• Information
  1. Evaluation of Anemia
  2. Clinical Indications for Blood Smear Examination (Table 1)
  3. Microcytosis
  4. Iron Deficiency versus Chronic Disease Anemia
  5. Macrocytosis
  6. Anisocytosis
  7. RBC Stippling Differential
  8. Schistocytosis and Helmet
  9. Nucleated Red Cells in Peripheral Smear
  10. Polycythemia
  11. Target Cells

A. Evaluation of Anemia
[Figure] "Evaluation of Anemia"

1. Attempt to categorize anemia into one of three groups:
   1. Decreased production
   2. Increased active destruction
   3. Increased blood loss
2. Laboratory abnormalities should be sought and evaluated as described below and in figure
   1. Reticulocyte Count
   2. Peripheral Blood Smear - see below for indications
   3. These are most useful parameters for clinical evaluation of anemia
3. Decreased Production
   1. Normal Bone Marrow: iron deficiency, copper poisoning
   2. Abnormal Bone Marrow: B12/folate deficiency, neoplastic infiltration
   3. Abnormal Marrow: other infiltrative diseases (infection, storage diseases)
   4. Bone Marrow Poisons: cancer chemotherapies, radiation effects, severe burns
   5. Chronic Renal Failure (CRF): erythropoietin (EPO) levels low
   6. Anti-EPO antibodies: in some patients with CRF treated with EPO [2]
   7. Reticulocyte levels are abnormally low (for given hematocrit level)
   8. Peripheral smear RBC generally unremarkable
   9. Normal or nearly normal lactate dehydrogenase (LDH), bilirubin
   10. RBC Distribution Width (RDW; see below) is normal or elevated
4. Increased Active Destruction
   1. Abnormal RBC: sickle cell anemia, thalassemia, HbSC Disease [3]
   2. Normal RBC: antibody mediated hemolytic anemia (autoimmune, drug-induced, others)
   3. Peripheral Smear shows abnormal cells, polychromasia
   4. Nucleated RBC may be present in peripheral smear in severe cases of hemolysis
   5. RDW always abnormally elevated
   6. Increased LDH, aspartate aminotransferase (AST), indirect (and total) bilirubin
   7. Splenic sequestration: hereditary spherocytosis, sickle cell anemia
5. Increased Blood Loss
   1. External Blood Loss: gastrointestinal bleeding is major cause, trauma, internal bleeding
   2. Also consider severe hematuria, hematemesis, chronic severe epistaxis (uncommon)
   3. Internal Blood Loss: post-surgical or traumatic bleeding
   4. Peripheral smear shows some polychromasia
   5. Reticulocytes increased
   6. RDW always abnormally increased, though not as much as with destruction
   7. Generally normal LDH, AST, bilirubin
6. Gastrointestinal (GI) Evaluation [4,5]
   1. Evaluation of GI tract is critical in patients with anemia
   2. Fecal occult blood testing should be done in ALL patients with anemia
   3. This is true regardless of other possible causes
   4. Anemia should never be attributed ONLY to menstruation in premenopausal women
   5. GI endoscopy showed important lesions in 12% of premenopausal women [4]
   6. All positive fecal occult blood tests should be followed up by colonoscopy first
   7. Upper GI endoscopy should be considered in patients negative for colonoscopy and positive on fecal occult blood testing [5]

B. Clinical Indications for Blood Smear Examination (Table 1, Ref [1])

1. Features suggestive of anemia and/or unexplained jaundice
2. Features suggestive of sickle cell disease
3. Features suggestive of thrombocytopenia or neutropenia
4. Features suggestive of lymphoproliferative disorder: lymphoma, myeloma, others
5. Features suggestive of myeloproliferative disease
6. Acute or recent onset renal failure or unexplained renal enlargement
7. Retinal examination: hemorrhages, exudates, hyperviscosity signs, optic atrophy
8. Suspicion of bacterial or parasitic disease that can be distinguished on blood smear
9. Feautres of disseminated nonhematopoietic cancer
10. General ill health, malaise, fever
    1. Possible viral infection (such as mononucleosis)
    2. Inflammatory disease
    3. Malignant disease

C. Microcytosis

1. Iron deficiency (hypochromic) [10]
2. Chronic inflammatory (disease) states
   1. Chronic Infections - bacterial endocarditis, osteomyelitis, tuberculosis, fungi, others
   2. Neoplasms, benign or malignant
   3. Idiopathic inflammatory diseases - especially rheumatoid arthritis, vasculitis
3. Blockage of heme synthesis by chemicals such as lead, pyrazinamide, isoniazid
4. Thalassemia of any type (anisocytosis)
5. Hereditary spherocytosis
6. Preleukemia
   1. Including myelodysplastic and myeloproliferative syndromes
   2. Sideroblastic Anemia - a myelodysplastic syndrome; usually with macrocytosis
7. Microspherosyctes
   1. Spherocytic anemia
   2. Burn victims
   3. Microangiopathic hemolytic anemia
8. Microangiopathic Hemolytic Anemia
   1. Red cell fragments, odd shaped red cells
   2. Disseminated intravascular coagulation (DIC)
   3. Hemolytic Uremic Syndrome (HUS)
   4. Thrombotic Thrombocytopenic Purpura (TTP)
   5. Pregnancy associated hypertension
   6. Disseminated malignancy
9. Bite cell: oxidative hemolysis, usually G6PD deficiency

D. Iron Deficiency versus Chronic Disease Anemia [6,10]

1. Iron deficiency anemia has the opposite transferrin/TIBC/Ferritin profile compared with anemia of chronic disease
2. Evaluation for Iron Deficiency [7,10]
   1. Serum ferritin level should be obtained for any anemic patient with MCV<96fL
   2. Endoscopic evaluation should follow a serum ferritin level <45 ng/mL
3. Transferrin receptor-ferritin index (TRFI) is superior to usual profiles to distinguish these types of anemia in the elderly [6]
   1. TRFI = transferrin receptor level ÷ Log(ferritin level)
   2. TRFI represents total body iron and iron available for erythropoiesis
   3. TRFI > 1.5 is 98% predictive of iron deficiency anemia
   4. TRFI <1.5 is 68% predictive that iron deficiency anemia is not present
4. Serum Chemistries for Iron Deficiency and Chronic Disease Anemias

   Property	Fe Deficiency	Chronic Disease
   Fe Serum Levels	very low	low
   Transferrin (serum TIBC)	high	low
   Transferrin Saturation	very low	low
   Ferritin (serum)	low	high / very high
   Erythrocyte Sedimentation Rate	normal	high / very high
   TRFI	>1.5	<1.5

E. Macrocytosis

1. Megaloblastic (abnormal maturation)
   1. B12 or folic acid deficiency (pernicious anemia) - usually with hypersegmented neutrophils
   2. Myelodysplastic Syndrome - blast cells in periphery, hyperlobulated neutrophil nuclei
   3. Malabsorption with vitamin deficiency
2. Liver disease
3. Alcoholism
4. Poor Nutrition - thrombosed off some part of gut
5. Immunohemolytic anemia
   1. Hemolytic syndromes with high reticulocyte counts
   2. Due to anti-erythrocyte antibodies
6. Hypothyroidism (severe forms only)
7. Congenital dyserythropoietic anemia Type 1

F. Anisocytosis

1. Means abnormal distribution of red cell sizes
2. Parameter measured is RBC Distribution Width (RDW)
   1. Normal RDW < 14%
   2. True Anisocytosis RDW >15%
3. Iron Deficiency - especially in combination with B12 and/or folate deficiency
4. Hemolytic Anemias
5. Mixed Anemia Disorders

G. RBC Stippling Differential

1. ß-Thalassemia
2. Lead poisoning - usually with basophilic stippling in RBC
3. Hemolytic Anemias

H. Schistocytosis and Helmet (Boat) Cells [1]

1. Microangiopathic Hemolytic Anemia
   1. Hemolytic Uremic Syndrome (HUS)
   2. Thrombotic Thrombocytopenic Purpura (TTP)
   3. Disseminated Intravascular Coagulopathy (DIC)
   4. Pregnancy associated hypertension: pre-ecclamsia (severe), HELLP syndrome
2. Toxin exposure
3. Burns

I. Nucleated Red Cells in Peripheral Smear

1. Ineffective erythropoiesis
2. HbSS (Sickle Cell) Disease and Related Syndromes
3. Hemolytic Anemia
4. Bone Marrow infiltration by Neoplastic Process
5. Severe Thalassemia (major)
6. Chronic blood loss

J. Polycythemia [8]

1. Definitions
   1. Polycythemia: abnormally increased red blood cell mass
   2. RBC mass is determined by chromium-51 labelled RBC Scan
   3. Hematocrit (HCT) >52% usually corresponds to polycythemia
   4. Primary erythrocytosis - decreased EPO levels
   5. Secondary erythrocytosis - increased EPO
   6. Hereditary erythrocytosis - often due to mutations in EPO receptor
2. Primary polycythemia (Polycythemia Vera)
   1. Clonal proliferative disorder
   2. One of the myeloproliferative syndromes
   3. EPO independence - EPO levels are normal or low
   4. Molecular basis is unclear
3. Secondary Polycythemia: normal and abnormal EPO levels
4. Secondary Polycythemia with Appropriate EPO Increase
   1. Smoking (hypoxia) - due to carboxyhemoglobin
   2. High altitude - responds to ACE inhibition [9]
   3. Renal Transplant Associated Polycythemia - responds to ACE inhibition
   4. Congenital cyanotic heart disease
   5. Gross obesity
   6. High-affinity hemoglobin (familiial erythrocytosis)
5. Secondary Polycythemia with Abnormal EPO Increase
   1. Hypernephroma (renal carcinoma)
   2. Hydronephrosis
   3. Polycystic kidney disease
   4. Post-renal transplant
   5. Hepatoma
   6. Uterine leiomyoma
   7. Cerebellar hemangioblastoma

K. Target Cells

1. HbSC disease, with occasional nucleated red cells
2. Hyposplenism

References

1. Bain BJ. 2005. NEJM. 353(5):498
2. Casadevall N, Nataf J, Viron B, et al. 2002. NEJM. 346(7):469
3. Weatherall DJ and Provan AB. 2000. Lancet. 355(9120):1169
4. Bini EJ, Micale PL, Weinshel EH. 1998. Am J Med. 105(4):281
5. Bini EJ, Rajapaksa RC, Valdes MT, Weinshel EH. 1999. Am J Med. 106(6):613
6. Rimon E, Levy S, Sapir A, et al. 2002. Arch Intern Med. 162:445
7. Ioannou GN, Spector J, Scott K, Rockey DC. 2002. Am J Med. 113(4):281
8. Provan D and Weatherall D. 2000. Lancet. 355(9211):1260
9. Plata R, Cornejo A, Arratia C, et al. 2002. Lancet. 359(9307):663
10. Zimmermann MB and Hurrell RF. 2007. Lancet. 370(9586):511