Title: APLASTIC ANEMIA
1APLASTIC ANEMIA
2Aplastic Anemia
- Aplastic anemia is a bone marrow failure syndrome
characterized by peripheral pancytopenia and
marrow hypoplasia. - Bone marrow failure is a term with a larger
meaning, referring to disorders of the
hematopoietic stem cell which involves either one
cell line or all of the myeloid cell lines
3History of Aplastic anaemia
- Paul Ehrlich (1854-1915) described the first case
of aplastic anaemia in a pregnant woman who died
of marrow failure in1888. - The term aplastic anaemia first used by Anatole
Chauffard in 1904.
4Aplastic Anemia epidemiology
- annual incidence in Europe and US - 2 cases per
million population, but 4 cases in Bangkok 6 in
Thailand and 14 in Japan. - no racial predisposition exists in the United
States however, prevalence is increased in the
Far East. - The male-to-female ratio is approximately 11.
- Aplastic anemia occurs in all age groups.
- a small peak in incidence in childhood.
- a peak incidence in people aged 20-25 years, and
a peak in people older than 60 years.
5Aplastic Anemia - Etiology
- Congenital/inherited (20)
- Patients usually have dysmorphic features or
physical stigmata. Occasionally, marrow failure
may be the initial presenting feature. - Fanconi anemia
- Dyskeratosis congenita
- Shwachman-Diamond syndrome
- Familial aplastic anemia
- Acquired
- Drugs
- - Cytotoxic drugs - Antibiotics
- - Chloramphenicol - Anti-inflammatory
- - Anti-convulsant - Sulphonamides
- - 2-3 months usually between exposure and the
development of aplastic anemia.
6Aplastic Anemia (Cont.)
- Acquired
- Radiations
- Chemicals e.g., Benzene and pesticides,
chloramphenicol, phenylbutazone, and gold, - Viruses
- Hepatitis A, Non-A and Non-B
- Herpes simplex
- E-B virus
- Parvovirus Transient
- Important clinically in patients with hemolytic
anemias - 5-10 of cases of AA in the West and 10-20 in
the Far East. - 2-3 months between exposure to the virus and the
development of AA. - Immune SLE, RA (rheumatoid arthritis)
- Pregnancy
- Idiopathic 75
- PNH
7Aplastic Anemia - Pathogenesis
- Potential mechanisms
- Absent or defective stem cells (stem cell
failure). - Abnormal marrow micro-environment.
- Inhibition by an abnormal clone of hemopoietic
cells. - Abnormal regulatory cells or factors.
- Immune mediated suppression of hematopoiesis.
- It is believed that genetic factors play a role.
- There is a higher incidence with HLA (11) histo
comp. - Antigen. Immune mechanism is involved.
8Aplastic Anemia - Pathogenesis (Cont)
- The latest theory is
- there is an intrinsic derangement of hemopoietic
proliferative capacity, which is consistent with
life. - the immune mechanism attempt to destroy the
abnormal cells (self cure) and the clinical
course and complications depend on the balance. - If the immune mechanism is strong, there will be
severe pancytopenia. - If not, there will be myelodysplasia.
9Aplastic Anemia - Forms of disease
- Inevitable
- dose related e.g. cytotoxic drugs, ionizing
radiation. The timing, duration of aplasia and
recovery depend on the dose. Recovery is usual
except with whole body irradiation. - Idiosyncratic
- unpredictable to drugs e.g., anti-inflammatory
antibiotics, anti-epileptic, these agents usually
do not produce marrow failure in the majority of
persons exposed to these agents.
10Common Traits To All Various Causes
- Aplasia due to any cause may recover after
immunosuppressive therapy indicating that immune
mechanisms are involved. - Transition to a clonal disorder of hemopoiesis
can occur in any patient who has recovered bone
marrow function, suggesting that fragility of the
hemopoietic system is common to all forms of
aplasia.
11Aplastic Anemia Clinical Features
- anemia ? pallor and/or signs of congestive heart
failure, such as shortness of breath. - thrombocytopenia ? bruising (eg, ecchymoses,
petechiae) on the skin, gum bleeding, or
nosebleeds. - neutropenia ? fever, cellulitis, pneumonia, or
sepsis - jaundice and evidence of clinical hepatitis in
subset of patients
12Aplastic Anemia Clinical Features
- adenopathy or organomegaly ?should suggest an
alternative diagnosis. - In any case of aplastic anemia, look for physical
stigmata of inherited marrow failure syndromes
such as - skin pigmentation,
- short stature,
- microcephaly,
- hypogonadism,
- mental retardation,
- skeletal anomalies.
13Aplastic Anemia investigations
- FBC
- Reticulocyte count
- Blood film.
- B12/folate.
- Liver function tests
- Virology
- Bone marrow aspirate trephine
- PNH screen.
14Aplastic Anemia FBC
- Anemia is common, and red cells appear
morphologically normal. The reticulocyte count
usually is less than 1. - Thrombocytopenia, with a paucity of platelets in
the blood smear. - Agranulocytosis (ie, decrease in all granular
white blood cells, including neutrophils,
eosinophils, and basophils) and a decrease in
monocytes are observed. A relative lymphocytosis
occurs. - The degree of cytopenia is useful in assessing
the severity of aplastic anemia.
15Bone marrow exam
- A bone marrow biopsy is performed in addition to
the aspiration. In aplastic anemia, these
specimens are hypocellular. - Aspirations alone may appear hypocellular because
of technical reasons (eg, dilution with
peripheral blood), or they may appear
hypercellular because of areas of focal residual
hematopoiesis. - A core biopsy provides a better idea of
cellularity the specimen is considered
hypocellular if it is less than 30 cellular in
individuals younger than 60 years or less than
20 in those older than 60 years.
16BM Aspiration
BM Biopsy
17(No Transcript)
18BM biopsyhypocellular ,increased fat spaces
19APLASTIC ANEMIA other investigations
- Hemoglobin electrophoresis - may show elevated
fetal hemoglobin. - Biochemical profile, including evaluation of
transaminases, bilirubin, lactic dehydrogenase,
Coombs test, and kidney function, is useful in
evaluating etiology and differential diagnosis. - Serologic testing for hepatitis EBV, CMV, and HIV
- Autoimmune disease evaluation for evidence of
collagen-vascular disease - The Ham test or sucrose hemolysis test frequently
is performed for excluding PNH. - Histocompatibility testing should be conducted
early to establish potential related donors,
especially in younger patients.
20Aplastic Anemia - Criteria for diagnosis (1)
- 1. Cytopenia - Hb lt10g/dL
- - ANC lt1,5 G/L
- - PL lt100 G/L
- 2. Bone marrow histology and cytology
- - decreased marrow cellularity (lt 25)
- - increased fat cells component
- - no extensive fibrosis
- - no malignancy or storage disease
21Aplastic Anemia - Criteria for diagnosis (2)
- 3. No preceding treatment with X-ray or
antyproliferative drugs - 4. No lymphadenopathy or hepatosplenomegaly
- 5. No deficiencies or metabolic diseases
- 6. No evidence of extramedullary hematopoiesis
22APLASTIC ANEMIA differential
- Pancytopenia
- Acute Myelogenous Leukemia
- Anemia
- Aplastic Anemia
- Hairy Cell Leukemia
- Paroxysmal Nocturnal Hemoglobinuria
- Immune pancytopenias in connective tissue
disorders (eg, systemic lupus erythematosus,
refractory anemia)
23Causes of pancytopenia
- 1.Failure of production of blood cells
- a) bone marrow infiltration
- - acute leukemias
- - hairy cell leukemia
- - multiple myeloma
- - lymphoma
- - myelofibrosis
- - metastatic carcinoma
- b) aplastic anemia
- 2. Ineffective hematopoesis
- - myelodysplastic syndrome
- - vit.B12 and folate deficiency
- 3. Increased destruction of blood cells
- - hipersplenism
- - autoimmune disorders
- - paroxysmal nocturnal hemoglobinuria
- 4. Myelosuppression after irradiation or
antiproliferative drugs
24Classification of aplastic anemia
- 1. Severe aplastic anemia is defined if at last
two of the following criteria are present - - ANC lt 0.5 G/l
- - PLT lt 20 G/l
- - RTC lt 1 (20 G/l)
- Hypoplastic bone marrow (less than 25) on
biopsy - 2. Very severe aplastic anemia
- - criteria as above but ANC lt 0.2 G/l
- 3. Non-severe aplastic anemia.
25Evolution of AA - Clinical course 1
- Stable AA
- Pancytopenia remains stable over months to years.
- Greater the degree of pancytopenia the worse the
prognosis. (see severe aplastic anaemia)
26Evolution of AA - Clinical course 2
- Progressive or fluctuating aplasia.
- Initially small degrees of pancytopenia or single
lineage cytopenia. - Progressive sometimes following viral infections.
- Occasionally single cytopenia e.g.
thrombocytopenia becomes true aplastic anaemia.
27Evolution of AA - Clinical course 3.
- Unstable Aplasia.
- Improvement in counts may be associated with
abnormal clones. - PNH clone in up to 20 of long term aplastic
anaemia. - Often only detected by lab tests and not
clinically significant.
28Aplastic Anemia - Treatment
- Withdrawal of etiological agents.
- Supportive.
- Restoration of marrow activity
- Bone marrow transplant
- Immunosuppressive treatment
- - Prednisolone - Antilymphocyte glob.
- - Cyclosporin - Anti T cells abs.
- - Splenectomy
- Androgens
- Growth factors
29APLASTIC ANEMIA treatment
- Supportiv care
- Transfusion
- Treatment of anemia
- Treatment of bleeding
- Prevention and treatment of infection
30HLA identical sibling BMT
- Age lt40 years.
- Conditioning with Cyclophosphamide
antithymocyte globulin, with cyclosporin and
methotrexate. - Long term overall survival 80-90
- Chronic graft versus host disease (GVHD) remains
a problem for 25-40 of patients.
31Hematopoietic stem cell transplatation in severe
aplastic anemia
- 1. Advantages
- - correction of hematopoietic defect
- - long-term survival 80 - 90 (HLA-matched
sibling donor) - - majority of the patients appear to be cured
- 2. Restrictions
- - age below 40
- - suitable donor available in less than 30
(sibling) - - 25-40 risk of GVHD
- - 5-15 risk of graft failure in
multitransfused patients - - high mortality after MUD-HSCT
- - solid tumors (12)
32Immunosuppressive therapy
- Indicated for patients gt 40 years
- Patients with no HLA matched sibling donors.
- Anti-Thymocyte Globulin(ATG) or anti-lymphocyte
globulin (ALG), cyclosporin, methylprednisolone. - Best results are for combination therapy.
- Response is slow, 4-12 weeks to see early
improvement.
33Immunosuppressive therapy
- Immunosuppressive therapy
- Antithymocyte globulin, equine (Atgam) - 10-20
mg/kg/day for 8-14 days. - Antithymocyte globulin, rabbit (Thymoglobulin) -
0,75 mg/kg/day for 8 days. - Cyclosporine (Sandimmune, Neoral) - 1.5-2 mg/kg
IV q12h, - Methylprednisolone (Medrol, Solu-Medrol) - 5
mg/kg IV on days 1-8 then tapered using PO 1
mg/kg on days 9-14 further tapering over days
15-29. Stop after 1 mo except in evidence of
serum sickness. - Cyclophosphamide (Cytoxan) 45 mg/kg/d IV for 4
d.
34Immunosuppressive therapy 2
- Response rates 60-70
- Relapses are common and continued supportive care
needed. - Up to 50 of relapsed patients will respond to
2nd course of immunosuppressive therapy.
35APLASTIC ANEMIA treatment
- Other treatments
- Androgens
- these agents push the resting hematopoietic stem
cells into cycle, making them more responsive to
differentiation by hematopoietic growth factors
and stimulate endogenous secretion of
erythropoietin. - most are masculinizing and poorly tolerated by
females and children. - The response rate is limited to approximately
45, and results may require 6-10 months of
therapy. - Hematopoietic growth factors - G-CSF and GM-CSF,
may be useful in patients with neutropenia who
have infections, without requiring a WBC
transfusion.
36Therapy of non-severe aplastic anemia
- 1. Watch and wait
- 2. Androgens (?)
- 3. Supportive care blood and platelet
transfusion, antibiotics, growth factors - 4. Immunosuppressive treatment in selected
patients
37APLASTIC ANEMIA complications
- Infections
- Bleeding
- Iron overload
- Complications of BMT
- Graft versus host disease
- Graft failure
38Treatment for adults with acquired severe
aplastic anaemia.
39Treatment for adults with acquired non severe
aplastic anaemia.