Aplastic Anemia
The term “a2plastic anemia” be reserved for cases in which pancytopenia exists,
in which there is evidence of decreased production of all the elements of the blood
formed in the marrow, including severe hypoplasia or aplasia of the marrow.
1 . Etiology
(l). Acquired Aplastic Anemia
1). Drug and chemical agents: It can be divided into two main categories:
A. Agents that regularly produce marrow hypoplasia and aplasia if a sufficient dose is
given.
B . Agents occasionally associated with hypoplasia or aplasia.
The pathogenesis of chloramphenicol-associated blood dyscrasias is obscure.
Although not all investigators agree, most believe that two types of reactions occur, a
reversible suppression of erythropoiesis and irreversible aplasia. Reversible bone
marrow suppression primarily involving erythropoiesis occurs in about 50% of
patients to whom chloramphenicol is given in large doses. Mitochondrial protein
synthesis and mitochondrial ultrastructure of both erythroid and myeloid cell
precursors are adversely affected by the usual clinical levels (10 to 16 μg/ ml) of
chloramphenicol. Severe and often irreversible bone marrow aplasia, frequently
resulting in death, is the second type of reaction to chloramphenicol. In most instances,
aplastic anemia becomes evident only after use of the drug has been discontinued.
Damage to a high percentage of stem cells has been postulated. Damage to the
chromosomes of human blood leukocytes cultured in vitro in the presence of
chloramphenicol in usual therapeutic concentrations (10 to 40 μg / ml) provides
support for this concept.
2). IONIZING RADIATION. The acute destructive is well known, as is the fact that
excessive exposure may result in severe and even fatal aplastic anemia, lower grades
of exposure lead to less serious or no detectable changes in the blood.
3 ). infections
Pancytopenia with a plastic or hypoplastic marrow has been reported occasionally
in association with such conditions as mycobacterial infection and, with increasing
frequency of infectious hepatitis.
4). Other cause. Some cases were reported in association with pregnancy, most of the
subjects improving after delivery or abortion.
(2). "Idiopathic" Aplastic Anemia
Although one may search carefully for a possible etiologic agent in cases of
pancytopenia, there remain approximately 50% of cases in which no cause is found or
suspected.
2. Pathophysiology
The basic defect in aplastic anemia appears to be a failure of blood cell
production that involves erythrocytes, platelets, and leukocytes.
(1). Stem cell deficiency
Stem cell population has been decimated or rendered incapable of repopulating
the marrow cell mass. The success of marrow transplants in some identical twins and
the increased incidence of nuclear abnormalities in some patients with idiopathic
marrow aplasia and of chromosome abnormalities in those with Fanconi’s anemia, as
well as the fact that defects have been found in all three cell lines in patients with
paroxysmal nocturnal hemoglobinuria and marrow hypoplasia, suggest a defect in
stem cells. In addition, the marrow content of stem cells capable of forming colonies
on in vitro culture is reduced in patients with aplastic anemia.
(2). Micro-environment deficiency
The failure of marrow infusions to repopulate areas of heavily irradiated marrow
(4,000 R) in animals, failure of marrow to regenerate in man after more than 2500 to
3500 Rads have been delivered, and the marrow hypoplasia observed in starvation
and in graft-versus-host rejection suggest that the marrow environment is important
and in some instances may to unable to support marrow cell growth.
(3). Immunological theory
The pathogenesis of some patients of aplastic anemia is related to the
immunologic mechanism. The marrow and peripheral blood lymphocytes of aplastic
anemia can inhibit the colonies formation of normal marrow culture in vitro. The
patient of aplastic anemia who received large doses of immunosuppressive drug
during transplantation, if the graft was rejected but the marrow function was
recovered dramatically. Some patients was treated by ATG or CTX or large doses of
steroid alone, will get remission. These evidence can support the immunological
mechanism of pathogenesis.
3. Symptoms and Signs
In the majority of patients the initial symptoms of acquired aplastic anemia are
manifestations of anemia and/or bleeding, but fever or infection are not uncommon.
The onset is insidious. The symptoms and signs depend on the rapidity with which the
anemia progresses and whether or not complicating infections and hemorrhage
develop. Infection and hemorrhage, in turn, depend in part on the degree of
granulocytopenia and thrombocytopenia.
4. Laboratory findings
(l). Blood changes
1). Hemoglobin and RBC were decreased. The anemia was normochromic normocytic
type.
2). Leukocytopenia----The leukocytes formed in the bone marrow are affected chiefly
and thus the differential count may contain as many as 70-90% lymphocyte.
3). Thrombocytopenia. The bleeding time is usually moderately prolonged and the
blood clot retracts poorly when thrombocytopenia is present.
(2). Bone Marrow
The majority, even 60 to 100%, of the nucleated cells are lymphocytes. In
marrow biopsy specimens from patients with typical aplastic anemia, only yellowish
white material, consisting chiefly of fat, fibrous tissue, and lymphocytes, is seen.
1. Acute and chronic type of aplastic anemia
Onset
Infection
Bleeding
WBC
Platelet
Reticulocyte
Anemia
Hb
Bone marrow
Prognosis
Acute type
Sudden
Almost every cases
Frequently and heavy
1.0x109/L
10 x109/L
0 or 0.1-0.2%
No or mild
Normal or mild decrease
Severe aplasia
Poor
Chronic type
Insidious
Rare and mild
Mild
9
2.0 x10 /L -3.0 x109/L
20 x109/L -30 x109/L
0.5%±
Moderate to severe
Decrease
Hypoplasia or aplasia
Better than acute type
6. Differential diagnosis
(l). Other diseases with pancytopenia----acute leukemia (subleukemic or aleukemic
type), megaloblastic anemia, histiocytosis, carcinoma metastasis to the marrow
(leukoerythroblastic reaction or anemia)
(2). Paroxysmal nocturnal hemoglobinuria----Ham’s test and Rous test will positive in
PNG. Peripheral blood was pancytopenia in PNH. The bone marrow in PNH was
hyperplasia, but in the late stage of PNH the bone marrow will hypoplasia.
(3). Thrombocytopenic purpura and aganulocyrosis----Occasionally only anemia or
leukopenia, thrombocytopenia or “bicytopenia” may be the first presenting sign in
aplastic anemia.
7. Treatment
Treatment involves
1). a thorough search for a possible cause and prohibition of further exposure to a
suspected drug or other toxic agent even if the evidence is not very impressive.
2). maintenance of hemoglobin levels by blood transfusion.
3). Prevention and management of hemorrhage and infection.
4). attempts to stimulate hematopoiesis and marrow regeneration.
5). evaluation of the possible role of the spleen in the destruction of transfused red
cells or platelets, and the removal of this organ if the evidence suggests that this may
be wise and the patient can tolerate the procedure.
6). Possible marrow transplantation in carefully selected patients.
(l). Avoidance of Further Exposure
Although it is obvious that the first requirement is the avoidance of further
exposure to an etiologic noxious agent, this is sometimes overlooked or the cause is
not recognized. Exposure to infections should be avoided if possible. This may
involve the restriction of visitors, reverse isolation, or the use of plastic isolators or
laminar air-flow units. The use of absorbable prophylactic antibiotics is not
recommended since this encourages the development of resistant strains and atypical
infections.
(2). Management of hemorrhage
When hemorrhage is a problem, administer of fresh blood, platelet-rich plasma,
or platelet concentrates in amounts is sufficient to maintain the platelet concentration.
(3). Relief of Anemia
The mainstay of treatment has been the transfusion of whole blood for the relief
of anemia. Currently specific blood components (leukocytepoor packed red cells,
platelet-rich plasma or concentrates, and less often leukocyte concentrates) are being
used in many centers. The available blood supplies were effectively utilized with
mininal side effects such as isoimmunization and undesirable blood volume
expansion.
(4). Stimulation of Hematopoiesis and Marrow Regeneration
The measures most widely employed to improve marrow function has been
administration of anabolic steroids (testosterone, oxymetholone, etc). Adrenal
corticosteroids have been used extensively in the treatment of patients with aplastic
anemia. Phytohemagglutinin has been used in an attempt to stimulate mitosis and
marrow regeneration with apparent good response in some subjects.
(5). Immunosuppressive agents
If the pathogenesis of aplastic anemia is due to immuno-mechanism,
immunosuppressive agents such as cyclophosphamide, anti-lymphocyte globulin
(ALG), antithymal globulin (ATG) and Cyclosporin A can be used.
(6). Chinese traditional medicine
(7). Splenectomy
(8). Heamtopoietic Grafts
There has been great interest in the use of hematopoietic grafts in humans and
many attempts to transplant bone marrow have been made in patients with leukemia
and marrow aplasia.
Zhonglu