ANEMIA, APLASTIC

ANEMIA, APLASTIC - Angie N. Ross, MD
BASICS
DESCRIPTION
• Aplastic anemia is defined as pancytopenia and hypocellular bone marrow in the absence of abnormal cell infiltrate. The 2 forms of aplastic anemia include congenital and acquired.
• Congenital forms are seen mainly in the pediatric population and are associated with physical manifestations. The exception is an atypical presentation of Fanconi syndrome later in adult life, up to the 30s in males and up to 48 years in females.
• Acquired aplastic anemia has an insidious onset and is caused by exogenous insult triggering an autoimmune reaction. This form is usually responsive to immunosuppressive agents.
• System(s) affected: Hemic/lymphatic/immunologic
• Synonym(s): Hypoplastic anemia; Panmyelophthisis; Refractory anemia; Aleukia hemorrhagica; Toxic paralytic anemia
ALERT
• Prednisolone should not be used in treatment of patients with aplastic anemia (1)[C]
• Hematopoietic growth factors should not be used without close supervision in newly diagnosed patients (1)[C]
Geriatric Considerations
The elderly are more exposed to large numbers of drugs and, therefore, are more susceptible to secondary aplastic anemia.
Pediatric Considerations
• Congenital aplastic anemia requires a different treatment regimen (1)[B]
• Idiopathic aplastic anemia is more common in adolescents.
• Secondary aplastic anemia is seen in children exposed to ionizing radiation or treated with cytotoxic chemotherapeutic agents.
Pregnancy Considerations
Pregnancy may be rarely associated with aplastic anemia. Symptoms usual resolve after delivery. Supportive care is the mainstay and platelet count should be maintained above 20  109/L with platelet transfusion.
GENERAL PREVENTION
• Avoid possible toxic industrial agents.
• Use safety measures when working with radiation.
EPIDEMIOLOGY
• Predominant age
- Congenital: Children and young adults
- Acquired: Biphasic 10-25 and >60
• Predominant sex: Male = Female
Incidence
• 2 new cases per million in Europe and North America.
• The incidence is 3-fold in Thailand and China, when compared to the Western world
RISK FACTORS
• Viral illness/ Immunocompromised
• Toxin exposure
• Tumors of thymus (red cell aplasia)
Genetics
• A small number of patients with acquired and congenital forms have been found to have telomerase mutations. Mutations render carriers more susceptible to environmental insults to replicating stem cells. HLA-DR2 is twice as frequent than in the normal population.
• Autosomal recessive in congenital form
PATHOPHYSIOLOGY
• Injury to pluripotent stem cells causing markedly reduced hematopiesis and replacement of bone marrow by fat cells
• Current hypothesis supports stem cell destruction caused by activated autoimmune lymphocytes. Activation can arise from several causes mentioned below.
• Patients have high levels of interferon- gamma and fewer natural killer cells.
• Intact stromal function with normal to increased levels of cytokines and erythropoietin.
ETIOLOGY
• Idiopathic (~50% of the cases)
• Drugs (antibiotics, antirheumatics, anticonvulsants, chemotherapeutics, NSAIDs, sulfonamides.)
• Viral (HIV; EBV; postinfectious hepatitis-nonA, B, or C; parvovirus B19, mostly in the immunocompromised; atypical mycobacterium)
• Toxic exposure (benzene, pesticides, arsenic)
• Radiation exposure
• Immune disorders(systemic lupus erythematous, eosinophilic fascitis, graft versus host disease)
• Pregnancy (rare)
• Congenital (Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond syndrome, amegakaryocytic thrombocytopenia)


DIAGNOSIS
SIGNS AND SYMPTOMS
History
Recurrent infections
Physical Exam
• Mucosal hemorrhage, petechiae
• Pallor
• Fatigue, fever
• Hemorrhage, menorrhagia, occult stool blood, melena, epistaxis
• Dyspnea
• Palpitations
• Progressive weakness
• Retinal flame hemorrhages
• Systolic ejection murmur
• Weight loss
• Congenital
- Short stature
- Microcephaly
- Radius and thumb anomalies
- Renal anomalies
- Skeletal anomalies
- Hyperpigmentation (cafe au lait spots)
- leukoplakia
TESTS
• Screening test to exclude other etiologies
• CBC and reticulocyte count
• Blood smear examination
- Cytogenetic studies of peripheral lymphocytes if 35 to exclude fanconi anemia
- Liver function test
- Viral serology: Hepatitis A, B, C, EBV, CMV, HIV
- Vitamin B12 and folate levels
- Autoantibody screening ANA and anti-DNA
- Flow cytometry or Ham test for PNH
- Fetal hemoglobin in children
- Red cell adenosine deaminase (pure red cell aplasia)
- Cytogenetic analysis of bone marrow
Lab
• Pancytopenia
• Anemia
• Leukopenia
• Neutropenia
• Thrombocytopenia
• Decreased reticulocytes
• Increased serum iron secondary to transfusion
• Normal total iron binding capacity (TIBC)
• Borderline high mean corpuscular volume (MCV) >104
• CD 34+ cells decreased in blood and marrow
• Hematuria
• Abnormal liver function tests (hepatitis)
• Increased fetal hemoglobin (Fanconi)
• Increased chromosomal breaks under specialized conditions (Fanconi)
• Molecular determination of abnormal gene (Fanconi)
Imaging
• CT of thymus region if thymoma-associated RBC aplasia suspected
• Radiographs of radius and thumbs (congenital anemia)
• Renal ultrasound (to rule out congenital anemia or malignant hematological disorder)
• Chest radiograph to exclude infection such as mycobacterial
Diagnostic Procedures/Surgery
Bone marrow aspirate and trephine biopsy
Pathological Findings
• Normochromic RBC
• Bone marrow
- Decreased cellularity (10%)
- Decreased megakaryocytes
- Decreased myelocytes
- Decreased erythroid precursors
- Prominent fat spaces
- Prominent lymphocytes, macrophages and plasma cells
DIFFERENTIAL DIAGNOSIS
• Myelodysplastic disorders and acute myeloid leukemia; dysplastic cells of the granulocytic and megakaryocytic lineages, blast cells in the marrow
• Paroxysmal nocturnal hemoglobinuria, hemolytic anemia (dark urine), pancytopenia venous thrombosis (classically hepatic veins)
• Acute lymphoblastic leukemia-neutropenia more pronounced than pancytopenia, may have an increase in reticulin in the bone marrow
• Hairy cell leukemia; increased reticulin and infiltration of hairy cells
• Systemic lupus erythematosus
• Lymphomas; gene rearrangements
• Prolonged starvation or anorexia nervosa; bone marrow is gelatinous with loss of fat cells and increased ground substance
• Transient erythroblastopenia of childhood
TREATMENT
STABILIZATION
Inpatient. Referral to an institution that has experience in treating these patients is recommended.
GENERAL MEASURES
• Supportive measures: RBC and platelet transfusions. Use only CMV negative blood initially if patient is candidate for BMT.
• Oxygen therapy for severe anemia
• Good oral hygiene
• Control menorrhagia with norethisterone
• Avoid causative agents/isolation if necessary
• Human leukocyte antigen (HLA) testing on all patients and their immediate families
• Transfusion support (judiciously prescribed RBCs for severe anemia, consider leukocyte depleted units; platelets for severe thrombocytopenia; WBCs)
- Transfuse when platelet count is 10  109 or if 20  109 with fever (1)[C]
• Immunosuppressive therapy (antithymocyte globulin [ATG] and cyclosporine) if no suitable donor
Diet
No special diet, but nutritious diet is important to improve resistance to infection.
Activity
Isolation procedures if neutropenic in addition to prophylactic antibiotic and antifungal
Nursing
If neutropenic, use antiseptic mouthwash such as chlorhexidine and give food low in bacterial content.
MEDICATION (DRUGS)
• Antithymocyte globulin (ATG):
- A horse serum containing polyclonal antibodies against human T cells. Skin test patients to determine any hypersensitivity.
- Treatment for patients >40 and patient without a compatible donor. Consider in patients 30-40.
- May be used as a single agent or in combination with cyclosporine. Increased efficacy with combination for children and patients with absolute neutropenia.
• Cyclosporine following initial ATG therapy for minimum of 6 months
- Monitor through blood levels. Normal values for assays vary.
- A 3-6 month trial may be necessary.
• Androgens
- Clinical trials are inconclusive.
- Useful for some patients lacking other options and less severe patients
• Oxymetholone: 1-2 mg/kg/d PO
- A 2-3 month trial is usually necessary to assess the response.
• Prednisone for pure red cell anemia
• Note: Relapses may occur after the initial response to the immunosuppressive therapy if cyclosporine is discontinued too early.
SURGERY
• Bone marrow transplantation for patients with severe aplastic anemia and an HLA-identical donor, 30 years old. Consider in patients 30-40 in good general medical condition
- Bone marrow stem cells and not mobilized peripheral stem cells should be used (B)
• Patients >40 have higher rates of graft versus host disease and graft rejection compared with children. Conditioning regimens are also poorly tolerated by older patients
• Unrelated donor transplants, if other therapy fails and/or 16 without HLA-matched sibling.
• Thymectomy for thymoma
FOLLOW-UP
PROGNOSIS
• Bone marrow transplantation with HLA-matched sibling: Long-term survival 75-80%
• Immunosuppressive therapy using ATG and cyclosporin: 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 leukemia or myelodysplasia (15-19% risk at 6-10 years
• Refractory pancytopenia
PATIENT MONITORING
Close monitoring for all treatments is recommended. Drugs and other forms of treatment have numerous and severe side effects.
REFERENCES
1. Marsh Ball, et al. Guidelines for diagnosis and treatment of acquired aplastic anemia. Br J Haematol. 2003;123(5):782-801.
2. Young, Abkowitz, Luzzatto. New insights into the pathophysiology of acquired aplastic anemia. Hematology. 2000;18-38.
3. Young NS. Acquired aplastic anemia. Ann Intern Med. 2002;136(7):534-546.