Bone Marrow — Clinical Features

Overview of Bone Marrow Failure Syndromes

Aplastic Anemia

Definition

• Physical/chemical damage (benzene, radiation, cytotoxic chemotherapy)
• Immune-mediated destruction (most common acquired form — cytotoxic T cells targeting hematopoietic stem cells)
• Constitutional/genetic defects (Fanconi anemia, dyskeratosis congenita, telomere biology disorders)

Epidemiology

• Bimodal age distribution: children/young adults + second peak >60 years
• Rare in West: <2 cases/million/year; higher in Asia: 5–6 cases/million/year
• Males and females equally affected

Clinical Manifestations (Symptoms of Pancytopenia)

• Fatigue, weakness, pallor, headaches, exertional dyspnea

• Petechiae of skin and mucous membranes
• Epistaxis (nosebleeds)
• Gum/mucosal bleeding

• Fever
• Recurrent or severe bacterial/fungal infections

Some patients are identified incidentally on routine laboratory testing before symptoms develop.

Causes (Acquired)

• Idiopathic (majority)
• Medications (e.g., chloramphenicol, NSAIDs, antiepileptics)
• Viral infections: EBV, CMV, hepatitis A/B/C
• Radiation
• Autoimmune disease
• Pregnancy-associated
• Paroxysmal nocturnal hemoglobinuria (PNH)

Pathobiology

• Autoimmune attack by cytotoxic T cells → apoptosis of HSCs
• Usually normal cytogenetics (abnormal karyotype suggests MDS)
• ~60–70% have acquired clonal mutations on next-generation sequencing at diagnosis — these clones persist and can cause relapse or malignant transformation

Severity Classification

Inherited Bone Marrow Failure Syndromes (IBMFS)

Bone Marrow Examination Findings

Hypocellular Marrow (Aplastic Anemia)

• Marrow replaced by fat cells
• Markedly reduced hematopoietic precursors across all lineages (trilineage hypoplasia)
• Biopsy preferred over aspirate for cellularity assessment

Hypercellular/Dysplastic Marrow (MDS)

• Increased cellularity with dysplastic morphology (ring sideroblasts, hypolobated neutrophils, micromegakaryocytes)
• Variable cytopenias despite hypercellular marrow — "ineffective hematopoiesis"

Key Clinical Relationships

• Aplastic anemia ↔ PNH ↔ MDS: These three conditions are closely related; one can evolve into another. PNH clones are detected in ~50% of aplastic anemia patients.
• Separation between hypoplastic MDS and aplastic anemia can be diagnostically difficult and requires correlation of morphology, cytogenetics, and molecular studies.
• Many syndromes share immune-mediated marrow destruction and genomic instability, driving higher rates of malignant transformation (e.g., AML).

Treatment Principles

Pancytopenia — Clinical Features

Definition

• Red blood cells (anemia)
• White blood cells / neutrophils (leukopenia/neutropenia)
• Platelets (thrombocytopenia)

Clinical Features (Symptoms by Cell Line)

Anemia (↓ RBCs)

• Fatigue, weakness, malaise
• Pallor (skin, conjunctiva, nail beds)
• Dyspnea on exertion
• Headaches, dizziness, tinnitus
• Palpitations, tachycardia

Thrombocytopenia (↓ Platelets)

• Petechiae (skin and mucous membranes)
• Purpura, ecchymoses
• Epistaxis (nosebleeds)
• Gingival / mucosal bleeding
• Menorrhagia
• Spontaneous bruising

Neutropenia (↓ WBCs)

• Recurrent or severe bacterial/fungal infections
• Fever (may be the presenting sign)
• Oral ulcers
• Perirectal infections
• Sepsis in severe cases

Differential Diagnosis by Bone Marrow Appearance

Pancytopenia with Hypocellular Bone Marrow

Pancytopenia with Cellular Bone Marrow

Hypocellular Marrow ± Pancytopenia (Other Causes)

• Q fever
• Legionnaires' disease
• Anorexia nervosa / starvation
• Mycobacterial infection

Common Specific Causes — Key Features

1. Aplastic Anemia

• Most common cause of pancytopenia with hypocellular marrow
• Immune-mediated destruction of hematopoietic stem cells by cytotoxic T cells
• Abrupt onset in a previously well young adult
• May be precipitated by seronegative hepatitis, EBV, CMV, or drugs

2. Megaloblastic Anemia (B12 / Folate Deficiency)

• Hypercellular marrow with ineffective erythropoiesis
• Peripheral blood: macrocytosis (MCV up to 125–130 fL)
• Elevated LDH and indirect bilirubin (intramedullary hemolysis)
• Neurological features with B12 deficiency (subacute combined degeneration)
• Responds rapidly to replacement (reticulocyte peak in 5–7 days)

3. Drug-Induced

• Chloramphenicol: bone marrow vacuolation + ringed sideroblasts; can be permanent
• Linezolid: similar but less severe
• Alcohol: reversible pancytopenia or selective thrombocytopenia via folate deficiency or direct toxicity
• NSAIDs (e.g., indomethacin): rare aplastic anemia

4. Myelodysplastic Syndrome (MDS)

• Dysplastic morphology in ≥1 cell line
• Hypercellular marrow despite peripheral cytopenias ("ineffective hematopoiesis")
• Risk of transformation to AML

5. Hypersplenism

• Splenic sequestration of all blood cell lines
• Splenomegaly on exam and imaging (spleen normally 9–10 cm)
• Marrow is normal or hypercellular

6. Hairy Cell Leukemia

• Classically causes pancytopenia with splenomegaly
• "Dry tap" on aspiration due to marrow fibrosis
• Hairy cells with tartrate-resistant acid phosphatase (TRAP) positivity

Diagnostic Approach

Bone marrow biopsy is far more frequently indicated in pancytopenia than in single-lineage cytopenia, especially when malignancy (MDS, AML, NHL) is suspected. Flow cytometry and chromosome analysis should be added.