Aplastic anemia (AA) is a life-threatening bone marrow failure syndrome characterized by pancytopenia and a hypocellular bone marrow, in the absence of marrow infiltration or fibrosis.

AA results from destruction or suppression of hematopoietic stem cells, leading to reduced production of red blood cells, white blood cells, and platelets.

The condition may be:

• Acquired (most common; often immune-mediated)

• Inherited (e.g., Fanconi anemia)

Common acquired causes include:

• Drugs (e.g., chloramphenicol, chemotherapy, antiepileptics)

• Viral infections (especially hepatitis, EBV, HIV, parvovirus B19)

• Autoimmune disorders

• Pregnancy

• Radiation exposure

• Idiopathic (majority of cases)

Splenomegaly is typically absent, and its presence suggests alternative diagnoses.

Pathophysiology

Most acquired AA is immune-mediated, involving cytotoxic T-cell destruction of hematopoietic stem cells.

Key mechanisms:

• Reduced stem cell number

• Increased apoptosis

• Elevated interferon-γ and TNF-α

• Bone marrow replaced by fat

Risk Factors

• Exposure to myelotoxic drugs (e.g., chloramphenicol)

• Viral hepatitis

• Connective tissue diseases

• Radiation

• Pregnancy

• Chemical exposure (benzene)

• Family history (inherited syndromes)

Clinical Presentation

Symptoms depend on severity and degree of cytopenia.

A. Anemia

• Fatigue

• Pallor

• Dyspnea on exertion

• Tachycardia

B. Thrombocytopenia

• Easy bruising

• Petechiae

• Epistaxis

• Gum bleeding

C. Neutropenia

• Recurrent infections

• Fever

• Sepsis

⚠ Splenomegaly is not a feature and suggests another cause (e.g., leukemia).

Diagnostic Criteria

Diagnosis requires:

1. Peripheral pancytopenia

2. Bone marrow hypocellularity

3. Exclusion of other causes

Bone Marrow Findings

• <30% hematopoietic cellularity (children/young adults)

• Fatty replacement

• No malignant infiltration

Confirmed by bone marrow trephine biopsy.

Classification by Severity

Severe Aplastic Anemia (SAA)

At least two of the following:

• Reticulocytes <60 × 10⁹/L (automated) or <20 × 10⁹/L (manual)

• Platelets <20 × 10⁹/L

• Absolute neutrophil count (ANC) <0.5 × 10⁹/L

Very Severe Aplastic Anemia (vSAA)

• Same as SAA

• ANC <0.2 × 10⁹/L

Moderate Aplastic Anemia

• Does not meet criteria for SAA

Investigations

A. Laboratory Tests

• Complete blood count (pancytopenia)

• Reticulocyte count (low)

• Peripheral blood smear

• Liver function tests

• Viral serology (hepatitis, HIV, EBV)

B. Bone Marrow Examination

• Aspirate and trephine biopsy

• Hypocellular marrow

C. Additional Tests

• Flow cytometry for PNH clone

• Cytogenetic analysis

• Autoimmune screening

Management

All patients should be referred to a tertiary hematology center.

A. Non-Pharmacological (Supportive) Management

• Irradiated, leukodepleted RBC transfusion when Hb <7 g/dL

• Platelet transfusion if bleeding or <10 × 10⁹/L

• Broad-spectrum antibiotics for febrile neutropenia

• Neutropenic precautions (mask, isolation)

• Avoid NSAIDs and intramuscular injections

B. Definitive Treatment

1. Hematopoietic Stem Cell Transplantation (HSCT)

• First-line for patients <40–50 years with matched sibling donor

• Curative therapy

• Best outcomes in younger patients

2. Immunosuppressive Therapy (IST)

Indicated when HSCT not available.

• Anti-thymocyte globulin (ATG)

  • 40 mg/kg/day IV for 4 days

• Cyclosporine

  • 3–7 mg/kg/day for at least 6 months

• Methylprednisolone

  • 5–10 mg/kg/day short course (to prevent serum sickness)

Combination ATG + Cyclosporine is standard first-line IST.

3. Additional Therapies

• Eltrombopag (thrombopoietin receptor agonist)

• G-CSF (selected cases)

• Androgens (Danazol) in limited-resource settings

Complications

• Severe infection

• Hemorrhage

• Clonal evolution to MDS or AML

• Paroxysmal nocturnal hemoglobinuria (PNH)

Prognosis

• Untreated severe AA has high mortality

• 5-year survival with HSCT >80% in young patients

• Response to IST in ~60–70% of cases

Prevention

• Avoid known myelotoxic drugs

• Limit radiation exposure

• Early treatment of viral hepatitis

• Genetic counseling in inherited cases

Referral

Immediate referral to tertiary hematology center is essential for:

• Bone marrow biopsy

• Transplant evaluation

• Advanced supportive care