1. c. von Willebrand disease causes prolonged bleeding time. The bleeding time is a test of primary hemostasis and is affected by platelet dysfunction and number and abnormal von Willebrand factor activity. Abnormalities in the extracellular matrix such as seen with Marfan syndrome can also prolong the bleeding time. Coagulation factor deficiencies do not affect the bleeding time.

2. c. Factor VII is part of the extrinsic coagulation pathway and its deficiency causes prolonged PT. The disorders in answers a, b, and d can prolong the activated partial thromboplastin time (aPTT). Factor XIII deficiency is not associated with prolongation of the PT or PTT.

3. b. von Willebrand disease is associated with prolonged aPTT. Bernard-Soulier syndrome, ITP, and TTP are associated with low platelet counts and not with disturbances in the PTT. Factor VII deficiency is associated with prolongation in the PT.

4. b. The neoplastic cells in Waldenstrom macroglobulinemia/ lymphoplasmacytic lymphoma usually do not express CD5.

5. c. The neutrophil’s half-life is 5 to 20 hours. This provides the basis for the daily granulocyte transfusions in patients who are febrile and not responding to broad spectrum antibiotics.

6. a. Most cases of Kikuchi disease are self-limiting and do not require treatment.

7. e. Increased methylmalonic acid is a sensitive test of cobalamin deficiency and is useful in early detection of vitamin B12 deficiency where levels of vitamin B12 are intermediate. Methylmalonic acid levels are normal in folate deficiency.

8. e. Bart hemoglobin, ρ₄ is commonly seen in the neonates who have alpha thalassemia with the absence of two or more alpha globin chains.

9. c. Hodgkin lymphoma associated with HIV infection is of the classical subtype, most commonly of the mixed cellularity or lymphocyte-depleted forms, but occasionally the nodular sclerosis subtype. Almost all cases of Hodgkin lymphoma in HIV patients are associated with Epstein-Barr virus (EBV).

10. c. Whipple disease may be associated with peripheral and/or internal lymphadenopathy. The morphology is characterized by lipogranulomas with foamy histiocytes containing PAS+ cytoplasm. Nonnecrotizing (sarcoidal) granulomas may be present in some cases.

11. d. Folic acid is absorbed in the proximal jejunum.

12. e. The mitochondria in the developing erythrocytes are found in a perinuclear distribution resulting in a characteristic ring of staining by Prussian blue stain.

13. e.

14. e. RBCs carry out anaerobic glycolysis as they have no mitochondria in order to produce ATP, which, in turn, is necessary to maintain normal electrolyte composition in the intracellular compartment via Na⁺/K⁺ ATPdependent pump activity.

17. c. Although a decreased MCHC can reflect a defect in hemoglobin synthesis, the MCHC is frequently normal in patients who have a microcytic anemia such as thalassemia minor. Defect in hemoglobin synthesis can therefore be seen in patients with MCH less than 27 pg or by the visual appearance of hypochromia. Decreased RBC count and hemoglobin level, although generally indicative of a hemoglobin synthesis defect, are usually late indicators of a synthesis problem and may not always reflect decreased hemoglobin synthesis such as in trauma or recent hemorrhage.

18. d. Coombs-negative anemia is nonimmune hemolytic anemia that should be investigated for possible glucose-6-phosphate dehydrogenase deficiency, paroxysmal nocturnal hemoglobinuria, red cell fragmentation, lead poisoning, hemoglobinopathy, and hereditary spherocytosis. Serum haptoglobin levels are helpful in determining if hemolysis is intravascular (undetectable haptoglobin level) or extravascular (normal haptoglobin level). Infection with mycoplasma may result in Coombs-positive hemolytic anemia.

19. a. Acquired sideroblastic anemia is associated with an abnormality in heme synthesis. Of the drugs listed above, only chloramphenicol interferes with heme synthesis via mitochondrial dysfunction.

20. a. Staging of Hodgkin lymphoma involves determining extent of lymph node and extralymphatic involvement along with clinical findings (weight loss, fever, night sweats). Radiographic studies are important for localization of disease. A minimum of two biopsies from each side of the iliac bones are required to evaluate bone marrow involvement.

21. b. Thalassemia minor may cause normal or increased iron with high iron stores. Iron-deficiency anemia will also result in low ferritin levels, while anemia of chronic disease will cause low iron and iron binding capacity with high ferritin and high bone marrow storage iron. RDW is usually normal in thalassemia minor. In comparison, sideroblastic anemia may have normal or increased RDW.

22. b. Thalassemia minor, repeated hemorrhages, and B12 deficiency although associated with anemia are not associated with decreased iron stores as reflected by normal ferritin levels. Ferritin is almost always low in patients with iron deficiency anemia. Sideroblastic anemias arise from secondary or primary mitochondrial defects, which cause abnormal heme synthesis and deposition of the iron in heme-containing cells. Prussian blue staining can demonstrate the deposition of iron in mitochondria. As a result of the formation of hydroxyl radicals through the Fenton reaction, cross-linking of the hydroxyl radicals to DNA, protein, and lipids takes place, resulting in membrane and organelle damage and a resulting hemolytic anemia.

23. d. Of all the answers listed above, the disorder that is unlikely to have major deficit in cell lineage is thalassemia minor. Alcoholic cirrhosis is associated with B12 deficiency, and often macrocytic anemia, neutropenia, and thrombocytopenia can be present. Hematologically, folic acid deficiency can present in a similar fashion as B12 deficiency. Both hairy cell leukemia and primary macroglobulinemia are lymphoproliferative disorders and can affect the bone marrow, resulting in pancytopenia.

24. c. Thrombocytosis is associated with iron deficiency anemia in approximately 30% of cases, in nearly all postsplenectomy cases, and as a reactive process in pancreatic cancer. Because pyruvate kinase deficiency is often associated with splenomegaly, patients often have thrombocytopenia but can develop thrombocytosis postsplenectomy for life-threatening anemia.

25. b. Additional poor prognostic signs include age <1 year, hypodiploidy, and the translocations t(4;ll)(q21;q23) and t(1;19)(q23;p13.3).

27. e. Any disorder that involves either bone marrow invasion or a brisk hemolytic process can result in a leukoerythroblastic picture; however, anemia of chronic disease (ACD), also called anemia of chronic inflammation, is usually associated with a mild to moderate normochromic normocytic anemia and variable presence of Pappenheimer and Howell-Jolly bodies. ACD is also associated with ineffective iron reutilization, which is evidenced by large deposits of iron in reticuloendothelial cells seen with Prussian blue staining. A recent key marker of ACD is hepcidin, which is produced in response to inflammatory cytokines. Hepcidin is thought to prevent ferroportin from releasing iron stores. However, in contrast to iron deficiency anemia, TIBC (total iron binding capacity) is usually low or normal with normal or high ferritin levels in ACD, whereas in iron deficiency anemia, TIBC is usually high with ferritin being low reflecting the bodies need to acquire iron.

28. b. CMV disease is the best answer, as viral suppression secondary to CMV can result in decreased platelet count. In all the other disorders, the platelet count is usually unaffected. Postsplenectomy usually results in a dramatic rise in platelet count.

29. e. Heparin accelerates the rate of inactivation of a number of activated clotting factors (such as IIa, Xa, IXa, XIa, and XIIa) by antithrombin III by causing a conformation change in antithrombin III. Thus, the presence of heparin in a citrated plasma specimen will inactivate thrombin, resulting in an apparent increase in the thrombin time.

30. d. Although high-performance liquid chromatography and isoelectric focusing or alkaline gel electrophoresis can demonstrate a fast-moving hemoglobin, the Heinz body test is required to demonstrate the unstable nature of hemoglobin H.

31. c. Patients with cold agglutinin disease commonly demonstrate a cold reactive IgM autoantibody, agglutination on peripheral smear, and a direct antiglobulin test that is positive for complement. Cold agglutinin disease comprises 16% to 32% of all autoimmune hemolytic anemias and is not associated with altered osmotic fragility, underlying hemoglobinopathy, or unstable hemoglobin. Howell-Jolly bodies are a sign of splenic dysfunction and are not seen in cold agglutinin disease.

33. b. Patients with hereditary spherocytosis often demonstrate a compensated hemolytic anemia with increased reticulocytosis and increased indirect bilirubin. These patients may have an increased MCHC and increased number of spherocytes on peripheral smear. Osmotic fragility testing demonstrates osmotic fragility at higher sodium chloride concentrations upon immediate incubation of sample compared with controls. This difference in osmotic fragility is more marked upon 24-hour incubation.

34. e. Increased plasma hemoglobin is commonly seen in intravascular hemolysis.

35. e. Urobilinogen results from intrahepatic circulation of the breakdown products of bilirubin in the gut that is excreted by the kidneys and usually occurs as a result of chronic hemolysis. When intravascular hemolysis occurs, hemoglobin is released from red blood cells resulting in elevated plasma hemoglobin. Hemoglobinuria results when the hemoglobin (Hb) released into the plasma exceeds the binding capacity of plasma-binding proteins. Unbound Hb is reabsorbed into renal tubular cells, where iron is converted to hemosiderin. Hemosiderin appears in the urine when the renal tubular cells slough off and can be seen with chronic intravascular hemolysis. Elevated plasma hemoglobin causes marked decrease of haptoglobin because of the binding of hemoglobin to haptoglobin and subsequent rapid clearance and glomerular filtration and deposition of the hemoglobin in the proximal tubules. Plasma methemalbumin increases because there is increased release of oxidized heme from unbound plasma hemoglobin and binding to albumin.

36. e. Pyruvate kinase deficiency is associated with chronic, nonspherocytic hemolytic anemia.

37. c. Paroxysmal nocturnal hemoglobinuria (PNH) is suspected in patients who have unexplained normocytic anemia with intravascular hemolysis, especially if leukopenia or thrombocytopenia is present. The sugarwater test, which relies on the enhanced hemolysis of C3-dependent systems in isotonic solution of low ionic strength, is usually the first test performed and demonstrates high sensitivity. However, because this test is not specific for PNH, positive results require confirmation by flow cytometric testing or, alternatively, the acid hemolysis test (Ham test), which demonstrates hemolysis upon acidification of a blood specimen in the presence of a fresh source of complement.

38. b. Methemoglobinemia is a condition in which the iron within hemoglobin is oxidized from the ferrous (Fe²⁺) state to the ferric (Fe³⁺) state, resulting in the inability to transport oxygen and carbon dioxide. Clinically, this condition causes cyanosis and often results in dark or brown-colored plasma. In children, methemoglobinemia usually results either from exposure to oxidizing substances (such as nitrates or nitrites, aniline dyes, or medications) or is the result of inborn errors of metabolism (such as glucose-6-phosphate dehydrogenase [G6PD] deficiency and cytochrome b5 oxidase deficiency) or severe acidosis, which causes an acquired dysfunction of cytochrome b5 oxidase.

39. e. Elevated Hb A₂ is commonly associated with beta thalassemia trait. All the other answers are seen with alpha thalassemia minor.

40. a. The earliest B-cell precursors can be identified by cCD22. This is followed by the appearance of CD19 and CD10. The subsequent maturation and differentiation of the B-cell lineage is characterized by gradual decrease in CD10 together with gradual gain in CD20. CD38 is a lineage nonspecific marker of hematopoietic cells.

41. d. Hemoglobin H disease is associated with 20% to 40% Hb Bart at birth; however, by 1 year of age, there is only a trace of Hb Bart present.

42. a. Because hemoglobin Lepore is a result of an event that results in a crossover (knockout) of one of the ο and genes, the expression of the hemoglobin A₂ is decreased and not increased. Because the hemoglobin Lepore molecule is not well expressed in cells, it is difficult to detect early in life but does result in a microcytic anemia similar to beta thalassemia.

43. e. Hemoglobin F is a tetramer composed of two alpha chains and two gamma chains. Hemoglobin H disease involves a deletion of three of four alpha globin genes. The other diagnoses are not associated with a deletion of alpha globin genes. Elevated hemoglobin F is also seen in β thalassemia, sickle cell anemia, chronic myelomonocytic leukemia, and οβ thalassemia.

44. d. These numbers are important to remember because a ratio other than 60:40 may represent a transfused sickle cell disease patient or sickle beta (+) thalassemia.

46. e. The RBC morphology in myelofibrosis includes all of the above except acanthocytes and also typically demonstrates teardrop cells. Acanthocytes are very rarely seen in normal peripheral smears and when seen in increased numbers, the diagnosis of abetalipoproteinemia should be entertained.

47. d. Unstable hemoglobins are associated with increased anisocytosis and poikilocytosis on peripheral smear. Because a hemolytic anemia is often involved, polychromasia (reticulocytosis) is often present. The Heinz body test is usually positive. Other tests that are used to evaluate the presence of an unstable hemoglobin include the isopropanol stability test and the heat stability test.

48. c. Schistocytes are usually associated with microangiopathic hemolytic anemia.

50. b. Hairy cell leukemia cells have a specific phenotype that makes the detection of leukemic cells easier. Cells are positive for mature B-cell markers such as CD19, CD20, and CD22. CD25 and CD11c are also positive. They also show bright CD45 expression and expression of surface immunoglobulins. CD5 is typically negative.

52. b. These markers are also seen on monocytes. Choice “a” could describe the phenotype of either a monoblast or myeloblast, while “c”, “d”, and “e” could describe a myelocytic, metamyelocyte/neutrophil, and promyelocyte phenotype, respectively.

53. c. The cells seen in acute promyelocytic leukemia are characteristically HLA-DR negative.

54. e. Most reactive disorders have a platelet count ×1000 × 10⁹

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