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threatening complications associated with acute ITP because of their low prevalence
rate.
Both the American Society of Hematology (ASH) and British Society of Haematology
have published guidelines for the management of ITP in children and adults. Both
societies acknowledge that published evidence for recommendations is weak. As a
result, both sets of guidelines are based primarily upon expert opinions and
observational studies.
The ASH guidelines (published in 1996) are based upon the risk of bleeding
associated with a given platelet count. They recognize that no therapeutic
intervention is generally needed for children with platelet counts greater
than 30,000/microL as they are unlikely to have serious bleeding.
Pharmacologic therapy is recommended for the following:
Any child with significant bleeding (eg, mucosal bleeding) regardless of the
platelet count
Children with platelet counts less than 10,000/microL and cutaneous
bleeding (bruising, petechiae, and/or purpura)
The British guidelines (published in 2003), in contrast to the ASH guidelines,
base treatment upon the severity of clinical symptoms without regard for
the platelet count of the patient. They reserve pharmacologic
interventions for children with severe bleeding or in children undergoing
procedures (such as surgery) likely to include blood loss.
In 2010, an international consensus report recommended that treatment be based
upon a composite of factors that includes clinical symptoms, circulating platelet
count, and the impact of ITP upon the patient's quality of life. This approach takes
into consideration the use of pharmacologic therapy in patients who partake in
strenuous activity. However, patients should not participate in competitive contact
activities that have a high risk of head trauma.
In our practice, treatment decisions are based upon the available data that suggest
most patients with platelet counts above 10,000/microL will not have serious
bleeding. Pharmacologic therapy is given to patients with serious bleeding and
those with a platelet count <10,000/microL and cutaneous bleeding (bruising,
petechiae, and/or purpura).
INITIAL MANAGEMENT
Supportive care Regardless of whether pharmacologic therapy is used,
restriction of activity (especially contact sports) should be recommended in all
children with ITP. In addition, medications with antiplatelet activity (including
aspirin-containing preparations, ibuprofen and other non-steroidal antiinflammatory drugs) or those with anticoagulant activity should be avoided.
Pharmacologic intervention As previously noted, there are limited data on the
use of pharmacologic intervention in children with ITP. In our practice, the presence
of one or more of the following factors is used as an indication for pharmacologic
intervention:
two treatment modalities were made at 24 hours (RR 0.63, 95% CI 0.480. 83) and at 72 hours after initiation of therapy (RR 0.83, 95% CI 0.760.91).
Chronic ITP, defined as a platelet count <150,000/microL, developed in 25
percent of patients treated with corticosteroids and 18 percent of those
with IVIG.
A retrospective study from the ICIS registry reported that children with acute ITP
who were treated with IVIG were more likely to have a normal platelet count six
months after diagnosis than those who did not receive IVIG (Odds ratio 1.81, 95%
CI 1.25 to 2.64).
Reported dose regimens for children with ITP range from 400 mg/kg per day for
five days to a single dose of 1000 mg/kg. A single dose regimen appears to be
preferable. In one study, a single dose of IVIG of 800 mg/kg was as effective as a
higher dose regimen of 1000 mg/kg per day for two days in raising the platelet
count. The response to therapy is usually within 24 hours of initiation of IVIG
therapy with the single dose of IVIG.
Side effects of IVIG include flu-like symptoms, such as nausea and vomiting (63
percent), headache (56 percent), or fever (19 percent). Adverse effects tend to be
more pronounced in older patients. Neutropenia (absolute neutrophil count
less than1500/microL) develops in about 30 percent of patients.
Cost/benefit ratios must be considered in the selection of therapy for ITP; the cost
of a course of IVIG is greater than that of a conventional oral corticosteroid
regimen. However this cost differential is lower when initial and retreatment costs
are combined.
In our center, we administer IVIG as a single dose of 1000 mg/kg per day for one
or two days in patients with significant bleeding manifestations including "wet
purpura".
Anti-Rho(D) immune globulin Based upon the premise that IVIG acts in part
by producing antibody-coated red cells that block antibody-coated platelets
sequestration by the reticuloendothelial system, trials were conducted to study the
effect of anti-Rho(D) immunoglobulin [anti-Rho(D) Ig] in patients with ITP who
were Rho(D)-positive.
These trials demonstrated that anti-Rho(D) Ig is effective in improving platelet
counts. Limited data comparing the efficacy of anti-Rho(D) Ig versus IVIG and
corticosteroids include the following two studies:
The first study was a randomized controlled trial in which 146 patients were
assigned to receive one of four treatments; IVIG (1000 mg/kg for two
doses on consecutive days), IVIG as a single dose (800 mg/kg), antiRho(D) Ig (25 microgram/kg for two doses on consecutive days), or oral
prednisone (initial dose 4 mg/kg tapered and weaned over 21 days). At 72
hours after the start of treatment, the groups treated with IVIG had the
best response to therapy. Response to treatment, as defined by the
percent of patients with a posttreatment platelet count greater than
20,000, was seen in 97, 94, 82, and 79 percent of patients treated with
one dose of IVIG (800 mg/kg), two doses of IVIG (each 1000 mg/kg), two
counts is lengthened, but monitoring should continue until the platelet count has
returned to normal (>150,000/microL) and is stable. This return occurs within one
month after presentation in one-half of children with ITP, and by three months in
about 70 percent of children.
In our practice, we stop monitoring after the platelet count has returned to normal
and has remained stable for two to three months. Recurrence of acute ITP is rare,
probably occurring in less than 1 percent of cases, although the possibility of wellcompensated chronic ITP cannot be ruled out.
Since all ITP therapies are temporizing interventions intended to reverse
expeditiously a real or perceived risk for hemorrhage, they do not need to be
continued until normal platelet counts are reached. Therapy is targeted to increase
the platelet count above a threshold (usually greater than20,000/microL) that stops
bleeding or eliminates the risk of serious bleeding.
Life-threatening bleeding Life-threatening bleeding is rare. Although
intracranial hemorrhage (ICH) has an incidence of only 0.1 to 0.5 percent, it is the
most serious consequence of ITP. The presence of significant headache should
prompt careful evaluation for any other neurologic signs, and early diagnostic
imaging should be considered to identify ICH.
If ICH or any other life-threatening hemorrhage occurs, immediate intervention
should be given to the affected patient. Our practice is consistent with the
recommendations of the previously mentioned 2010 International consensus report
and includes the following:
Platelet transfusions
IVIG 1000 mg/kg per day for two days
Methylprednisolone 30 mg/kg per day administered intravenously for
three days
For ITP patients with unstable or progressive ICH, emergency craniotomy may be
necessary. Emergency splenectomy may be considered in selected clinical situations
but only as a last resort.
CHRONIC ITP Approximately 20 to 30 percent of children who present with ITP
will have chronic ITP, defined as persistent thrombocytopenia (platelet count less
than 150,000/microL) beyond six months from the time of presentation. Patients
with chronic ITP are usually clinically indistinguishable from those with acute ITP at
presentation.
Individuals with chronic ITP should undergo evaluation to exclude other causes of
thrombocytopenia, such as chronic infections (including HIV), bone marrow failure,
collagen vascular disorders, and other autoimmune or immunodeficiency disorders.
Studies should include viral antibody titers, bone marrow examination, and studies
for collagen vascular disorders (eg, antinuclear antibody test).
Management In up to one-third of children with chronic ITP, spontaneous
remission will occur months or even years later. Children younger than 10 years of
age are more likely to remit than older patients and treatment is usually not
necessary. Children older than 10 years of age, especially adolescent females, have
a disease course more like that seen in adults with ITP and should be treated in a
similar manner.
In chronic ITP, platelet counts tend to range between 20,000
and 75,000/microL; consequently, many patients will require no treatment. It is
very uncommon for an individual with chronic ITP to have a platelet count less
than 10,000/microl.
Management of children with chronic ITP should focus on minimizing the individual's
risk for bleeding. Pharmacologic intervention is used as a temporizing measure. In
some cases, such as patients with chronic severe ITP, splenectomy is performed
because of persistent significant hemorrhagic symptoms that require repeated,
sometimes almost continuous, pharmacologic interventions.
Pharmacologic therapy In children with chronic ITP, pharmacologic therapy
usually is used when patients have significant bleeding, or require surgery or dental
extraction. Adolescent girls may have excessive bleeding during their menses and
may require therapeutic intervention. Therapy generally raises the platelet count
temporarily.
Pharmacologic options are similar to those used in the initial management of
patients with ITP at presentation and include the following:
Corticosteroids Patients may receive periodic short courses or pulses of
corticosteroids. For patients who are steroid dependent in order to remain
symptom free, alternate day dosing may be effective in preventing
bleeding while reducing side effects. Prolonged daily steroid treatment is
to be avoided because of its adverse effects, especially poor growth. In
our practice, we prefer to avoid the prolonged use of glucocorticoid
therapy.
Immunoglobulin therapy Intravenous IgG (IVIG) or anti-Rho(D) also have
been effective in chronic ITP patients, even those who are resistant to
steroids. All of these strategies offer temporary alleviation of symptoms
and improvement in platelet numbers, but no data demonstrate an effect
on resolution of chronic ITP.
In our practice, IVIG is administered at a dose of 500 mg/kg per day for two days
and repeated when symptoms recur.
Splenectomy A small percentage of patients with chronic ITP will have
persistent significant hemorrhagic symptoms and require repeated, sometimes
almost continuous, pharmacologic interventions. For such patients, the risks and
benefits of splenectomy must be considered.
Splenectomy is effective in improving the platelet count and reducing the
associated risk of bleeding in 60 to 90 percent of children with chronic ITP. No
universally accepted standards for the timing of splenectomy in chronic ITP exist,
but the American Society of Hematology guidelines recommend waiting until at
least 12 months after diagnosis, if possible. When possible, surgery should be
performed using laparoscopic techniques.
In the original cohort of 501 patients from the Nordic Society for Pediatric
Haematology and Oncology (NSPHO) study, 285 patients (57 percent) received
pharmacologic treatment within two weeks of diagnosis; in most cases one or two
doses of IVIG were administered. Six-month follow-up data were available for 409
patients. The following findings were noted:
Of the 409 patients, 376 children had a platelet count less
than 20,000/microL during the course of their disease and were classified
as being at risk for serious bleeding.
In the high-risk group of patients, the risk period for serious bleeding lasted
less than one month in 75 percent of patients and persisted for more than
six months in 10 percent.
There were 141 events that required medical attention during the six-month
follow-up period. More than half of the events (74 reports) were
accounted for by the 101 patients with chronic ITP.
Most of the reported events were due to cutaneous bleeding (bruising,
petechiae, and/or purpura). There were 33 episodes of mucosal bleeding,
which included 23 reports of epistaxis, 6 reports of oral bleeding, 1 report
of menorrhagia, and 1 report of rectal bleeding.
None of the events were life-threatening and there were no reports of
intracranial hemorrhage or significant trauma. In 15 cases, blood
transfusions were required.
In the 409 patients with complete follow-up data, there was no difference in
the risk of developing chronic ITP in patients who did not receive
treatment compared to those who did (23 versus 26 percent).
In the Intercontinental Childhood ITP Study (ICIS) study, three of the 1742 patients
with available six-month follow-up data had intracranial hemorrhage. The following
findings were noted:
Initial platelet counts for the three patients were 8000, 11,000,
and 16,000/microL.
Management varied with one patient receiving no pharmacologic therapy,
one treated with corticosteroids, and one received a combination of
corticosteroids and IVIG.
Subsequent follow-up data were only available for two of the three patients.
The patient who received both corticosteroids and IVIG died within the
first week of diagnosis of ITP and the patient who received corticosteroid
alone fully recovered without neurologic sequelae.
A small number of children with acute ITP (<5 percent), who initially remit with
recovery of a normal platelet count, will have an episode of recurrent acute
thrombocytopenia. When it occurs, it usually is a self-limited event and
management principles remain the same as for the initial acute episode. Prolonged
monitoring of such patients is necessary to eliminate the possibility that chronic ITP
is the actual diagnosis.
McWilliams
and Mauner
Stu
dy
N
Pop
.
age
Foll
owup
27
6 yr
mea
n
NR
Randomized
treatment arms
Prednisone (2
mg/kg/d x 21 d)
Outcome measure
No treatment
Sartorius
93
60
mo16
yr
>6
mo
Prednisone (60
mg/m2/d x 21 d, then
tapered)
Platelet
count
27
<11
yr
28 d
Prednisone (2
mg/kg/d x 14 d, then
taper to d 21)
94
<16
yr
1 yr
Prednisone (60
mg/m2/d x 21 d,
follow-up protocol for
poor response/
Deaths
NR
NR
(p .03) 60
d
NR
NR
Prednisone
> Placebo
(p <.01)
Prednisone
< placebo
(by
RumpelLeede test
NR
NR
Prednisone
< placebo
(p < .05)
only at d 7
(bleeding
time and
clinical
score)
Increased
appetite,
weight gain
NR
77 percent
weight gain
or acne
Prednisone
> placebo
(p <.05)
only at d 7
Placebo
Imbach et al
Adverse
Effects
21 d
Placebo
Buchanan
and
Holtkamp
Bleeding
symptom
s
77 percent
remissions)
IVIg (0.4 g/kg/d x 5
d, follow-up protocol
for poor response/
remissions
Mazzucconi
et al
61
2-12
yr
>6
mo
Prednisone (0.5
mg/kg/d x 1 mo or
until platelet
normalization)
Prednisone (1.5
mg/kg/d x 1 mo or
until platelet
normalization)
83 percent
(no
difference)
NR
22 percent
with
headache,
fever,
vomiting,
vertigo
1 died on
day 6,
excluded
from
analysis
62 percent
NR
NR
NR
81 percent
(p <.05)
NR
NR
NR
Study
N
160
Pop.
age
<15 yr
Followup
>12 mo
Randomized treatment
arms
Prednisone (0.25 mg/kg/d x
3 wk)
Outcome measure
Proportion with platelet
count >100K for >3 mo
Ozsoyle et
al
30
20
2 mo-15
yr
2 mo-11
yr
>6 mo
>6 mo
53
7 mo14 yr
180 d
146
6 mo18yr
6-32 mo
Deaths
NR
77 percent
(no difference)
NR
NR
NR
NR
Prednisone (2 mg/kg/d x 4
wk)
NR
NR
NR
NR
60 percent, 90
percent (no
difference)
None
NR
60 percent, 75
percent
NR
NR
2 d, 4d
NR
Weight gain,
behavioral
change 75
percent with
nausea,
vomiting,
headache, fever
M'prednisolone (IV, 10
mg/kg/d x 5 d)
M'prednisolone (po, 30
mg/kg/d x 3 d, then 20
mg/kg/d x 4 d)
Prednisone (4 mg/kg/d x 7
d, then tapered to d 21) IVIg
(1 g/kg/d x 2 d)
No therapy
Blanchette
Adverse
Effects
NR
Blanchette
et al
Bleeding
symptoms
71 percent
Prednisone (1 mg/kg/d x 3
wk)
Khalifa et
al
Platelet
count
Prednisone (4 mg/kg/d x 7
d, then tapered to d 21)
1 d, 2 d (p< .
01 vs
prednisone) 4
d, 16 d (p
<0.1 vs either
treatment)
Median time to platelet
count >20K, >50K
2 d, 3 d
NR
None
IVIg (1 g/kg/d x 2 d)
2 d, 2 d
NR
16-18 percent
with fever,
nausea,
vomiting,
headache
1 d, 2 d (p
<.05 vs.
prednisone)
NR
2 d, 2.5 d (p <
.05 vs. both
NR
24 percent with
hemoglobin
IVIg
regimens)
<10 g/dL
Stud
yN
Albayra
k et al
57
Pop.
age
2 mo17 yr
Follo
w-up
6 mo
Randomized
treatment arms
Outcome
measure
Platelet
count
M'prednisolone
(po, 30 mg/kg/d x
7d)
Mean platelet
count on
days 0-30
Mean
>100K by d
4. No
difference
among
groups
M'prednisolone
(po, 50 mg/kg/d x
7 d)
Bleeding
symptoms
Adverse
Effects
Deat
hs
NR
Increased
appetite and
Cushingoid
appearance
1 ICH
Increased
appetite and
Cushingoid
appearance
NR
1 pt with
aseptic
meningitis; 2
with
headache,
vomiting