What is the approach to evaluating pancytopenia?

Evaluation of Pancytopenia

Begin with a complete blood count with differential and peripheral blood smear examination, followed by bone marrow aspiration and biopsy performed simultaneously, as these are essential and complementary procedures that should not be separated. 1, 2

Initial Laboratory Assessment

Confirm true pancytopenia by obtaining a complete blood count with manual differential to exclude pseudothrombocytopenia from EDTA-dependent platelet clumping, which can falsely suggest thrombocytopenia. 1, 3

Peripheral blood smear examination by a qualified hematologist or pathologist is paramount to identify: 1, 3

• Schistocytes suggesting microangiopathic hemolytic anemia
• Giant platelets indicating peripheral destruction
• Dysplastic features suggesting myelodysplastic syndrome
• Abnormal cells indicating leukemia or lymphoma
• Megaloblastic changes from B12/folate deficiency

Reticulocyte count differentiates decreased bone marrow production (low reticulocyte count) from peripheral destruction (elevated reticulocyte count). 1, 3

Critical Reversible Causes to Exclude Early

Vitamin B12 and folate levels must be checked early, as severe B12 deficiency can mimic hematologic malignancy with pancytopenia, lymphadenopathy, and fever—a completely reversible cause if identified. 4, 1, 3

Infectious disease screening should include: 1

• HIV testing for all adult patients regardless of geographic location
• Hepatitis B and C virus screening
• Consider testing for other chronic infections based on exposure history

Medication and Exposure History

Document all prescription medications, over-the-counter drugs, alcohol consumption, and environmental toxins, as these are common reversible causes of pancytopenia. 3, 5

Bone Marrow Examination (Essential)

Both bone marrow aspiration and biopsy must be performed simultaneously in most cases of pancytopenia, as aspiration alone may be inadequate. 4, 1, 2

The bone marrow evaluation should include: 4, 1

• Morphological assessment with Prussian blue stain for iron
• Assessment of cellularity (hypocellular vs. hypercellular)
• Percentage of marrow blasts
• Presence or absence of ringed sideroblasts
• Degree of fibrosis
• Immunophenotyping by flow cytometry
• Cytogenetic analysis (mandatory for prognosis)
• Reticulin staining to evaluate fibrosis

Important caveat: Flow cytometry blast percentages should not replace morphologic blast percentage determination by an experienced hematopathologist for prognostic purposes. 4

Autoimmune Evaluation (When Clinically Indicated)

When systemic symptoms or clinical features suggest autoimmune disease: 1, 5

• Antinuclear antibodies (ANA) and anti-dsDNA antibodies
• Direct antiglobulin test (Coombs) to rule out concurrent Evans syndrome

Imaging Studies

Chest X-ray to rule out pulmonary infections, malignancies, or thymoma. 1, 5

Abdominal imaging if hepatosplenomegaly is present: 3

• Start with ultrasound with Doppler to assess liver/spleen morphology and portal blood flow
• Proceed to CT or MRI if ultrasound is inadequate or lymphadenopathy is suspected

Specialized Testing Based on Clinical Context

For suspected hemophagocytic lymphohistiocytosis (HLH): 1, 3

• Ferritin (markedly elevated)
• Triglycerides (elevated)
• Fibrinogen (decreased)
• Fever and hepatosplenomegaly clinically

For potential stem cell transplant candidates: 4

• HLA typing (A, B, C, DR, and DQ) of patient and potential donors
• CMV status
• Full HLA typing

For young patients with hypoplastic MDS and normal cytogenetics: 4

• Screening for paroxysmal nocturnal hemoglobinuria (PNH)
• HLA-DR15 testing (may predict response to immunosuppressive therapy)

Additional Laboratory Studies

• Serum erythropoietin level 4
• Serum ferritin, iron levels, and total iron binding capacity 4
• Liver function tests (AST, ALT, bilirubin, alkaline phosphatase) 3

Admission Criteria

Hospital admission is recommended for patients with newly diagnosed pancytopenia and: 1

• Platelet count <20 × 10⁹/L with asymptomatic or minor mucocutaneous bleeding
• Social concerns or diagnostic uncertainty
• Significant comorbidities
• More significant mucosal bleeding

Immediate management considerations include: 1, 5

• Temperature monitoring every 4 hours
• Strict infection control measures
• Prophylactic antibiotics if neutropenia persists (ANC <500/μL)
• Immediate broad-spectrum antibiotics for fever in neutropenic patients

Common Diagnostic Pitfalls

Do not miss megaloblastic anemia, which is the most common cause of pancytopenia in many studies and is completely reversible with vitamin replacement. 5, 6, 7

Do not rely on clinical symptoms alone for fungal infections in pancytopenic patients, as signs are non-specific and bacterial versus fungal bloodstream infections cannot be clinically differentiated. 4

Do not delay bone marrow examination waiting for other test results, as it is essential for definitive diagnosis and should be performed early in the evaluation. 2, 8