I. Problem/Condition

Pancytopenia is defined by low counts of all cell lines including leukocytes, erythrocytes, and platelets.

II. Diagnostic Approach

A. What is the differential diagnosis for this problem?

Given pancytopenia is a sign, not a particular diagnosis, it has a broad differential diagnosis. These diagnoses can be broadly divided between inherited and acquired causes, but for providers who focus on adults, inherited causes will be a rare finding as most of these cases present in childhood.

The categories of diseases and conditions that can cause pancytopenia can be used to divide it into broad categories. Physiologic mechanism, unfortunately, tends to be less useful as pancytopenia (unlike other cytopenias) is rarely caused by specific targeting or destruction of cell lines in the periphery and most often is caused by decreased production of multiple cell lines from primary damage to the marrow stem cell pool.

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Hypersplenism and sepsis (which likely involves a degree of primary hypoproduction from the marrow as well as increased peripheral destruction) are the two major conditions that cause pancytopenia without primary deficits in the marrow stem cell pool.

Pancytopenia due to failure of hematopoietic stem cells

The most common congenital cause of bone marrow failure that could be seen initially in the inpatient setting is Fanconi anemia, an inherited defect in DNA repair, that leads to high rates of acute myeloid leukemia (52% risk of developing AML by age 40) and other cancers, as well as bone marrow failure in 90% of those affected by age 40. Most individuals will present in the first decade but some may present later. Ashkenazi Jews and individuals of Afrikaans extraction have the highest prevalence of Fanconi anemia.

Dyskeratosis congenita is another inherited marrow failure disorder that may not present in childhood and can be caused by several different alterations in telomerase genes leading to shortened telomeres. The classic triad of this disorder consists of nail changes, oral leukoplakia, and a reticulated skin rash. Along with death caused by marrow failure or development of acute leukemia, pulmonary fibrosis may also be present and is life-threatening in a subset.

The most concerning causes of pancytopenia are neoplastic conditions. Myelodysplastic syndromes are a cluster of conditions where mutations in stem cell lines cause ineffectual hematopoiesis and cytopenias of any individual or all cell lines. Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are both on the differential of pancytopenia despite the fact they will usually present with leukocytosis. Aleukemic variants, where the leukemic blasts are confined to the marrow, and pancytopenia are seen. Acute promyelocytic leukemia is particularly prone to presenting with leukopenia as opposed to high white counts and can quickly turn to a medical emergency due to the coagulopathy it can cause. High-grade lymphomas and plasma cell myeloma also commonly replace the bone marrow and can cause pancytopenia.

Myelofibrosis, the replacement of the marrow hematopoietic cells with fibrous material, seems to be a common pathway of chronically overstimulated marrow and thus may result from almost any myeloproliferative disease (essential thrombocytosis, polycythemia vera, chronic myelomonocytic leukemia, or chronic myeloid leukemia). Primary myelofibrosis, in which malignant megakaryocytes cause a primary fibrotic process, is also on the differential diagnosis.

Aside from hematologic malignancies, almost any solid tumor can cause pancytopenia by marrow replacement and myelophthisis, though this is relatively uncommon as an index symptom. Pancytopenia from marrow replacement is far more likely to occur late in the disease course as the burden of disease increases.

Infectious causes of pancytopenia can be broadly split into three categories. The first major cause of infectious pancytopenia in the inpatient setting is sepsis and the systemic inflammatory response, which cause mild to moderate cytopenias through a combination of mechanisms (i.e., consumptive coagulopathy, hypersplenism, and marrow suppression).

The second major cause of infectious pancytopenia is through the effect of viral infections. Essentially, any virus can cause suppression of multiple cell lines but the herpes viruses, including Epstein-Barr virus (EBV) and cytomegalovirus (CMV), as well as viral hepatitides are the most commonly implicated. Generally, these cytopenias are self-limited and coincide with infection. Mononucleosis may present with large reactive lymphocytes that may be classified incorrectly as myeloid or lymphoid blasts, falsely suggesting a diagnosis of acute leukemia.

Finally, infections may cause pancytopenia through marrow replacement with infectious organisms. For this degree of organism burden to develop without septic death, less fulminant infections are typically invoked (i.e., fungal infections, particularly histoplasmosis, or non-tuberculosis mycobacteria). This is far less common than myelophthisic anemia due to malignant causes in developed countries.

Hemophagocytic syndrome (also known as hemophagocytic lymphohistiocytosis or HLH) is a syndrome of marked inflammatory activation characterized by cytopenias (including potentially pancytopenia), fever, and hepatosplenomegaly that is diagnosed by a constellation of findings including high ferritin and triglycerides, as well as the hemophagocytic macrophages in the bone marrow and spleen consuming erythrocytes and other cells. It can be caused by rare genetic defects or occur spontaneously in reaction to infections, various malignancies, and rheumatologic conditions.

Autoimmune or inflammatory causes of pancytopenia include aplastic anemia, a relatively rare condition, where immune destruction of stem cells is thought to be the primary cause of pancytopenia. Of note, myelodysplastic syndromes are increasingly felt to have an immune-mediated component, though for our purposes it has been listed with neoplastic causes of pancytopenia (mostly due to their role as precursors of AML). Sarcoid, included here, though its actual status as an inflammatory disease is somewhat questioned, can also cause pancytopenia through myelophthisis, as granulomas can occupy the bone marrow. Finally, severe B12 deficiency, whether associated with pernicious anemia or other causes, is a known cause of pancytopenia.

Paroxysmal nocturnal hemoglobinuria (PNH) can present with aplastic anemia and is caused by a genetic defect in the PIGA gene, which is involved in the production of glycosylphosphatidylinositol (GPI) anchors on erythrocytes. The deficiency of these anchors leads to the loss of several key cell surface proteins including CD55 (delay accelerating factor) and CD59 (membrane inhibitor of reactive lysis) which protect cells from complement-mediated lysis. This leads to intravascular hemolytic anemia, which may be dramatic. The pancytopenia in PNH is still somewhat imperfectly understood and may precede the genetic defect and loss of PIGA. Thrombosis, including in the splanchnic or cerebral vasculature, is the third primary manifestation of PNH.

Environmental or toxic causes of pancytopenia consist of a wide variety of causes. Among the most common chemical exposures that cause pancytopenia, are medications. Chemotherapeutic agents almost all cause some degree of myelosuppression and pancytopenia but are highly unlikely to cause a diagnostic dilemma. Hydroxyurea, which may be given for non-malignant causes, is also a cause of myelofibrosis and long-term marrow toxicity. Among other medications, almost any can cause idiopathic bone marrow toxicity and thus pancytopenia, but the most commonly implicated agents include antiepileptics and antibiotics.

Chloramphenicol, which remains an important broad-spectrum antibiotic in the developing world, has seen its use largely curtailed in the developed world due to a low but noted rate of causing irreversible aplastic anemia with oral dosing. Benzene is strongly associated with bone marrow toxicity as well as increased risk of AML. Finally, radiation toxicity from uranium mining or industrial exposures can cause pancytopenia through bone marrow toxicity and can cause complete bone marrow failure.

Hypersplenism, either due to portal hypertension or other causes, is another cause of pancytopenia, as increased numbers of cells are consumed and sequestered and/or destroyed in the spleen. This usually disproportionately affects erythrocytes and platelets more than leukocytes. This may occur due to portal hypertension and secondary splenomegaly as well as hypersplenism due to infiltration with myeloproliferative disorders, leukemia, or other diseases.

B. Describe a diagnostic approach/method to the patient with this problem

Pancytopenia is defined by a CBC showing low numbers of platelets, white blood cells, and red blood cells. A full differential should typically be included to exclude the presence of grossly abnormal forms given the presence of acute leukemia on the differential as a catastrophic illness that requires prompt treatment.

Assessment of red blood cell indices can also be very useful to assess for macrocytosis given that B12 deficiency can cause deficiencies in multiple cell lines and macrocytosis may be an early clue. Macrocytosis may also occur with liver disease or in the presence of certain medications but its presence without these risk factors raises significant concern for myelodysplastic syndrome. Manual review of the peripheral smear is ideal to assess for RBC pathology and for immature WBC and blasts, which may be misattributed by standard cell counters.

The need for further work-up should be based on the clinical situation and severity of the defects. Mild pancytopenia in patients with a recent viral illness and who appear well, without other abnormalities, likely do not require further testing but should be followed to document resolution of the cytopenias. Similarly, provided there are no immature forms circulating and pancytopenia is not very severe, the utility of an acute hematologic work-up for pancytopenia in the midst of a severe infection or sepsis is rarely indicated, as mild to moderate pancytopenia is extremely likely to be a result of underlying illness rather than a separate problem.

1. Historical information important in the diagnosis of this problem

For immediate management, the most important historical questions to ask are about symptoms of the cytopenias and thus assessing the need to directly address them with transfusions. For example, questions about chest pain, shortness of breath, light headedness, or fainting can help determine the need for red blood cell transfusions. Similarly, the patient should be asked about any unusual bruising or bleeding, petechiae, or rashes.

Dark urine or jaundice, which may suggest underlying hemolysis, are other important symptoms, as are lymphadenopathy or fevers. Pain may suggest an expanding mass or bone lesions, which can accompany marrow involvement. Skin lesions, cough, or hemoptysis can suggest a disseminated fungal or mycobacterial infection.

Asking about weight loss, fever, and night sweats is important as both tuberculosis and lymphoma can cause pancytopenia. Fever in the setting of leukopenia and severe neutropenia (generally defined as an absolute neutrophil count <500/uL) is an urgent situation due to the risk of septic death and patients should receive empiric, broad-spectrum antibiotic coverage.

Finally, asking about conditions that predispose to acute leukemias (i.e., myelodysplastic syndromes, previous chemotherapy, previous myeloproliferative disorders) are key as they may allow shortcuts to the final diagnosis.

2. Physical examination maneuvers that are likely to be useful in diagnosing the cause of this problem

Careful ear, nose, and throat exam can reveal clues to etiologies of cytopenia. Palatal petechiae are suggestive of nonspecific thrombocytopenia. Though rarely seen, gum hypertrophy may suggest monocytic infiltration of leukemia.

An exam for lymphadenopathy throughout cervical, supraclavicular, axillary, and inguinal chains may raise concern for lymphoma as a cause of pancytopenia, and/or reveal a spot to biopsy. Detection of hepatosplenomegaly can be helpful, as splenomegaly can dramatically drop cell counts by sequestration, and can guide the clinician to evaluate for causes of a primary hematologic process, such as lymphoma, versus a secondary splenomegaly (i.e., portal hypertension).

Skin examination for nonspecific lesions (such as petechiae, which are a result of thrombocytopenia) versus more specific lesions from fungal infections or malignant infiltration is important.

Neurological exam, particularly of the peripheral nerves, may also be helpful as degradation of joint position sense and a positive Romberg in the setting of macrocytic anemia may well suggest B12 deficiency. Generalized peripheral neuropathy may suggest a paraprotein-elaborating malignancy such as myeloma.

Finally, any areas of pain should be closely examined for mass.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem

As pancytopenia is a finding and not a single illness, the acuity and intensity of the work-up should be commensurate to the extent, acuity, and severity of the pancytopenia. For patients with more severe cytopenias, those who are more ill, or those with acute onset and symptomatology, further work-up of pancytopenia must be performed urgently and efficiently to intervene with acutely dangerous processes.

After full a CBC and differential, as well as manual review of the peripheral smear, work-up should be aimed at searching for etiologies based on possible historical clues and clues from that first look (e.g., macrocytosis suggesting B12 deficiency, myeloblasts suggesting AML, etc.,) should guide further work-up. Elevations in PT and PTT may be helpful in suggesting a consumptive coagulopathy or disseminated intravascular coagulation (DIC), which may be suggestive of a septic process causing overall systemic inflammatory response and increased destruction/decreased production.

DIC may also suggest acute promyelocytic leukemia (APML), a subtype of AML particularly associated with leukopenia (as opposed to leukocytosis). Liver function tests should also be checked as they may reveal signs of acute hepatitis, which could cause reactive splenomegaly and sequestration, or signs of cirrhosis, which can predispose to cytopenias that may worsen in the setting of acute illness. Aplastic anemia can also proceed from hepatitis, though usually not from a detectable viral pathogen. This can cause profound cytopenia and transaminitis but is usually self-limited. A B12 level is also important in order to exclude B12 deficiency, particularly in the presence of risk factors for malabsorption, autoimmunity, or macrocytosis. This is particularly important in order to avoid neurological toxicity from B12 deficiency, which is often irreversible.

Ultimately, a bone marrow biopsy should be performed for any cases of unexplained, persistent, or severe cytopenia in order to assess the status of the bone marrow pool of stem cells. This should typically be done with the input of a hematologist/oncologist, as an important part of this assessment is looking for occult malignancy and cytogenetic/molecular studies may be crucial to help make a definitive diagnosis.

Lymphadenopathy, an elevated calcium, a high LDH, abnormal forms on the differential, or high uric acid should increase suspicion for a primarily malignant etiology and should move bone marrow biopsy earlier in the evaluation. Peripheral flow cytometry may also be helpful in detecting a malignancy as it may detect a clonal population of cells, though sensitivity is typically lower than on a sample from the bone marrow. Gram stain, acid fast smear, and fungal stains, along with cultures may help detect an infectious cause of pancytopenia due to myelophthisis.

Imaging may be useful for working-up pancytopenia when there is concern for particular clinical entities. When concern for lymphoma is high or concern for lymphadenopathy is palpable, imaging to discover other nodes is generally performed, although biopsy will ultimately be required and should be the major priority. While lymphomatous disease that is extensive enough to cause cytopenias can be detected on bone marrow biopsy, a sampling error still exists, and thus, if suspicion for lymphoma remains high, an additional biopsy of a superficial node may help with diagnosis. Unfortunately, the sensitivity of nodal biopsy is also imperfect due to typically spotty involvement of nodes; lymphomatous nodes may be surrounded by reactive nodes and therefore, multiple biopsies may be needed.

Fine needle aspiration is never adequate for the diagnosis of lymphoma. PET computed tomography (CT) to evaluate metabolically active nodules may also be helpful, and in cases where there is lymphadenopathy with negative biopsies, PET CT may help identify an involved node. It is expensive, however, and typically difficult to obtain as an inpatient.

C. Criteria for diagnosing each diagnosis in the methods above

Fanconi anemia was historically tested for by exposing chromosomes to chemotherapy and assessing for excessive structural damage, but it can now be assessed by genetic testing. Dyskeratosis similarly can be checked for by genetic testing.

Diagnosing malignant or neoplastic causes may be simplified if there are circulating lymphoblasts or myeloblasts, which are highly suggestive of acute leukemia. Malignant causes of pancytopenia will often be detected by pathological examination of the bone marrow biopsy and the detection of a clonal population of cells and/or by imaging and detection and sampling of the primary malignant site. The presence of greater than 20% blasts on bone marrow examination is pathognomonic of acute leukemia, as is the presence of certain cytogenetic abnormalities (8:21 translocation, inv16:16, and t15:17) that define AML even without circulating blasts or an increased population of blasts in the bone marrow.

Bone marrow involvement of lymphoma may be suggested by pathology and abnormal lymphoid aggregates on pathology. Flow cytometry on a bone marrow aspirate or on peripheral blood may allow faster detection of a hematologic malignancy by detecting a clonal population of cells. Pancytopenia caused by myelophthisis from solid tumors will similarly be detected either by pathologic evaluation of the marrow, showing involvement of the primary malignancy, or by pathologic confirmation of a neoplasm elsewhere, with highly suspicious imaging findings for bone disease.

Pathologic evaluation of the bone can also reveal an acellular marrow without malignant cells (consistent with aplastic anemia); granulomas from tuberculosis, sarcoidosis, or fungal infection; and dysplastic forms consistent with myelodysplastic syndromes. Replacement of the marrow with fibroblasts suggests myelofibrosis, though whether this is a secondary defect or a primary process will depend mostly on the history.

PNH may be diagnosed by flow cytometry on the peripheral blood assessing for loss of CD55 and/or CD59. Of note, small PNH clones without any evidence of hemolysis or thrombosis are unlikely to be clinically significant.

B12 deficiency as a cause of pancytopenia is suggested by a low B12 level and/or elevated methylmalonic acid level.

Viral serologies for mononucleosis or the viral hepatitides may help diagnose these conditions, though pancytopenia with these conditions will usually manifest in the acute context when serologies remain negative and PCR may be necessary. It is almost impossible in these cases to prove causality with the virus and careful monitoring of CBC throughout improvement may be necessary. Similarly, if non-testable viral infections are suspected, careful correlation of the cytopenia to a viral syndrome and careful monitoring through resolution and improvement is crucial. The presence of reactive lymphocytes in the context of presumed viral infections causing pancytopenia is suggestive but not conclusive.

Hemophagocytic lymphohistiocytosis is diagnosed by marked elevations in the ferritin and triglycerides, associated with the clinical syndrome of fever, hepatosplenomegaly, and cytopenias, with hemophagocytic cells seen on biopsy from the spleen or marrow.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem

Evaluation for a specific etiology of pancytopenia in the context of profound systemic illness or sepsis is rarely indicated. Analogous to shock liver, acute tubular necrosis, or systemic inflammation, the hematopoietic system undergoes profound stress and dysfunction in the septic patient and even moderate pancytopenia is far more likely to be consequent to the underlying condition than a separate primary problem. In such patients, peripheral smear evaluation to exclude an acute leukemia and careful follow-up (provided an underlying cause for the patient’s underlying sepsis or profound illness is known and addressed) is generally the optimal course.

III. Management while the diagnostic process is proceeding

A. Management of clinical problem pancytopenia

Initial management of the pancytopenic patient must focus on stabilizing the physiologic derangements due to the lack of important blood cell components. Most treatments for the underlying disorders will not take effect for some time and thus, immediate stabilization is important.

Immediate management of anemia will typically focus on transfusion. As in other cases of anemia transfusion, threshold should be determined based on symptomatology and work to the alleviation of symptoms and perfusion of vital structures. In patients with a reasonable suspicion of an underlying hematologic malignancy, myelodysplastic, or myeloproliferative process, the use of leukoreduced products is recommended as it reduces febrile transfusion reactions, CMV transfer, and alloimmunization, all of which are crucial to reducing complications of the further transfusions these patients are likely to need. Further, given that many of these patients have leukopenia and possibly neutropenia and are immuno-suppressed, the use of irradiated blood to kill donor lymphocytes and prevent transfusion-associated graft versus host disease (GVHD) is similarly recommended.

Management of thrombocytopenia similarly depends somewhat on symptomatology. An actively bleeding patient should be transfused platelets until bleeding resolves. Typically, patients with a platelet count of less than 10,000/mL are transfused to prevent spontaneous intracranial bleeding. Other transfusion cut-off values are highly subjective and largely dependent on situation. Single donor platelets, if available, reduce alloimmunization, which is particularly important in patients with hematologic disorders who are likely to need further platelet transfusions. Still, such products are expensive and not always available outside of tertiary centers.

Patients with leukopenia should have assessment of a differential and an absolute neutrophil count. Patients who are severely neutropenic (typically defined as ANC <500/mL) are at very high risk of death from fulminant infection. These patients should receive prompt, broad-spectrum antibiotic coverage pending diagnostic work-up. Stable patients may await blood cultures before starting antibiotics if these can be obtained expeditiously. Front-line therapy is typically with a broad-spectrum beta-lactam with activity against a broad range of gram negative organisms, including Pseudomonas. Cefepime, ceftazadime, piperacillin-tazobactam, or carbapenems are currently recommended by the Infectious Diseases Society of America (IDSA) as first-line therapy for neutropenic fever.

Patients with mouth sores or any signs of irritation around peripheral lines or other signs of skin infection should additionally receive gram positive coverage against methicillin-resistant Staphylococcus aureus (typically with vancomycin). Patients with continued fevers despite broad-spectrum antibacterial coverage and persistent neutropenia (typically >72 hours) should have fungal markers (glucan and galactomannan) ordered and typically should receive empirical antifungal coverage with an echinocandin or later generation azole that will treat aspergillus.

Granulocyte infusions have largely fallen out of favor as a treatment for neutropenia in the United States due to high rates of complications. Growth factors or GCSF analogues, such as filgrastim, are the primary means of boosting WBC counts though their use depends on the underlying clinical situation. Despite some controversy, these agents are likely not harmful even in the context of acute leukemia but they may significantly interfere with diagnostic accuracy and should typically be deferred until a presumptive diagnosis is made and used with the supervision and advice from a hematologist or oncologist.

Patients with neutropenia should avoid raw or undercooked meats, soft cheeses, and fruits/vegetables that cannot be peeled due to the increased vulnerability to infection and fear about bacterial contamination or occult molds respectively.

B. Common pitfalls and side-effects of management of this clinical problem

Side effects of transfusion are covered elsewhere and consist largely of acute hemolytic reactions and non-hemolytic febrile reactions. TRALI (transfusion associated acute lung injury) is particularly associated with platelet transfusions.

VII. What's the evidence?

Freifeld, AG, Bow, EJ. “Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America”. Clinical Infectious Diseases. vol. 52. 2011. pp. 56-93.

Greinacher, A, Selleng, K. “Thrombocytopenia in the Intensive Care Unit Patient”. Hematology / The Education Program of the American Society of Hematology. 2010. pp. 135-143.

Istiaq, O, Bagai, HZ, Anwer, F, Hussain, N. “Patterns of pancytopenia patients in a general medical ward and a proposed diagnostic approach”. Journal Ayub Medical College Abbottabad. vol. 16. 2004. pp. 8-13.

Janka, JE. “Hemophagocytic syndromes”. Blood Reviews. vol. 21. 2007. pp. 245-253.