eMedicine Specialties > Hematology > Red Blood Cells and Disorders

Aplastic Anemia

Author: Sameer Bakhshi, MD, Associate Professor of Pediatric Oncology, Department of Medical Oncology, Dr BRA Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, India
Coauthor(s): Esteban Abella, MD, Consulting Staff, Arizona Pediatric Hematology/Oncology, PLLC
Contributor Information and Disclosures

Updated: Oct 4, 2009

Introduction

Background

Aplastic anemia is a syndrome of bone marrow failure characterized by peripheral pancytopenia and marrow hypoplasia, and mild macrocytosis is observed in association with stress erythropoiesis and an elevated fetal hemoglobin levels. 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 Anatole Chauffard named this disorder aplastic anemia.

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Anemia.

Pathophysiology

The theoretical basis for marrow failure includes primary defects in or damage to the stem cell or the marrow microenvironment.1,2,3 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.

On morphologic evaluation, 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 substantially reduced.2,4 Data from in vitro colony-culture assays suggest profound functional loss of the hematopoietic progenitors, so much so that they are unresponsive even to 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 (SAA), stromal cells have normal function, including growth factor production. Adequate stromal function is implicit in the success of bone marrow transplantation (BMT) in aplastic anemia because the stromal elements are frequently of host origin.

The role of an immune dysfunction was suggested in 1970, when autologous recovery was documented in a patient with aplastic anemia in whom engrafting failed after BMT. Mathe proposed that the immunosuppressive regimen used for conditioning promoted the return of normal marrow function. Since then, numerous studies have shown that, in approximately 70% of patients with acquired aplastic anemia, immunosuppressive therapy improves marrow function.3,5,6,7,8
 
Immunity is genetically regulated (by immune response genes), and it is also influenced by environment (eg, nutrition, aging, previous exposure).9,10 Although the inciting antigens that breach immune tolerance with subsequent autoimmunity are unknown, human leukocyte antigen (HLA)-DR2 is overrepresented among European and United States patients with aplastic anemia, suggesting a role for antigen recognition, and its presence is predictive of a better response to cyclosporine.

Suppression of hematopoiesis is likely mediated by an expanded population of the following cytotoxic T lymphocytes (CTLs): CD8 and 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 can suppressing progenitor cell growth. Polymorphisms in these cytokine genes, associated with an increased immune response, are more prevalent in patients with aplastic anemia. These cytokines suppress hematopoiesis by affecting the mitotic cycle and cell killing by inducing Fas-mediated apoptosis. In addition, these cytokines induce nitric oxide synthase and nitric oxide production by marrow cells, which contributes to immune-mediated cytotoxicity and the elimination of hematopoietic cells.

Constitutive expression of Tbet, a transcriptional regulator that is critical to Th1 polarization, occurs in a majority of aplastic anemia patients.5 Perforin is a cytolytic protein expressed mainly in activated cytotoxic lymphocytes and natural-killer cells. Mutations in perforin gene are responsible for some cases of familial hemophagocytosis11 ; mutations in SAP, a gene encoding for a small modulator protein that inhibits undefined-interferon production, underlie X-linked lymphoproliferation, a fatal illness associated with an aberrant immune response to herpesviruses and aplastic anemia. Perforin and SAP protein levels are markedly diminished in a majority of acquired aplastic anemia cases.

Frequency

United States

No accurate prospective data are available regarding the incidence of aplastic anemia in the United States. Findings from several retrospective studies suggest that the incidence is 0.6-6.1 cases per million population; this rate was largely based on data from retrospective reviews of death registries.

International

The annual incidence of aplastic anemia in Europe, as detailed in large, formal epidemiologic studies, is similar to that in the United States, with 2 cases per million population. Aplastic anemia is thought to be more common in Asia than in the West. The incidence was accurately determined to be 4 cases per million population in Bangkok, but it may be closer to 6 cases per million population in the rural areas of Thailand and as high as 14 cases per million population in Japan, based on prospective studies. This increased incidence may be related to environmental factors, such as increased exposure to toxic chemicals, rather than to genetic factors because this increase is not observed in people of Asian ancestry who are presently living in the United States.

Mortality/Morbidity

The major causes of morbidity and mortality from aplastic anemia include infection and bleeding. Patients who undergo BMT have additional issues related to toxicity from the conditioning regimen and graft versus host disease (GVHD).10,12,13,14,15,16 With immunosuppression, aplastic anemia in approximately one third of patients does not respond. For the responders, relapse and late-onset clonal disease, such as paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndrome (MDS), and leukemia, are risks.6,17,18,19,20

Race

No racial predisposition is reported in the United States. However, the prevalence is increased in the Far East.

Sex

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

Age

Aplastic anemia occurs in all age groups.

  • A small peak in the incidence is observed in childhood because of the inclusion of inherited marrow-failure syndromes.
  • The incidence of aplastic anemia peaks in people aged 20-25 years, and a subsequent peak is observed in people older than 60 years. The latter peak may be due to the inclusion of MDSs, which are syndromes of stem-cell failure unrelated to aplastic anemia. These syndromes must be considered in the differential diagnosis of any marrow-failure syndrome.

Clinical

History

The clinical presentation of patients with aplastic anemia includes symptoms related to the decrease in bone-marrow production of hematopoietic cells. The onset is insidious, and the initial symptom is related to anemia or bleeding, although fever or infections are also often noted at presentation.

  • Anemia may manifest as pallor, headache, palpitations, dyspnea, fatigue, or foot swelling.
  • Thrombocytopenia may result in mucosal and gingival bleeding or petechial rashes.
  • Neutropenia may manifest as overt infections, recurrent infections, or mouth and pharyngeal ulcerations.
  • Although the search for an etiologic agent is often unproductive, an appropriately detailed work history, with emphasis on solvent and radiation exposure should be obtained, as should a family, environmental, travel, and infectious disease history.
  • In the absence of obvious phenotypic features, the presentation of a patient with an inherited marrow-failure syndrome is subtle, and a thorough family history may first suggest the condition.
  • With regard to environmental agents, the time course of aplastic anemia and exposure to the offending agent varies greatly, and only rarely is an environmental etiology identified.

Physical

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

  • A subset of patients with aplastic anemia present with jaundice and evidence of clinical hepatitis.21,22
  • Findings of adenopathy or organomegaly should suggest an alternative diagnosis (eg, hepatosplenomegaly and supraclavicular adenopathy are observed more frequently in cases of leukemia and lymphoma than in cases of aplastic anemia).
  • In any case of aplastic anemia, look for physical stigmata of inherited marrow-failure syndromes, such as skin pigmentation, short stature, microcephaly, hypogonadism, mental retardation, and skeletal anomalies. The oral pharynx, hands, and nail beds should be carefully examined for clues of dyskeratosis congenita. Oral leukoplakia is shown in the image below.

    • Oral leukoplakia in dyskeratosis congenita.

      Oral leukoplakia in dyskeratosis congenita.

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      Oral leukoplakia in dyskeratosis congenita.

      Oral leukoplakia in dyskeratosis congenita.

Causes

  • Congenital or inherited causes of aplastic anemia (20%)
  • Acquired causes of aplastic anemia (80%)
    • Idiopathic factors
    • Infectious causes, such as hepatitis viruses, Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), parvovirus, and mycobacteria
    • Toxic exposure to radiation and chemicals, such as benzene
    • Drugs and elements, such as chloramphenicol, phenylbutazone, and gold may cause aplasia of the marrow. The immune mechanism does not account for 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.
    • PNH is caused by an acquired genetic defect limited to the stem-cell compartment affecting the PIGA gene. Mutations in the PIGA gene 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 means of flow cytometry. Furthermore, patients whose disease responds after immunosuppressive therapy frequently recover with clonal hematopiesis and PNH.
    • Transfusional GVHD
    • Orthotopic liver transplantation for fulminant hepatitis
    • Pregnancy
    • Eosinophilic fasciitis

More on Aplastic Anemia

Overview: Aplastic Anemia
Differential Diagnoses & Workup: Aplastic Anemia
Treatment & Medication: Aplastic Anemia
Follow-up: Aplastic Anemia
Multimedia: Aplastic Anemia
References
Further Reading
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References

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Keywords

aplastic anemia; anemia; anemia, aplastic; hypoplastic anemia; bone marrow disease; bone marrow failure; bone marrow failure syndrome; severe aplastic anemia; SAA; progressive hypocythemia; aregeneratory anemia; aleukia hemorrhagica; panmyelophthisis; toxic paralytic anemia; peripheral pancytopenia; myelodysplastic syndrome; MDS

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Contributor Information and Disclosures

Author

Sameer Bakhshi, MD, Associate Professor of Pediatric Oncology, Department of Medical Oncology, Dr BRA Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, India
Disclosure: Nothing to disclose.

Coauthor(s)

Esteban Abella, MD, Consulting Staff, Arizona Pediatric Hematology/Oncology, PLLC
Esteban Abella, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Hematology, American Society of Pediatric Hematology/Oncology, and West Virginia State Medical Association
Disclosure: Nothing to disclose.

Medical Editor

David Aboulafia, MD, Medical Director, Bailey-Boushay House; Clinical Professor, Department of Medicine, Division of Hematology, University of Washington
David Aboulafia, MD is a member of the following medical societies: American College of Physicians, American Medical Association, American Medical Directors Association, American Society of Hematology, Infectious Diseases Society of America, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Troy H Guthrie, Jr, MD, Director of Cancer Institute, Baptist Medical Center
Troy H Guthrie, Jr, MD is a member of the following medical societies: American Federation for Medical Research, American Medical Association, American Society of Hematology, Florida Medical Association, Medical Association of Georgia, and Southern Medical Association
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

 
 
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