What are the causes of pancytopenia?

Pancytopenia Causes

Pancytopenia is most commonly caused by bone marrow disorders (megaloblastic anemia, aplastic anemia, myelodysplastic syndromes, and hematological malignancies), followed by peripheral destruction/sequestration mechanisms, with infections being a leading cause in some populations. 1

Primary Etiological Categories

Bone Marrow Production Disorders (Most Common)

• Megaloblastic anemia from vitamin B12 or folate deficiency represents one of the most frequent reversible causes, accounting for 20.5% of cases in some series 2
• Aplastic anemia causes pancytopenia through bone marrow failure, with idiopathic aplastic anemia representing 20.72% of cases 3
• Myelodysplastic syndromes are characterized by ineffective hematopoiesis and dysplastic changes, affecting 10.7% of cases 1
• Hematological malignancies including acute leukemia, lymphoma, multiple myeloma, and hairy cell leukemia account for 16% of cases 2
• Metastatic solid organ tumors infiltrating bone marrow represent 3.6% of cases 2

Peripheral Destruction and Sequestration

• Hypersplenism from chronic liver disease causes peripheral sequestration and destruction, accounting for 20.5% of cases alongside B12 deficiency 2
• Autoimmune destruction from systemic lupus erythematosus represents 4.5% of cases 2

Infectious Causes

• Kala-azar (visceral leishmaniasis) accounts for 9% of cases in endemic regions 3
• 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 and thrombocytopenia 1
• HIV and HCV infections can cause pancytopenia through multiple mechanisms 1
• Hemophagocytic lymphohistiocytosis presents with pancytopenia, fever, hepatosplenomegaly, hypertriglyceridemia, hypofibrinogenemia, and elevated ferritin 1
• Falciparum malaria and enteric fever represent treatable infectious causes 3

Drug-Induced Causes

• Chemotherapy agents cause pancytopenia through direct bone marrow suppression and mucosal barrier disruption 1
• Methotrexate can rarely cause pancytopenia even with low-dose weekly therapy or after single doses, particularly in patients with impaired renal function, medication errors, or concomitant sulfonamide-based medications, typically occurring 4-6 weeks after dose increases 1
• Immune checkpoint inhibitors (anti-CTLA-4 and anti-PD-L1 agents) cause immune-related hematological toxicity in less than 5% of patients, but with significant mortality risk 1
• Drug-induced pancytopenia from various medications accounts for 5.4% of cases 2

Radiation Exposure

• Acute radiation syndrome with hematopoietic failure occurs at doses exceeding 1 Gy 1, 4

Inherited Disorders (Primarily Pediatric)

• SAMD9/SAMD9L-Associated Syndromes account for 8-18% of childhood MDS cases, presenting with cytopenias, immunodeficiency, and risk for childhood-onset bone marrow failure 1
• Chediak-Higashi syndrome presents with partial oculocutaneous albinism, bacterial infections, and pancytopenia during the accelerated phase (HLH) 1
• Griscelli syndrome type 2 manifests with pigmentary dilution, neurological abnormalities, pyogenic infections, and potential HLH development 1

Critical Diagnostic Pitfalls

Vitamin B12 Deficiency Can Mimic Malignancy

• Severe vitamin B12 deficiency can present with B-symptoms (night sweats, fever), lymphadenopathy, and pancytopenia, clinically mimicking hematologic malignancies like leukemia or lymphoma 5
• This can occur even in the absence of typical signs like macrocytosis and hypersegmented neutrophils 5
• Nutritional deficiencies should be considered first as differentials in pancytopenia before opting for more invasive measures like bone marrow biopsy 5

High-Risk Populations Requiring Special Consideration

• Children under 10 years have the highest case-fatality rate despite frequently having milder infections 1
• Immunosuppressed patients (HIV, organ transplant, splenectomy) experience more severe symptoms and higher mortality 1
• Patients receiving sulfonamide antimicrobials may be predisposed to severe ehrlichial illness 1
• Patients with impaired renal function are at increased risk of drug-induced pancytopenia 1

Regional and Population-Specific Variations

The frequency of pancytopenia causes varies significantly by geographic region and population characteristics, making it essential to consider local epidemiology when formulating differential diagnoses 2, 6. In some populations, infections represent the leading cause, while in others, nutritional deficiencies or bone marrow disorders predominate 1, 3.