3 Lesson 3 - Aplastic Anemia

LuJiZhou

Bone marrow failure  It implies that peripheral blood

cytopenia has arisend primarily as a result of a specific failure happened in the bone marrow precursor cells to produce mature cells  It composes the aplastic anemia and the single-cell cytopenias

Definition  Aplastic anemia defined as the

presence of the pancytopenia in the perapheral blood and a hypocellular marrow in which the normal haemotapoietic marrow is replaced by the fat cells .  No abnormal cell can be found .

Background  Paul Ehrlich, MD, introduced the

concept of aplastic anemia in 1888 when he studied the case of a pregnant woman who died of bone marrow failure. However, it was not until 1904 that this disorder was termed aplastic anemia by Chauffard.

Incidence and Prevalence  A. Frequency Internationally In China

 B. Race No racial predisposition exists

 C. Sex The male-to-female ratio in acquired aplastic anemia is approximately 1:1

 D. Age Aplastic anemia occurs in all age groups.

Etiology and Classification (1)  Inherited aplastic anemia fanconi anemia , estrendameshek anemia , schwachman-diamond sydrome (2)  Acquired aplastic anemia(50% Idiopathic) ※

Etiology  Radiation  X-ray  Drugs and chemistry  benzene, antineoplastic

agent  Idiosyncratic reaction  sulfa drug(nimesulide), NSAID  (non-steroid anti –inflammatory drug) et.

Etiology  Viruses  Epstein-Barr virus  (infectious mononucleosis)  Parvovirus B19※  Hepatitis virus※  Human immunodeficiency

vivrus(AIDS)

Etiology  Immune diseases  Eosinophilic fasciitis  Hypoimmunoglobinemia  Thyoma and thymic

carcinoma  Graft-versus-host disease in immunodeficiency  Paroxysmal nocturnal hemoglobinuria  Pregnancy

Pathogenesis 1.Seed theory Defect in hemopoietic stem cells 1.Soil theory Defect in the stromal microenvironment 3. Insect theory

Immune Impairment CD8 、 CD25 , CD4 Abnormal Cytokines

Etiology and pathogenesis Cholormycetin 1.Drugs Sedative anti-cancer

(-)

division quantity and/or synthesis of protein (-) quality abnormality of mRNA stem cells (seed theory; defective stem cell)

2.Chemical toxic Beyene Substance inorganic arsenic (-) 3.Virus infection (+) antibodies resisting stem cells (EB;hepatitis) self-immunition (+) IFN↑ (-) (insect theory; disorder immunine function) 4.Physical factors copy of DNA (-) regeneration of hematopoietic (X-ray,r-ray) (-) cells damage microenviroment (-)hypoproliferation or failure of BM (soil theory; defect of hemopoietic microenviroment)

Clinical Manifestations A. Symptoms 1.  Bleeding-----The most common early symptom 2. Anemia-----Lassitude, weakness, shortness of breath, and a pounding sensation in the ears. 3.  Infection A striking feature of aplastic anemia is the restriction of symptoms to the hematologic system-----Patients often feel and look remarkably well despite drastically reduced blood counts.

e B. Physical examination 1.Petechiae and ecchymoses 2.Pallor of the skin and mucous membranes 3.Fever and signs of systemic or local infection 4.Lymphadenopathy and splenomegaly----rarely

Laboratory feature 1.   Blood finding (1)   Pancytopenia ①The total leukocyte count is decreased ②Neutrophil% decreased ③lymphocyte% increased ④Platelet decreased (2)   Low reticulocyte index

2.   Marrow findings (1)The marrow aspirate typically contains numerous spicules with empty fatty spaces and relatively few hemopoietic cells. (2) Lymphocytes, plasma cells, macrophges, and mast cells may be prominent, but this probably reflects a lack of other cells rather than an increase in these element. (3)On ocassion, some spicules are celluar or even hypercellular, but magakaryocytes are usually reduced. (4)Marrow biopsy is essential to confirm the overall hypocellularity.

Diagnosis and Differential diagnosis  The

ultimate diagnosis of aplastic anemia rests on the interpretation of an adequate bone marrow biopsy specimen.



According to the laboratory data, classify aplastic anemia into two kinds of type: Severe AA and Moderate AA.

The diagnostic criteria of Aplastic anemia Severe AA

Bone marrow cellularity <30% Two of three peripheral blood criteria ANC<500/mm3 Platelet<20,000/mm3 Reticulocytes<15,000/ mm3 No other hematologic disease

Moderate AA Patients with pancytopenia who do not fufill the criteria of severe disease

Before make a diagnosis ,we should exclude other causes of pancytopenia, as the followings:

Table2 Differential Pancytopenia

Diagnosis

of

Pancytopenia with hypocellular bone marrow Acquired aplastic anemia Inherited aplastic anemia Some myelodysplasia syndromes Some acutue myelogenous leukemia Some acute lymphoblastic leukemia in childhood Some lymphomas of bone marrow

Pancytopenia with cellular bone marrow  Paroxysmal nocturnal hemoglobinuria  Myelofibrosis  Some acute myelogenous leukemia  Bone marrow lymphoma  Hairy cell leukemia  Systemic lupus erythematouus  hypersplenism  VitaminB12, folate deficiency  Overwhelming infection  AIDS  Alcoholism  Brucellosis  Sarcoidosis  Tuberculosis

(1)Myelodysplastic syndromes: Approximately 10% of patients with myelodysplastic syndromes present with hypoplasia rather than a hyper cellular marrow . But in myelodysplasia marrow erythroid precusors have both megablastoid and dysplastic features with dumbell nuclei, Howell-Jolly bodies and increased siderotic granules. Granulocyte precusors have reduced granulation, with abnormal blue cytoplasma in the promyelocytes and megaloblastoid features. Cytogenetic abnormalities are often found.

(2) Acute lymphocytic leukemia This disease may have initially have a hypoplastic phase, but we may found many clumps of lymphocytic cells. Sometimes hairy-cell leukemia maybe preceded by a hypoplastic phase. Both conditions can be differentiated from severe aplastic anemia by using of special stains.

Therapy 1.   Marrow transplantation 

Stem cell transplantation offers the best therapy for a young patient with a fully histocompatible dibbling donor.



Survival of patients younger than 20 years old following stem cell transplantion is about 65~70%.



Early consideration of the transplantation option in a child or adolescent can avoid unnecessary transfusions.

 Transfusion increased the risk of graft

rejection, already peculiarly high in patients with aplastic anemia.  Graft rejection is the major determinant of a successful clinical outcome.  It is usually not recommended for patients with AA who are more than 45 years old. Because after 45, the complications of transplantation are increased.  Management of patients in the intermediate range, 20~45 years old, depends on their transfusion history, on their general clinical condition

2.   Immune suppressive therapy (1)   The evidence for verifying the effectiveness 

Improvement occurred in benzene-induced AA in rabbits after ALG(Antilymphocyte globulin) treatment.



Many investigations found evidence of Tcell mediated suppressor mechanisms by in vitro marrow culture studies.

(2)      ATG (anti-thymocyte globulin )  It is reported ATG not only act by reducing

cytotoxic T cells but also releasing hemopoietic growth factors from certain T cells.  ATG therapy leads to recovery of autologous

BM function in about 50% of patients, usually with independence from transfusion and a leukocyte count adequate to prevent infection.  ATG can be given intravenously in a regimen

3-5mg/kg weigh for 5 days.

(3)      Cyclosporine A  CsA can inhibit IL-2 production by T

cells and prevents expansions of cytotoixc T cells in response to IL-2.  The recommended dosage is administered orally at an initial dose of 3~5 mg/kg weigh in adults with subsequent adjustment.  The most serious side-effects are nephrotoxicity, hypertension, seizures nd opportunistic infections.

(4)      ATG+CsA The combination of ATG and CsA is superior to ATG alone as initial therapy for severe aplastic anemia, prodcing hematologic responses in about 70% of cases. Improvement in granulocytes number is generally apparent within 2 months of treatment.

(5)Other combinations of immunosuppressive agents: cyclophosphamide

3.   4.   5.   6.  

Androgen therapy Hemopoietic growth factors Other therapy Supportive principles

(1) Control the infection (2) Platelet transfusion and stop bleeding a. Platelet levels can be maintained by transfusion b. Inhibitors of fibrinolysis (3) Red blood cells transfusion

Course and prognosis  The median survival of untreated patients

with AA is 3 to 6 months, with only 20% percent surviving beyond a year. Very severe AA has an extremely poor prognosis.  The estimated 5-year survival rate for the

typical patient receiving immunosuppression is 75% and for matched sibling donor BMT is greater than 90%.

Key points  The definition of aplastic anemia  The clinical manifestation of

aplastic anemia  The diagnostic criteria of severe aplastic anemia