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Anemia, Aplastic

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  • Early intervention for aplastic anemia greatly improves the chances of treatment success.

  • Hematopoietic growth factors require close monitoring in newly diagnosed patients.

 
Geriatric Considerations

The elderly are often exposed to large numbers of drugs and therefore, may be more susceptible to acquired aplastic anemia.

 
Pediatric Considerations

  • Congenital forms of aplastic anemia require different treatment regimens than acquired forms.

  • Acquired aplastic anemia is seen in children exposed to ionizing radiation or treated with cytotoxic chemotherapeutic agents.

 
Pregnancy Considerations

  • Pregnancy is a real but rare cause of aplastic anemia. Symptoms may resolve after delivery and with termination.

  • Complications in pregnancy can occur from low platelet counts and paroxysmal nocturnal hemoglobinuria-associated aplastic anemia.

 

EPIDEMIOLOGY


  • Predominant age: (1) biphasic 15 to 25 years (more common) and >60 years
  • Predominant sex: male = female

Incidence
  • 2 to 3 new cases per million per year in Europe and North America
  • The incidence is 3-fold higher in Thailand and China versus the Western world.

ETIOLOGY AND PATHOPHYSIOLOGY


  • Idiopathic (~70% of the cases)
  • Drugs: phenylbutazone, chloramphenicol, sulfonamides, gold, cytotoxic drugs, antiepileptics (felbamate, carbamazepine, valproic acid, phenytoin)
  • Viral: HIV, Epstein-Barr virus (EBV), nontypeable postinfectious hepatitis (not A, B, or C), parvovirus B19 (mostly in the immunocompromised), atypical mycobacterium
  • Toxic exposure (benzene, pesticides, arsenic)
  • Radiation exposure
  • Immune disorders (systemic lupus erythematosus, eosinophilic fasciitis, graft vs. host disease)
  • Pregnancy (rare)
  • Congenital (Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond syndrome, amegakaryocytic thrombocytopenia)
  • The immune hypothesis: Activation of T cells with associated cytokine production leading to destruction or injury of hematopoietic stem cells. This leads to a hypocellular bone marrow without marrow fibrosis (2).
  • The activation of T cells likely occurs because of both genetic and environmental factors. Exposure to specific environmental precipitants, diverse host, genetic risk factors, and individual differences in characteristics of immune response likely account for variations in its clinical manifestations and patterns of responsiveness to treatment.
  • Telomerase deficiency leads to short telomeres. This leads to impaired regenerative capacity and hence, a reduction in marrow progenitors and qualitative deficiency in the repair capacity of hematopoietic tissue.
  • Reduction of natural killer cells in the bone marrow

Genetics
  • Telomerase mutations found in a small number of patients with acquired and congenital forms. These mutations render carriers more susceptible to environmental insults.
  • Mutations in genes called TERC and TERT were found in pedigrees of adults with acquired aplastic anemia who lacked the physical abnormalities or a family history typical of inherited forms of bone marrow failure. These genes encode for the RNA component of telomerase.
  • HLA-DR2 incidence in aplastic anemia is twice that in the normal population.

RISK FACTORS


  • Treatment with high-dose radiation or chemotherapy
  • Exposure to toxic chemicals
  • Use of certain medications
  • Certain blood diseases, autoimmune disorders, and serious infections
  • Tumors of thymus (red cell aplasia)
  • Pregnancy, rarely

GENERAL PREVENTION


  • Avoid possible toxic industrial agents.
  • Use safety measures when working with radiation.

DIAGNOSIS


HISTORY


  • Solvent and radiation history; family, environmental, travel, and infectious disease history
  • Patients are often asymptomatic but may have frequent infections, fatigue, shortness of breath, headache, or bleeding/bruising.

PHYSICAL EXAM


  • Mucosal hemorrhage, petechiae
  • Pallor
  • Fever
  • Hemorrhage, menorrhagia, occult stool blood, melena, epistaxis
  • Dyspnea
  • Palpitations
  • Progressive weakness
  • Retinal flame hemorrhages
  • Systolic ejection murmur
  • Weight loss
  • Signs of congenital aplastic anemia
    • Short stature
    • Microcephaly
    • Nail dystrophy
    • Abnormal thumbs
    • Oral leukoplakia
    • Hyperpigmentation (caf © au lait spots) or hypopigmentation

DIFFERENTIAL DIAGNOSIS


Includes other causes of bone marrow failure and pancytopenia  
  • Marrow replacement
    • Acute lymphoblastic leukemia
    • Lymphoma
    • Hairy cell leukemia (increased reticulin and infiltration of hairy cells)
    • Large granular lymphocyte leukemia
    • Fibrosis
  • Megaloblastic hematopoiesis
    • Folate deficiency
    • Vitamin B12 deficiency
  • Paroxysmal nocturnal hemoglobinuria, hemolytic anemia (dark urine), pancytopenia, and venous thrombosis (classically hepatic veins)
  • Systemic lupus erythematosus
  • Prolonged starvation or anorexia nervosa (bone marrow is gelatinous with loss of fat cells and increased ground substance)
  • Transient erythroblastopenia of childhood
  • Drug-induced agranulocytosis that may be reversible on withdrawal of drug.
  • Overwhelming infection
    • HIV with myelodysplasia
    • Viral hemophagocytic syndrome

DIAGNOSTIC TESTS & INTERPRETATION


Screening tests to exclude other etiologies  
  • CBC and absolute reticulocyte count
  • Blood smear exam
  • Cytogenetic studies of peripheral lymphocytes if <35 years of age to exclude Fanconi anemia
  • Liver function test
  • Viral serology: hepatitis A, B, C; EBV; cytomegalovirus (CMV); HIV
  • Vitamin B12 and folate levels
  • Autoantibody screening antinuclear antibody (ANA) and anti-DNA
  • Flow cytometry looking for glycosylphosphatidylinositol (GPI), negative neutrophils and RBCs for detecting paroxysmal nocturnal hemoglobinuria
  • Fetal hemoglobin in children
  • Red cell adenosine deaminase (pure red cell aplasia)
  • Cytogenetic analysis of bone marrow

Initial Tests (lab, imaging)
  • CBC: pancytopenia, anemia (usually normocytic), leukopenia, neutropenia, thrombocytopenia
  • Decreased absolute number of reticulocytes
  • Increased serum iron secondary to transfusion
  • Normal total iron-binding capacity (TIBC)
  • High mean corpuscular volume (MCV) >104
  • CD 34+ cells decreased in blood and marrow
  • Urinalysis: hematuria
  • Abnormal liver function tests (hepatitis)
  • Increased fetal hemoglobin (Fanconi)
  • Increased chromosomal breaks under specialized conditions (Fanconi)
  • Molecular determination of abnormal gene (Fanconi)
  • CT of thymus region if thymoma-associated RBC aplasia suspected
  • Radiographs of radius and thumbs (if congenital anemia suspected)
  • Renal ultrasound (to rule out congenital anemia or malignant hematologic disorder)
  • Chest x-ray to exclude infections such as mycobacterial infection

Diagnostic Procedures/Other
Bone marrow aspiration and biopsy  
Test Interpretation
  • Normochromic RBC
  • Bone marrow
    • Decreased cellularity (<10%): no fibrosis, no malignant cells seen
    • Decreased megakaryocytes
    • Decreased myeloid precursors
    • Decreased erythroid precursors
    • Prominent fat spaces and marrow stroma, polyclonal plasma cells

TREATMENT


Early treatment increases the chance of success. Two major options: immunosuppressive therapy (1) and hematopoietic stem cell transplantation. Treatment decisions are based on age of the patient, severity of disease, and availability of a human leukocyte antigen (HLA)-matched sibling donor for transplantation.  

GENERAL MEASURES


  • Supportive measures: RBC and platelet transfusions. Use only irradiated leuko-reduced or CMV-negative blood initially if patient is a candidate for hematopoietic stem cell transplantation.
  • Antibiotics, antifungals, antivirals when appropriate, especially if ANC <200 cells/μL
  • Oxygen therapy for severe anemia
  • Good oral hygiene
  • Control menorrhagia with norethisterone or oral contraceptive pills.
  • Avoid/discontinue causative agents/isolation if necessary.
  • HLA testing on all patients and their immediate families
  • Transfusion support (judiciously prescribed RBCs for severe anemia; platelets for severe thrombocytopenia)
    • Transfuse when
      • Hb <8 g/dL or if Hb <9 g/dL and symptomatic ± CHF (congestive heart failure)
      • Platelet count is <10 — 109 or if <20 — 109 with fever

MEDICATION


First Line
  • Corticosteroids (methylprednisolone) are often given with immunosuppressive regimens.
  • Immunosuppressive therapy (3)
    • A combination of antithymocyte globulin (ATG) plus cyclosporine. ATG eliminates lymphocytes, and cyclosporine blocks T-cell function.
  • ATG
    • Horse serum containing polyclonal antibodies against human T cells
    • First choice treatment for patients >40 years of age and for younger patients without a compatible donor. Consider in patients 30 to 40 years of age.
    • May be used as a single agent but has better response in combination with cyclosporine
  • Cyclosporine following initial ATG therapy for minimum of 6 months (4)
    • Monitor through blood levels. Normal values for assays vary.
    • Granulocyte-colony stimulating factor (G-CSF)
      • May be used in conjunction with ATG and cyclosporine
      • Shows faster neutrophil recovery but survival is not improved.
      • Treatment is costly and is disputed in two randomized trials.
    • Note: Relapses may occur after the initial response to the immunosuppressive therapy if cyclosporine is discontinued too early. Restarting cyclosporine can lead to a response in up to 25% of patients.
  • Stem cell transplant: matched sibling allogeneic stem cell transplant for age <20 years and absolute neutrophil count (ANC) <500 or age 20 to 40 years and ANC <200

Second Line
  • Rabbit ATG + cyclosporine
  • Campath
  • Androgen in a subset of patients who have anemia as a predominant feature
  • Matched unrelated donor stem cell transplant
  • Eltrombopag (5)
  • Clinical trials: thrombopoietin (TPO) receptor agonists (6): http://patientrecruitment.nhlbi.nih.gov/AplasticAnemia.aspx

SURGERY/OTHER PROCEDURES


  • First-line hematopoietic stem cell transplantation is recommended for patients with an HLA-identical donor and severe aplastic anemia when age <20 years and ANC <500 or age 20 to 40 years and ANC <200. Consider in patients 40 to 50 years of age in good general medical condition.
  • Patients >40 years of age have higher rates of graft versus host disease and graft rejection.
  • Unrelated donor transplants should be considered for patients age <40 years without HLA-matched sibling donor who failed first-line immunosuppressive therapy.
  • Thymectomy for thymoma

INPATIENT CONSIDERATIONS


Nursing
If neutropenic, use antiseptic mouthwash such as chlorhexidine.  

ONGOING CARE


DIET


If neutropenic, avoid foods that can expose patient to bacteria, such as uncooked foods.  

PATIENT EDUCATION


  • Stay away from people who are sick; avoid large crowds.
  • Wash your hands often.
  • Brush and floss your teeth; get regular dental care to reduce risk of infections.
  • Pneumonia vaccine and annual flu shot.
  • Printed patient information available from Aplastic Anemia & MDS International Foundation, Inc., 800-747-2828. Web site: http://www.aamds.org/aplastic

PROGNOSIS


  • Hematopoietic stem cell transplantation with HLA-matched sibling
    • Age <16 years, 91% at 5 years
    • Age >16 years, 70-80% at 5 years
  • Immunosuppressive therapy using ATG and cyclosporine: overall survival of 75%; 90% among responders at 5 years

COMPLICATIONS


  • Infection (fungal, sepsis)
  • Graft versus host disease in bone marrow transplant recipients (acute 18%; chronic 26%)
  • Side effects of immunosuppressant medications
  • Hemorrhage
  • Transfusion hemosiderosis
  • Transfusion hepatitis
  • Heart failure
  • Development of secondary cancer: leukemia or myelodysplasia (15-19% risk at 6 to 10 years)
  • Refractory pancytopenia

REFERENCES


11 Bacigalupo  A, Passweg  J. Diagnosis and treatment of acquired aplastic anemia. Hematol Oncol Clin North Am.  2009;23(2):159-170.22 Townsley  DM, Desmond  R, Dunbar  CE, et al. Pathophysiology and management of thrombocytopenia in bone marrow failure: possible clinical applications of TPO receptor agonists in aplastic anemia and myelodysplastic syndromes. Int J Hematol.  2013;98(1):48-55.33 Brodsky  RA, Jones  RJ. Aplastic anaemia. Lancet.  2005;365(9471):1647-1656.44 Bueno  C, Roldan  M, Anguita  E, et al. Bone marrow mesenchymal stem cells from patient with aplastic anemia maintain functional and immune properties and do not contribute to the pathogenesis of the disease. Haematologica.  2014;99(7):1168-1175.55 Desmond  R, Townsley  DM, Dunbar  C, et al. Eltrombopag in aplastic anemia. Semin Hematol.  2015;52(1):31-37.66 Scheinberg  P, Young  NS. How I treat acquired aplastic anemia. Blood.  2012;120(6):1185-1196.

SEE ALSO


  • Myelodysplastic Syndromes; Lupus Erythematosus, Systemic (SLE)
  • Algorithm: Anemia

CODES


ICD10


  • D61.9 Aplastic anemia, unspecified
  • D61.89 Oth aplastic anemias and other bone marrow failure syndromes
  • D61.01 Constitutional (pure) red blood cell aplasia
  • D61.1 Drug-induced aplastic anemia
  • D61.2 Aplastic anemia due to other external agents
  • D61.09 Other constitutional aplastic anemia
  • D60.9 Acquired pure red cell aplasia, unspecified
  • D61.3 Idiopathic aplastic anemia

ICD9


  • 284.9 Aplastic anemia, unspecified
  • 284.89 Other specified aplastic anemias
  • 284.01 Constitutional red blood cell aplasia
  • 284.09 Other constitutional aplastic anemia
  • 648.20 Anemia of mother, unspecified as to episode of care or not applicable
  • 284.81 Red cell aplasia (acquired)(adult)(with thymoma)

SNOMED


  • 306058006 Aplastic anemia (disorder)
  • 55907008 Acquired aplastic anemia
  • 28975000 Constitutional aplastic anemia (disorder)
  • 267527002 Aplastic anemia due to drugs (disorder)
  • 191247005 Aplastic anemia due to radiation (disorder)

CLINICAL PEARLS


  • Acquired aplastic anemia has an insidious onset, and is caused by an exogenous insult triggering an autoimmune reaction. This form is usually responsive to immunosuppressive therapy.
  • Immunosuppressive therapy using ATG and cyclosporine: overall survival of 75%; 90% among responders at 5 years
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