Anemia, defined as a reduced concentration of hemoglobin in the blood, is a common clinical problem with diverse causes. Accurate diagnosis requires understanding the type of anemia, its underlying mechanism, and its possible etiologies.
One of the most effective frameworks for approaching anemia is based on two critical laboratory parameters:
- Reticulocyte count – indicating bone marrow production response
- MCV (Mean Corpuscular Volume) – indicating red cell size classification
This article will walk through the step-by-step diagnostic logic shown in the chart, breaking down each category with clinical explanations, mechanisms, and common causes.
Step 1: Reticulocyte Count – The First Branch Point
Reticulocytes are immature red blood cells recently released from the bone marrow.
- Appropriate reticulocyte response = Bone marrow is working normally and producing more RBCs to compensate for loss.
- Inappropriate reticulocyte response = Bone marrow is not adequately producing RBCs.
A. Appropriate Reticulocyte Response
This suggests that anemia is due to increased destruction or loss of RBCs rather than decreased production.
1. Bleeding
- Acute blood loss (e.g., trauma, gastrointestinal hemorrhage, postpartum bleeding)
- Chronic blood loss (e.g., peptic ulcers, heavy menstruation, colon cancer)
- Bone marrow responds by releasing more reticulocytes to replace lost RBCs.
2. Hemolysis
Red blood cell destruction can be:
- Immune-mediated (positive Direct Antiglobulin Test, DAT)
- Non-immune-mediated (negative DAT)
a. Immune Hemolytic Anemia (IHA)
- Autoimmune Hemolytic Anemia (AIHA) – Autoantibodies target patient’s RBCs (warm or cold type).
- Alloimmune Hemolytic Anemia – Due to transfusion reactions or hemolytic disease of the newborn.
b. Non-Immune Hemolysis
Divided into extracorpuscular (external factors damaging RBCs) and intracorpuscular (intrinsic RBC defects):
Extracorpuscular Causes:
- TMA (Thrombotic Microangiopathy) – RBC fragmentation in microcirculation (e.g., TTP, HUS).
- MAHA (Microangiopathic Hemolytic Anemia) – Overlaps with TMA; schistocytes on smear.
- Liver Disease – Altered lipid metabolism affecting RBC membranes.
- Infection – e.g., malaria, clostridial sepsis.
- Thermal Injury – Burns causing RBC membrane damage.
Intracorpuscular Causes:
1. Hemoglobin Defects
- SCD (Sickle Cell Disease) – Abnormal hemoglobin S causing sickling.
- Thalassemia – Imbalance of alpha/beta globin chain production.
2. Membrane Defects
- HS (Hereditary Spherocytosis) – RBCs lose biconcave shape.
- HE (Hereditary Elliptocytosis) – Elliptical RBCs due to membrane protein defects.
- PNH (Paroxysmal Nocturnal Hemoglobinuria) – Complement-mediated lysis due to GPI-anchor deficiency.
- G6PD Deficiency – Oxidative stress triggers hemolysis.
- PKD (Pyruvate Kinase Deficiency) – Impaired glycolysis leading to RBC death.
B. Inappropriate Reticulocyte Response
This indicates a bone marrow production problem — RBCs are not being replaced effectively.
We use MCV to classify:
1. Microcytic Anemia (Low MCV)
Small red blood cells due to impaired hemoglobin synthesis.
- Iron Deficiency Anemia – Most common worldwide; due to poor intake, chronic bleeding, or increased demand.
- Thalassemia – Genetic disorders affecting globin chain production.
- Anemia of Chronic Inflammation – Inflammatory cytokines reduce iron availability.
2. Normocytic Anemia (Normal MCV)
Normal-sized RBCs but fewer in number.
- Anemia of Chronic Disease/Inflammation – Cytokine-mediated suppression.
- Liver Disease – Altered metabolism affects RBC production.
- Kidney Dysfunction – Low erythropoietin production.
- Primary Bone Marrow Disorders – Aplastic anemia, myelofibrosis.
3. Macrocytic Anemia (High MCV)
Large red blood cells due to defective DNA synthesis or other causes.
- Vitamin B12 Deficiency – Megaloblastic anemia, neurological symptoms.
- Alcoholism – Direct marrow toxicity.
- Liver Disease – Alters RBC lipid composition.
- Hypothyroidism – Slows RBC production.
- Medications – Chemotherapy, antiretrovirals.
- Primary Bone Marrow Disorders – Myelodysplastic syndrome.
Table: Summary of Differential Diagnosis of Anemia
| Parameter | Category | Causes |
|---|---|---|
| Appropriate Retic Response | Bleeding | Acute trauma, GI bleed, menorrhagia |
| Hemolysis – Immune | Autoimmune HA, Alloimmune HA | |
| Hemolysis – Non-immune Extracorpuscular | TMA, MAHA, liver disease, infection, burns | |
| Hemolysis – Non-immune Intracorpuscular – Hemoglobin | SCD, Thalassemia | |
| Hemolysis – Non-immune Intracorpuscular – Membrane | HS, HE, PNH | |
| Hemolysis – Non-immune Intracorpuscular – Enzyme | G6PD deficiency, PKD | |
| Inappropriate Retic Response | Microcytic | Iron deficiency, thalassemia, inflammation |
| Normocytic | Chronic inflammation, liver disease, kidney dysfunction, primary BM | |
| Macrocytic | B12 deficiency, alcohol, liver disease, hypothyroidism, medications, primary BM |
Clinical Approach Using This Algorithm
Step 1: Order a CBC with reticulocyte count.
Step 2: If reticulocytes are high → think loss/destruction (bleeding or hemolysis).
Step 3: If reticulocytes are low → check MCV to guide toward microcytic, normocytic, or macrocytic causes.
Step 4: Use additional tests (iron studies, vitamin B12 levels, hemolysis panel, bone marrow biopsy) as needed.
Key Points for Clinicians
- Always rule out acute bleeding in sudden anemia.
- Hemolysis clues: jaundice, high LDH, low haptoglobin, indirect hyperbilirubinemia.
- Macrocytosis should prompt B12 and folate testing to prevent irreversible nerve damage.
- Chronic disease anemia often overlaps categories — treat the underlying disease.
FAQ Section
1. Why is reticulocyte count important in anemia?
It tells us if the bone marrow is responding appropriately to anemia.
2. Can a patient have both microcytic and macrocytic anemia?
Yes — mixed anemia can normalize MCV, masking underlying dual deficiencies.
3. What’s the most common cause of anemia worldwide?
Iron deficiency anemia.
4. When should a bone marrow biopsy be done?
When anemia is unexplained after initial tests or when marrow failure is suspected.
5. Is all macrocytic anemia due to vitamin deficiency?
No — alcohol, liver disease, hypothyroidism, and medications are also common causes.
