Causes of Pancytopenia
Pancytopenia is most commonly caused by bone marrow disorders (megaloblastic anemia, aplastic anemia, myelodysplastic syndromes, and hematological malignancies), followed by peripheral destruction/sequestration mechanisms and infections. 1
Primary Etiological Categories
Bone Marrow Production Disorders (Most Common)
Megaloblastic anemia is the leading cause in many populations, accounting for 33% of cases, and is critically important because it is rapidly correctable and can present acutely in critically ill patients. 2, 3 This nutritional deficiency should never be missed given its reversibility. 2
Aplastic anemia represents the second most common cause (14-49% of cases depending on population studied), characterized by hypocellular bone marrow and can remain stable for years but may transform into myelodysplastic syndrome, acute leukemia, or paroxysmal nocturnal hemoglobinuria. 4, 2, 3
Myelodysplastic syndromes affect 10.7% of cases and are characterized by ineffective hematopoiesis with dysplastic changes. 1 These require bone marrow examination for diagnosis, particularly in patients over 60 years. 1
Hematological malignancies including aleukemic leukemia and lymphoma account for approximately 5-30% of cases. 2, 3 The American Association for Cancer Research notes that SAMD9/SAMD9L-Associated Syndromes account for 8-18% of childhood MDS cases presenting with cytopenias. 1
Peripheral Destruction and Sequestration
Hypersplenism causes 10-19% of pancytopenia cases through sequestration of blood cells in an enlarged spleen. 2, 3
Hemophagocytic syndrome can present with pancytopenia and requires prompt immunosuppressive treatment. 1
Infectious Causes
Infections are a leading cause in some populations, including HIV, HCV, sepsis (9% of cases), disseminated tuberculosis, dengue, and viral hepatitis. 1, 3 HIV and HCV testing is recommended in all adult patients with pancytopenia. 1
Brucellosis commonly presents with mild transaminitis and pancytopenia, with bone marrow culture having the highest diagnostic sensitivity. 5
Drug-Induced Causes
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. 5 Pancytopenia may occur 4-6 weeks after dose increases. 5
Chemotherapy agents cause pancytopenia through direct bone marrow suppression and mucosal barrier disruption. 1 The American Academy of Dermatology identifies tetracycline antibiotics (minocycline, doxycycline) and azathioprine as causing blood abnormalities including pancytopenia. 6
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
Autoimmune and Systemic Disorders
Systemic lupus erythematosus and other rheumatologic diseases can cause pancytopenia. 4, 3 Autoimmune workup including ANA and anti-dsDNA should be considered if systemic symptoms suggest autoimmune disease. 1
Less Common Causes
Nutritional deficiencies beyond megaloblastic anemia (including copper deficiency) account for 16% of cases. 3, 7
Alcoholic liver disease, hemolytic anemia, and multiple myeloma are less frequent causes. 3
Radiation exposure can cause acute radiation syndrome with hematopoietic failure. 1
Critical Diagnostic Pitfalls
The European Society for Medical Oncology emphasizes maintaining a low threshold for bone marrow examination in immunotherapy-treated patients to rule out marrow infiltration, secondary MDS, or aplastic anemia. 1 Both bone marrow aspiration and biopsy should be performed simultaneously when diagnosis is elusive, as aspiration often fails to obtain adequate samples while biopsy is usually diagnostic. 2
Peripheral blood smear examination is critical to exclude pseudothrombocytopenia and identify morphological abnormalities like schistocytes or blasts. 1 Reticulocyte count helps differentiate between production defects and peripheral destruction. 1