What causes pancytopenia, characterized by low White Blood Cell (WBC) count, low Red Blood Cell (RBC) count, low hemoglobin, low hematocrit, and low platelet count?

Pancytopenia: Causes and Urgent Diagnostic Approach

Pancytopenia (low WBC, RBC, hemoglobin, hematocrit, and platelets) requires immediate bone marrow examination to differentiate between life-threatening hematologic malignancies (acute leukemia, myelodysplastic syndrome) and other causes including bone marrow failure syndromes, drug toxicity, infections, and autoimmune disorders. 1

Immediate Life-Threatening Causes Requiring Urgent Workup

Hematologic Malignancies

• Acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) are critical diagnoses that present with pancytopenia and require immediate bone marrow aspirate and biopsy with flow cytometry and cytogenetic testing 2, 1
• Nucleated RBCs in peripheral blood indicate severe marrow stress or infiltration, strongly suggesting malignancy 1
• Bone marrow examination must assess blast percentage, evaluate for dysplasia, and perform karyotype analysis for prognostic chromosomal abnormalities 2, 1

Aplastic Anemia

• Bone marrow failure presents with marked hypocellularity on bone marrow aspirate and biopsy without infiltration of abnormal cells 3
• Requires exclusion through bone marrow examination showing severely reduced cellularity across all lineages 2

Drug-Induced Causes

Chemotherapy Agents

• Hydroxyurea toxicity causes pancytopenia with absolute neutrophil count <1.0 × 10⁹/L, platelet count <100 × 10⁹/L, or hemoglobin <10 g/dL at doses required for therapeutic response 2
• Oxaliplatin can induce immune-mediated pancytopenia through drug-dependent antibodies against platelets, RBCs, and WBCs, with rapid onset (within hours) after infusion 4

Other Medications

• Fidaxomicin has been associated with pancytopenia, with blood counts returning to normal within 3 days of discontinuation 5
• Any new medication should be considered as a potential cause, particularly if temporal relationship exists 4

Toxic Exposures

Benzene Poisoning

• Chronic benzene exposure (concentrations 30-210 ppm) causes pancytopenia in 2.76% of exposed workers, with leucopenia being the most common finding (9.70%), followed by thrombocytopenia (1.84%) 6
• Benzene primarily affects leucocytes first, platelets second, and eventually all three cell lines causing pancytopenia 6

Infectious Causes

Viral Infections

• Parvovirus B19 causes transient aplastic crisis characterized by exacerbation of baseline anemia with substantially decreased reticulocyte count (typically <1%) 2
• HIV, cytomegalovirus, and hepatitis viruses should be tested as part of the diagnostic workup 2

Autoimmune and Immune-Mediated Causes

Immune Checkpoint Inhibitor Toxicity

• Immune-related hematologic toxicities from checkpoint inhibitors can affect multiple cell lines, requiring evaluation for pure red cell aplasia, autoantibodies, aplastic anemia, and myelodysplasia 2
• Hemolytic anemia with autoantibody development can occur, commonly treated by withholding the agent, corticosteroids, and IVIG 2

Mandatory Diagnostic Workup

Essential Laboratory Tests

• Complete blood count with differential, reticulocyte count, RBC indices (mean cell volume), and peripheral blood smear evaluation for dysplasia and blasts 2
• Biochemical tests including RBC-folate/serum-folic acid, cobalamin, iron studies (iron, total iron binding capacity, ferritin), lactate dehydrogenase, bilirubin, and haptoglobin 2
• Viral serologies for anti-HIV, anti-parvovirus B19, cytomegalovirus, hepatitis B antigen, and anti-hepatitis C virus 2

Bone Marrow Examination (Mandatory)

• Bone marrow aspirate and biopsy must be performed urgently to establish diagnosis, as pancytopenia does not fit benign causes of cytopenia 1
• Evaluation must include assessment of cellularity, CD34+ cells, fibrosis, enumeration of blasts and ring sideroblasts, and evaluation of dysplasia in hematopoietic cell lines 2
• Cytogenetic analysis to detect nonrandom chromosomal abnormalities is mandatory 2

Additional Specialized Testing

• Paroxysmal nocturnal hemoglobinuria (PNH) clone testing should be performed 2
• Specific genetic analyses in patients with suspected inherited bone marrow failure disorders (Fanconi anemia, telomere disorders) 2

Immediate Supportive Management Priorities

Transfusion Support

• RBC transfusions should be initiated immediately for symptomatic severe anemia using leukocyte-reduced blood products; irradiate all blood products if stem cell transplantation is a future consideration 1
• Platelet transfusions are indicated if active bleeding occurs, platelet count drops below 10,000/μL, or invasive procedures are planned with platelets <50,000/μL 1

Infection Prevention

• Broad-spectrum antibiotics should be administered immediately if fever develops in patients with profound neutropenia or lymphopenia 1
• Central venous catheterization and invasive procedures should be avoided due to high risk of hemorrhagic and infectious complications 2

Critical Pitfalls to Avoid

• Never delay bone marrow examination waiting for other test results when pancytopenia is present, as this delays diagnosis of potentially fatal conditions like acute leukemia 1
• Do not attribute anemia to iron deficiency without biochemical proof; iron supplementation in the absence of documented deficiency risks iron overload, particularly if transfusions become necessary 2
• Avoid assuming a single cause; drug-induced pancytopenia can occur rapidly (within hours to days) and requires immediate discontinuation of the offending agent 4, 5
• Do not overlook occupational or environmental exposures to benzene or other toxins, which require detailed exposure history 6