What are the causes of bicytopenia?

Causes of Bicytopenia

Primary Etiological Categories

Bicytopenia results from four major categories: non-malignant hematologic disorders (most common), infectious diseases, malignant conditions, and drug-induced causes. 1

Non-Malignant Hematologic Disorders (56% of cases)

• Megaloblastic anemia is the predominant non-malignant cause of bicytopenia, resulting from vitamin B12 or folate deficiency affecting erythrocyte and leukocyte production 1
• Immune thrombocytopenic purpura (ITP) frequently presents with bicytopenia when combined with anemia from bleeding or autoimmune hemolysis 2, 1
• Aplastic anemia causes pancytopenia through immune-mediated destruction of hematopoietic stem cells, but may initially present as bicytopenia 3, 4
• Alcoholic liver disease produces bicytopenia through multiple mechanisms including direct marrow toxicity, hypersplenism, and nutritional deficiencies 1
• Myelodysplastic syndromes (MDS) characteristically present with refractory cytopenias affecting one or two lineages before progressing to pancytopenia 5

Infectious Causes (31.7% of cases)

• Dengue fever is the most common infectious cause (12% of all bicytopenia cases), producing thrombocytopenia with leukopenia through direct viral bone marrow suppression 1, 6
• HIV infection causes bicytopenia through multiple mechanisms including direct marrow suppression, immune-mediated destruction, and opportunistic infections 5, 7
• Hepatitis C virus (HCV) produces thrombocytopenia with anemia that is clinically indistinguishable from primary ITP 2, 8
• Parvovirus B19 causes red cell aplasia with associated leukopenia, particularly in immunocompromised patients 4
• Miliary tuberculosis produces bicytopenia through bone marrow infiltration and granuloma formation 4
• Cytomegalovirus (CMV) infection leads to cytopenias including bicytopenia through direct marrow suppression 7

Malignant Conditions (8.3% of cases)

• Acute lymphoblastic leukemia (ALL) presents with bicytopenia when blast infiltration suppresses normal hematopoiesis while one cell line remains relatively preserved 4, 1
• Chronic lymphocytic leukemia (CLL) causes bicytopenia through bone marrow infiltration or autoimmune mechanisms, with autoimmune cytopenias occurring more commonly than granulocytopenia 7
• Lymphoma produces bicytopenia through marrow infiltration, hypersplenism, or autoimmune mechanisms 5, 1
• Myelodysplastic syndromes are classified by the WHO as refractory cytopenia with unilineage or multilineage dysplasia, frequently presenting as bicytopenia before progression 5

Drug-Induced Causes (4% of cases)

• Chemotherapy agents commonly cause bone marrow suppression leading to bicytopenia or pancytopenia through direct cytotoxic effects 5, 7
• Immune checkpoint inhibitors induce hematologic immune-related adverse events including bicytopenia in up to 70% of patients receiving CAR T-cell therapy 5
• Azathioprine and 6-mercaptopurine cause bone marrow toxicity with leukopenia in approximately 3.2% of patients, with severe cases occurring in 5.3% of rheumatoid arthritis patients 7
• Immunosuppressive medications used in autoimmune disorders and post-transplant settings produce bicytopenia through direct marrow suppression 7
• Heparin causes thrombocytopenia with associated anemia in heparin-induced thrombocytopenia (HIT), typically occurring 5-10 days after initiation 2

Autoimmune and Systemic Diseases

• Systemic lupus erythematosus (SLE) produces bicytopenia through autoimmune destruction of blood cells, with peripheral cytopenias being common but bone marrow involvement rarely reported 3, 4
• Antiphospholipid syndrome causes thrombocytopenia with associated anemia through thrombotic microangiopathy mechanisms 2
• Common variable immunodeficiency (CVID) presents with ITP as a feature, potentially causing bicytopenia when combined with anemia 2

Specific Bicytopenia Patterns and Their Significance

Anemia with Thrombocytopenia (61% of bicytopenia cases)

• This is the most common bicytopenia pattern, typically seen in megaloblastic anemia, ITP with bleeding, alcoholic liver disease, and MDS 1
• Pallor, bleeding, hepatomegaly, and splenomegaly are the most frequent clinical signs in non-malignant conditions causing this pattern 1

Anemia with Leukopenia (26% of bicytopenia cases)

• This pattern suggests bone marrow infiltration, nutritional deficiencies (particularly B12/folate), or viral infections affecting both erythroid and myeloid lineages 1
• Fever and lymphadenopathy are most frequently associated with infectious causes of this pattern 1

Leukopenia with Thrombocytopenia (13% of bicytopenia cases)

• This pattern is characteristic of viral infections (especially dengue), drug-induced marrow suppression, and early aplastic anemia 1, 6
• Lymphadenopathy, splenomegaly, and hepatomegaly are most significantly associated with hematological malignancies presenting with this pattern 1

Age-Specific Considerations

• Pediatric bicytopenia occurs in 6% of neonates, 7% of infants, 25% of children, and 17% of teenagers, with infections being the predominant cause (65.84%) 4, 1, 6
• Adult bicytopenia (85% of cases) most commonly results from non-malignant causes, particularly megaloblastic anemia and alcoholic liver disease 1
• Elderly patients (>60 years) with bicytopenia require bone marrow examination to exclude myelodysplastic syndromes, leukemias, or other malignancies 2, 8

Critical Diagnostic Red Flags

• Lymphadenopathy, splenomegaly, and hepatomegaly are most significantly associated with hematological malignancies (p < 0.001) and mandate immediate bone marrow evaluation 1
• Systemic symptoms including fever, weight loss, night sweats, or bone pain suggest malignancy or systemic disease rather than isolated hematologic disorders 8, 1
• Severe cytopenia at presentation correlates with more serious underlying etiologies, with pancytopenia showing more severe cell line depression than bicytopenia 6

Iatrogenic and Treatment-Related Causes

• CAR T-cell therapy produces prolonged cytopenias including bicytopenia in weeks to months after infusion, with factors including CRS severity, disease burden, and prior therapies contributing 5
• Post-transplant immunosuppression causes bicytopenia through direct marrow suppression, with graft failure resulting in severe leukopenia and mortality up to 80% 7
• Corticosteroid treatment for immune-related adverse events can paradoxically worsen cytopenias while treating the underlying inflammatory condition 5

Nutritional Deficiencies

• Vitamin B12 and folate deficiency cause megaloblastic anemia with associated leukopenia, representing the predominant non-malignant cause of bicytopenia 1
• Copper deficiency can cause cytopenias including bicytopenia through impaired hematopoiesis 9

Hypersplenism and Portal Hypertension

• Alcoholic liver disease with portal hypertension produces bicytopenia through hypersplenism, direct marrow toxicity, and nutritional deficiencies 1
• Moderate or massive splenomegaly indicates alternative diagnoses such as lymphoproliferative disease or portal hypertension rather than primary hematologic disorders 8