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Aplastic Anemia
Terminology:
• -aplastic anemia or hypoplastic anemia : pancytopenia in peripheral blood,
due to bone marrow hypoplasia . It is a complex nonregenerative anemia,
involving all the blood cell lines, but without infiltration of the bone marrow
with abnormal blood cells or nonhematopoietic cells;
• -synonymous : bone marrow insufficiency; bone marrow aplasia;
• -pure red blood cell anemia : aplastic anemia involving the erythroid
precursors only; the other hematopoietic lineages are normal;
• -hypoproliferative anemias : a heterogenous group of anemias, characterized
by a deficient or a lack of response to erythropoietin and related cytokines and
humoral stimuli;
• -myelophthisic anemia : anemia associated with quantitative and sometimes,
qualitative abnormalities of the WBC and platelets, generated by infiltration
of the bone marrow with abnormal hematopoietic or nonhematopoietic cells;
Etiology.
Pathophysiology
The bone marrow might be compared with the soil : the harvest is poor if the soil is
inadequate, the grains are impaired , there are pests or no fertilizers, namely :
• a defective hematopoietic microenvironment (“the soil”)
• quantitative or qualitative intrinsic defect of the stem cells (“the grains”);
• immunologic suppression of hematopoiesis (“pests”):
• humoral (antibody-mediated);
• cell-mediated;
• lymphokine-mediated;
• abnormalities of cytokine production (“no fertilizers”).
In aplastic anemia the great majority of patients presents not an unique, but a
complex of pathophysiological factors which act , possibly, in a peculiar genetic
condition to generate the disease.
Clinical aspect.
Due to pancytopenia, clinical features at presentation are difficult, if not impossibly,
to differentiate from acute leukemia. The classical aspect of both nosological entities
associates the well-known three syndromes:
• anemic;
• infectious;
• hemorrhagic,
but, in aplastic anemia, there are also three negative clinical features :
• no lymph nodes enlargement,
• nor splenic enlargement,
• neither liver enlargement.
If splenomegaly or lymph nodes enlargement appear during evolution of aplastic
anemia, it’s necessary to investigate the association of another disease (infectious or
neoplastic).
Laboratory aspect .
A.-Peripheral blood:
• red blood cells (RBC) : anemia, usually severe, is normochromic, normocytic (at
least at the onset; in evolution, a slight macrocytosis can appear) and aregenerative
(reticulocytes < 5% ; in absolute number ,<50,000/µ L); RBC are normal as
morphological aspect; the presence of nucleated RBC ,associated or not with
myelocytes , metamyelocytes and band neutrophils suggests extramedullary
hematopoiesis, as in osteomyelofibrosis or in slow-progressive neoplasia;
• white blood cells (WBC): granulocytes are decreased (in absolute count
<1,500/µ L), associated with monocytopenia; in isolated cases, abnormalities of
the granulocyte granules and increased values for the alkaline phosphatase (ALP)
may be observed; lymphocytes may be normal in absolute count, but in some
cases, functionally impaired on disparate subsets , acting very probably as a
pathogenic factor for aplastic anemia;
• platelets : thrombocytopenia is always present, but at a variable degree; in aplastic
anemia, platelets are functionally normal, so that the bleeding appear if the
medullary insuficiency has a sudden onset - in some hours or days and at very low
platelets count (below 50,000/µ L ); a severe hemorrhagic syndrome suggests
usually another disease; on the blood smear, platelets appear morphologically
normal ; the presence of bizarre-shaped platelets suggests another disease,
eventually with extramedullary hematopoiesis;
B.-Bone marrow:
1.- by aspiration : hypoplastic or aplastic; in some cases, slightly infiltrated with
lymphocytes, morphologically normal; the presence of a greater count of
lymphocytes (over 20%) in bone marrow or infiltration with altered
hematopoietic cells or non-hematopoietic cells reveals another disease;
2.- by biopsy : the bone marrow may appear infiltrated with fat cells; between
the hexagons of the fat cells, some scanty hematopoietic cells may appear ,
associated or not with lymphocytes and plasma cells. The medullary fibrosis may
appear, in rapport to the etiology (e.g., ionizing radiation), but without
neoosteogenesis, which permits the differential diagnosis with myeloid metaplasia
with myelofibrosis. If islands or active hematopiesis are identified, it is necessary
to continue investigations for differential diagnosis with myelodisplastic or
myeloproliferative syndromes.
Diagnosis:
a.-the presence of the aplastic anemia may be ascertained by:
b.-the differential diagnosis should be made with all other causes of pancytopenia :
• the desertic bone marrow excludes a hypersplenismus (in that case, the bone
marrow would be hyperplastic);
• the absence of atypical cells in the bone marrow excludes a proliferative
syndrome, either hematologic or non-hematologic;
• the anamnesis , evolution and specific biochemical data (bilirubin; Hb
electroforesis ; red blood cells enzymes etc.) exclude the aplastic crisis in
hemolytic anemia;
Natural course :
• the major risk of exitus exists during the first two years, because of complications
due to severe pancytopenia : infections, bleeding (especially cerebral), ischemic
alterations in the vital organs due to persistent and severe anemia; 25% of patients
only, survives after 1 year from the onset (the maximum mortality -50%- appears
during the first 10 months from the onset); if the patient survives , after this period
the lethal risk decreases, due to adaptive measures the organism develops; in 10 %
of cases, the complete recover may appear;
• another category of risk is evolution into acute leukemias (even after many years
of evolution), myelodysplastic syndromes, solid tumors;
• less frequent, the aplastic anemia may be complicated in evolution with
paraproteinemias, connective tissue diseases (which might be also a pre- or
paraneoplastic syndrome), hemolytic anemias ( which may precede an acute
leukemia);
• another category of risk is correlated with therapy : it is considered that
immunosupressive treatment is more frequently associated with malignancy, as
compared with bone marrow transplantation, but that one, in turn, is associated
with graft-versus-host disease, risk of precocious death because of the
conditionning therapy for transplantation and a remote risk of malignancy ;
Prognosis :
• depends on etiology :
- aplastic anemia secondary to ionizing radiation exposure has frequently a
short-term evolution to an acute leukemia;
- aplastic anemia associated with hepatitis has a high incidence of mortality;
- aplastic anemia due to drugs has a somehow more favorable prognostic
features;
• there is no an absolute correlation with age and sex.
The International Aplastic Anemia Study Group (IAAG) appreciates the following
criteria to ascertain a severe aplastic anemia (any two blood criteria + either
marrow criterion denote a severe prognostic for aplastic anemia) :
Blood :
• neutrophils < 500/µ L;
• platelets <20,000/µ L;
• reticulocytes < 1% (as corrected value)* ;
Bone marrow:
• severe hypocellularity;
• moderate hypocellularity with < 30% of residual cells being hematopoietic;
Treatment
Immediately after the diagnosis, the patient with severe aplastic anemia (according
to the above criteria), should be evaluated for bone marrow transplantation and if it
is possible, blood transfusions should be avoided or extremely limited , because it
rises the risk of rejection.
I.-Etiologic therapy;
II.-Pathogenic therapy:
1.-bone marrow transplantation;
2.-immunomodulatory therapy;
3.-hematopoietic stimulatory therapy;
III.-Symptomatic therapy:
1.-antianemic;
2.-antiinfectious;
3.-hemostatic;
4.-Cytostatics :
• are difficult to use as immunodepressors, because of hematological secondary effects, except the
Vinca Rosea alkaloids, which are well tolerated; indication : cases with documented immune
pathogeny (bone marrow infiltration with mononuclear cells); dosage : 0.5 mg in saline
physiological solution in intravenous infusion for 20 min.; if well tolerated, without decrease of
platelets and WBC, the same dose can be repeated every 4 to 7 days, for 4 times at least (risk :
peripheral polyneuropathy);
• “heroic” chemotherapy : because during the preparative therapy for bone marrow transplantation,
some cases recover “spontaneously”, high-dose Cyclophosphamide has been used as unique
therapy : 45 mg /Kg /day for 4 days, with or without Cyclosporine A for an additional 100 days .
In this trial (presented by Williams), 7/10 patients recovered completely and remain in remission
11 years later.
c.-Hematopoietic stimulators :
1.—cytokines : are inconstantly efficient and for short periods only , but should be tried however
in patients which are not suitable for bone marrow transplantation because of peculiar reasons. It
has been used recombinant erythropoietin, GM-CSF (250-350 µ g daily by subcutaneous
injection), IL-1 , a potent stimulator of marrow cell production and IL-3 . It has been suggested
that the poor and inconstant response is due to the deficiency of the bone marrow stem cells, so
that because of the impaired maturation, the cytokines are not able to act because the target
( the more “mature” cells) is poor ;
2.- androgens : stimulate erythropoietin production. A great variety of androgens are in use:
testosterone, methyl-testosterone, oxymetholone, fluoxymesterone, testosterone enanthate ,
nandrolone , according to different schedules :
• Nandrolone decanoate , 400 mg intramuscularly per week for at least 3 to 6 months; risk : local
hematoma; impairment of the liver functional tests : hepatocytolysis, hyperbilirubinemia ;
• or : oxymetholone 1-2 mg/Kg per day for 3-6 months;
3.-Lithium Carbonicum: acts similarly to the CSF-GM :
• dosage : 600 mg per day, orally, for at least 10 to 21 days;
• risk : precipitates a hepato-renal insufficiency ; therefore, the lithium-therapy is forbidden during
functional hepato-renal impairment, as well as in the ECG alteration (risk of paroxysmal rhythm
disturbances).
3.-The symptomatic therapy:
a.-Antianemic therapy : a long-term treatment with folic acid may be followed, eventually in
association with B-12 vitamin (but generally the plasmatic level of the B-12 is increased during
aplastic anemia). The administration of iron is forbidden, because of the risk of hypersideremia
with secondary hemochromatosis (hypersideremia is already present in aplastic anemia and
repeated blood transfusions increase it);
• blood transfusions : packed red blood cells, platelets concentrates and white blood cells
concentrates are indicated only during a severe impairment of the general condition (severe blood
loss, infection etc. ), because of :
• allergic risk with rapid progression of cytopenia;
• inhibition of the still active hematopoietic islands of the bone marrow;
• hemochromatosis;
• iso-immunization;
Patients to whom a bone marrow transplantation is intended, should not to be transfused, if
possible.
b.-antiinfectious therapy: broad-spectrum antibiotics, associated with granulocytic concentrates,
according to the same schedules as in acute leukemia;
c.- hemostatic therapy : systemic hemostatics, including Vitamin K, fibrin stabilizers( tranexamic
acid, epsilon-aminocaproic acid), platelet proaggregants (Etamsilat*, Dicynone*), platelet
concentrates, even fresh plasma transfusions may be used , according to the severity of bleeding.
Splenectomy: doesn’t increase the hematopoiesis, but improves sometimes the platelet and
granulocyte number, but the immediate high mortality during surgery because of bleeding or later,
because of severe infections, makes this an exceptional therapeutical procedure.
Post-therapeutical course and prognosis. Bone marrow transplantation and immunosupressive
therapy improved significantly the prognosis : marrow transplantation is successful in 50-75 % of
cases, but complications appear as graft-vs-host reaction or graft rejection. The highest mortality
still appears during the first two years after diagnosis , even in transplanted patients. After this
period, the organism adapted himself to the low values of neutrophils and platelets and can survive
for longer periods, even over 10 years.
REMEMBER!
• Etiology : especially radiation , chemicals and thymoma;
• Diagnosis : pancytopenia + desertic bone marrow;
• Therapy : bone marrow transplantation in patients <40 y old; immunomodulators;
• associated therapies : hematopietic stimulators, supportive care (symptomatic therapy);
• major risk of death : during the first two years.