What is the appropriate workup and management for a patient presenting with decreased hemoglobin (Hb) levels?

Workup and Management of Decreased Hemoglobin

Begin by confirming anemia using standardized thresholds: hemoglobin <13.5 g/dL in adult males and <12.0 g/dL in adult females, then immediately initiate a systematic evaluation to identify the underlying cause before considering treatment. 1, 2

Initial Diagnostic Approach

Confirm Anemia and Classify by MCV

• Obtain a complete blood count with differential to assess mean corpuscular volume (MCV) and evaluate other cell lines for myeloproliferative disorders 2, 3
• Classification by MCV guides the differential diagnosis: microcytic (<80 fL), normocytic (80-100 fL), or macrocytic (>100 fL) 3, 4
• Check reticulocyte count to distinguish regenerative (>100 × 10⁹/L) from non-regenerative causes 2

Essential History and Physical Examination

Take a thorough drug exposure history focusing on anticoagulants, antiplatelets, NSAIDs, chemotherapy agents, and medications causing bone marrow suppression 1

Assess for bleeding sources:

• Occult gastrointestinal blood loss (melena, hematochezia, hematemesis) 1, 2
• Menstrual history in premenopausal women 3
• History of blood donation 2

Review for chronic diseases:

• Chronic kidney disease symptoms (uremia, decreased urine output) 1
• Inflammatory conditions (rheumatoid arthritis, inflammatory bowel disease) 5, 4
• Malignancy symptoms (weight loss, night sweats, lymphadenopathy) 3, 6

Carefully review the peripheral blood smear (and bone marrow in selected cases) for morphologic abnormalities 1

Laboratory Workup Based on MCV Classification

Microcytic Anemia (MCV <80 fL)

Iron studies are mandatory:

• Serum ferritin <30 μg/L confirms absolute iron deficiency 2
• Transferrin saturation (TSAT) <20% indicates inadequate iron availability for erythropoiesis 2
• If ferritin >100 μg/L but TSAT <20%, this suggests anemia of chronic inflammation with functional iron deficiency 2

Additional testing:

• Tissue transglutaminase (tTG) antibody to screen for celiac disease, as approximately 5% of iron deficiency anemia patients have celiac disease 2
• Thyroid-stimulating hormone (TSH) to exclude hypothyroidism 2

Normocytic Anemia (MCV 80-100 fL)

If reticulocyte count >100 × 10⁹/L, evaluate for:

• Hemolysis: LDH, haptoglobin, indirect bilirubin, peripheral smear, Coombs' test 2, 7
• Acute blood loss: assess vital signs, orthostatic changes, clinical bleeding 7

If reticulocyte count is low:

• Measure serum creatinine and calculate GFR in all patients with normocytic anemia 2
• Iron studies (ferritin, TSAT) to assess for functional iron deficiency 2
• Consider bone marrow examination if unexplained 1, 3

Coombs' testing is appropriate for patients with chronic lymphocytic leukemia, non-Hodgkin's lymphoma, or history of autoimmune disease 1

Macrocytic Anemia (MCV >100 fL)

Assess for nutritional deficiencies:

• Vitamin B12 level 1, 3
• Folate level 1, 3

Consider additional causes:

• Alcohol use history 3, 8
• Thyroid disease (TSH) 3
• Medications: hydroxyurea, antiretroviral drugs 3
• Myelodysplastic syndrome (may require bone marrow biopsy) 3, 6

Chronic Kidney Disease Considerations

Anemia develops consistently when GFR <60 mL/min/1.73 m² (CKD stage 3), with prevalence increasing at later stages 1

• If GFR <30 mL/min/1.73 m², refer to nephrology for evaluation of anemia of chronic kidney disease 2
• Hemoglobin levels should be measured at least annually in all CKD patients, with more frequent monitoring for those with greater disease burden or unstable clinical course 1
• Anemia among patients with diabetes is more prevalent, more severe, and occurs earlier in the course of CKD 1

Mandatory Referrals

Gastroenterology referral is essential:

• Immediate referral for men with hemoglobin <12 g/dL and postmenopausal women with hemoglobin <10 g/dL with iron deficiency to exclude gastrointestinal malignancy 2
• A gastrointestinal bleeding source is found in 60-70% of patients with iron deficiency anemia referred for endoscopy 3
• Do not delay referral, as dual pathology (upper and lower GI sources) occurs in 1-10% of patients 2

Nephrology referral:

• Patients with abnormal creatinine or GFR suggesting chronic kidney disease 2

Hematology referral:

• Unexplained anemia after initial workup 2
• Suspected hemolysis 2
• Suspected myelodysplastic syndrome or hematologic malignancy 3, 6

Initial Management Principles

Before initiating any treatment, identify and address correctable causes of anemia aside from the primary diagnosis 1

Iron Deficiency Anemia

• Oral iron supplementation is first-line treatment 2
• Lower-dose formulations may be as effective with fewer adverse effects 6
• Normalization of hemoglobin typically occurs by 8 weeks in most patients 6
• Intravenous iron is indicated for oral iron intolerance, malabsorption, or chronic inflammatory conditions 2
• Ensure ferritin >100 μg/L and TSAT >20% before considering erythropoietin therapy if anemia persists 2

Transfusion Thresholds

• Transfuse if hemoglobin <7.0 g/dL in the absence of extenuating circumstances 7
• For hemoglobin 7.0-10.0 g/dL, consider transfusion if myocardial ischemia, severe hypoxemia, or acute hemorrhage are present 7
• Each 400 mL unit of packed RBCs raises hemoglobin by approximately 1.5 g/dL 7

Common Pitfalls to Avoid

Do not assume lower hemoglobin is normal in elderly patients without investigation, as anemia contributes to morbidity and mortality in this population 1, 8, 6

Do not delay gastroenterology evaluation in patients with iron deficiency anemia, particularly men and postmenopausal women 2, 3

Do not transfuse prophylactically above 7.0 g/dL in stable patients, as this increases mortality risk without benefit 7

In patients with cardiac disease or ongoing ischemia, do not delay transfusion, as these patients require higher hemoglobin thresholds 7

Recognize that anemia is often multifactorial, particularly in elderly patients where nutritional deficiency, chronic disease, and unexplained anemia each account for approximately one-third of cases 8, 4