A. Introduction. Pancytopenia is defined as a reduction in all blood cell lines.
B. Clinical Manifestations of Pancytopenia
a. Pancytopenia usually presents with signs and symptoms that relate to a reduction in a particular cell line.
1. Defined as a hemoglobin <13.5 g/dL or a hematocrit <41.0% in men and a hemoglobin <12.0 g/dL or hematocrit <36.0% in women in most laboratories.
2. Can result in increased fatigue, shortness of breath, lightheadedness, and pallor.
1. Defined as a platelet count of <150,000 cells/μL.
2. Patients with platelet counts >100,000 cells/μL often have normal bleeding times (unless platelet function is abnormal) and usually do not have symptoms.
3. Easy bruising may be noted as the platelet count approaches 50,000 cells/μL.
4. Counts below 10,000–20,000 cells/μL can be associated with petechiae, mucosal bleeding, hemarthrosis, and spontaneous internal bleeds.
1. Defined as an absolute neutrophil count of <1500 cells/μL.
2. Predisposes patients to bacterial infections (however, patients usually present with symptoms related to anemia or thrombocytopenia first).
3. The risk for infection increases substantially after the neutrophil count falls below 500 cells/μL.
b. Disease-specific symptoms (e.g., neurologic symptoms in vitamin B12 deficiency, cachexia in malignancy) may also be present.
Pancytopenia is a great reminder that even mild, nonspecific symptoms can be the harbinger of a serious illness. You should therefore consider getting a complete blood count (CBC) with a differential on all patients with a prolonged or recurring illness.
C. Causes of Pancytopenia. Many textbooks attempt to differentiate causes of decreased production from those of increased destruction. For pancytopenia, this distinction is not very useful because both processes are often involved. The mnemonic “PANCYTO” can help you remember the most common causes of pancytopenia.
MNEMONIC: Common Causes of Pancytopenia (“PANCYTO”)
Paroxysmal nocturnal hemoglobinuria (PNH)
Neoplasms and Near neoplasms
Vitamin deficiencies (the “V” looks like a “Y”)
Toxins, drugs, and radiation therapy
a. PNH is a disorder of stem cells that results in an increased sensitivity to complement-mediated cell lysis. The etiology relates to a somatically acquired loss of the PIGA (phosphatidylinositol N-acetylglucosaminyltransferase subunit A) gene in hematopoietic progenitor cells. PNH can clinically manifest as an isolated Coombs test–negative intravascular hemolysis, a hypercoagulable state, and/or bone marrow aplasia.
b. Aplastic anemia is one of the misnomers in medicine because it involves a disorder of stem cells and therefore affects all cell lines. The etiology of idiopathic aplastic anemia is unknown, but an immune-mediated reduction in hematopoietic progenitors has been proposed. Exposures and secondary disorders associated with aplastic anemia are listed next; many cases of aplastic anemia have no identifiable cause.
i. Fanconi’s anemia is an autosomal recessive or X-linked disease that usually appears in childhood and is often associated with other congenital abnormalities (e.g., cardiac and renal malformations, hypoplastic thumbs, hyperpigmented skin). Fanconi’s anemia is associated with an increased risk for solid tumors and leukemias as well as aplastic anemia.
ii. Drugs and toxins. Chemotherapeutic agents, chloramphenicol, sulfa drugs, gold, nonsteroidal antiinflammatory drugs, certain antiepileptic drugs, ionizing radiation, benzene, and various other drugs have been associated with aplastic anemia.
iii. Infections. Parvovirus B19 is the most frequently documented viral cause of aplastic anemia. Hepatitis, HIV, cytomegalovirus (CMV), and, Epstein-Barr virus (EBV) infections have also been seen; however, the specific type of hepatitis virus associated with aplastic anemia has not been identified.
iv. Immune disorders. Disorders of the immune system and immune dysregulation may also play a role in the development of aplastic anemia.
v. Idiopathic. Despite an extensive workup, the cause remains unclear in a large number of patients. In these cases, the leading hypothesis is that a host immune response against hematopoietic progenitor cells leads to the aplastic anemia.
c. Neoplasms (e.g., leukemia, metastatic malignancies) and near neoplasms (i.e., myelodysplastic syndrome) can cause pancytopenia.
i. Hypersplenism (see Chapter 31).
ii. Immune-mediated destruction usually results in decreases of one or two cell lines but can also cause pancytopenia.
e. Vitamin deficiencies (e.g., vitamin B12 and folate deficiencies) should always be considered in patients with pancytopenia.
f. Toxins, drugs, and radiation therapy. For example, ethanol use may result in pancytopenia. Many chemotherapeutic agents, and commonly used medications such as chloramphenicol and linezolid can also cause pancytopenia
g. Overwhelming infections. Sepsis, tuberculosis, or fungal infection can cause pancytopenia. HIV infection can also result in pancytopenia from the infection itself, superimposed infections, or medications used to treat the infection.
Pancytopenia should be considered a primary bone marrow failure until proven otherwise.
a. Patient history. Inquire about medications, exposures, and HIV risk factors. Perform a review of systems, asking the patient about cachexia and other symptoms of an occult malignancy. Inquire about recent bruising, bleeding, or recurrent infections.
b. Physical examination. Carefully examine the spleen and lymph nodes. The presence of splenomegaly increases the likelihood of malignancy and essentially rules out aplastic anemia.
c. Laboratory studies. Although a bone marrow biopsy is usually necessary to establish the diagnosis, in some patients, a routine peripheral blood smear and other less invasive tests may be helpful.
i. Peripheral blood smear
1. Megaloblastosis increases the likelihood of vitamin B12 or folate deficiency, but can also be seen in other primary bone marrow disorders.
2. Blasts implicate a possible myelodysplastic syndrome or acute leukemia.
3. Leukoerythroblastic smear. A leukoerythroblastic smear, which reveals early (nucleated) red blood cells (RBCs) and early white blood cells (WBCs) (i.e., bands, metamyelocytes, myelocytes), implies marrow invasion by malignancy (either a solid organ cancer or a hematologic neoplasm), fibrosis, or infection. Teardrop cells (i.e., RBCs shaped like a teardrop from being “squeezed” out of the bone marrow) are frequently seen with leukoerythroblastosis.
4. Pseudo–Pelger-Huet anomaly (i.e., neutrophils with bilobed nuclei) is seen in patients with myelodysplasia (see Chapter 70).
ii. Vitamin B12 and folate levels are often obtained.
iii. HIV test. An HIV test should be performed in patients with risk factors given its association with a wide array of hematologic disorders, including pancytopenia
iv. Viral serologies. Assessment for viral exposures often by quantitative polymerase chain reaction (PCR) testing for EBV, CMV, and parvovirus B19.
v. PNH workup. PNH results in intravascular hemolysis that can be precipitated by infections or acidosis (e.g., while sleeping at night) resulting in hemosiderinuria; therefore, PNH should be evaluated in all patients with pancytopenia, especially those describing episodes of dark urine. The diagnostic test of choice utilizes flow cytometry to test for the presence of GPI-anchored proteins, which are present in normal cells but absent in PNH.
d. Bone marrow biopsy. Because a “dry tap” may occur (i.e., one in which bone marrow aspirate is unobtainable as a result of aplasia, fibrosis, or malignancy), a core marrow biopsy is essential to determine the etiology of pancytopenia. Patients with HIV and pancytopenia often still undergo bone marrow biopsy to rule out a contributing infection or malignancy.
i. Increased cellularity suggests peripheral destruction (hypersplenism or an immune-mediated disorder) or inadequate differentiation (acute leukemia and myelodysplasia). PNH, acute leukemia, and some forms of myelodysplasia can demonstrate either a hypercellular or hypocellular marrow.
ii. Decreased cellularity is the common finding in aplastic anemia, but can also be seen in PNH, myelodysplasia, and, occasionally, hypoplastic acute leukemia.
iii. Cytogenetic analysis may help establish the diagnosis of a myelodysplastic syndrome or acute leukemia by finding a clonal abnormality and is also used for prognostic purposes. However, up to half of all acute leukemias may have a normal karyotype.
iv. Other findings. Metastatic solid organ malignancies can cause pancytopenia via bone marrow infiltration, which can be seen on biopsy. Furthermore, bone marrow samples can be sent for molecular analyses or culture to evaluate for infectious processes as a cause of pancytopenia.
a. General treatment is aimed at preventing complications associated with a decrease in each cell line.
i. Packed RBC transfusions are usually given to maintain the hemoglobin above 7 gm/dl in most patients and greater than 8 gm/dl in older patients or those with known or suspected coronary artery disease. Younger patients may tolerate a lower hemoglobin. For each unit of packed RBCs transfused, the hemoglobin is expected to rise by approximately 1 g/dL and the hematocrit by 3%.
ii. Platelet transfusions may be necessary to control bleeding or when the platelet count falls below 10,000 cells/μL to reduce the risk for spontaneous bleeding (see Chapter 60).
iii. Infection prevention and treatment
1. Granulocyte colony-stimulating factor (G-CSF) is sometimes used to increase neutrophil counts.
2. Neutropenic precautions (e.g., handwashing and minimizing exposure to those with infectious symptoms) should be used for patients at the highest risk for neutropenia (i.e., neutrophil count <500 cells/uL).s. Prophylactic antibiotics in the absence of signs or symptoms of infection are not recommended.
3. Broad-spectrum antibiotics should be used for patients with fever in the setting of neutropenia, which is a medical emergency.
b. Specific treatment is aimed at the underlying illness. Specific treatments for most of the causes of pancytopenia are found in the relevant chapters. Therapies for PNH and aplastic anemia will be briefly discussed here.
i. PNH carries approximately a 40% lifetime risk for thrombosis, and the median survival is 10–15 years. Approximately 50% of patients with PNH die from either a thrombotic event or complications of cytopenias. Spontaneous remission may occur in approximately 15% of patients.
1. The constant hemolysis and hemosiderinuria/hematuria can actually result in iron deficiency that may require iron replacement. Likewise, folate replacement is recommended in all patients with chronic hemolysis regardless of the cause.
2. Chronic anticoagulation therapy is indicated for all patients who have a history of thrombosis.Patients with a history of thrombosis should be managed similarly to other patients with a hypercoagulable state.
3. Eculizumab is a monoclonal antibody approved by the Food and Drug Administration (FDA) that binds to the C5 component of complement and inhibits complement activation. It has been demonstrated to reduce the rate of hemolysis, transfusion requirements, and rate of thrombotic complications in patients with PNH. Patients receiving eculizumab require prophylaxis against neisseria.
4. Bone marrow transplantation may be curative but carries significant morbidity and mortality. Therefore, it is often only used for late-stage complications of PNH, including aplastic anemia, or acute leukemia, or in cases of eculizumab resistant PNH.
1. Removal of potential etiologies (e.g., offending medications) is always important.
2. Transfusion support and appropriate antibiotic therapy for infectious complications is necessary.
3. Pharmacologic therapy. Decisions regarding therapy are dependent on the severity of the aplastic anemia as well as the age of the patient. Pharmacologic therapy is the preferred treatment for patients who are greater than 40 years of age, or in younger patients without a sibling-matched donor for allogeneic stem cell transplantation.
a. Antithymocyte globulin is usually the first-line pharmacologic treatment for patients with severe aplastic anemia. Two forms of the antibody exist (ATGAM, derived from horses, and thymoglobulin, derived from rabbits).
b. Immunosuppressive agents (e.g., cyclosporine) are used in conjunction with antithymocyte globulin and increase the likelihood of remission.
4. Bone marrow transplantation may cure 80% of patients, but morbidity and mortality increase with patient age and with the use of unrelated allogeneic donors, compared to transplantation with HLA-matched, related donors. Because blood product transfusions may increase risk for graft rejection, transplant candidates should only receive transfusions when it is absolutely necessary. When whole blood or platelet transfusions are required, they should have the leukocytes removed using a special filter (a process called “leukoreduction”). Such “leuko-poor” transfusions decrease the risk for HLA-antigen immunization and risk for viral infections. If the patient is neutropenic, irradiating the blood product may lessen the chance of graft-versus-host reaction. Transfusions from potential organ donors should never be given. Matched-related donor allogeneic hematopoietic stem cell transplantations are typically considered as first-line therapy for patients younger than 40 years. For those older than 40 year, they are considered for use as second-line or later therapy. For those younger than 40 years without a matched-related donor, immunosuppressive therapy is the current first-line treatment option.
5. Spontaneous recovery is uncommon and usually seen only in mild or moderate cases.
Suggested Further Readings
Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood 2014;124:2804.Find this resource:
McMahon B, Kamath S. Pancytopenia in a patient with hypothyroidism. JAMA 2016;315:1648–9.Find this resource:
Scheinberg P, Young NS. How I treat acquired aplastic anemia. Blood 2012;120:1185.Find this resource: