Dr. Zaira Hussain discusses aplastic anemia, a bone marrow failure syndrome characterized by pancytopenia and bone marrow hypocellularity. She covers the epidemiology, causes, clinical presentation, diagnostic workup, and treatment options including supportive care, immunosuppressive therapy, growth factors, and bone marrow transplant. Prognosis depends on the treatment received, with improved outcomes seen with hematopoietic cell transplantation or immunosuppression compared to supportive care alone.

1. Dr zaira Hussain
FCPS trainee @Gmmmc Sukkur

10. Dr Zaira Hussain
FCPS trainee@ GMMMC civil hospital sukkur

11. 1. Introduction to aplastic anemia
2. Pathophysiology
3. Diagnostic workup
4. Treatment Options
5. Future directions/challenges

12.  Aplastic anemia is a syndrome of bone marrow
failure Characterixed by pancytopenia with bone
marrow hypocellularity.
INTRODUCTION

13. Epidemiology
 Aplastic anemia is a less common cause
of anemia in children
 Male and Female are affected with equal
frequency
 Incidencs:it is more common in Asia then
in west about 1-5 children per million
population per year
 Age distribution is biphasic, with the major
peak in the teens and twenties and a
second rise in older adults.

15. CAUSES
 INHERITED-30%
 Fanconi's anemia
 Dyskeratosis congenita
 Shwachman-Diamond syndrome
 Reticular dysgenesis
 Amegakaryocytic thrombocytopenia
 Familial aplastic anemias
 Preleukemia (monosomy 7)
 Nonhematologic syndrome (Down syndrome)

16.  ACQUIRED-80%
Radiations,drugs, chemicals
Predictable: chemotherapy,benzene, idiosyncratic:
chloramphenicol, antieipileptic,gold,3-4methylene,NSAIDS,
antibiotics
 Virusus(CMV,ebv,HepB,c) hepatitis nonA nonB
nonC(seronegative)
 Hiv
 Immunedisease.. Eosinophilic
fascitis,hypoimmunoglobulinemia,thymoma
 PNH
 Marrow replacement (leukemia, myelofibrosis)

17.  Nutritional
Vit b12,folate, copper
 Other
 Cryptic dyskeratosis congenita
 Tekomeras reverse transcriptase
haLoinsufficiency

18. Case senerio
 A 5 year old child present with palor and
hyperpigmentation
 He has bifid thumb and numerary digits
 What is your diagnosis??

19. Inherited Aplastic anemia

20. FANCONI’s ANEMIA-
 Autosomal recessive disorder 99% rarely x-linked
 Presentation
1. Abnormal physical anomalies with abnormal
hematologic anomalies
2. Physical anomalies +no hematologic anomalies
3. Hematologic + no Physical anomalies
✓ Pathigenesis: abnormal chromosomal fragility
FNAC (prefix) these genes code for protein which
protect chromosomes from the breakage
 loss of ability to irradicate O2 radicals this leads to
oxidative damage

21.  Clinical features
1. MC 55% hyoopigmentation of trunk(
neck,interoginous areas + caif lair spots,vitligo
2. Growth failure51%..short stature(GH Def)
3. Absent radi,thumb,bifid thumb,redumentary
thumb(abnormalities in thumb and
radius)40_45%
4. Congenital disclocation of hip
5. In males (esp)30% undecended testes,
hypospadias, underdeveloped penis,atrophic
testes In females abnormalities of
uterus/vagina/ovary
6. Fanconi anemia facies 25-30%
microcephaly,small eyes
7. Renal...horahe kidney/ectopic

23. Laboratory finding
 CBC—anemia, thrombocytopenia,leukopenia
 Chromosomal breakage study-- increase
breakage of chromosomes
 Flow cytometry
 AFP... Increase but not specific
 Gene sequence---FANC(a.b.c)
 Complications.. Increase risk of Cancer MC:solid
tumor/SCC of head,neck and upper
esophagus)...this will followed by Ca of
vulva,anus,cervix(HPV)
 Androgen therapy causes(hepatic tumors)
 Peliosis hepatitis

24. Treatment
 Supportive( BT,single donor platelates)
 Growth velocity
 Glucose intolerance/hyperinsulinemia
 Bone marrow evaluation yearly
 HPV vaccine...to prevent SCC
 Specific...HST...cure as early as possible
 <10yr survival rate>80%
 >10yr survival rate<80%
 Androgen (oxymethaolone) in HN by 1-2month
 Gene therapy

25. Schwachman diamond syndrome
 Etiology
 inheritance AR
 Gene SBDS (ribosomal gene) on 7q11
chromosome
 Failure of development of pancreatic acinar cells
 Bone marrow failure
 Neutrophil abnormalities (adhesion) leukopenia

26. Clinical manifestation
 Pancreatic insufficiency...fat malabsorption since
birth
 Infections▶️ Inc chance of developing infec
 Short stature..less than 3rd centile,adult height<25
centile
 Skeletal abnormalities..delayed bone
maturation,thoracic dystrophies
 Hepatitis/increase liver enzyme/dental
abnormalities

27. Laboratory finding
 CBC.. Pancytopenia
 Neutropenia...chronic persistent, intermittent
 On U/S CT...fatty replacement of pancreatic
tissue (so Dec tripsinogen/amylase Dec IgG,Dec
or absent B lymphocyte
 Complications
 MDS or Leukemia

28. Treatment and prognosis
 Pancreatic enzyme replacement
 Fat soluble vitamins
 NeutropenIa..GCS(filgastrim)...Inc chance of
developing leukemia
 Cure...HSCT
 Prognosis..50 PT pancreatic insufficiency
patient improves with replacement therapy

30. Dyskeratosis congenita
 Inherited multisystem disorder
 X linked,AD,AR
 DKC1 gene
 2 of 4 feature..skin pigmentation nail dystrophy,
leukoplakia and bone marrow failure
 Mucocutaneous abnormalities
 Bone marrow failure
 Increase risk of Cancer and MDS
 Pathology...genes which code for telomerase
complex are affected

31. Clinical manifestation
 Skin pigmentation (upper part of body)
 Nail dystrophy
 Mucosal leukoplakia
 Inc tearing from eyes
 Eye abnormalities(conjunctivitis, blepharitis,optic
Atrophy strasbismus)
 Skeletal.. Osteoporosis, mandibular
hypoplasia,Avascular necrosis
 GU...(horshshoe kidney phemosos, undecended
testes,hypospadias
 Children can have hepatomegaly
fibrosis/Pulmonary fibrosis

32. Investigations
 CBC... Pancytopenia
 Short stature
 Overlaping syndromes
1. Hoyeral heirdarson syndrom
DKC1gene(AA+microcephaly+intrauterine
growth retardation, BM failure) cereberallar
symptoms
2. Revez syndrome (exudative retinopathy)
3. Coats plus syndrome ( CTC1 gene retinal
telangiectasia, exudates and intracranial
calcification, leukodystrophy,brain
cysts,osteopenia,Portal HTN,GI bleeding)

33. Treatment
 Androgen
 Cytokine therapy with GCST
 GCF with erythropoietin
 HSCT... Fibrosis•
 Complication and prognosis
 increase risk of SCC ,MDS and other life
threatening complications like pulmo/liver fibrosis,
severe GI bleeding)
 ▶️median age...30yrs

34. CLINICAL PRESENTATION
 The onset is insidious and intial symptom is frequently related to
anemia or bleeding
 Bleeding is the most common early symptom. Easy bruising,
oozing from the gums, epistaxis, heavy menstrual flow, and
sometimes petechie (massive hemorrhage is unusual)
 Symptoms of anemia are also frequent, including lassitude,
weakness & shortness of breath.
 Infection (due to leukopenia) is an unusual first symptom in
aplastic anemia. may manifest As overt infections recurrent
infection or mouth and pharyngeal ulceration

35. CLINICAL EXAMINATION continue
 Petechiae and ecchymoses
 Pallor
 Retinal hemorrhage
 Look for other features associated with inherited causes
 Finding of adenopathy or organomegaly should suggest an
alternative diagnosis (Eg hepatosplenomegaly and
supramolecular adenopathy are observed more frequently in
case of leukemia and lymphoma than in case of aplastic
anemia

37. Investigations

39. • Bone marrow aspiration (hypocellular aspiration sample
alone may appear hypocellular bcz of technical reasons Eg
dilution with peripheral blood or may appear hypercellullar
because of residual hematopoiessi
• Bone marrow biopsy: core biopsy better reavels cellularity
and thus it helps to confirm the diagnosis of Aplastic
anemia the specimen less then 30% cellularity is
considered hypocellular
• MRI used in small minority of PT in which there are pockets
of hypercellularity which can give false negative results of
bone marrow biopsy if it the sample is taken from one of
those areas

41. Aplastic anemia
with hypoplastic
bone marrow
fatty infiltrations

42. TREATMENT
Supportive:
1. RBC, Platelates, Plasma, granulocyte transfusion
2. Treatmemt of infection
3. Neutropenic precaution
4. Prophylactic antifungals
 Definative
1. BMT
2. immunosuppressive therapy
3. Hematopoietic GF’s

43. Supportive
 Blood transfusion:if Hn is less then 8g/l or
patient is symptomatic
 Platelate transfusion:The British committee
For standards in hematology recommended
prophylactic transfusion in patient whose PLT
count fall below 10x10⁹/l
 Granulocyte transfusion: irradiate blood
products for all patients receiving anti
thymocyte globulin or in patients with life-
threatening neutropenia,sepsis

44. Think to consider for transfusion
 Avoid transfusion from related
donor(because of possible sensitisation
against non HLA tissue antigen of potential
donor’s)
 Minimum transfusions if BMT plan(because
minimally transfused subject have achieved
superior therapeutic outcomes because of
alloimunization)

45.  Iron chelation therapy
 if patient is prolong transfusion dependent
iron Chelation therapy should be considered
when serum ferritin>1000ug/l
 Deferoxamine(stable complex,readily soluble
and renally excreAted
 Deferasirox(it chelates trivalent ions,treat
chronic iron overload, monitor patient renal
and hepatic function

46. Treatment of infections
 Infections are major cause of mortality in patients
with Aplastic anemia
 Give prophylactic antibiotics antifungal agents for
patients whose neutrophil count are below
0.2x10⁹/l
 Emperic antibiotic therapy should be broad based
with gram negative and staphylococcal coverage
based on local microbial sensitivities
 For febrile neutropenia consider antipseudomonal
coverage at the start of the treatment
 Consider early introduction of antifungal agents
for individual with persistent fever
 Maintain hygien to reduce risk

47. Definative treatment
1.Bone marrow transplant
 There are 3 types of bone marrow transplant
1. Autologous transplant(self donated)
2. Allogeneic transplant (recieved from a
donor)
3. Umbilical cord transplant

48. Autologous transplant
 Low risk of infection
 Common for disease like lymphoma
 12 to 18 month Recovery

49. Allogeneic transplant
 In this process bone marrow is recieved from a
donor , Donor maybe a sister, brother, parent or
other relative
 There is a chance of infection (recovery in 3 to 6
month)

51. Umbilical cord transplant

52. Precautions
Take prescribed
medication, wear mask,
Freqeny hand
washing,ovoid crowded
places have healthy and
well balanced diet
maintain personal and
orall hygiene

53. Complications
 GVHD
 Seconfary tumors
 Effect on growth and development
 Effecy on endocrine function
 Effect on gonadal function
 Preexisting Anti HLA antibodies affect
outcome

54. Follow up
 For at least one year posttransplant
1. Fever
2. pneumocystis prophylaxis...one year
3. Anti viral prophylaxis...one year
2. After one year
1. Assessment of growth
2. Endocrine function
3. pulmonary function
4. bone health
5. Cancer screening

55. 2 immunesuppressive therapy
 Indication
1. Pt with non severe AA who are dependent on
blood/,PLT transfusion
2. Pt with non severe AA who although not
transfusion dependent may have significant
neutropenia and be at risk of infection
3. PT with severe or Very severe disease who
lack an HLA compatible sibling donor

56. Continue
• Anti thymocyte globulin modify T cell function
• Cyclosporin A cyclic polypeptide that
suppresses some humoral immunity and to a
greater extent cell mediated immune reaction
Eg(delayed Hypersensitivity,allograft rejection,
experimental allergic encephalomyelitis,graft
versus host disease)for a variety of organs
• Steroid
• Combined immunesuppressive Therapy

57. Continue
• Methyl prednisolone alone is given in single dose of 5
mg/kg/day PO or I/V for 8 days followed by single
dose of 1 mg /kg/day for 6 days taper dose in next 6
days then discontinue, steroid response alone is 25 %.
• ALG is given as 40mg/kg/dose continuous I/V infusion
over 12 hours with methyl prednisolone 1mg/kg/day
I/V for 4 days .ALG alone gives about 50% response
rate.
• Cyclosporin is given orally in a dose of 8 mg/kg/day for
initial 14 days then 15mg/kg/day. Continue treatment
for minimum 3 months .

58.  Hematopoietic growth factor
 Eltrombopag A thrombopoeitin receptor agoint
 It is FDA approved for severe Aplastic anemia in
patients who fail to respond adequately to atleast one
prior immunosuppressive therapy
 Filgrastin A GCS that activates and stimulates the
production, maturation, migration and cytotoxicity of
neutrophils
 Other Are
 Intravenous immunoglobulins
 Recombination human IL-3
 Gene therapy

59.  Cyclosporin alone response 39%
 Rabbit Anti thymocyte globulin response 37%
 Tacrolimus in combination with ATG and
steroids response 54%

60. Prognosis
 Faconi anemia—Shortened life span
 Out of patients with Aplastic anemia has substantially
improved because of improved Supportive care
however observational supportive care therapy alone
is rarely indicated
 The estimated 10yr survival for the typical patient
recieving Immunosuppression is 68% ,compared with
73% for hematopoietic cell transplantation(HST)
 however there’s significantly improved outcome for
HCT overtime for matched sibling and alternative
donor’s and with young age.
 In case of Immunosuppression relapse and late clonal
disease are risks

61. Mortality /morbidity
 Major cause of morbidity and mortality from
Aplastic anemia include infection and bleeding
 If left untreated severe pancytopenia has an
overall mortality under 6 month of age is 50%