What are the differential diagnoses for pancytopenia?

Differential Diagnosis for Pancytopenia

The differential diagnosis for pancytopenia must systematically distinguish between bone marrow failure syndromes, hematologic malignancies, nutritional deficiencies, and secondary causes through a structured evaluation prioritizing bone marrow examination alongside targeted laboratory testing. 1, 2

Primary Hematologic Disorders

Bone Marrow Failure Syndromes

• Aplastic anemia represents a major cause of pancytopenia, characterized by hypocellular bone marrow with reduced hematopoietic precursors across all lineages 1, 3
• Myelodysplastic syndrome (MDS) commonly presents with pancytopenia in elderly patients (median age ~70 years), typically showing hypercellular marrow with dysplastic features in ≥10% of cells 1, 2
• Paroxysmal nocturnal hemoglobinuria (PNH) should be considered, as small PNH clones can accompany MDS or aplastic anemia 1

Hematologic Malignancies

• Acute leukemia (both myeloid and lymphoblastic) frequently presents with pancytopenia and is defined by >20% blasts in peripheral blood or bone marrow 2, 4
• Aleukemic leukemia or lymphoma can present without circulating blasts but with bone marrow infiltration causing pancytopenia 3
• Lymphoproliferative disorders including non-Hodgkin lymphoma and Hodgkin's lymphoma with marrow involvement 4, 5

Nutritional and Metabolic Causes

Megaloblastic Anemia

• Vitamin B12 or folate deficiency is a major and rapidly correctable cause of pancytopenia that should not be missed, particularly in critically ill patients 1, 3, 6
• This can present acutely with markedly elevated LDH and may mimic thrombotic microangiopathy with schistocytes but demonstrates reticulocytopenia rather than reticulocytosis 2

Secondary Causes Requiring Exclusion

Medication and Toxic Exposures

• Drug-induced bone marrow suppression from chemotherapy agents (especially alkylating agents and purine analogues), other medications, or alcohol ingestion 1
• Occupational exposures to benzene and its derivatives, particularly in agricultural and industrial workers 1
• Environmental toxins and radiation exposure 1

Systemic Diseases

• Autoimmune disorders including systemic lupus erythematosus and other immunologic conditions 1
• Chronic infections including HIV, hepatitis C, and other persistent infections 1
• Renal failure causing anemia and contributing to cytopenias 1
• Liver disease including alcoholic cirrhosis and chronic hepatic dysfunction 1

Hypersplenism

• Splenic sequestration from various causes including portal hypertension, chronic liver disease, or infiltrative disorders 3, 6

Rare and Inherited Causes

Inherited Bone Marrow Failure Syndromes

• Fanconi anemia should be considered in younger patients or those with family history of MDS, AML, or aplastic anemia 1, 7
• Dyskeratosis congenita with telomerase complex gene mutations (TERC, TERT) 1, 7
• Congenital amegakaryocytic thrombocytopenia and other inherited cytopenias 7

Hemophagocytic Syndromes

• Hemophagocytic lymphohistiocytosis associated with infection or immunological diseases 5, 7

Essential Diagnostic Algorithm

Initial Laboratory Evaluation

• Complete blood count with differential and peripheral blood smear examination by a qualified hematologist 1, 2
• Reticulocyte count to distinguish production failure (low) from peripheral destruction (high) 1, 2
• Vitamin B12, folate, ferritin, transferrin saturation to exclude nutritional deficiencies 1, 2
• Haptoglobin, indirect bilirubin, LDH to assess for hemolysis or ineffective erythropoiesis 1, 2
• Creatinine and liver function tests to identify systemic causes 1, 2

Bone Marrow Examination (Mandatory)

• Bone marrow aspiration with cytomorphology examining 200 cells from blood film and up to 500 from bone marrow 1, 2
• Trephine biopsy to assess cellularity and exclude infiltrative processes 1, 2
• Cytogenetics to identify clonal abnormalities, particularly involving chromosomes 5,7, or 17p 1, 2
• Iron staining (Prussian blue/Perls stain) to evaluate for ring sideroblasts 1
• Flow cytometry for PNH markers (CD55/CD59) and lymphoproliferative disorders 1, 2

Advanced Testing When Initial Workup Is Inconclusive

• Next-generation sequencing to demonstrate clonality in cases with unspecific morphological changes and no cytogenetic abnormalities 1, 2
• Direct antiglobulin test (Coombs) if hemolysis is suspected despite reticulocytopenia 2
• ADAMTS13 activity if thrombotic microangiopathy features are present 2

Critical Pitfalls to Avoid

• Do not delay bone marrow examination, as it is the definitive diagnostic procedure to distinguish between MDS, aplastic anemia, acute leukemia, and infiltrative processes 2
• Do not assume hemolysis based solely on elevated LDH, as reticulocytopenia excludes peripheral hemolytic processes and indicates bone marrow failure 2
• Do not overlook megaloblastic anemia, which can present as pseudo-thrombotic microangiopathy with pancytopenia, elevated LDH, and schistocytes but with reticulocytopenia 2, 3
• Perform both bone marrow aspiration and biopsy simultaneously, as aspiration often fails to obtain adequate samples while biopsy is usually diagnostic 3
• Obtain detailed medication history including prescription and non-prescription drugs, alcohol use, and occupational exposures 1, 2