What every physician needs to know:

A reduction in red cells, white cells, and platelets is referred to as pancytopenia.

Pancytopenia usually reflects the bone marrow’s response to non-hematologic conditions (for example, infection, drugs, inflammation, malignancy, nutritional changes). It is important to rule out these conditions before considering much less common hematological diseases. The setting in which the abnormal counts occur influences whether treatment is needed before pinning down the cause (for example, hematocrit (Hct) below 25% in someone having angina, or platelets less that 5,000 in a patient with melena, etc.,).

Most diagnoses are made by performing a careful history, physical exam, simple blood work, and review of the peripheral blood smear. Ascertaining the underlying cause is important before administering specific therapy.

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What features of the presentation will guide me toward possible causes and next treatment steps:

Signs and symptoms of pancytopenia are usually directly proportional to the degree of cytopenias; patients with mild pancytopenia are often asymptomatic.

Signs and symptoms associated with anemia

Most patients with a hemoglobin over 10g/dl have little in the way of signs and symptoms, especially if the anemia has developed gradually; acute blood loss leads to more acute symptoms. The following are common sign and symptoms associated with anemia: fatigue, headache, dyspnea on exertion, pallor (skin, conjunctiva, nail beds), palpitations, weakness, and sometimes angina in older individuals or those with underlying coronary artery disease.

Signs and symptoms associated with thrombocytopenia

Thrombocytopenia seldom produces signs or symptoms as long as the platelet count is over 30,000 per microliter. Exceptions include instances where there is concomitant acquired or primary platelet dysfunction (for example, myelodysplastic syndromes [MDS] or administration of antiplatelet agents such as aspirin, clopidogrel, etc.,). The following are common signs and symptoms attributable to thrombocytopenia: epistaxis, bleeding gums, petechiae (usually best seen on the pretibial areas and posterior pharynx), heavy menstrual bleeding, gastrointestinal bleeding, headache from intracranial bleed (rare, and usually only with severe thrombocytopenia).

Signs and symptoms associated with leukopenia

Leukopenia is usually secondary to a reduction in the number of neutrophils. Neutropenia that is not induced by chemotherapeutic agents seldom leads to signs or symptoms until the neutrophil count falls below 300 per microliter. Common signs and symptoms of severe neutropenia include fever, chills, and frequent infections. Patients with severe neutropenia are predisposed to bacterial and fungal infections. Febrile neutropenia represents a medical urgency/emergency and is usually an indication for admission to the hospital.

Critical information to obtain in the history of a patient with pancytopenia

Obtaining a detailed history is essential. Time of onset, age of the patient, recent drug or environment exposure, family history of cytopenias, and the setting in which the pancytopenia developed (hospital- versus community-acquired) are all important factors to help focus the work-up and narrow the differential diagnosis.

Obtaining previous blood counts can be especially helpful in determining whether this is an acute, subacute, or chronic process. Community-acquired severe pancytopenia, developing over days to weeks, is more suspicious for leukemia, aplastic anemia, or drug/toxin exposure. Alternatively, community-acquired pancytopenia that has been present for many months to years is more likely to be due to nutritional deficiencies or low-grade hematologic disorders (such as low grade MDS, low grade lymphoma, hypersplenism, large granular lymphocyte [LGL] leukemia, etc.,).

Pancytopenia is common in hospitalized patients and is especially common in patients with septicemia, patients in the intensive care unit, and patients with severe liver disease. Usually the pancytopenia in this population is related to the septicemia, disseminated intravascular coagulation, hypersplenism, or drugs.

Age is also an important consideration in the differential diagnosis of pancytopenia. Aplastic anemia (both congenital and acquired) and viral infections (HIV, Epstein-Barr virus [EBV], Cytomegalovirus [CMV]) are more common in children and young adults; diseases such as myelodysplastic syndromes, hairy cell leukemia, LGL leukemia and myelofibrosis are seldom seen in children and young adults.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

The work-up of pancytopenia should begin with:

  • a complete blood count (CBC) with differential
  • a reticulocyte count
  • a comprehensive metabolic panel
  • a careful review of the peripheral blood smear
  • B12 and red cell folate assays

The importance of perusal of the peripheral blood smear with an experienced hematologist or pathologist cannot be over-emphasized.

Acute pancytopenia in a patient without an obvious etiology from the history is almost always an indication for a bone marrow aspirate and biopsy. Tests for HIV and other viral illnesses (EBV, CMV, etc.,) should be considered in patients at risk.

Insight gained from the peripheral smear: Important clues from red cell and platelet morphology can be missed in a patient who has been transfused so it is best, if possible, to review the peripheral smear before transfusion.

Red cell abnormalities

Macrocytosis is common in liver disease, B12 deficiency, folate deficiency, and congenital and acquired bone marrow failure disorders (for example, aplastic anemia, paroxysmal nocturnal hemoglobinuria [PNH], MDS). Nucleated red cells in the peripheral smear suggest a myelophthisic process, myelofibrosis, or other infiltrating marrow disorder.

White cell abnormalities

Peripheral blasts are an indication for a bone marrow biopsy and usually signify the presence of leukemia, MDS, or other infiltrative marrow disease. The presence of large granular lymphocytes should lead to the suspicion of a viral illness or LGL leukemia. Pseudo Pelger-Huet cells, hypogranular, and/or dysmorphic neutrophils should raise suspicion for MDS. Hyperlobated neutrophils can be associated with B12 deficiency, drugs, or MDS. Toxic granulations and Dohle bodies can be seen in patients with sepsis.

Platelet abnormalities

Giant platelets can be seen in myelofibrosis and MDS. The immature platelet fraction (IPF) is a measure of platelet production. The IPF is low in primary bone marrow failure disorders and elevated in the setting of peripheral destruction.

The reticulocyte count

This is a measure of red cell production, and needs to be corrected for the degree of anemia. Most patients with pancytopenia have a low absolute reticulocyte count. Notable exceptions include diseases like PNH, myelophthisic anemias, and myelofibrosis.

What conditions can underlie pancytopenia:

Differential diagnosis of pancytopenia:

Pancytopenia with a hypocellular bone marrow:
  • Inherited aplastic anemia (for example, Fanconi anemia, Shwachman-Diamond syndrome, dyskeratosis congenita, amegakaryocytic thrombocytopenia)
  • acquired aplastic anemia
  • MDS (15% of cases)
  • PNH
  • Leukemia (rarely)
  • LGL leukemia (rarely)
  • Anorexia nervosa (rare)
Pancytopenia with normocellular or hypercellular bone marrow

Primary bone marrow disorders

  • MDS
  • Myelofibrosis
  • Acute myeloid leukemia
  • Acute lymphocytic leukemia
  • Myelophthisis
  • Lymphoproliferative disorders
  • Multiple myeloma
  • LGL leukemia
  • Hypersplenism
  • Hairy cell leukemia
  • Hemophagocytic syndrome

Secondary to systemic illness

  • Lupus
  • Hypersplenism
  • Nutritional deficiency (B12 or folate)
  • Viral infections (HIV, CMV, EBV, etc.,)
  • Sepsis
  • Excess alcohol
  • Sarcoidosis
  • Brucellosis
  • Tuberculosis

When do you need to get more aggressive tests?

A bone marrow exam consists of an aspirate (to assess morphology and to perform special studies such as flow cytometry, cytogenetics, fluorescent in-situ hybridization, etc.,), and a biopsy in order to assess cellularity (a rough rule of thumb is that marrow cellularity should be equal to 100 minus the patients age). A bone marrow examination is recommended for virtually all cases of unexplained pancytopenia, especially in patients with severe symptomatic pancytopenia. Patients with sepsis, severe liver disease, pancytopenia due to cytotoxic chemotherapy, nutritional deficiencies, and lupus do not necessarily need bone marrow examination.

In patients suspected of having a primary bone marrow failure disorder, a bone marrow aspirate, biopsy (1 to 2 cm core), flow cytometry, cytogenetics, and often a fluorescence in situ hybridization (FISH) exam should be performed.

In patients suspected of having an inherited bone marrow failure disorder, peripheral blood chromosomal fragility studies (for example, diepoxybutane or mitomycin-C) should be performed to rule out Fanconi anemia. Telomere length on peripheral blood can help exclude dyskeratosis congenita, and genetic analysis to look for mutations in ribosomal protein genes can help diagnosis of Shwachman-Diamond syndrome.

Peripheral blood flow cytometry to look for PNH should be performed on all patients with aplastic anemia, suspected PNH, and certain forms of MDS, including hypoplastic MDS and some refractory anemia patients.

Peripheral blood flow cytometry and T cell gene rearrangement studies for LGL should be performed in patients with persistently elevated numbers of large granular lymphocytes.

Patients with B12 and folate deficiency should have methylmalonic acid and homocysteine levels tested, if the diagnosis is ambiguous.

Note: Parvovirus B19 causes red cell aplasia in patients with shortened red cell survival (for example, sickle cell disease) and in patients with immunodeficiency. It is not a common cause of pancytopenia/aplastic anemia. The unfortunate term aplastic crisis (red cell aplasia in a patient with sickle cell disease) has led to the erroneous assumption that this is a common cause of pancytopenia.

What imaging studies (if any) will be helpful?

Imaging studies are usually not required in the work-up of pancytopenia, unless one suspects a lymphoproliferative disorder or splenomegaly. Computed tomography (CT) scans of the chest, abdomen, pelvis and/or abdominal ultrasound may be helpful in these situations.

What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?

Blood products such as packed red blood cells (PRBCs) and platelets should be used judiciously. In the acute setting, PRBCs should be administered to avoid life-threatening anemia, and platelet transfusions should be administered to prevent life-threatening bleeding. Thereafter, blood products are indicated to prevent symptoms of anemia and thrombocytopenia. Hematopoietic growth factors, especially granulocyte colony-stimulating factor (G-CSF) and granulocyte-monocyte colony-stimulating factor (GM-CSF) should not be administered before the etiology of pancytopenia is known.

Blood products should be irradiated for patients who are immunosuppressed or who may have an underlying primary bone marrow failure disorder to prevent transfusional graft-versus-host disease. All blood products should be leukoreduced to mitigate alloimmunization and to decrease the risk of viral transmission such as CMV. If there is a possibility that stem cell transplantation will be needed in the future, it is especially important to avoid family blood donation.

What other therapies are helpful for reducing complications?

Alloimmunized patients who are refractory to platelet transfusion and who are at risk of bleeding may benefit from aminocaproic acid.

What should you tell the patient and the family about prognosis?

The prognosis of pancytopenia depends on the depth of cytopenias and the underlying disease. Determining the mechanism of pancytopenia is critical before one begins definitive therapy that can either obscure the diagnosis, or in some cases harm the patient.

“What if” scenarios.

What if I’ve performed the initial work-up including a bone marrow aspirate, biopsy and cytogenetics and the diagnosis is still not clear?

In diseases such as aplastic anemia, MDS, inherited bone marrow failure disorders, autoimmune diseases, etc., making a definitive diagnosis is often challenging. It is important to emphasize to the patient that in some cases a single bone marrow examination is not sufficient to make a definitive diagnosis. Occasionally two or three bone marrows performed over time are necessary to establish an etiology. Referral to a center that specializes in bone marrow failure disorders is indicated is such cases. While it is often tempting to try various therapies empirically in such cases, it is always better to establish a diagnosis before embarking on therapy, even if that means some additional transfusions.


The pathophysiology of pancytopenia is variable and is discussed in detail in specific disease oriented chapters.

What other clinical manifestations may help me to diagnose pancytopenia?

Important or unusual questions/symptoms to ask on history
  • Family history of cytopenia and/or early onset leukemia/MDS can suggest an inherited bone marrow failure disorder
  • Family history of pulmonary fibrosis or premature graying of the hair can be a clue for dyskeratosis congenita
  • Obtaining old CBCs is always helpful in determining the chronicity of the illness
  • Short stature is a clue that you may be dealing with an inherited bone marrow failure disease; ask about the height of parents and siblings
  • PNH patients may have abdominal pain paroxysms, back pain, hemoglobinuria, difficulty swallowing, and erectile dysfunction
  • Hair loss, butterfly rash, and/or oral ulcers should raise suspicion of lupus
Important or unusual signs or findings on physical exam
  • Fevers, night sweats, weight loss, lymphadenopathy, and musculoskeletal pain are unusual presenting features of aplastic anemia. These signs and symptoms are more typical of autoimmune disease, infections, lymphomas, or leukemia
  • Café-au-lait spots, hypoplastic nails, gray hair in young patients, horseshoe kidneys, abnormal thumbs/digits, short statue, etc., should raise suspicion of an inherited bone marrow failure disorder
  • A high reticulocyte count and LDH should raise suspicion for PNH
  • Abnormal proprioception, decreased knee jerks, and numbness or paresthesias should raise suspicion for B-12 deficiency
  • A history of major gastric surgery, removal of the terminal ileum or gastric bypass surgery, should raise suspicion for a nutritional deficiency
  • A palpable spleen is unusual in patients with aplastic anemia, MDS, or nutritional deficiencies. An enlarged spleen should prompt a search for a lymphoproliferative disease, hypersplenism, cirrhosis, etc.

What other additional laboratory studies may be ordered?


What’s the evidence?

Brodsky, RA, Jones, RJ. “Aplastic anaemia”. Lancet. vol. 365. 2005. pp. 1647-1656. (Comprehensive review of diagnosis and treatment of acquired aplastic anemia.)

Brodsky, RA. “Paroxysmal nocturnal hemoglobinuira”. Blood. vol. 124. 2014. pp. 2804-2811. (Review of the pathophysiology, diagnosis, and management of paroxysmal nocturnal hemoglobinuria.)

Borowitz, MJ, Fiona, EC, DiGuiseppe, JA. ” Guideline for the diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria and related disorders by flow cytometry”. Cytometry Part B Clin Cytom. vol. 78. 2010. pp. 211-230. (Consensus paper on behalf of the Clinical Cytometry Society on the proper diagnosis and monitoring of PNH.)

Townsley, DM, Dumitriu, B, Young, NS. “Bone marrow failure and the telomeropathies”. Blood . vol. 124. 2014. pp. 2775-83. (Review of the role of telomere dysfunction in bone marrow failure.)

Alter, BP. “Diagnosis, genetics, and management of inherited bone marrow failure”. Hematology Am Soc Hematol Educ Program. 2007. pp. 29-39. (Review of diagnostic approach and management of inherited bone marrow failure.)

Matsui, WT, Brodsky, RA, Smith, BD, Borowitz, MJ, Jones, RJ. “Quantitative analysis of bone marrow CD34 cells in aplastic anemia and hypoplastic myelodysplastic syndromes”. Leukemia. vol. 20. 2006. pp. 458-462. (Demonstration that bone marrow CD34 count may help distinguish aplastic anemia and hypoplastic myelodysplastic syndromes. The percentage of CD34+ cells in the marrow of patients with aplastic anemia is markedly reduced. In contrast, the percentage of CD34+ cells in the marrow of patients with MDS is usually normal or elevated.)

Vardiman, JW, Thiele, J, Arber, DA. “The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes”. Blood. vol. 114. 2009. pp. 937-951. (Consensus paper from the WHO on the classification of myeloid neoplasms. Good section on the classification of myelodysplastic syndromes.)

Lamy, T, Loughran, TP. “How I treat LGL leukemia”. Blood. vol. 117. 2011. pp. 2764-2774. (Review of diagnosis and management of LGL leukemia.)

DeZern, AE, Symons, HJ, Resar, LS, Borowitz, MJ, Armanios, MY, Brodsky, RA. “Detection of paroxysmal nocturnal hemoglobinuria clones to exclude inherited bone marrow failure syndromes”. Eur J Haematol. vol. 92. 2014. pp. 467-70. (Demonstration that detection of PNH cells in bone marrow failure states helps to exclude congenital forms of aplastic anemia.)

Dezern, AE, Pu, J, McDevitt, MA, Jones, RJ, Brodsky, RA. “Burst-forming unit-erythroid assays to distinguish cellular bone marrow failure disorders”. Exp Hematol. vol. 41. 2013. pp. 808-816. (Demonstration that BFU-E assays can help distinguish primary stem cell defects like MDS from pure red cell aplasia andLGL.)