Overview
Definition:
Aplastic anemia (AA) is a rare, life-threatening condition characterized by bone marrow failure, resulting in pancytopenia (deficiency of all three blood cell lines: red blood cells, white blood cells, and platelets)
In pediatrics, it can be acquired or inherited.
Epidemiology:
The incidence in children is estimated to be 2-5 per million per year
Acquired AA is more common than inherited forms
It can occur at any age but has bimodal peaks in childhood and late adulthood.
Clinical Significance:
Aplastic anemia is a critical pediatric emergency due to the high risk of severe infections, hemorrhage, and eventual death if not promptly diagnosed and managed
Early identification and appropriate referral for bone marrow transplantation (BMT) are crucial for survival.
Clinical Presentation
Symptoms:
Pallor and fatigue due to anemia
Recurrent or persistent infections, often severe, due to neutropenia
Bleeding manifestations such as petechiae, purpura, epistaxis, gingival bleeding, or menorrhagia due to thrombocytopenia
Fever, especially if unexplained.
Signs:
Pallor of conjunctivae and skin
Petechiae, ecchymoses, or signs of active bleeding
Signs of infection (e.g., pharyngitis, pneumonia)
Splenomegaly or hepatomegaly are uncommon in acquired AA but may be present in inherited syndromes.
Diagnostic Criteria:
The International Bone Marrow Transplant Registry (IBMTR) criteria for severe aplastic anemia (SAA) require: Peripheral blood counts: absolute neutrophil count (ANC) < 500/µL, platelet count < 20,000/µL, and corrected reticulocyte count < 1% (or absolute reticulocyte count < 10^9/L)
Bone marrow biopsy showing <25% cellularity or <10% residual hematopoiesis
Absence of significant myelodysplasia or overt leukemia by morphology.
Diagnostic Approach
History Taking:
Detailed birth history (congenital anomalies, consanguinity)
Family history of blood disorders, infections, or bone marrow failure
Exposure to toxins, drugs (e.g., chloramphenicol, anticonvulsants), or radiation
History of recent viral illnesses (e.g., parvovirus B19, Epstein-Barr virus, hepatitis)
Timeline of symptom onset and progression
Prior blood transfusions and reactions.
Physical Examination:
Complete blood count (CBC) with differential and peripheral blood smear for morphology
Review for pallor, petechiae, ecchymoses, signs of infection
Assess for congenital anomalies (e.g., thumb abnormalities, short stature, café-au-lait spots, radial ray anomalies), which may suggest inherited syndromes
Check for signs of liver disease or cardiac defects.
Investigations:
Complete Blood Count (CBC) with peripheral smear: Pancytopenia with normocytic, normochromic anemia, absent reticulocytes, neutropenia, and thrombocytopenia
Bone Marrow Aspiration and Biopsy: Essential for diagnosis
Should show marked hypocellularity (<25% cellularity) with replacement by fatty marrow, and absence of significant blasts or dysplastic features
Cytogenetics and FISH: To rule out chromosomal abnormalities suggestive of malignancy or inherited syndromes
Flow cytometry: To rule out paroxysmal nocturnal hemoglobinuria (PNH) or other clonal disorders
Viral serologies: EBV, CMV, Hepatitis A, B, C, parvovirus B19, HIV
Other specific tests for inherited syndromes: e.g., genetic testing for Fanconi anemia (FA) or Shwachman-Diamond syndrome (SDS)
Liver function tests, renal function tests, electrolytes
Chest X-ray and ECG to assess for associated anomalies or complications.
Differential Diagnosis:
Severe aplastic anemia vs
Myelodysplastic syndromes (MDS) in children
Bone marrow infiltration by leukemia or lymphoma
Severe nutritional deficiencies (e.g., Vitamin B12, folate)
Transient erythroblastopenia of childhood (TEC)
Megaloblastic anemia
Acute infections causing transient bone marrow suppression
Inherited bone marrow failure syndromes (e.g., Fanconi anemia, Shwachman-Diamond syndrome, Dyskeratosis congenita)
Paroxysmal nocturnal hemoglobinuria (PNH) - can be a clone arising in aplastic anemia.
Management
Initial Management:
Immediate hospitalization and isolation precautions
Aggressive supportive care: Red blood cell transfusions (leukoreduced, CMV-negative, irradiated) for symptomatic anemia
Platelet transfusions (preferable with HLA-matched donors for those anticipating BMT) for active bleeding or platelet count <10,000-20,000/µL
Broad-spectrum antibiotics for fever or suspected infection
Antifungal and antiviral prophylaxis as indicated.
Medical Management:
Immunosuppressive therapy (IST): For SAA/VSAA not immediately eligible for BMT
Standard regimen includes cyclosporine A (CSA) and corticosteroids (e.g., prednisolone)
Eltrombopag, a thrombopoietin receptor agonist, is increasingly used in combination with IST, showing good response rates and possibly delaying or avoiding BMT in some patients
Dose of CSA: 3-5 mg/kg/day divided every 12 hours
Dose of Eltrombopag: starting 50 mg/day, titrate up to 150 mg/day.
Transplant Referral:
Hematopoietic stem cell transplantation (HSCT) is the treatment of choice for SAA and very severe aplastic anemia (VSAA), especially in younger patients with a matched sibling donor
Referral to a specialized pediatric BMT center should occur as soon as the diagnosis is confirmed
Timing of referral depends on the severity of AA and donor availability
Unrelated donor searches are initiated if no matched sibling donor is available
GVHD prophylaxis is crucial post-transplant.
Supportive Care:
Meticulous hygiene
Prophylaxis against Pneumocystis jirovecii pneumonia (PJP) with trimethoprim-sulfamethoxazole
Monitoring of vital signs, fluid balance, and signs of infection
Nutritional support
Psychological support for the child and family.
Complications
Early Complications:
Severe infections (sepsis, pneumonia, fungal infections)
Hemorrhage (gastrointestinal, intracranial, pulmonary)
Transfusion reactions
Graft-versus-host disease (GVHD) if BMT is performed.
Late Complications:
Relapse of aplastic anemia
Development of myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) after IST or in the long-term survivors of BMT
Chronic GVHD
Infertility post-BMT
Complications related to long-term immunosuppression.
Prevention Strategies:
Prompt and appropriate antibiotic management for infections
Judicious use of blood products
Strict adherence to infection control protocols
Careful monitoring for signs of relapse or secondary malignancies
Counseling regarding reproductive health for survivors.
Prognosis
Factors Affecting Prognosis:
Severity of aplastic anemia (SAA vs
VSAA)
Age of the patient
Availability and match of a hematopoietic stem cell donor
Response to immunosuppressive therapy
Presence of congenital anomalies
Complications such as severe infections or hemorrhage.
Outcomes:
With allogeneic HSCT from a matched sibling donor, survival rates can be as high as 80-90%
Response rates to IST vary, with a significant proportion achieving hematologic recovery, while others may require BMT or have poorer outcomes
Long-term survival for responders to IST is generally good, but risk of secondary malignancies exists.
Follow Up:
Long-term follow-up is essential for all patients with aplastic anemia, whether treated with IST or BMT
This includes regular blood counts, monitoring for infections, screening for MDS/AML, assessment of growth and development, and evaluation for late complications of therapy and potential infertility.
Key Points
Exam Focus:
Key features of aplastic anemia: pancytopenia, hypocellular marrow, reticulocytopenia
Differentiate acquired vs
inherited causes
Recognize criteria for SAA/VSAA
Understand the role of IST (cyclosporine, eltrombopag) and HSCT
DNB/NEET SS questions often focus on diagnostic workup and immediate management of pancytopenia.
Clinical Pearls:
Always consider inherited bone marrow failure syndromes in young children with aplastic anemia, looking for dysmorphic features and family history
Early referral for BMT is critical for eligible patients
Be aware of the evolving role of eltrombopag in IST regimens.
Common Mistakes:
Misdiagnosing aplastic anemia as acute leukemia or MDS based on initial smear findings without a bone marrow biopsy
Delaying referral for BMT
Inadequate supportive care, especially prompt antibiotic administration for febrile neutropenia
Forgetting to investigate for inherited syndromes in young children.