Overview
Definition:
Idiopathic aplastic anemia (SAA) is a rare, life-threatening condition characterized by bone marrow failure, resulting in pancytopenia (deficiency of all three blood cell types: red blood cells, white blood cells, and platelets)
In most cases, it is immune-mediated, where the body's immune system mistakenly attacks and destroys hematopoietic stem cells.
Epidemiology:
While SAA can occur at any age, it is more common in adolescents and young adults
The incidence varies geographically, but it is estimated to be around 1-6 cases per million per year
In pediatrics, acquired SAA is less common than inherited bone marrow failure syndromes, but it remains a significant cause of severe cytopenias.
Clinical Significance:
SAA presents a critical diagnostic and therapeutic challenge due to its high mortality rate if untreated
Prompt recognition and appropriate management are crucial for improving survival and quality of life in affected children
The decision between immunosuppressive therapy (IST) and allogeneic hematopoietic stem cell transplantation (HSCT) is pivotal and depends on multiple factors.
Clinical Presentation
Symptoms:
Pallor and fatigue due to anemia
Recurrent infections and fever due to neutropenia
Bleeding manifestations such as petechiae, purpura, epistaxis, and gingival bleeding due to thrombocytopenia
Bone pain may also be present.
Signs:
Pale conjunctivae and skin
Tachycardia
Fever
Bruising and petechiae
Splenomegaly is uncommon but can be present in some cases
Signs of infection.
Diagnostic Criteria:
Severe aplastic anemia (SAA) is typically diagnosed based on meeting specific criteria: severe anemia (hemoglobin < 10 g/dL), severe neutropenia (absolute neutrophil count < 0.5 x 10^9/L), severe thrombocytopenia (platelet count < 20 x 10^9/L), and peripheral blood stem cell count < 20% of normal
Bone marrow biopsy showing profound hypocellularity (<25% of normal cellularity, or <10% if trilineage dysphasia is present) with replacement by fat, and absence of significant reticulin fibrosis or malignant infiltration.
Diagnostic Approach
History Taking:
Detailed history should include recent viral illnesses, exposure to toxins (e.g., pesticides, benzene, certain medications like chloramphenicol), radiation exposure, family history of bone marrow failure or autoimmune disorders, and a history of drug intake
Recent blood transfusions and any prior treatment should be noted.
Physical Examination:
Comprehensive physical examination focusing on signs of anemia (pallor), infection (fever, pharyngeal erythema), and bleeding (petechiae, purpura, hematomas)
Examination of lymph nodes and liver for enlargement, although these are less common in typical SAA
Neurological examination for any signs of central nervous system bleeding.
Investigations:
Complete blood count (CBC) with differential and reticulocyte count to assess pancytopenia
Peripheral smear review for morphology of blood cells and to exclude dysplastic changes
Bone marrow aspiration and biopsy for cellularity, morphology, and to rule out other causes of marrow failure
Cytogenetic analysis and molecular studies on bone marrow aspirate to identify potential constitutional marrow failure syndromes or acquired abnormalities
HLA typing for potential stem cell transplant donors
Serological tests for viral hepatitis (A, B, C, E), parvovirus B19, EBV, CMV, and HIV to rule out secondary causes
Autoimmune markers (ANA, ESR, CRP) may be helpful in select cases.
Differential Diagnosis:
Inherited bone marrow failure syndromes (e.g., Fanconi anemia, Diamond-Blackfan anemia, dyskeratosis congenita)
Myelodysplastic syndromes (MDS)
Acute leukemia
Paroxysmal nocturnal hemoglobinuria (PNH) can present with aplasia
Viral infections (e.g., hepatitis, parvovirus B19)
Drug-induced bone marrow suppression
Nutritional deficiencies (e.g., severe B12/folate deficiency, though rare causes of pancytopenia).
Management
Initial Management:
Immediate supportive care is paramount
This includes prophylactic antibiotics to prevent infections, isolation precautions for neutropenic patients, platelet transfusions for active bleeding or platelet count < 10-20 x 10^9/L, and red blood cell transfusions to maintain hemoglobin levels (e.g., >7-8 g/dL).
Medical Management:
Immunosuppressive therapy (IST) is the mainstay of treatment for patients not eligible for immediate HSCT
The standard IST regimen typically includes cyclosporine (or tacrolimus) combined with corticosteroids (e.g., prednisolone)
Eltrombopag, a thrombopoietin receptor agonist, has shown efficacy in improving hematological response and survival, often added to standard IST, especially for refractory cases
Antithymocyte globulin (ATG) is also used, often in combination with corticosteroids and cyclosporine
Dosages for cyclosporine: 3-5 mg/kg/day, for prednisolone: 1 mg/kg/day
Eltrombopag: initial dose 50 mg/day, adjusted based on response.
Transplant Management:
Allogeneic hematopoietic stem cell transplantation (HSCT) is the preferred curative option for younger patients (typically < 40-50 years) with a matched sibling donor (MSD)
For patients without an MSD, matched unrelated donors (MUD) or alternative donors like haploidentical donors can be considered
The conditioning regimen and immunosuppression post-transplant are crucial to prevent graft-versus-host disease (GVHD) and graft rejection
Early transplant in SAA is associated with better outcomes.
Supportive Care:
Meticulous infection control and monitoring
Early detection and management of infections with appropriate antibiotics, antifungals, and antivirals
Regular monitoring of blood counts and organ function
Nutritional support and management of psychological distress
Management of iron overload if multiple transfusions are required.
Complications
Early Complications:
Severe infections (sepsis, pneumonia, fungal infections) leading to organ damage or death
Hemorrhagic complications (intracranial, gastrointestinal)
Graft failure or rejection post-transplant
Graft-versus-host disease (GVHD) post-transplant.
Late Complications:
Myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) transformation (increased risk after IST or HSCT)
PNH clone development
Chronic GVHD
Infertility (especially post-HSCT).
Prevention Strategies:
Judicious use of prophylactic antibiotics and antifungals
Prompt recognition and aggressive treatment of infections
Careful monitoring of transfusion support
Careful donor selection and conditioning regimens for HSCT
Judicious use of immunosuppression post-transplant to minimize GVHD while preventing rejection.
Prognosis
Factors Affecting Prognosis:
Severity of pancytopenia at diagnosis
Age of the patient (younger patients tend to have better outcomes)
Availability of a matched donor for HSCT
Response to initial IST
Presence of PNH clone (larger clones are associated with better outcomes)..
Outcomes:
With modern management, including HSCT and improved IST regimens with eltrombopag, survival rates for SAA have significantly improved
Survival rates for HSCT from an MSD can exceed 80-90%
Response to IST varies, but can achieve durable remissions in a significant proportion of patients
Untreated SAA has a very poor prognosis.
Follow Up:
Long-term follow-up is essential for all patients
This includes regular hematological monitoring for relapse or transformation to MDS/AML
Monitoring for chronic GVHD and other complications of HSCT
Surveillance for PNH clone development
Regular assessment of growth and development in pediatric survivors.
Key Points
Exam Focus:
Distinguish SAA from inherited bone marrow failure syndromes and other causes of pancytopenia
Understand the criteria for SAA
Key components of IST (cyclosporine, steroids, eltrombopag) and their indications
Indications for HSCT in pediatric SAA (age, donor availability, severity)
Potential complications of IST and HSCT (infections, GVHD, transformation).
Clinical Pearls:
Always consider inherited causes in young children with aplastic anemia
Early referral to a specialized center for bone marrow transplant evaluation is crucial
Eltrombopag has revolutionized the treatment of SAA, improving response rates with IST
Monitor for iron overload in transfused patients
Be vigilant for infections in neutropenic patients.
Common Mistakes:
Delaying HSCT referral in eligible patients
Inadequate supportive care (especially infection prophylaxis and management)
Misinterpreting bone marrow biopsy findings
Not considering inherited syndromes in the differential diagnosis
Underestimating the risk of MDS/AML transformation after IST.