A. Introduction [6]

1. Refers to reduction in red blood cell (RBC, erythrocyte) counts
2. Common medical problem
3. Distinguish between acute and chronic anemia
4. In evaluating anemia, consider RBC production versus destruction or loss
5. Compensatory Mechanisms in Anemia
   1. Cardiac output increases
   2. Tissues increase oxygen extraction (mixed venous oxygen decreases)
   3. Blood flow redistributed to vital organs (brain, heart, kidney)
6. Normally, hemoglobin (Hb) is ~14gm/dL for men and ~12gm/dL for women

B. Symptoms of Anemia

1. Depends on magnitude and duration of anemia
2. Acute anemia leads to marked, acute symptoms
3. Chronic anemia tolerated to ~5gm/dL Hb levels
4. Dyspnea on exertion and shortness of breath often initial symptom with acute anemia
5. Fatigue - may be most prominent symptom with chronic anemia
6. Tachypnea
7. Tachycardia / palpitations
8. Diaphoresis
9. Lightheadedness and dizziness
10. Near syncope / syncope
11. Delirium
12. Untreated severe anemia can cause organ dsyfunction and death

C. Treatment

1. Underlying cause
2. Severe anemia should be treated with blood transfusion [6]
   1. Goal is typically Hb > 8-10gm/dL
   2. Each unit of packed RBC increases Hb ~1gm/dL
3. Chronic Anemia
   1. Treat underlying cause
   2. Erythropoietin (EPO) and other RBC-generating agents
   3. Critically ill patients often receive transfusions; EPO of minor benefit

CLASSIFICATION OF ANEMIAS [7]
[Figure] "Evaluation of Anemia"

A. Hemoglobinopathy [2,13]

1. Hemoglobin (Hb) Sickle Cell (HbSS)
2. HbSC Disease
3. Sickle-Thalassemia
4. Thalassemia (alpha or beta)
5. Overall, ~5% of world's population carry globin variant mutations [2]
   1. ~1.9% carry HbSS; 0.2% have sickle cell anemia
   2. ~1% carry HbE
   3. ~0.3% carry HbC
   4. ~0.044 have thalassemia

B. Enzyme Or Protein Abnormalities

1. Pyruvate Kinase Deficiency
2. Glucose-6-Phosphate Dehydrogenase Deficiency
3. Abnormal red blood cell (RBC) skeletal proteins
4. Many others, far less common

C. Microcytic

1. Iron (Fe) Deficiency
2. Thalassemia
3. Anemia of Chronic Disease
4. Thalassemia Trait
5. Lead Poisoning

D. Macrocytic

1. Reticulocytosis - any cause of enhanced destruction
   1. Hemolytic Anemia
   2. Hemoglobinopathies
   3. Enzyme deficiencies
   4. Recovery from acute hemorrhage
2. Hypothyroidism
3. Chronic Liver Disease
4. Megaloblastic
   1. Folate Deficiency - rare in USA [17]
   2. Vitamin B12 Deficiency
   3. Myelodysplastic Syndrome

E. Microangiopathic Hemolytic Anemias

1. Hemolytic Uremic Syndrome (HUS)
2. Thrombobotic Thrombocytopenic Purpura (TTP)
3. Disseminated Intravascular Coagulopathy (DIC)
4. Pregnancy Induced Hypertension: Severe pre-eclamsia (HELLP Syndrome)
5. Disseminated malignancy

1. Hypochromic, microcytic anemia in patients with chronic inflammation of any type
   1. Hallmark of ACD is disturbance of iron homeostasis
   2. Increased uptake and retention of iron in cells of reticulendothelial system
   3. Impaired proliferation of erythroid progenitor cells
2. Pathogenesis [12,15]
   1. Chronic production of Interleukin 1, tumor necrosis factor alpha (TNFa), interferon gamma
   2. These inflammatory cytokines suppress production of erythropoietin (EPO)
   3. Inflammatory cytokines also block development of RBC from precursor cells
   4. Iron mobilization is inhibited, but iron stores in the body are normal
3. Characteristics of Anemia of Chronic Disease:
   1. Low serum iron levels
   2. Low or normal serum transferrin levels
   3. Transferrin saturation reduced (<16%)
   4. Ferritin normal to increased
   5. Soluble transferrin receptor normal
   6. Ratio of soluble transferrin receptor to log ferritin (low, <1)
   7. Cytokine levels and C-reactive protein increased
   8. EPO levels often reduced
   9. Low total iron binding capacity (TIBC)
4. Anemia of Chronic Disease and Iron Deficiency Anemia [1,19]
   1. Iron deficiency anemia has the opposite transferrin/TIBC/Ferritin profile
   2. Transferrin receptor-ferritin index (TRFI) is superior to usual profiles to distinguish these types of anemia in the elderly [19]
   3. TRFI = transferrin receptor level ÷ Log(ferritin level)
   4. TRFI represents total body iron and iron available for erythropoiesis
   5. TRFI > 1.5 is 98% predictive of iron deficiency anemia
   6. TRFI <1.5 is 68% predictive that iron deficiency anemia is not present
   7. Iron defficiency often coexists with ACD and both may need to be treated
5. Evaluation of Anemia with Reduced Serum Iron [1]
   1. Determine if evidence of inflammation present, clinical and/or laboratory
   2. Transferrin saturation <16%
   3. Rule out other causes of anemia
   4. Ferritin <30ng/mL indicates iron deficiency anemia
   5. Ferritin >100ng/mL indicates ACD
   6. Ferritin 30-100ng/mL --> determine soluble transferrin receptor and TRFI
   7. TRFI <1 means ACD; TRFI >2 means ACD with true iron deficiency anemia
6. Treatment
   1. Transfusions should be given for severe anemia (as in any anemia)
   2. Goal Hb levels are 11-12gm/dL
   3. Suppression of inflammation also leads to reversal of anemia
   4. Reversal of inflammation leads to normalization of iron metabolism
   5. Treatment with EPO has some efficacy (iron may also need to be given)
   6. Recombinant EPO can reduce transfusion requirements in critically ill anemia patients [20]
   7. In another study, recombinant EPO did not reduce transfusion requirements overall in critically ill patients, but did reduce transfusions in trauma patients [8]
   8. Recombinant EPO increased Hb levels from 1.2gm/dL placebo versus 1.6gm/dL, and increased thrombotic events by 40% in critically ill patients [8]

B. Acquired Red Cell Aplasia

1. Usually in middle aged adults
2. 33% have thymomas
3. Failure of red cell development
4. May be caused by viral infection (? parvovirus B19)

C. Aplastic Anemia

1. Complete failure of bone marrow
2. Manifestations include autoimmune form, viral infection (Parovirus B19), drug reaction
3. Treatment solumedrol 20mg/kg/day, anti-thymocyte globulin in severe cases
4. Intravenous immunolobulin (IVIg) has little or no effect
5. May require bone marrow transplantation

D. Blackfan-Diamond Syndrome

1. Idiopathic pure red cell aplasia, usually in young children
2. Increased MCV (size of red cells)
3. May be treated with glucocorticoids, transfusions, other agents
4. Usually resolves spontaneously

E. Burr Cell Anemia

1. Echinocytes - "urchin" shaped, uniform projections from RBC surface
2. Most commonly seen in uremia, some hemolytic anemias
3. May also be artifact of RBC storage

F. Elliptocytosis (hereditary) [13]

1. Structural defect, ovalocytes, with various forms of disease
2. Reduced RBC survival, large spleen
3. Several genetic mutations can lead to elliptocytosis
   1. Diminished spectrin interactions due to defects in alpha or beta spectrin
   2. Deficiency or dysfunction of protein 4.1
   3. Deficiency of glycophorin C
4. Variable responses to splenectomy

G. Fanconi's Anemia (FA) [21]

1. Most common type of aplastic anemia, childhood onset:
   1. Aplastic anemia
   2. Developmental defects
   3. Cancer susceptibility
   4. Cellular hypersensitivity to DNA-cross-linking agents
2. Autosomal recessive inherited disease [22]
   1. At least 8 complementation groups:
   2. FA-A, -B, -C, -D1, -D2, -E, -F, -G
   3. FA proteins encoded by 6 cloned FA genes (-A, -C, -D2, -E, -F, -G)
   4. These genes cooperate in common pathway involving DNA repair
   5. Monoubiquitination of FNAC-D2 protein and colocalization with BRCA1 in nuclear foci
   6. BRCA1 and BRCA2 implicated in DNA repair via homologous recombination
3. Developmental abnormalities of kidney, bone, and digits most common
4. Gene therapy being investigated

H. Glucose 6 Phosphate Dehydrogenase (G6PD) Deficiency [13]

1. G6PD is an X chromosome-linked enzyme
   1. Catalyzes first reaction in hexose monophosphate shunt (ribose production) pathway
   2. Provides reducing power to all cells in the form of NADPH
   3. NADPH allows cells to counter oxidative stress and preserved reduced glutathione (GSH)
   4. Defence against oxidative damage depends on G6PD
2. Deficiency primarily manifests in males
   1. Occurs in ~15% of American Black males and ~2% in black females
   2. Fairly common in Mediterranean heritages, tropical Africa, middle east
   3. Also in subtropical Asia
   4. Estimated 400 million persons worldwide carry G6PD mutation causing deficiency
   5. Possible that G6PD mutations confer resistance to malaria
3. G6PD Mutations
   1. Various mutations lead to protein variants with different levels of enzymatic activity
   2. Level of activity associated with severity of illness
   3. Usually manifests as neonatal janudice and acute hemolytic anemia
   4. Hemolytic anemia usually triggered by exogenous agents
4. Severe acute drops in Hb can occur with:
   1. Infection - hepatitis A and B viruses, cytomegalovirus, pneumonia, typhoid fever
   2. Various drugs (see below)
   3. Ingestion of fava beans (earliest recognized association)
5. Hemolysis occurs with various oxidant drugs including:
   1. Sulfa drugs
   2. Plaquenil
   3. Dapsone
   4. Nitrofurantoin
6. Treatment / Prevention
   1. Avoidance of triggering situations is required
   2. Splenectomy may be considered in the rare cases that are severe
   3. Neonatal jaundice treated as other causes; phototherapy at bilirubin >150µmol/L
   4. However, most patients are completely asymptomatic with normal blood values

I. Hemoglobin SC Disease

1. Mild anemia, macrocytic, hypochromic
2. Teardrop (oat), target, and boat (helmet) cells often seen
3. HbC involves ßGlu6 to Lys substitution

J. Hemolytic Anemia

1. Autoimmune (Coombs' Direct Antiglobin Positive)
   1. Idiopathic (isolated)
   2. Associated with systemic lupus erythematosus (SLE)
   3. Associated with B cell neoplasms and dysglobulinemias
   4. Associated with congenital immunodefiency syndromes
2. Infection - mycoplasma, infectious mononucleosis
3. Microangiopathic Hemolytic Anemia
   1. Hemolytic Uremic Syndrome (HUS)
   2. Thrombobotic Thrombocytopenic Purpura (TTP)
   3. Disseminated Intravascular Coagulopathy (DIC)
   4. Pregnancy Induced Hypertension: Severe pre-eclamsia (HELLP Syndrome)
4. Paroxysmal Nocturnal Hemoglobinuria (PNH) [3]
5. Transfusion associated (Coombs' Indirect Antiglobin Positive)
6. Structural Anomaly: spherocytosis, ovalocytosis
7. Drugs: penicillin, oxacillin, alpha-methyldopa, hydralazine

K. Hemolytic Uremic Syndrome

1. RBC have small, regular, spiny projections (burr cells, echinocytes), macrocytes
2. Severe hemolysis, renal dysfunction, thrombocytopenia
3. Similar findings in TTP (which usually includes fevers and mental status changes as well)

L. Iron Deficiency Anemia [5,12,14]

1. Epidemiology
   1. Found in ~2% of men and ~5% of women in USA
   2. 500 million cases of iron deficiency anemia worldwide (most common anemia)
2. Findings on Serum Chemistry [1]
   1. Free erythrocyte protoporphyrin (FEP) and transferrin high
   2. Ferritin low
   3. Normal total iron binding capacity (TIBC)
   4. Serum iron low
   5. TRFI is best test to distinguish from anemia of chronic disease (ACD, see above) [19]
   6. Key issue is to rule out other concomitant causes of anemia such as ACD
3. Evaluation [9]
   1. Anemia should be aggressively evaluated
   2. Serum ferritin level should be obtained for any anemic patient with MCV<96fL
   3. Endoscopic evaluation should follow a serum ferritin level <45 ng/mL
   4. Computerized tomographic (CT) scan is very useful in asymptomatic iron deficiency [24]
   5. CT was more useful in identifying cause than endoscopy in asymptomatic disease [24]
4. Gastrointestinal Evaluation
   1. Should be carried out in adults with clear iron deficiency anemia [10]
   2. Anemia should not be attributed only to menstruation in premenopausal women
   3. Endoscopy reveals important lesions in ~10% of premenopausal women
   4. Gastritis related to Helicobacter pylori may be cause of Fe deficiency anemia [11]
   5. Celiac sprue may present with significant Fe deficiency anemia [26]
5. Peripheral Blood Smear
   1. Microcytosis, hypochromia, anisocytosis
   2. Reticulocyte count often depressed (or inappropriately normal)
   3. May be due to chronic iron deficiency due to chronic blood loss
   4. Also present in persons recovering from acute hemorrhage with inadequate iron intake
6. Symptoms
   1. Fatigue due to anemia
   2. Patients rarely manifest pica, a desire to eat soil or other iron-rich materials
   3. Manifestations of bleeding from GI tract
   4. Severe symptoms of anemia (such as cardiac ischemia) may necessitate transfusion
7. Treatment
   1. Evaluation and treatment of underlying cause
   2. Iron replacement therapy
   3. Transfusion only for severe symptoms
   4. Iron replacement in adolescents with iron deficiency (no anemia) improved cognition
   5. Eradication of Helicobacter pylori in patients with gastritis can reverse anemia [11]
8. Plummer-Vinson Syndrome
   1. Iron deficiency anemia
   2. Esophageal pain
   3. Glossitis
   4. Increased risk for esophageal cancer

M. Lead Poisoning Anemia

1. Microcytosis, basophilic coarse stippling
2. Neurologic symptoms
3. Free Erythrocyte Protoporphyrin (FEP) increased
4. This is due to displacement of heme iron from globin by lead

N. Liver Disease and Anemia [15]

1. Macrocytes, uniform size (exacerbated by alcoholism)
2. Non-megaloblastic
3. Burr cells may occur
4. EPO production is reduced
5. Marrow iron stores increased, similar to anemia of chronic disease
6. Synthesis of coagulation factors is reduced, and bleeding is increased

O. Megaloblastic Anemia [14]

1. Oval macrocytes with lesser numbers small teardrop shaped cells
2. Metabolic failure of maturation
3. Due to deficiency of Folic acid or Vitamin B12, or to myelodysplasia
4. Bone marrow may show uncorrelated nuclear / cytoplasmic maturation stages
5. Vitamin B12 deficiency is common in the elderly
6. Vitamin B12 malabsorption occurs with long term proton pump inhibitor therapy

P. Parson's Aplastic Anemia

1. Mitochondrial defect
2. Vacuolated cells

Q. Pernicious Anemia

1. Most common cause of Vitamin B12 deficiency
2. Due to autoantibodies against gastric parietal cell proteins
   1. These antibodies are directed against H+/K+ ATPase and against intrinsic factor
   2. Intrinsic Factor is a 60K glycoprotein produced only by parietal cells in stomach
   3. IF binds vitamin B12; the complex is carried to the terminal ileum
   4. Malabsorption of vitamin B12 in pernicious anemia is due to IF deficiency
   5. Genetic predisposition has been found
   6. Vitamin B12 deficiency may present as paresthesias with anemia [25]
3. Associated with Chronic Atrophic Gastritis (CAG)
   1. Type A CAG is autoimmune and includes pernicious anemia
   2. Type A CAG affects the fundus and body of stomach but spares the antrum
   3. Type B CAG is nonautoimmune and involves all areas of the stomach
   4. Type B CAG is usually associated with Helicobacter pylori infection and low gastrin
4. Associated with Gastric Carcinoids [16]
   1. In Type A CAG, parietal cell destruction leads to achlorhydria (lack of hydrochloric acid)
   2. Achlorhydria leads to increased secretion of gastrin from stomach and duodenum
   3. Chronic hypersecretion of gastrin can lead to gastrinoma formation
5. Other Autoimmune Associations
   1. Autoimmune (Hashimoto) thyroiditis
   2. Type 1 DM
   3. Addison's Disease
   4. Primary ovarian failure
   5. Hypoparathyroidism
6. Diagnosis
   1. Anemia and/or macrocytosis on blood smear
   2. Hypersegmented neutrophils, thrombocytopenia or pancytopenia may be present
   3. Bone marrow shows megaloblasts with large myeloid precursors
   4. Serum Vitamin B12 concentration is low
   5. In pernicious anemia, Schilling Test Part 1 is abnormal, Part 2 is normal
   6. Elevated serum gastrin levels and gastric achlorhydria are found
   7. Gastric biopsy should be done to evaluate for CAG and for gastric adenocarcinoma [16]
   8. Serum pepsinogen I concentration is reduced due to gastric chief cell destruction
7. Schilling Test
   1. This is a Vitamin B12 absorption test is done in two parts
   2. In part 1, the patient is given vitamin B12 alone and urinary excretion measured
   3. In part 2, the patient is given vitamin B12 with IF, and urine B12 measured
   4. Patients with normal IF have a normal part 1
   5. Patients who do not have IF have a normal part 2
   6. Patients who cannot bind B12-IF complex have abnormal parts 1 and 2
8. Treatment
   1. Correction of disease with injection of Vitamin B12 parenterally
   2. Vitamin B12 100µg monthly is given as intramuscular injection
   3. Nasal cyanocobalamin (500µg per 0.1mL, Nasonex®) is now available for mainentance
   4. In less severe disease, oral Vitamin B12 25-1000µg/d may correct deficiency
   5. Vitamin B12 levels should be monitored monthly until stable, then every ~3 months
   6. Monitor for hypokalemia during initial treatment phase (increased RBC soaks of K+)
9. Increased risk for gastric adenocarcinoma as well as gastric carcinoids [16]

R. Pure Red Cell Aplasia

1. Normal granulopoiesis and megakaryocytopoiesis
2. Severe reticulocytopenia exists, normochromic normocytic anemia
3. EPO levels are typically very high
4. Virtual absence of mature types or erythroid precursors in bone marrow
5. Parvovirus B19 associated disease may be most common
6. Antibodies to EPO may occur
7. May be associated with (mainly hematologic) malignancies [27]
   1. Non-Hodgkin's Lymphoma (NHL)
   2. Thymoma
   3. Hodgkin's Lymphoma
8. Increased risk in HIV infected persons
9. ~15% of cases in adults associated with thymoma [23]

S. Pyruvate Kinase Deficiency [13]

1. Autosomal recessive disroder caused by several different mutations
2. Second most common erythrocyte enzyme disorder 3, Moderate to severe chronic hemolytic anemia
3. Provides protection against infection and replication of Plasmodium falciparum malaria [28]
4. Variable response to splenectomy

T. Renal Disease and Anemia

1. Failure of EPO production
2. Usually occurs when creatinine is >3.0mg/dL
3. Burr Cells may be present
4. MCV is usually normal, reticulocyte count is low
5. Erythropoietin (EPO, Epogen®, Procrit®) Therapy
   1. EPO typically given three times / week is very effective in increasing hematocrit (HCT)
   2. Darbepoetin, a long acting EPO (Aranesp®), given once weekly 12.5-200µg/week IV or SC [18]
   3. Target hemoglobin (Hb) no higher than 12gm/dL [4]
   4. Hb >12gm/dL associated with increased mortality rates [4]

U. Sickle Cell Anemia

1. Sickle shaped cells predominate, some nucleated RBC
2. Increased polychromasia
3. Cell deformability is much reduced
4. Howell-Jolly bodies often present due to spleen infarction
5. Due to ßGlu6 to Val substitution

V. Sideroblastic Anemia

1. Failure to incorporate iron into heme within erythroblast due to metabolic defect
2. Iron accumulates within mitochondria
3. Ringed sideroblasts
   1. Definition: Iron in cells >2/3 of circumference
   2. Found in certain myelodysplastic syndromes (MDS)
   3. Most common in MDS: refractory anemia with ringed sideroblasts (RARS)

W. Spherocytosis (hereditary) [13]

1. RBC cytoskeletal defects
2. Causes
   1. About 65% of cases have combined spectrin and ankyrin deficiency
   2. Ankyrin mutations account for many cases of hereditary spherocytosis
   3. These are inherited as autosomal dominant traits
   4. Deficiency of band 3 (RBC anion exchanger 1, gene SLC4A1) occurs in 15-20%
   5. Abnormal pallidin (protein band 4.2, gene EPB42) also found in a minority of cases
3. RBC Appearance on Blood Smear
   1. Small, dense RBC, no central pallor
   2. Coarse stippling (lots of purple dots)
   3. Microspherocytosis
   4. Anisocytosis
   5. Mean corpuscular volume (MCV) usually within normal range
4. Laboratory Features
   1. Hemolytic anemia - elevated reticulocytes
   2. Increased osmotic fragility (tested in hypotonic solution)
   3. Osmotic fragility usually improves after splenectomy
   4. Mean corpuscular hemoglobin concentration (MCHC) increased in ~50% of patients
   5. Spectrin immunoassay is sensitive for some patients, particularly with mild disease
   6. Increased risk of gallstones due to indirect bilirubinemia
5. Nearly all patients respond well to splenectomy

X. Spur Cell Anemia

1. Acanthocytes
2. These are cells with irregularly distributed thornlike projections
3. Usually found in chronic diseases including liver disease, renal failure, heart failure
4. Also occurs in abetalipoproteinemia

Y. Thalassemias [13]

1. Alpha Thalassemia
   1. Microcytic, hypochromic cells
   2. Often severe anemia
   3. Difficult to diagnose since heterozygous states show no electrophoretic anomalies
2. Beta Thalassemia
   1. Microcytic, hypochromic cells
   2. Elliptical (ovalocytes) teardrop shaped
   3. Target cells, nucleated red cells and reticulocytosis
   4. Stippling is coarse
   5. Sickle-ß-thalassemia compound heterozygotes can occur and are symptomatic

Z. Traumatic Hemolysis

1. Mechanical damage, results in schizocytes, helmut cells
2. Occurrance
   1. Metal heart valves
   2. Disseminated intravascular coagulopathy (DIC)
   3. Thrombotic thrombocytopenic purpura (TTP) / Hemolytic Uremic Syndrome

1. Many viruses adversely affect RBCs
2. Epstein-Barr Virus - hemolytic anemia, aplastic anemia, mononucleosis with anemia
3. Parvovirus B19 - aplastic anemia
4. Hepatitis Viruses - mononucleosis with anemia, cold agglutinin disease (HCV)
5. Human Immunodeficiency Virus (HIV)
   1. Acute viral syndrome with atypical lymphocytes ± lymphadenopathy
   2. Anemia is frequent complication as disease progresses
   3. Due to inhibition of normal RBC production
   4. Immunodeficiency with HIV allows bone marrow infiltration by many infectious agents
   5. Zidovudine (AZT) can also cause anemia

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