangiopathic hemolytic anemia most commonly results from direct red cell trauma due to an abnormal vascular surface (e.g., prosthetic heart valve). The other choices are not an expected complication of a prosthetic valve.

A 22-year-old woman from a large Italian family is screened for a familial blood disorder. The results of laboratory studies include a hemoglobin of 9.5 g/dL and a smear displaying mild microcytosis, hypochromia, and a few target cells. Hemoglo- bin electrophoresis shows a mild increase in hemoglobin A2 (7.5%). What is the appropriate diagnosis? (A) Anemia of chronic disease (B) G6PD defi ciency (C) Heterozygous b-thalassemia (D) Homozygous b-thalassemia (E) Silent carrier a-thalassemia

C: Heterozygous b-thalassemia. A normal hemoglobin molecule contains four globin chains, consist- ing of two α- and two non-α-chains. Three normal variants of hemoglobin are encountered, based on the nature of the non-α-chains. Hemoglobin A (α2 β2) accounts for 95% to 98% of the total hemoglobin in adults; only minor amounts of hemoglobin F (α2 γ2) and hemoglobin A2 (α2 δ2) are present. Heterozygous β-thalassemia is associated with micro- cytosis and hypochromia, and the degree of microcytosis is disproportionate to the severity of the anemia, which is gener- ally mild. Target cells, basophilic stippling, and a mild increase in hemoglobin A2 are present. Most patients are asymptom- atic. Choice D (homozygous β-thalassemia) is a more seri- ous disease and choice E (silent carrier for α-thalassemia) is asymptomatic.

21 A 36-year-old man from China presents with increasing fatigue. He has a 3-year history of tuberculosis, and CBC shows a mild microcytic anemia. Blood work-up demonstrates low serum iron, low iron-binding capacity, and increased serum ferri- tin. The pathogenesis of anemia in this patient is most likely caused by which of the following mechanisms? (A) Clonal stem cell defect (B) Hypoxemia (C) Impaired utilization of iron from storage sites (D) Synthesis of structurally abnormal globin chains (E) Toxic damage to bone marrow stem cells

C: Impaired utilization of iron from storage sites. Anemia of chronic disease arises in association with chronic infl ammatory diseases (e.g., tuberculosis and rheu- matoid arthritis) and malignant conditions. Chronic disease leads to ineffective use of iron from macrophage stores in the bone marrow, resulting in a functional iron defi ciency, although storage iron is normal or even increased. The ane- mia of chronic disease is mild to moderate, and the red cells are often microcytic. Serum iron levels tend to be reduced. However, in contrast to iron defi ciency anemia, total iron- binding capacity also tends to be decreased (as is the serum albumin level). The other choices are not related to anemia of chronic disease.

A 9-year-old girl develops widespread pinpoint skin hemorrhages. She recovered from a flu-like illness 1 week earlier. Laboratory findings reveal a platelet count of 20,000/mL but no other abnormalities. Her bone marrow shows an increased number of megakaryocytes. The platelet count is normal after 2 months. Which of the following is the appropriate diagnosis? (A) Antiphospholipid antibody syndrome (B) Disseminated intravascular coagulation (C) Hemolytic-uremic syndrome (D) Idiopathic thrombocytopenic purpura (E) Thrombotic thrombocytopenic purpura

D: Idiopathic thrombocytopenic purpura (ITP). ITP is a quantitative disorder of platelets caused by antibodies directed against platelet or megakaryocytic anti- gens. Similar to autoimmune hemolytic anemia, the etiology of ITP is related to antibody-mediated immune destruction of platelets or their precursors. In adults with acute ITP, the plate- let count is typically less than 20,000/μL. In chronic adult ITP, the platelet count varies from a few thousand to 100,000/μL. The peripheral blood smear in ITP exhibits numerous large platelets, and the bone marrow shows a compensatory increase in megakaryocytes. Acute ITP in children typically appears after a viral illness and presents with sudden onset of petechiae and purpura without other symptoms. Spontaneous recovery can be expected in more than 80% of cases within 6 months. Thrombocytopenia may be observed in the other choices but is usually associated with other systemic signs and symptoms.

A 6-year-old girl is brought into the emergency room after an automobile accident. Physical examination shows bleed- ing from multiple wounds, and a CBC reveals a normocytic, normochromic anemia. Which of the following indices is most helpful in defi ning this patient's anemia as normocytic? (A) Hematocrit (B) Hemoglobin (C) Mean corpuscular hemoglobin concentration (D) Mean corpuscular volume (E) Red blood cell count

D: Mean corpuscular volume (MCV). MCV is the index used to measure the volume of a red blood cell. It cat- egorizes RBCs by size. Cells with normal size are called nor- mocytic, smaller cells are termed microcytic, and larger cells are referred to as macrocytic. Mean corpuscular hemoglobin concentration (choice C) measures hemoglobin content.

A 10-month-old boy of Arabic extraction is brought to the physician by his parents who complain that their child is fail- ing to thrive. Physical examination reveals splenomegaly and jaundice. A CBC shows a microcytic, hypochromic anemia (hemoglobin = 7.4 g/dL). Fetal hemoglobin accounts for most of the hemoglobin. A peripheral blood smear shows presence of target cells. Which of the following is the appropriate diagnosis? (A) G6PD defi ciency (B) Hereditary elliptocytosis (C) Hereditary spherocytosis (D) Iron defi ciency anemia (E) β-Thalassemia

E: b-Thalassemia. The β-thalassemias are a heterogeneous group of disorders that most often arise secondary to point mutations affecting the β-globin gene. Accord- ingly, hemoglobin A (α2 β2) is not formed. Unpaired α-chains precipitate in red blood cells, accounting for ineffective eryth- ropoiesis and increased hemolysis. The blood smear shows features characteristic of thalassemia, including hypochromic and microcytic RBCs, with anisocytosis, poikilocytosis, and target cells. In homozygous β-thalassemia, fetal hemoglobin (hemoglobin F) accounts for most of the hemoglobin, although increased levels of hemoglobin A2 are also present. Symptoms of the disease appear early in life, and affected children require constant transfusions. A heterozygous state for thalassemia may provide a protective effect against malaria and increase the reproductive potential of heterozygotes, thereby explain- ing the persistence of thalassemic disorders.