What is the initial step in the workup of pancytopenia?

Initial Workup of Pancytopenia

The initial step in the workup of pancytopenia is a complete blood count with differential and peripheral blood smear examination, followed by bone marrow aspiration and biopsy in most cases to identify the underlying etiology. 1, 2

Essential Initial Laboratory Studies

• Complete blood count with differential is mandatory to confirm the presence of pancytopenia and quantify the severity of cytopenias across all three cell lines 1
• Peripheral blood smear examination is critical to exclude pseudothrombocytopenia from platelet clumping, identify morphological abnormalities such as schistocytes, blasts, or dysplastic features, and assess red blood cell morphology 1, 3
• Reticulocyte count helps differentiate between bone marrow production defects (low reticulocyte count) and peripheral destruction mechanisms (elevated reticulocyte count) 1

Bone Marrow Examination

Bone marrow aspiration and biopsy should be performed simultaneously in most cases of pancytopenia, as aspiration alone may be insufficient or unsuccessful in obtaining adequate samples. 2, 4

• Bone marrow examination is specifically indicated in patients over 60 years of age, those with systemic symptoms or abnormal physical findings, and cases where diagnosis remains unclear after initial testing 1
• The bone marrow aspirate provides adequate diagnosis in approximately 55% of cases, while trephine biopsy is necessary in an additional 30% of cases, particularly to identify myelofibrosis or assess cellularity accurately 3
• Bone marrow cellularity assessment distinguishes hypocellular conditions (aplastic anemia) from hypercellular states (megaloblastic anemia, myelodysplastic syndromes, leukemias) 5

Additional Diagnostic Testing

• Cytogenetic analysis of bone marrow is essential for diagnosing myelodysplastic syndromes and identifying specific chromosomal abnormalities that guide prognosis and treatment 6
• HIV and hepatitis C virus testing is recommended in all adult patients presenting with pancytopenia 1
• Vitamin B12 and folate levels should be assessed, as megaloblastic anemia is one of the most common causes of pancytopenia (33-74% in various studies) and is rapidly correctable 2, 4, 5
• Autoimmune workup including ANA and anti-dsDNA should be considered if systemic symptoms suggest autoimmune disease 1
• Copper and ceruloplasmin levels may be indicated in select cases, particularly with history of gastrointestinal surgery, vitamin B12 deficiency, or vacuolation of myeloid/erythroid precursors on bone marrow examination 6

Common Diagnostic Pitfalls

The presence of blast cells or abnormal lymphoid cells on peripheral smear is highly discriminatory and should prompt immediate bone marrow evaluation for acute leukemia or lymphoproliferative disorders 3. Bone marrow aspiration frequently yields inadequate samples ("dry tap") in conditions with myelofibrosis or packed marrow, making simultaneous biopsy essential rather than optional 4. In patients receiving immunotherapy, maintain a low threshold for bone marrow examination to rule out marrow infiltration, secondary myelodysplastic syndromes, or aplastic anemia 1.

Specific Clinical Contexts

• In cases with accompanying eosinophilia, optical genome mapping or FISH may be superior to conventional cytogenetics for detecting entity-defining abnormalities such as BCR::ABL1, PDGFRA, PDGFRB, FGFR1, and JAK2 rearrangements 6
• Brucellosis should be considered in endemic areas, as bone marrow culture has the highest diagnostic sensitivity for this infection 1
• Drug-induced pancytopenia, particularly from methotrexate, can occur 4-6 weeks after dose increases and should be considered in the medication history 1