What are the causes of pancytopenia?

Causes of Pancytopenia

Pancytopenia results from three main mechanisms: bone marrow disorders (most common), peripheral destruction/sequestration, and infections, with bone marrow examination being essential for diagnosis in most cases. 1

Primary Etiological Categories

Bone Marrow Disorders (Most Common)

Nutritional Deficiencies:

• Vitamin B12 deficiency and folate deficiency causing megaloblastic anemia represent the most common preventable causes, accounting for 20.5% of cases in some populations 2
• Copper deficiency should be considered, particularly in patients with gastrointestinal surgery history or vitamin B12 deficiency 1

Hematological Malignancies:

• Acute myeloid leukemia (AML) is the leading malignant cause, comprising 21.4% of acute leukemia cases presenting with pancytopenia 3
• Acute lymphoblastic leukemia (ALL) predominates in patients under 20 years (38.7% of cases) 3
• Myelodysplastic syndromes (MDS) account for 10.7-15% of cases, characterized by ineffective hematopoiesis and dysplastic changes 1, 2
• Lymphomas and multiple myeloma collectively represent approximately 16% of cases 2

Bone Marrow Failure Syndromes:

• Aplastic anemia occurs in 1.8% of cases and requires distinction between severe and non-severe forms for treatment planning 2
• SAMD9/SAMD9L-associated syndromes account for 8-18% of childhood MDS cases, presenting with cytopenias and immunodeficiency 1

Peripheral Destruction and Sequestration

Hypersplenism:

• Represents 20.5% of pancytopenia cases, equal in frequency to vitamin B12 deficiency 2
• Results from splenic sequestration of blood cells in conditions causing splenomegaly 1

Autoimmune Disorders:

• Systemic lupus erythematosus accounts for 4.5% of cases 2
• Hemophagocytic lymphohistiocytosis (HLH) presents with pancytopenia, fever, hepatosplenomegaly, hypertriglyceridemia, hypofibrinogenemia, and elevated ferritin 4

Infectious Causes

Specific Infections:

• Brucellosis commonly presents with mild transaminitis and pancytopenia, with bone marrow culture having the highest diagnostic sensitivity 1
• Ehrlichiosis (E. chaffeensis) causes pancytopenia with leukopenia (nadir 1,300-4,000 cells/μL) and thrombocytopenia (nadir 50,000-140,000 platelets/μL) 4
• HIV and HCV should be tested in all adult patients with pancytopenia 1
• Miliary tuberculosis and parvovirus B19 are notable pediatric causes 5

Drug-Induced Pancytopenia

Chemotherapy Agents:

• Melphalan causes marked bone marrow suppression as its most significant toxicity, requiring frequent blood count monitoring 6
• High-dose chemotherapy (>100 mg/m²) produces severe mucositis, colitis, and hemorrhage with bone marrow suppression lasting 3-6 weeks 6
• Methotrexate can cause pancytopenia even with low-dose weekly therapy, particularly in patients with impaired renal function or concomitant sulfonamide medications, typically occurring 4-6 weeks after dose increases 1

Immunotherapy:

• Immune checkpoint inhibitors (anti-CTLA-4 and anti-PD-L1 agents) cause immune-related hematological toxicity in less than 5% of patients but carry significant mortality risk 1
• Drug-induced pancytopenia accounts for 5.4% of cases overall 2

Rare and Genetic Causes

Immune Dysregulation Syndromes:

• Chediak-Higashi syndrome presents with partial oculocutaneous albinism, bacterial infections, and pancytopenia during the accelerated phase (HLH) 4
• Griscelli syndrome type 2 manifests with pigmentary dilution, neurological abnormalities, pyogenic infections, and potential HLH development 4

Metastatic Disease:

• Solid organ tumor metastases to bone marrow account for 3.6% of cases 2

Critical Diagnostic Considerations

Age-Related Patterns:

• In patients under 20 years, ALL is the most common cause (38.7%) 3
• In adults over 45 years, AML accounts for 53.5% of leukemia-related pancytopenia 3
• Children under 10 years have the highest case-fatality rate despite frequently having milder infections 4

High-Risk Populations:

• Immunosuppressed patients (HIV, organ transplant, splenectomy) experience more severe symptoms and higher mortality 4
• Patients receiving sulfonamide antimicrobials may be predisposed to severe ehrlichial illness 4

Regional Variations:

• Geographic and population-specific etiological patterns exist, making understanding of local epidemiology crucial for diagnostic prioritization 2