aplastic anemia prevails in children in south east asia frequently .... with bone marrow transplantation as the life saving procedure

1. Maj Dr Bishwo Raj Kunwar
(Assistant Professor)
Nepalese Army Institute of Health Sciences
APLASTIC ANAEMIA

2. Objective
• By the end of this class, students should be
able to:
– Enlist causes of aplastic anemia
– Enumerate clinical findings
– Enlist investigations and treatment measures of
aplastic anemia

3. VIGNETTE
• A 9-year-old boy is brought to the pediatric outpatient
clinic with complaints of persistent fatigue, repeated
nosebleeds, and occasional gum bleeding for the past
3 weeks.
• His mother also noticed that he has been developing
bruises on his arms and legs without any history of
trauma. He has no history of fever, weight loss, join
swelling, or recent infections.

4. VIGNETTE
• On examination:
• Pale conjunctiva
• Multiple ecchymotic patches over the limbs
• No lymphadenopathy
• No hepatosplenomegaly

5. VIGNETTE
Investigations:
• CBC:
– Hemoglobin: 6.2 g/dL (low)
– WBC: 3,200/mm³ (low)
– Platelets: 25,000/mm³ (low)
• Peripheral smear: Normocytic, normochromic
anemia, reduced leukocytes and platelets, no
abnormal cells
• Bone marrow aspiration: Hypocellular marrow with
marked reduction in all cell lines

6. VIGNETTE
QUESTIONS:
• What is the most likely diagnosis?
• Which investigation confirmed the diagnosis?
• List two common causes of aplastic anemia in children.
• Mention two clinical features seen in aplastic anemia.
• Name two important differential diagnoses for this
case.
• Outline one principle of management for this patient.

7. BONE WITH BONE MARROW ANATOMY

8. Haematopoietic Stem Cell Differentiation

9. Introduction
• A group of disorders of the hematopoietic stem
cells resulting in the suppression of one or
more of erythroid, myeloid and megakaryocytic
cell lines
• Inherited or acquired

10. Etiopathogenesis
• Deficient hematopoietic stem cells due to
– Acquired injury from viruses, toxins or chemicals, or
– Abnormal marrow microenvironment, or
– Immunologic suppression of hematopoiesis (mediated
by antibodies or cytotoxic T cells), or
– Mutations in genes controlling hematopoiesis
(resulting in inherited bone marrow failure syndromes)
Bone marrow failure

11. History
• Family history of neonatal thrombocytopenia
(Inherited bone marrow failure syndrome)
• History of exposure to toxins, drugs like
Chloramphenicol, environmental hazards
• History of viral infections (Hepatitis B & C, EBV,
Parvovirus B19)

12. Epidemiology (Global & Asia)
• Incidence: 2–6 per million/year
• Higher rates in Asia (3–4x more common)
• Common in teenagers and young adults
• No significant gender difference

13. Prevalence in Nepal
• No national registry
• Case series from Kanti Children's Hospital:
rising detection
• Increased awareness, better diagnostics
• Resource constraints in rural areas

14. Clinical Features- Symptoms
• Pallor
• Symptoms of severe anemia
• Skin rashes
• Gum bleeding/nose bleeds
• Fever

15. Clinical Features- Signs
• Pallor
• Fever (neutropenia)
• Signs of Congestive heart failure (severe anemia)
• Ecchymosis, petechiae (thrombocytopenia)
• Characteristic congenital physical anomalies
(Inherited bone marrow failure syndrome)
• Signs of infection (pneumonia/sepsis)
• No Lymphadenopathy/ Hepatosplenomegaly

16. Red Flags in Children
• Sudden fatigue, frequent infections
• Easy bruising or bleeding
• Recurrent fever
• Non-resolving anemia despite iron therapy

17. Congenital syndromes associated with bone
marrow failure
Syndrome Inheritance Associated features Risk of malignancy
Associated with pancytopenia
Fanconi anemia AR Absent thumbs, absent
radius, microcephaly,
renal anomalies, short
stature
High risk of acute
myeloid leukemia,
myelodysplasia,
oral or liver cancer
Dyskeratosis
congenita
X-linked recessive,
AD, AR
Dystrophic nails,
leukoplakia
Skin cancer
(usually squamous
cell),
myelodysplasia

19. Congenital syndromes associated with bone
marrow failure…
Syndrome Inheritance Associated features Risk of malignancy
Single lineage cytopenias
Amegakaryocytic
thrombocytopenia
AR None None
Diamond- Blackfan
syndrome
(pure red cell aplasia)
AD ,AR Short stature,
congenital anomalies in
one-third, macrocytosis,
elevated fetal
hemoglobin, raised
adenosine deaminase
Leukemia,
myelodysplasia,
other cancers
Thrombocytopenia
absent radii
AR Absent radius None

20. Severity Classification
• Non-Severe: moderate cytopenia
• Severe:
– ANC < 500/µL
– Platelets < 20,000/µL
– Retic count < 20,000
• Very Severe: ANC < 200/µL

21. Differential Diagnosis
• Acute leukemia
• MDS (Myelodysplastic syndrome)
• Megaloblastic anemia
• Hypersplenism
• Sepsis-related bone marrow suppression

22. Investigations
• Hemoglobin, Total leukocyte count, Differential
leukocyte count, Platelets
• Peripheral Blood Smear (anemia, thrombocytopenia,
agranulocytosis)
• Reticulocyte count <1% (indicates reduced red cell
production)
• Bone marrow aspiration and biopsy: hypocellular (very
few hematopoietic cells and is replaced with fat cells
and lymphocytes)
• No malignant cells.

25. Investigations: Specific Tests
• Fanconi anemia:
– Chromosomal breakage study
• Congenital dyserythropoietic anemia:
– Ham’s test

27. Treatment
• Supportive:
– Packed Red cell transfusion
– Platelet transfusion
– Antibiotics (management of infections)
• Definitive therapy:
– Hematopoietic Stem Cell Transplant (HSCT)
– Antithymocyte globulin (ATG)
– Granulocyte- colony stimulating factor (G-CSF)

28. Treatment…
• Criteria for referral for HSCT:
– Young age
– Severe aplastic anemia
– Availability of matched sibling
• Antithymocyte globulin (ATG):
– Patients with severe acquired aplastic anemia who cannot
undergo HSCT may benefit from ATG along with oral
cyclosporine
• Granulocyte- colony stimulating factor (G-CSF):
– Patients with neutropenia and infection should receive a trial
of G-CSF
– Should be discontinued after seven days (risk of malignant
transformation)

29. Prognosis
• Determined by severity and extent of
cytopenias
• Patients with severe aplasia at risk of:
– high output cardiac failure due to anemia;
– bacterial & fungal infections due to neutropenia;
– and severe bleeding due to thrombocytopenia
• With current transplantation regimen, long-
term survival in patients with severe aplastic
anemia 60-70%, with survival rates exceeding
80% in favorable subgroups.

30. Recent Advances
• Eltrombopag (TPO receptor agonist):
enhances hematopoiesis
• Gene therapy trials (in Fanconi anemia)
• Improved transplant conditioning protocols
• Early use of triple therapy: ATG + CyA +
Eltrombopag

31. Follow-up Care
• Monthly CBC monitoring
• Iron overload monitoring (Ferritin)
• Screen for late effects: cancer, marrow failure
relapse
• Psychosocial support and counseling

32. Hypoplastic Anemia (Differentiation)
• Milder form of marrow suppression
• Often viral or transient (e.g., Parvovirus B19)
• May resolve spontaneously
• Does not usually require transplant

33. Questions & Answers
• What is the most likely diagnosis?
→ Aplastic anemia.
• Which investigation confirmed the diagnosis?
→ Bone marrow aspiration showing hypocellularity with
decreased all hematopoietic cell lines.
• List two common causes of aplastic anemia in children.
→ Idiopathic (most common)
→ Viral infections (e.g., hepatitis viruses, Epstein–Barr
virus)
→ (Other acceptable: drug-induced, Fanconi anemia).

34. Questions & Answers
•Mention two clinical features seen in aplastic anemia.
→ Pallor (due to anemia)
→ Bleeding manifestations such as petechiae, purpura, epistaxis
(due to thrombocytopenia)
→ (Also acceptable: recurrent infections due to neutropenia).
•Name two important differential diagnoses for this case.
→ Acute leukemia
→ Megaloblastic anemia
•Outline one principle of management for this patient.
→ Supportive care (packed RBC transfusion, platelet transfusion),
infection control, avoidance of offending drugs, and definitive
therapy with immunosuppressive therapy or hematopoietic stem
cell transplantation in suitable cases.

35. Objective
• By the end of this class, students should be
able to:
– Enlist causes of aplastic anemia
– Enumerate clinical findings
– Enlist investigations and treatment measures of
aplastic anemia

36. References
• Nelson Textbook of Pediatrics, 21st Ed
• Kanti Children’s Hospital Clinical Reports
• Nepal Journal of Hematology and Oncology
• WHO Global Health Observatory
• NIH Clinical Guidelines

38. Thank you