Aplastic Anemia Facts and Statistics

AUTHOR INFORMATION

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Authored by Sameer Bakhshi, MD, Fellow, Department of Pediatric Hematology/Oncology, Children's Hospital of Michigan, Wayne State University

Coauthored by Roy Baynes, MB, BCh, PhD, FACP, Charles Martin Professor of Cancer Research, Department of Internal Medicine, Division of Hematology and Oncology, Karmanos Cancer Institute, Wayne State University; Esteban Abella, MD, Medical Director of Inpatient Care Unit Pediatric Hematology Oncology, Associate Professor, Departments of Internal Medicine and Pediatrics, Childrens Hospital of Michigan, Wayne State University

Edited by David Aboulafia, MD, Medical Director, Bailey-Boushay House; Clinical Professor, Department of Medicine, Division of Hematology, University of Washington; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Troy H Guthrie, Jr, MD, Chief, Professor of Medicine, Division of Hematology/Oncology, University of Florida Health Science Center; Rajalaxmi McKenna, MD, FACP, Director, Hemophilia Center, Special Hematology and Hemostasis Laboratory; Clinical Professor, Department of Medicine, Cardeza Foundation for Hematological Research, Thomas Jefferson University and Hospital; and Emmanuel C Besa, MD, Professor, Department of Internal Medicine, Division of Hematology and Oncology, Medical College of Pennsylvania Hahnemann University

 

Author's Email:	Sameer Bakhshi, MD
Editor's Email:	David Aboulafia, MD

eMedicine Journal, June 19 2001, Volume 2, Number 6

INTRODUCTION

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Background: Aplastic anemia is a marrow failure syndrome characterized by peripheral pancytopenia and marrow hypoplasia. Dr Paul Ehrlich introduced the concept of aplastic anemia in 1888 when he studied the case of a pregnant woman who died of bone marrow failure. However, it was not until 1904 that this disorder was termed aplastic anemia by Chauffard.

Pathophysiology: The theoretical basis for marrow failure includes primary defects in, or damage to, the stem cell or the marrow microenvironment. The distinction between acquired and inherited disease may present a clinical challenge, but more than 80% of cases are acquired. In acquired aplastic anemia, clinical and laboratory observations suggest that this is an autoimmune disease.

Morphologically, the bone marrow is devoid of hematopoietic elements, showing largely fat cells. Flow-cytometry shows that the CD34 cell population, which contains the stem cells and the early committed progenitors, is significantly reduced. In vitro colony culture assays suggest profound functional loss of the hematopoietic progenitors, so much so that they are unresponsive even to very high levels of hematopoietic growth factors.

Little evidence points to a defective microenvironment as a cause of aplastic anemia. In patients with severe aplastic anemia, the stromal cell function is normal, including growth factor production. Adequate stromal function is implicit in the success of marrow transplantation in aplastic anemia because frequently the stromal elements remain of host origin.

The role of an immune dysfunction was suggested in 1970, when autologous recovery was documented in a patient with aplastic anemia who had failed to engraft after marrow transplantation; Mathe proposed that the immunosuppressive regimen used for conditioning promoted the return of normal marrow function. Subsequently, numerous studies have shown that in approximately 70% of patients with acquired aplastic anemia, immunosuppressive therapy improves marrow function. Immunity is regulated genetically (by immune response genes) and also influenced by environment (eg, nutrition, aging, previous exposure). Although the inciting antigens that breach immune tolerance with subsequent autoimmunity are unknown, human leukocyte antigen (HLA)-DR2 is overrepresented among European and American patients with aplastic anemia.

Suppression of hematopoiesis likely is mediated by an expanded population of cytotoxic T lymphocytes: cluster of differentiation 8, HLA-DR+ (CTLs: CD8, HLA-DR+), which are detectable in both the blood and bone marrow of patients with aplastic anemia. These cells produce inhibitory cytokines, such as gamma interferon and tumor necrosis factor, which are capable of suppressing progenitor cell growth. These cytokines suppress hematopoiesis by affecting the mitotic cycle and cell killing through induction Fas-mediated apoptosis. It also has been shown that these cytokines induce nitric oxide synthase and nitric oxide production by marrow cells, which contributes to immune-mediated cytotoxicity and elimination of hematopoietic cells.

Frequency:

• In the US: No accurate prospective data are available regarding the incidence of aplastic anemia in the US. Several retrospective studies suggest that the incidence ranges from 0.6-6.1 per million, largely based on data from retrospective reviews of death registries.

• Internationally: The annual incidence of aplastic anemia in Europe as detailed in large, formal epidemiological studies is similar to the US data at 2 per million. Aplastic anemia is thought to be more common in the Orient than in the West. The incidence was accurately determined at 4 per million in Bangkok but may be closer to 6 per million in the rural areas of Thailand and as high a 14 per million in Japan, based on prospective studies. This increased incidence may be related to environmental factors, such as increased exposure to toxic chemicals, rather than genetic factors since this increase is not seen in people of Oriental ancestry presently living in US.

Mortality/Morbidity: The major causes of morbidity and mortality from aplastic anemia include infection and bleeding. Patients who undergo bone marrow transplantation have additional issues related to conditioning regimen toxicity and graft-versus-host disease. With immunosuppression, approximately one third of patients do not respond, and for the responders risks exist of relapse and late onset clonal disease such as paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndrome (MDS), and leukemia.

Race: No racial predisposition in US; however, increased prevalence in the Far East

Sex: The male-to-female ratio in acquired aplastic anemia is approximately 1:1, although some data suggest that there may be a male preponderance in the Far East.

Age: Aplastic anemia occurs in all age groups.

• A small peak in childhood is seen due to the inclusion of inherited marrow failure syndromes.

• The peak incidence of aplastic anemia is seen in the 20-25 years age group, and a subsequent peak is seen after the age of 60 years. The latter peak may be due to inclusion of MDS, which are stem cell failure syndromes unrelated to aplastic anemia. These must be considered in the differential diagnosis of any marrow failure syndrome.

CLINICAL

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History: The clinical presentation of aplastic anemia includes symptoms related to the decrease in bone marrow production of hematopoietic cells. The onset is insidious, with the initial symptom relating to anemia or bleeding, but fever or infections often are noted at presentation.

• Anemia may manifest as pallor, headache, palpitations, dyspnea, fatigue, or foot swelling.

• Thrombocytopenia may present as mucosal and gingival bleeding or petechial rashes.

• Neutropenia may manifest as overt infections, recurrent infections, or mouth and pharyngeal ulcerations.

• Even though the search for an etiologic agent often is unproductive, an appropriately detailed work history with emphasis on solvent and radiation exposure, family, environmental, travel, and infectious disease history should be obtained.

• Significantly, in the absence of obvious phenotypic features, the presentation of an inherited marrow failure syndrome is subtle, and it may first be suggested by a thorough family history.

• With regard to environmental agents, it is important to remember that much variation is seen in the time course of the occurrence of aplastic anemia and the exposure to the offending agent, and only rarely is an environmental etiology identified.

Physical: The physical examination may show signs of anemia, such as pallor and tachycardia, and of thrombocytopenia, such as petechiae, purpura, or ecchymoses. Overt signs of infection usually are not apparent at diagnosis.

• A subset of patients with aplastic anemia present with jaundice and evidence of clinical hepatitis.

• Findings of adenopathy or organomegaly should suggest an alternative diagnosis.

• In any case of aplastic anemia, one should look for physical stigmata of inherited marrow failure syndromes such as skin pigmentation, short stature, microcephaly, hypogonadism, mental retardation, and skeletal anomalies. A careful examination of the oral pharynx, hands, and nailbeds should be preformed looking for clues of dyskeratosis congenita.

Causes:

• Congenital/inherited (20%)

• Patients usually have dysmorphic features or physical stigmata. Occasionally, marrow failure may be the initial presenting feature.

   

• Fanconi anemia

• Dyskeratosis congenita

• Cartilage hair hypoplasia

• Pearson syndrome

• Amegakaryocytic thrombocytopenia (TAR syndrome)

• Shwachman-Diamond syndrome

• Dubowitz syndrome

• Diamond-Blackfan syndrome

• Familial aplastic anemia

• Acquired (80%)

• Idiopathic

• Infectious causes such as hepatitis viruses, Ebstein-Barr virus (EBV), HIV, parvovirus, and mycobacterial infections

• Toxic exposure to radiation and chemicals such as benzene

• Drugs such as chloramphenicol, phenylbutazone, and gold may cause aplasia of the marrow. The immune mechanism does not explain the marrow failure in idiosyncratic drug reactions. In such cases direct toxicity may occur, perhaps due to genetically determined differences in metabolic detoxification pathways; for example, the null phenotype of certain glutathione transferases is overrepresented among patients with aplastic anemia.

• Paroxysmal nocturnal hemoglobinuria (PNH) is caused by an acquired genetic defect limited to the stem cell compartment affecting the PIGA gene. The PIGA gene mutations render cells of hematopoietic origin sensitive to increased complement lysis. Approximately 20% of patients with aplastic anemia have evidence of PNH at presentation as detected by flow cytometry. Furthermore, patients who respond following immunosuppressive therapy frequently recover with clonal hematopiesis and PNH.

• Transfusional graft-versus-host disease

• Orthotopic liver transplantation for fulminant hepatitis

• Pregnancy

• Eosinophilic fascitis

DIFFERENTIALS

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Acute Lymphoblastic Leukemia
Acute Myelogenous Leukemia
Agnogenic Myeloid Metaplasia with Myelofibrosis
Human Herpesvirus Type 6 (HHV-6)
Lymphoma, Non-Hodgkin
Megaloblastic Anemia
Myelodysplastic Syndrome
Myelophthisic Anemia
Osteopetrosis

Other Problems to be Considered:

Multiple myeloma
Congestive splenomegaly resulting in hypersplenism
Sepsis
Disseminated lupus erythematosus
Infectious etiology such as HIV, mycobacterial infections, cytomegalovirus (CMV), EBV

WORKUP

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Lab Studies:

• CBC and peripheral smear

• A paucity of platelets, red blood cells, granulocytes, monocytes, and reticulocytes is found. Mild macrocytosis sometimes is encountered. The degree of cytopenia is useful in assessing the severity of aplastic anemia. The corrected reticulocyte count is uniformly low in aplastic anemia.

• The peripheral blood smear often is helpful in resolving aplasia from infiltrative and dysplastic causes. The presence of teardrop poikilocytes and leucoerythroblastic changes is suggestive of an infiltrative process.

• Patients with MDS often show certain characteristic abnormalities: dyserythropoietic red blood cells; neutrophils with hypogranulation, hypolobulation, or apoptotic nuclei reaching to the edges of the cytoplasm. Monocytes are similarly hypogranular and their nuclei may contain nucleoli.

• A leukemic process may show evidence of blasts on the peripheral smear.

• Bone marrow aspiration and biopsy

• A bone marrow biopsy is performed in addition to the aspiration so that the cellularity may be assessed both qualitatively and quantitatively. In aplastic anemia, these specimens are hypocellular. Aspirations alone may appear hypocellular owing to technical reasons (eg, dilution with peripheral blood), or they may look hypercellular because of areas of focal residual hematopoiesis. A core biopsy gives a better idea of cellularity; the specimen is considered hypocellular if it is less than 30% cellular in individuals younger than 60 years or less than 20% in those older than 60 years. A relative or absolute increase in mast cells may be observed around the hypoplastic spicules. A proportion of marrow lymphocytes greater than 70% has been correlated with poor prognosis in aplastic anemia. Some dyserythropoiesis with megaloblastosis may be seen in aplastic anemia.

• In MDS, the cellularity may be increased or decreased. Myelodysplastic features usually are observed in hematopoietic precursors and progeny. Islands of immature cells or abnormal localization of immature progenitors (ALIPS) are indicative of MDS. These patients may have megakaryocytic abnormalities (micromegakaryocytes, megakaryocytes with dyskaryorrhexis); greater than 5% ring sideroblasts (seen only on iron stains); granulocytic abnormalities (pseudo-Pelger-Huët cells, hypogranulation, excess of blasts); occasionally, marrow fibrosis may be observed.

• Patients with leukemia and metastatic cancers also may be diagnosed with bone marrow examination.

• Chromosomal rearrangements are considered diagnostic of MDS, with trisomies of 8 and 21 and deletions of 5, 7, and 20 being most common. However, the conventional karyotype technique reveals abnormalities in only about 50% of patients with MDS. In hypoplastic marrows, it often is difficult to obtain sufficient sample for karyotyping.

• The issue of malignant versus nonmalignant clonality in aplastic anemia can at times be resolved using fluorescent in situ hybridization (FISH) to visualize chromosomal abnormalities in interphase cells.

• Bone marrow culture is useful in diagnosing mycobacterial and viral infections. However, the yield generally is low.

• Peripheral blood

• Hemoglobin electrophoresis and blood group testing may show elevated fetal hemoglobin and red cell I antigen suggesting stress erythropoiesis, which is seen in both aplastic anemia and MDS and often is proportional to the macrocytosis.

• Biochemical profile including evaluation of transaminases, bilirubin, lactic dehydrogenase, Coombs test, and kidney function is useful in evaluating etiology and differential diagnosis.

• Serologic testing for hepatitis and other viral entities such as EBV, CMV, and HIV

• Autoimmune disease evaluation for evidence of collagen-vascular disease

• Ham test or sucrose hemolysis test frequently are performed, but currently fluorescent activated cell sorter profile of PIGA gene anchor proteins such as CD55 and CD59 may be more accurate for excluding PNH.

• Diepoxybutane incubation is performed to assess chromosomal breakage for Fanconi anemia. This test is required even in the absence of phenotypic features of Fanconi anemia because 30% of such patients may not have any clinical stigmata.

• Histocompatibility testing should be conducted early to establish potential related donors, especially in younger patients. Because the outcome of patients undergoing allogenic bone marrow transplantation for aplastic anemia is significantly affected by the extent of prior transfusion, the rapidity with which these data are obtained is crucial.

Imaging Studies:

• Radiological studies generally are not needed to establish a diagnosis of aplastic anemia. A skeletal survey is especially useful for the inherited marrow failure syndromes, many of which show skeletal abnormalities.

Procedures:

• Review of peripheral smear

• Bone marrow aspiration and biopsy

Staging: Based on International Aplastic Anemia Study Group (Camitta et al)

• Blood

• Neutrophils - Less than 0.5x10'9/L

• Platelets - Less than 20x10'9/L

• Reticulocytes - Less than 1% (corrected) (percentage of actual Hct/normal Hct)

• Marrow

• Severe hypocellularity

• Moderate hypocellularity with hematopoietic cells representing less than 30% of res