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

Bone Marrow Disorders (Most Common)

Bone marrow pathology represents the leading cause of pancytopenia, accounting for the majority of cases across all age groups. 2

Megaloblastic Anemia (Leading Reversible Cause)

Megaloblastic anemia is the single most common cause of pancytopenia, representing 33–74% of cases in large series. 3, 4
Vitamin B12 deficiency produces pancytopenia through ineffective hematopoiesis with intramedullary hemolysis, manifesting as macrocytosis, hypersegmented neutrophils, elevated LDH, and indirect hyperbilirubinemia. 5
Folate deficiency produces an identical hematologic picture. 2
Obtain vitamin B12, folate, and iron studies prior to bone marrow examination in all patients, as nutritional deficiencies are highly reversible. 2

Aplastic Anemia (14–18% of Cases)

Aplastic anemia results from cytotoxic T-cell–mediated destruction of hematopoietic stem cells, producing type I cytokine release and progressive marrow hypoplasia. 6
Screen for paroxysmal nocturnal hemoglobinuria (PNH) and HLA-DR15 in all suspected aplastic anemia cases, as these markers identify patients—particularly younger individuals with normal cytogenetics and hypoplastic marrow—who are most likely to respond to immunosuppressive therapy. 2
Non-severe aplastic anemia responds to immunosuppressive therapy with antilymphocyte globulin or high-dose cyclophosphamide. 2, 6
Severe aplastic anemia requires hematopoietic stem cell transplantation in appropriate candidates. 2

Myelodysplastic Syndromes (10.7% of Cases)

MDS accounts for approximately 10% of pancytopenia cases and is defined by ineffective hematopoiesis, dysplastic changes in ≥10% of cells in one or more lineages, and characteristic cytogenetic abnormalities (del(5q), del(20q), trisomy 8, monosomy 7/del(7q)). 2
Higher-risk MDS subtypes progress to acute myeloid leukemia in 25–55% of cases within the first year. 2
Routine cytogenetic analysis of bone marrow is mandatory because specific chromosomal abnormalities are essential for confirming MDS diagnosis and prognostic risk stratification (IPSS-R). 2
Hypomethylating agents (azacitidine) are recommended for higher-risk MDS patients not eligible for stem cell transplantation. 2

Hematological Malignancies

Acute and chronic leukemias suppress normal hematopoiesis through bone marrow infiltration, producing pancytopenia despite elevated white blood cell counts composed of non-functional blasts. 2
Detection of blasts on peripheral smear mandates urgent hematology consultation and same-day bone marrow aspiration with flow cytometry, cytogenetics, and molecular studies. 2
Chronic lymphocytic leukemia can present with leukocytosis and secondary autoimmune cytopenias (Evans syndrome), producing pancytopenia despite high lymphocyte counts. 2
Non-Hodgkin lymphoma requires excisional or incisional lymph node biopsy with immunophenotyping and cytogenetics; fine-needle aspiration alone is insufficient. 2

Peripheral Destruction and Sequestration

Hypersplenism (10–16% of Cases)

Hypersplenism with sequestration is a common cause of hematologic abnormalities in sarcoidosis and chronic liver disease, often more frequent than bone marrow involvement. 2, 7
Splenomegaly on physical examination suggests sequestration as the mechanism. 3, 4

Hemophagocytic Lymphohistiocytosis

HLH presents with pancytopenia, fever, hepatosplenomegaly, hypertriglyceridemia, hypofibrinogenemia, and markedly elevated ferritin (often >10,000 ng/mL). 2
Prompt immunosuppressive treatment is required to prevent mortality. 2

Autoimmune Destruction

Systemic lupus erythematosus and other autoimmune diseases cause pancytopenia through antibody-mediated destruction of all three lineages. 2, 4
If systemic manifestations (fever, rash, arthralgia, serositis, lymphadenopathy) are present, test for antinuclear antibodies, anti-dsDNA, and antiphospholipid antibodies. 2

Infectious Causes (Leading Cause in Some Populations)

Infections represent the leading etiology in developing countries (17.9% of cases), with enteric fever being the most frequently observed infectious cause. 7

Viral Infections

HIV and hepatitis C commonly cause secondary cytopenias through multiple mechanisms. Perform HIV and HCV testing in all adult patients with pancytopenia. 2
Cytomegalovirus causes post-transfusion mononucleosis syndrome with high fever, pancytopenia, and atypical lymphocytosis, typically starting one month after transfusion. 2
Parvovirus B19 produces hypoplastic bone marrow and should be tested in cases with reticulocytopenia. 2
Epstein-Barr virus can trigger hemophagocytic syndrome. 2

Bacterial Infections

Brucellosis commonly presents with mild transaminitis and pancytopenia; bone marrow culture has the highest diagnostic sensitivity. 2
Ehrlichiosis (E. chaffeensis) causes pancytopenia with leukopenia and thrombocytopenia, particularly in immunosuppressed patients and those receiving sulfonamide antimicrobials. 2
Disseminated Mycobacterium avium complex in HIV patients usually presents with fever of unknown origin; suppurative lymphadenopathy after antiretroviral therapy reflects immune reconstitution inflammatory syndrome. 2

Sepsis

Sepsis from any source accounts for 9% of pancytopenia cases through bone marrow suppression and peripheral consumption. 4

Drug-Induced and Toxic Causes

Chemotherapy Agents

Chemotherapy causes pancytopenia through direct bone marrow suppression and mucosal barrier disruption. 2
Purine analog-based therapies and alemtuzumab produce prolonged granulocytopenia; in patients with active infection, consider less myelosuppressive regimens. 2

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. 2
Monitor CBC at treatment initiation, at intervals during therapy, and periodically in long-term survivors. 2
Maintain a low threshold for bone marrow examination in immunotherapy-treated patients to rule out marrow infiltration, secondary MDS, or aplastic anemia. 2
Discontinue immunotherapy immediately and obtain early hematology consultation when significant hematological toxicity is detected. 2
40% of immune-related autoimmune hemolytic anemia cases are direct antiglobulin test (Coombs) negative, requiring alternative diagnostic approaches. 2

Methotrexate

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. 2
Methotrexate-induced pancytopenia may occur 4–6 weeks after dose increases. 2

Alcohol

Alcoholic liver disease causes pancytopenia through direct marrow toxicity, folate deficiency, and hypersplenism. 4

Radiation Exposure

Radiation exposure causes acute radiation syndrome with hematopoietic failure through stem cell depletion. 2

Genetic and Congenital Disorders

SAMD9/SAMD9L-Associated Syndromes

These syndromes account for 8–18% of childhood MDS cases, presenting with cytopenias, immunodeficiency, and risk for childhood-onset bone marrow failure. 2

Autoimmune Lymphoproliferative Syndrome (ALPS)

ALPS presents in childhood with chronic lymphadenopathy, splenomegaly, and multilineage cytopenias caused by sequestration and autoimmune destruction; confirmation requires testing for FAS gene mutations. 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

Copper and ceruloplasmin levels should be measured in select cases, particularly with history of gastrointestinal surgery, vitamin B12 deficiency, or vacuolation of myeloid/erythroid precursors on bone marrow examination. 2

Endocrine Disorders

Hypothyroidism or autoimmune thyroiditis can contribute to cytopenias. Assess thyroid dysfunction by measuring thyroid-stimulating hormone and antithyroid antibodies. 2

Diagnostic Algorithm

Step 1: Confirm True Pancytopenia

Repeat CBC in a heparin or citrate tube to exclude EDTA-dependent pseudothrombocytopenia before initiating therapy. 2
Obtain a hematopathology review of the peripheral blood smear to exclude pseudothrombocytopenia from platelet clumping and to detect blasts, schistocytes, dysplasia, or toxic changes. 2

Step 2: Assess Reticulocyte Count

Reticulocyte count <1.5% without obvious nutritional deficiency suggests production defect and mandates bone marrow examination. 2
Reticulocyte count helps differentiate between production defects and peripheral destruction. 2

Step 3: Evaluate for Hemolysis and Ineffective Hematopoiesis

Measure lactate dehydrogenase, haptoglobin, indirect bilirubin, and direct antiglobulin test to identify hemolytic or ineffective hematopoiesis. 2
When thrombotic thrombocytopenic purpura is suspected (schistocytes on smear, hemolysis, renal impairment), obtain ADAMTS13 activity and inhibitor testing immediately. 2

Step 4: Obtain Nutritional and Infectious Screening

Measure vitamin B12, folate, and iron studies prior to bone marrow examination, as megaloblastic anemia is a common reversible cause. 2
Perform HIV and HCV testing in all adult patients with pancytopenia. 2

Step 5: Autoimmune and Endocrine Evaluation

If systemic manifestations are present, test for ANA, anti-dsDNA, and antiphospholipid antibodies. 2
Measure thyroid-stimulating hormone and antithyroid antibodies. 2

Step 6: Bone Marrow Examination (Mandatory in Most Cases)

Perform bone marrow aspiration and biopsy with cytogenetic analysis in any of the following situations: 2

Age >60 years
Presence of systemic symptoms (fever, night sweats, weight loss) or abnormal physical findings (hepatosplenomegaly, lymphadenopathy)
Unclear diagnosis after initial laboratory work-up
Reticulocyte count <1.5% without an obvious nutritional deficiency
Any patient with blasts identified on peripheral smear

Routine cytogenetic testing of bone marrow specimens is mandatory because specific chromosomal abnormalities are essential for confirming MDS diagnosis and determining prognosis; omission of cytogenetics may lead to misclassification and suboptimal therapy selection. 2

Flow cytometric analysis for CD34+ cells and comprehensive immunophenotyping should be incorporated into the bone marrow evaluation to aid in the diagnosis of lymphoproliferative disorders (acute leukemias, lymphomas, chronic lymphocytic leukemia). 2

Step 7: Immediate Hematology Consultation

Same-day referral is required for suspected acute leukemia, hyperleukocytosis, or unexplained pancytopenia with blasts on peripheral smear. 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
Do not assume a reactive process in the presence of concurrent anemia and thrombocytopenia without smear and marrow evaluation. 2
Never omit HIV or hepatitis C testing in this context, as they are frequent contributors to secondary cytopenias. 2
Do not rely on fine-needle aspiration alone for lymph node evaluation in the setting of pancytopenia, as architectural preservation is essential for diagnosing lymphomas and histiocytic disorders. 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
Do not delay hematology consultation for unexplained cytopenias or when bone marrow examination is indicated. 2

Management Priorities

Treat the underlying cause as the primary focus of management, with supportive care including transfusions for symptomatic anemia or severe thrombocytopenia. 2
Appropriate supportive care is essential to ensure full-dose chemotherapy is delivered on schedule in adjuvant and neoadjuvant settings. 2
Antimicrobial therapy should be directed at the specific pathogen in infection-related pancytopenia, with eradication therapy for H. pylori if positive, and antiviral therapy for HIV/HCV. 2

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