Thrombocytopenia
Thrombocytopenia maybe defined as a subnormal number of platelets in the circulating
blood. It is the most common cause of abnormal bleeding. In general, the severity and
frequency of hemorrhagic manifestations correlate to the platelet count. Platelet counts
below 20×109/L usually are associated with spontaneous hemorrhage.
Thrombocytopenia results from three processes: (1) deficient platelet production. Those
that depopulate the stem cell or megakaryocyte compartments are the most common, e.g.,
marrow injury by myelosuppressive drugs or irradiation and aplastic anemia.(2) accelerated
platelet destrucion, utilizaton or loss, e.g., idiopathic thrombocytopenia purpura, diffuse
intravascular coagulaton, thrombotic thrombocytopenia purpura. (3) abnormal distribution or
pooling of the platelets within the body. This type of thrombocytopenia is seen in the various
disorders associated with splenomegaly.
Idiopathic thrombocytopenic purpura
Idiopathic thrombocytopenic purpura ia an acquired disease of children and adults
characterized by a low platelet count ,an normal or increased numbers of megakaryocytes in
the bone marrow, and absence of evidence for other disease. Although this disease is also
referred to as immune thrombocytopenic purpura and autoimmune thrombocytopenic
purpura, idiopathic thrombocytopenic purpura remains the most common designation. The
clinical syndromes of ITP are divided into acute and chronic types.
[Etiology and pathogenesis]
Evidence is mow convincing that the syndrome of ITP is caused by platelet destruction
as the result of an immunologic process.
1. Platelet survival
Platelet survival is greatly shortened in ITP. The survival time of isologous platelets
labeled with 51Cr-chromate ranges from 2 to 3days to a matter of minutes.
2. Platelet antibodies
Thrombocytopenia in ITP appears to result from the action of a platelet antibody. The
infusion of plasma from patients with ITP predictably induces thrombocytopenia in normal
recipients. The responsible factor is an immunoglobulin of the IgG class that is species
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specific. Increased quantities of IgG have been demonstrated on the platelet surface, and the
rate of platelet destruction in ITP is proportional to levels of such platelet-associated IgG.
3. Immune complexes
The frequency with which acute ITP is associated with antecedent viral infection have
led to the suggestion that a viral antigen-antibody complex, may be responsible for platelet
sensitization and destruction in this form of the disorder.
4. Role of the spleen
When 51Cr-chromate-labeled isologous platelets are administered to patients with ITP,
external scintillation counting reveals a rapid accumulation of radioactivity predominantly in
the spleen. Platelet phagocytosis by splenic leukocytes has been demonstrated in vitro.
Hepatic sequestration of platelets has been demonstrated in association with ITP, usually in
patients with severe thrombocytopenia and markedly shortened platelet survival.
The spleen also is important in ITP as a site of production of platelet antibodies.
Splenic tissue from patients with ITP produces more immunoglobulin than that of normal
control subjects, and a significant percentage of that formed binds to homologous platelets.
5. Impaired thrombopoiesis
In chronic ITP, an immunoglobulin has been demonstrated on the surface of the
megakaryocytes by means of immunofluorescence and other techniques. Conceivably, the
attachment of antibody may impair platelet production. Thus, total megakaryocyte mass and
the platelet turnover rate were several times greater than normal.
[Clinical features]
1. Acute ITP
Acute ITP occurs most frequently in children 2 t0 6 years, it rarely affects adults and
has no gender predilection. In patients with acute ITP, the onset of the disorder usually is
sudden. A history of infection preceding the onset of bleeding has been documented
repeatedly. Acute ITP usually is self-limited; spontaneous remissions occur in as many as
93% of patients. The duration of the disease ranges from a few days to a few months, with an
average of 4 to 6 weeks.
2. Chronic ITP
Chronic ITP affects persons of all ages, but it is relatively more common between
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puberty and 50 years of age. It occurs more frequently in women than in men, a ratio of
approximately 3:1 having been found repeatedly. The onset of the chronic form of the
disorder usually is insidious. Patients usually have a fluctuating clinical course. Episodes of
bleeding may last a few days of a few weeks, and may be intermittent or even cyclic.
Spontaneous remissions are uncommon and are likely to be incomplete.
3. Bleeding manifestation
Bleeding into the skin in the form of petechiae is characteristec. Petechiae are
asymptomatic, not palpable, and occur most in dependent region. Symptoms and signs are
predictable from the known pattern of bleeding associated with platelet disorders: purpura,
menorrhagia, epistaxis, and gingival bleeding are common; gastrointestinal bleeding and
hematuria are less common. Intracerebral hemorrhage is uncommon, but it is the most
common cause of death and may occur acutely or at any time during a prolonged course.
4. Others
Repeated bleeding may lead to anemia of iron deficiency type. The spleen is
occasionally palpable on deep inspiration but never greater.
[laboratory Finding]
1. The blood
Isolated thrombocytopenia is the essential abnormality. Abnormalities in platelet size
and morphologic appearance are common. The platelets often are abnormally large, e.g., 3 to
4 μm in diameter, and reveal more than normal variation in size and shape. Other
morphologic changes may be seen in some patients, e.g., “giant”forms (10μm or more in
diameter), bizarre shapes, and deeply stained forms. The white blood cell count and
hemoglobin concentration are usually normal unless significant hemorrhage due to the
thrombocytopenia has occurred. Eosinophilia of blood and marrow may be noted, but this is
more common in the acute ITP of childhood.
Tests of hemostasis and blood coagulation reveal only changes attributable to
thrombocytopenia, such as a prolonged bleeding time, absent or deficient clot retraction, a
positive reaction to the tourniquet test, and deficient prothrombin consumption. The results
of tests of blood coagulation, e.g., prothrombin time, partial thromboplastin time, and
coagulation time, are normal in patients with uncomplicated thrombocytopenia.
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2. The marrow
Alterations in the bone marrow are limited to the megakaryocytes, with the exception
of the normoblastic hyperplasia that may develop as the results of blood loss. Increased
marrow megakaryocytes with a shift to younger, less polyploid megakaryocytes and fewer
mature, platelet-producing megakaryocytes has been commonly reported.
3. Tests for platelet antibodies
Assays of PAIgG represent the first sensitive and reproducible method for
demonstrating antibodies in ITP. PAIgG is increased in patients with ITP, and the magnitude
of increase is greater in patients with more severe thrombocytopenia.
[Differential diagnosis]
The diagnosis of ITP is made by excluding other causes of thrombocytopenia, e.g.,
acute
infectious
illness,
myelodysplastic
syndrome,
hypersplenism,
disseminated
intravascular coagulation, aplastic anemia, acute leukemia, systemic lupus erythematous.
Several differences exist between acute ITP and chronic ITP that are of particular
significance in the interpretation of data concerning the incidence of the disorder, its
prognosis, and the results of therapy (see Table).
Table. Features of acute and chronic ITP
Features
Acute ITP
Chronic ITP
Peak age incidence
Children 2-6 years of age
Adults, 20-40 years of age
Sex predilection
None
3:1, female to male patients
Antecedent infection
Common 1-3 weeks before Unusual
onset
Onset of bleeding
Hemorrhagic
bullae
Abrupt
in Present in severe cases
Insidious
Usually absent
mouth
Platelet count
<20×109/L
30-80×109/L
Duration
2-6 weeks; rarely longer
Months or years
Spontaneous remissions
Occur in 80% of cases
Uncommon; fluctuating course
common
[Treatment]
Physical activity should be restricted to minimize the hazards of trauma, particularly
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head injury. Drugs that impair platelet functions should be avoided. Blood loss should be
treated as otherwise indicated.
Observation: Most patients who are incidentally discovered to have asymptomatic mild
or moderate thrombocytopenia can safely be followed with no treatment.
1. Corticosteroids
Corticosteroids are widely used as the initial means of therapy. Mechanism of action:
(1) significantly diminish immunoglobulin synthesis. (2) inhibit the binding of antibodies to
platelets. (3) impair reticuloendothelial function and thereby to diminish platelet destruction.
One commonly used in initiation therapy consists of administering 40 to 60mg of prednisone
daily to adults, and 1mg/kg body weight to children. The initial course of steroids should be
maintained for 3 to 4 weeks, followed by a gradual tapering of the dosage. Steroid therapy
should not be maintained for long periods, a reasonable rule of thumb being 6 months at
most. Some increase in platelet numbers and a favorable clinical response can be expected in
70 to 90% of patients with ITP who receive adrenal corticosteroid therapy. However, most
patients will relapse when prednisone is tapered or discontinued.
2. Splenectomy
The major effects of splenectomy are twofold: (1) removal of the major site of
destruction of antibody-sensitized platelets. (2) removal of a major site of antibody
synthesis.
The indications for splenectomy in patients with ITP may be stated as follows: (1)
failure of spontaneous remission to occur after 6 months of observation in patients with
moderate or severe bleeding. (2) failure to respond to steroid therapy, relapse after
discontinuance of steroid therapy or reduction in the dosage, or the necessity of high doses
for maintenance of a clinical status free of serious hemorrhage. (3) difficulty in assuring
adequate follow-up care. (4) overriding contraindications due to the use of steroids.
Splenectomy is contraindicated in the following situations: (1) early in the first episode
of bleeding, especially in children, because of the frequency of spontaneous remissions. (2)
in patients with cardiac or other complications who are at risk of serious sequelae from any
major surgical procedure. (3) in children under 2 years of age, in whom the hazard of
fulminating infection after splenectomy is greater than at a later age. (4) in many cases of
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ITP in pregnant women. (5) in patients with acute ITP and major uncontrolled bleeding in
whom the mortality rate after splenectomy is high.
Most patients who will respond to splenectomy do so within several days. Complete
and sustained remissions have occurred after splenectomy in from 50 to over 90% of patients.
By measuring the pattern of splenic versus hepatic sequestration with radiolabeled platelets
may predict the response to splenectomy.
3. Immunosuppressive drugs
Cyclophosphamide (50 to 200mg/day orally or 300 to 600 mg/m2 intravenously every 2
weeks) has induced remissions in from 44 to 55% of patients.
Vincristine (0.025mg/kg not to exceed a total dose of 2mg) and vinblastine
(0.0125mg/kg), administered intravenously at weekly intervals, appear to be as effective as
cyclophosphamide, but act more rapidly.
Azathioprine, actinomycin, and other immunosuppressive agents, either alone or in
combination with corticosteroids, have been administered to patients with ITP, with variable
success. All of these immunosuppressive agents may be leukemogenic and/or carcinogenic.
4. Emergency treatment of acute bleeding
In patients with severe bleeding, in addition to conventional critical care measures,
appropriate treatment includes platelet transfusions, high-dose parenteral glucocorticoids,
and IVIg.
Platelet transfusions: Platelet transfusions may produce some increase in platelet
numbers in many patients, often diminish bleeding for a time, and can be effective in the
management of serious complications, e.g., subarachnoid hemorrhage. They should be
reserved for such life-threatening emergencies or for the immediate preoperative treatment
of patients with serious hemorrhage before splenectomy. In patients with platelet counts
above 50×109/L, preoperative platelet transfusions are not indicated. Platelet replacement
should be avoided in patients with chronic ITP because of the possible development of
alloantibodies.
High-dose immunoglobulin. The mechanism of this therapeutic effect is not entirely
clear, but most evidence points to blockade of the Fc receptors of the reticuloendothelial
cells, and perhaps neutralization of antiplatelet autoantibodies by antiidiotypic antibodies in
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the preparations. A regimen of 400mg/kg/day for 5 days usually is recommended. Treatment
with immunoglobulin appears to be effective in patients who failed to respond to
splenectomy, in pregnant women, and in some patients who are refractory to all other modes
of treatment.
High doses of glucocorticoids, such as 1 g of methylprednisolone given by intravenous
infusion daily for 3 days, may also cause a rapid increase of the platelet count and may
ameliorate bleeding even if platelet counts remain low due to an effect on the vasculature.
5. Others
Danazol, an androgen with minimal virilizing side effects, has proved effective in the
treatment of ITP. In doses of 400 to 800mg/day, presumably acts by inducing
reticuloendothelial dysfunction, possibly by diminishing Fc (IgG) receptors.
Exchange plasmapheresis. It may be valuable in critically ill patients, and may be
particularly effective in children.
Anti-D. Intravenous Rh (D) immune globulin has been studied in children with acute
ITP and refractory chronic ITP as an alternative to intravenous Ig. The mechanism of action
is unknown; however, it is believed that the antibody coats the red blood cells of Rh-positive
patients and either blocks the reticuloendothelial clearance of the patients platelets or
modulates the immune system, resulting in an increase in the platelet count. Children
respond better than adults, and nonsplenectomized patients respond better than
splenectomized patients. The only clinically important side effect of anti-Rh(D) is the
predictable alloimmune hemolysis.
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