aplastic-anemia-lecture-1a.ppt

7/28/2019 aplastic-anemia-lecture-1a.ppt

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APLASTIC ANEMIA


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Aplastic Anemia

Aplastic anemia is a bone marrow failuresyndrome characterized by peripheralpancytopenia and marrow hypoplasia.

Bone marrow failure is a term with a largermeaning, referring to disorders of the

hematopoietic stem cell which involveseither one cell line or all of the myeloid celllines


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History 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.


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Aplastic Anemiaepidemiology

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 1:1.

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.


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Aplastic 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:

1. Drugs- Cytotoxic drugs - Antibiotics

- Chloramphenicol - Anti-inflammatory

- Anti-convulsant - Sulphonamides

- 2-3 months usually between exposure and the development of aplastic anemia.


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Aplastic 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


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Aplastic Anemia - Pathogenesis

Potential mechanisms:

Absent or defective stem cells (stem cellfailure).

Abnormal marrow micro-environment.

Inhibition by an abnormal clone ofhemopoietic 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.


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Aplastic Anemia - Pathogenesis (Cont)

The latest theory is: there is an intrinsic derangement of

hemopoietic proliferative capacity, whichis consistent with life.

the immune mechanism attempt to destroythe abnormal cells (self cure) and theclinical course and complications dependon the balance.

If the immune mechanism is strong, there willbe severe pancytopenia.

If not, there will be myelodysplasia.


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Aplastic Anemia - Forms of disease: Inevitable:

dose related e.g. cytotoxic drugs, ionizingradiation. The timing, duration of aplasia andrecovery 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 donot produce marrow failure in the majority of

persons exposed to these agents.


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Common 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.


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Aplastic AnemiaClinical Features

anemia pallor and/or signs of congestiveheart failure, such as shortness of breath.

thrombocytopenia bruising (eg,

ecchymoses, petechiae) on the skin, gumbleeding, or nosebleeds.

neutropenia

fever, cellulitis, pneumonia, orsepsis

jaundice and evidence of clinical hepatitis in

subset of patients


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Aplastic AnemiaClinical Features adenopathy or organomegaly should

suggest an alternative diagnosis.

In any case of aplastic anemia, look for

physical stigmata of inherited marrowfailure syndromes such asskin pigmentation,

short stature,

microcephaly,hypogonadism,

mental retardation,

skeletal anomalies.


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Aplastic Anemiainvestigations

FBC

Reticulocyte count

Blood film. B12/folate.

Liver function tests

Virology Bone marrow aspirate & trephine

PNH screen.


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Aplastic AnemiaFBC

Anemia is common, and red cells appearmorphologically normal. The reticulocyte countusually 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 lymphocytosisoccurs.

The degree of cytopenia is useful in assessing theseverity of aplastic anemia.


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Bone marrow exam

A bone marrow biopsy is performed in addition to theaspiration. 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; thespecimen 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.


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BM Aspiration BM Biopsy


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BM biopsy

hypocellular ,increased fat spaces


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APLASTIC ANEMIAother

investigations

Hemoglobin electrophoresis - may show elevated fetalhemoglobin.

Biochemical profile, including evaluation of transaminases,bilirubin, lactic dehydrogenase, Coombs test, and kidneyfunction, 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 performedfor excluding PNH.

Histocompatibility testing should be conducted early to establishpotential related donors, especially in younger patients.


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Aplastic Anemia - Criteria for

diagnosis (1)

1. Cytopenia - Hb


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Aplastic Anemia - Criteria for

diagnosis (2)

3.No preceding treatment with X-ray orantyproliferative drugs

4. No lymphadenopathy or hepatosplenomegaly

5. No deficiencies or metabolic diseases

6. No evidence of extramedullary hematopoiesis


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APLASTIC ANEMIAdifferential

Pancytopenia Acute Myelogenous Leukemia

Anemia

Aplastic Anemia Hairy Cell Leukemia

Paroxysmal Nocturnal Hemoglobinuria

Immune pancytopenias in connective tissuedisorders (eg, systemic lupuserythematosus, refractory anemia)
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Causes 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 deficiency3. Increased destruction of blood cells

- hipersplenism

- autoimmune disorders

- paroxysmal nocturnal hemoglobinuria

4. Myelosuppression after irradiation or antiproliferative drugs


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Classification of aplastic anemia

1. Severe aplastic anemia is defined if at last two

of the following criteria are present:

- ANC < 0.5 G/l

- PLT < 20 G/l- RTC < 1% (20 G/l)

Hypoplastic bone marrow (less than 25%) on

biopsy

2. Very severe aplastic anemia

- criteria as above but ANC < 0.2 G/l

3. Non-severe aplastic anemia.


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Evolution 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)


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Evolution 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.


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Evolution 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.


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Aplastic 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


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APLASTIC ANEMIAtreatment

Supportiv care

TransfusionTreatment of anemia

Treatment of bleeding

Prevention and treatment of infection


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HLA identical sibling BMT

Age


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Hematopoietic 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 cured2. 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%)


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Immunosuppressive therapy

Indicated for patients > 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.


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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.


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Immunosuppressive 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.


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APLASTIC ANEMIAtreatment

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 endogenoussecretion 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.


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Therapy of non-severe aplastic

anemia1. Watch and wait

2. Androgens (?)3. Supportive care: blood and platelet

transfusion, antibiotics, growth factors

4. Immunosuppressive treatment in selectedpatients


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APLASTIC ANEMIAcomplications

Infections

Bleeding Iron overload

Complications of BMT

Graft versus host disease

Graft failure

T f d l i h i d


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Treatment for adults with acquired severe

aplastic anaemia.

T t t f d lt ith i d


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Treatment for adults with acquired non

severe aplastic anaemia.

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aplastic-anemia-lecture-1a.ppt