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, chest pain. Leukopenia manifests as increased infections, while thrombocytopenia presents with bruising, petechiae, and 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, 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.[20]

Initial workup includes a complete blood count, along with 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. The workup should also include vitamin B12 and folate levels, liver chemistry, lactate dehydrogenase. Infectious workup should be done as pancytopenia can be associated with infections such as HIV, malaria, and tuberculosis.[3][21][22][23]

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 the pancytopenia is most likely the sepsis result. The termination of the infection and sepsis will correct the pancytopenia.

Further evaluation for undiagnosed hepatitis and autoimmune conditions or malignancies should be pursued if suspected.[24] Serum calcium and parathyroid hormone levels can help patients with a negative workup, as there are cases of hyperparathyroidism causing pancytopenia.[25][26] A thyroid profile should also be obtained as hyperthyroidism is associated with pancytopenia.[27][28]

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 for pancytopenia in 75% of cases.[1][15][29] 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.

Treatment is based on the underlying etiology for the 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. For patients with severe aplastic anemia, treatment options could include 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 septic death.

Multiple conditions can present with pancytopenia; hence, when someone shows 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's 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, there is a replacement of the bone marrow cells 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, 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 any 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.[30]

Complications of pancytopenia include 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.[31]

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.

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. 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 increased risk for infections, bleeding, and manifestations of anemia. These patients should also be advised against using any other medications that may worsen pancytopenia.

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 always 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 work together sometimes in these patients. Rheumatologists play a role in managing pancytopenia secondary to autoimmune diseases or side effects of medications used for autoimmune diseases. Pharmacists help with medications and dose-dependent adverse reactions. 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 specialists.