Congenital and Aquired Hemolytic Anemias Questions

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    Congenital and Acquired Hemolytic Anemias

    2002

    Ware

    1. A four year old Caucasian male is referred to you for jaundice and possiblehemolytic anemia. The referring pediatrician says that the child has always

    had mild scleral icterus and now has a palpable spleen. Recent laboratorystudies include the following: hemoglobin concentration = 9.8 gm/dL;

    absolute reticulocyte count = 313 x 109/L; total bilirubin = 4.0 mg/dL (direct

    fraction = 0.4 mg/dL, indirect fraction = 3.6 mg/dL). A hemoglobin

    electrophoresis on cellulose acetate shows predominantly hemoglobin A but

    several additional faint bands that could not be identified. Which of thefollowing tests would be the most informative?

    A. Osmotic fragility testing

    B. Hemoglobin electrophoresis on acid citrateC. Autohemolysis testing

    D.

    Heinz body preparationE. Quantitative G6PD assay

    2. A ten week old African American male is referred to you for evaluation and

    management of an abnormal FS newborn hemoglobinopathy screen. Familytesting reveals that the father has HbAS, while the mother has only HbA. You

    repeat the infants studies and the lab now reports an FSA pattern on

    hemoglobin electrophoresis. The most likely diagnosis that explains this

    infants laboratory studies is:

    A.Non-paternity

    B.

    +

    thalassemiaC.0thalassemia

    D. Sickle cell trait

    E. Sickle cell anemia

    3. A nine year old Caucasian female is referred to you for evaluation of anemia

    found on a routine physical examination. She is active and the fastest person

    on her soccer team. Your exam reveals mild icterus, a palpable spleen 2 cmbelow the left costal margin, and the following laboratory studies:

    hemoglobin concentration = 8.8 gm/dL; reticulocyte count = 423 x 109/L;

    MCV = 91 fL. On peripheral blood smear you note polychromasia, with

    several echinocytes and an occasional spherocyte. There is no family historyof blood dyscrasia. The most likely diagnosis is:

    A. Congenital spherocytosis from a spontaneous mutationB. 5 nucleotidase deficiency

    C. G6PD deficiency with extreme lyonization

    D. Hereditary elliptocytosis

    E. Pyruvate kinase deficiency

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    A.

    Hemoglobin H disease that warrants a prompt appointment for transfusion

    therapy

    B. Hemoglobin H disease that needs no further follow-up

    C.D. t needs education and counseling only

    E.

    7. A previously healthy 16 year old Caucasian male is referred to you forevaluation of abnormal laboratory studies. He is an active football player who

    was evaluated for a pre-sports physical. Review of systems reveals only

    occasional abdominal pain. The abnormal laboratory studies include:hemoglobin concentration = 9.9 gm/dL; MCV = 104 fL; reticulocyte count =

    117 x 109/L; WBC = 3.0 with 26% polys, 58% lymphs, 15% monocytes, and

    1% eosinophil. The platelet count is 119 x 109/L. Urinalysis specific gravity

    = 1.009, pH = 6.5, 2+ blood on dipstick, occasional casts but no RBCs orWBCs on microscopic analysis. The best diagnostic test to order is which of

    the following:

    A. CD59 testing on erythrocytes

    B. Hepatitis B serologies

    C. Direct platelet antibody measurementD. Erythrocyte adenosine deaminase activity

    E. Direct antiglobulin test

    8. A six week old Pakistani male is referred to you for evaluation of an abnormalHbF only result on newborn hemoglobinopathy screening. The infant

    appears healthy, and the only abnormality you detect on physician

    examination is a palpable spleen tip 1-2 cm below the left costal margin. Theinfants hemoglobin concentration is 9.5 gm/dL. Repeat hemoglobinelectrophoresis confirms HbF only. The mothers electrophoresis reveals

    HbA with 6.1% HbA2, but the father is unavailable for testing. The most

    likely diagnosis is:

    A.

    B.C. assemia

    D.

    E.

    9. 2 2) has a decreased affinity for oxygen in

    which of the following settings?

    A. Carbon monoxide intoxication

    B. Exposure to sulfa drugs

    C. Increased 2,3 DPG

    D. MethemoglobinemiaE. Alkalosis

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    10.

    You are called by a local pediatrician regarding a five year old African-

    American male with recurrent otitis media. The physician is currently treating

    him for his fourth episode of otitis media over the past 6 months. The doctor

    would like to prescribe trimethoprim/sulfamethoxazole prophylaxis, but isunsure about its safety since the G6PD status of the child is unknown. Which

    of the following responses is correct?

    A. All African-American children should be tested for G6PD activity beforeinitiating sulfa therapy

    B. African-American males and females should be tested if there is a family

    history of hemolysis after sulfa exposureC. Only African-American males should be tested before using sulfa

    D.No testing is warranted since the African-American variant of G6PD is

    relatively mild

    E. No testing is warranted since measurement of G6PD activity does notpredict hemolysis

    11. Hemoglobin Constant Spring is best described as which of the following:

    A. -chain variant with a 2 kb DNA deletion

    B. -chain variant with a point mutation in the promoterC. -chain variant with a point mutation at the stop codon

    D. -

    E. -chain variant with increased HbF levels

    12. Hemoglobin E is best described as which of the following:

    A.

    Thalassemia found in Southeast AsiaB. Thalassemia found in Mediterranean regionsC. Hemoglobinopathy found in Southeast Asia

    D. Hemoglobinopathy found in Mediterranean regions

    E. Thalassemic hemoglobinopathy

    13. What is the0thalassemia trait?

    A. Hb F on newborn hemoglobinopathy screening

    B. Hb A2on newborn hemoglobinopathy screening

    C. Hb Barts on newborn hemoglobinopathy screening

    D.

    Hb A2after one year of lifeE.

    Hb Barts after one year of life

    14. Compared to normal erythrocytes, spherocytes have:A. Increased osmotic fragility at all saline concentrations

    B. Increased osmotic fragility at 0.5% saline

    C. Decreased osmotic fragility at 0.9% saline

    D. Increased levels of 2,3 DPGE. More Howell-Jolly bodies

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    15. Hemoglobin H is most commonly present in which of the following

    situations?

    A.

    B.C.

    D.

    0 +

    thalassemia intermediaE.

    16. In the deoxygenated state, the mutation in sickle hemoglobin primarily affects

    which of the following interactions?

    A.

    B.

    C. Hemoglobin tetramer to Hemoglobin tetramer

    D. Heme ring to hemoglobinE. Erythrocyte to erythrocyte

    2004

    WareA ten week old African American male is referred for evaluation and management of

    an abnormal FS newborn hemoglobinopathy screen. Family testing reveals that thefather has HbAS, while the mother has only HbA. You repeat the infants studies and

    the lab now reports an FSA pattern on hemoglobin electrophoresis. The most likely

    diagnosis for this infant that explains these laboratory studies is:

    A.Non-paternity

    B.+thalassemia

    C.

    0

    thalassemiaD. Sickle cell traitE. Sickle cell anemia

    2. A six week old Pakistani male is referred to you for evaluation of an abnormal HbF

    only result on newborn hemoglobinopathy screening. The infant appears healthy,and the only abnormality you detect on physician examination is a palpable spleen tip

    1-2 cm below the left costal margin. The infants hemoglobin concentration is 9.5

    gm/dL. Repeat hemoglobin electrophoresis confirms HbF only. The mothers

    electrophoresis reveals HbA with 6.1% HbA2, but the father is currently unavailablefor testing. The most likely diagnosis is:

    A.B.

    C.

    D.

    E.

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    3. 2 2) has a decreased affinity for oxygen in which of the

    following settings?

    A. Carbon monoxide intoxication

    B.

    Exposure to sulfa drugsC. Increased 2,3 DPG

    D. MethemoglobinemiaE. Alkalosis

    4. A pediatrician calls you for telephone advice about a 26 month old African-American

    male with microcytic hypochromic anemia. The anemia was detected on routinescreening at one year of life, and intermittent trials of oral iron supplementation have

    not improved the blood counts. Latest laboratory evaluation reveals hemoglobinconcentration = 9.7 gm/dL; MCV = 66 fL; reticulocyte count = 80 x 109/L. The

    hemoglobin electrophoresis shows only normal HbA and the serum ferritin = 51

    ng/ml. Review of the newborn hemoglobinopathy screen reveals an FA pattern and a

    fast band. The most likely diagnosis and follow-up is:

    A. rants a prompt appointment for

    transfusion therapy

    B. -upC.

    D.

    E.

    On

    5. Hemoglobin Constant Spring is best described as which of the following:

    A. -chain variant with a 2 kb DNA deletion

    B. -chain variant with a point mutation in the promoterC. -chain variant with a point mutation at the stop codon

    D. -

    E. -chain variant with increased HbF levels

    6. Homozygous Hemoglobin E is best described as which of the following:

    A. Thalassemia found in Southeast Asia

    B. Thalassemia found in Mediterranean regions

    C. Hemoglobinopathy found in Southeast AsiaD. Hemoglobinopathy found in Mediterranean regions

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    E. Thalassemic hemoglobinopathy

    7.0thalassemia trait?

    A.

    Hb F on newborn hemoglobinopathy screeningB. Hb A2on newborn hemoglobinopathy screening

    C. Hb Barts on newborn hemoglobinopathy screeningD. Elevated Hb A2after one year of life

    E. Presence of Hb Barts after one year of life

    8. Hemoglobin H is most easily identified in which of the following situations?A. 3-g

    B.

    C.D.

    0 +thalassemia intermedia

    E.

    9. In the deoxygenated state, the mutation in sickle hemoglobin primarily affects which

    of the following interactions?

    A.

    B.

    C. Hemoglobin tetramer to Hemoglobin tetramerD. Heme ring to hemoglobin

    E. Erythrocyte to erythrocyte

    ANSWER KEY:

    1. B

    2. A

    3. C4. D

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    5. C6. E

    7. D

    8. A

    9. C

    Questions for Pediatric Hematology/Oncology Board Review 2004

    Hemolytic Anemia Russell E. Ware, MD, PhD

    1. A four year old Caucasian male is referred for jaundice and possible hemolyticanemia. The referring pediatrician says that the child has always had mild scleralicterus and now has a palpable spleen. Recent laboratory studies include the

    following: hemoglobin concentration = 9.8 gm/dL; absolute reticulocyte count = 313

    x 109/L; total bilirubin = 4.0 mg/dL (direct fraction = 0.4 mg/dL, indirect fraction =

    3.6 mg/dL). A hemoglobin electrophoresis on cellulose acetate shows predominantly

    hemoglobin A but several additional faint bands that could not be identified. Which

    of the following tests would be the most informative?

    A. Osmotic fragility testing

    B. Hemoglobin electrophoresis on acid citrate

    C.

    Autohemolysis testingD. Heinz body preparationE. Quantitative G6PD assay

    2. A nine year old Caucasian female is referred for evaluation of anemia found on a

    routine physical examination. She is active and the fastest person on her soccer team.Your exam reveals mild icterus, a palpable spleen 2 cm below the left costal margin,

    and the following laboratory studies: hemoglobin concentration = 8.8 gm/dL;

    reticulocyte count = 423 x 109/L; MCV = 91 fL. On peripheral blood smear you note

    polychromasia, with several echinocytes and an occasional spherocyte. There is noknown family history of blood dyscrasia. The most likely diagnosis is:

    A. Congenital spherocytosisB. 5 nucleotidase deficiency

    C. G6PD deficiency with extreme lyonization

    D. Hereditary elliptocytosis

    E. Pyruvate kinase deficiency

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    3. Compared to normal erythrocytes, spherocytes have:

    A. Increased osmotic fragility at all saline concentrationsB. Increased osmotic fragility at 0.5% saline

    C.

    Decreased osmotic fragility at 0.9% salineD. Increased levels of 2,3 DPG

    E. More Howell-Jolly bodies

    4. You are called by a local pediatrician regarding a five year old African-American

    male with recurrent otitis media. The physician is currently treating him for his

    fourth episode of otitis media over the past 6 months. The doctor would like to

    prescribe trimethoprim/sulfamethoxazole prophylaxis, but is unsure about its safetysince the G6PD status of the child is unknown. Which of the following responses is

    correct?

    A. All African-American children should be tested for G6PD activity before

    initiating sulfa therapy

    B. African-American males and females should be tested if there is a familyhistory of hemolysis after sulfa exposure

    C. Routine testing is not warranted since the African-American variant of

    G6PD is relatively mild

    D. Only African-American males should be tested before using sulfaE. No testing is warranted since measurement of G6PD activity does not

    predict hemolysis

    5. A previously well three year old Caucasian male presents with pallor, fatigue, and

    dark urine. One day earlier, he was evaluated by his local pediatrician whoprescribed amoxicillin for a possible urinary tract infection, based on dark amber

    urine and a urine dipstick with 3+ blood. At your evaluation, you learn that the child

    has not been on any other medications and there is no family history of blooddisorders. His exam shows pallor, minimal scleral icterus, and no

    hepatosplenomegaly. Hemoglobin concentration = 5.5 gm/dL; reticulocyte count =

    178 x 109/L; WBC = 12.1 x 10

    9/L with a left shift; platelets = 291 x 10

    9/L. The urine

    is reddish brown with 2+ protein and 4+ blood on dipstick, and 3 RBCs and 3WBCs per high power field on microscopic analysis. You suspect an autoimmune

    hemolytic process as the etiology for this sudden-onsent hemoglobinuria, but the

    direct antiglobulin test (DAT) performed at room temperature is negative. To test thischild for a Donath-Landsteiner antibody, you would need to do which of the

    following:

    A. Collect the blood at 37oC and repeat the DAT at 37

    oC

    B. Collect the blood at 37oC; incubate serum and cells at 4

    oC, then 37

    oC

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    C. Repeat the DAT at 4oC

    D.

    Collect the blood at 4oC and repeat the DAT at 37

    oC

    E. Collect the blood at 37oC, then test the serum at 37

    oC in an indirect

    antiglobulin test

    6. A term 3.1 kilogram Hispanic female infant is noted to have jaundice at 18 hours of

    life. The mothers blood group is A+ and the babys is O+; the infants DAT isnegative. Laboratory evaluation on the baby reveals the following: hemoglobin =

    14.9 gm/dL; total bilirubin = 15 mg/dL (all indirect). The peripheral blood smear

    shows numerous spherocytes. The infant does well with phototherapy and supportivecare, and is discharged home at 4 days of life. Three weeks later, the infant is

    thriving with a hemoglobin concentration of 13.4 gm/dL and total bilirubin

    concentration of 3.1 mg/dL. What is the best diagnostic test to help establish the

    etiology of this infants hemolysis?

    A.

    Repeat DAT on the infants RBCsB. Screening of the maternal serum for RBC antibodiesC. Tagged RBC study

    D. Osmotic fragility testing at 1 month of life

    E. Osmotic fragility testing at 6-12 months of life

    7. A previously healthy 16 year old Caucasian male is referred to you for evaluation of

    abnormal laboratory studies. He is an active football player who was evaluated for apre-sports physical. Review of systems reveals only occasional abdominal pain. The

    abnormal laboratory studies include: hemoglobin concentration = 9.9 gm/dL; MCV =

    104 fL; reticulocyte count = 117 x 10

    9

    /L; WBC = 3.0 with 26% polys, 58% lymphs,15% monocytes, and 1% eosinophil. The platelet count is 119 x 109/L. Urinalysis

    specific gravity = 1.009, pH = 6.5, 2+ blood on dipstick, occasional casts but no

    RBCs or WBCs on microscopic analysis. Which of the following diagnostic test

    would be reasonable to order next:

    A. CD59 testing on erythrocytes

    B. Hepatitis B serologiesC. Direct platelet antibody measurement

    D. Erythrocyte adenosine deaminase activity

    E. Direct antiglobulin test

    ANSWER KEY:

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    1. D

    2. E

    3. B

    4. C5. B

    6. E7. A

    2006

    Zimmerman

    1. Which of the following improves oxygen delivery to tissues?

    a. Increased concentration of fetal hemoglobinb. Increased production of 2,3-DPG

    c. Increased pHd. Hypothermiae. Methemoglobinemia

    ANSWER: bFetal hemoglobin binds less 2,3-DPG than adult hemoglobin, thus effectively shifting the

    oxygen dissociation curve to the left. This provides an advantage in utero for shunting

    oxygen from the mother to fetus. This left shift of the oxygen dissociation curve results

    in tighter binding of oxygen and decreased tissue oxygen delivery. Shifting the oxygendissociation curve to the right such that at a given pO2, the hemoglobin is less saturated

    results in increased tissue oxygen delivery. The curve is right shifted by increased

    temperature, increased production of 2,3-DPG in the Rapoport Luebering shunt, byincreased acid production (decreased pH). Methemoglobin is the derivative ofhemoglobin in which the iron is oxidized from the ferrous (2+) to ferric (3+) state, which

    leads to left shift in the oxygen dissociation curve with increased oxygen affinity and thus

    decreased oxygen delivery.

    2. A previously healthy 6 year old girl presents to her local physician with complaint of

    pallor, fatigue, and yellow eyes following a viral infection 10 days ago. Her exam isremarkable for scleral icterus, mild tachycardia, a II/VI systolic ejection murmur, and a

    spleen palpable at the left costal margin. Complete blood count reveals a hemoglobin of

    6.1 gm/dL, MCV of 104fL, WBC of 20K, and platelet count of 460K. There is no family

    history of anemia and she had a normal CBC just before starting kindergarten last year.Her blood smear is shown:

    Which of the following would be the most appropriate treatment?

    a. Plasmapheresis

    b. Transfusion of 1 unit of PRBCs immediately

    c. Rituximab, 375 mg/m2 weekly times 4 weeks

    d. Prednisone, 2 mg/kg/day POe. IVIG 0.4 mg/kg IV x 5 days

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    ANSWER: d Based on the history and peripheral blood smear, this patient most likelyhas autoimmune hemolytic anemia, likely related to her recent viral illness. The Direct

    Antiglobulin test would likely be positive with the polyspecific serum as well as anti-IgG.Some warm reactive erythrocyte autoantibodies also fix complement, however. Although

    she is mildly tachycardic, she does not have a gallop and has an acceptable hemoglobinconcentration. Steroids, then provide the most appropriate treatment for her, reserving

    the use of PRBCs for worsening anemia or increased symptoms. IVIG is not generally

    useful for the treatment of AIHA. Plasmapheresis is most helpful for IgM mediateddiseases, and only for severe, refractory IgG mediated diseases when a brief response is

    needed. Although there have been case reports of success using Rituximab for refractory

    AIHA, it is not first line therapy and would therefore not be appropriate in this scenario.

    3. Which of the following enzyme disorders is associated with neurological symptoms?

    a. Pyruvate kinase deficiencyb. Glucose-6-Phosphate dehydrogenase deficiency

    c. Triose phosphate isomerase deficiency

    d. Pyrimidine 5-nucleotidase deficiencye. Hexokinase deficiency

    ANSWER: c. Triose phosphate isomerase (TPI) is an enzyme in the Embden-Myerhof

    pathway, catalyzing the interconversion of glyceraldehyde-3-phosphate and DHAP(dihydroxyacetone phosphate). Deficiency of TPI is a rare autosomal disorder,

    characterized by hemolytic anemia, neonatal hyperbilirubinemia, progressive

    neurological dysfunction, increased susceptibility to infection, and cardiomyopathy.Pyruvate kinase converts phosphoenolpyruvate to pyruvate in the glycolytic pathway.PK deficiency is the most common cause of hemolytic anemia due to defective glycolysis

    and is inherited as an autosomal recessive disorder. Glucose-6-phosphate dehydrogenase

    deficiency is inherited as an X-linked disorder and is necessary for the production ofNADPH in the Hexose Monophosphate Shunt. NADPH is used for production of

    glutathione which helps to prevent oxidative damage to erythrocytes. Pyrimidine-5-

    nucleotidase participates in RNA degradation in reticulocytes. Deficiency of pyrimidine-5-nucleotidase is inherited in an autosomal recessive manner and is associated with the

    presence of basophilic stippling in the erythrocytes. Lead is also a powerful inhibitor of

    pyrimidine-5-nucleotidase, and is also associated with basophilic stippling on the

    peripheral smear. Hexokinase deficiency is a rare autosomal recessive disorderassociated with variable degrees of hemolysis.

    4. Which of the following relationships is incorrect?a. Howell-Jolly bodies Sickle Cell Anemia

    b. Heinz bodies Glucose-6-phosphate dehydrogenase Deficiency

    c. Basophilic stippling Pyrimidine-5nucleotidase Deficiency

    d. Pappenheimer bodies Hemoglobin Klne. Ring forms Malaria

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    ANSWER: d. Howell Jolly bodies are nuclear remnants that are seen most

    commonly in patients with congenital, surgical, or functional asplenia, as seen in

    patients with sickle cell anemia, usually by 2 years of age. Heinz bodies occur whenhemoglobin precipitates, damaging the red cell membrane and can be visualized

    following supravital stain with methyl violet. They are present in disorders ofunstable hemoglobin, G6PD deficiency, and Hemoglobin H disease (3 gene deletionalpha thalassemia). Basophilic stippling reflects residual RNA in the erythrocyte and

    can be seen in patients with lead toxicity, thalassemia (or any other ineffective

    erythropoiesis), and Pyrimidine-5-nucleotidase deficiency. Pappenheimer bodies arecomposed of degenerating cellular remnants which contain iron and are most likely

    related to accelerated red cell division, or impaired hemoglobin synthesis. They can

    be seen in patients with severe anemia, with thalassemia, and status post splenectomy

    in otherwise normal individuals. Hb Kln is an unstable hemoglobin, so would bemost likely to lead to formation of Heinz bodies, not Pappenheimer bodies. Ring

    forms are the trophozoites that can be seen as erythrocyte inclusions in association

    with malaria.

    5. A 4 year old boy is referred to a Gastroenterologist for evaluation of persistent

    jaundice. The family reports that the boy had neonatal jaundice in the first day of life,

    treated with phototherapy. He has always had mild scleral icterus, but recently theynoted it to be a bit more prominent, prompting the GI evaluation. The laboratory

    evaluation reveals a Total bilirubin of 1.7 mg/dL, AST of 65 IU/L, ALT of 30 IU/L,

    Hemoglobin of 11.2 gm/dL, MCV of 84 fL, MCHC of 36.5%, and reticulocyte count

    of 230,000 (6%). Urinalysis is negative. There is no family history of anemia,

    gallstones, or splenomegaly. The Gastroenterologist calls you for assistance indetermining which test to order next?

    a. Autohemolysis

    b Indirect antiglobulin test

    c. Osmotic fragility testingd. PNH screen

    e. Heinz body preparation

    ANSWER: c. Based on the history and laboratory results, this patient most likely

    has Hereditary Spherocytosis, which would be diagnosed with Osmotic Fragility

    testing. Patients with HS often have a history of neonatal jaundice, occurring usuallyin the first 24 hours of life. They may have exaggerated and prolonged jaundice aswell. Often there is a family history of anemia, early gallstones, or splenectomy, but

    lack of a family history does not eliminate this diagnosis, since approximately of

    patients will have either an autosomal recessive form of HS or a spontaneousmutation. An MCHC > 36% is also very suggestive (almost diagnostic) of

    spheroctyosis. Osmotic fragility testing is helpful since erythrocytes from patients

    with HS are more sensitive to lysis under osmotic stresses. Caution must be taken in

    interpreting the results in patients under 6-12 months of age since the macrocytosis of

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    infants may lead to falsely normal results. The autohemolysis test is most useful indetection of RBC enzyme disorders. Indirect antiglobulin test would not be useful in

    this case since it is used to detect antibodies circulating in the serum of the individual.

    It is important to be sure the Direct Antiglobulin Test is negative before performing

    osmotic fragility testing, since spherocytes from any cause, including autoimmunehemolytic anemia, will demonstrate increased sensitivity to osmotic stress. In this

    case, however, given the history since birth, acquired AIHA is not very likely. Thehistory and laboratory parameters are not typical of PNH, thus the PNH screen is less

    likely to be useful. A Heinz body preparation would be useful if you suspected anunstable hemoglobin or Hb H disease (3 gene deletion alpha thalassemia), but again,

    these diagnoses are unlikely given the Hgb, MCV, and MCHC.

    6. A 5 yo girl presents to her pediatrician with acute onset of pallor and fatigue.

    Laboratory evaluation reveals a hemogloboin concentration of 5.2 gm/dL, MCV of

    90fL, Reticulocyte count of 325K. Her urine is dark brown in color with 2+ blood ondipstick. Her Direct Antiglobulin Test reveals 3+ polyspecific, negative IgG and 3+

    C3. Monospot is negative. Cold agglutinin titers are also negative. Stools are guiaicnegative.

    Which of the following laboratory tests are most likely to reveal the diagnosis?

    a. Absence of CD55 and CD59 on erythrocytes by flow cytometryb. Detection of an antibody with anti I specificity in the patients serum

    c. Detection of a warm reactive panagglutinin in the patients serum

    d. Detection of a Donath-Landsteiner antibody in the patients serum

    e. Increased susceptibility to lysis on osmotic fragility testing

    ANSWER: d. This presentation is most consistent with the diagnosis of Paroxysmal

    Cold Hemoglobinuria (PCH) which is characterized by a cold reactive IgG antibodythat binds at 4 C in the extremities or the face and then activates complement when

    warmed to 37 C centrally. PCH is usually an acute, self-limited illness and often

    occurs after infectious illnesses such as upper respiratory infections, varicella,

    mumps, influenza, or infectious mononucleosis. The diagnostic testing requires that

    the blood sample be kept warm until delivered to the laboratory, where it will be

    tested at both 4 C and 37 C for presence of a biphasic hemolysin, the Donath-Landsteiner antibody, which is usually directed against antigens of the P antigen

    system, with lysis occurring when the sample is warmed.

    Paroxysmal nocturnal hemoglobinuria (PNH) would be diagnosed by the absenceof CD55 or CD59 on the cells, but would not be common at this age and would not be

    associated with a positive DAT. Patients with cold agglutinin disease often have IgMantibodies with anti-I specificity, but in this case, the cold agglutinin titers were

    negative. Osmotic fragility testing can be abnormal in any disorder with productionof spherocytes, including warm antibody mediated immune hemolytic disease as well

    as hereditary spherocytosis, but is not likely useful in this scenario.

    7. Which of the following are most likely to result in a patient with hemolytic disease

    of the newborn born to a G0P0 mom?

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    a. Group O+ mom with Group A+ infantb. Group O- mom with Group B+ infant

    c. Group A- mom with Group A+ infant

    d. Group O- mom with Group O+ infant

    e. Group A+ mom with Group B+ infant

    ANSWER: a. Hemolytic disease of the newborn occurs when there is transplacentalpassage of maternal antibody directed against fetal red cell antigens not shared by the

    mom. The antibodies that cross the placenta are IgG antibodies and may be againsteither the ABO group or against the Rh antigens. Although ABO incompatibility is

    more common than Rh disease, it is usually less severe. ABO setup occurs

    typically with a Group O mom and a Group A or B infant since individuals withgroup O blood make naturally occurring anti-A and anti-B isohemagglutinins. It is

    very uncommon in incompatible infants born to Group A or B mothers, probably

    because the naturally occurring isohemagglutinins in these individuals are more likely

    IgM than IgG, and clear any fetal cells that might get into the maternal circulation,but cannot cross the placenta. HDN occurs more commonly with Group O moms and

    Group A infants, than with Group B infants, perhaps related to the density of theantigens on fetal red cells. When the mother is Rh- and the infant Rh+ there is alsothe possibility of Rh sensitization, but that does not occur in the first born child since

    Rh sensitization requires exposure of maternal circulation to Rh+ cells for antibodies

    to form. To prevent this exposure, Rh negative mothers are given antiDimmunoglobulin (RhoGam) at 28 weeks and at delivery. Doses of RhoGam should

    also be given after abortions, amniocentesis, or any other trauma likely to expose the

    mother to fetal blood cells.

    8. A 16 yo black female presents to the ER with complaints of fatigue and yellow

    eyes. She reports a severe headache for the last 24 hours and her mother is

    concerned that she is not acting like herself. She has no significant past medicalhistory prior to this acute illness. She had a temperature to 102 F on admission to theEmergency Department, BP 148/92, HR 120, RR 20. Laboratory evaluation reveals:

    Hemoglobin concentration of 6.7 gm/dL, Reticulocyte count of 408K, MCV 92fL,

    WBC 19.4K, Platelets 72K, BUN 24 mg/dL, Creatinine 2.1 mg/dL, LDH 2076 IU/L,Total Bilirubin 1.4 mg/dL. Review of the peripheral blood smear reveals

    schistocytes, polychromasia, nucleated RBCs, and large platelets.

    Which of the following therapies would you initiate as soon as possible?

    a. IVIG, 1 gm/kg daily for 2 days

    b. Prednisone 2 mg/kg/day for 1 monthc. Plasmapheresisd. Infusion of FFP, 10 cc/kg x 1

    e. Platelet transfusion x 1

    ANSWER: c. This clinical scenario is most consistent with a diagnosis of

    Thrombotic Thrombocytopenic Purpura (TTP), with presenting symptoms of fever,

    hemolytic anemia, thrombocytopenia, renal insufficiency, and mild neurologicsymptoms. The appropriate therapy is plasmapheresis until laboratory parameters

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    improve. TTP occurs when there is an absence of the von Willebrand factor cleavingprotease, which can be a congenital absence of the protein or due to an acquired

    inhibitor to the protease, which is more likely in this scenario. Plasmapheresis helps

    remove the inhibitor and replaces the missing protease, found in FFP. If you were

    unable to begin plasmapheresis, infusion of FFP might be temporizing measure untilthe patient could be moved to a facility capable of performing plasmapheresis.

    Steroids are sometimes used in patients refractory to plasmapheresis, but are not firstline therapy.

    9. Which of the following laboratory profiles is most consistent with hemolytic

    anemia?

    a. Decreased hemoglobin, decreased reticulocyte count, increased MCV, increased

    bilirubin, decreased haptoglobin

    b. Decreased hemoglobin, increased reticulocyte count, decreased MCV, increasedbilirubin, decreased haptoglobin

    c. Normal hemoglobin, increased reticulocyte count, normal MCV, increasedbilirubin, increased haptoglobin

    d. Normal hemoglobin, increased reticulocyte count, normal MCV, increasedbilirubin, decreased haptoglobin

    e. Decreased hemoglobin, normal reticulocyte count, high MCV, normal bilirubin,

    normal haptoglobin.

    ANSWER: d. Despite the normal hemoglobin in scenario (d), which suggests

    compensated hemolysis, the increased reticulocyte count, increased bilirubin, anddecreased haptoglobin are most consistent with a diagnosis of hemolytic anemia. Forscenario (a), the decreased reticulocyte count is not typical. For scenario (b), the

    decreased MCV is not typical of hemolytic anemia. For scenario (c), the increased

    haptoglobin, although an acute phase reactant, is less suggestive of hemolytic anemia.For scenario (e), the normal reticulocyte count, high MCV, and normal haptoglobin

    suggest the possibility of bone marrow failure or megaloblastic anemia rather than

    hemolytic anemia.

    10. Which of the following statements about warm reactive antibodies against

    erythrocytes is incorrect?

    a. They are usually of IgG specificity

    b. They bind best at 37C.

    c. They are most commonly of anti-I specificity.d. They result in clearance of the antibody coated erythrocytes by the spleen.

    e. They can fix complement.

    ANSWER: c. Warm reactive antibodies are of IgG specificity and react best at body

    temperature of 37 C. They typically result in extravascular hemolysis with clearance

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    of antibody coated erythrocytes by the reticuloendothelial system, primarily thespleen and liver. Some IgG antibodies can fix complement, including some warm

    reactive antibodies as well as the cold-reactive biphasic hemolysin, the Donath-

    Landsteiner antibody. Most warm reactive antibodies are against Rh antigens, but

    can also be anti-U, anti-Kell, anti-Jkaor Fy

    a. Antibodies of anti-I specificity are most

    typically cold reactive IgM antibodies.

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    2009

    Congenital and Acquired Hemolytic Anemias

    Ellis J. Neufeld, MD PhD

    1. A 15-year-old girl presents with 3-day history of fevers, abdominal pain, fatigue,pallor, and 1 day of severe headache. She was previously well, has consumed no red

    meat in weeks, and has had neither diarrhea nor urinary symptoms. Nobody in thefamily has had anything like this in the past. Laboratory studies reveal Hb 7.1 g/dl,

    reticulocytes 14%, platelets 60k/mm3, normal WBC count and differential. Theprothrombin time is normal, as is the PTT. The peripheral smear features numerous

    schistocytes, occasional nucleated RBC, and large platelets. Chemistry studies

    include total bilirubin 2.5 mg/dl (1.9 indirect, 0.6 direct), LDH 1400U/l, andcreatinine 1.1 mg/dl. A pregnancy test is negative. Stool studies and antinuclear

    antibody studies are pending. Which of the following approaches would be most

    correct in this clinical scenario?

    A. Send and wait for ADAMTS13 enzyme and inhibitor studies. This could be TTPand the etiology should be proven before initiation of therapy.

    B. Microangiopathy and thrombocytopenia suggest DIC, therefore, admit to the ICUfor supportive care and launch a search for etiology, e.g. infection or malignancy.C. Initiate treatment for TTP immediately, with plasmapheresis (+/- concomitant

    steroids) because the diagnosis of TTP best fits this scenario, the diagnosis is

    clinical, and the disorder can be life threatening. Send ADAMTS13 studies butdont wait.

    D. Follow renal function and provide supportive care for HUS, which is more

    common than TTP in pediatrics, and initiate a search for E coli O57H7 strains,

    which produce HUS-inducing toxins.E. Transfuse for symptomatic anemia but only after saving blood for enzymatic

    studies because a congenital hemolytic anemia is likely.

    Answer:C

    Explanation: Initiate treatment for TTP immediately, with plasmapheresis (+/-

    concomitant steroids), because the diagnosis of TTP best fits this scenario, the diagnosis

    is clinical, and the disorder can be life threatening. Send ADAMTS13 studies but dontwait. This scenario is very typical for TTP, which can be life-threatening. In this case,

    primary antibody-mediated TTP is likely because there is no history of drugs, pregnancy,

    or congenital causes.Answer A is incorrect because the screening tests for the antibody to the von

    Willebrand cleaving protease, and the functional consequences of the antibody (low

    levels) are not good enough or fast enough in 2009 to be used for real-time diagnosis,

    though they are helpful in research settings. Answer B is incorrect because the normal PTand PTT rule out DIC, although the smears cannot necessarily be differentiated. Answer

    D is incorrect as a management strategy, although it is true that taking pediatrics as a

    whole, HUS is more common than TTP. In post-pubertal patients with no clinicalexposures to suggest HUS, it is prudent to start down the TTP road immediately, and in

    variant cases, to pursue supportive studies even as pheresis and often steroids are begun.

    Answer E would be correct for many kinds of hemolytic anemias, but this is the wrong

    clinical scenario based on the clinical history and the lab findings which supportintravascular hemolysis.

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    2. A newborn infant female presents with jaundice on the second day of life, with total

    bilirubin 14 mg/dl, and hemoglobin 12 g/dl. She is nursing vigorously and otherwise

    well. The peripheral smear reveals numerous bizarre forms, as if the cells had beenthrough a Waring blender, with schistocytes, tiny fragments, many ovalocytes,

    marked polychromasia, and NRBCs 60 per 100 WBC. Mothers blood type is Opositive, the child is A negative. The DAT is negative. The reticulocyte count is 14%.

    Family history reveals that the G1P1 mother has been told she has elliptocytosis,that she was transfused in the newborn period, and has been well ever since. A quick

    trip to the chart archives of the hospital discovers mothers old chart and confirms her

    story. Both parents are of Sicilian descent, and not known to be related. Father has nohistory of jaundice. Which of the following statements about this case is correct?

    A. Although the mother had elliptocytosis, this newborn smear seems (by

    description) to be much too severe for ordinary autosomal domininat HS due to

    spectin mutations. This must be a recessive Ankyirin mutation affecting verticalinteractions in the membrane.

    B. Ordinary (mild) dominant HE is often more severe in the newborn period. It ispossible that the newborn will have the same clinical course as mother, although amore severe course (due to a silent mutation from father, for example) cant be

    ruled out until the clinical course is followed for months or longer.

    C. The severity of early jaundice strongly suggests that there is not onlyelliptocytosis, but also an antibody-mediated hemolysis due to anti-A.

    D. The smear as described is most suggestive of severe G6PD deficiency, which

    would account for the jaundice.

    E. The Sicilian ancestry would support the likelihood of beta thalassemia major,even without consanguinity, because thalassemia alleles are extremely common in

    Southern Italy.

    Answer:B

    Explanation: Ordinary (mild) dominant HE is often more severe in the newborn period.

    It is possible that the newborn will have the same clinical course as mother, although a

    more severe course (due to a silent mutation from father, for example) cant be ruled outuntil the clinical course is followed for months or longer.

    Answer A is incorrect because vertical interaction problems in the red cell

    membrane cause spherocytosis (loss of membrane) whereas lateral interactions causeelliptocytosis. Answer C is incorrect because the DAT is negative (despite the A-O

    setup), and ABO antibodies are rarely of substantial import in primiparous mothers.

    When they are significant, the DAT should be discernable, even if subtle. ABO

    incompatibility is much more common than anti-A or B hemolysis. Answer D is incorrectbecause the smear is not really compatible with G6PD as the major problem, and this is a

    girl with an apparently unaffected father. Answer E is incorrect because beta

    hemoglobinopathies are essentially never apparent at birth, and only manifest as beta isexpressed during the first year or more of life. The smear doesnt suggest thalassemia

    either. Severe hypochromia and microcytosis is present in symptomatic thalassemia

    syndromes (at an appropriate age).

    This particular patient did have dominant elliptocytosis, but went on to havesevere, transfusion-dependent hemolysis and eventually evidence of myopathy, with

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    dramatically elevated serum CPK but low serum Aldolase. She proved to be a compoundheterozygote for two distinct mutations in the Aldolase A gene, for which her parents

    were asymptomatic carriers. She ultimately succumbed to severe rhabdomyolysis with a

    febrile illness. See Yao et al.,Blood, 2004. Sometimes patients have more than one

    hemolytic disorder!

    3. A 17-year-old with no significant past medical history presents after her pediatrician

    notes that her lips are blue at an annual check up. Oxymetry readings are 84% inroom air. A quick emergency room visit leads to the following data: Hb 15.3 g/dl.

    PaO298 by a blood gas machine. The blood is chocolate-brown in color, as noted by

    the lab techs. The retic count is 2.1%. Methemoglobin by co-oximetry is 12% (normalless than 1%). The peripheral smear reveals normal morphology. The patient s father

    is a dentist, and his office is off the garage of the family home. She works at an ice

    cream parlor. She denies recreational drug use. She started smoking cigarettes at age

    15, and now smokes pack a day. Which of the following statements is true?A. The markedly elevated methb could be due to eithera congenital deficiency of

    cytochrome b5 reductase, orsurreptitious use of nitrous oxide or other nitrates, towhich she may have access at home or at her job.B. The role of the cytochrome reductase is to keep Hb in its oxidized (Fe+3) state.

    C. Hemoglobin M rarely presents as cyanosis.

    D. High affinity hemoglobins must be kept in the differential diagnosis ofmethemoglobin.

    E. Low affinity hemoglobins cause not only cyanosis but poor tissue oxygenation.

    Answer:A

    Explanation: The markedly elevated methb could be due to eithera congenital

    deficiency of cytochrome b5 reductase, orsurreptitious use of nitrous oxide or other

    nitrates, to which she may have access at home or at her job.The differential diagnosis for met hb includes drugs, defects in the system thatkeeps hemoglobin REDUCED (not oxidized) and abnormal hemoglobins which oxidize

    spontaneously. Answer B is wrong because the reductase helps keep hemoglobin in its

    reduced, Fe2+ state. Answer C is wrong as this disorder often causes cyanosis, though itis rare. Answer D is incorrect because high affinity hemoglobins cause poor tissue

    oxygen delivery, but the blood is very red, saturations is not falsely measured as low, and

    cyanosis is not seen. Answer D is only half right. Cyanosis is found with some lowaffinity hemoglobins, but tissue oxygen delivery is very good at the capillary-tissue

    boundary.

    4. A 3-year-old girl has had transfusion-dependent anemia since age 6 months. She is

    found to have an unstable hemoglobin by sequence analysis (Hb Hammersmith, beta

    Phe42Ser). She has bony deformity from extramedullary hematopoiesis and markedsplenomegaly. Her urine is tinged pink with no red cells due to brisk intravascular

    hemolysis. Her hemoglobin is 7 g/dl 4 weeks after a transfusion, and her reticulocyte

    count is 18%. A Heinz body prep is positive. Nucleated reds number 35/100 WBC.

    Which of the following statements is correct?

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    A. As in Hereditary Spherocytosis, anemia will be entirely ameliorated bysplenectomy and her gallstone risk will be reduced.

    B. As in pyruvate kinase deficiency, splenectomy may result in an apparent increase

    in reticulocytosis.

    C. This diagnosis might have been made by newborn screening (by electrophoresis,isoelectric focusing, or HPLC), just as can be done with sickle trait, C trait, and

    other beta hemoglobinopathies.D. A decision about splenectomy should take into account growth status, transfusion

    requirements, interval change in spleen size, and potential long-term risks ofinfection and thrombosis.

    E. Heinz bodies are nuclear remnants which increase in all hemolytic anemias.

    Answer:D

    Explanation: A decision about splenectomy should take into account growth status,

    transfusion requirements, interval change in spleen size, and potential long-term risks of

    infection and thrombosis.Answer A is incorrect for most hemolytic states except HS. However, transfusion

    requirements and growth problems may be partially ameliorated by splenectomy. AnswerB is probably incorrect because PK deficiency is unique for the death of reticulated formsin the spleen, and paradoxical increase in the periphery after splenectomy. Answer C is

    wrong on two fronts. First, the amino acid substitution HbHammersmith is isoelectric (no

    change in charge) so that it may not be distinguishable by some methods, further, veryunstable hemoglobins are hard to detect in the periphery, particularly when beta is a small

    minority in the newborn period.

    Answer E is wrong. Howell-Jolly bodies are nuclear remnants. Heinz bodies are

    precipitated hemoglobin seen only with supravital stains.

    5. A previously healthy 5-year-old boy has sudden onset of dark urine, pallor, andtachycardia a week after a respiratory illness with pronounced cough and low-gradefever, treated with azithromycin. On presentation, he is pale and has a heart rate of

    140/min. His spleen is just below the costal margin. His hemoglobin is 5.5 g/dl,

    reticulocytes 12%, bilirubin 5.2 mg/dl, with direct fraction 0.3 mg/dl. His DAT ispositive for complement C3, and negative for IgG. You suspect either cold agglutinin

    disease or a Donath Landsteiner antibody (paroxysmal cold hemoglobinuria). The

    blood bank receives from your student a warm blood sample to be spun promptly.They report a cold-reacting IgG of high thermal amplitude, which fixes

    complement upon warming. Which of the following statements is correct about this

    case?

    A. Because this is not a cold agglutinin, there is no need to use a blood warmer, andcold will not be a factor for the patient upon discharge.

    B. Donath Landsteiner antibodies are readily removed by plasmapheresis.

    C. The DAT (Coombs) reagent must be defective if the IgG cant be detected on thecells, as the blood bank found it there on the specific testing.

    D. PCH in children nearly always resolves spontaneously and may not respond well

    to steroids.

    E. Extravascular hemolysis is the rule in PCH and leads to impressive splenomegalyin some cases.

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    Answer: D

    Explanation: Answer A is wrong because cold-reacting IgGs do bind better in the cold

    and will fix complement when they get warm centrally. Fastidious attention to keeping

    the extremities warm, and to warming blood will help. Answer B is wrong because IgGsdistribute in extravascular space as well as intravascular. Thus, IgM is easy to remove by

    pheresis, but IgG much less so. Answer C is wrong. This lab scenario defines the DonathLandsteiner antibody. DAT reagents are used at room temperature, and if all the coated

    cells have lysed from complement the cells wont agglutinate with the Coombs reagent.Answer E is wrong because the hemolysis in this circumstance (in contrast to most IgGs

    which dont fix complement well) is often entirely intravascular, and the spleen may be

    indifferent.

    6. Three months after liver transplantation for TPN-induced cholestatic liver disease, a

    4-year-old boy becomes pale and jaundiced. His ALT remains in its stable range of50-70 U/L, but his hemoglobin has dropped to 7 g/dl, his bilirubin is 5.8 mg/dl with

    1.2 mg/dl direct. The reticulocyte count is 6%. He is immunosuppressed withtacroimus and on a tapering dose of prednisone, currently 0.25 mg/kg/day. The liver,from a cadaveric donor, was blood type O+, as is the patient. Direct antiglobulin test

    is positive for a warm-reacting IgG antibody of broad (untype-able) specificity.

    Which of the following statements is correct about this scenario?A. The positive DAT rules out drug-related mechanisms of hemolysis.

    B. AIHA following solid organ transplant may respond to changes in the

    immunosuppresion regimen.

    C. When the blood bank cant determine a specific target antigen, transfusion isprecluded by positive cross-match.

    D. The elevated direct bilirubin suggests that intravascular hemolysis may be part of

    the problem.E. The Donor/recipient ABO blood type match rules out immune hemolysis basedon host-vs-graft hematopoiesis or graft-vs host equivalents.

    Answer:B

    Explanation: Tacrolimus may be the offending agent and various substitutes or increases

    in other immunosuppressants may be helpful.

    A is wrong because it is not uncommon for drugs to cause AIHA by one ofseveral mechanisms, including haptenizing effects such as penicillins, and

    immunomodulation, such as tacrolimus. C is incorrect. Bloodbanks may provide least

    badly matched blood for emergencies, and hemolysis wont necessarily be worse than

    that seen for endogenous bl ood. D is incorrect. The direct hyperbilirubinemia depends onhepatic excretion of conjugated bilirubin, not on the site of hemolysis. E is wrong

    because there are many potential blood group interactions besides ABO. In principle, if

    either donor or host lacked a common blood antigen, this scenario might result. This ismore commonly an issue in hematopoietic stem cell transplantation.

    7. The monoclonal antibody therapeutic, Eculizumab, blocks hemolysis in paroxysmalnocturnal hemoglobinuria by blocking C5 binding to C3 coated red cells (in PNH,

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    loss of PI-linked proteins includes loss of complement protection mechanisms).Without the terminal components of complement, the cells no longer lyse but

    circulate coated with C3. At the American Society of Hematology meetings in 2008,

    Eculizumab investigators reported that some patients on this drug get a secondary

    hemolytic anemia. A reasonable explanation is splenic clearance of C3-coated redcells. Because PNH is a clonal disorder, patients are chimeric for normal red cells and

    PNH red cells without the protective mechanism. Which of the following is areasonable prediction about the enhanced hemolysis in these patients?

    A. The DAT will be positive for C3 in both clones in the chimeric patients, namelyPNH clones(CD59 neg) and normal (CD59+) red cells.

    B. The DAT will be positive for C3 only on PNH cells in Eculizumab treated

    patients.C. The DAT for C3 is always positive in PNH patients, with or without the new

    agent.

    D. Steroids would not be effective for extravascular hemolysis of C3 coated red

    cells, by analogy to AIHA.

    Answer: BExplanation:A is incorrect because the normal (non-PNH cells) wont accumulatecomplement, just as normal individuals should not have a C3+ DAT. Choice C is

    incorrect, because complement fixation usually lyses the C3 coated cells, so they are not

    detectable by the DAT reagent. The antiC5 antibody blocks this lysis, and allowsdetection of the coated cells. D is incorrect in that by analogy to AIHA, steroids should

    be very effective, and indeed, this is the case.

    8. Consider a 6-year-old Caucasian girl who is admitted to the hospital for acute onset of

    dark urine and anemia after eating fresh fava beans at a farmers market. She has

    impressive indirect hyperbilirubinemia and requires a transfusion for Hb 5 g/dl.Which of the following statements is true?A. For a girl to be affected with symptomatic G6PD deficiency (an X-linked

    recessive trait), one of her parents has most likely passed on the gene (affected

    father or carrier mother) but it need not be the case that both carry the gene.B. Her G6PD level should be measured immediately upon hospitalization, or else

    one would run the risk of missing the deficiency when the fava bean effect

    dissipates.C. If she wasnt jaundiced in the newborn period, this cant be G6PD deficiency.

    D. If anemia this severe results from eating fava beans, then this patient probably has

    chronic hemolytic anemia all the time.

    E. G6PD deficiency is equally severe in all populations in which it arose (Asia,Mediterranean, Sub-Saharan Africa).

    Answer: A

    Explanation: All women who carry a sex-linked mutant allele are chimeric for normal

    and abnormal red cells. Unequal X-chromosome inactivation can lead to more than half

    of red cell precursors carrying the abnormal gene, and such women may be symptomatic

    under stress. B is incorrect. It is best to wait for RBC recovery to test the enzyme, as forsome variants, newer cells have much more enzyme. C is incorrect because the kinetics

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    of bilirubin production and clearance vary within individuals, and the fresh fava beansmay have been a greater stress for this patient than was birth. D is incorrect for the same

    reason as C. The acute stress may be more of a problem than the oxidant burden of daily

    life. E is incorrect. The African variant is milder than the other two regions of high G6PD

    prevalence.

    9. A 2-week-old boy is so pale at his pediatricians visit that he gets a CBC, which

    reveals Hb 6.0 g/dl, retics 2%, MCV 99 fl. The MCHC is mildly elevated at 37 g/dl.The smear has a few spherocytes, moderate anisocytosis, and some poikilocytosis. He

    was mildly jaundiced as a newborn, maximum bilirubin 12 mg/dl and no blood type

    mismatch setup was noted (mother and patient O negative). The bilirubin is nownormal, as are the WBC, differential, and platelet counts. The child otherwise seems

    to be thriving. Family history is negative for transfusions, splenectomy,

    cholecystectomy, and positive for neonatal jaundice requiring only lights in a cousin.

    Which of the following statements is correct?A. This cant be hereditary spherocytosis, as the reticulocyte count is too low to

    suggest hemolysis.B. This cant be hereditary spherocytosis, as the jaundice history is much too mild.C. This has a good chance of representing hereditary spherocytosis during the

    neonatal nadir period when reticulocyte counts arent helpful.

    D. He should have a non-incubated osmotic fragility test right away, before you givehim a transfusion.

    E. Testing the parents should confirm or rule out HS in this case.

    Answer:C

    Explanation: Pronounced anemia a couple of weeks after birth is very common in HS

    for reasons not entirely clear. The mutation does not need to be severe to cause this

    effect, and about 1/3 of HS patients have new mutations so that testing the family maynot suffice (so E is incorrect). A is incorrect because the nadir renders retic countsrelatively useless for several weeks. Normal goes down to zero. B is incorrect because the

    kinetics of newborn jaundice vary from individual to individual. D is incorrect because

    the incubated test is much more sensitive, and the test has relatively poor predictivecharacteristics in the newborn period compared to a few months later, though if positive

    now, an incubated test would be conclusive.

    10. A 12-year-old boy with a history of ITP 3 years ago presents with 2-week history of

    fatigue and pallor, and is found to have tachycardia and modest splenomegaly (2 cm

    below the costal margin). His growth has been good. His diet is varied. Hes had nofevers, night sweats, adenopathy, or GI symptoms. His labs include a hemoglobin of

    6 g/dl, MCV 97 fl, plts 68,000/mm3, LDH 1100 U/L, uric acid normal, and minimally

    elevated indirect bilirubin 2 mg/dl. The retic count is 9%. The smear shows noschistocytes, no teardrops or blasts, and lots of polychromatophilic red cells. Some

    giant platelets are seen. Anisocytosis is present. Hypersegmentation is absent. DAT is

    positive for IgG. You suspect Evans syndrome, perhaps related to underlying

    immunologic disturbance. His prior ITP responded promptly to 5 days of

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    prednisone, but hes not been seen much in the interim. Which of the followingstatements is most likely to be true about this patient?

    A. He should promptly have a bone marrow to rule out leukemia, and certainly

    before he receives steroids.

    B. The macrocytosis suggests a primary nutritional or bowel absorption problem.C. His apparent AIHA is likely to respond to prednisone, but the kinetics of response

    may be different for red cells and platelets, and higher doses and longer course areindicated than when he had ITP alone in the past.

    D. This cant be due to a mutation in the Fas system (i.e., autoimmunelymphoproliferative syndrome, ALPS) because he has no massive adenopathy.

    E. The AIHA is likely to be short-lived/self resolving. No therapy is necessary.

    Answer:C

    Explanation: Most hematologists would take a positive DAT and reassuring peripheral

    blood film as evidence against leukemia in this clinical setting. Although folate and B12

    deficiency are theoretically possible, the history and smear findings dont support theseas likely primary problems. D is based on the clinical versus mutation analyses of ALPS

    patients. FAS pathway mutations are common in Evans syndrome, even when overtadenopathy or other problems of ALPS are not present. In contrast to PCH and someother pediatric immune cytopenias, the AIHA associated with Evans syndrome could be

    protracted and require immunosuppression for months or longer.

    11. The second child to a woman whose first infant was jaundiced has evidence of

    hydrops in utero at 35 weeks. The child is delivered urgently and found to have

    ascites and severe anemia, with hemoglobin of 6 g/dl. Both child and mother aretyped as O positive but the mother has a circulating anti-e (little e) andtibody and

    genotyping reveals that she is E/E while the infant is E/e. the child is transfused

    slowly with crossmatch compatible O negative blood (e/e). She makes a promptrecovery. Which of the following is true about this scenario?A. If the mother had received antiD globulin (WinRho or Rhogam) previously, this

    hemolytic disease of the newborn could have been avoided.

    B. The anemia and transfusion requirements could go on for 6 months or more.C. There is a 25% chance of chronic anemia.

    D. Almost invariably, the anemia will be entirely resolved by 3 months of age.

    E. The child has a 50% chance of having the same problem when she has children.

    Answer:D

    Explanation: Anti-D does not protect against variance in Rh Ee or Cc systems, so A is

    wrong. Maternal antibodies acquired passively across the placenta are nearly always goneby 3 months when they are being constantly cleared on the infants red cells. 6 months

    (choice B) is extremely unlikely. HDN is not a situation that leads to chronic anemia in

    and of itself, so C is incorrect, and the child is heterozygous, so that the E/e system wontbe a problem for her children, thus E is incorrect.

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    2011

    Congenital and Acquired Hemolytic AnemiasEllis J. Neufeld, MD PhD

    1. A 15-year-old girl presents with 3-day history of fevers, abdominal pain, fatigue,

    pallor, and 1 day of severe headache. She was previously well, has consumed no redmeat in weeks, and has had neither diarrhea nor urinary symptoms. Nobody in the

    family has had anything like this in the past. Laboratory studies reveal Hb 7.1 g/dl,reticulocytes 14%, platelets 60k/mm3, normal WBC count and differential. The

    prothrombin time is normal, as is the PTT. The peripheral smear features numerous

    schistocytes, occasional nucleated RBC, and large platelets. Chemistry studiesinclude total bilirubin 2.5 mg/dl (1.9 indirect, 0.6 direct), LDH 1400U/l, and

    creatinine 1.1 mg/dl. A pregnancy test is negative. Stool studies and antinuclear

    antibody studies are pending. Which of the following approaches would be most

    correct in this clinical scenario?A. Send and wait for ADAMTS13 enzyme and inhibitor studies. This could be TTP

    and the etiology should be proven before initiation of therapy.B. Microangiopathy and thrombocytopenia suggest DIC, therefore, admit to the ICUfor supportive care and launch a search for etiology, e.g. infection or malignancy.

    *C. Initiate treatment for TTP immediately, with plasmapheresis (+/- concomitant

    steroids) because the diagnosis of TTP best fits this scenario, the diagnosis isclinical, and the disorder can be life threatening. Send ADAMTS13 studies but

    dont wait.

    D. Follow renal function and provide supportive care for HUS, which is more

    common than TTP in pediatrics, and initiate a search for E coli O57H7 strains,which produce HUS-inducing toxins.

    E. Transfuse for symptomatic anemia but only after saving blood for enzymatic

    studies because a congenital hemolytic anemia is likely.

    Answer:C

    Explanation: Initiate treatment for TTP immediately, with plasmapheresis (+/-

    concomitant steroids), because the diagnosis of TTP best fits this scenario, the diagnosisis clinical, and the disorder can be life threatening. Send ADAMTS13 studies but dont

    wait. This scenario is very typical for TTP, which can be life-threatening. In this case,

    primary antibody-mediated TTP is likely because there is no history of drugs, pregnancy,or congenital causes.

    Answer A is incorrect because the screening tests for the antibody to the von

    Willebrand cleaving protease, and the functional consequences of the antibody (low

    levels) are not good enough or fast enough in 2009 to be used for real-time diagnosis,though they are helpful in research settings. Answer B is incorrect because the normal PT

    and PTT rule out DIC, although the smears cannot necessarily be differentiated. Answer

    D is incorrect as a management strategy, although it is true that taking pediatrics as awhole, HUS is more common than TTP. In post-pubertal patients with no clinical

    exposures to suggest HUS, it is prudent to start down the TTP road immediately, and in

    variant cases, to pursue supportive studies even as pheresis and often steroids are begun.

    Answer E would be correct for many kinds of hemolytic anemias, but this is the wrong

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    clinical scenario based on the clinical history and the lab findings which supportintravascular hemolysis.

    2. A newborn infant female presents with jaundice on the second day of life, with totalbilirubin 14 mg/dl, and hemoglobin 12 g/dl. She is nursing vigorously and otherwise

    well. The peripheral smear reveals numerous bizarre forms, as if the cells had beenthrough a Waring blender, with schistocytes, tiny fragments, many ovalocytes,

    marked polychromasia, and NRBCs 60 per 100 WBC. Mothers blood type is Opositive, the child is A negative. The DAT is negative. The reticulocyte count is 14%.

    Family history reveals that the G1P1 mother has been told she has elliptocytosis,

    that she was transfused in the newborn period, and has been well ever since. A quicktrip to the chart archives of the hospital discovers mothers old chart and confirms her

    story. Both parents are of Sicilian descent, and not known to be related. Father has no

    history of jaundice. Which of the following statements about this case is correct?

    A. Although the mother had elliptocytosis, this newborn smear seems (bydescription) to be much too severe for ordinary autosomal dominant HS due to

    spectrin mutations. This must be a recessive Ankyrin mutation affecting verticalinteractions in the membrane.*B. Ordinary (mild) dominant HE is often more severe in the newborn period. It is

    possible that the newborn will have the same clinical course as mother, although a

    more severe course (due to a silent mutation from father, for example) cant beruled out until the clinical course is followed for months or longer.

    C. The severity of early jaundice strongly suggests that there is not only

    elliptocytosis, but also an antibody-mediated hemolysis due to anti-A.

    D. The smear as described is most suggestive of severe G6PD deficiency, whichwould account for the jaundice.

    E. The Sicilian ancestry would support the likelihood of beta thalassemia major,

    even without consanguinity, because thalassemia alleles are extremely common inSouthern Italy.

    Answer:B

    Explanation: Ordinary (mild) dominant HE is often more severe in the newborn period.It is possible that the newborn will have the same clinical course as mother, although a

    more severe course (due to a silent mutation from father, for example) cant be ruled out

    until the clinical course is followed for months or longer.Answer A is incorrect because vertical interaction problems in the red cell

    membrane cause spherocytosis (loss of membrane) whereas lateral interactions cause

    elliptocytosis. Answer C is incorrect because the DAT is negative (despite the A-O

    setup), and ABO antibodies are rarely of substantial import in primiparous mothers.When they are significant, the DAT should be discernable, even if subtle. ABO

    incompatibility is much more common than anti-A or B hemolysis. Answer D is incorrect

    because the smear is not really compatible with G6PD as the major problem, and this is agirl with an apparently unaffected father. Answer E is incorrect because beta

    hemoglobinopathies are essentially never apparent at birth, and only manifest as beta is

    expressed during the first year or more of life. The smear doesnt suggest thalassemia

    either. Severe hypochromia and microcytosis is present in symptomatic thalassemiasyndromes (at an appropriate age).

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    This particular patient did have dominant elliptocytosis, but went on to havesevere, transfusion-dependent hemolysis and eventually evidence of myopathy, with

    dramatically elevated serum CPK but low serum Aldolase. She proved to be a compound

    heterozygote for two distinct mutations in the Aldolase A gene, for which her parents

    were asymptomatic carriers. She ultimately succumbed to severe rhabdomyolysis with afebrile illness. See Yao et al.,Blood, 2004. Sometimes patients have more than one

    hemolytic disorder!

    3. A 17-year-old with no significant past medical history presents after her pediatrician

    notes that her lips are blue at an annual checkup. Oxymetry readings are 84% in room

    air. A quick emergency room visit leads to the following data: Hb 15.3 g/dl. PaO298by a blood gas machine. The blood is chocolate-brown in color, as noted by the lab

    techs. The retic count is 2.1%. Methemoglobin by co-oximetry is 12% (normal less

    than 1%). The peripheral smear reveals normal morphology. The patients father is a

    dentist, and his office is off the garage of the family home. She works at an ice creamparlor. She denies recreational drug use. She started smoking cigarettes at age 15, and

    now smokes pack a day. Which of the following statements is true?*A. The markedly elevated methb could be due to eithera congenital deficiency ofcytochrome b5 reductase, orsurreptitious use of nitrous oxide or other nitrates, to

    which she may have access at home or at her job.

    B. The role of the cytochrome reductase is to keep Hb in its oxidized (Fe+3) state.C. Hemoglobin M rarely presents as cyanosis.

    D. High affinity hemoglobins must be kept in the differential diagnosis of

    methemoglobin.

    E. Low affinity hemoglobins cause not only cyanosis but poor tissue oxygenation.

    Answer:A

    Explanation: The markedly elevated methb could be due to eithera congenitaldeficiency of cytochrome b5 reductase, orsurreptitious use of nitrous oxide or othernitrates, to which she may have access at home or at her job.

    The differential diagnosis for met hb includes drugs, defects in the system that

    keeps hemoglobin REDUCED (not oxidized) and abnormal hemoglobins which oxidizespontaneously. Answer B is wrong because the reductase helps keep hemoglobin in its

    reduced, Fe2+ state. Answer C is wrong as this disorder often causes cyanosis, though it

    is rare. Answer D is incorrect because high affinity hemoglobins cause poor tissueoxygen delivery, but the blood is very red, saturations is not falsely measured as low, and

    cyanosis is not seen. Answer D is only half right. Cyanosis is found with some low

    affinity hemoglobins, but tissue oxygen delivery is very good at the capillary-tissue

    boundary.

    4. A 3-year-old girl has had transfusion-dependent anemia since age 6 months. She isfound to have an unstable hemoglobin by sequence analysis (Hb Hammersmith, beta

    Phe42Ser). She has bony deformity from extramedullary hematopoiesis and marked

    splenomegaly. Her urine is tinged pink with no red cells due to brisk intravascular

    hemolysis. Her hemoglobin is 7 g/dl 4 weeks after a transfusion, and her reticulocyte

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    count is 18%. A Heinz body prep is positive. Nucleated reds number 35/100 WBC.Which of the following statements is correct?

    A. As in Hereditary Spherocytosis, anemia will be entirely ameliorated by

    splenectomy and her gallstone risk will be reduced.

    B. As in pyruvate kinase deficiency, splenectomy may result in an apparent increasein reticulocytosis.

    C. This diagnosis might have been made by newborn screening (by electrophoresis,isoelectric focusing, or HPLC), just as can be done with sickle trait, C trait, and

    other beta hemoglobinopathies.*D. A decision about splenectomy should take into account growth status, transfusion

    requirements, interval change in spleen size, and potential long-term risks of

    infection and thrombosis.E. Heinz bodies are nuclear remnants which increase in all hemolytic anemias.

    Answer:D

    Explanation: A decision about splenectomy should take into account growth status,transfusion requirements, interval change in spleen size, and potential long-term risks of

    infection and thrombosis.Answer A is incorrect for most hemolytic states except HS. However, transfusionrequirements and growth problems may be partially ameliorated by splenectomy. Answer

    B is probably incorrect because PK deficiency is unique for the death of reticulated forms

    in the spleen, and paradoxical increase in the periphery after splenectomy. Answer C iswrong on two fronts. First, the amino acid substitution HbHammersmith is isoelectric (no

    change in charge) so that it may not be distinguishable by some methods, further, very

    unstable hemoglobins are hard to detect in the periphery, particularly when beta is a small

    minority in the newborn period.Answer E is wrong. Howell-Jolly bodies are nuclear remnants. Heinz bodies are

    precipitated hemoglobin seen only with supravital stains.

    5. A previously healthy 5-year-old boy has sudden onset of dark urine, pallor, and

    tachycardia a week after a respiratory illness with pronounced cough and low-grade

    fever, treated with azithromycin. On presentation, he is pale and has a heart rate of140/min. His spleen is just below the costal margin. His hemoglobin is 5.5 g/dl,

    reticulocytes 12%, bilirubin 5.2 mg/dl, with direct fraction 0.3 mg/dl. His DAT is

    positive for complement C3, and negative for IgG. You suspect either cold agglutinindisease or a Donath Landsteiner antibody (paroxysmal cold hemoglobinuria). The

    blood bank receives from your student a warm blood sample to be spun promptly.

    They report a cold-reacting IgG of high thermal amplitude, which fixes

    complement upon warming. Which of the following statements is correct about thiscase?

    A. Because this is not a cold agglutinin, there is no need to use a blood warmer, and

    cold will not be a factor for the patient upon discharge.B. Donath Landsteiner antibodies are readily removed by plasmapheresis.

    C. The DAT (Coombs) reagent must be defective if the IgG cant be detected on the

    cells, as the blood bank found it there on the specific testing.

    *D. PCH in children nearly always resolves spontaneously and may not respond wellto steroids.

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    E. Extravascular hemolysis is the rule in PCH and leads to impressive splenomegalyin some cases.

    Answer: D

    Explanation: Answer A is wrong because cold-reacting IgGs do bind better in the coldand will fix complement when they get warm centrally. Fastidious attention to keeping

    the extremities warm, and to warming blood will help. Answer B is wrong because IgGsdistribute in extravascular space as well as intravascular. Thus, IgM is easy to remove by

    pheresis, but IgG much less so. Answer C is wrong. This lab scenario defines the DonathLandsteiner antibody. DAT reagents are used at room temperature, and if all the coated

    cells have lysed from complement the cells wont agglutinate with the Coombs reagent.

    Answer E is wrong because the hemolysis in this circumstance (in contrast to most IgGswhich dont fix complement well) is often entirely intravascular, and the spleen may be

    indifferent.

    6. Three months after liver transplantation for TPN-induced cholestatic liver disease, a

    4-year-old boy becomes pale and jaundiced. His ALT remains in its stable range of50-70 U/L, but his hemoglobin has dropped to 7 g/dl, his bilirubin is 5.8 mg/dl with1.2 mg/dl direct. The reticulocyte count is 6%. He is immunosuppressed with

    tacrolimus and on a tapering dose of prednisone, currently 0.25 mg/kg/day. The liver,

    from a cadaveric donor, was blood type O+, as is the patient. Direct antiglobulin testis positive for a warm-reacting IgG antibody of broad (untype-able) specificity.

    Which of the following statements is correct about this scenario?

    A. The positive DAT rules out drug-related mechanisms of hemolysis.

    *B. AIHA following solid organ transplant may respond to changes in theimmunosuppression regimen.

    C. When the blood bank cant determine a specific target antigen, transfusion is

    precluded by positive cross-match.D. The elevated direct bilirubin suggests that intravascular hemolysis may be part ofthe problem.

    E. The Donor/recipient ABO blood type match rules out immune hemolysis based

    on host-vs-graft hematopoiesis or graft-vs host equivalents.

    Answer:B

    Explanation: Tacrolimus may be the offending agent and various substitutes or increasesin other immunosuppressants may be helpful.

    A is wrong because it is not uncommon for drugs to cause AIHA by one of

    several mechanisms, including haptenizing effects such as penicillins, and

    immunomodulation, such as tacrolimus. C is incorrect. Blood banks may provide leastbadly matched blood for emergencies, and hemolysis wont necessarily be worse than

    that seen for endogenous blood. D is incorrect. The direct hyperbilirubinemia depends on

    hepatic excretion of conjugated bilirubin, not on the site of hemolysis. E is wrongbecause there are many potential blood group interactions besides ABO. In principle, if

    either donor or host lacked a common blood antigen, this scenario might result. This is

    more commonly an issue in hematopoietic stem cell transplantation.

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    7. The monoclonal antibody therapeutic, Eculizumab, blocks hemolysis in paroxysmalnocturnal hemoglobinuria by blocking C5 binding to C3 coated red cells (in PNH,

    loss of PI-linked proteins includes loss of complement protection mechanisms).

    Without the terminal components of complement, the cells no longer lyse but

    circulate coated with C3. At the American Society of Hematology meetings in 2008,and in subsequent reports, Eculizumab investigators reported that some patients on

    this drug get a secondary hemolytic anemia. A reasonable explanation is splenicclearance of C3-coated red cells. Because PNH is a clonal disorder, patients are

    chimeric for normal red cells and PNH red cells without the protective mechanism.Which of the following is a reasonable prediction about the enhanced hemolysis in

    these patients?

    A. The DAT will be positive for C3 in both clones in the chimeric patients, namelyPNH clones(CD59 neg) and normal (CD59+) red cells.

    *B. The DAT will be positive for C3 only on PNH cells in Eculizumab treated

    patients.

    C. The DAT for C3 is always positive in PNH patients, with or without the newagent.

    D. Steroids would not be effective for extravascular hemolysis of C3 coated redcells, by analogy to AIHA.

    Answer: B

    Explanation:A is incorrect because the normal (non-PNH cells) wont accumulatecomplement, just as normal individuals should not have a C3+ DAT. Choice C is

    incorrect, because complement fixation usually lyses the C3 coated cells, so they are not

    detectable by the DAT reagent. The antiC5 antibody blocks this lysis, and allows

    detection of the coated cells. D is incorrect in that by analogy to AIHA, steroids shouldbe very effective, and indeed, this is the case.

    8. Consider a 6-year-old Caucasian girl who is admitted to the hospital for acute onset ofdark urine and anemia after eating fresh fava beans at a farmers market. She has

    impressive indirect hyperbilirubinemia and requires a transfusion for Hb 5 g/dl.

    Which of the following statements is true?*A. For a girl to be affected with symptomatic G6PD deficiency (an X-linked

    recessive trait), one of her parents has most likely passed on the gene (affected

    father or carrier mother) but it need not be the case that both carry the gene.B. Her G6PD level should be measured immediately upon hospitalization, or else

    one would run the risk of missing the deficiency when the fava bean effect

    dissipates.

    C. If she wasnt jaundiced in the newborn period, this cant be G6PD deficiency.D. If anemia this severe results from eating fava beans, then this patient probably has

    chronic hemolytic anemia all the time.

    E. G6PD deficiency is equally severe in all populations in which it arose (Asia,Mediterranean, Sub-Saharan Africa).

    Answer: A

    Explanation: All women who carry a sex-linked mutant allele are chimeric for normaland abnormal red cells. Unequal X-chromosome inactivation can lead to more than half

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    of red cell precursors carrying the abnormal gene, and such women may be symptomaticunder stress. B is incorrect. It is best to wait for RBC recovery to test the enzyme, as for

    some variants, newer cells have much more enzyme. C is incorrect because the kinetics

    of bilirubin production and clearance vary within individuals, and the fresh fava beans

    may have been a greater stress for this patient than was birth. D is incorrect for the samereason as C. The acute stress may be more of a problem than the oxidant burden of daily

    life. E is incorrect. The African variant is milder than the other two regions of high G6PDprevalence.

    9. A 2-week-old boy is so pale at his pediatricians visit that he gets a CBC, which

    reveals Hb 6.0 g/dl, retics 2%, MCV 99 fl. The MCHC is mildly elevated at 37 g/dl.The smear has a few spherocytes, moderate anisocytosis, and some poikilocytosis. He

    was mildly jaundiced as a newborn, maximum bilirubin 12 mg/dl and no blood type

    mismatch setup was noted (mother and patient O negative). The bilirubin is now

    normal, as are the WBC, differential, and platelet counts. The child otherwise seemsto be thriving. Family history is negative for transfusions, splenectomy,

    cholecystectomy, and positive for neonatal jaundice requiring only lights in a cousin.Which of the following statements is correct?A. This cant be hereditary spherocytosis, as the reticulocyte count is too low to

    suggest hemolysis.

    B. This cant be hereditary spherocytosis, as the jaundice history is much too mild.*C. This has a good chance of representing hereditary spherocytosis during the

    neonatal nadir period when reticulocyte counts arent helpful.

    D. He should have a non-incubated osmotic fragility test right away, before you give

    him a transfusion.E. Testing the parents should confirm or rule out HS in this case.

    Answer:CExplanation: Pronounced anemia a couple of weeks after birth is very common in HSfor reasons not entirely clear. The mutation does not need to be severe to cause this

    effect, and about 1/3 of HS patients have new mutations so that testing the family may

    not suffice (so E is incorrect). A is incorrect because the normal newborn nadir rendersretic counts relatively useless for several weeks. Normal goes down to zero. B is incorrect

    because the kinetics of newborn jaundice vary from individual to individual. D is

    incorrect because the incubated test is much more sensitive, and the test has relativelypoor predictive characteristics in the newborn period compared to a few months later,

    though if positive now, an incubated test would be conclusive.

    10. A 12-year-old boy with a history of ITP 3 years ago presents with 2-week history of

    fatigue and pallor, and is found to have tachycardia and modest splenomegaly (2 cm

    below the costal margin). His growth has been good. His diet is varied. Hes had nofevers, night sweats, adenopathy, or GI symptoms. His labs include a hemoglobin of

    6 g/dl, MCV 97 fl, plts 68,000/mm3, LDH 1100 U/L, uric acid normal, and minimally

    elevated indirect bilirubin 2 mg/dl. The retic count is 9%. The smear shows no

    schistocytes, no teardrops or blasts, and lots of polychromatophilic red cells. Somegiant platelets are seen. Anisocytosis is present. Hypersegmentation is absent. DAT is

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    positive for IgG. You suspect Evans syndrome, perhaps related to underlyingimmunologic disturbance. His prior ITP responded promptly to 5 days of

    prednisone, but hes not been seen much in the interim. Which of the following

    statements is most likely to be true about this patient?

    A. He should promptly have a bone marrow to rule out leukemia, and certainlybefore he receives steroids.

    B. The macrocytosis suggests a primary nutritional or bowel absorption problem.*C. His apparent AIHA is likely to respond to prednisone, but the kinetics of response

    may be different for red cells and platelets, and higher doses and longer course areindicated than when he had ITP alone in the past.

    D. This cant be due to a mutation in the Fas system (i.e., autoimmune

    lymphoproliferative syndrome, ALPS) because he has no massive adenopathy.E. The AIHA is likely to be short-lived/self resolving. No therapy is necessary.

    Answer:C

    Explanation: Most hematologists would take a positive DAT and reassuring peripheralblood film as evidence against leukemia in this clinical setting. Although folate and B12

    deficiency are theoretically possible, the history and smear findings dont support theseas likely primary problems. D is based on the clinical versus mutation analyses of ALPSpatients. FAS pathway mutations are common in Evans syndrome, even when overt

    adenopathy or other problems of ALPS are not present. In contrast to PCH and some

    other pediatric immune cytopenias, the AIHA associated with Evans syndrome could beprotracted and require immunosuppression for months or longer.

    11. The second child to a woman whose first infant was jaundiced has evidence ofhydrops in utero at 35 weeks. The child is delivered urgently and found to have

    ascites and severe anemia, with hemoglobin of 6 g/dl. Both child and mother are

    typed as O positive but the mother has a circulating anti-e (little e) antibody andgenotyping reveals that she is E/E while the infant is E/e. The child is transfusedslowly with crossmatch compatible O negative blood (e/e). She makes a prompt

    recovery. Which of the following is true about this scenario?

    A. If the mother had received anti-D globulin (WinRho or Rhogam) previously, thishemolytic disease of the newborn could have been avoided.

    B. The anemia and transfusion requirements could go on for 6 months or more.

    C. There is a 25% chance of chronic anemia.*D. Almost invariably, the anemia will be entirely resolved by 3 months of age.

    E. The child has a 50% chance of having the same problem when she has children.

    Answer:DExplanation: Anti-D does not protect against variants in Rh Ee or Cc systems, so A is

    wrong. Maternal antibodies acquired passively across the placenta are nearly always gone

    by 3 months when they are being constantly cleared on the infants red cells. 6 months(choice B) is extremely unlikely. HDN is not a situation that leads to chronic anemia in

    and of itself, so C is incorrect, and the child is heterozygous, so that the E/e system wont

    be a problem for her children, thus E is incorrect.

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    12. A previously well three year old Caucasian male presents with pallor, fatigue, anddark urine. One day earlier, he was evaluated by his local pediatrician who

    prescribed amoxicillin for a possible urinary tract infection, based on dark amber

    urine and a urine di