Etiology, classification, investigations, types of management with guidelines and prognosis of aplastic anemia

1. APLASTIC ANEMIA
Dr. RUBAB NAZ
MBBS
CIVIL Hospital,
Karachis

2. ANEMIA
Anemia is the condition marked by the following:
 Hematocrit <41% in men or <36% in women, or
 Hemoglobin <13.5 g/dL in men or <12 g/dL in women

3. APLASTIC ANEMIA
 First described in 1888 by Dr. Paul Ehrlich
 Chauffard (1904) named it APLASTIC ANEMIA from the Greek, πλαϑώ
απλαστκη (platho aplastike): “shape unformed”
 Aplastic anemia is defined as bone marrow failure causing
pancytopenia and marrow hypoplasia.
 Incidence: It is more common in Asia than west
 Male:Female: 1:1
 Biphasic peak age: Childhood and 20-25 yrs of age

4. ETIOLOGY:
1) Acquired: (> 80%)
 Idiopathic: Most common cause
 Infections :
 Hepatitis-associated, typically seronegative
 Epstein-Barr Virus
 Cytomegalovirus
 Parvovirus
 Mycobacterial Infections
 Human Immunodeficiency Virus
 Human Herpes Virus 6
 Varicella Zoster Virus
 Measles
 Adenovirus

5.  Nutritional:
 Copper deficiency
 Vitamin B12
 Folic acid
 Chemicals:
 Benzene
 Insecticides
 Pesticides
 Radiation
 Other Associations:
 Pregnancy
 Inflammatory and autoimmune (e.g. systemic lupus erythematosus)
 Graft-versus-Host-Disease
 Drugs:

7. 2) Genetic: (around 25% in children and 10% in adults)
 Fanconi anemia:
 Autosomal Recessive
 Multiple congenital abnormalities: short stature, thumb/radial defects, café-
au-lait spots
 Increase incidence of malignancy: AML or solid tumors of head and neck
 Dyskeratosis congenita:
 Autosomal Dominant, Autosomal Recessive or X-linked Genetic Disorder
 Signs of premature aging, pulmonary fibrosis, risk of malignancy
 Classic Triad • Abnormal skin pigmentation • Dystrophic Nails • Leukoplakia
 Shwachman-Diamond syndrome:
 Autosomal Recessive Genetic Disorder
 Classic Triad •Exocrine pancreatic insufficiency •Neutropenia •Metaphyseal
dysostosis

8. PATHOGENESIS:
 Overproduction of cytokines
 Low CD4 regulatory cells
 Oligoclonal CD8 cytotoxic T cells
 Progenitor cells
 Shortened telomeres
 Immune susceptibility
 loss of heterozygosity of the short arm of chromosome 6

10. CLINICAL PRESENTATION:
The onset is insidious, and the initial symptom is frequently related to anemia
or bleeding, although fever or infections may be noted at presentation.
Specific manifestations include the following:
 Anemia: May manifest as pallor, headache, palpitations, dyspnea, fatigue,
or foot swelling
 Thrombocytopenia: May result in mucosal and gingival bleeding or
petechial rashes
 Neutropenia: May manifest as overt infections, recurrent infections, or
mouth and pharyngeal ulcerations.
Findings of adenopathy or organomegaly should suggest an
alternative diagnosis (eg, hepatosplenomegaly and supraclavicular
adenopathy are observed more frequently in cases of leukemia and
lymphoma than in cases of aplastic anemia).

11. DIFFERENTIAL DIAGNOSES:
 Acute Lymphoblastic Leukemia (ALL)
 Acute Myeloid Leukemia (AML)
 Myelodysplastic Syndrome
 Non-Hodgkin Lymphoma
 Paroxysmal Nocturnal Hemoglobinuria
 Primary Myelofibrosis
 Human Herpesvirus 6 (HHV-6) Infection
 Megaloblastic Anemia
 Multiple Myeloma
 Osteoporosis

12. WORKUP:
CBC AND PERIPHERAL SMEAR:
A paucity of platelets, red blood cells (RBCs), granulocytes,
monocytes, and reticulocytes is found in patients with aplastic anemia in
CBC. Mild macrocytosis is occasionally observed.
A peripheral blood smear may be helpful in distinguishing
aplasia from infiltrative disease causes. In aplastic anemia, there will be
no abnormal cells. Teardrop poikilocytes and leukoerythroblastic changes
suggest an infiltrative process.

13. PERIPHERAL BLOOD TESTS:
Peripheral blood tests in patients with suspected aplastic anemia may
include the following:
 Hemoglobin electrophoresis and blood-group testing:
may show elevated levels of fetal hemoglobin and red cell I antigen,
suggesting stress erythropoiesis.
 Biochemical profile:
LDH levels, LFTs, bilirubin levels, pregnancy test, copper and zinc levels,
vitamin B12 and folate levels.

14.  Viral Serology:
hepatitis virus panel, CMV, EBV, parvovirus, VZV, HSV, HHV6, HIV,
adenovirus.
 Flow cytometry of peripheral blood:
for Paroxysmal Nocturnal Hemoglobinuria (PNH)
 Histocompatibility testing:
should be conducted early to identify potential related donors,
those for young patients.

15. BONE MARROW ASPIRATION AND BIOPSY:
BONE MARROW ASPIRATION: In aplastic anaemia, the specimens
are hypocellular. Aspiration samples alone may appear hypocellular
because of technical reasons (eg, dilution with peripheral blood), or
they may appear hypercellular because of areas of focal residual
haematopoiesis.
BONE MARROW BIOPSY: By comparison, core biopsy better
reveals cellularity and thus It helps to confirms the diagnosis of
aplastic anemia. The specimen is considered hypocellular if it is less
than 30% cellular in individuals younger than 60 years or if it is less
than 20% cellular in those older than 60 years.

17. MRI:
It is used in a small minority of pts. 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.

18. STAGING:
Staging of aplastic anemia is based on the criteria of the International
Aplastic Anemia Study Group (IAASG).

19. Table 1: Classification of Aplastic Anemia (two out of three criteria must be fulfilled)
nSAA SAA vSAA
Neutrophils < 1.0 G/L < 0.5 G/L < 0.2 G/L *
Platelets < 50 G/L < 20 G/L < 20 G/L
Reticulocytes < 20 G/L < 20 G/L < 20 G/L

20. MANAGEMENT
SUPPORTIVE DEFINITIVE
Blood Transfusions
Treatment of infections
Neutropenic precaution
Prophylactic antifungals
 Bone Marrow
Transplantation
 Immunosuppressive Therapy
 Hematopoietic GF’s

21. SUPPORTIVE MANAGEMENT:
BLOOD TRANSFUSION:
 RBCs TRANSFUSION: If pts. Hb is <8g/dl or pt. is symptomatic.
 PLATELETS TRANSFUSION: The British Committee for Standards in
Haematology recommends prophylactic transfusions in patients whose
platelet counts fall below 10 × 109/L (or < 20 × 109/L in febrile patients).
 GRANULOCYTES TRANSFUSION:The British Committee for Standards in
Haematology also recommends irradiated blood products for all patients
receiving antithymocyte globulin (ATG) therapy. In patients with life-
threatening neutropenic sepsis, the committee suggests consideration of
irradiated granulocyte transfusions

22. Thinks to consider for transfusion:
 Avoid transfusion from related donor(because of possible sensitization
against non-HLA (human leukocyte antigen) tissue antigens of potential
donors).
 Minimum transfusions if BMT plan (because minimally transfused
subjects have achieved superior therapeutic outcomes. Because of
alloimmunization)

23. Iron Chelation Therapy:
 If pt is prolong transfusion dependent. Iron chelation therapy should
be considered when the serum ferritin is >1000 ug/l.
 Deferoxamine (Desferal)
Deferoxamine chelates iron by forming a stable complex that prevents
the iron from entering into further chemical reactions; The chelate is
readily soluble and is renally excreted.
 Deferasirox (Exjade)s
Deferasirox chelates trivalent iron. This agent is used to treat chronic
iron overload due to blood transfusions. Monitor patients' renal and
hepatic function.

25. TREATMENT OF INFECTIONS:
 Infections are a major cause of mortality in patients with aplastic
anemia.
 Risk factors include prolonged neutropenia and the indwelling
catheters used for specific therapy. Fungal infections, especially those
due to Aspergillus species, pose a major risk. Patients should maintain
hygiene to reduce infection risk.
 The British Committee for Standards in Haematology recommends
prophylactic antibiotic and antifungal agents for patients whose
neutrophil counts are below 0.2 ×109/L.

26. Thinks to consider:
 Empirical antibiotic therapy should be broad based, with gram-
negative and staphylococcal coverage based on local microbial
sensitivities.
 Especially consider including antipseudomonal coverage at the start
of treatment for patients with febrile neutropenia.
 Also consider early introduction of antifungal agents for individuals
with persistent fever.

27. DEFINITIVE TREATMENT:
Haematopoetic stem cell transplantation:
Allogeneic BMT from an HLA-identical sibling donor is the initial treatment
of choice for newly diagnosed patients if they have severe or very severe
aplastic anaemia, are < 40 years old and have an HLA-compatible sibling
donor.
 <20yrs & HLA matched donors
5yr survival rate 88-97%
 Matched unrelated donors, unrelated cordblood
5yr survival rate <50%

28. STEPS:
 HLA matching
 Preoperative conditioning regimen
ATG + cyclophosphamide + cyclosporine
 Transplantation

29. TRANSPLANT MATERIAL:
 Maternal related donor bone marrow
 Unrelated donor bone marrow
 Autologous cord blood
 Unrelated cord blood transplantation (CBT)
 Haploidentical stem cell transplantation

30. UMBLICAL CORD BLOOD TRANSPLANTATION:
 Umbilical cord blood transplantation (CBT) is not yet recommended
as first- or second-line therapy for aplastic anemia. This treatment
should be used as experimental therapy for patients who do not
have a human leukocyte antigen (HLA)–matched donor and who
have 1-2 courses of failed immunosuppressive therapy, and it
should be evaluated only through prospective clinical
trials. Controlled trials are needed to better define the role and timing
of CBT in aplastic anemia.

31. COMPLICATIONS:
 GVHD
 Secondary solid tumors
 Effect on growth and development
 Effect on endocrine function
 Effect on gonadal function
 Preexisting anti HLA antibodies affect outcome

32. FOLLOW UP:
 For at least one year post-transplant
Fever
Pneumocystis prophylaxis- one year
Antiviral prophylaxis-one year
 After one year-
• Assessments of growth
• Endocrine function
• Pulmonary function
• Bone health
• Cancer screening

33. IMMUNOSUPPRESSIVE THERAPY:
Indications:
(i) Patients with non-severe aplastic anaemia who are dependent on red
cell and/or platelet transfusions.
(ii) patients with non-severe aplastic anaemia who, although not
transfusion -dependent, may have significant neutropenia and be at risk of
infection.
(iii) patients with severe or very severe aplastic anaemia who are >40 years
of age.
(iv) younger patients with severe or very severe disease who lack an HLA-
compatible sibling donor.

34.  ANTI-THYMOCYTE GLOBULIN (ATG):
Modify T-cell function
 CYCLOSPORINE (CSA):
A cyclic polypeptide that suppresses some humoral immunity
and, to a greater extent, cell-mediated immune reactions (eg,
delayed hypersensitivity, allograft rejection, experimental allergic
encephalomyelitis, graft versus host disease) for a variety of organs
 COMBINED IMMUNOSUPPRESSIVE THERAPY (CIST):

35. Response criteria to immunosuppressive therapy in
aplastic anemia:

36. HAEMATOPOEITIC GROWTH FACTORS:
 ELTROMBOPAG:
A thrombopoeitin-receptor agonist. It is FDA approved for
severe aplastic anaemia in patients who fail to respond adequately
to at least 1 prior immunosuppressive therapy.
 FILGRASTIM:
A G-CSF that activates and stimulates the production,
maturation, migration, and cytotoxicity of neutrophils.

37. MANAGEMENT OF SEVERE AA:

38. MANAGEMENT OF NON-SEVERE AA:

40. PROGNOSIS:
The outcome of patients with aplastic anemia has substantially
improved because of improved supportive care. however, observational and/or
supportive care therapy alone is rarely indicated.
The estimated 10-year survival rate for the typical patient receiving
immunosuppression is 68%, compared with 73% for hematopoietic cell
transplantation (HCT).
However, there is a significantly improved outcome for HCT over time,
for matched sibling and alternative donors, and with younger age. In cases of
immunosuppression, relapse and late clonal disease are risks.

41. MORBIDITY/MORTALITY:
The major causes of morbidity and mortality from aplastic anemia
include infection and bleeding.
Patients who undergo HCT have additional issues related to acute
and chronic toxicity from the conditioning regimen and graft versus host
disease (GVHD), as well as a potential for graft failure.
In approximately 25-30% of patients with aplastic anemia, the condition
does not respond to immunosuppression. In cases with a treatment response,
relapse and late-onset clonal disease, such as paroxysmal nocturnal
hemoglobinuria (PNH), myelodysplastic syndrome (MDS), and leukemia, are
risks—regardless of the treatment response or degree of response.

42. REFERRENCE:
 MEDSCAPE
 WEBMD
 MAYOCLINIC
 NEW ENGLAND JOURNAL OF MEDICINE( NEJM)
 BRITISH JOURNAL OF HEMATOLOGY