What are the causes of pancytopenia?

Causes of Pancytopenia

Pancytopenia results from either bone marrow production failure (hypocellular or ineffective hematopoiesis) or peripheral destruction/sequestration of blood cells, with megaloblastic anemia being the most common reversible cause, followed by aplastic anemia, myelodysplastic syndromes, and hematological malignancies. 1, 2

Primary Etiological Categories

Bone Marrow Disorders (Most Common)

Nutritional/Megaloblastic Causes:

• Vitamin B12 deficiency and folate deficiency are the leading reversible causes, accounting for up to 74% of cases in some populations 1, 3
• Vitamin B12 deficiency can present with pancytopenia even without typical macrocytosis or hypersegmented neutrophils, and may mimic hematologic malignancy with fever, lymphadenopathy, and B-symptoms 4
• Iron deficiency contributes to dimorphic anemia patterns 3

Bone Marrow Failure Syndromes:

• Aplastic anemia represents 14-18% of cases and carries significant mortality risk 1, 3, 5
• Myelodysplastic syndromes (MDS) affect approximately 10.7% of cases, characterized by ineffective hematopoiesis and dysplastic changes 1, 6
• SAMD9/SAMD9L-associated syndromes account for 8-18% of childhood MDS cases 1

Hematological Malignancies:

• Acute and chronic leukemias, lymphomas, and multiple myeloma account for approximately 16% of cases through direct bone marrow infiltration 1, 6
• These suppress normal hematopoiesis and determine mortality both through the malignancy itself and infection/bleeding complications 7

Peripheral Destruction and Sequestration

Hypersplenism:

• Accounts for 10-20% of cases and represents the most common cause of hematologic abnormalities in sarcoidosis 1, 6, 5
• Results from sequestration rather than production defects 1

Autoimmune Disorders:

• Systemic lupus erythematosus causes approximately 4.5% of cases 6
• Hemophagocytic lymphohistiocytosis (HLH) presents with pancytopenia, fever, hepatosplenomegaly, hypertriglyceridemia, hypofibrinogenemia, and markedly elevated ferritin, requiring prompt immunosuppressive treatment 1, 7

Infectious Causes

Viral Infections:

• HIV and HCV should be tested in all adult patients with pancytopenia 1
• Dengue, viral hepatitis, and disseminated tuberculosis are documented causes 5

Bacterial Infections:

• Brucellosis commonly presents with mild transaminitis and pancytopenia, with bone marrow culture having highest diagnostic sensitivity 1
• Ehrlichiosis (E. chaffeensis) causes pancytopenia with leukopenia and thrombocytopenia, particularly in immunosuppressed patients 1
• Sepsis itself accounts for 9% of cases 5

Drug-Induced Causes

Chemotherapy Agents:

• Cause pancytopenia through direct bone marrow suppression and mucosal barrier disruption 1, 7
• Purine analog-based therapies and alemtuzumab require monitoring for myelosuppression 1

Drug Interactions:

• Concurrent allopurinol and mercaptopurine use causes life-threatening pancytopenia—mercaptopurine dose must be reduced to 25% when given with allopurinol 8
• Methotrexate can cause pancytopenia even with low-dose weekly therapy, particularly with impaired renal function or concomitant sulfonamide medications, typically 4-6 weeks after dose increases 1

Immunotherapy:

• Immune checkpoint inhibitors (anti-CTLA-4 and anti-PD-L1) cause immune-related hematological toxicity in less than 5% of patients but with significant mortality risk 1

Radiation Exposure

• Acute radiation syndrome causes hematopoietic failure 1

Rare Genetic Syndromes

• Chediak-Higashi syndrome presents with partial oculocutaneous albinism, bacterial infections, and pancytopenia during accelerated phase 1
• Griscelli syndrome type 2 manifests with pigmentary dilution and potential HLH development 1

Critical Mortality Considerations

Sepsis is the leading cause of death in pancytopenic patients, with mortality rates of 1.9% in first-line therapy settings, occurring most commonly with severe neutropenia below 100/mcL. 7

• Approximately 10-20% of patients with neutrophil counts below 100/mcL develop bloodstream infections that can rapidly progress to septic shock 7
• Fever may be the only early sign of life-threatening infection due to absent inflammatory responses 7
• Fatal hemorrhage is the second major cause of death (0.4-0.9%), highest when platelets fall below 10,000/μL, with intracranial and gastrointestinal bleeding being most life-threatening 7

High-Risk Populations

• Children under 10 years have the highest case-fatality rates despite milder initial presentations 1, 7
• Immunosuppressed patients (HIV, organ transplant, splenectomy) experience more severe symptoms and higher mortality 1, 7
• Patients with impaired renal function are at increased risk of drug-induced pancytopenia 7