What is the appropriate work‑up and management for a patient with low hemoglobin and low red blood cell count?

Workup and Management of Low Hemoglobin with Low RBC Count

Begin immediate diagnostic workup with complete blood count including MCV, MCH, RDW, and reticulocyte count, followed by serum ferritin, transferrin saturation, CRP, vitamin B12, and folate levels to identify the underlying cause and guide treatment. 1, 2, 3

Initial Diagnostic Algorithm

Step 1: Classify by Mean Corpuscular Volume (MCV)

Microcytic (MCV < 80 fL):

• Check serum ferritin and transferrin saturation immediately 1, 3
• Ferritin < 30 μg/L without inflammation confirms absolute iron deficiency 1, 3
• In presence of inflammation (elevated CRP), ferritin up to 100 μg/L may still indicate iron deficiency 1
• Transferrin saturation < 20% indicates inadequate iron availability for erythropoiesis 1, 3
• Review peripheral blood smear for red cell morphology 1

Macrocytic (MCV > 100 fL):

• Check vitamin B12 and folate levels urgently 2
• Critical: Treat B12 deficiency BEFORE folate supplementation to prevent irreversible neurological damage 2
• Review medication history for anticonvulsants, methotrexate, chemotherapeutic agents, thiopurines 1, 2
• Consider thyroid function testing 3

Normocytic (MCV 80-100 fL):

• Check reticulocyte count first to distinguish regenerative from non-regenerative causes 1, 3, 4
• If reticulocytes > 100 × 10⁹/L, evaluate for hemolysis (haptoglobin, LDH, bilirubin) or acute blood loss 1, 3, 4
• Measure serum creatinine and calculate GFR in all patients 3

Step 2: Essential Laboratory Workup

Minimum initial testing includes: 1

• Complete blood count with RBC indices (MCV, MCH, RDW)
• Reticulocyte count
• Serum ferritin
• Transferrin saturation
• C-reactive protein (CRP)
• Peripheral blood smear review

Extended workup when cause unclear: 1

• Vitamin B12 and folate levels
• Haptoglobin, lactate dehydrogenase
• Serum creatinine and urea
• Differential white blood cell count
• Consider bone marrow examination if hematological malignancy suspected 2

Step 3: Assess for Correctable Causes

Before initiating any treatment, systematically evaluate: 1

• Thorough drug exposure history (NSAIDs, aspirin, chemotherapy agents) 1, 3
• Occult blood loss assessment 1
• Renal function (creatinine, GFR) 1, 3
• Nutritional deficiencies (iron, B12, folate) 1
• Coombs testing if chronic lymphocytic leukemia, non-Hodgkin's lymphoma, or autoimmune disease history 1

Treatment Based on Etiology

Iron Deficiency Anemia

Oral iron is first-line treatment: 3, 5

• Intermittent dosing (every other day) is as effective as daily dosing with fewer side effects 5
• Ensure ferritin > 100 μg/L and transferrin saturation > 20% for optimal response 1, 3

Intravenous iron indicated for: 3, 5

• Oral iron intolerance or malabsorption
• Chronic inflammatory conditions with functional iron deficiency
• Failure to respond to oral iron

Mandatory gastroenterology referral: 3

• All men with iron deficiency anemia
• Postmenopausal women with iron deficiency
• Rule out gastrointestinal malignancy (dual pathology occurs in 1-10% of patients)
• Screen for celiac disease with tissue transglutaminase antibody 3

Vitamin B12 Deficiency

With neurological symptoms: 2

• Hydroxocobalamin 1 mg intramuscularly on alternate days until no further improvement
• Maintenance: 1 mg IM every 2 months for life

Without neurological symptoms: 2

• Hydroxocobalamin 1 mg intramuscularly three times weekly for 2 weeks
• Maintenance: 1 mg IM every 2-3 months for life

Folate Deficiency

Treatment protocol: 2

• Oral folic acid 5 mg daily for minimum 4 months
• Only after excluding or treating B12 deficiency first to prevent masking severe B12 depletion and neurological progression

Anemia of Chronic Kidney Disease

If GFR < 30 mL/min/1.73 m²: 3, 4

• Nephrology referral for evaluation
• Erythropoiesis-stimulating agents should not be initiated in asymptomatic patients until hemoglobin < 10 g/dL 4
• Individualize use based on symptoms and thromboembolism risk 1, 4

Transfusion Thresholds

Red blood cell transfusion indicated when: 1

• Hemoglobin < 7.0 g/dL in absence of extenuating circumstances
• Hemoglobin < 7.5 g/dL with clinical symptoms or hemodynamic instability 1
• Active myocardial ischemia, severe hypoxemia, or acute hemorrhage regardless of hemoglobin level 1

Transfusion strategy: 1

• Each 400 mL unit should raise hemoglobin by approximately 1.5 g/dL
• Transfuse 2-3 units to resolve acute episode while avoiding volume overload
• Lower pre-transfusion hemoglobin results in greater hemoglobin rise per unit 6

Critical Pitfalls to Avoid

Never treat folate deficiency before excluding B12 deficiency - this can precipitate irreversible neurological damage despite hematological improvement 2

Do not delay gastroenterology referral in iron deficiency - gastrointestinal malignancy must be excluded, particularly in men and postmenopausal women 3

Avoid erythropoietin therapy without adequate iron stores - ferritin must be > 100 μg/L and transferrin saturation > 20% for response 1, 3

Consider thromboembolism risk with erythropoiesis-stimulating agents - increased risk in patients with previous thrombosis, surgery, immobilization, or multiple myeloma patients on thalidomide/lenalidomide 1

Specialist Referral Indications

Hematology referral when: 1, 3

• Cause remains unclear after initial workup
• Suspected hemolysis
• Bone marrow examination needed
• Consideration of erythropoiesis-stimulating agents

Immediate referral required for: 3

• Men with hemoglobin < 12 g/dL and iron deficiency
• Postmenopausal women with hemoglobin < 10 g/dL and iron deficiency
• GFR < 30 mL/min/1.73 m² suggesting chronic kidney disease