Determining the Type of Anemia: A Systematic Approach
To determine what type of anemia your patient has, you must systematically classify it using MCV (mean corpuscular volume), reticulocyte count, and specific laboratory markers to distinguish between iron deficiency anemia, anemia of chronic disease, hemolytic anemia, nutritional deficiencies, or bone marrow dysfunction. 1
Initial Classification by MCV
The first step is to categorize the anemia based on red blood cell size 1:
Microcytic Anemia (Low MCV)
- Iron deficiency anemia (IDA): Most common cause, characterized by low serum ferritin (<30 μg/L without inflammation, <100 μg/L with inflammation) and transferrin saturation <15% 1
- Anemia of chronic disease (ACD): Can be microcytic or normocytic, associated with inflammation (elevated CRP), normal or elevated ferritin, and low transferrin saturation 1
- Thalassemia: Identified through hemoglobin electrophoresis and family history 1
- Sideroblastic anemia: Ring sideroblasts present on bone marrow biopsy 1
Normocytic Anemia (Normal MCV)
- Anemia of chronic disease: Most common in inflammatory conditions, malignancy, or chronic infections 1
- Acute blood loss: Identified by clinical history and positive stool guaiac or endoscopic findings 1
- Hemolytic anemia: Requires further workup (see below) 1, 2
- Kidney disease: GFR <60 mL/min/1.73 m² with low erythropoietin levels 1
- Bone marrow suppression: From chemotherapy, radiation, or marrow infiltration 1
Macrocytic Anemia (High MCV)
- Vitamin B12 or folate deficiency: Confirmed by low serum B12 or folate levels, often megaloblastic on smear 1
- Medication-induced: Particularly thiopurines (azathioprine, 6-mercaptopurine), hydroxyurea, or diphenytoin 1
- Myelodysplastic syndrome (MDS): Requires bone marrow examination 1
- Alcohol abuse, hypothyroidism, or reticulocytosis: Identified through history and additional testing 1
Second Step: Reticulocyte Count Assessment
The reticulocyte index (RI) or absolute reticulocyte count distinguishes production versus destruction problems 1:
Low or Normal Reticulocytes (RI <2.0)
Indicates decreased RBC production 1:
- Iron deficiency
- Vitamin B12/folate deficiency
- Bone marrow dysfunction (aplastic anemia, MDS, marrow infiltration)
- Anemia of chronic disease
- Renal insufficiency
Elevated Reticulocytes (RI >2.0)
Indicates increased RBC destruction or loss 1:
- Hemolysis: Confirm with low haptoglobin, elevated LDH, elevated indirect bilirubin, positive Coombs test (if immune-mediated) 1, 2
- Acute hemorrhage: Clinical evidence of bleeding 1
Essential Laboratory Workup
Minimum initial tests 1:
- Complete blood count with RBC indices (MCV, MCH, RDW)
- Reticulocyte count
- Serum ferritin
- Transferrin saturation (TfS)
- CRP (to assess inflammation)
Extended workup when diagnosis unclear 1:
- Vitamin B12 and folate levels
- Haptoglobin, LDH, indirect bilirubin (for hemolysis)
- Peripheral blood smear
- Renal function (creatinine, GFR)
- Stool guaiac (for occult bleeding)
- Coombs test (if hemolysis suspected, especially in lymphoproliferative disorders) 1
- Bone marrow examination (if primary marrow disorder suspected)
Critical Diagnostic Distinctions
Iron Deficiency vs. Anemia of Chronic Disease
This is particularly important as both commonly coexist 1:
Iron Deficiency Anemia 1:
- Ferritin <30 μg/L (without inflammation) or <100 μg/L (with inflammation)
- Transferrin saturation <15%
- High RDW (indicates variable RBC size)
- Microcytic, hypochromic RBCs
Anemia of Chronic Disease 1:
- Ferritin normal or elevated (>100 μg/L)
- Transferrin saturation <20%
- Elevated CRP/inflammatory markers
- Normocytic or mildly microcytic
Functional Iron Deficiency 1:
- Ferritin >100 μg/L but transferrin saturation <20%
- Soluble transferrin receptor >5 mg/dL
- Iron trapped in macrophages due to inflammation (hepcidin-mediated)
Hemolytic Anemia Confirmation
When reticulocytes are elevated, confirm hemolysis with 1, 2:
- Low haptoglobin (most sensitive)
- Elevated LDH
- Elevated indirect bilirubin
- Positive Coombs test (if immune-mediated)
- Peripheral smear showing schistocytes, spherocytes, or other abnormal morphology
Common Pitfalls to Avoid
Ferritin interpretation in inflammation: Ferritin acts as an acute phase reactant and can be falsely elevated despite true iron deficiency; use the higher threshold of <100 μg/L in inflammatory states 1
Combined deficiencies: Microcytosis and macrocytosis can coexist and neutralize each other, resulting in normal MCV; high RDW suggests this scenario 1
Reticulocyte count timing: Must be corrected for degree of anemia (reticulocyte index) to accurately assess bone marrow response 1
Cancer-related anemia: Often multifactorial, combining ACD, nutritional deficiencies, blood loss, and chemotherapy effects; requires comprehensive evaluation 1
Chronic kidney disease: Anemia workup should begin when Hgb <12 g/dL in adult males/postmenopausal females or <11 g/dL in premenopausal females 1
When to Consult Hematology
Seek hematology consultation when 1:
- Cause remains unclear after extended workup
- Suspected primary bone marrow disorder (MDS, aplastic anemia)
- Suspected hereditary anemia (thalassemia, sickle cell, hereditary spherocytosis)
- Complex hemolytic process
- Sideroblastic anemia suspected