Causes of Pancytopenia

Definition and Pathophysiologic Framework

Pancytopenia reflects either bone marrow production failure (hypocellular or ineffective hematopoiesis) or peripheral destruction/sequestration of blood cells, requiring simultaneous reduction of all three hematopoietic lineages. 1

Major Etiological Categories

I. Bone Marrow Production Disorders (Most Common)

A. Nutritional Deficiencies (Leading Reversible Cause)

Vitamin B12 deficiency and folate deficiency cause megaloblastic anemia with ineffective hematopoiesis, representing 20–33% of pancytopenia cases in large series. 2, 3, 4
Vitamin B12 deficiency can present with macrocytosis, hypersegmented neutrophils, elevated lactate dehydrogenase (LDH), and indirect hyperbilirubinemia due to intramedullary hemolysis. 5, 6
Pernicious anemia (intrinsic factor antibody-positive) can mimic hematologic malignancy with fever, lymphadenopathy, and B-symptoms, making it a critical differential before invasive bone marrow procedures. 6
Iron deficiency rarely causes isolated pancytopenia but contributes when combined with other nutritional deficits. 2

B. Aplastic Anemia

Aplastic anemia accounts for 1.8–14% of pancytopenia cases and presents with hypocellular bone marrow and reticulocyte count typically <1.5%. 2, 4
Immunosuppressive therapy is recommended for non-severe aplastic anemia, while hematopoietic stem cell transplantation is considered for severe cases in appropriate candidates. 2
Screening for paroxysmal nocturnal hemoglobinuria (PNH) and HLA-DR15 is useful for identifying patients responsive to immunosuppressive therapy, particularly young patients with normal cytogenetics and hypoplastic marrow. 7

C. Myelodysplastic Syndromes (MDS)

MDS affects 10.7% of pancytopenia cases and is characterized by ineffective hematopoiesis, dysplastic changes in ≥10% of cells in one or more lineages, and specific cytogenetic abnormalities such as del(5q), del(20q), +8, or −7/del(7q). 7, 2, 4
MDS with multilineage dysplasia (MDS-MLD) affects two or more myeloid lineages, while MDS with excess blasts (MDS-EB-1 and MDS-EB-2) carries 25–55% risk of progression to acute myeloid leukemia within one year. 8
Bone marrow aspiration with cytogenetic analysis is mandatory in patients >60 years, those with systemic symptoms, abnormal physical findings, or when diagnosis remains unclear after initial workup. 7, 2
Hypomethylating agents such as azacitidine are recommended for higher-risk MDS patients not eligible for stem cell transplantation. 2, 8

D. Hematologic Malignancies

Acute leukemias, lymphomas, chronic lymphocytic leukemia, and multiple myeloma account for 16–21% of pancytopenia cases through direct bone marrow infiltration and suppression of normal hematopoiesis. 2, 3, 4
Detection of blasts on peripheral smear mandates urgent hematology consultation and same-day bone marrow examination with flow cytometry, cytogenetics, and molecular studies. 2
Chronic myelomonocytic leukemia (CMML) presents with leukocytosis, peripheral monocytosis ≥1 × 10⁹/L, anemia, and thrombocytopenia, representing an MDS/myeloproliferative neoplasm overlap. 2

II. Peripheral Destruction and Sequestration

A. Hypersplenism

Hypersplenism with sequestration accounts for 10–20.5% of pancytopenia cases and is more frequent than bone marrow involvement in conditions like sarcoidosis. 2, 3, 4
Splenomegaly from cirrhosis, portal hypertension, or infiltrative diseases causes pooling and destruction of all three cell lines. 2

B. Autoimmune Disorders

Systemic lupus erythematosus causes pancytopenia in 4.5% of cases through autoantibody-mediated destruction and bone marrow suppression. 3, 4
Autoimmune lymphoproliferative syndrome (ALPS) presents in childhood with chronic lymphadenopathy, splenomegaly, and multilineage cytopenias caused by sequestration and autoimmune destruction; confirmation requires FAS gene mutation testing. 2
Autoimmune workup including antinuclear antibodies (ANA) and anti-dsDNA should be performed when systemic symptoms suggest autoimmune disease. 2

C. Hemophagocytic Syndromes

Hemophagocytic lymphohistiocytosis (HLH) presents with pancytopenia, fever, hepatosplenomegaly, hypertriglyceridemia, hypofibrinogenemia, and markedly elevated ferritin (often >10,000 ng/mL), requiring prompt immunosuppressive treatment. 2
Secondary HLH can be triggered by infections (Epstein-Barr virus, cytomegalovirus), malignancies, or autoimmune conditions. 2, 9

III. Infectious Causes

HIV and hepatitis C virus (HCV) testing is recommended in all adult patients with pancytopenia, as these infections commonly cause secondary cytopenias through direct marrow suppression and immune-mediated mechanisms. 2
Brucellosis commonly presents with mild transaminitis and pancytopenia, with bone marrow culture having the highest diagnostic sensitivity. 2
Ehrlichiosis (Ehrlichia chaffeensis) causes pancytopenia with leukopenia and thrombocytopenia; immunosuppressed patients (HIV, organ transplant, splenectomy) experience more severe symptoms and higher mortality. 2
Cytomegalovirus (CMV) can cause post-transfusion mononucleosis syndrome with high fever, pancytopenia, and atypical lymphocytosis, typically starting one month after transfusion; ganciclovir or valganciclovir is recommended for severe disease in immunocompromised patients. 2
Parvovirus B19 should be tested in cases showing hypoplastic bone marrow pattern. 2
Disseminated tuberculosis, dengue, and viral hepatitis are less common infectious causes. 4

IV. Drug-Induced and Toxic Causes

Drug-induced pancytopenia accounts for 5.4% of cases; a comprehensive medication history including prescription drugs, over-the-counter agents, herbal supplements, alcohol, and recent chemotherapy or immune checkpoint inhibitor therapy must be obtained. 2, 3
Methotrexate can rarely cause pancytopenia even with low-dose weekly therapy, particularly in patients with impaired renal function, medication errors, or concomitant sulfonamide-based medications, typically occurring 4–6 weeks after dose increases. 2
Chemotherapy agents cause pancytopenia through direct bone marrow suppression; purine analog-based therapies and alemtuzumab require monitoring for myelosuppression. 2
Immune checkpoint inhibitors (anti-CTLA-4 and anti-PD-L1 agents) cause immune-related hematological toxicity in <5% of patients but carry significant mortality risk; early hematology consultation is mandatory and immunotherapy should be discontinued while investigating significant hematological toxicity. 2
Radiation exposure causes acute radiation syndrome with hematopoietic failure. 2

V. Rare and Genetic Causes

SAMD9/SAMD9L-associated syndromes account for 8–18% of childhood MDS cases, presenting with cytopenias, immunodeficiency, and risk for childhood-onset bone marrow failure. 2
Chediak-Higashi syndrome presents with partial oculocutaneous albinism, bacterial infections, and pancytopenia during the accelerated phase (HLH). 2
Griscelli syndrome type 2 manifests with pigmentary dilution, neurological abnormalities, pyogenic infections, and potential HLH development. 2
Copper deficiency may be indicated in select cases, particularly with history of gastrointestinal surgery, vitamin B12 deficiency, or vacuolation of myeloid/erythroid precursors on bone marrow examination. 2

Diagnostic Algorithm

Step 1: Confirm True Pancytopenia

Repeat complete blood count in a heparin or citrate tube to exclude EDTA-dependent pseudothrombocytopenia before initiating therapy. 2
Peripheral blood smear examination is critical to exclude pseudothrombocytopenia from platelet clumping and identify morphological abnormalities like schistocytes, blasts, hypersegmented neutrophils, or dysplastic changes. 2

Step 2: Assess Reticulocyte Count

Reticulocyte count <1.5% without obvious nutritional deficiency indicates bone marrow production failure and mandates bone marrow examination. 2
Elevated reticulocyte count suggests peripheral destruction or hemolysis. 2

Step 3: Screen for Reversible Causes

Obtain vitamin B12, folate, and iron studies prior to invasive procedures, as megaloblastic anemia is a common reversible cause. 2
Measure lactate dehydrogenase, haptoglobin, indirect bilirubin, and direct antiglobulin test (Coombs) to assess for hemolysis and ineffective hematopoiesis. 2
HIV and HCV testing is mandatory in all adults. 2

Step 4: Peripheral Smear Review by Hematopathologist

Presence of blasts mandates immediate hematology consultation and same-day bone marrow aspiration with flow cytometry, cytogenetics, and molecular studies. 2
Schistocytes with thrombocytopenia suggest thrombotic microangiopathy (TTP, HUS, DIC); obtain ADAMTS13 activity, LDH, haptoglobin, PT/aPTT, fibrinogen, and D-dimer. 2
Dysplastic changes in ≥2 lineages are characteristic of MDS, especially in patients >60 years. 2

Step 5: Bone Marrow Examination

Perform bone marrow aspiration and biopsy with cytogenetic analysis in:
- Age >60 years
- Presence of systemic symptoms (fever, night sweats, weight loss) or abnormal physical findings (hepatosplenomegaly, lymphadenopathy)
- Unclear diagnosis after initial laboratory workup
- Reticulocyte count <1.5% without obvious nutritional deficiency
- Any patient with blasts on peripheral smear 2
Routine cytogenetic analysis is mandatory because specific chromosomal abnormalities are essential for diagnosing MDS and determining prognosis. 7, 2
Bone marrow flow cytometry for CD34+ cells and immunophenotyping helps diagnose lymphoproliferative disorders. 7

Step 6: Additional Testing Based on Clinical Context

If systemic manifestations (fever, rash, arthralgia, serositis, lymphadenopathy) are present, test for ANA, anti-dsDNA, and antiphospholipid antibodies. 2
Thyroid-stimulating hormone and antithyroid antibodies should be measured, as hypothyroidism can contribute to cytopenias. 2
In immunotherapy-treated patients, monitor CBC at treatment initiation, at intervals during therapy, and periodically in long-term survivors; maintain a low threshold for bone marrow examination to rule out marrow infiltration, secondary MDS, or aplastic anemia. 2
For suspected atypical hemolytic-uremic syndrome or complement-mediated hemolysis, measure complement components (C3, C4, CH50). 2

Critical Pitfalls to Avoid

Do not delay peripheral smear review while awaiting additional tests; early detection of blasts prevents tumor lysis syndrome and leukostasis. 2
Never omit HIV or HCV testing in adults with pancytopenia, as they are frequent contributors to secondary cytopenias. 2
Do not assume reactive leukocytosis in the presence of concurrent anemia and thrombocytopenia without smear and marrow evaluation. 2
Do not rely on fine-needle aspiration alone for lymph node evaluation in the setting of pancytopenia; excisional biopsy with architectural preservation is essential for diagnosing lymphomas and histiocytic disorders. 2
In immunotherapy patients, 40% of immune-related autoimmune hemolytic anemia cases are direct antiglobulin test (Coombs) negative, requiring alternative diagnostic approaches. 2
Do not postpone bone marrow examination in patients >60 years with unexplained cytopenias, given the high prevalence of MDS and acute leukemia. 2
Avoid platelet or red-cell transfusion in suspected TTP before ADAMTS13 results, because transfusion may exacerbate microvascular thrombosis. 2

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