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Aplastic Anemia

Contents
  1. Read book excerpt
  2. Proximal Renal Tubular Acidosis: Introduction
  3. Proximal Renal Tubular Acidosis Causes
  4. Proximal Renal Tubular Acidosis Complications
  5. Proximal Renal Tubular Acidosis Treatments
  6. Proximal Renal Tubular Acidosis Overview
  7. More book excerpts for Proximal Renal Tubular Acidosis

Aplastic Anemia: Excerpt from The 5-Minute Pediatric Consult

Janet L. Kwiatkowski, MD

Aplastic Anemia - BASICS

Aplastic Anemia - description

  • A heterogeneous disorder within the bone marrow failure syndromes
  • Characterized by a marked decrease or absence of blood precursors in the bone marrow and peripheral pancytopenia. The disorder exists in both acquired and congenital forms.

Aplastic Anemia - epidemiology

Aplastic Anemia - incidence

  • Annual incidence of 2 new cases per 1 million in US and Europe
  • Incidence in Asia is ~3-fold higher than in western countries, likely related to environmental/infectious exposures.

Aplastic Anemia - prevalence

  • 2 major age peaks: 15–25 years and >60 years
  • Male = Female

Aplastic Anemia - risk factors

Aplastic Anemia - genetics

  • Most cases are sporadic.
  • Moderately correlated with specific histocompatibility antigen frequency (human leukocyte antigen-DR2 antigen twice as frequent in aplastic anemia patients as in the unaffected population)
  • May be associated with heritable conditions including Fanconi anemia, Dyskeratosis congenital, and others

Aplastic Anemia - pathophysiology

  • An inciting event, such as infection or medication, provokes an aberrant immune response.
  • This results in oligoclonal expansion of cytotoxic T lymphocytes.
  • Aberrant cytokine production by T lymphocytes suppresses hematopoietic cell proliferation and triggers apoptosis of CD34-progenitor cells.
  • This results in a marked reduction in the number of hematopoietic stem cells (CD34+).
  • Stromal (supporting) cells within the bone marrow microenvironment are usually normal.

Aplastic Anemia - etiology

  • Acquired:
    • Idiopathic (70% of cases)
    • Idiosyncratic drug side effects (e.g., chloramphenicol, nonsteroidal anti-inflammatory drugs, antiepileptics, quinacrine, cimetidine)
    • Hepatitis (usually non-A, non-B, and non-C)
    • Human immunodeficiency virus, Epstein-Barr virus, human herpes virus-6, cytomegalovirus
    • Chemicals/toxins such as insecticides (dichlorodiphenyltrichloroethane [DDT], parathion); benzene, carbon tetrachloride
    • Radiation
    • Malnutrition: Kwashiorkor, marasmus, anorexia nervosa
    • Paroxysmal nocturnal hemoglobinuria (PNH)
    • Pregnancy
    • Autoimmune mechanisms
    • Preleukemia, myelodysplastic syndrome (MDS)
  • Congenital:
    • Fanconi anemia
    • Dyskeratosis congenita
    • Shwachman-Diamond syndrome
    • Reticular dysgenesis
    • Amegakaryocytic thrombocytopenia
    • Familial

Aplastic Anemia - DIAGNOSIS

Aplastic Anemia - signs & symptoms

Aplastic Anemia - history

  • Evidence of bone marrow failure:
    • Pallor, lethargy, easy fatigue, weakness, and loss of appetite are signs of anemia. These may not be noticed by patient/parent due to slow onset of anemia (with compensation).
    • Petechiae, easy and excessive bruising, prolonged epistaxis, gingival bleeding, hematuria, and bloody stools are signs/symptoms of thrombocytopenia.
    • Infections that do not respond to antibiotics, oral ulcers, and gingival hyperplasia may be signs of neutropenia.
  • Evidence of cause:
    • Drug or toxin exposure (although usually not identified)
    • History of hepatitis, jaundice, or other viral infections

Aplastic Anemia - physical exam

  • Cachexia suggests another etiology, such as malignancy.
  • Excessive bruising, petechiae, and pallor as signs of severe thrombocytopenia and anemia. Skin hyper- or hypopigmentation may be seen with Fanconi anemia.
  • Oral mucosal ulcerations and bleeding, thrush, palatal petechiae, and gingival hypertrophy as signs of neutropenia and thrombocytopenia
  • Tachycardia and systolic ejection murmur from anemia
  • Lymphadenopathy and hepatosplenomegaly suggest acute leukemia/malignant process, and are not associated with aplastic anemia.
  • Perianal ulcerations/infection from neutropenia
  • Skeletal anomalies and dysmorphic features may be signs of Fanconi anemia.

Aplastic Anemia - tests

Aplastic Anemia - lab

  • To confirm the diagnosis:
    • CBC with differential and reticulocyte count—severe aplastic anemia (at least 2 of the following: granulocyte count <500/mm3, platelet count <20,000/mm3, or reticulocyte count [corrected for hematocrit] <1%, mild or moderate aplastic anemia [hypoplastic anemia], less severe cytopenias)
    • Supplemental laboratory studies—liver function tests, hepatitis A, B, and C antibody panel; viral serologies (e.g., Epstein-Barr virus, parvovirus B19 [IgG and IgM], varicella Zoster virus, cytomegalovirus, human immunodeficiency virus, human herpes virus-6)
  • To exclude other causes:
    • Bone marrow aspirate for chromosomal analysis to rule out MDS, acute leukemia
    • Diepoxybutane chromosome breakage study (on peripheral blood) to test for Fanconi anemia
    • Flow cytometry to exclude PNH
    • Red cell folate and vitamin B

    Aplastic Anemia - imaging

    Usually not needed. Magnetic resonance imaging of thoracic and lumbar spine will show increased fatty infiltration of marrow space. This test may be helpful when bone marrow aspirate shows patchy cellularity.

    Aplastic Anemia - diag proced-surgery

    Bone marrow aspirate and biopsy

    Aplastic Anemia - pathological findings

    Bone marrow aspirate and biopsy in severe aplastic anemia marrow will be hypocellular with fatty infiltration, <25% cellularity on biopsy.

    Aplastic Anemia - differencial diagnosis

    • Acute leukemia
    • MDS
    • PNH
    • Folate or BAcute drug reaction with bone marrow suppression
    • Acute infection (viral) with bone marrow suppression (e.g., human immunodeficiency virus-1, cytomegalovirus, parvovirus B19, Epstein-Barr virus)
    • Marrow infiltration by malignant tumors (e.g., non-Hodgkin lymphoma, neuroblastoma)
    • Hemophagocytic lymphohistiocytosis (i.e., familial erythrophagocytic lymphohistiocytosis)

    Aplastic Anemia - TREATMENT

    Aplastic Anemia - initial stabilization

    • Broad-spectrum antibiotics for febrile neutropenic patients; Consider antifungal therapy for patients with prolonged fevers.
    • Platelet transfusions for bleeding; maintain platelet count >10,000/mm3 in nonbleeding adolescent/adult patients (single-donor units, irradiated, leukocyte depleted)
    • Red cell transfusions in severely anemic patients should be given slowly, to prevent congestive heart failure (unless anemia is acute and due to blood loss rather than lack of production). Use irradiated, leukocyte-depleted, cytomegalovirus-safe red cell product from unrelated donors.

    Aplastic Anemia - general measures

    • Bone marrow transplantation:
      • Treatment of choice for patients <40 years of age with severe aplastic anemia and human leukocyte antigen-identical sibling
      • Transplant early, minimize supportive transfusions.
      • Alternative donor bone marrow transplantation should be used only for patients who have failed immunosuppressive therapy.
      • Peripheral blood stem cell and umbilical cord blood regimens are currently being tested.
    • Immunosuppressive therapy:
      • Antithymocyte globulin (ATG) and cyclosporine. Growth factors (G-CSF or granulocyte macrophage colony-stimulating factor) are often given if severely neutropenic, although addition of growth factors has not been shown to improve survival.
      • High-dose cyclophosphamide without bone marrow transplantation. This treatment was associated with a greater number of early deaths from infection than was treatment with antithymocyte globulin/cyclosporine.
    • Androgens:
      • Used for the treatment of Fanconi anemia
      • Effective in moderate and mild aplastic anemia, particularly if anemia is the most significant cytopenia
    • Supportive therapy:
      • Transfusion support: Family donors should not be used (to avoid alloimmunization); use cytomegalovirus-safe, irradiated, leukodepleted product; minimize number of transfusions
      • Infectious disease support: pan culture and institute broad-spectrum parenteral antibiotics for fever/neutropenia; antifungal therapy for persistent fevers. The addition of G-CSF may lead to more rapid rise in neutrophil counts, although there are some reports of increased clonal transformation with its use. Maintain good hand washing and oral hygiene. Avoid rectal temperatures. Long-term prophylactic antibiotics are not recommended.

    Aplastic Anemia - diet

    Avoid raw fish, fruits, and vegetables in neutropenic patients.

    Aplastic Anemia - medication

    Aplastic Anemia - first line

    ATG and cyclosporine are first-line medications for treatment of severe aplastic anemia in those without an HLA-identical sibling donor.

    Aplastic Anemia - second line

    For refractory aplastic anemia:

    • Repeat course of ATG/cyclosporine
    • Stem cell transplantation from unrelated donor
    • High dose cyclophosphamide
    • Alemtuzumab (a humanized monoclonal antibody specific for CD52, which is present on lymphocytes) is in clinical trials.

    Aplastic Anemia - FOLLOW UP

    Aplastic Anemia - prognosis

    • In patients with severe aplastic anemia, 80–90% mortality at 2 years if untreated
    • Bone marrow transplant from human leukocyte antigen-identical sibling donor:
      • 79% overall survival in children
      • 80–90% survival for the young, uninfected, and minimally transfused patient
    • Bone marrow transplant from human leukocyte antigen-identical unrelated donor: 30–55% survival (due to older population, frequent graft rejection, more severe graft-versus-host disease, infection from delayed engraftment with prolonged neutropenia)
    • Immunosuppressive therapy:
      • 60–80% response rate (initial treatment)
      • Higher response rate in children
    • Factors associated with poor outcome:
      • Bleeding at presentation
      • Severe pancytopenia (absolute neutrophil count <200/mm3, platelet <20,000/mm3)
      • Prolonged pancytopenia (>1 month)
      • Active infection at diagnosis

    Aplastic Anemia - complications

    • Infection: Overwhelming bacterial sepsis and fungal (Aspergillus) infections are most frequent cause of death.
    • Hemorrhage: Intracranial, especially if refractory to platelet transfusions
    • Iron overload secondary to long-term RBC transfusions, with subsequent organ dysfunction if untreated

    Aplastic Anemia - patient monitoring

    • Time to recovery: Response to medical therapy is not immediate, but most responses to medical therapy, with some degree of blood count recovery, occur within 3 months of treatment. Hematologic recovery may be incomplete, and some patients may remain cyclosporine dependent.
    • Signs of recovery include normalization of mean corpuscular volume (MCV), increasing reticulocyte, neutrophil, and monocyte counts. Full platelet recovery may take months.
    • Relapse:
      • Risk of relapse is 30–40% at 5 years; many respond to salvage therapy.
      • Salvage therapy: 2nd course of immunosuppressive therapy (50% salvage), matched unrelated-donor bone marrow transplantation (30–55% overall survival)
    • Other:
      • 8–15% risk of MDS and/or myeloid leukemia at 10 years. May be lower in children
      • 15% risk of PNH at 5 years. May be lower in children
      • Risk of relapse and of development of clonal bone marrow disorders is higher in patients treated with immunosuppressive therapy than in those treated with stem cell transplantation.

    Aplastic Anemia - bibliography

    1. Alter BP. Bone marrow failure syndromes in children. Pediatr Clin North Am. 2002;49(5):973–988.
    2. Brodsky RA, Jones RJ. Aplastic anemia. Lancet. 2005;365:1647–1656.
    3. Frickhofen N, Rosenfeld SJ. Immunosuppressive treatment of aplastic anemia with antithymocyte globulin and cyclosporine. Semin Hematol. 2000;37:56–68.
    4. Young NS, Calado RT, Scheinberg P. Current concepts in the pathophysiology and treatment of aplastic anemia. Blood. 2006;108(8):2509–2519.

    Aplastic Anemia - CODES

    Aplastic Anemia - icd9

    284.9 Aplastic anemia, unspecified

    Aplastic Anemia - FAQ

    • Q: Can family members donate blood for a child with aplastic anemia?
    • A: This is not recommended, as transfusion with blood products from parents or siblings increases the risk of graft rejection of bone marrow in the setting of a related-donor bone marrow transplant.
    • Q: What activities should a child with aplastic anemia avoid?
    • A: Patients with low RBC counts should avoid excessive exercise or high-altitude exposure. Patients with low WBC counts are more susceptible to bacterial infections. Patients should avoid dental work, as this may introduce bacteria into the bloodstream through the mouth. Patients with low platelet counts should avoid contact sports (e.g., football, hockey, lacrosse, skiing).
    • Q: How does one learn more about experimental therapies for the treatment of aplastic anemia?
    • A: Inquiries to the National Institutes of Health (NIH) in Bethesda, Maryland, or to the hematology division of the nearest medical school or National Institutes of Health-designated cancer center should result in information about the availability of experimental therapies.
    >>>>>>>

    Book Source Details

    • Book Title: The 5-Minute Pediatric Consult
    • Author(s): M. William Schwartz MD; et al.
    • Year of Publication: 2008
    • Copyright Details: The 5-Minute Pediatric Consult, Copyright © 2008 Lippincott Williams & Wilkins.

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    Copyright notice for book excerpts: Copyright © 2008 Lippincott Williams & Wilkins. All rights reserved.



    More About This Book:
    Title: The 5-Minute Pediatric Consult
    Authors: M. William Schwartz MD; et al.
    Publisher: Lippincott Williams & Wilkins
    Copyright: 2008
    ISBN: 0-7817-7577-9

     » Next page: Renal Tubular Acidosis (The 5-Minute Pediatric Consult)

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