Clinical Subject Page

Aplastic Anemia (AA)

Aplastic Anemia (AA) is a rare, life-threatening bone marrow failure disorder characterized by pancytopenia and a markedly hypocellular bone marrow. It results from failure of hematopoietic stem cells to produce red blood cells, white blood cells, and platelets.

Also called

Bone Marrow Failure Syndrome

ICD-10

D61.9

Specialty

Hematology

Onset

Acute & Chronic

Reviewed

August 2026

Overview

Overview
Etiology & Risk Factors

Etiology & Risk Factors
Pathophysiology

Pathophysiology
Clinical Presentation

Clinical Presentation
History Taking

History Taking
Physical Examination

Physical Examination
Investigations

Investigations
Diagnosis

Diagnosis
Management

Management
Complications

Complications
Prognosis

Prognosis
Key Points / Clinical Pearls

Key Points / Clinical Pearls

Overview

Aplastic Anemia (AA) occurs when the bone marrow fails to produce adequate blood cells, leading to anemia, leukopenia, and thrombocytopenia (pancytopenia). Most acquired cases result from immune-mediated destruction of hematopoietic stem cells, although drugs, toxins, viral infections, radiation, and inherited disorders may also cause the disease.

Patients commonly present with fatigue, recurrent infections, and bleeding, while hepatosplenomegaly and lymphadenopathy are usually absent.

Teaching point Aplastic Anemia (AA) causes pancytopenia due to bone marrow failure, not peripheral destruction of blood cells.

Etiology & Risk Factors

Idiopathic (Most Common) cause of Aplastic Anemia (AA)

No identifiable cause
Thought to be immune-mediated

Drug-Induced

Chloramphenicol
Carbamazepine
Phenytoin
Sulfonamides
Methimazole
Chemotherapy agents

Chemical Exposure

Benzene
Organic solvents
Pesticides

Radiation

Ionizing radiation
Radiotherapy

Viral Infections

Hepatitis viruses
Epstein-Barr virus (EBV)
Cytomegalovirus (CMV)
HIV
Parvovirus B19

Autoimmune Diseases

Systemic lupus erythematosus
Other autoimmune disorders

Inherited Disorders

Fanconi anemia
Dyskeratosis congenita
Shwachman-Diamond syndrome

-Risk Factors for Aplastic Anemia (AA)

Exposure to toxic chemicals
Cytotoxic drugs
Radiation exposure
Viral infections
Autoimmune disease
Family history of inherited bone marrow failure syndromes

Pathophysiology

Immune-mediated destruction or direct injury of hematopoietic stem cells → marked reduction in bone marrow stem cell population → hypocellular bone marrow with fatty replacement → decreased production of erythrocytes, leukocytes, and platelets → pancytopenia → anemia causes fatigue, neutropenia predisposes to infections, and thrombocytopenia leads to bleeding.

Clinical Presentation

-Symptoms of Aplastic Anemia (AA)

Fatigue
Weakness
Shortness of breath
Dizziness
Fever
Recurrent infections
Easy bruising
Gum bleeding
Epistaxis
Prolonged bleeding
Menorrhagia

-Signs of Aplastic Anemia (AA)

Pallor
Petechiae
Purpura
Ecchymoses
Fever (if infection is present)

-Usually absent in Aplastic Anemia (AA):

Lymphadenopathy
Hepatomegaly
Splenomegaly

Important Note The absence of lymphadenopathy and splenomegaly helps distinguish Aplastic Anemia (AA) from leukemia and many other hematological disorders

History Taking

-Ask about:

Fatigue
Fever
Recurrent infections
Bleeding episodes
Easy bruising
Drug exposure
Occupational chemical exposure
Radiation exposure
Recent viral illness
Autoimmune disease
Previous chemotherapy

Physical Examination

-General Examination

Look for:

Pallor
Fever
Petechiae
Purpura
Ecchymoses

-Systemic Examination

Assess for:

Signs of infection
Mucosal bleeding

-Confirm absence of:

Lymphadenopathy
Hepatomegaly
Splenomegaly

Investigations

Complete Blood Count (CBC)

Typical findings:

Low hemoglobin
Low white blood cell count
Low neutrophil count
Low platelet count
Pancytopenia
Low reticulocyte count

Peripheral Blood Film

May show:

Pancytopenia
Normocytic or mildly macrocytic red cells
No abnormal blast cells

Bone Marrow Aspiration and Biopsy (Gold Standard)

Characteristic findings:

Markedly hypocellular marrow
Fatty replacement
Marked reduction in hematopoietic cells
No malignant infiltration

Reticulocyte Count

Markedly reduced

Additional Laboratory Tests

Vitamin B12
Folate
Iron studies
Liver function tests
Renal function tests
Viral serology (HBV, HCV, HIV, EBV, CMV, Parvovirus B19)
Autoimmune screen

Flow Cytometry

Evaluate for paroxysmal nocturnal hemoglobinuria (PNH) clone

Cytogenetic Analysis

Exclude myelodysplastic syndrome and other marrow disorders

Diagnosis

Aplastic Anaemia · Classification by Cause

Acquired AA — Classification by Cause

Idiopathic / Autoimmune (70–80%)

Most common — CD8+ T-cells attack HSCs via IFN-γ and TNF-α
Often follows viral illness (trigger unknown)
Associated with HLA-DR2 alleles
Responds to immunosuppression (ATG + CsA)

Drug-Induced

Dose-dependent:

Cytotoxic chemotherapy (busulfan, cyclophosphamide)
Benzene (industrial)

Idiosyncratic:

Chloramphenicol — classic cause
NSAIDs (phenylbutazone, indomethacin)
Carbamazepine, phenytoin
Gold salts, sulfonamides, clozapine

Viral / Infectious

Seronegative hepatitis (non-A/B/C) — most common viral cause
EBV, CMV
HIV — direct HSC infection
Parvovirus B19 — pure red cell aplasia (selective)
Dengue fever — transient suppression

Radiation & Toxins

Ionising radiation — dose-dependent direct HSC DNA damage
Benzene — occupational (petroleum, rubber)
Pesticides (organophosphates, DDT)
Arsenic, toluene (glue sniffing)

Pregnancy-Associated

Rare — may remit after delivery
Immune tolerance shift during pregnancy
High maternal and foetal mortality if untreated
HSCT deferred until post-partum if possible

Immune Disorders

PNH — ~50% of AA have GPI-anchor deficient clone
Eosinophilic fasciitis (Shulman syndrome)
Thymoma (Good's syndrome)
SLE — immune complex-mediated suppression
Transfusion-associated GvHD

Inherited / Constitutional AA

Fanconi Anaemia (FA)

Most common inherited AA — AR (FANCA mutation)
DNA repair defect → HSC instability
AA onset: childhood (median age 7–8 yrs)
Café-au-lait spots, thumb/radial anomalies, short stature, microcephaly, renal anomalies
↑ Risk AML + solid tumours (HPV-related)
Dx: DEB/MMC chromosomal breakage test

Dyskeratosis Congenita (DC)

Telomere biology disorder — DKC1, TERT, TERC, RTEL1
Triad: nail dystrophy + oral leucoplakia + reticulate skin pigmentation
AA in 80–90% by age 30
Pulmonary fibrosis, liver disease, early greying
Dx: lymphocyte telomere length (very short)

Other Inherited Syndromes

Diamond-Blackfan Anaemia:

Pure red cell aplasia; RPS19 mutation; steroid-responsive

Shwachman-Diamond:

SBDS; neutropenia + exocrine pancreatic insufficiency

Kostmann syndrome:

ELANE/HAX1; neutropenia; G-CSF responsive

Reticular Dysgenesis:

AK2; absent myeloid + lymphoid; HSCT only

Aplastic Anaemia · Diagnostic Workup

Stepwise Diagnostic Workup

CBC + Blood Film

Pancytopenia — all 3 lines low
Reticulocytes ↓↓ — inappropriately low (key)
Film: no dysplasia, no blasts
MCV may be ↑ (stress erythropoiesis)
No dysplasia = distinguishes from MDS

Bone Marrow Trephine Biopsy

Trephine essential — aspirate alone insufficient (dry tap)
Hypocellularity <25% + fat cell replacement
No fibrosis, no infiltration, no dysplasia
Residual lymphocytes + plasma cells only

Exclude Other Causes

B12 + Folate — megaloblastic anaemia
Viral serology — hepatitis A/B/C, EBV, CMV, HIV, Parvovirus B19
ANA, dsDNA — SLE
TFTs — hypothyroidism
LDH, uric acid — leukaemia/lymphoma
CT chest/abdomen — lymphadenopathy, thymoma

Flow Cytometry — PNH Clone

CD55⁻ CD59⁻ cells on RBCs and WBCs
Present in ~50% of acquired AA
PNH clone >50% → eculizumab
Always test — changes management

Cytogenetics + Molecular

BM cytogenetics — exclude MDS (monosomy 7, del5q)
NGS panel — DNMT3A, ASXL1, BCOR, PIGA
Telomere length — if DC suspected
DEB/MMC breakage test — if Fanconi suspected (age <40)

HLA Typing + Transplant Workup

HLA typing patient + siblings — if SAA/VSAA
Unrelated donor search if no sibling match
Echo + PFTs — pre-transplant fitness
Ferritin — iron overload from transfusions
Minimise transfusions pre-HSCT

Differential Diagnosis

Condition	Marrow Cellularity	Blasts	Dysplasia	Key distinguishing feature
Aplastic Anaemia	Hypocellular <25%	Absent	Absent	Fat replacement, empty marrow
MDS	Normo / hypercellular	<20%	Present	Dysplastic cells, cytogenetic abnormalities
AML	Hypercellular	≥20%	Variable	Blast infiltration
B12 / Folate deficiency	Hypercellular	Absent	Megaloblastic	Macro-ovalocytes, hypersegmented neutrophils
PNH	Variable	Absent	Absent	CD55⁻/CD59⁻ on flow, haemolysis, thrombosis
Hypersplenism	Normal / ↑	Absent	Absent	Massive splenomegaly

Home Home Clinical Cases Hematology System Clinical Cases Aplastic Anemia (AA)

Management

Supportive Care

Blood transfusions as required
Platelet transfusions
Prompt treatment of infections
Broad-spectrum antibiotics for febrile neutropenia
Good infection prevention measures

Immunosuppressive Therapy

For patients not suitable for transplantation:

Antithymocyte globulin (ATG)
Cyclosporine
Eltrombopag (in selected patients)

Hematopoietic Stem Cell Transplantation

First-line treatment for:

Severe Aplastic Anemia (AA)
Young patients
Suitable matched sibling donor available

Treat the Underlying Cause

Stop causative drugs
Avoid toxic chemical exposure
Treat associated infections
Manage autoimmune disease

Complications

Severe bacterial infections
Fungal infections
Sepsis
Major bleeding
Intracranial hemorrhage
Iron overload from repeated transfusions
Relapse
Evolution to myelodysplastic syndrome
Acute myeloid leukemia
Paroxysmal nocturnal hemoglobinuria (PNH)

Prognosis

The prognosis depends on disease severity, patient age, and response to treatment. With modern immunosuppressive therapy and hematopoietic stem cell transplantation, long-term survival has improved significantly. Severe untreated Aplastic Anemia (AA) has a high mortality due to infection and bleeding.

Key Points / Clinical Pearls

Aplastic Anemia (AA) is a bone marrow failure syndrome causing pancytopenia.
Most acquired cases are immune-mediated.
Patients present with fatigue, infections, and bleeding.
Lymphadenopathy and splenomegaly are usually absent.
CBC shows pancytopenia with a low reticulocyte count.
Bone marrow biopsy demonstrates a markedly hypocellular marrow.
Stem cell transplantation is the preferred treatment for eligible patients with severe disease.
Immunosuppressive therapy is the main alternative for non-transplant candidates.
Prompt treatment of infections and bleeding is essential.
Long-term follow-up is needed because of relapse and clonal evolution risks.

Nimmana BK, Penney SW. National Center for Biotechnology Information (NIH). Aplastic Anemia, StatPearls.
Killick SB, Cavenagh J, Ho A, et al. Guidelines for the Diagnosis and Management of Adult Aplastic Anaemia: A British Society for Haematology Guideline. Br J Haematol. 2024;204:784-804.
MedlinePlus, National Library of Medicine (NIH). Aplastic Anemia: Medical Encyclopedia.
National Center for Biotechnology Information (NIH). Hematopoietic Stem Cell Transplantation, StatPearls.
National Center for Biotechnology Information (NIH). Fanconi Anemia, StatPearls.