RBC Pathology

Target

Types of cells in β-thalassemia= ___ A. Spherocyte B. Bite C. Tear Drop D. Sickle E. Target

Heinz Bodies Bite Cells Explanation: Peripheral blood film may reveal the following poikilocytes: - Heinz Bodies (intracytoplasmic aggregates of precipitated hemoglobin) - Degmacytes ("bite cells")

What are the 2 classic findings seen on peripheral blood film in patients with G6PD deficiency? Spherocytes Schistocytes Target Cells Heinz Bodies Biconcave Cells Bite Cells

B.Autosomal Dominant Explanation: Hereditary spherocytosis is most commonly an autosomal dominant disorder that has the highest prevalence in individuals of Northern European descent. It is the most common hemolytic anemia due to an intrinsic red cell membrane defect.

What is the most common inheritance pattern of hereditary spherocytosis? A.Autosomal Recessive B.Autosomal Dominant C.X-Linked recessive D.X-Linked dominant E.Mitochondrial

B. Bone marrow Explanation: Hematopoiesis is the process of producing blood cells. The monophyletic theory of hematopoiesis states that a single pluripotent stem cell can form all mature blood cell types. In adults, hematopoiesis normally takes place exclusively in the bone marrow.

Where in the body does hematopoiesis normally take place in adults? A. Spleen B. Bone marrow C. Liver sinusoids D. Kidney cortex E. Thymus cortex and medulla

D.Atrophic gastritis Explanation: Pernicious anemia is strongly associated with autoimmune atrophic gastritis, in which autoantibodies against hydrogen-potassium ATPases (H+-K+-ATPases) of gastric parietal cells are formed.

Which autoimmune condition is strongly associated with pernicious anemia? A.SLE B.Rheumatoid Arthritis C.Hashimoto Thyroiditis D.Atrophic gastritis E.Addison Disease

C. Antiglobulin (Coombs) Explanation: Differentiating immune- and non-immune-mediated hemolytic anemia requires use of the antiglobulin (Coombs) tests.

Which lab test helps differentiate immune- and non-immune- mediated hemolytic anemia? A. Osmolar fragility test B. Bisulfite test C. Antiglobulin (Coombs) D. Sucrose test

High mean cell hemoglobin concentration and red blood cell distribution width

Which of the following additional findings is most likely in a patient with Hereditary Spherocytosis/Elliptocytosis? Low serum iron and ferritin levels Absent CD55 on red blood cell membrane High mean corpuscular volume High hemoglobin A2 and hemoglobin F levels High mean cell hemoglobin concentration and red blood cell distribution width

A Imbalance in α-globin and β-globin chain production 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.

Which of the following is the most likely cause of a child with β-thalassemia major illness? A Imbalance in α-globin and β-globin chain production B Increased fragility of erythrocyte membranes C Reduced synthesis of hemoglobin F D Relative deficiency of vitamin B12 E Sequestration of iron in reticuloendothelial cells

A Diminished nuclear maturation from impaired DNA synthesis Chronic alcohol abuse can lead to folate deficiency, giving rise to megaloblastic anemia. Folic acid and vitamin B12 act as coenzymes in DNA synthetic pathways. A deficiency of either impairs the normal process of nuclear maturation. The hematopoietic cell nuclei remain large and primitive looking, giving rise to megaloblasts. The mature RBCs are larger than normal (macrocytes). Neutrophils often show defective segmentation, manifested by extra nuclear lobes. The nuclear maturation defect affects all rapidly dividing cells in the body. Patients with chronic alcohol abuse can have thrombocytopenia and leukopenia, often because of secondary hypersplenism (alcoholic cirrhosis, leading to splenomegaly). Polychromatophilic RBCs represent reticulocytes, and their number is reduced because of the failure of marrow to produce adequate numbers of RBCs despite anemia.

Which of the following is the most likely explanation of findings in his peripheral blood cells in folate deficiency? A Diminished nuclear maturation from impaired DNA synthesis B Extravascular hemolysis of antibody-coated cells C Imbalance in synthesis of α-globin and β-globin chains D Increased susceptibility to lysis by complement E Reduced deformability of RBC membranes

F Oxidative injury to hemoglobin Glucose-6-phosphate dehydrogenase (G6PD) deficiency predisposes the hemoglobin in RBCs to oxidative injury from drugs such as primaquine, and 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 damaged RBCs have reduced membrane deformability, and they are removed from the circulation by the spleen.

Which of the following is the most likely explanation of the findings of Glucose-6-phosphate dehydrogenase (G6PD) deficiency? A Antibody-mediated hemolysis B Impaired DNA synthesis C Impaired globin chain synthesis D Increased susceptibility to complement-induced lysis E Mechanical fragmentation of RBCs as a result of vascular narrowing F Oxidative injury to hemoglobin G Reduced deformability of RBC membrane

Damage to stem cells The bone marrow is aplastic, consisting largely of fat cells and lacking normal hematopoietic activity. Patients with aplastic anemia present with severe pancytopenia and clinical symptoms related to the various cytopenias, including fatigue (anemia), fever (neutropenia), and petechiae (thrombocytopenia). The lack of an appropriate reticulocyte response to the anemia indicates decreased or ineffective hematopoiesis as the mechanism for the pancytopenia. Injury to bone marrow stem cells is idiopathic (two thirds of cases), toxic (as in this case), immunologic, or hereditary (Fanconi anemia). Diagnosis: Aplastic anemia

Which of the following is the most likely underlying mechanism in the development of a patient with Aplastic Anemia? Neoplastic proliferation of committed stem cells Impaired globin chain synthesis Damage to stem cells Decreased erythropoietin production by the kidneys Folate deficiency

C. Schistocytes Explanation: - Spherocytes are more common in Extravascular hemolytic anemia - Schistocytes are more common in Intravascular hemolytic anemia

Which type of poikilocyte (abnormally shaped red cell) is more common in intravascular hemolytic anemia? A. Spherocytes B. Target cells C. Schistocytes D. Biconcave

A.B12 Explanation: Laboratory findings in vitamin B12 and folate deficiencies include: Hypersegmented neutrophils, Increased serum homocysteine, Increased serum methylmalonic acid (vitamin B12 deficiency only)

Which vitamin deficiency is characterized by an increased serum methylmalonic acid? A.B12 B.Folic Acid C.B1 D.B6 E.Nicotinic acid

β-thalassemia Major/Mediterranean (Cooley) Anemia: - 2 beta chain genes involvement - β0/β0 is the most severe form HbA (α2,β2): 0% (N: 97%) HbF (α2,γ2): 90% (N: 1%) HbA2 (α2,δ2): 10% (N: 2%)

___ has a presentation of increased HbF (α2γ2) and A2 (α2δ2) and no HbA on Hb electrophoresis β-thalassemia Major β-thalassemia Minor Hemoglobin H Disease Hydrops Fetalis

β-thalassemia Minor: - 1 beta chain gene involvement - Chain may be truncated (β+) or deleted (β0) - β/β+ is the most benign form HbA (α2,β2): 93% (N: 97%) HbF (α2,γ2): 2% (N: 1%) HbA2 (α2,δ2): 5% (N: 2%)

___ has a presentation of increased HbF (α2γ2) and A2 (α2δ2) and slightly decreased HbA on Hb electrophoresis β-thalassemia Major β-thalassemia Minor Hemoglobin H Disease Hydrops Fetalis

Hemoglobin H Disease: - Alpha Thalassemia - Deletion of 3 alpha chain genes

___ has a presentation of increased HbH on Hb electrophoresis β-thalassemia Major β-thalassemia Minor Hemoglobin H Disease Hydrops Fetalis

Hydrops Fetalis/Bart Syndrome: - MOST SEVERE form of Alpha Thalassemia - Deletion of 4 alpha chain genes

___ has a presentation of ~80% Hb Barts (γ4) on Hb electrophoresis β-thalassemia Major β-thalassemia Minor Hemoglobin H Disease Hydrops Fetalis

Ischemia

A 10-year-old black girl is brought to the emergency room. She complains of severe pain in her chest, abdomen, and bones. Physical examination reveals jaundice and anemia. Her parents state that she has been anemic since birth. A CBC shows normocytic anemia with marked poikilocytosis. A peripheral blood smear is shown in the image. Hemoglobin electrophoresis demonstrates hemoglobin S. This child's chest and bone pain is most likely caused by which of the following mechanisms? Amyloidosis Ischemia Vasculitis Infection Coagulopathy

D Loss of normal splenic function In sickle cell anemia, the cumulative ischemic 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 risk for infection with encapsulated bacterial organisms. Immunodeficiency results from lack of splenic function, not from lack of immunoglobulins. Endothelium can be damaged with sickling, and adhesion between endothelial cells and RBCs is increased in sickle cell anemia. Complement proteins are part of innate immune responses in acute inflammation. There is no impairment in production or function of neutrophils.

A 10-year-old child has experienced multiple episodes of pneumonia and meningitis with septicemia since infancy. Causative organisms 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 Absent endothelial cell expression of adhesion molecules B Diminished hepatic synthesis of complement proteins C Impaired neutrophil production D Loss of normal splenic function E Reduced synthesis of immunoglobulins

Autoantibodies directed against the erythrocyte membrane The peripheral blood smear from this patient shows clumped red cells caused by cold agglutinins (autoantibodies). Cold agglutinins are mostly IgM, are directed against the I/I antigen system, and act optimally at 4°C. Cold agglutinins may be idiopathic or develop secondary to an underlying condition, most frequently infections (Epstein-Barr virus) or lymphoproliferative disorders. However, most autoimmune accumulahemolytic anemias are mediated by IgG antibodies that exert their maximal effect at body temperature (warm agglutinins).

A 22-year-old man presents with a 6-day history of sore throat, fever, and general malaise. Physical examination reveals generalized lymphadenopathy, which is most prominent in the cervical lymph nodes. A CBC demonstrates atypical lymphocytes. The monospot test is positive. Two weeks later, the patient complains of intermittent pain and tingling in the tips of his fingers. A CBC discloses a mild, macrocytic anemia. The peripheral blood smear is shown in the image. Which of the following is the most likely cause of anemia in this patient? Clonal plasma cell dyscrasia with circulating paraprotein Autoantibodies directed against the erythrocyte membrane Increased susceptibility to complement-mediated hemolysis Decreased activity of an enzyme in the glycolytic pathway Defect in the erythrocyte cytoskeleton

Malaria - Plasmodium vivax This is benign tertian malaria. The bite of the Anopheles mosquito introduces sporozoites, which travel to the liver to reproduce. The resulting merozoites are released into the bloodstream and infect RBCs. Asexual reproduction within 219the RBCs yields trophozoites, and periodic hemolysis with release of the parasites produces the characteristic clinical findings.

A 22-year-old woman after returning from a trip to Africa has experienced febrile episodes over the past 2 weeks. On physical examination, her temperature is 37.5° C, pulse is 82/min, respirations are 18/min, and blood pressure is 105/65 mm Hg. Laboratory studies show hemoglobin of 10.8 g/dL, hematocrit of 32.5%, platelet count of 245,700/mm3, and WBC count of 8320/mm3. The serum haptoglobin level is decreased, and direct and indirect Coombs test results are negative. The reticulocyte count is increased. The prothrombin time is 12 seconds, and the partial thromboplastin time is 31 seconds. She is observed over the next week and found to have temperature spikes to 39.1° C, with shaking chills every 48 hours. Which of the following is the most likely diagnosis? A. Aplastic Anemia B. G6PD Deficiency C. Hemoglobin C D. Hemolytic Disease of the Newborn E. Hereditary Spherocytosis/Elliptocytosis F. Sickle Cell Anemia G. Sickle Cell Trait H. Malaria I. Myelophthisic Anemia J. Cold Agglutinins Immune hemolytic anemia K. Warm Agglutinins Immune hemolytic anemia L. Paroxysmal Nocturnal Hemoglobinuria (PNH) M. Microangiopathic/Thrombotic Hemolytic Anemia

B Complement C3b Cold agglutinin disease has antibody (usually IgM) coating RBCs. The IgM antibodies bind to the RBCs at low temperature at peripheral body sites and fix complement; however, complement is not lytic at this temperature. With an increase in temperature within core internal organs, the IgM is dissociated from the cell, leaving behind C3b. Most of the hemolysis occurs extravascularly in the cells of the mononuclear phagocyte system, such as Kupffer cells in the liver, or splenic macrophages, because the coating of complement C3b acts as an opsonin. IgG is typically involved in warm antibody hemolytic anemia, which is chronic and is not triggered by cold. Raynaud phenomenon occurs in exposed, colder areas of the body, such as the fingers and toes. The patient probably has an elevated cold agglutinin titer.

A 22-year-old woman has experienced malaise and a sore throat for 2 weeks. Her fingers turn white on exposure to cold. On physical examination, she has a temperature of 37.8° C, and the pharynx is erythematous. Laboratory findings include a positive monospot (heterophile antibody) test result. Direct and indirect Coombs test results are positive at 4° C, although not at 37° C. Which of the following molecules bound on the surfaces of the RBCs most likely accounts for these findings? A α2-Macroglobulin B Complement C3b C Fibronectin D Histamine E IgE

Glucose-6-phosphate dehydrogenase deficiency Glucose-6-phosphate dehydrogenase (G6PD) 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 can also cause oxidative damage to hemoglobin. Heinz bodies are denatured hemoglobin, and they 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.

A 23-year-old African-American man passes dark reddish brown urine 3 days after taking an anti-inflammatory medication that includes phenacetin. He is surprised, 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. Aplastic Anemia B. G6PD Deficiency C. Hemoglobin C D. Hemolytic Disease of the Newborn E. Hereditary Spherocytosis/Elliptocytosis F. Sickle Cell Anemia G. Sickle Cell Trait H. Malaria I. Myelophthisic Anemia J. Cold Agglutinins Immune hemolytic anemia K. Warm Agglutinins Immune hemolytic anemia L. Paroxysmal Nocturnal Hemoglobinuria (PNH) M. Microangiopathic/Thrombotic Hemolytic Anemia

Iron studies

A 25-year-old female presents to your office complaining of exertional dyspnea and fatigue Her past medical history is insignificant. She does not smoke or consume alcohol Her blood pressure is 110/70 mmHg and heart rate is 90/min. Physical examination reveals pale conjunctiva . The laboratory values are: ESR 15 mm/hr Hemoglobin 7.5 g/dL MCV 70 fl MCHC 29% Leukocyte count 7,000/cmm Segmented Neutrophils 55% Bands 3% Eosinophils 3% Basophils 0% Lymphocytes 32% Monocytes 7% What is the best next step in the management of this patient? Serum folate level Iron studies HbA2 measurement Schilling test Bone marrow sampling

β-Thalassemia minor

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 is shown. What is the most likely diagnosis? Anemia of Chronic Disease β-thalassemia Major β-thalassemia Minor Folate Deficiency Hemoglobin H Disease Hydrops Fetalis Iron Deficiency Anemia Pernicious anemia Sideroblastic Anemia Vitamin B12 Deficiency

β-Thalassemia Minor Although β-thalassemia minor and iron deficiency anemia are both 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 with β-thalassemia minor. Diseases that produce hemolysis and increase erythropoiesis (e.g., autoimmune hemolytic anemia, malaria) do not alter the composition of β-globin chain production. Anemia of chronic disease may mimic iron deficiency and thalassemia minor with respect to hypochromia and microcytosis; however, anemia of chronic disease is associated with an increase in the serum concentration of ferritin.

A 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 93% hemoglobin A1 with elevated hemoglobin A2 level of 5.8% and hemoglobin F level of 1.2%. What is the most likely diagnosis? Anemia of Chronic Disease β-thalassemia Major β-thalassemia Minor Folate Deficiency Hemoglobin H Disease Hydrops Fetalis Iron Deficiency Anemia Pernicious anemia Sideroblastic Anemia Vitamin B12 Deficiency

Abnormal polymerization of spectrin molecules Abnormal polymerization of spectrin molecules. The smear displays elliptical erythrocytes. Hereditary elliptocytosis (HE) refers to a heterogeneous group of inherited disorders involving the erythrocyte cytoskeleton, all of which feature a horizontal abnormality within the cytoskeleton. Variants of HE include defects in self-assembly of spectrin, spectrin- ankyrin binding, protein 4.1, and glycophorin C. Hereditary Elliptocytosis = Spectrin Defect Hereditary Spherocytosis = Ankyrin Defect

A 27-year-old pregnant woman comes to the obstetrician for a prenatal check-up. Routine laboratory testing reveals a mild normocytic anemia. The peripheral blood smear is shown in the image. Which of the following best explains the pathogenesis of anemia seen in this patient? Oxidative denaturation of hemoglobin Abnormal polymerization of ankyrin molecules Abnormal polymerization of spectrin molecules Decreased iron release in the bone marrow Destabilization of the lipid bilayer of the RBC membrane

Erythroblasts Diagnosis: Hemolytic disease of newborn, erythroblastosis fetalis The peripheral blood smear displays erythroid precursors, which are normally confined to the bone marrow. Hemolytic disease of the newborn reflects a histoincompatibility between the mother and the developing fetus. The mother lacks an antigen that is expressed by the fetus. Maternal IgG alloantibodies cross the placenta, causing complement-mediated hemolysis of fetal erythrocytes and resulting in the release of numerous erythroid precursors (erythroblasts). The other choices represent normal immune cells.

A 28-year-old woman delivers a male neonate at 36 weeks of gestation. The mother has a history of poor prenatal care and several previous miscarriages. Examination of the neonate reveals marked pallor and generalized edema (anasarca), and the peripheral blood smear is shown in the image. The nucleated cells in this blood smear are which of the following? Eosinophils B lymphocytes Monocytes Erythroblasts T lymphocytes

Hereditary Spherocytosis/Elliptocytosis

A 28-year-old woman has had a constant feeling of lethargy since childhood. On physical examination, she is afebrile and has a pulse of 80/min, respirations of 15/min, and blood pressure of 110/70 mm Hg. The spleen tip is palpable, but there is no abdominal pain or tenderness. Laboratory studies show hemoglobin of 11.7 g/dL, platelet count of 159,000/mm3, and WBC count of 5390/mm3. The peripheral blood smear shows small round erythrocytes that lack a zone of central pallor. Which of the following is the most likely diagnosis? A. Aplastic Anemia B. G6PD Deficiency C. Hemoglobin C D. Hemolytic Disease of the Newborn E. Hereditary Spherocytosis/Elliptocytosis F. Sickle Cell Anemia G. Sickle Cell Trait H. Malaria I. Myelophthisic Anemia J. Cold Agglutinins Immune hemolytic anemia K. Warm Agglutinins Immune hemolytic anemia L. Paroxysmal Nocturnal Hemoglobinuria (PNH) M. Microangiopathic/Thrombotic Hemolytic Anemia

B Intravascular disruption Mechanical trauma to RBCs is possible, but typically is not severe. It can follow strenuous exercises involving repeated blows to body parts. Complement-mediated lysis is a feature of immunohemolytic anemias. Increased osmotic fragility is noted in spherocytes. Sickle cell anemia is not likely to be found in the population groups in the countries noted, and persons with this disease are not likely to be playing rugby. Splenic sequestration is a feature of hemolytic anemias due to membrane defects and antibodies.

A 29-year-old rugby player takes part in a particularly contentious game between New Zealand and South Africa. He is the forward prop in the scrums, hitting hard and being hit hard by other players. He feels better after downing several pints of beer following the game, but notes darker urine. Urinalysis is positive for blood. Which of the following pathogenic mechanisms underlies change in the color of urine? A Complement lysis B Intravascular disruption C Osmotic fragility D Sinusoidal sickling E Splenic sequestration

Warm Agglutinins Immune hemolytic anemia She has a circulating antibody against her RBCs leading to hemolytic anemia. The indirect antiglobulin (Coombs) test detects antibody in the plasma. The direct antiglobulin (Coombs) test detects antibody bound to RBCs. Autoimmune hemolytic anemias can be a feature of autoimmune diseases, such as systemic lupus erythematosus in this woman. Most of the hemolysis is extravascular in the spleen, but some can be intravascular. The reticulocyte count is typically increased (polychromasia) with hemolysis, and serum haptoglobin is diminished.

A 29-year-old woman has had fatigue with dizziness for the past 5 months. On physical examination, she has an erythematous malar rash. She has no lymphadenopathy, but there is a palpable spleen tip. She is afebrile. Laboratory studies show hemoglobin, 8.9 g/dL; hematocrit, 27.8%; MCV, 103 μm3; RBC distribution width index, 22; WBC count, 8650/mm3; platelet count, 222,000/mm3; and reticulocyte count, 3.3%. The peripheral blood smear shows polychromasia, but no schistocytes. Her serum total bilirubin is 3.2 mg/dL with direct bilirubin 0.8 mg/dL, and haptoglobin is 5 mg/dL. Antinuclear antibody and anti-double-stranded DNA tests are positive. What is the most likely diagnosis? Aplastic Anemia G6PD Deficiency Hemoglobin C Hemolytic Disease of the Newborn Hereditary Spherocytosis/Elliptocytosis Sickle Cell Anemia Sickle Cell Trait Malaria Myelophthisic Anemia Cold Agglutinins Immune hemolytic anemia Warm Agglutinins Immune hemolytic anemia Paroxysmal Nocturnal Hemoglobinuria (PNH) Microangiopathic/Thrombotic Hemolytic Anemia

β-thalassemia Major

A 3-year-old boy from Sicily 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 expanded marrow spaces. What is the most likely diagnosis? Anemia of Chronic Disease β-thalassemia Major β-thalassemia Minor Folate Deficiency Hemoglobin H Disease Hydrops Fetalis Iron Deficiency Anemia Pernicious anemia Sideroblastic Anemia Vitamin B12 Deficiency

Aplastic Anemia

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. Which of the following is the most likely diagnosis? A. Aplastic Anemia B. G6PD Deficiency C. Hemoglobin C D. Hemolytic Disease of the Newborn E. Hereditary Spherocytosis/Elliptocytosis F. Sickle Cell Anemia G. Sickle Cell Trait H. Malaria I. Myelophthisic Anemia J. Cold Agglutinins Immune hemolytic anemia K. Warm Agglutinins Immune hemolytic anemia L. Paroxysmal Nocturnal Hemoglobinuria (PNH) M. Microangiopathic/Thrombotic Hemolytic Anemia

G6PD Deficiency

A 30-year-old, previously healthy man from Lagos, Nigeria, passes dark brown urine 2 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 diagnosis? A. Aplastic Anemia B. G6PD Deficiency C. Hemoglobin C D. Hemolytic Disease of the Newborn E. Hereditary Spherocytosis/Elliptocytosis F. Sickle Cell Anemia G. Sickle Cell Trait H. Malaria I. Myelophthisic Anemia J. Cold Agglutinins Immune hemolytic anemia K. Warm Agglutinins Immune hemolytic anemia L. Paroxysmal Nocturnal Hemoglobinuria (PNH) M. Microangiopathic/Thrombotic Hemolytic Anemia

Folic acid

A 32-year-old Caucasian female presents to your office for a routine check-up Her past medical history is significant for generalized seizures controlled with chronic phenytoin therapy. The last seizure was six months ago. She does not smoke or consume alcohol. Physical examination is insignificant, except mild pallor Laboratory values are: Hb 10.8 g/dL MCV 105 fl Platelet count 180.000/cmm Leukocyte count 7.500/cmm Segmented neutrophils 68% Bands 1% Eosinophils 1% Lymphocytes 24% Monocytes 6% Which of the following supplementations could have prevented this patient's anemia? Vitamin B12 Vitamin B1 Iron Folic acid Vitamin B6

Aplastic Anemia

A 32-year-old man presents with mild fever and increasing fatigue. He has a history of working at the chemical plant producing benzene. Physical examination does not reveal lymphadenopathy or splenomegaly, but petechial skin lesions are noted. A CBC demonstrates severe pancytopenia, with normocytic red cell indices. Which of the following is the most likely diagnosis? A. Aplastic Anemia B. G6PD Deficiency C. Hemoglobin C D. Hemolytic Disease of the Newborn E. Hereditary Spherocytosis/Elliptocytosis F. Sickle Cell Anemia G. Sickle Cell Trait H. Malaria I. Myelophthisic Anemia J. Cold Agglutinins Immune hemolytic anemia K. Warm Agglutinins Immune hemolytic anemia L. Paroxysmal Nocturnal Hemoglobinuria (PNH) M. Microangiopathic/Thrombotic Hemolytic Anemia

Hydrops Fetalis: - α-thalassemia Major - Hemoglobin Bart's The infant had α-thalassemia major, which is most likely to 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. Hemoglobin E disease produces mild hemolytic anemias

A 32-year-old woman from Hanoi, 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. What is the most likely diagnosis? Anemia of Chronic Disease β-thalassemia Major β-thalassemia Minor Folate Deficiency Hemoglobin H Disease Hydrops Fetalis Iron Deficiency Anemia Pernicious anemia Sideroblastic Anemia Vitamin B12 Deficiency

C Immune-mediated hemolysis Drug-induced hemolytic anemias are neither common nor severe enough to be recognized, since the hemolysis is mainly extravascular. However, many patients receive drugs, so the potential for a drug reaction exists, and this immune-mediated mechanism must be distinguished from other causes for anemia. Cephalosporins are the most frequent drugs implicated. Treatment consists of cessation of therapy with the drug, because most cases are due to drug-dependent antibody formation.

A 33-year-old previously healthy man with persistent fever and heart murmur is diagnosed with infective endocarditis. He receives a high dosage of a cephalosporin antibiotic during the next 10 days. He now has increasing fatigue. On physical examination he has tachycardia and scleral icterus. Laboratory studies show a hemoglobin level of 7.5 g/dL, platelet count of 261,000/mm3, and total WBC count of 8300/mm3. The direct Coombs test is positive. The periperal blood smear shows reticulocytosis. Which of the following is the most likely cause for his anemia? A Dietary nutrient deficiency B Disseminated intravascular coagulopathy C Immune-mediated hemolysis D Infection with parvovirus E Inherited hemoglobinopathy F RBC cytoskeletal protein disorder

E Systemic lupus erythematosus This patient has a warm autoimmune hemolytic anemia secondary to systemic lupus erythematosus (SLE). A positive Coombs test result indicates the presence of anti-RBC antibodies in the serum and on the RBC surface. Most cases of warm autoimmune hemolytic anemia are idiopathic, but one fourth occur in individuals with an identifiable autoimmune disease, such as SLE; in other cases, drugs are the cause. The immunoglobulin coating the RBCs acts as an opsonin to promote splenic phagocytosis. Nucleated RBCs can be seen in active hemolysis because the marrow compensates by releasing immature RBCs. Septicemia is more likely to lead to a microangiopathic hemolytic anemia. The increased RBC destruction in hereditary spherocytosis is extravascular and not immune mediated. Infections such as mononucleosis and Mycoplasma are associated with cold autoimmune hemolytic anemia (with an elevated cold agglutinin titer).

A 34-year-old woman reports becoming increasingly tired for the past 5 months. On physical examination, she is afebrile and has mild splenomegaly. Laboratory studies show a hemoglobin concentration of 10.7 g/dL and hematocrit of 32.3%. The peripheral blood smear shows spherocytes and rare nucleated RBCs. Direct and indirect Coombs test results are positive at 37° C, although not at 4° C. Which of the following underlying diseases is most likely to be diagnosed in this patient? A Escherichia coli septicemia B Hereditary spherocytosis C Infectious mononucleosis D Mycoplasma pneumoniae infection E Systemic lupus erythematosus

Chronic liver disease Diagnosis: Acanthocytosis 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 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 45-year-old chronic alcoholic man presents with mental confusion. The peripheral blood smear is shown in the image. The morphologic abnormalities demonstrated in this blood smear are most likely associated with which of the following conditions? Microthrombi in capillaries Chronic renal failure Abnormal spectrin in red cell membranes Vitamin B12 deficiency Chronic liver disease

C Inadequate usage of stored iron 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. In this case, the chronic disease is rheumatoid arthritis. 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. Autoantibody hemolytic anemias occur in several autoimmune diseases, such as systemic lupus erythematosus, but not usually in patients with rheumatoid arthritis, as in this case. Normal serum haptoglobin rules out intravascular hemolysis; iron is recycled at a rapid rate. Impaired synthesis of β-globin chains gives rise to β-thalassemias, also characterized by hemolysis. 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. Metastases are space-occupying lesions (myelophthisic process) that can lead to leukoerythroblastosis, with nucleated RBCs and immature WBCs appearing on the peripheral blood smear.

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 Autoantibodies against RBC membranes B Impaired synthesis of β-globin chains C Inadequate usage of stored iron D Mutation in the phosphatidylinositol glycan A (PIGA) gene E Sequestration of RBCs in splenic sinusoids F Space-occupying lesions in the bone marrow

A.Hypersegmented neutrophils Explanation: The MCV points to a macrocytic anemia such as a megaloblastic anemia that can have hypersegmented PMNs

A 51-year-old man has become increasingly fatigued for the past 10 months. On physical examination there are no abnormal findings. Laboratory studies show his Hgb is 9.2, Hct 27.9%, MCV 132 fL, platelet count 242,000/microliter, and WBC count 7590/microliter. Which of the following morphologic findings is most likely to be present on examination of his peripheral blood smear? A.Hypersegmented neutrophils B.Nucleated red blood cells C.Blasts D.Hypochromic, microcytic RBC's E.Schistocytes

C Serum ferritin With RBC microcytosis, iron deficiency anemia must be considered. It could be a nutritional deficiency in children and pregnant women, but more likely is due to chronic blood loss in adults. 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. Individuals with severe liver disease can have an elevated serum ferritin level because of its release from liver stores. 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. The serum haptoglobin level is decreased with intravascular hemolysis, but the anemia is normocytic because the iron can be recycled. 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. Transferrin, a serum transport protein for iron, usually has about 33% iron saturation.

A 54-year-old, previously healthy man has experienced minor fatigue on exertion for the past 9 months. On physical examination, there are no remarkable findings. Laboratory studies show hemoglobin of 11.7 g/dL, hematocrit of 34.8%, MCV of 73 μm3, platelet count of 315,000/mm3, and WBC count of 8035/mm3. Which of the following is the most sensitive and cost-effective test that the physician should order to help to determine the cause of these findings? A Bone marrow biopsy B Hemoglobin electrophoresis C Serum ferritin D Serum haptoglobin E Serum iron F Serum transferrin

Folate deficiency

A 55-year-old male comes to you with complaint of fatigue for the past month. He also complains of occasional heartburn. His past medical history is significant for hepatomegaly secondary to fatty liver. He has been drinking 3-4 shots of alcohol per day for the past 30 years. He denies smoking. His physical examination reveals pallor of skin and mucous membranes, and mild hepatomegaly. His laboratory report shows: What is the most likely diagnosis? Anemia of Chronic Disease β-thalassemia Major β-thalassemia Minor Folate Deficiency Hemoglobin H Disease Hydrops Fetalis Iron Deficiency Anemia Pernicious anemia Sideroblastic Anemia Vitamin B12 Deficiency

Reticulocyte count

A 55-year-old man undergoing evaluation for fatigue and exertional dyspnea is diagnosed with macrocytic anemia. Upper gastrointestinal endoscopy is consistent with atrophic gastritis. He is started on intramuscular cyanocobalamin with the resulting changes in his blood parameters shown in the graph below: The blue curve most likely corresponds to which of the following parameters? Erythrocyte count Methylmalonic acid Haptoglobin Reticulocyte count Gastrin

Mean corpuscular volume MCV is the index used to measure the volume of a red blood cell. It categorizes RBCs by size. Cells with normal size are called normocytic, smaller cells are termed microcytic, and larger cells are referred to as macrocytic. Mean corpuscular hemoglobin concentration (choice C) measures hemoglobin content. Diagnosis: Anemia

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

Alcoholism 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). Other possible causes of macrocytic anemia include liver disease, hypothyroidism, and primary bone marrow disease. None of the other choices are associated with macrocytic anemia. Chronic disease (choice B) and renal disease (choice D) cause normochromic, normocytic anemia. Iron defi ciency (choice C) and thalassemia (choice E) are microcytic anemias. Diagnosis: Macrocytic anemia

A 60-year-old man presents with a 6-month history of increasing 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? Thalassemia Chronic disease Renal disease Alcoholism Iron deficiency

Cold Agglutinins Immune hemolytic anemia The findings point to Coombs-positive immune hemolytic anemia with indirect hyperbilirubinemia. Cold agglutinin immunohemolytic anemia can be seen with lymphoid neoplasms and infections such as Mycoplasma, Epstein-Barr virus, HIV, influenza virus, and cytomegalovirus (CMV). IgM binds to RBCs at cooler peripheral body regions and then fixes complement. At warmer central regions, the antibody is eluted, but the complement marks the RBCs for extravascular destruction in the spleen, but 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. Although this patient has CMV infection, CMV 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 65-year-old man diagnosed with follicular non-Hodgkin lymphoma is treated with chemotherapy. He develops fever and cough of a week's duration. On examination, there are bilateral pulmonary rales. A chest radiograph shows diffuse interstitial infiltrates. A sputum specimen is positive for cytomegalovirus. He develops scleral icterus and Raynaud phenomenon. 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 test is positive. Which of the following is the most likely diagnosis? A. Aplastic Anemia B. G6PD Deficiency C. Hemoglobin C D. Hemolytic Disease of the Newborn E. Hereditary Spherocytosis/Elliptocytosis F. Sickle Cell Anemia G. Sickle Cell Trait H. Malaria I. Myelophthisic Anemia J. Cold Agglutinins Immune hemolytic anemia K. Warm Agglutinins Immune hemolytic anemia L. Paroxysmal Nocturnal Hemoglobinuria (PNH) M. Microangiopathic/Thrombotic Hemolytic Anemia

C Chronic blood loss 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.

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 18.3%, MCV of 99 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 Aplastic anemia B Autoimmune hemolytic anemia C Chronic blood loss D Iron deficiency anemia E Metastatic carcinoma

Colonoscopy The patient has a microcytic anemia. The basic differential diagnosis includes iron deficiency, thalassemia, anemia of chronic disease, and the sideroblastic anemias (typically lead poisoning). Her prior testing is normal, ruling out congenital diseases like thalassemia. No history of a chronic illness is given, and she has no exposure to lead. This makes iron deficiency the most likely cause of her anemia. At the age of 65. she is postmenopausal, so menorrhagia is an unlikely source of blood loss. The next most likely cause of insensible blood loss is colon cancer. Colonoscopy, therefore, would be the best answer for this question. In a clinical setting, serum ferritin is indicated to confirm the diagnosis of iron deficiency.

A 65-year-old woman presents to her physician complaining of a lack of energy and easy fatigability. She has previously been well and prior laboratory testing has been completely normal. Physical examination is unremarkable. Her CBC is seen below. The investigation most likely to find the cause of her anemia is: Chest x-ray Pelvic examination Bone marrow biopsy Colonoscopy Reticulocyte and Coombs test

Macroangiopathic hemolytic anemia 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. Although choice E (microangiopathic hemolytic anemia) results in morphologically-similar red blood cells, it refl ects changes in small blood vessels.

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? Microangiopathic hemolytic anemia Macroangiopathic hemolytic anemia Idiopathic thrombocytopenic purpura Henoch-Schönlein purpura Acanthocytosis

B.Hepatitis C infection Explanation: He has findings of anemia of chronic disease, with a high % iron saturation and increased iron stores. Hepatitis C is a chronic disease which can cause anemia of chronic disease.

A 68-year-old man has had malaise for over a year. On physical examination, there are no abnormal findings. A CBC shows: Hgb 10.5 g/dL, Hct 31.5%, MCV 85 fL, platelet count 211,000/microliter, and WBC count 6980/microliter. A bone marrow biopsy is performed and microscopic examination shows that maturation is occuring in all cell lines and there are no abnormal cells seen. Stainable iron in the bone marrow is increased. He has a total serum iron of 130 microgm/dL and total iron binding capacity (TIBC) of 230 microgm/dL. Which of the following underlying diseases is he most likely to have? A.Diverticulosis B.Hepatitis C infection C.Systemic lupus erythematosus D.Atrophic gastritis E.Fanconi anemia

D Plasmodium falciparum This child has cerebral malaria, and the smear shows numerous ring forms of the parasites in RBCs. Infection occurs via the bite of an Anopheles mosquito. Malarial parasites infect RBCs, causing hemolysis and anemia. Falciparum malaria is the worst form. The parasites tend to be released from cells at periodic intervals, leading to periodic fever and chills. The parasites adhere to the vascular endothelium and lead to ischemia in various organs, including the brain with consequent acute cerebral edema. There is hemolytic anemia. The liver and spleen become progressively enlarged. Babesiosis is a rare, tick-borne disease found in the northeastern United States, which can produce a hemolytic anemia, but the organisms produce a classic "tetrad" in RBCs. Lyme disease, caused by Borrelia burgdorferi, is best known for producing chronic arthritis, but meningoencephalitis, neuritis, and neuropathy may complicate this illness. Leishmaniasis, caused by Leishmania donovani, produces mainly visceral disease without cerebral findings. Sleeping sickness, caused by Trypanosoma brucei, can be a chronic disease or a more acute disease causing brain dysfunction (sleeping sickness). Wuchereria bancrofti produces lymphatic filariasis with elephantiasis.

A 7-year-old child has had worsening headaches and is obtunded for the past 2 days. Physical examination shows temperature of 39.5° C, pulse of 103/min, respirations of 18/min, and blood pressure of 90/55 mm Hg. There is bilateral papilledema on funduscopic examination. No focal neurologic deficits are noted. Palpation of the abdomen reveals hepatosplenomegaly. Laboratory findings show hemoglobin, 9.5 g/dL; hematocrit, 28.8%; MCV, 101 μm3; platelet count, 145,000/mm3; WBC count, 6920/mm3; Na+, 146 mmol/L; K+, 5.5 mmol/L; Cl-, 106 mmol/L; CO2, 26 mmol/L; creatinine, 2.3 mg/dL; urea nitrogen, 22 mg/dL; LDH, 1095 U/L; and amylase, 45 U/L. The peripheral blood smear is shown in the figure. What infectious agent is most likely to produce these findings? A Babesia microti B Borrelia burgdorferi C Leishmania donovani D Plasmodium falciparum E Trypanosoma brucei F Wuchereria bancrofti

E Occult malignancy The figure shows RBC hypochromia and microcytosis, consistent with iron deficiency, the most common cause for anemia worldwide, either from nutritional deficiency or chronic blood loss. 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, such as a colonic adenocarcinoma, should be strongly suspected as the cause of iron deficiency.

A 73-year-old man takes no medications and has had no prior major illnesses or surgeries. For the past year, he has become increasingly tired and listless. Physical examination shows that he appears pale but has 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. His peripheral blood smear is shown in the figure. Which of the following is the most likely underlying condition causing this patient's findings? A Autoimmune hemolytic anemia B Chronic alcohol abuse C β-Thalassemia major D Hemophilia A E Occult malignancy F Vitamin B12 deficiency

E Vitamin C deficiency Platelet number and function in this case are normal, and there is no detectable abnormality in the extrinsic or intrinsic pathways of coagulation as measured by the prothrombin time or partial thromboplastin time. Petechiae and ecchymoses can result from increased vascular fragility, a consequence of nutritional deficiency (e.g., vitamin C), infection (e.g., meningococcemia), and vasculitic diseases.

A 77-year-old woman notices that small, pinpoint-to-blotchy areas of superficial hemorrhage have appeared on her gums and on the skin of her arms and legs over the past 3 weeks. On physical examination, she is afebrile and has no organomegaly. Laboratory studies show a normal prothrombin time and partial thromboplastin time. CBC shows hemoglobin of 12.7 g/dL, hematocrit of 37.2%, MCV of 80 μm3, platelet count of 276,000/mm3, and WBC count of 5600/mm3. Platelet function studies and fibrinogen level are normal, and no fibrin split products are detectable. Which of the following conditions best explains these findings? A Chronic renal failure B Macronodular cirrhosis C Meningococcemia D Metastatic carcinoma E Vitamin C deficiency

B RBC Howell-Jolly bodies Explanation: Increased numbers of red blood cell inclusions such as nuclear fragments (Howell-Jolly bodies) and degenerated hemoglobin (Heinz bodies) appear following splenectomy.

A clinical study is conducted involving adults from 18 to 80 years of age who underwent splenectomy for blunt force abdominal trauma. An age-matched control group of patients consists of patients who have congestive splenomegaly. The laboratory findings from these subjects are analyzed. Which of the following laboratory test findings is most likely to be observed in the study group following splenectomy? A Thrombocytopenia B RBC Howell-Jolly bodies C Decreased RBC distribution width D Leukopenia E Nucleated RBCs

D Reduced erythropoiesis from parvovirus infection Patients with hereditary spherocytosis may have an 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 there is an underlying RBC production defect, then RBC production is shut down by parvovirus, and there is no reticulocytosis.

An 18-year-old woman from Copenhagen, Denmark, has had malaise and a low-grade fever for the past week, along with arthralgias. On physical examination, she appears very pale, except for a bright red malar facial rash. 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 Accelerated extravascular hemolysis in the spleen B Development of anti-RBC antibodies C Disseminated intravascular coagulation D Reduced erythropoiesis from parvovirus infection E Superimposed dietary iron deficiency

Myelophthisic Anemia

An 83-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 63% segmented neutrophils, 7% bands, 2% metamyelocytes, 1% myelocytes, 22% lymphocytes, 5% monocytes, and 3 nucleated RBCs per 100 WBCs. The peripheral blood smear shows occasional teardrop cells. Which of the following is the most likely diagnosis? A. Aplastic Anemia B. G6PD Deficiency C. Hemoglobin C D. Hemolytic Disease of the Newborn E. Hereditary Spherocytosis/Elliptocytosis F. Sickle Cell Anemia G. Sickle Cell Trait H. Malaria I. Myelophthisic Anemia J. Cold Agglutinins Immune hemolytic anemia K. Warm Agglutinins Immune hemolytic anemia L. Paroxysmal Nocturnal Hemoglobinuria (PNH) M. Microangiopathic/Thrombotic Hemolytic Anemia

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

An examination of the bone marrow biopsy specimen and smear of a patient with a myelophthisic disorder is most likely to show which of the following findings? A Erythroid hyperplasia B Extensive fibrosis C Fatty replacement D Many megaloblasts E Numerous myeloblasts

A Hemolysis of antibody-coated cells The infant most likely has erythroblastosis fetalis because maternal antibodies are coating fetal RBCs. A fetal-maternal hemorrhage in utero or at the time of delivery in a previous pregnancy (or with previous transfusion of incompatible blood) can sensitize the mother, resulting in production of irregular IgG antibodies. In subsequent pregnancies, these antibodies (in contrast to the naturally occurring IgM antibodies) can cross the placenta to attach to fetal cells, leading to hemolysis. In the past, most cases were caused by Rh incompatibility (e.g., Rh-negative mother, Rh-positive infant), but the use of RhoGAM administered at birth to Rh-negative mothers has eliminated almost all such cases when recognized. Other, less common blood group antigens can be involved in this process, however. The other conditions listed are not antibody mediated. A stem cell defect results in aplastic anemia and immunodeficiency. Impaired globin synthesis occurs in thalassemias. Mechanical fragmentation of RBCs is typical of microangiopathic hemolytic anemias, such as disseminated intravascular coagulation, which is more typical of pregnant women with obstetric complications. Oxidative injury to hemoglobin is typical of glucose-6-phosphate dehydrogenase (G6PD) deficiency. Reduced RBC membrane deformability is seen in patients with abnormalities in cytoskeletal proteins, such as spectrin; the latter causes hereditary spherocytosis.

An infant is born at 34 weeks' gestation to a 28-year-old woman, G3, P2. At birth, the infant is observed to be markedly hydropic and icteric. A cord blood sample is taken, and direct Coombs test result is positive for the infant's RBCs. Which of the following is the most likely mechanism for the findings in this infant? A Hemolysis of antibody-coated cells B Hematopoietic stem cell defect C Impaired globin synthesis D Mechanical fragmentation of RBCs E Oxidative injury to hemoglobin F Reduced deformability of RBC membranes

[↓] Serum Iron [↑] Serum Ferritin (Stored Form) [↑] Serum Hepcidin (Secreted from Liver when High Stored Iron) [↓] TIBC (Transferrin) (Secreted from Liver when Low Iron) [↓] % Transferrin Saturation [↓] Serum Erythropoietin [↓] Reticulocyte Count [NC] Platelet Count

Anemia of Chronic Disease: [↑, ↓, or NC] Serum Iron [↑, ↓, or NC] Serum Ferritin [↑, ↓, or NC] Serum Hepcidin [↑, ↓, or NC] TIBC (Transferrin) [↑, ↓, or NC] % Transferrin Saturation [↑, ↓, or NC] Serum Erythropoietin [↑, ↓, or NC] Reticulocyte Count [↑, ↓, or NC] Platelet Count

Dietary cobalamin deficiency

Atrophic gastritis Fish tapeworm infestation Chronic low-volume Gl bleeding Dietary cobalamin deficiency Nontropical sprue

Ileal disease Vitamin B12 (Cobalamin) Deficiency: Causes: (1): Chronic pancreatitis → lack of pancreatic proteases (can not free B12 from R binders) (2): Intrinsic factor deficiency: Pernicious anemia (MCC) or Gastrectomy (3): Destruction of IF-B12 complex by: bacterial overgrowth, or competitive parasite uptake by fish tapeworm (Diphyllobothrium latum) (4): Terminal ileal disease: Crohn's disease

Atrophic gastritis Ileal disease Myelodysplasia Dietary cobalamin deficiency Chronic low-volume Gl bleeding

Hepatic parenchymal cells

Biliary lining cells Intestinal epithelial cells Bone marrow macrophages Hepatic parenchymal cells Renal tubular cells Bone marrow stem cells

Folate deficiency

Blood lipid abnormality Hypothyroidism Folate deficiency Myelodysplasia Chronic blood loss Cobalamin deficiency

C Neurologic injury must be prevented Although folate and vitamin B12 deficiency both 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. In some cases this deficiency will only be revealed by elevated levels of homocysteine and methylmalonic acid in the serum, because these are more sensitive indicators, particularly earlier in the disease. 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 221folate deficiency, however. An aplastic anemia is unlikely to result from a nutritional deficiency. 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 disease can affect vitamin B12 absorption more than folate. The peripheral smear could appear the same and offers no means for distinguishing these deficiencies.

A clinical study is performed to assess outcomes in patients who have macrocytic anemias as a result of Vitamin 12 or folate deficiency. A comparison of laboratory testing strategies shows that the best strategy includes testing for serum homocysteine, methylmalonic acid, vitamin B12 (cobalamin), and folate. What is the most important reason for ordering these tests simultaneously? A Aplastic anemia can result from lack of either nutrient B Both nutrients are absorbed similarly C Neurologic injury must be prevented D Life-threatening thrombocytopenia can occur in both E Therapy for one deficiency also treats the other

C Hepcidin 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.

A clinical study is performed using adult patients diagnosed with peptic ulcer disease, chronic blood loss, and hypochromic microcytic anemia. Their serum ferritin levels average 5 to 7 ng/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 30 to 35 ng/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 decreased in the study group patients before therapy, and returned to normal after therapy? A Divalent metal transporter-1 (DMT-1) B Hemosiderin C Hepcidin D HLA-like transmembrane protein E Transferrin

E.Microcytic anemia Explanation: Microcytic anemia is usually an iron deficient state not associated with drug usage.

A clinical study is performed with subjects who are adults found to have anemia. Their clinical histories and laboratory findings are reviewed. It is observed that ingestion of a drug preceded development of the anemia in some of the subjects, but not in others. Which of the following conditions is most likely to be found in persons without a history of drug ingestion? A.G6PD deficiency B.Autoimmune hemolytic anemia C.Macrocytic anemia D.Aplastic anemia E.Microcytic anemia

C Decrease in splenic RBC sequestration and lysis In patients with hereditary spherocytosis, spheroidal cells are trapped and destroyed in the spleen because the abnormal RBCs have reduced deformability. Splenectomy is beneficial because the spherocytes are no longer detained by the spleen. Splenectomy has no effect on the synthesis of spectrin or RBC deformability; the RBCs in spherocytosis are not killed by opsonization. In warm antibody hemolytic anemias, opsonized RBCs are removed by the spleen. Reactive oxygen species do not play a role in anemias. Iron is not the rate-limiting step to RBC production when the iron can be recycled within the body.

A clinical study of patients who inherit mutations that reduce the level of ankyrin, the principal binding site for spectrin, in the RBC membrane cytoskeleton shows an increased prevalence of chronic anemia with splenomegaly. For many patients, it is observed that splenectomy reduces the severity of anemia. This beneficial effect of splenectomy is most likely related to which of the following processes? A Decrease in opsonization of RBCs and lysis in spleen B Decrease in production of reactive oxygen species by splenic macrophages C Decrease in splenic RBC sequestration and lysis D Increase in deformability of RBCs within splenic sinusoids E Increase in splenic storage of iron

D Reticulocytosis The acute blood loss, in this case intraperitoneal hemorrhage, results in a reticulocytosis from marrow stimulation by anemia. 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 if iron stores and diet are adequate. Leukoerythroblastosis is typical of a myelophthisic process in the marrow, with both immature WBCs (myelocytes) and RBCs (nucleated forms) present. Schistocytes suggest a microangiopathic hemolytic anemia, which can accompany shock or sepsis.

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 the peripheral blood? A Basophilic stippling of red cells B Hypochromic red cells C Leukoerythroblastosis D Reticulocytosis E Schistocytosis

Phosphatidylinositol glycan A (PIGA)

A mutation affecting which of the following gene products is most likely to give rise to Paroxysmal nocturnal hemoglobinuria (PNH)? A β-Globin chain B Factor V C Glucose-6-phosphate dehydrogenase D Phosphatidylinositol glycan A (PIGA) E Prothrombin G20210A F Spectrin

Folic acid deficiency Folic acid de! 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 megaloblastic transformation of hematopoietic cells. Macrocytosis and hypersegmented neutrophils are not features of the other choices. Diagnosis: Megaloblastic anemia

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 (results shown in the image). A Schilling test is normal. What is the most likely diagnosis? Anemia of Chronic Disease β-thalassemia Major β-thalassemia Minor Folate Deficiency Hemoglobin H Disease Hydrops Fetalis Iron Deficiency Anemia Pernicious anemia Sideroblastic Anemia Vitamin B12 Deficiency

D Plasmodium falciparum Throughout human history, malaria has influenced the increasing gene frequency of hemoglobin S. Individuals who are heterozygous for hemoglobin S have the sickle cell trait. They are more resistant to malaria, particularly the most malignant form caused by P. falciparum, because the parasites grow poorly or die at low oxygen concentrations, perhaps because of low potassium levels caused by potassium efflux from RBCs on hemoglobin sickling. The malarial parasite has difficulty completing its life cycle, even in cells with moderate amounts of hemoglobin S, as found in heterozygotes, giving a selective advantage to such persons living in endemic areas for falciparum malaria. Borrelia burgdorferi is the spirochete that causes Lyme disease. Clostridium perfringens may produce gas gangrene after soft-tissue injuries. Cryptococcus neoformans can cause granulomatous disease in immunocompromised individuals. Treponema pallidum is the infectious agent causing syphilis. Trypanosoma brucei infection causes sleeping sickness.

In an epidemiologic study of anemias, the findings show that there is an increased prevalence of anemia in individuals of West African ancestry. By hemoglobin electrophoresis, some individuals within this region have increased hemoglobin S levels. The same regions also have a high prevalence of an infectious disease. Which of the following infectious agents is most likely to be endemic in the region where such anemia shows increased prevalence? A Borrelia burgdorferi B Clostridium perfringens C Cryptococcus neoformans D Plasmodium falciparum E Treponema pallidum F Trypanosoma brucei

C.Rt count low, EPO high Explanation: A reduced reticulocyte count and elevated serum EPO are characteristic of aplastic anemia

In patients with aplastic anemia, what are the relative levels (reduced/elevated) of the reticulocyte count and EPO? A.Rt count low; EPO low B.Rt count normal, EPO normal C.Rt count low, EPO high D.Rt count high, EPO high

[↓] Serum Iron [↓] Serum Ferritin (Stored Form) [↓] Serum Hepcidin (Secreted from Liver when High Stored Iron) [↑] TIBC (Transferrin) (Secreted from Liver when Low Iron) [↓] % Transferrin Saturation [↑] Serum EPO [↑] Platelet Count

Iron Deficiency Anemia: [↑, ↓, or NC] Serum Iron [↑, ↓, or NC] Serum Ferritin [↑, ↓, or NC] Serum Hepcidin [↑, ↓, or NC] TIBC (Transferrin) [↑, ↓, or NC] % Transferrin Saturation [↑, ↓, or NC] Serum Erythropoietin [↑, ↓, or NC] Platelet Count

Beta-thalassemia trait

Iron deficiency Poor glycemic control Hepatitis C Sickle cell trait Diabetic nephropathy Beta-thalassemia trait

Chronic hemolysis

Portal hypertension Immune deficiency Erythropoietin deficiency Frequent transfusions Chronic hemolysis Iron deficiency Cyanocobalamin deficiency

A Decreased haptoglobin 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. Systemic lupus erythematosus (SLE) is an autoimmune disease that can result in hemolysis by means of autoantibodies directed at RBCs, and the Coombs test result is often positive. SLE is best known to afflict young women, but it has a broad age range.

During the past 6 months, a 25-year-old woman has noticed a malar skin rash that is made worse by sun exposure. She also has had arthralgias and myalgias. On physical examination, she 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 laboratory findings is most likely to be present? A Decreased haptoglobin B Decreased iron C Decreased reticulocytosis D Elevated D dimer E Elevated hemoglobin F F Elevated protoporphyrin

Aplastic anemia

Hairy cell leukemia Myelofibrosis Aplastic anemia Myelodysplastic syndrome Folic acid deficiency Acute lymphocyte leukemia Myelophthisic anemia

Erythropoietin Aplastic Anemia

Haptoglobin Erythropoietin Eosinophil count Reticulocyte index Iron Lactate dehydrogenase

CD34 Explanation: Hematopoietic progenitor cells universally express cluster of differentiation (CD) surface marker CD34

Hematopoietic progenitor cells universally express which cluster of differentiation (CD) surface marker? CD4 CD8 CD20 CD34 CD56

Occult blood loss

Hemolysis Drug abuse Liver disease poor nutrition Hematologic malignancy Occult blood loss

Hereditary erythrocyte enzyme deficiency

Hereditary erythrocyte enzyme deficiency Hereditary erythrocyte membrane defect Hemoglobin structure abnormality Antibody-mediated erythrocyte destruction Microangiopathic hemolytic anemia

F Spectrin cytoskeletal protein

Hereditary spherocytosis is an inherited abnormality in which of the following RBC components? A α-Globin chain B β-Globin chain C Carbonic anhydrase D Glucose-6-phosphate dehydrogenase E Heme with porphyrin ring F Spectrin cytoskeletal protein

β-thalassemia Intermedia This patient has β-thalassemia, probably of at least intermediate severity. There is decreased β-globin chain formation, with increased hemoglobin A2 and F to compensate. There is ineffective erythropoiesis and increased erythropoietin to drive increased iron absorption, leading to iron overload. Chronic anemia requiring transfusion therapy exacerbates hemochromatosis. Iron deposited in endocrine tissues can lead to gonadal, pituitary, thyroid, islet cell, and adrenal failure. Secondary hypersplenism can result from the splenomegaly, with sequestration of platelets and leukocytes.

A 17-year-old girl has had a history of fatigue and weakness for her entire life. She has not undergone puberty. On physical examination, secondary sex characteristics are not well developed. She has hepatosplenomegaly. CBC shows hemoglobin of 9.1 g/dL, hematocrit of 26.7%, MCV of 66 μm3, platelet count of 89,000/mm3, and WBC count of 3670/mm3. The appearance of the peripheral blood smear is shown in the figure. Additional laboratory findings include serum glucose of 144 mg/dL, TSH of 6.2 mU/mL, and ferritin of 679 ng/mL. What is the most likely diagnosis? Anemia of Chronic Disease β-thalassemia Major β-thalassemia Intermedia β-thalassemia Minor Folate Deficiency Hemoglobin H Disease Hydrops Fetalis Iron Deficiency Anemia Pernicious anemia Sideroblastic Anemia Vitamin B12 Deficiency

E Production of hemoglobin F 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 that promotes vasodilation. Because hemoglobin F levels remain high through the first 5 to 6 months of life, patients with sickle cell anemia typically do not manifest the disease during infancy. Because both β-globin chains are affected, no hemoglobin A1 is produced, and A2 levels are never high. Globin synthesis overall is not going to increase, and globin synthesis must be balanced to produce normal hemoglobin. The hemolysis associated with sickling promotes erythropoiesis, but the concentration of hemoglobin S is not changed. Hydroxyurea does not significantly shift the oxygen dissociation curve or change the oxygen affinity of the various hemoglobins.

A 12-year-old boy has a history of episodes of severe abdominal, chest, 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. An increase in which of the following is the most likely basis for its therapeutic efficacy? A Erythrocyte production B Overall globin chain synthesis C Oxygen affinity of hemoglobin D Production of hemoglobin A E Production of hemoglobin F

C Extensive RBC adhesion to endothelium The crescent-shaped RBCs (sickled RBCs) are characteristic of hemoglobin SS. This disease is most common in individuals of African and eastern Arabian descent. The sickled RBCs are susceptible to hemolysis (mainly vascular, in the spleen), but they also can cause microvascular occlusions anywhere in the body, most commonly bone, lungs, liver, and brain, leading to ischemia and severe pain. Vascular occlusions in the lungs are often accompanied by infection and lead to "acute chest syndrome." Abdominal pain and back pain are common and severe, requiring prompt and effective analgesia. The cell membranes of reversibly sickled cells are abnormally "sticky," and they adhere to capillary endothelium, especially in lungs. Vasoconstriction is caused by depletion of NO by free hemoglobin. Adhesion of RBCs to endothelium retards blood flow, creates hypoxia, and precipitates local sickling and vascular occlusion. Chronic tissue hypoxia does occur in sickle cell anemia, but it produces insidious impairment of function in organs such as heart, kidneys, and lungs. Defects in the alternative pathway of complement activation predispose to infection with encapsulated bacteria, such as Haemophilus influenzae and Streptococcus pneumoniae. Autoantibodies to alveolar basement membrane can be part of Goodpasture syndrome, which also affects kidneys. The most severe intravascular hemolysis occurs with major transfusion reactions.

A 13-year-old boy has the sudden onset of severe abdominal pain and cramping accompanied by chest pain, nonproductive cough, and fever. On physical examination, his temperature is 39° C, pulse is 110/min, respirations are 22/min, and blood pressure is 80/50 mm Hg. He has diffuse abdominal tenderness, but no masses or organomegaly. Laboratory studies show a hematocrit of 18%. The peripheral blood smear is shown in the figure. A chest radiograph shows bilateral pulmonary infiltrates. Which of the following is the most likely mechanism for initiation of his pulmonary problems? A Chronic hypoxia of the pulmonary parenchyma B Defects in the alternative pathway of complement activation C Extensive RBC adhesion to endothelium D Formation of autoantibodies to alveolar basement membrane E Intravascular antibody-induced hemolysis

B.Beta-thalassemia Explanation: Reduced beta-globin chain synthesis from beta-thalassemia leads to RBC microcytosis, hypochromia, ineffective erythropoiesis, and excessive iron absorption.

A 16-year-old boy has had a low energy level for as long as he can remember. On physical examination he has a palpable spleen tip. A CBC shows Hgb of 8.8 g/dL, Hct 24.1%, MCV 65 fL, platelet count 187,000/microliter, and WBC count 7400/microliter. His serum ferritin is 3740 ng/mL. A bone marrow biopsy is performed and on microscopic examination reveals a myeloid:erythroid ratio of 1:4, and there is 4+ stainable iron. Which of the following is the most likely diagnosis? A.G6PD deficiency B.Beta-thalassemia C.Sickle cell anemia D.Iron Deficient anemia E.Anemia of chronic disease

Paroxysmal Nocturnal Hemoglobinuria (PNH) - Phosphatidylinositol glycan A (PIGA) gene mutation Paroxysmal nocturnal hemoglobinuria (PNH) is a disorder that results from an acquired stem cell membrane defect produced by a PIGA gene mutation that 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, so 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 PNH may develop acute leukemia or aplastic anemia as complications.

A 16-year-old boy notes passage of dark urine. 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. Which of the following is the most likely diagnosis? A. Aplastic Anemia B. G6PD Deficiency C. Hemoglobin C D. Hemolytic Disease of the Newborn E. Hereditary Spherocytosis/Elliptocytosis F. Sickle Cell Anemia G. Sickle Cell Trait H. Malaria I. Myelophthisic Anemia J. Cold Agglutinins Immune hemolytic anemia K. Warm Agglutinins Immune hemolytic anemia L. Paroxysmal Nocturnal Hemoglobinuria (PNH) M. Microangiopathic/Thrombotic Hemolytic Anemia

Sickle cell trait

A 17-year-old African American man comes to the physician after an episode of gross hematuria that resolved spontaneously. He has no other complaints. His past medical history is insignificant. He takes no medications. He smokes occasionally. He does not use drugs or alcohol. His temperature is 36° C (98°F), blood pressure is 120/70 mm Hg, pulse is 70/min, and respirations are 14/min. Physical examination shows no abnormalities. Urinalysis shows many unchanged red blood cells/HPF but is otherwise normal. Laboratory studies show a creatinine level of 0.9 mg/dL . Which of the following is the most likely diagnosis? A. Aplastic Anemia B. G6PD Deficiency C. Hemoglobin C D. Hemolytic Disease of the Newborn E. Hereditary Spherocytosis/Elliptocytosis F. Sickle Cell Anemia G. Sickle Cell Trait H. Malaria I. Myelophthisic Anemia J. Cold Agglutinins Immune hemolytic anemia K. Warm Agglutinins Immune hemolytic anemia L. Paroxysmal Nocturnal Hemoglobinuria (PNH) M. Microangiopathic/Thrombotic Hemolytic Anemia

Hereditary Spherocytosis/Elliptocytosis

A 20-year-old immigrant from Eastern Europe comes to the emergency department with intermittent right upper-quadrant pain for the last 2 months. His past medical history is unremarkable and he considers himself healthy. His mother had "her gallbladder removed" at a young age. His abdominal ultrasound shows cholelithiasis. Laboratory results show hemoglobin of 10.2 g'/dL. Peripheral blood smear is shown in the image below. Which of the following is the most likely diagnosis? A. Aplastic Anemia B. G6PD Deficiency C. Hemoglobin C D. Hemolytic Disease of the Newborn E. Hereditary Spherocytosis/Elliptocytosis F. Sickle Cell Anemia G. Sickle Cell Trait H. Malaria I. Myelophthisic Anemia J. Cold Agglutinins Immune hemolytic anemia K. Warm Agglutinins Immune hemolytic anemia L. Paroxysmal Nocturnal Hemoglobinuria (PNH) M. Microangiopathic/Thrombotic Hemolytic Anemia

E Vitamin B12 deficiency The high MCV indicates a marked macrocytosis, greater than expected from 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 complexed with intrinsic factor is absorbed in the terminal ileum, its removal can cause vitamin B12 deficiency. Anemia of chronic disease is generally a normocytic anemia. Chronic blood loss and iron deficiency produce a microcytic pattern of anemia, as does dietary iron deficiency. Hemolytic anemia is unlikely several weeks after blood transfusion. 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 37-year-old woman 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 disease. She does not respond to medical therapy, and part of the colon and terminal ileum are removed. She is transfused with 2 U of packed RBCs during surgery. Three 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 hematologic findings? A Anemia of chronic disease B Chronic blood loss C Hemolytic anemia D Myelophthisic anemia E Vitamin B12 deficiency

Anemia of Chronic Disease 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 lead to increased hepatic production of hepcidin that stops ferroportin from releasing storage iron, promoting 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 and reduced hepcidin production.

A 39-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, 10.0 g/dL; hematocrit, 30.3%; MCV, 91 μm3; platelet count, 240,000/mm3; WBC count, 7550/mm3; serum iron 80 μg/dL; total iron-binding capacity, 145 μg/dL; and serum ferritin, 565 ng/mL. Serum erythropoetin levels are low for the level of Hb and hepcidin levels are elevated. What is the most likely diagnosis? Anemia of Chronic Disease β-thalassemia Major β-thalassemia Minor Folate Deficiency Hemoglobin H Disease Hydrops Fetalis Iron Deficiency Anemia Pernicious anemia Sideroblastic Anemia Vitamin B12 Deficiency

Paroxysmal nocturnal hemoglobinuria Despite its name, the disorder is nocturnal in only a minority of cases. PNH is a clonal stem cell disorder characterized by episodic intravascular hemolytic anemia that is secondary to increased sensitivity of erythrocytes to complement- mediated lysis. The underlying defect involves somatic mutation of the phosphatidylinositol glycan-class A (PIG-A) gene. PNH may develop as a primary disorder or evolve from preexisting cases of aplastic anemia. During hemolytic episodes, patients develop normocytic or macrocytic anemia, accompanied by an appropriate reticulocyte response. The traditional diagnostic tests for PNH, hemolysis in sucrose (sucrose hemolysis test) or acidifi ed serum (Ham test), are now more easily diagnosed by demonstrating loss of GPI-anchored proteins on blood cells by fl ow cytofl uorometry. Choices B and C, which are hemolytic conditions, do not show increased lysis in the described laboratory studies.

A 39-year-old man reports seeing red-colored urine in the morning. The CBC reveals anemia, low serum iron, and an elevated reticulocyte count. Laboratory studies show increased lysis of erythrocytes when incubated with either sucrose or acidified serum. Which of the following is the most likely diagnosis? A. Aplastic Anemia B. G6PD Deficiency C. Hemoglobin C D. Hemolytic Disease of the Newborn E. Hereditary Spherocytosis/Elliptocytosis F. Sickle Cell Anemia G. Sickle Cell Trait H. Malaria I. Myelophthisic Anemia J. Cold Agglutinins Immune hemolytic anemia K. Warm Agglutinins Immune hemolytic anemia L. Paroxysmal Nocturnal Hemoglobinuria (PNH) M. Microangiopathic/Thrombotic Hemolytic Anemia

Hypercellularity with megaloblastic erythroid maturation Diagnosis: Megaloblastic anemia, pernicious anemia Hypercellularity with megaloblastic erythroid maturation. Pernicious anemia is an autoimmune disorder in which patients develop antibodies directed against gastric parietal cells and intrinsic factor. Parietal cell antibodies lead to atrophic gastritis with achlorhydria. Defi ciency of vitamin B12 or folic acid results in megaloblastic anemia. The peripheral blood smear shows macrocytosis and hypersegmentation of neutrophils. Megaloblastic maturation, characterized by cellular enlargement with asynchronous maturation between the nucleus and cytoplasm, is noted in bone marrow precursors from all lineages. Although the bone marrow tends to be hypercellular, the blood demonstrates pancytopenia because of ineffective hematopoiesis. Neurologic symptoms develop in vitamin B12 defi ciency, secondary to degeneration of the posterior and lateral columns of the spinal cord. The other choices are not seen in pernicious anemia.

A 43-year-old woman of Scandinavian descent complains of constant tiredness, light-headedness, and occasional palpitations and shortness of breath while ascending the stairs. Physical examination shows pallor of the oral mucosa and a raspberry-red tongue (glossitis). Neurologic examination reveals paresthesias, numbness, decreased vibration sensation, and loss of deep tendon reflexes. The results of laboratory studies include hemoglobin of 7.2 g/dL, WBC of 4,500/mL, platelets of 140,000/mL, erythrocyte folate of 220 ng/mL, serum vitamin B12 of 40 pg/mL (normal >200 pg/mL), serum anti-intrinsic factor of 1:128, and serum anti-parietal cell antibody of 1:64. Examination of peripheral blood shows macrocytic anemia, with poikilocytosis of RBCs and hypersegmented neutrophils. Atrophic gastritis is diagnosed by gastric biopsy. Bone marrow examination in this patient will reveal which of the following pathologic findings? Atypical megakaryocytes with fibrosis Myeloid hyperplasia with increased basophils Hypocellularity with absence of erythroid precursors Hypercellularity with megaloblastic erythroid maturation Absent stainable bone marrow iron

Impaired DNA synthesis Diagnosis: Megaloblastic anemia Impaired DNA synthesis. Megaloblastic anemias are caused by impaired DNA synthesis, usually due to a deficiency of either vitamin B12 or folic acid. In the face of defective DNA synthesis, nuclear development is impaired, whereas cytoplasmic maturation proceeds normally. This situation, termed nuclear to cytoplasmic asynchrony, results in the formation of megaloblasts. Because the megaloblastic precursors do not mature enough to be released into the blood, they undergo intramedullary destruction. Pernicious anemia is not related to any of the other choices.

A 43-year-old woman of Scandinavian descent complains of constant tiredness, light-headedness, and occasional palpitations and shortness of breath while ascending the stairs. Physical examination shows pallor of the oral mucosa and a raspberry-red tongue (glossitis). Neurologic examination reveals paresthesias, numbness, decreased vibration sensation, and loss of deep tendon reflexes. The results of laboratory studies include hemoglobin of 7.2 g/dL, WBC of 4,500/mL, platelets of 140,000/mL, erythrocyte folate of 220 ng/mL, serum vitamin B12 of 40 pg/mL (normal >200 pg/mL), serum anti-intrinsic factor of 1:128, and serum anti-parietal cell antibody of 1:64. Examination of peripheral blood shows macrocytic anemia, with poikilocytosis of RBCs and hypersegmented neutrophils. Atrophic gastritis is diagnosed by gastric biopsy. Which of the following mechanisms of disease best describes the pathogenesis of anemia in the patient? Defective heme synthesis Clonal stem cell abnormality Bone marrow fibrosis Impaired DNA synthesis Immune destruction of circulating erythrocytes

Monocytes Megakaryocytes Dendritic cells (Both Myeloid & Lymphoid Precursors) Granulocytic leukocytes (e.g. neutrophils, basophils, eosinophils, mast cells) Erythrocytes Lymphoid Precursors: Dendritic cells (Both Myeloid & Lymphoid Precursors) B-Lymphocytes T-Lymphocytes NK-cells

Select all of the types of hematopoietic cells are derived from the common myeloid progenitor (CMP): Monocytes Megakaryocytes Dendritic cells B-Lymphocytes T-Lymphocytes NK-cells Granulocytic leukocytes (e.g. neutrophils, basophils, eosinophils, mast cells) Erythrocytes

[↑] Serum Iron [↑] Serum Ferritin (Stored Form) [↑] Serum Hepcidin (Secreted from Liver when High Stored Iron) [↓] TIBC (Transferrin) (Secreted from Liver when Low Iron) [↑, ↓, or NC] % Transferrin Saturation???

Sideroblastic Anemia: [↑, ↓, or NC] Serum Iron [↑, ↓, or NC] Serum Ferritin [↑, ↓, or NC] Serum Hepcidin [↑, ↓, or NC] TIBC (Transferrin) [↑, ↓, or NC] % Transferrin Saturation

C Splice site This is one mechanism for β+ thalassemia. Because the introns are usually involved, the flanking exons remain, and some normal splicing can occur, so that some β-globin chain synthesis can occur, but not sufficient for adequate hemoglobin production. The other listed mutations lead to a block in translation, with no functional β-globin chain synthesis, typical for β0 thalassemia.

Since childhood, a 30-year-old man has been easily fatigued with minimal exercise. Laboratory studies show hypochromic microcytic anemia. Hemoglobin electrophoresis reveals decreased Hgb A1 with increased Hgb A2 and Hgb F. His serum ferritin is markedly increased. Which of the following mutations is most likely to be present in the β-globin gene of this man? A New stop codon B Single base insertion, with frameshift C Splice site D Three-base deletion E Trinucleotide repeat

Kidneys

Spleen Bone marrow Liver Lungs Brain Kidneys