Aplastic Anemia

Definition and classification

• Characterized by marked decrease or absolute absence of blood-forming elements.
• Results in peripheral pancytopenia coupled with hypoplastic or aplastic bone marrow.
• Classified by severity based on peripheral blood counts and marrow cellularity.

Severity classification criteria

Category	Bone marrow cellularity	Cytopenia criteria (requires at least two)
Severe	Less than 25-30%	Granulocytes less than 500 per microliter; Platelets less than 20,000 per microliter; Reticulocytes less than 20,000 per microliter (or less than 1% corrected)
Very severe	Less than 25-30%	Meets severe criteria plus granulocytes strictly less than 200 per microliter
Moderate	Greater than 30%	Hypoplastic marrow not meeting criteria for severe disease

Etiopathogenesis

Pathophysiologic mechanisms

• Results from immunologically mediated, tissue-specific, organ-destructive mechanism.
• Exposure to inciting antigen triggers immune cascade.
• Cytotoxic T lymphocytes undergo clonal expansion.
• Activated T cells secrete gamma-interferon and tumor necrosis factor.
• Cytokines potently inhibit early and late hematopoietic progenitor cells.
• Cell killing mediated primarily through apoptosis pathways.
• Abnormal telomere length and telomerase activity observed in granulocytic precursors.
• Somatic genetic variants identified in telomere complex genes, Bcor, Piga, Dnmt3a, and Asxl1.

Etiologic factors

Category	Specific agents and associations
Idiopathic	Accounts for greater than 70% of acquired cases; immune-mediated.
Drugs (predictable)	Antineoplastic agents, alkylating agents, antimetabolites, benzene.
Drugs (idiosyncratic)	Chloramphenicol, antiepileptics, gold, nonsteroidal anti-inflammatory drugs, antithyroid medications.
Infectious	Seronegative hepatitis, Epstein-barr virus, Cytomegalovirus, Human immunodeficiency virus, Parvovirus b19.
Immunologic	Eosinophilic fasciitis, thymoma, systemic lupus erythematosus.

Clinical manifestations

• Onset typically gradual and insidious.
• Symptoms directly relate to specific cytopenias.
• Anemia manifests as progressive pallor, easy fatigability, weakness, loss of appetite, and high-output cardiac failure.
• Thrombocytopenia manifests as petechiae, ecchymoses, severe epistaxis, gastrointestinal hemorrhage, and hematuria.
• Leukopenia manifests as increased susceptibility to bacterial and fungal infections, oral ulcerations, and severe gingivitis responding poorly to antibiotics.
• Hepatosplenomegaly and lymphadenopathy generally strictly absent.
• Presence of organomegaly strongly suggests alternative malignant, rheumatologic, or metabolic diagnoses.

Laboratory investigations

Primary hematologic evaluation

• Hemoglobin: Normocytic or macrocytic, normochromic.
• Reticulocytes: Absolute reticulocytopenia.
• Leukocytes: Severe granulocytopenia.
• Platelets: Severe thrombocytopenia.
• Fetal hemoglobin: Mildly to moderately elevated.

Bone marrow evaluation

• Aspiration and trephine biopsy absolutely essential for diagnosis.
• Marked depression or total absence of hematopoietic precursor cells.
• Severe fatty tissue replacement.
• Residual cells consist primarily of reticulum cells, lymphocytes, plasma cells, and tissue mast cells.
• Megaloblastic changes frequently seen in residual erythroid precursors.

Specialized diagnostic testing

• Chromosome breakage assay (diepoxybutane or mitomycin c stimulation): Essential to exclude Fanconi anemia.
• Telomere length determination: Essential to exclude Dyskeratosis congenita.
• Flow cytometry (cluster of differentiation 55 and 59): Essential to exclude Paroxysmal nocturnal hemoglobinuria.
• Cytogenetics and fluorescent in situ hybridization: Essential to exclude hypoplastic Myelodysplastic syndrome.
• Viral serologies and polymerase chain reaction: Evaluate for hepatitis, Epstein-barr virus, Cytomegalovirus, Human immunodeficiency virus.

Differential diagnosis

Disease category	Distinguishing clinical and laboratory features
Inherited bone marrow failure	Fanconi anemia (skeletal anomalies, chromosome breakage), Dyskeratosis congenita (mucocutaneous triad, short telomeres), Shwachman-diamond syndrome (pancreatic insufficiency).
Myelodysplastic syndrome	Hypoplastic variant mimics aplasia; distinguished by clonal cytogenetic abnormalities, prominent dysplasia, and increased blast percentage.
Marrow infiltrative disease	Acute leukemia, neuroblastoma, osteopetrosis, myelofibrosis. Often present with leukoerythroblastic blood smear, bone pain, or organomegaly.
Paroxysmal nocturnal hemoglobinuria	Chronic intravascular hemolysis, hemoglobinuria, thrombosis, absent cluster of differentiation 59 on flow cytometry.
Infection-induced cytopenia	Transient erythroblastopenia of childhood, Parvovirus b19 aplastic crisis. Usually isolated red cell aplasia, spontaneous recovery.

Management

Supportive care

• Minimize transfusions to prevent alloimmunization and iron overload.
• Utilize strictly leukocyte-depleted, irradiated blood products.
• Avoid blood products from blood relatives to prevent sensitization against potential transplant donors.
• Single donor platelets preferred.
• Provide rigorous antimicrobial and antifungal therapy for febrile neutropenia.
• Suppress menses with oral contraceptives to prevent severe blood loss.
• Avoid medications impairing platelet function (aspirin, nonsteroidal anti-inflammatory drugs).

Definitive therapy algorithms

Hematopoietic stem cell transplant

• Treatment of absolute choice for severe and very severe disease when human leukocyte antigen-matched sibling donor available.
• Perform rapidly to avoid risks of prolonged neutropenia and transfusion sensitization.
• Offers 90% chance of long-term disease-free survival.
• Preparative regimens typically utilize cyclophosphamide, fludarabine, and antithymocyte globulin without radiation.
• Alemtuzumab-based conditioning shows preliminary success.

Immunosuppressive therapy

• Indicated for patients lacking matched sibling donor.
• Standard regimen includes horse antithymocyte globulin combined with cyclosporine a.
• Intravenous methylprednisolone administered concurrently to prevent severe serum sickness.
• Response rate approximately 60-70%.
• Median time to hematologic response approximates 6 months.
• Cyclosporine requires rigorous therapeutic drug monitoring (trough levels 200-400 nanograms per milliliter) and extremely slow tapering to prevent relapse.

Novel and adjunctive therapies

• Eltrombopag (thrombopoietin receptor agonist): Approved as first-line adjunctive therapy combined with standard immunosuppression for patients older than 2 years.
• Eltrombopag induces robust trilineage hematopoiesis in refractory disease.
• Granulocyte colony-stimulating factor: May accelerate initial neutrophil recovery but provides no overall survival advantage; prolonged use associated with malignant transformation risk.

Salvage therapy for refractory disease

• Matched unrelated donor stem cell transplant recommended for non-responders or relapsed patients.
• T-cell depleted haploidentical family donor transplant serves as viable alternative.
• High-dose cyclophosphamide utilized for non-transplant candidates failing immunosuppression.
• Alemtuzumab monotherapy demonstrates efficacy in relapsed settings.

Prognosis and complications

• Untreated severe disease carries 50% mortality within 6 months and greater than 75% overall mortality.
• Hemorrhage and severe sepsis represent primary causes of death.
• Immunosuppressive therapy carries 30-60% relapse rate upon medication discontinuation.
• Clonal evolution represents most severe long-term complication of immunosuppressive therapy.
• 10-40% of immunosuppression responders eventually develop Paroxysmal nocturnal hemoglobinuria, Myelodysplastic syndrome, or Acute myeloid leukemia.
• Transplant recipients experience excellent long-term survival but face risks of chronic graft-versus-host disease, gonadal dysfunction, and secondary solid tumors.