AnemiaAnemiaRobb Friedman, MDRobb Friedman, MD

Modified by Sean Hesselbacher, Modified by Sean Hesselbacher, MD, Eyal Oren, MD, David MD, Eyal Oren, MD, David

Antonetti, MD and Cathy Okuliar, Antonetti, MD and Cathy Okuliar, MDMD

What is Anemia?What is Anemia?

ANEMIA IS NEVER NORMALANEMIA IS NEVER NORMAL Reduction below normal in the mass Reduction below normal in the mass

of red blood cells in the circulationof red blood cells in the circulation Hemoglobin concentration, Hemoglobin concentration,

hematocrit, RBC counthematocrit, RBC count Men: HGB < 14 or HCT < 41%Men: HGB < 14 or HCT < 41% Women: HGB < 12.0 or HCT < 36%Women: HGB < 12.0 or HCT < 36%

Anemia and Volume StatusAnemia and Volume Status

HGB and HCT are CONCENTRATIONSHGB and HCT are CONCENTRATIONS Therefore dependent upon plasma volumeTherefore dependent upon plasma volume Acute bleeds not reflected for 24-36 hrsAcute bleeds not reflected for 24-36 hrs

– Due to volume deficit being slowly repaired via Due to volume deficit being slowly repaired via movement of fluid from extravascular space to movement of fluid from extravascular space to intravascularintravascular

Anemic patients who are dehydrated will Anemic patients who are dehydrated will not appear anemicnot appear anemic

Pregnant women expand RBCs 25% but Pregnant women expand RBCs 25% but plasma volume increases 50%, producing plasma volume increases 50%, producing “physiologic anemia”“physiologic anemia”

Anemia: Special CasesAnemia: Special Cases

ErythrocytosisErythrocytosis– People who live at high altitude have greater People who live at high altitude have greater

RBC volumeRBC volume– Smokers have increased HCT – impairs the Smokers have increased HCT – impairs the

ability of the RBCs to deliver O2ability of the RBCs to deliver O2 African-American HGBs are 0.5 to 1.0g/dL African-American HGBs are 0.5 to 1.0g/dL

lower than Caucasianslower than Caucasians Athletes (increased plasma volume, Fe Athletes (increased plasma volume, Fe

deficiency, hemolysis, polycythemia, use deficiency, hemolysis, polycythemia, use of performance enhancing agents)of performance enhancing agents)

Anemia and the ElderlyAnemia and the Elderly

Multiple studies show that the elderly Multiple studies show that the elderly do do notnot have a “lower normal range” have a “lower normal range”

Anemia, while common in the Anemia, while common in the elderly, is still abnormalelderly, is still abnormal

HGB < 13 in males and < 12 in HGB < 13 in males and < 12 in females associated with an increased females associated with an increased relative risk of mortality (1.6 and 2.3 relative risk of mortality (1.6 and 2.3 respectively)respectively)

Anemia: HistoryAnemia: History Is the patient bleeding?Is the patient bleeding?

– NSAIDs, ASANSAIDs, ASA– Menstrual history, if applicable (include older Menstrual history, if applicable (include older

women)women)– Prior intestinal surgery?Prior intestinal surgery?– Hx of hemorrhoids, hematochezia, or melena?Hx of hemorrhoids, hematochezia, or melena?

Past medical history of anemia? Family history?Past medical history of anemia? Family history? Alcohol, nutritional questionsAlcohol, nutritional questions Liver, renal diseasesLiver, renal diseases EthnicityEthnicity Environmental/work toxins (ie lead)Environmental/work toxins (ie lead)

Symptoms of AnemiaSymptoms of Anemia

Decreased O2 deliveryDecreased O2 delivery Hypovolemia if acute lossHypovolemia if acute loss Exertional dyspnea, fatigue, Exertional dyspnea, fatigue,

palpitations, lightheadednesspalpitations, lightheadedness Severe: heart failure, anginaSevere: heart failure, angina ““Pica”– craving for clay or paper Pica”– craving for clay or paper

productsproducts Pagophagia– craving for icePagophagia– craving for ice

Signs of AnemiaSigns of Anemia

Tachycardia, tachypnea, orthostasisTachycardia, tachypnea, orthostasis PallorPallor JaundiceJaundice MurmurMurmur Koilonychia or “Spoon nails”Koilonychia or “Spoon nails” Splenomegaly, lymphadenopathySplenomegaly, lymphadenopathy Petechiae, ecchymosesPetechiae, ecchymoses Atrophy of tongue papillaeAtrophy of tongue papillae Heme + stoolHeme + stool

The Four Causes of AnemiaThe Four Causes of Anemia

Decreased red blood cell Decreased red blood cell productionproduction

Increased red blood cell Increased red blood cell destructiondestruction

Red blood cell lossRed blood cell lossRed blood cell sequestrationRed blood cell sequestration

* Underlying disorder is abnormal production vs. premature loss

Decreased RBC productionDecreased RBC production

Deficiency of iron, B12, folateDeficiency of iron, B12, folate Marrow is dysfunctional from Marrow is dysfunctional from

myelodysplasia, tumor infiltration, myelodysplasia, tumor infiltration, aplastic anemia, etc.aplastic anemia, etc.

Bone marrow is suppressed by Bone marrow is suppressed by chemotherapy or radiationchemotherapy or radiation

Low levels of erythropoeitin, thyroid Low levels of erythropoeitin, thyroid hormone, or androgenshormone, or androgens

Increased RBC destructionIncreased RBC destruction

RBCs live about 100 daysRBCs live about 100 days Acquired: autoimmune hemolytic Acquired: autoimmune hemolytic

anemia, TTP-HUS, DIC, malariaanemia, TTP-HUS, DIC, malaria Inherited: spherocytosis, sickle cell, Inherited: spherocytosis, sickle cell,

thalassemiathalassemia

RBC LossRBC Loss

Bleeding!Bleeding! Obvious vs occultObvious vs occult Iatrogenic: venesection e.g. daily Iatrogenic: venesection e.g. daily

CBC, surgical, hemodialysisCBC, surgical, hemodialysis RetroperitonealRetroperitoneal

Approach to AnemiaApproach to AnemiaCBC

Reticulocyte countMCV

RI < 2% RI > 2%

Underproduction Increased destruction or loss

MCV < 80Microcytic

MCV > 100Macrocytic

MCV 81 – 99Normocytic

MCVFurther work upBased on history, Physical, other

Approach to AnemiaApproach to Anemia LOOK AT THE LOOK AT THE

SMEAR!!!!SMEAR!!!! Convenient to separate Convenient to separate

into three classes based into three classes based on the size of the RBCon the size of the RBC

MCV and RDWMCV and RDW Microcytosis: < 80 fLMicrocytosis: < 80 fL Normocytosis: 80-100 Normocytosis: 80-100

fLfL Macrocytosis: >100 fLMacrocytosis: >100 fL CBC, reticulocyte count, CBC, reticulocyte count,

Fe, Ferritin, TIBC, folate, Fe, Ferritin, TIBC, folate, B12, LDH, CMP, ESR…B12, LDH, CMP, ESR…

ReticulocytesReticulocytes

Nucleated RBCs – form in marrow where Nucleated RBCs – form in marrow where they mature for 3 days and then spend 1 they mature for 3 days and then spend 1 day in circulation (before maturing to RBC)day in circulation (before maturing to RBC)

Given avg life span of RBC of 100 days, Given avg life span of RBC of 100 days, 1% of RBCs are destroyed each day1% of RBCs are destroyed each day

Retics form 1% of circulating RBCs qdRetics form 1% of circulating RBCs qd Nl RBC count is 5 million/uL so marrow Nl RBC count is 5 million/uL so marrow

makes 50,000 reticulocytes/uL blood qdmakes 50,000 reticulocytes/uL blood qd– With epo, can increase to 250,000 retics/uL With epo, can increase to 250,000 retics/uL

blood qd (given nl marrow and replete iron, blood qd (given nl marrow and replete iron, folate, b12)folate, b12)

Reticulocyte CountReticulocyte Count

Assess adequacy of bone marrow response to anemiaAssess adequacy of bone marrow response to anemia Must adjust for the degree of anemia, use Must adjust for the degree of anemia, use

Reticulocyte Production IndexReticulocyte Production Index RI = (measured retic) x (Hct/45) / (Correction Factor)RI = (measured retic) x (Hct/45) / (Correction Factor)

– CF: Hct 41-50 (1); 30-40 (1.5); 20-29 (2); 10-19 (2.5) CF: Hct 41-50 (1); 30-40 (1.5); 20-29 (2); 10-19 (2.5) – Reflects increased circulating time for retics as Epo pushes Reflects increased circulating time for retics as Epo pushes

them out of the marrow earlierthem out of the marrow earlier RI < 1.0 is abnormally low and indicates inadequate RI < 1.0 is abnormally low and indicates inadequate

marrow responsemarrow response

Microcytic AnemiaMicrocytic Anemia

Iron Deficiency Iron Deficiency AnemiaAnemia

Thallasemia Thallasemia Anemia of chronic Anemia of chronic

diseasedisease Sideroblastic Sideroblastic

anemia anemia

Iron Deficiency AnemiaIron Deficiency Anemia The definitive test is serum The definitive test is serum

ferritinferritin Low serum ferritin (<12 Low serum ferritin (<12

ug/L)is diagnostic of iron ug/L)is diagnostic of iron deficiencydeficiency

Although ferritin is an acute Although ferritin is an acute phase reactant, it will still be phase reactant, it will still be low in iron deficiencylow in iron deficiency

Also, high TIBCAlso, high TIBC– Fe saturation = Fe/TIBC < Fe saturation = Fe/TIBC <

10% in Fe deficiency10% in Fe deficiency– If ferritin is indeterminateIf ferritin is indeterminate

Low serum Fe is not in itself Low serum Fe is not in itself diagnostic, neither is marrow diagnostic, neither is marrow stainingstaining

Anisocytosis (heterogeneous Anisocytosis (heterogeneous in shape) and poikilocytosis in shape) and poikilocytosis (abnormal shape)(abnormal shape)

Reactive thrombocytosisReactive thrombocytosis

Iron deficiencyIron deficiency

ThalassemiaThalassemia

Decreased production of either Decreased production of either αα--globin or globin or ββ-globin chains-globin chains

Abnormal hemoglobin Abnormal hemoglobin electrophoresiselectrophoresis

Polychromasia (dark staining retics), Polychromasia (dark staining retics), target cells, basophilic stipplingtarget cells, basophilic stippling

Normal/increased RBC massNormal/increased RBC mass Mentzer index: MCV/RBC ct < 13Mentzer index: MCV/RBC ct < 13

AlphaAlpha-Thalassemia-Thalassemia

AlphaAlpha-Thalassemia: 4 genes-Thalassemia: 4 genes 1/4: silent carrier1/4: silent carrier 2/4: 2/4: AlphaAlpha-Thalassemia trait, -Thalassemia trait,

microcytosis and mild anemiamicrocytosis and mild anemia 3/4: excess 3/4: excess BetaBeta-chains form -chains form

tetramers, results in severe anemia tetramers, results in severe anemia and microcytosisand microcytosis

4/4: hydrops fetalis4/4: hydrops fetalis Most common in SE Asian populationsMost common in SE Asian populations

Basophilic stipplingBasophilic stippling

BetaBeta-Thalassemia-Thalassemia

2 genes2 genes 1/2 mutation: 1/2 mutation: BetaBeta-Thal trait, -Thal trait,

increased Hgb A2, rarely anemic, mild increased Hgb A2, rarely anemic, mild microcytosismicrocytosis

2/2 mutation: 2/2 mutation: BetaBeta-Thalassemia -Thalassemia disease, Hgb F, microcytosis, anemiadisease, Hgb F, microcytosis, anemia

Usually found in people of African or Usually found in people of African or Mediterranean descent but has world-Mediterranean descent but has world-wide distributionwide distribution

Beta - Beta - ThalassemiaThalassemia

Sideroblastic AnemiaSideroblastic Anemia

Failure of synthesis of porphyrin ring

Hereditary

Acquired (INH, EtOH, B6 deficiency, Lead)

Smear: sideroblasts and basophilic stippling

Macrocytic Anemia Macrocytic Anemia (MCV>100)(MCV>100)

Drug Induced (hydroxyurea, AZT, Drug Induced (hydroxyurea, AZT, MTX, chemotherapy, MTX, chemotherapy, anticonvulsants)anticonvulsants)

B12 / folate deficiencyB12 / folate deficiency Myelodysplastic syndromeMyelodysplastic syndrome Liver diseaseLiver disease Alcohol abuseAlcohol abuse Reticulocytes Reticulocytes HypothyroidismHypothyroidism

Folate and B12Folate and B12 Serum folate usually sufficient, but if folate Serum folate usually sufficient, but if folate

level is normal but folate deficiency is level is normal but folate deficiency is suspected, check serum homocysteine suspected, check serum homocysteine (elevated because of impaired folate (elevated because of impaired folate dependent conversion of homocysteine to dependent conversion of homocysteine to methionine) or RBC-folate.methionine) or RBC-folate.

B12 can be spuriously low– a more sensitive B12 can be spuriously low– a more sensitive and specific test is serum methylmalonic acid and specific test is serum methylmalonic acid level, will be increased if B12 is low.level, will be increased if B12 is low.

Classically check Schilling Test for B12 Classically check Schilling Test for B12 deficiency (parietal cell antibody or Intrinsic deficiency (parietal cell antibody or Intrinsic Factor antibody)Factor antibody)

B12 and Folate DeficiencyB12 and Folate Deficiency

Myelodysplastic SyndromeMyelodysplastic Syndrome

Primary bone Primary bone marrow disorder, marrow disorder, often found in often found in elderlyelderly

Macrocytosis, Macrocytosis, anemiaanemia

Pseudo-Pelger-Huet Pseudo-Pelger-Huet abnormality– the abnormality– the bilobed nucleusbilobed nucleus

Normocytic AnemiaNormocytic Anemia

Large and complicated group of Large and complicated group of disorders!disorders!

Hemolytic anemiasHemolytic anemias Anemia of chronic diseaseAnemia of chronic disease Bone marrow disorderBone marrow disorder Nutritional (early Fe, B12, folate Nutritional (early Fe, B12, folate

deficiency)deficiency) Renal insufficiencyRenal insufficiency

Nutritional AnemiasNutritional Anemias

Iron deficiency and B12/folate Iron deficiency and B12/folate deficiency can present with deficiency can present with normocytic anemia– esp. if both normocytic anemia– esp. if both deficiencies are concurrent.deficiencies are concurrent.

Check iron studies and B12, folate Check iron studies and B12, folate levels.levels.

Anemia of Renal Anemia of Renal InsufficiencyInsufficiency

Unremarkable peripheral blood smearUnremarkable peripheral blood smear Inappropriately normal erythropoietin Inappropriately normal erythropoietin

levellevel Anemia usually severe and symptomatic Anemia usually severe and symptomatic

when Cr > 3.0when Cr > 3.0 Mild to moderate anemia found in Cr Mild to moderate anemia found in Cr

1.5-3.01.5-3.0 Tx: Epogen or similar, Fe (oral, IV) if iron Tx: Epogen or similar, Fe (oral, IV) if iron

stores are found to be lowstores are found to be low

Hemolytic AnemiasHemolytic Anemias

Evaluation of HemolysisEvaluation of Hemolysis LDH: increasesLDH: increases Indirect bilirubin increases Indirect bilirubin increases

(increased Hgb catabolism)(increased Hgb catabolism) Haptoglobin decreasesHaptoglobin decreases Reticulocyte count Reticulocyte count

increasesincreases Urine hemosiderin test = Urine hemosiderin test =

present in intravascular, present in intravascular, absent in extravascular absent in extravascular hemolysis!hemolysis!

Coombs test:Coombs test:– (+) = autoimmune (+) = autoimmune

hemolytic anemiahemolytic anemia– (-) consider PNH (abnormal (-) consider PNH (abnormal

GPI protein, send flow for GPI protein, send flow for CD55 and CD59)CD55 and CD59)

Hemolytic Anemia: Intrinsic Hemolytic Anemia: Intrinsic causescauses

Spherocytosis, Sickle CellSpherocytosis, Sickle Cell

More hemolytic anemiasMore hemolytic anemias

Anemia of Chronic DiseaseAnemia of Chronic Disease

Thought to be a cytokine mediated process Thought to be a cytokine mediated process which inhibits red blood cell production or which inhibits red blood cell production or interferes with action of erythropoietininterferes with action of erythropoietin– Therefore, the disease needs to be inflammatoryTherefore, the disease needs to be inflammatory

Decreased iron utilization/mobilizationDecreased iron utilization/mobilization Seen with rheumatologic diseases, chronic Seen with rheumatologic diseases, chronic

infections, malignancyinfections, malignancy Indices: Low Fe, Low TIBC, Nl/increased Indices: Low Fe, Low TIBC, Nl/increased

FerritinFerritin May be seen in conjunction with Fe-deficiencyMay be seen in conjunction with Fe-deficiency

Anemia due to Primary Bone Anemia due to Primary Bone Marrow DisorderMarrow Disorder

Myelodysplastic Myelodysplastic syndromesyndrome

Bone marrow Bone marrow infiltration: nucleated infiltration: nucleated red blood cells found in red blood cells found in circulationcirculation

Might see “rouleaux” Might see “rouleaux” formation in multiple formation in multiple myelomamyeloma

WBC, plts often WBC, plts often abnormalabnormal

Bone marrow biopsyBone marrow biopsy

Anemia: TreatmentsAnemia: Treatments

““Transfusion triggers”Transfusion triggers”– CAD: Hgb > 10CAD: Hgb > 10– All pts: Hgb > 7.0All pts: Hgb > 7.0

Iron supplementationIron supplementation Erythropoietin analogsErythropoietin analogs B12, folateB12, folate

What in the world is a Howell-What in the world is a Howell-Jolly Body?Jolly Body?

Acanthocytes vs Acanthocytes vs EchinocytesEchinocytes

Acanthocytes: “spur cells” found in liver diseaseAcanthocytes: “spur cells” found in liver disease Echinocytes: “burr cells” found in renal diseaseEchinocytes: “burr cells” found in renal disease

Helmet vs. Teardrop CellsHelmet vs. Teardrop Cells

Anemia: SummaryAnemia: Summary

ANEMIA IS NEVER NORMALANEMIA IS NEVER NORMAL Determine if ACUTE or CHRONICDetermine if ACUTE or CHRONIC CONSIDER THE FOUR CAUSESCONSIDER THE FOUR CAUSES CALCULATE the RETIC INDEXCALCULATE the RETIC INDEX LOOK AT THE SMEARLOOK AT THE SMEAR CONSIDER THE ETIOLOGY BASED ON RBC CONSIDER THE ETIOLOGY BASED ON RBC

MORPHOLOGY AND LABORATORY STUDIESMORPHOLOGY AND LABORATORY STUDIES TREAT APPROPRIATELYTREAT APPROPRIATELY

MKSAP QuestionsMKSAP Questions

An 80-year-old man who had a hemicolectomy for colon An 80-year-old man who had a hemicolectomy for colon cancer is evaluated because of a 4-month history of cancer is evaluated because of a 4-month history of diarrhea, anorexia, and fatigue. He had a remote history of diarrhea, anorexia, and fatigue. He had a remote history of alcoholism. alcoholism.

On physical examination, he is cachectic and mildly On physical examination, he is cachectic and mildly confused. His pulse rate is 70/min, and blood pressure is confused. His pulse rate is 70/min, and blood pressure is 140/85 mm Hg. His tongue is smooth. The abdomen is soft; 140/85 mm Hg. His tongue is smooth. The abdomen is soft; there are no palpable masses or hepatosplenomegaly. A there are no palpable masses or hepatosplenomegaly. A stool specimen is negative for occult blood. Neurologic stool specimen is negative for occult blood. Neurologic examination shows loss of position sense in the feet. He has examination shows loss of position sense in the feet. He has a wide-based gait. The Romberg test is positive. His a wide-based gait. The Romberg test is positive. His hemoglobin is 9.4 g/dL, reticulocyte count is 2.5%, mean hemoglobin is 9.4 g/dL, reticulocyte count is 2.5%, mean corpuscular volume is 125 fL, and serum lactate corpuscular volume is 125 fL, and serum lactate dehydrogenase is 400 U/L. dehydrogenase is 400 U/L.

Which of the following is the most likely cause for his Which of the following is the most likely cause for his symptoms?symptoms?

( A ) Alcoholic cerebellar degeneration( A ) Alcoholic cerebellar degeneration( B ) Vitamin B12 deficiency( B ) Vitamin B12 deficiency( C ) Brain metastases( C ) Brain metastases( D ) Folate deficiency( D ) Folate deficiency( E ) Liver metastases( E ) Liver metastases

CritiqueCritique (Correct Answer = (Correct Answer = BB))

The patient most likely has vitamin B12 deficiency, based on the degree of macrocytosis and The patient most likely has vitamin B12 deficiency, based on the degree of macrocytosis and neurologic findings. An elevated serum lactate dehydrogenase level, due to intramarrow cell death neurologic findings. An elevated serum lactate dehydrogenase level, due to intramarrow cell death from ineffective erythropoiesis, is consistent with this diagnosis. from ineffective erythropoiesis, is consistent with this diagnosis.

Severe macrocytosis (mean corpuscular volume > 120 fL) is often associated with vitamin B12 Severe macrocytosis (mean corpuscular volume > 120 fL) is often associated with vitamin B12 deficiency or folate deficiency (megaloblastic anemia), usually seen in conjunction with “oval” deficiency or folate deficiency (megaloblastic anemia), usually seen in conjunction with “oval” macrocytes. The presence of frequent hypersegmented neutrophils (> 5 segments) is strongly macrocytes. The presence of frequent hypersegmented neutrophils (> 5 segments) is strongly suggestive of vitamin B12 or folate deficiency. suggestive of vitamin B12 or folate deficiency.

Bone marrow morphology in patients with vitamin B12 or folate deficiency is referred to as Bone marrow morphology in patients with vitamin B12 or folate deficiency is referred to as “megaloblastic” and is characterized by the presence of large cells with immature nuclear “megaloblastic” and is characterized by the presence of large cells with immature nuclear chromatin but maturing erythrocyte cytoplasm (nuclear-cytoplasmic dissociation). Anemia chromatin but maturing erythrocyte cytoplasm (nuclear-cytoplasmic dissociation). Anemia accompanies this process; hence the term “ineffective erythropoiesis.” The intramarrow death of accompanies this process; hence the term “ineffective erythropoiesis.” The intramarrow death of megaloblastic cells causes the serum lactate dehydrogenase level to rise. If a patient has a low megaloblastic cells causes the serum lactate dehydrogenase level to rise. If a patient has a low serum vitamin B12 or folate level, a bone marrow examination is probably unnecessary. However, serum vitamin B12 or folate level, a bone marrow examination is probably unnecessary. However, the physician should determine the cause of the deficiency. If a patient has a normal serum the physician should determine the cause of the deficiency. If a patient has a normal serum vitamin B12 or folate level, a bone marrow examination is frequently helpful to exclude vitamin B12 or folate level, a bone marrow examination is frequently helpful to exclude myelodysplastic syndromes or other infiltrative marrow disorders. myelodysplastic syndromes or other infiltrative marrow disorders.

Folate deficiency can induce megaloblastosis within weeks to months, whereas vitamin B12 Folate deficiency can induce megaloblastosis within weeks to months, whereas vitamin B12 deficiency requires years to cause megaloblastosis since stores of vitamin B12 persist for years in deficiency requires years to cause megaloblastosis since stores of vitamin B12 persist for years in the liver and other tissues. In patients with vitamin B12 or folate deficiency, parenteral or oral the liver and other tissues. In patients with vitamin B12 or folate deficiency, parenteral or oral repletion of vitamin B12 or folate reverses some morphologic abnormalities within hours. Serum repletion of vitamin B12 or folate reverses some morphologic abnormalities within hours. Serum folate levels fluctuate quickly with changes in dietary consumption. Low erythrocyte folate levels folate levels fluctuate quickly with changes in dietary consumption. Low erythrocyte folate levels often reflect prior nutritional depletion. In patients who are hospitalized and are begun on regular often reflect prior nutritional depletion. In patients who are hospitalized and are begun on regular diets, the erythrocyte folate test may provide a better assessment of tissue folate levels than diets, the erythrocyte folate test may provide a better assessment of tissue folate levels than determination of the serum folate level. The erythrocyte folate test often requires a special determination of the serum folate level. The erythrocyte folate test often requires a special laboratory, and results often are not quickly available. laboratory, and results often are not quickly available.

In patients with megaloblastic anemias, erythrocyte production is diminished and a “corrected” In patients with megaloblastic anemias, erythrocyte production is diminished and a “corrected” reticulocyte count is inappropriately low for the degree of anemia. This patient had a corrected reticulocyte count is inappropriately low for the degree of anemia. This patient had a corrected reticulocyte count of 1% (inappropriately low for a hemoglobin level of 9.4 g/dL). reticulocyte count of 1% (inappropriately low for a hemoglobin level of 9.4 g/dL).

In addition to changes in the blood, the epithelial cells in patients with megaloblastic anemias may In addition to changes in the blood, the epithelial cells in patients with megaloblastic anemias may become atrophic and cause a smooth tongue and cheilosis. Posterior column dysfunction, become atrophic and cause a smooth tongue and cheilosis. Posterior column dysfunction, particularly in patients with vitamin B12 deficiency, may lead to changes in vibratory or position particularly in patients with vitamin B12 deficiency, may lead to changes in vibratory or position sense, causing ataxia. Signs of dementia may appear. However, neurologic dysfunction is very sense, causing ataxia. Signs of dementia may appear. However, neurologic dysfunction is very uncommon in adults with folate deficiency. uncommon in adults with folate deficiency.

Alcoholic cerebellar degeneration results in ataxia but not position loss. Although liver metastases Alcoholic cerebellar degeneration results in ataxia but not position loss. Although liver metastases are possible in a patient with a history of colon cancer, their presence would not account for the are possible in a patient with a history of colon cancer, their presence would not account for the neurological findings in this patient. Brain metastases would most likely produce focal neurological neurological findings in this patient. Brain metastases would most likely produce focal neurological findings and also would not account for the blood findings. findings and also would not account for the blood findings.

A 26-year-old man is evaluated because of progressive A 26-year-old man is evaluated because of progressive fatigue, dyspnea on exertion, and orthostatic dizziness for fatigue, dyspnea on exertion, and orthostatic dizziness for the past 2 to 3 weeks. He takes no medications. Physical the past 2 to 3 weeks. He takes no medications. Physical examination is normal except for pallor. examination is normal except for pallor.

Laboratory Studies: Laboratory Studies: Hematocrit 13%Leukocyte count Hematocrit 13%Leukocyte count 8300/μL; normal differential. Reticulocyte count: 0, Platelet 8300/μL; normal differential. Reticulocyte count: 0, Platelet count 320,000/μL. A routine biochemical profile, including count 320,000/μL. A routine biochemical profile, including liver function tests, is normal. A chest radiograph shows liver function tests, is normal. A chest radiograph shows normal lung fields and a widened mediastinum, suggestive normal lung fields and a widened mediastinum, suggestive of an anterior mediastinal mass. Bone marrow biopsy shows of an anterior mediastinal mass. Bone marrow biopsy shows absent erythrocyte precursors, normal megakaryocytes, absent erythrocyte precursors, normal megakaryocytes, and normal leukocyte numbers and maturation. and normal leukocyte numbers and maturation.

Which of the following is the most likely cause of the Which of the following is the most likely cause of the mediastinal mass and anemia?mediastinal mass and anemia?

( A ) Hodgkin’s disease( A ) Hodgkin’s disease( B ) Non-Hodgkin’s lymphoma( B ) Non-Hodgkin’s lymphoma( C ) Thyroid carcinoma( C ) Thyroid carcinoma( D ) Thymoma( D ) Thymoma( E ) Germ cell carcinoma( E ) Germ cell carcinoma

CritiqueCritique (Correct Answer = (Correct Answer = DD))

Each of the listed neoplasms may present as an anterior Each of the listed neoplasms may present as an anterior mediastinal mass and may be associated with anemia of mediastinal mass and may be associated with anemia of chronic disease. However, pure red cell aplasia (which chronic disease. However, pure red cell aplasia (which this patient has) is often associated with a benign or this patient has) is often associated with a benign or invasive thymoma. Approximately 5% to 15% of invasive thymoma. Approximately 5% to 15% of thymomas occur in patients with pure red cell aplasia. thymomas occur in patients with pure red cell aplasia. Other thymoma-associated autoimmune disorders Other thymoma-associated autoimmune disorders include myasthenia gravis, systemic lupus include myasthenia gravis, systemic lupus erythematosus, thrombocytopenia, and, rarely, erythematosus, thrombocytopenia, and, rarely, malabsorption states. A careful search by CT or MRI is malabsorption states. A careful search by CT or MRI is always warranted in patients with newly diagnosed or always warranted in patients with newly diagnosed or relapsing red cell aplasia or myasthenia. relapsing red cell aplasia or myasthenia.

The other listed entities are also included in the The other listed entities are also included in the differential diagnosis for an anterior mediastinal mass. differential diagnosis for an anterior mediastinal mass. Germ cell tumors have not been associated with pure red Germ cell tumors have not been associated with pure red cell aplasia, and Hodgkin’s disease, non-Hodgkin’s cell aplasia, and Hodgkin’s disease, non-Hodgkin’s lymphoma, and thyroid carcinoma are rarely associated lymphoma, and thyroid carcinoma are rarely associated with this disorder. Chronic lymphocytic leukemia is also with this disorder. Chronic lymphocytic leukemia is also commonly associated with red cell aplasia and may commonly associated with red cell aplasia and may present with variable degrees of lymphadenopathy but present with variable degrees of lymphadenopathy but not with an isolated anterior mediastinal mass, as in the not with an isolated anterior mediastinal mass, as in the patient discussed here. patient discussed here.

A 36-year-old black man with known sickle cell anemia is A 36-year-old black man with known sickle cell anemia is evaluated because of a 2-week history of fever, a macular evaluated because of a 2-week history of fever, a macular rash on his trunk, and arthralgias. Subsequently, he rash on his trunk, and arthralgias. Subsequently, he developed weakness and dyspnea on exertion. Several of developed weakness and dyspnea on exertion. Several of his children had febrile illnesses with associated rashes and his children had febrile illnesses with associated rashes and fatigue over the past month. These illnesses resolved fatigue over the past month. These illnesses resolved spontaneously without sequelae. spontaneously without sequelae.

On physical examination, his temperature is 38.8 °C (101.8 On physical examination, his temperature is 38.8 °C (101.8 °F), pulse rate is 100/min, and blood pressure is 160/70 mm °F), pulse rate is 100/min, and blood pressure is 160/70 mm Hg. A maculopapular, truncal rash is noted. There is Hg. A maculopapular, truncal rash is noted. There is conjunctival pallor. The remainder of his examination is conjunctival pallor. The remainder of his examination is unremarkable. unremarkable.

Laboratory StudiesLaboratory StudiesHemoglobin 5.2 g/dLLeukocyte count Hemoglobin 5.2 g/dLLeukocyte count 5000/μLReticulocyte count 0%Platelet count 5000/μLReticulocyte count 0%Platelet count 130,000/μLSerum lactate dehydrogenase 622 U/L130,000/μLSerum lactate dehydrogenase 622 U/LWhich of Which of the following is the most likely diagnosis?the following is the most likely diagnosis?

( A ) Paroxysmal nocturnal hemoglobinuria( A ) Paroxysmal nocturnal hemoglobinuria( B ) Parvovirus infection( B ) Parvovirus infection( C ) Glucose-6-phosphate dehydrogenase deficiency( C ) Glucose-6-phosphate dehydrogenase deficiency( D ) Aplastic anemia( D ) Aplastic anemia

CritiqueCritique (Correct Answer = (Correct Answer = BB))

Patients with hemolytic disorders may occasionally present with reticulocytopenia and an Patients with hemolytic disorders may occasionally present with reticulocytopenia and an “aplastic crisis.” This patient has sickle cell anemia with parvovirus infection, which is causing “aplastic crisis.” This patient has sickle cell anemia with parvovirus infection, which is causing an aplastic crisis. Parvovirus may infect patients with hemolytic anemias (for example, patients an aplastic crisis. Parvovirus may infect patients with hemolytic anemias (for example, patients with hereditary spherocytosis, sickle cell disease, or thalassemia). In children with sickle cell with hereditary spherocytosis, sickle cell disease, or thalassemia). In children with sickle cell anemia, over 80% of aplastic crises may be attributed to parvovirus infections. In adults, the anemia, over 80% of aplastic crises may be attributed to parvovirus infections. In adults, the usual presenting features are rash, arthritis, and anemia. The “slapped cheek” syndrome is usual presenting features are rash, arthritis, and anemia. The “slapped cheek” syndrome is rarely a presenting feature. There is usually a complete suppression of erythropoiesis to a rarely a presenting feature. There is usually a complete suppression of erythropoiesis to a reticulocyte level of 0%. The bone marrow shows giant dysplastic (megaloblastoid) reticulocyte level of 0%. The bone marrow shows giant dysplastic (megaloblastoid) erythroblasts, occasionally with viral inclusions. The diagnosis is usually made by erythroblasts, occasionally with viral inclusions. The diagnosis is usually made by demonstrating IgM antibodies to the virus. IgG antibodies appear later during the course of the demonstrating IgM antibodies to the virus. IgG antibodies appear later during the course of the infection and persist. Parvovirus in the blood may be detected by the polymerase chain infection and persist. Parvovirus in the blood may be detected by the polymerase chain reaction, which is the definitive diagnostic method. Occasionally, other blood components such reaction, which is the definitive diagnostic method. Occasionally, other blood components such as leukocytes and platelets are affected and result in mild to moderate pancytopenia. as leukocytes and platelets are affected and result in mild to moderate pancytopenia.

The diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) should be considered in patients The diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) should be considered in patients with bone marrow failure or aplasia, unusual location of thromboses, and unexplained with bone marrow failure or aplasia, unusual location of thromboses, and unexplained hemolysis. The anemia may be severe, and patients with PNH typically have reticulocytopenia. hemolysis. The anemia may be severe, and patients with PNH typically have reticulocytopenia. There is no characteristic finding on bone marrow examination, although the bone marrow of There is no characteristic finding on bone marrow examination, although the bone marrow of patients with PNH may demonstrate myelodysplastic changes. The diagnosis is based on patients with PNH may demonstrate myelodysplastic changes. The diagnosis is based on demonstration of exquisite sensitivity to complement-mediated lysis by the sucrose lysis test or demonstration of exquisite sensitivity to complement-mediated lysis by the sucrose lysis test or the acidified serum lysis test (Ham’s test). the acidified serum lysis test (Ham’s test).

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is another cause of hemolysis that Glucose-6-phosphate dehydrogenase (G6PD) deficiency is another cause of hemolysis that occasionally is associated with reticulocytopenia. In patients with G6PD deficiency, erythrocytes occasionally is associated with reticulocytopenia. In patients with G6PD deficiency, erythrocytes are subject to oxidative stresses. Hemoglobin becomes oxidized and precipitates within the are subject to oxidative stresses. Hemoglobin becomes oxidized and precipitates within the erythrocytes, which then undergo destruction by the reticuloendothelial system. G6PD erythrocytes, which then undergo destruction by the reticuloendothelial system. G6PD deficiency is an autosomal recessive disorder that predominantly affects males. After a deficiency is an autosomal recessive disorder that predominantly affects males. After a hemolytic episode, qualitative assays may be normal because only erythrocytes that are hemolytic episode, qualitative assays may be normal because only erythrocytes that are resistant to G6PD remain. The African variant of G6PD is associated with a mild form of resistant to G6PD remain. The African variant of G6PD is associated with a mild form of hemolysis, whereas the Mediterranean variant is usually severe. Causes include infectious hemolysis, whereas the Mediterranean variant is usually severe. Causes include infectious stresses, drugs such as quinidine and sulfonamides, or, in the Mediterranean variant, favism stresses, drugs such as quinidine and sulfonamides, or, in the Mediterranean variant, favism (consumption of fava beans). Therapy requires avoiding certain medications and supportive (consumption of fava beans). Therapy requires avoiding certain medications and supportive care in crisis situations. care in crisis situations.

In contrast to this patient’s presentation, patients with aplastic anemia have pancytopenia with In contrast to this patient’s presentation, patients with aplastic anemia have pancytopenia with severe anemia, reticulocytopenia, thrombocytopenia, and granulocytopenia. In patients with severe anemia, reticulocytopenia, thrombocytopenia, and granulocytopenia. In patients with severe aplastic anemia, the bone marrow examination shows less than 5% cellularity with only severe aplastic anemia, the bone marrow examination shows less than 5% cellularity with only residual lymphocytes and plasma cells. The abnormal cells described above that are residual lymphocytes and plasma cells. The abnormal cells described above that are attributable to parvovirus infection are not seen. attributable to parvovirus infection are not seen.

A 36-year-old man is evaluated because of fatigue. He has had A 36-year-old man is evaluated because of fatigue. He has had two episodes of acute gouty arthritis over the past 6 months. He two episodes of acute gouty arthritis over the past 6 months. He has a 10-year history of significant alcohol use, but he quit has a 10-year history of significant alcohol use, but he quit drinking 4 months ago. He works in a factory making battery drinking 4 months ago. He works in a factory making battery products. A complete blood count obtained prior to elective hernia products. A complete blood count obtained prior to elective hernia repair surgery 4 years ago was normal. He takes no medications. repair surgery 4 years ago was normal. He takes no medications.

On physical examination, his temperature is 37.3 °C (99.1 °F), On physical examination, his temperature is 37.3 °C (99.1 °F), pulse is 60/min, and blood pressure is 135/70 mm Hg. His skin is pulse is 60/min, and blood pressure is 135/70 mm Hg. His skin is normal. There is slight scleral icterus. There is a blue line at the normal. There is slight scleral icterus. There is a blue line at the edge of his gums. edge of his gums.

The remainder of the examination is normal. Stool specimens are The remainder of the examination is normal. Stool specimens are negative for blood on three occasions. negative for blood on three occasions.

Laboratory StudiesLaboratory StudiesHemoglobin 7.5 g/dLMean corpuscular Hemoglobin 7.5 g/dLMean corpuscular volume 71 flLeukocyte count 9400/µLReticulocyte count volume 71 flLeukocyte count 9400/µLReticulocyte count 5.3%Platelet count 435,000/µLSerum lactate dehydrogenase 553 5.3%Platelet count 435,000/µLSerum lactate dehydrogenase 553 U/LSerum uric acid 11 mg/dLA peripheral blood smear is shown. U/LSerum uric acid 11 mg/dLA peripheral blood smear is shown.

Which of the following diagnostic studies is most useful for Which of the following diagnostic studies is most useful for determining the cause of this patient’s anemia?determining the cause of this patient’s anemia?

( A ) Serum iron, total iron-binding capacity, and ferritin levels( A ) Serum iron, total iron-binding capacity, and ferritin levels( B ) Serum lead levels( B ) Serum lead levels( C ) Direct and indirect antiglobulin tests( C ) Direct and indirect antiglobulin tests( D ) Hemoglobin A2 quantitation( D ) Hemoglobin A2 quantitation( E ) Serum ethanol and folic acid levels( E ) Serum ethanol and folic acid levels

CritiqueCritique (Correct Answer = (Correct Answer = BB))

The patient has chronic lead intoxication that can be confirmed by measuring serum The patient has chronic lead intoxication that can be confirmed by measuring serum lead levels. He has a hypochromic, microcytic anemia with coarse basophilic lead levels. He has a hypochromic, microcytic anemia with coarse basophilic stippling and reticulocytosis. He also has evidence of hemolytic anemia with stippling and reticulocytosis. He also has evidence of hemolytic anemia with increased serum lactate dehydrogenase and indirect bilirubin levels. His physical increased serum lactate dehydrogenase and indirect bilirubin levels. His physical examination is remarkable for gingival “lead lines.” Bone marrow examination examination is remarkable for gingival “lead lines.” Bone marrow examination shows erythroid hyperplasia and ringed sideroblasts. The anemia of lead poisoning shows erythroid hyperplasia and ringed sideroblasts. The anemia of lead poisoning fits this description. Sideroblastic anemia with hypochromic indices is typical. fits this description. Sideroblastic anemia with hypochromic indices is typical. Hemolysis is common, and basophilic stippling, blue staining polyribosomal Hemolysis is common, and basophilic stippling, blue staining polyribosomal aggregates with mitochondrial fragments in the erythrocytes, is frequently seen. aggregates with mitochondrial fragments in the erythrocytes, is frequently seen. Lead inhibits pyrimidine 5′-nucleotidase which normally clears ribosomal fragments. Lead inhibits pyrimidine 5′-nucleotidase which normally clears ribosomal fragments. Occupational exposures to lead are relatively uncommon today. However, workers Occupational exposures to lead are relatively uncommon today. However, workers who produce batteries or are exposed to paint, particularly those who remove who produce batteries or are exposed to paint, particularly those who remove leaded paint from old buildings, are at greatest risk if they are not protected from leaded paint from old buildings, are at greatest risk if they are not protected from inhalation of paint particles during the sanding process. Other manifestations of inhalation of paint particles during the sanding process. Other manifestations of lead toxicity in adults include peripheral neuropathy, abdominal colic, and saturnine lead toxicity in adults include peripheral neuropathy, abdominal colic, and saturnine gout (effects of lead on renal tubules that prevent the excretion of uric acid). gout (effects of lead on renal tubules that prevent the excretion of uric acid). Chelation therapy is indicated for patients with serum lead levels exceeding 70 Chelation therapy is indicated for patients with serum lead levels exceeding 70 µg/dL and should be continued until lead levels fall below 40 µg/dL. Agents such as µg/dL and should be continued until lead levels fall below 40 µg/dL. Agents such as EDTA or dimercaprol may also be effective. EDTA or dimercaprol may also be effective.

This patient is unlikely to have iron deficiency since his reticulocytes are increased. This patient is unlikely to have iron deficiency since his reticulocytes are increased. In addition, basophilic stippling usually is not seen in patients with iron deficiency. In addition, basophilic stippling usually is not seen in patients with iron deficiency.

Thalassemia is associated with a microcytic anemia, reticulocytosis, and basophilic Thalassemia is associated with a microcytic anemia, reticulocytosis, and basophilic stippling. However, a normal complete blood count 4 years ago rules out this stippling. However, a normal complete blood count 4 years ago rules out this possibility. Therefore, quantitative studies to measure hemoglobin A2 are not possibility. Therefore, quantitative studies to measure hemoglobin A2 are not necessary. necessary.

Autoimmune hemolytic anemia should be excluded by performing a direct Autoimmune hemolytic anemia should be excluded by performing a direct antiglobulin test in any patient who has evidence of hemolysis on a peripheral blood antiglobulin test in any patient who has evidence of hemolysis on a peripheral blood smear. However, the “lead lines” on this patient’s gingivae are classic for lead smear. However, the “lead lines” on this patient’s gingivae are classic for lead poisoning, and autoimmune hemolytic anemia therefore is less likely. poisoning, and autoimmune hemolytic anemia therefore is less likely.

Alcoholism may cause a transient sideroblastic anemia, which resolves with Alcoholism may cause a transient sideroblastic anemia, which resolves with cessation of alcohol intake. Folic acid deficiency may complicate alcoholism but cessation of alcohol intake. Folic acid deficiency may complicate alcoholism but usually presents with macrocytosis. usually presents with macrocytosis.

A 22-year-old man is evaluated in the intensive care unit A 22-year-old man is evaluated in the intensive care unit because of bleeding immediately after scoliosis surgery. because of bleeding immediately after scoliosis surgery. During surgery, 12 units of packed red blood cells and 12 During surgery, 12 units of packed red blood cells and 12 units of fresh frozen plasma were transfused. There is no units of fresh frozen plasma were transfused. There is no history of a bleeding disorder or of drug administration that history of a bleeding disorder or of drug administration that could affect platelet function. could affect platelet function.

On physical examination, the patient is afebrile. His pulse On physical examination, the patient is afebrile. His pulse rate is 100/min, and blood pressure is 110/72 mm Hg. rate is 100/min, and blood pressure is 110/72 mm Hg. Petechiae are present on his arms, and blood is oozing from Petechiae are present on his arms, and blood is oozing from the drains. the drains.

Laboratory StudiesLaboratory StudiesHemoglobin 9.0 g/dLPlatelet count Hemoglobin 9.0 g/dLPlatelet count 43,000/µLProthrombin time 12 sActivated partial 43,000/µLProthrombin time 12 sActivated partial thromboplastin time 32 sPlasma fibrinogen 400 g/dLd-thromboplastin time 32 sPlasma fibrinogen 400 g/dLd-Dimers NegativeDimers NegativeWhich of the following is the most Which of the following is the most likely cause of the thrombocytopenia and bleeding?likely cause of the thrombocytopenia and bleeding?

( A ) Dilutional thrombocytopenia( A ) Dilutional thrombocytopenia( B ) Incompatible blood transfusion( B ) Incompatible blood transfusion( C ) Posttransfusion purpura( C ) Posttransfusion purpura( D ) Septic transfusion reaction( D ) Septic transfusion reaction

CritiqueCritique (Correct Answer = (Correct Answer = AA))

Approximately a 50% reduction in the platelet count occurs when Approximately a 50% reduction in the platelet count occurs when transfusions of 1.5 to 2 times the blood volume are given over 4 to 8 transfusions of 1.5 to 2 times the blood volume are given over 4 to 8 hours. Blood stored for more that 2 to 3 days has essentially no hours. Blood stored for more that 2 to 3 days has essentially no platelets, which explains the thrombocytopenia. Fresh frozen plasma platelets, which explains the thrombocytopenia. Fresh frozen plasma contains all of the clotting proteins in normal concentrations. This contains all of the clotting proteins in normal concentrations. This patient received one unit of fresh frozen plasma for each unit of patient received one unit of fresh frozen plasma for each unit of transfused red blood cells, which resulted in no measurable transfused red blood cells, which resulted in no measurable alteration in the prothrombin time or activated partial alteration in the prothrombin time or activated partial thromboplastin time. Incompatible red blood cell transfusions can thromboplastin time. Incompatible red blood cell transfusions can lead to the development of disseminated intravascular coagulation, lead to the development of disseminated intravascular coagulation, which is characterized by thrombocytopenia. The other hallmarks of which is characterized by thrombocytopenia. The other hallmarks of disseminated intravascular coagulation are absent in this patient, disseminated intravascular coagulation are absent in this patient, namely, he has a normal fibrinogen, prothrombin time, activated namely, he has a normal fibrinogen, prothrombin time, activated partial thromboplastin time, and negative d-dimers. Posttransfusion partial thromboplastin time, and negative d-dimers. Posttransfusion purpura is characterized by profound thrombocytopenia that purpura is characterized by profound thrombocytopenia that develops 5 to 7 days after a transfusion. It occurs in patients who develops 5 to 7 days after a transfusion. It occurs in patients who are negative for the PLA-1 human platelet antigen and have been are negative for the PLA-1 human platelet antigen and have been transfused or pregnant in the past. Posttransfusion purpura almost transfused or pregnant in the past. Posttransfusion purpura almost always occurs in women. always occurs in women.

Septic transfusion reactions can be associated with Septic transfusion reactions can be associated with thrombocytopenia when either bacteremia or endotoxemia causes thrombocytopenia when either bacteremia or endotoxemia causes disseminated intravascular coagulation. This patient has no disseminated intravascular coagulation. This patient has no indication of either sepsis or disseminated intravascular coagulation. indication of either sepsis or disseminated intravascular coagulation.