What are the causes of pancytopenia?

Causes of Pancytopenia

Pancytopenia is most commonly caused by bone marrow disorders including megaloblastic anemia (particularly vitamin B12 deficiency), hypersplenism, myelodysplastic syndromes, and hematological malignancies, with the specific distribution varying by population and age group. 1, 2

Primary Etiological Categories

Bone Marrow Production Disorders

Nutritional Deficiencies:

• Megaloblastic anemia from vitamin B12 deficiency represents the leading cause in many populations, accounting for 20-33% of cases 1, 2, 3
• Folate deficiency also contributes to megaloblastic changes 3
• These nutritional causes are often preventable with appropriate supplementation 4

Aplastic Anemia:

• Characterized by hypocellular bone marrow with ineffective hematopoiesis 1
• Accounts for 1.8-14% of pancytopenia cases depending on the population studied 2, 3
• Can be idiopathic, drug-induced, or related to viral infections 5

Myelodysplastic Syndromes (MDS):

• MDS is characterized by ineffective hematopoiesis and dysplastic changes, affecting approximately 10-15% of pancytopenia cases 1, 2
• MDS with multilineage dysplasia (MDS-DML) affects two or more myeloid cell lines 6
• MDS with excess blasts (MDS-EB-1 and MDS-EB-2) presents with multiple cytopenias and higher risk of progression to acute myeloid leukemia 6
• WHO classifies cases with pancytopenia and single-lineage dysplasia as MDS-unclassifiable (MDS-U) 6

Hematological Malignancies:

• Acute leukemia (both myeloid and lymphoid) represents 16-35% of pancytopenia cases, with acute myeloid leukemia (AML) being the predominant subtype in adults 2, 7
• In patients under 20 years, acute lymphoblastic leukemia (ALL) is more common (38.7% of cases) 7
• In adults over 45 years, AML accounts for 53.5% of leukemia-related pancytopenia 7
• Lymphomas and multiple myeloma also cause pancytopenia through marrow infiltration 2, 3

Peripheral Destruction and Sequestration

Hypersplenism:

• Represents 10-20% of pancytopenia cases, often secondary to chronic liver disease or portal hypertension 2, 3
• Results in sequestration and destruction of blood cells in an enlarged spleen 1

Autoimmune Disorders:

• Systemic lupus erythematosus accounts for 4.5% of cases 2
• Autoimmune hemolytic anemia can present with pancytopenia 3
• Hemophagocytic lymphohistiocytosis (HLH) causes peripheral destruction and requires prompt immunosuppressive treatment 1

Infectious Causes

Viral Infections:

• HIV and hepatitis C virus (HCV) are important causes requiring testing in all adult patients 1
• Parvovirus B19 causes transient bone marrow suppression 4
• Dengue fever can present with pancytopenia 3

Bacterial and Mycobacterial Infections:

• Sepsis accounts for approximately 9% of cases 3
• Miliary tuberculosis can infiltrate bone marrow 3, 4
• Helicobacter pylori has been associated with pancytopenia in some cases 1

Drug-Induced and Toxic Causes

• Chemotherapy agents cause pancytopenia through direct bone marrow suppression and mucosal barrier disruption 8
• Drug-induced pancytopenia accounts for 5.4% of cases 2
• Radiation exposure causes acute radiation syndrome with hematopoietic failure 1

Immunotherapy-Related Causes

• 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 8
• Median time to onset is approximately 12 weeks with combination therapy versus 25 weeks with monotherapy 8
• Presentations include aplastic anemia, autoimmune hemolytic anemia, and pancytopenia 8

Inherited Predisposition Syndromes (Pediatric)

SAMD9/SAMD9L-Associated Syndromes:

• Account for 8-18% of childhood MDS cases 8
• Present with cytopenias, immunodeficiency, and risk for childhood-onset bone marrow failure 8
• SAMD9 variants cause MIRAGE syndrome with adrenal hypoplasia 8
• SAMD9L variants cause ataxia-pancytopenia syndrome 8

IKAROS-Associated Predisposition:

• Rare autosomal dominant condition with 10% cumulative incidence of malignancies by age 20 8
• Predominantly causes B-cell ALL but can present with pancytopenia 8

Other Genetic Syndromes:

• Trisomy 21 (Down syndrome) predisposes to myeloid and lymphoid neoplasms 8
• Ataxia-telangiectasia, Nijmegen breakage syndrome, and Bloom syndrome increase lymphoid malignancy risk 8

Metastatic Solid Tumors

• Bone marrow infiltration by metastatic solid organ tumors accounts for 3.6% of cases 2
• Common primary sites include breast, lung, and prostate cancers 5

Common Pitfalls and Caveats

• Bone marrow examination is essential in most cases, particularly in patients over 60 years, those with systemic symptoms, or when diagnosis remains unclear after initial testing 1
• Peripheral blood smear is critical to exclude pseudothrombocytopenia from platelet clumping 1
• In immunotherapy-treated patients, maintain a low threshold for bone marrow examination to rule out marrow infiltration, secondary MDS, or aplastic anemia 8
• Regional variations exist: vitamin B12 deficiency and hypersplenism dominate in some populations, while acute leukemia predominates in others 2, 7
• In patients with active infection and pancytopenia, consider less myelosuppressive regimens (such as BRAF inhibitors for BRAF V600E-mutated hairy cell leukemia) rather than purine analogs to avoid prolonged granulocytopenia 8