Anemia

Anemia is characterized by decreased red blood cell mass, causing symptoms resulting from tissue hypoxia.

Definition (World Health Organization)

All definitions are sea-level measurements
- Males ≥18 years – hemoglobin <13 g/dL
- Nonpregnant females ≥18 years – hemoglobin <12 g/dL

Epidemiology

Incidence
- Females – 29-30/1,000
- Males – 6/1,000 at <45 years; 18.5/1,000 at >75 years
Age – different peaks depending on etiology of anemia
Sex – M<F during childbearing years

Classification

Based on morphology of red blood cell (RBC)
- Mean cell volume (MCV)
  - Low MCV – microcytic
  - Normal MCV – normocytic
  - High MCV – macrocytic
- Mean cell hemoglobin (MCH) and MCH concentration (MCHC)
  - Low MCH/MCHC – hypochromic
  - Normal MCH/MCHC – normochromic
Based on RBC production rate (measure of hemolysis)
- Measured by reticulocyte count
- Reticulocyte count formula (with correction for anemia) – ReticCount% x (Hgb/Htc) x (1/maturation time correction*)
  - * Use 2% for most patients

Morphologic Etiology

Macrocytic
- Drug effect (hydroxyurea, azido-thymidine [AZT])
- Nutrient deficiency – folate, B12
- Hemolytic anemia
- Hypothyroidism
- Alcohol abuse
- Myelodysplasia
Normocytic
- Acute blood loss
- Hemolysis
- Renal insufficiency
- Chronic disease (inflammatory or malignant)
- Bone marrow infiltration – leukemia/lymphoma, metastatic disease, granulomatous disease
- Hemoglobinopathies
Microcytic
- Iron deficiency
- Chronic disease (inflammatory or malignant) occurs in a minority of the cases
- Thalassemia

Clinical Presentation

Acute loss – hypotension, tachycardia, confusion, diaphoresis
- May not have obvious source of blood loss at presentation
Chronic loss – fatigue, pallor, lack of stamina, breathlessness
- Younger patients
  - May not have clinical symptoms until anemia is severe
  - Fatigue, pallor, dyspnea with strenuous exercise
  - Pica
- Older patients – may first manifest with angina, dyspnea
Other signs and symptoms depend on etiology
- Angular stomatitis, glossitis – iron or B12 deficiency
- Splenomegaly – hemolytic anemia
- Vitiligo – pernicious anemia
- Splinter hemorrhage in nails – chronic infection (endocarditis)

Treatment

Based on diagnosis
Acute loss may require transfusion to maintain circulation

Indications for Testing

Patient with fatigue, weakness, pallor, dizziness, fainting

Laboratory Testing

Initial evaluation – CBC with red blood cell indices combined with cell morphology on peripheral smear
- Classify by indices (normocytic, macrocytic, microcytic)
  - Normocytic, normochromic – suggests hypoproliferation
    - Consider the following
      - Bone marrow disorder
      - Inflammation
      - Autoimmune disease (eg, SLE)
      - Chronic renal disease
      - Critical illness
      - Chronic endocrine disorders (eg, thyroid disease)
      - Aplastic anemia, pure red cell aplasia
  - Microcytic, hypochromic – suggests maturation defects
    - Consider the following
      - Iron deficiency
      - Chronic disease – autoimmune disease, celiac disease, inflammatory bowel disease
      - Thalassemia
      - Sideroblastic anemia
      - Lead toxicity
  - Macrocytic – suggests maturation defects
    - Consider the following
      - Folate, B12 deficiency
      - Drug effect
      - Alcohol abuse
      - Hypothyroidism
      - Myelodysplasia
  - Peripheral smear may give clues to the nature of anemia
    - Hypersegmented neutrophils suggest megaloblastic anemia
    - Fragmented RBCs (schistocytes, helmet cells) suggest hemolytic disease
    - RBC pallor suggests microcytic anemia
    - Teardrops in RBCs suggest myelofibrosis
    - Burr cells seen in liver disease
- Reticulocyte count
  - Elevated in hemolytic etiologies – consider further testing based on history and clinical presentation
Further testing based on results of CBC and reticulocyte count
- Normocytic or normochromic; microcytic or hypochromic
  - Iron and iron binding capacity, ferritin
    - Low/normal total iron binding capacity (TIBC), normal/high ferritin, low/normal iron – inflammation, chronic disease
      - If no obvious chronic disease present, consider bone marrow biopsy
    - High TIBC, low iron, low ferritin
      - Iron deficiency
- Macrocytic
  - B12, folate testing
- If abnormal peripheral smear, workup based on smear characteristics (regardless of indices)
  - Bone marrow biopsy may be necessary

Differential Diagnosis

See Morphologic Etiology in Clinical Background for differential diagnoses

Annual CBC testing is appropriate for patients with chronic comorbidity
In the absence of chronic comorbidity, CBC testing is appropriate every 5 years in all females, men >50 years, and patients with anemia signs and symptoms

Tests generally appear in the order most useful for common clinical situations

Test name: CBC with Platelet Count & Automated Differential

ARUP #: 0040003

Methodology: Automated Cell Count with Flow Cell Differential

Use:

Identify presence of anemia; establish morphology indices

Test name: Reticulocytes, Percent & Number

ARUP #: 0040022

Methodology: Flow Cytometry

Use:

Identify presence of immature RBCs and hemolysis as etiology of anemia

Test name: Iron & Iron Binding Capacity

ARUP #: 0020420

Methodology: Quantitative Spectrophotometry/Calculation

Use:

Identify iron deficiency as etiology of anemia

Test name: Ferritin

ARUP #: 0070065

Methodology: Quantitative Chemiluminescent Immunoassay

Use:

May be useful in differentiating iron deficiency anemia from anemia of chronic disease when combined with other tests of iron status

Test name: Vitamin B₁₂ & Folate

ARUP #: 0070160

Methodology: Quantitative Chemiluminescent Immunoassay

Use:

Identify nutrient deficiency in macrocytic anemia

Additional Tests Available

Test name: Soluble Transferrin Receptor

ARUP #: 0070283

Methodology: Quantitative Immunoturbidimetric

Comments:

Test name: Transferrin, Serum

ARUP #: 0050570

Methodology: Quantitative Immunoturbidimetric

Comments:

Test name: Hemoglobin, Serum

ARUP #: 0020057

Methodology: Quantitative Spectrophotometry

Comments:

Test name: Hemoglobin

ARUP #: 0040085

Methodology: Automated Flow Cytometry

Comments:

Test name: Manual Differential

ARUP #: 0040005

Methodology: Microscopic

Comments:

Test name: Hematocrit

ARUP #: 0040080

Methodology: Automated Cell Counter

Comments:

Guidelines

General

ARUP Institute for Clinical and Experimental Pathology®

Comprehensive Review: April 2011
Last Update: April 2011

Hemolytic Anemias

Malabsorption

Megaloblastic Anemia

Myeloproliferative Neoplasms

Thrombotic Microangiopathies

Unstable Hemoglobinopathies

Vitamins