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Continuing Education Activity

Pancytopenia is defined as a decrease in all three hematologic cell lines. The condition is not a disease in itself but a common pathway caused by various etiologies that can be infectious, autoimmune, genetic, nutritional, and/or malignant. Determining the cause of pancytopenia is a challenge and is key in determining the proper treatment regimen and estimating prognosis. Pancytopenia could be a result of decreased production of the cells or increased destruction. Anyone presenting with pancytopenia requires a thorough evaluation to identify the underlying etiology. This activity reviews the most common etiologies of pancytopenia, outlines potential pathways in determining the underlying diagnosis, and highlights the interprofessional team's importance in evaluating and treating these patients.


  • Identify the etiology of pancytopenia.
  • Describe the evaluation of patients with pancytopenia.
  • Review the management options available for pancytopenia.
  • Explain the differentials or pancytopenia and their management.


Pancytopenia is a hematologic condition characterized by a decrease in all three peripheral blood cell lines. It is characterized by a hemoglobin value of less than 12 g/dL in women and 13 g/dL in men, platelets of less than 150,000 per mcL, and leukocytes of less than 4000 per ml (or absolute neutrophil count of less than 1800 per ml).[1][2] However, these thresholds mainly depend on age, sex, race, and varying clinical scenarios.

Leukopenia is primarily seen as neutropenia since neutrophils constitute the majority of leukocytes. Pancytopenia is not a disease but a manifestation of other underlying conditions.[3] It is commonly associated with multiple benign and malignant conditions.[1] Pancytopenia could be a result of decreased production of the cells or increased destruction. Anyone presenting with pancytopenia requires a thorough evaluation to identify the underlying etiology.


The etiology of pancytopenia can be broadly categorized as a central type that involves production disorders or a peripheral type that involves disorders of increased destruction.[4] These causes could contribute to pancytopenia independently or as a combination.

Decreased production (central type): Pancytopenia due to decreased production is mainly secondary to nutritional deficiencies. Pancytopenia caused by bone marrow failure is known as aplastic anemia. Aplastic anemia could be idiopathic/autoimmune, secondary to infections (such as parvovirus B19, hepatitis, human immunodeficiency virus (HIV), cytomegalovirus, or Epstein-Barr virus), after drug toxicity, or chemotherapeutic agents (methotrexate, dapsone, carbimazole, carbamazepine, chloramphenicol). Pancytopenia can also be related to inadequate intake (as seen in eating disorders and alcoholics) or malabsorption.[5]

Bone marrow infiltration/replacement: The production of cell lines is also impaired when the bone marrow is infiltrated by malignancies (lymphoma, leukemia, multiple myeloma) or granulomatous disorders. Metastatic tumors can also cause bone marrow replacement late in the disease, thus producing pancytopenia.

Increased destruction (peripheral type): Peripheral destruction of cells can be associated with many autoimmune conditions (such as systemic lupus erythematosus, rheumatoid arthritis) and splenic sequestration (alcoholic liver cirrhosis, HIV, tuberculosis, malaria). Hypersplenism affects platelets and erythrocytes more than leukocytes.

With the current Covid-19 pandemic, pancytopenia has been reported secondary to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).[6][7][8] Bone marrow aspiration had shown viral infection and infiltration with SARS-CoV-2.[9]

Despite extensive workup, a subset of patients has unexplained cytopenia, classified as idiopathic cytopenias of unknown significance.[10]

The table below summarizes the causes of pancytopenia according to the mechanisms involved:

Mechanisms Causes
Decreased production (central type)
  • Autoimmune disorders (e.g., systemic lupus erythematosus [SLE], rheumatoid arthritis [RA], sarcoidosis)
  • Hemophagocytic lymphohistiocytosis (HLH)
  • Aplastic anemia/paroxysmal nocturnal hemoglobinuria
  • Drugs
    • Cytotoxic drugs
    • Idiosyncratic reactions to medications
  • Large granular lymphocyte leukemia
  • Nutritional abnormalities (B12 and folate deficiencies, excessive alcohol, malnutrition)
  • Viral infections[11][12]
Bone marrow infiltration/replacement


  • Non-malignant
    • Myelofibrosis
    • Infectious (e.g., fungal, tuberculous)
    • Storage diseases
  • Malignant
    • Acute leukemias
    • Chronic leukemias/myeloproliferative neoplasms (MPN)
    • Myelodysplastic syndromes (MDS)
    • Multiple myeloma
    • Metastatic cancer
Increased destruction (peripheral type)
  • Consumption
    • Disseminated intravascular coagulation (e.g., associated with sepsis, acute promyelocytic leukemia)
  • Splenomegaly
    • Portal hypertension/cirrhosis
    • Infections (e.g., EBV)
    • Autoimmune disorders (e.g., SLE, RA/Felty syndrome)
    • Myelofibrosis with myeloid metaplasia
    • Storage diseases (e.g., Gaucher)
    • Malignancies (e.g., lymphomas, MPN)

 Table 1. Mechanisms of pancytopenia

Category Drugs
Nonsteroidal anti-inflammatory drugs
  • Aspirin
  • Salicylates
  • Ibuprofen
  • Indomethacin
  • Diclofenac
  • Sulindac
Cardiovascular (including diuretics)
  • Aspirin
  • Lisinopril
  • Amiodarone
  • Nifedipine
  • Captopril
  • Quinidine
  • Thiazides
  • Acetazolamide
  • Furosemide
  • Albendazole
  • Cidofovir
  • Dapsone
  • Ganciclovir             
  • Foscarnet
  • Sulfonamides
  • Quinidine
  • Quinine             
  • Zidovudine
  • Allopurinol
  • Colchicine
  • Carbamazepine
  • Fosphenytoin
  • Phenytoin
  • Phenobarbital
  • Valproate
  • Levetiracetam
  • Leflunomide
  • Methotrexate
  • Sulfasalazine
  • Penicillamine
  • Bupropion
  • Lithium
  • Valproate
  • Carbamazepine 
  • Methimazole
  • Propylthiouracil

Table 2. Drugs causing pancytopenia


Pancytopenia incidence frequently has a bi-modal presentation in children and adults in the 3rd and 4th decades. Literature has reported a between 1.4 and 2.6 to 1 male to female predominance. While conditions such as multiple myeloma and myelodysplastic syndrome are more prevalent in older patients, acute leukemia and parvovirus B19 infection are more common in younger patients.

In North America, the most common etiologies are myeloid neoplasms (acute myeloid leukemia, myelodysplasia, non-Hodgkin lymphoma, hairy cell leukemia, and precursor B acute lymphoblastic leukemia), followed by aplastic anemia, megaloblastic anemia, and HIV infections.[13]

Geographic and sociocultural influences determine the significant pancytopenia causes, especially for megaloblastic anemia.[13][14] For megaloblastic anemia, there is usually no gender predominance. There seem to be more cases in the East than in the West, most likely due to the higher incidence of infections and drugs causing pancytopenia used in developing countries.

A study from 2013 in India showed that the most common causes are hypersplenism, infections, myelosuppression (cancer, chemotherapy, drug toxicity, or radiotherapy), and megaloblastic anemia.[3] A previous study in India showed megaloblastic anemia as the most frequent cause, followed by aplastic anemia.[14] In Mexico, the most common causes are myelodysplastic syndromes and megaloblastic anemia, followed by acute myeloblastic leukemia, acute lymphoblastic leukemia, hypersplenism, and aplastic anemia. In Turkey, the most common cause is megaloblastic anemia, followed by acute myeloid leukemia and aplastic anemia.[2]


The underlying pathophysiology depends on the cause of pancytopenia. The pathophysiology of aplastic anemia is an autoimmune-mediated T-cell activation, which leads to the destruction of the hematopoietic stem cells. Bone marrow suppression is also caused by the direct cytotoxic effects of medications such as methotrexate, anticonvulsants, and chemotherapeutic agents. Ineffective hematopoiesis is seen in the bone marrow of myelodysplastic syndrome.

Sepsis causes pancytopenias through several mechanisms (marrow suppression, hypersplenism, and consumptive coagulopathy), which usually act in combination. The virus causes pancytopenia through several mechanisms that modulate the hematopoietic stem cells.[15] A massive cytokine storm syndrome had been implicated in cases of SARS-CoV-2.[12][16][8] Paroxysmal nocturnal hemoglobinuria is a genetic disease caused by the absence of glycophosphatidylinositol-linked proteins, such as CD55 and CD59, which prevent complement-mediated destruction of the cells. It involves the mutation of phosphatidylinositol glycan class A proteins.

History and Physical

The clinical presentation can be variable, with mild pancytopenia being asymptomatic to life-threatening emergencies in severe pancytopenia. Patients can present with manifestations of any of the decreased cell lines. Anemia can present as shortness of breath, fatigue, and chest pain. Leukopenia manifests as increased infections, while thrombocytopenia presents with bruising, petechiae, and a propensity for bleeding. Patients with severe neutropenia can present with severe infections. Patients with underlying liver disease can present with anorexia, nausea, or lethargy. Patients with splenic sequestration can present with left upper quadrant pain. Constitutional symptoms can be seen in patients with underlying autoimmune disorders or malignancies.

History is of utmost importance in the evaluation of pancytopenia. This should include investigating symptoms of autoimmune conditions, malignancies, recent infections, medications, chemotherapy, or radiation therapy. A detailed history of nutritional status should be taken. It should be noted that the presentation of malabsorption could be subtle, and pancytopenia may be the only presentation. Family history should be taken into account as well for inherited aplastic anemia. 

Physical examination may reveal pallor, petechiae, ulcers, and rash. Signs of underlying liver disease may be seen in patients with cirrhosis. Splenomegaly may be seen in patients with splenic sequestration. Lymphadenopathy can be seen in patients with infections and lymphoma. Attention must be paid to signs of nutritional deficiencies in patients with eating disorders and alcoholism. The neurological examination is essential as it may show impairment of proprioception with a positive Romberg test and ataxia, suggesting subacute combined degeneration of the spinal cord secondary to vitamin B12 (cobalamin) deficiency and macrocytic anemia.[17]


The initial workup includes a complete blood count, along with a reticulocyte count. This will help to determine if the pancytopenia is secondary to decreased production. The mean corpuscular volume would point towards megaloblastic anemia. A peripheral blood smear can show abnormal cells such as blasts, dysplastic leukocytes, and immature cells. These abnormal cells may be related to conditions described in table 3. The diagnosis related to abnormal cells may require further investigations:

  1. Bone marrow aspirate and biopsy
  2. Cytogenetic testing (fluorescent in situ hybridization [FISH] or karyotype) of bone marrow or peripheral blood
  3. Flow cytometry of bone marrow and/or peripheral blood
  4. Molecular studies (e.g., mutation analysis, gene expression profiling)
  5. The workup should also include vitamin B12 and folate levels, liver chemistry, and lactate dehydrogenase.

Infectious workup should be done as pancytopenia can be associated with infections such as HIV, malaria, and tuberculosis.[18][19][20]

In pancytopenia cases secondary to an acute viral infection, no further workup should be performed as most resolved rapidly. Follow-up laboratories can be performed to confirm the resolution of the pancytopenia. Similarly, in severe infections with sepsis, further workup should not be performed as pancytopenia is most likely the result of sepsis. The termination of the infection/sepsis will correct the pancytopenia.

Further evaluation for undiagnosed hepatitis and autoimmune conditions or malignancies should be pursued if suspected.[21] Serum calcium and parathyroid hormone levels can help patients with a negative workup, as there are cases of hyperparathyroidism causing pancytopenia.[22][23] A thyroid profile should also be obtained, as hyperthyroidism is associated with pancytopenia.[24][25]

Bone marrow aspiration and biopsy can be done if no specific etiology is found to evaluate the status of the bone marrow stem cells. Bone marrow aspiration establishes the diagnosis of pancytopenia in 75% of cases.[13][26] The most common etiologies found are hypoplastic marrow, followed by megaloblastic anemia and hematological malignancies. Pathological examination of the bone marrow biopsy is helpful in malignant etiologies. It can show a clonal population of cells, primary/secondary malignant cells, acellular marrow, fibroblasts, granulomas from tuberculosis, sarcoidosis, or fungal infections.

Type of cells Associated conditions
Circulating blasts Acute leukemias, hairy cell leukemia, or other hematologic malignancies[13]
Dysplastic leukocytes, including pseudo-Pelger-Huët cells Myelodysplastic syndromes 
Immature myeloid cells, such as promyelocytes, myelocytes, and metamyelocytes Myeloproliferative neoplasm (MPN), such as primary myelofibrosis
Nucleated red blood cells Myelofibrosis or other MPNs
Hypersegmented neutrophils Deficiencies of folate and/or vitamin B12
Schistocytes or other evidence of microangiopathic hemolytic anemia (MAHA) Disseminated intravascular coagulation
Leukoerythroblastic appearance of the blood smear, with RBC teardrops, nucleated RBCs, and MAHA Metastatic cancer or myelofibrosis[27]

Table 3. Abnormal cells on blood smear with associated conditions

Treatment / Management

Treatment is based on the underlying etiology of pancytopenia. Nutritional deficiencies should be corrected. Any offending drug should be discontinued. Treatment for infections such as HIV or tuberculosis should be started immediately. If an autoimmune condition or malignancy is diagnosed, it should be treated. Aplastic anemia secondary to viral infections such as parvovirus is transient and symptomatic treatment should suffice. Treatment options for patients with severe aplastic anemia could include a hematopoietic stem cell transplant and immunosuppression. Hematology referral should be sought for these patients.

Supportive care for patients includes red blood cell transfusion for anemia to alleviate symptoms and perfuse vital structures. Platelet transfusion is indicated for thrombocytopenia of less than 10,000 per mcL to prevent spontaneous intracranial bleeding. Prompt initiation of broad-spectrum antibiotic therapy is recommended for patients with neutropenic fever or severe neutropenia with an absolute neutrophil count of less than 500 per ml due to the risk of death from sepsis.

Differential Diagnosis

Multiple conditions can present with pancytopenia; hence, when someone shows up with pancytopenia, a complete evaluation is performed to detect the cause of pancytopenia. Bone marrow disorders such as aplastic anemia, myelodysplastic syndrome, acute leukemia, myelofibrosis, megaloblastic anemia, paroxysmal nocturnal hemoglobinuria, and Fanconi anemia can present with pancytopenia.

Fanconi anemia is the most common congenital cause of bone marrow failure with an autosomal recessive inheritance pattern. In myelofibrosis, the bone marrow cells are replaced with fibrotic tissue. Malignancies such as lymphoma, multiple myeloma, and hairy cell leukemia can also present with pancytopenia. Non-bone marrow conditions present with pancytopenia include systemic lupus erythematosus and infections (such as parvovirus B19, Epstein Barr virus, HIV, hepatitis, leishmaniasis, tuberculosis, malaria, and histoplasmosis).[3]


The prognosis of pancytopenia depends on the underlying condition. The prognosis is excellent in conditions like viral infections, where the pancytopenia improves without intervention. The prognosis in patients with myelodysplastic syndrome depends on the degree of pancytopenia and the percentage of blasts in the marrow. Patients receiving chemotherapy or drugs causing pancytopenia (methotrexate, linezolid, or anticonvulsants) may have to discontinue the treatment if alternative agents are available. Most of the time, pancytopenia is reversible with the discontinuation of the therapy.[28]


Complications of pancytopenia include an increased risk of infections, life-threatening anemia, and bleeding. Patients presenting with fever will need broad-spectrum antibiotics and antifungals with pan cultures. Supportive transfusions with packed red blood cells and platelets should be initiated promptly if severe anemia or thrombocytopenia with bleeding is present. Other complications include tumor lysis syndrome seen in patients receiving chemotherapy for substantial tumors like high-grade lymphoma and acute leukemia.[29]


Patients with pancytopenia will need a hematology/oncologist consult. Additionally, patients with infections may need an infectious disease consult. Patients with rheumatological conditions and on treatment with methotrexate will need a rheumatology consult. If patients have undiagnosed or newly diagnosed thyroid or hypercalcemia, these patients will need an endocrinology consult.

Deterrence and Patient Education

Patients should be educated about the adverse reactions and toxicities of medications and over-the-counter supplements. The importance of periodic evaluations and blood work must be explained to a patient if started on drugs such as methotrexate or linezolid. In addition, patients with underlying hematologic malignancies (such as multiple myeloma, myelodysplastic syndrome, lymphoma, or acute leukemias) should be cautioned about the possibility of pancytopenia.

If a patient is found with pancytopenia, the patient should be counseled on the complications of pancytopenia and the increased risk for infections, bleeding, and manifestations of anemia. These patients should also be advised against other medications that may worsen pancytopenia.

Pearls and Other Issues

Pancytopenia may present with the following emergencies:

  • Neutropenia (new diagnosis or associated with fever/infection)
  • Metabolic emergencies (e.g., symptomatic hyperkalemia, hypercalcemia, tumor lysis syndrome)
  • Disseminated intravascular coagulation
  • Hemophagocytic lymphohistiocytosis
  • Abnormal peripheral blood smear (e.g., microangiopathy, blasts)
  • Severe aplastic anemia
  • Symptomatic anemia (e.g., cardiac ischemia, hemodynamic instability, worsening congestive heart failure)
  • Thrombocytopenia (platelets <10,000/microL, or <50,000/microL associated with bleeding)

Enhancing Healthcare Team Outcomes

Pancytopenia is a tricky manifestation with multiple etiological factors. Patients can present with symptoms of anemia, thrombocytopenia, and leukopenia. History taking is essential in this condition to determine the underlying cause of pancytopenia. While the hospitalist or the primary care provider is usually the first physician to contact the patient, it is imperative to involve multiple teams and specialists such as hematologists/oncologists, rheumatologists, pathologists, radiologists, and pharmacists. Hematologists help in the diagnosis and management of pancytopenia. They can also perform bone marrow biopsy if the etiology is inconclusive.

Pathologists and hematologists sometimes work together with these patients. Rheumatologists play a role in managing pancytopenia secondary to autoimmune diseases or the side effects of medications used for autoimmune diseases. Pharmacists help with drugs and dose-dependent adverse reactions. Finally, nurses play a huge role in managing these patients; not only do they monitor the patient's vitals (especially fever), but they also help with patient counseling and education about the adverse effects of the potential culprit drugs. 

While pancytopenia treatment depends on the underlying cause, improved outcomes are seen with prompt consultation with an interprofessional group of clinicians and specialists, and nursing staff, engaging in coordinated activity and open communication to ensure accurate diagnosis and appropriate treatment based on the underlying cause of pancytopenia. This interprofessional approach will yield the most optimal patient outcomes. [Level 5]



8/23/2023 12:39:11 PM



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