Low hb workup
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Low Hemoglobin (Anemia) - Diagnostic Workup
Definition of Anemia
Anemia is defined as a reduction in hemoglobin/hematocrit below age- and sex-adjusted normal values. Normal values differ between men and women (after puberty due to testosterone sensitizing erythroid progenitors to EPO), and between adults, children, and newborns. Altitude also affects norms.
| Population | Approximate Hb threshold |
|---|---|
| Adult men | < 13.5 g/dL |
| Adult women | < 12.0 g/dL |
| Pregnant women | < 11.0 g/dL |
Step 1 - History
A targeted history provides critical diagnostic clues before a single lab is ordered.
General
- Duration (lifelong suggests congenital; chronic vs. acute)
- Prior anemia, transfusions, or iron supplementation
- Family history (hemoglobinopathy, spherocytosis)
- Blood donation history
Clues to Iron Deficiency / Blood Loss
- Menstrual history: duration, pad/tampon count, large clots
- GI symptoms: change in bowel habits, melena, hematochezia, diarrhea
- Other bleeding sources (surgical history)
- Pica (especially ice - pagophagia)
- Restless leg syndrome
Clues to Hemolysis
- Episodic jaundice (or family history)
- Dark/cola-colored urine (hemoglobinuria)
- Early cholelithiasis/cholecystectomy
Clues to Systemic Disorders
- Rheumatologic/inflammatory disease → anemia of inflammation
- Renal disease → EPO deficiency
- Endocrinopathy (thyroid, adrenal)
- Malignancy, weight loss, recurrent infections
Symptoms of Anemia Itself
- Fatigue, dyspnea on exertion, palpitations
- Angina/TIA in patients with atherosclerosis
- Pica or neuropathy (nutritional deficiencies)
Step 2 - Physical Examination
| Finding | What It Suggests |
|---|---|
| Pallor (conjunctiva, mucosa) | Confirms anemia (but unreliable for severity) |
| Tachycardia, flow murmur | Cardiovascular compensation |
| Splenomegaly | Hemolysis, hematologic malignancy |
| Jaundice | Hemolysis |
| Frontal bossing | Hemoglobinopathy / thalassemia |
| Glossitis | B12 or folate deficiency |
| Decreased vibration/proprioception | B12 deficiency |
| Purpura/petechiae, oral thrush, lymphadenopathy | Systemic hematologic disease |
| Heme-positive stool, telangiectasias | GI blood loss |
| Orthostatic hypotension, poor turgor | Volume depletion/acute blood loss |
| Edema / signs of CHF | May mask or cause apparent anemia |
Step 3 - Initial Laboratory Evaluation
Tier 1: Always Order
- CBC with indices - the cornerstone
- Peripheral blood smear - mandatory; cannot be replaced by automated counters
- Reticulocyte count (preferably absolute)
- Iron studies (serum iron, TIBC, ferritin, transferrin saturation) - recommended upfront given that iron deficiency anemia and anemia of inflammation are the two most common causes and both can be normocytic or microcytic
Step 4 - Classify by MCV (Size-Based Approach)
| MCV | Category | Common Causes |
|---|---|---|
| < 80 fL | Microcytic | Iron deficiency, thalassemia, anemia of chronic disease, sideroblastic anemia, lead poisoning |
| 80-100 fL | Normocytic | Anemia of inflammation, renal disease (EPO deficiency), early nutritional deficiency, bone marrow failure, hemolysis, acute blood loss |
| > 100 fL | Macrocytic | B12 deficiency, folate deficiency, hypothyroidism, liver disease, medications (hydroxyurea, methotrexate, antiretrovirals), myelodysplastic syndrome |
Note on RDW: The red cell distribution width (RDW) reflects anisocytosis (size variation). A high RDW with low MCV strongly suggests iron deficiency; a normal RDW with low MCV suggests thalassemia trait.
Step 5 - Classify by Reticulocyte Count (Bone Marrow Response)
This is the key functional split:
Elevated Reticulocytes (Reticulocyte Production Index > 2-3) = Adequate Marrow Response
The marrow is working - the problem is peripheral destruction or loss:
- Blood loss (acute or chronic)
- Hemolysis → proceed to hemolysis workup
Low/Normal Reticulocytes (RPI < 2) = Hypoproliferative / Underproduction
The marrow is not responding adequately:
- Nutritional deficiency (iron, B12, folate)
- Anemia of inflammation
- Renal disease
- Bone marrow failure (aplasia, infiltration, fibrosis)
- Endocrine causes
Corrected Reticulocyte Count:
Corrected count = Measured % × (Patient Hct ÷ 45)
Step 6 - Second-Tier Tests by Category
Microcytic Anemia Workup
| Test | Interpretation |
|---|---|
| Serum ferritin | Low (< 12-15 ng/mL) = iron deficiency; elevated in inflammation |
| Serum iron + TIBC | Low iron + high TIBC = iron deficiency |
| Transferrin saturation | < 15% in iron deficiency |
| Hemoglobin electrophoresis | Elevated HbA2 (> 3.5%) = beta-thalassemia trait |
| Peripheral smear | Hypochromia, microcytosis, target cells (thalassemia), pencil cells (iron deficiency) |
Macrocytic Anemia Workup
| Test | Purpose |
|---|---|
| Serum B12 | Deficiency in pernicious anemia, malabsorption, strict veganism |
| Serum folate (or RBC folate) | Folate deficiency |
| Methylmalonic acid (MMA) | Elevated in B12 deficiency (even with normal B12 levels) |
| Homocysteine | Elevated in both B12 and folate deficiency |
| TSH | Rule out hypothyroidism |
| LFTs | Liver disease |
| Peripheral smear | Macro-ovalocytes, hypersegmented neutrophils (> 5 lobes) → megaloblastic |
Hemolytic Anemia Workup
| Test | Purpose |
|---|---|
| LDH | Elevated with hemolysis |
| Indirect bilirubin | Elevated (unconjugated) |
| Haptoglobin | Low or absent (binds free Hb) |
| Direct Coombs (DAT) | Positive = autoimmune hemolytic anemia (AIHA) |
| Peripheral smear | Spherocytes (AIHA, hereditary spherocytosis), schistocytes (TTP/HUS, MAHA), sickle cells, target cells |
| G6PD level | Suspect in males with oxidant-triggered hemolysis |
| Osmotic fragility | Hereditary spherocytosis |
| Urine hemosiderin/hemoglobin | Intravascular hemolysis |
Normocytic Anemia / Bone Marrow Failure Workup
| Test | Purpose |
|---|---|
| Renal function (BMP/CMP) | CKD-related anemia |
| EPO level | Inappropriate if low for degree of anemia |
| Serum protein electrophoresis (SPEP) | Multiple myeloma |
| TSH | Hypothyroidism |
| ANA, ESR, CRP | Connective tissue disease / anemia of inflammation |
| Bone marrow aspiration + biopsy | Aplastic anemia, myelodysplastic syndrome, leukemia, marrow infiltration, fibrosis |
Step 7 - Peripheral Blood Smear Morphology Guide
| Morphology | Significance |
|---|---|
| Hypochromia + microcytosis | Iron deficiency, thalassemia |
| Macro-ovalocytes + hypersegmented neutrophils | Megaloblastic (B12/folate) |
| Spherocytes | AIHA, hereditary spherocytosis |
| Schistocytes | TTP, HUS, DIC, mechanical valve, HELLP |
| Target cells | Thalassemia, liver disease, hemoglobinopathy |
| Sickle cells | Sickle cell disease |
| Basophilic stippling | Thalassemia, lead poisoning |
| Bite cells / blister cells | G6PD deficiency (Heinz body hemolysis) |
| Burr cells (echinocytes) | Uremia, liver disease |
| Nucleated RBCs | Asplenia, severe marrow stress, fibrosis/infiltration |
| Polychromasia (grayish-blue cells) | Reticulocytosis - active hemolysis or response to EPO |
| Howell-Jolly bodies | Asplenia or functional hyposplenism |
Step 8 - Bone Marrow Examination
Indicated when:
- Pancytopenia (all cell lines low)
- Suspected aplastic anemia, myelodysplasia, or leukemia
- Unexplained normocytic/macrocytic anemia after exhausting peripheral workup
- Suspected marrow infiltration (metastatic cancer, lymphoma, myeloma, TB, fungal)
- Unexplained splenomegaly + anemia
Aspiration provides: cell morphology, differential, M:E ratio (normal 2.5:1), iron stores
Biopsy provides: marrow architecture, cellularity (normal ~50%), fibrosis, infiltrates
Biopsy provides: marrow architecture, cellularity (normal ~50%), fibrosis, infiltrates
Summary Algorithm
Low Hemoglobin
↓
History + PE + CBC + Retic + Smear + Iron studies
↓
Reticulocyte count
├── HIGH (RPI >2) → Blood loss or Hemolysis
│ └── Hemolysis panel (LDH, bili, haptoglobin, Coombs, smear)
└── LOW (RPI <2) → Hypoproliferative
↓
MCV-based classification
├── Microcytic → Iron studies, Hb electrophoresis
├── Normocytic → Renal fn, EPO, SPEP, bone marrow
└── Macrocytic → B12, folate, MMA, TSH, LFTs
Sources: Harrison's Principles of Internal Medicine 22E (2025), Ch. 66 | Goldman-Cecil Medicine, Ch. 144
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