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REVIEW ARTICLE
Idiopathic Thrombocytopenic Purpura: A Practice Guideline Developed by Explicit
Methods for The American Society of Hematology
By James N. George, Steven H. Woolf, Gary E. Raskob, Jeffrey S. Wasser, Louis M.
Aledort, Penny J. Ballem, Victor S. Blanchette, James B. Bussel, Douglas B.
Cines, John G. Kelton, Alan E. Lichtin, Robert McMillan, John A. Okerbloom,
David H. Regan, and Indira Warrier
IDIOPATHIC thrombocytopenic purpura (ITP, also known as primary immune
thrombocytopenic purpura) is a hematologic disorder for which appropriate
diagnostic and treatment strategies are uncertain. In 1994, the American Society
of Hematology (ASH) established a panel to produce explicitly developed practice
guidelines for the diagnosis and management of ITP. "Explicitly developed,"
evidence-based practice guidelines, which are being issued increasingly by
medical specialty societies, combine a critical appraisal of scientific evidence
with practice recommendations that state clearly to what extent the guidelines
are based either on published scientific evidence or opinion (eg, clinical
experience).1-4 More details about the clinical practice guideline movement are
provided elsewhere.5-7
SUMMARY OF RECOMMENDATIONS
Children
Diagnosis
The diagnosis of ITP is based principally on the history, physical examination,
complete blood count, and examination of the peripheral smear, which should
exclude other causes of thrombocytopenia. Further diagnostic studies (see Table
7) are generally not indicated in the routine work-up of patients with suspected
ITP, assuming that the history, physical examination, and blood counts are
compatible with the diagnosis of ITP and do not include atypical findings that
are uncommon in ITP or suggest other etiologies. Patients with risk factors for
human immunodeficiency virus (HIV) infection should be tested for HIV antibody,
and an abdominal computed tomographic (CT) scan or ultrasound examination is
appropriate in patients with suspected splenomegaly on initial physical
examination. Bone marrow aspiration should be performed to establish the
diagnosis in patients with persistent thrombocytopenia (lasting more than 6 to
12 months) and in those unresponsive to intravenous Ig (IVIg), but it should not
be performed to establish the diagnosis before initiating IVIg therapy.
Additional testing is also generally unnecessary, and sometimes inappropriate,
when performed on a routine basis to establish the diagnosis before splenectomy
or to evaluate patients who have not responded to glucocorticoid therapy, IVIg,
and splenectomy (see Table 7).
Treatment
Children with platelet counts >30,000 should not be hospitalized and do not
routinely require treatment if they are asymptomatic or have only minor purpura;
they should not be given glucocorticoids, IVIg, or anti-Rh(D) as routine initial
treatment. Children with platelet counts <20,000 and significant mucous membrane
bleeding and those with counts <10,000 and minor purpura should be treated with
specific regimens of IVIg or glucocorticoids (see text). Patients with severe,
life-threatening bleeding should be hospitalized and receive conventional
critical care measures, along with treatment for ITP: appropriate regimens
include high-dose parenteral glucocorticoid therapy, IVIg, and platelet
transfusions.
Splenectomy is clearly appropriate or inappropriate in specific clinical
situations (see text). If an elective splenectomy is planned, appropriate
preoperative therapy includes prophylactic IVIg therapy for patients with
platelet counts <30,000, and IVIg, parental glucocorticoids, and anti-Rh(D) for
patients with platelet counts <10,000. Inappropriate preoperative prophylaxis
includes IVIg, oral glucocorticoid therapy, or anti-Rh(D) when platelet counts
exceed 50,000, parenteral glucocorticoid therapy when platelet counts exceed
30,000, and platelet transfusions when platelet counts exceed 20,000.
When ITP symptoms persist after primary treatment (glucocorticoid, IVIg) and
splenectomy, further treatment is indicated in children with platelet counts
<30,000 who have active bleeding. Panel members suggested many treatments as
reasonable options but did not reach consensus on any single regimen, reflecting
the lack of evidence that any single treatment is more effective than another.
Adults
Diagnosis
The diagnosis of ITP is based principally on the history, physical examination,
complete blood count, and examination of the peripheral smear, which should
exclude other causes of thrombocytopenia. Further diagnostic studies (see Table
7) are generally not indicated in the routine work-up of patients with suspected
ITP, assuming that the history, physical examination, and blood counts are
compatible with the diagnosis of ITP and do not include atypical findings that
are uncommon in ITP or suggest other etiologies. Patients with risk factors for
HIV infection should be tested for HIV antibody. Bone marrow aspiration is
appropriate to establish the diagnosis in patients over age 60 and in patients
considering splenectomy. Additional testing is also generally unnecessary, and
sometimes inappropriate, when performed on a routine basis to establish the
diagnosis before splenectomy or to evaluate patients who have not responded to
glucocorticoid therapy and splenectomy (see Table 7). Preoperative thyroid
function testing is appropriate to rule out occult hyperthyroidism or
hypothyroidism before elective splenectomy.
Treatment
Patients with platelet counts >20,000 should not be hospitalized if they are
either asymptomatic or have only minor purpura. Patients with counts >50,000 do
not routinely require treatment; they should not be given glucocorticoids or
IVIg as routine initial treatment. IVIg is also inappropriate as initial
treatment in patients with counts >30,000 who are asymptomatic or have only
minor purpura. However, treatment is indicated in patients with platelet counts
<20,000 to 30,000, and those with counts <50,000 and significant mucous membrane
bleeding (or risk factors for bleeding, such as hypertension, peptic ulcer
disease, or a vigorous lifestyle). Initial therapy with glucocorticoids (eg,
prednisone) is appropriate in such patients. Hospitalization is appropriate for
patients with platelet counts <20,000 who have significant mucous membrane
bleeding. Patients with severe, life-threatening bleeding should also be
hospitalized and should receive conventional critical care measures, along with
treatment for ITP: appropriate regimens include high-dose parenteral
glucocorticoid therapy, IVIg, and platelet transfusions.
Splenectomy is clearly appropriate or inappropriate in specific clinical
situations (see text). It should not be performed as initial therapy in patients
who have no bleeding, minor purpura, or even mucous membrane bleeding. In a
patient who has had bleeding symptoms (eg, epistaxis, menorrhagia), splenectomy
is often appropriate if platelet counts remain below 30,000 after 4 to 6 weeks
of medical treatment. If an elective splenectomy is planned, appropriate
preoperative therapy includes prophylactic IVIg or oral glucocorticoid therapy
for patients with platelet counts <20,000. Inappropriate preoperative
prophylaxis includes IVIg, oral or parenteral glucocorticoid therapy, and anti-Rh(D)
when platelet counts exceed 50,000, and platelet transfusions when platelet
counts exceed 10,000.
When ITP symptoms persist after primary treatment (glucocorticoid) and
splenectomy, further therapy is recommended in patients with platelet counts
<30,000 who have active bleeding. The most commonly recommended first-choice
treatment options include IVIg, glucocorticoids, accessory splenectomy, and no
additional treatment, but other agents may also be appropriate (see text). Women
with ITP who are of childbearing age and have counts <10,000 after splenectomy
and other treatments should be discouraged from becoming pregnant.
Pregnant Women
Diagnosis
The diagnosis of ITP during pregnancy generally does not require special
laboratory testing (see Table 7). The patient's blood pressure should be
measured to rule out preeclampsia as an alternative diagnosis; liver function
testing is also appropriate. Patients with risk factors for HIV infection should
be tested for HIV antibody.
Treatment
Recommendations for pregnant women are different from other adults in some
situations. Pregnant women with ITP and platelet counts >50,000 do not routinely
require treatment and should not receive glucocorticoids or IVIg as routine
initial therapy. Women with counts of 30,000 to 50,000 in the first or second
trimester also should not receive routine initial treatment. Treatment is
required for women with platelet counts <10,000, and for those with platelet
counts of 10,000 to 30,000 who are in their second or third trimester or are
bleeding. IVIg is appropriate initial treatment for women with platelet counts
<10,000 in the third trimester, and for those with counts of 10,000 to 30,000
who are bleeding. In pregnant women who have failed glucocorticoid and IVIg
therapy, splenectomy is appropriate in the second trimester in women with
platelet counts <10,000 who are bleeding. Splenectomy should not be performed in
asymptomatic pregnant women with platelet counts >10,000.
As labor and delivery approach, women with ITP do not require testing for
maternal platelet antibodies. Percutaneous umbilical vein blood sampling (PUBS)
or fetal scalp vein sampling to measure the fetal platelet count and predict the
risk of neonatal bleeding are not necessarily required. PUBS and fetal scalp
vein sampling are unnecessary in pregnant women without known ITP even with
platelet counts as low as 40,000 at term. Women with ITP should be delivered by
cesarean section in selected circumstances (see text). In general, assuming the
fetal platelet count (and the platelet count of previous babies) is unknown,
cesarean section is not indicated when the maternal platelet count is >50,000.
If the fetal platelet count is known, cesarean section is appropriate if the
fetal count is <20,000. A maternal platelet count of >50,000 is considered
sufficient to prevent complications from excessive maternal bleeding at vaginal
delivery or cesarian section. Prophylactic platelet transfusions before delivery
are appropriate in women with counts <10,000 who (1) have a planned cesarean
section or (2) have epistaxis or other mucous membrane bleeding and are expected
to deliver vaginally, but are unnecessary in women with platelet counts >30,000
and no bleeding symptoms.
Newborns (of Mothers With ITP)
Diagnosis
The neonatal platelet count should generally be measured for 3 to 4 days after
birth. Brain imaging (eg, ultrasound) should be performed if the platelet count
at birth is <20,000; brain imaging is also appropriate if the count is 20,000 to
50,000, even in the absence of neurologic abnormalities.
Treatment
In newborns without evidence of intracranial hemorrhage (ICH), treatment with
IVIg is appropriate if the infant's platelet count is <20,000. Newborns with
platelet counts of 20,000 to 50,000 do not necessarily require IVIg treatment.
Newborns with counts >50,000 should not be treated with IVIg or glucocorticoids.
Newborns with imaging evidence of ICH should be treated with combined
glucocorticoid and IVIg therapy if the platelet count is <20,000; they should
not be treated with glucocorticoids alone. Women with ITP should not be
discouraged from breast feeding.
METHODOLOGY FOR GUIDELINE DEVELOPMENT
Topic Selection and Objectives
The ASH selected ITP because of the frequency with which it is encountered by
hematologists and because of uncertainty regarding the relative effectiveness
and safety of current diagnostic tests and treatments. Although there are no
reliable epidemiologic data on the incidence of ITP, estimates are that 10 to
125 per 1,000,000 persons (children and adults) develop ITP each year.8 The goal
of the panel was to issue explicitly developed recommendations, based as much as
possible on published, scientific evidence, regarding the diagnosis and
treatment of patients with known or suspected ITP.
Panel Composition
The 15-member panel included 13 hematologists selected to represent the ASH
membership. The hematologists included both university-affiliated physicians
with research interests in ITP and private practitioners. Panel members
represented both pediatric and adult medicine perspectives. The panel also
included two members with expertise in clinical epidemiology and practice
guideline methodology.
Definition of Target Condition
The panel defined ITP as isolated thrombocytopenia with no clinically apparent
associated conditions or other causes of thrombocytopenia (eg, HIV infection,
systemic lupus erythematosus, lymphoproliferative disorders, myelodysplasia,
agammaglobulinemia or hypogammaglobulinemia, drug-induced thrombocytopenia,
alloimmune thrombocytopenia, congenital/hereditary nonimmune thrombocytopenia).
No specific criteria establish the diagnosis of ITP; the diagnosis relies on the
exclusion of other causes of thrombocytopenia. For purposes of this review, the
panel excluded from consideration patients with clinically apparent coexisting
conditions that can cause immune thrombocytopenia (eg, systemic lupus
erythematosus). Patients with isolated abnormalities on serologic tests (eg,
antinuclear or antiphospholipid antibodies) but without a clinically evident
disorder such as systemic lupus erythematosus were not excluded because positive
serologic tests are frequently encountered in patients with typical ITP.9,10
However, the panel recognized that patients with thrombocytopenia and an
associated autoimmune disease may have an illness comparable to ITP.
Literature Search
A computerized search of the MEDLINE database, performed in April 1994, sought
English-language articles published between 1966 and 1994. Search terms (Medical
Subject Headings) included: "THROMBOCYTOPENIA," "PLATELET COUNT," "AUTOIMMUNE
THROMBOCYTOPENIC PURPURA," "COMPLETE BLOOD COUNT," "BONE MARROW EXAMINATION," "RETICULOCYTE
COUNT," "ANTINUCLEAR ANTIBODY TEST," "IGG," "DIAGNOSIS (SH)," and "THERAPY (SH)."
The database was also searched on the text word "ITP." The computerized search
retrieved 581 articles. This initial reference list underwent substantial
expansion after being supplemented with relevant articles from the files of
panel members, publications from 1989 through 1995 retrieved with alternate
search software ("Reference Update"), and cross-checking against the
bibliographies of retrieved articles to identify additional publications
(especially those published before 1966). Case reports, case series of less than
five patients, review articles, and letters-to-the-editor without primary data
were excluded from review. Statements in this report about the number of studies
that have examined the efficacy of specific treatments and statements that "no
published evidence is available" do not include case reports and other
categories of inadmissible evidence.
Literature Review and Assessment of Evidence
Each article was evaluated independently by two panel members (J.N.G., G.E.R.)
to assess scientific validity and verify results. Scientific validity was
assessed using published guidelines.11-15 Literature on the clinical course of
ITP was evaluated for the presence of an inception cohort of consecutive
patients, an explicit referral pattern, complete follow-up, and use of objective
outcome criteria. The term "inception cohort" refers to a group of patients
identified at an early and uniform point in the course of their disease so that
patients who die or completely recover are included with patients in whom the
disease persists. Most of the ITP literature reviewed in this report pertains to
therapy. The strength of the evidence for individual therapeutic approaches was
assessed using the "level of evidence" criteria outlined in Table 1.13,14
Evidence tables in the Results section only present data from level I and level
II studies. TABLE 1
Levels of Evidence for Studies Evaluating Effectiveness of Treatment
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Level of Evidence
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Study Design
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I Strongest Randomized trials with low false-positive and false-negative errors.
II Randomized trials with high false-positive and false-negative errors.
III Nonrandomized studies with concurrent control group.
IV Nonrandomized studies with historical control group.
V Weakest Case series without a control group.
--------------------------------------------------------------------------------
Data from refs 11, 12, and 14.
--------------------------------------------------------------------------------
Assessment of Opinion
Most of the literature on the treatment of ITP consists of case series without a
control group (level V). For those therapies for which only level V evidence is
available, or for which no evidence is available, and for issues on diagnosis
that have not been addressed by clinical studies, the opinion of the panel was
assessed. Survey instruments were used to assess quantitatively the opinion and
strength of consensus of the panel, and these data provide the basis for
statements about opinion in the text and tables. The survey instruments were
designed at panel meetings in which members were asked to identify the key
diagnostic and treatment practices for which opinion would be assessed. The
appropriateness of these practices was intentionally not discussed at the
meeting to avoid influencing the responses by the opinions of more assertive
panel members. A 41-page questionnaire addressing these practices was mailed to
panel members in 1994 to be completed independently, without discussion with one
another. The questionnaire, which included separate pediatric and adult
sections, asked respondents to measure the necessity and appropriateness of
diagnosis or treatment in over 1,300 clinical scenarios. In these surveys,
"Necessary" was defined as a test or treatment that should be performed;
"Appropriate" was defined as a test or treatment that may or may not be
necessary, but performing it is not wrong; "Unnecessary" was defined as a test
or treatment that need not be performed, but is not necessarily inappropriate;
"Inappropriate" was defined as a test or treatment that should not be performed.
Questions relating to adult patients were completed by 11 panel members, and
questions relating to pediatric patients were completed by six respondents. A
second, 25-page questionnaire was circulated in early 1995 to examine opinions
regarding pregnancy and newborn care and to clarify opinions regarding issues
identified in the 1994 survey. The 1995 survey examined over 600 issues and was
completed by 13 panel members.
Using a modified RAND scoring system,16,17 the questionnaire asked panelists to
quantify the strength of their opinion on a 1 to 9 scale; "9" represented strong
agreement with the appropriateness/necessity of the practice and "1" represented
strong disagreement. The mean response for each question provided an overall
assessment of the panel's opinion regarding the necessity and appropriateness of
specific practices. Panel votes are presented in this report only when there was
agreement among the panel regarding the necessity or appropriateness of an
intervention (mean panel score of 7.0 to 9.0) or agreement that the intervention
is unnecessary or inappropriate (mean panel score of 1.0 to 3.0).
The strength of the panel's inter-observer agreement about the
appropriateness/necessity of tests or treatments was graded using the standard
deviations (SDs) for responses to each question (Table 2). Panel responses were
classified as category A ("Complete or Almost Complete Unanimity"), for example,
if the variance in panel member responses to a specific question was more than
two SDs below the mean variance. Thus, a score of "1.5, A" signified strong
agreement among the panel that the intervention is unnecessary/inappropriate,
with most panelists assigning scores close to 1.0. A score of 7.5, D meant that,
on average, the panel considered the intervention necessary/appropriate, but
that wide variation in the responses of individual panel members was noted.
These scores were arbitrarily considered as representing a consensus if the mean
score was 3 or less or 7 or more. TABLE 2
Panel Opinion Rating System
--------------------------------------------------------------------------------
Score
--------------------------------------------------------------------------------
Definition
--------------------------------------------------------------------------------
Appropriateness of Necessity Scores*
1.0-3.0 "Inappropriate" or "unnecessary" (depending on question).
3.01-6.99 Uncertain appropriateness or necessity.
7.0-9.0 "Appropriate" or "necessary" (depending on question).
Consensus Codes[dagger]
A "Complete or almost complete unanimity" (panel variance more than 2 SD below
the mean variance).
B "Strong agreement" (panel variance 1 to 2 SD below the mean variance).
C "Moderate agreement" (panel variance less than 1 SD below the mean variance).
D "Moderate disagreement" (panel variance less than 1 SD above the mean
variance).
E "Strong disagreement" (panel variance greater than 1 SD above the mean
variance).
--------------------------------------------------------------------------------
*Represents mean panel score for response to questions asking for ranking of
appropriateness/necessity on a scale of "1" to "9," with "1" representing most
"inappropriate/unnecessary" and "9" representing most "appropriate/necessary."
Separate scores were obtained for appropriateness and necessity by asking
separate, individually worded questions. "Necessary" = test should be performed,
"Appropriate" = test may or may not be necessary, but performing it is not
wrong, "Unnecessary" = test need not be performed (but is not necessarily
inappropriate), "In appropriate" = test should not be performed.
[dagger]Strength of agreement among the panel members about
appropriateness/necessity, ie, the variance of responses around the mean panel
score.
--------------------------------------------------------------------------------
Figures 1 and 2 display data on two specific questions to illustrate the use of
this method to assess opinion and the range of opinions among panel members. For
example, when asked to rate the appropriateness of performing a bone marrow
aspirate/biopsy in all adult patients at presentation to establish the diagnosis
of ITP, the mean panel score (on a scale of 1 to 9) was 5.3. However, the range
of opinion on the panel was wide (category "E"), with one cluster of panel
members labeling the practice as inappropriate and another considering it
appropriate (Fig 1). Figure 1 also illustrates that scores for necessity are
lower than for appropriateness. The results also illustrate trends in opinion
across different clinical scenarios. For example, Fig 2 presents mean panel
scores in response to a question about the appropriateness of not initiating
specific treatment for ITP in children with various platelet counts. A trend of
opinion is clear but agreement among the panel is not strong except at the
highest platelet counts. At the lowest and higher platelet counts there is a
consensus for inappropriateness (mean score <3) and appropriateness (mean score
>7), respectively, for withholding initial treatment. Although these views
reflect opinion more than science, the panel believes that a structured approach
to defining and expressing its opinion is more precise and less subject to bias
than arriving at recommendations through open discussion, in which decisions are
more likely to be influenced by the opinions of more assertive panel members.
FIGURE 1. Panel responses to the question, "Is it necessary/appropriate to order
a bone marrow aspiration/biopsy to establish the diagnosis of ITP in all adult
patients at presentation?" This question assumed that the history, physical
examination, and initial blood counts with examination of the blood smear are
compatible with the diagnosis of ITP and do not include atypical findings that
are uncommon in ITP or suggest other etiologies. Data points ([bullet])
represent the responses of individual panel members (N = 11) on a scale of 1-9,
with 1 reflecting complete disagreement and 9 reflecting complete agreement.
Horizontal lines ([line]) represent the mean panel score. Letter codes, which
describe the variance, are defined in Table 4.
FIGURE 2. Panel responses to a question regarding the appropriateness of
offering no specific initial treatment for children presenting with ITP and
symptoms of only minor purpura. Data points ([bullet]) represent the responses
of individual panel members (N = 6) on a scale of 1-9, with 1 reflecting
complete disagreement and 9 reflecting complete agreement. Horizontal lines
([line]) represent the mean panel score. Letter codes, which describe the
variance, are defined in Table 4.
Recommendations
In almost all aspects of ITP level I evidence is lacking, and there are few
level II, III, or IV studies to allow firm, evidence-based recommendations. In
general, only level V evidence, or no studies, were available for making
recommendations. Therefore, the panel issued recommendations based on opinion,
indicating the mean panel score and variance to permit readers to judge the
strength of the consensus. Although the sample sizes of voting members were
small and some confidence intervals for panel votes were wide, the results can
help readers assess the strength of opinion behind specific recommendations. The
basis of recommendations is explicitly labeled in the text so that reader can
appreciate which recommendations are based on evidence and which are based on
opinion. The inherent weakness of opinion-based recommendations is acknowledged;
these recommendations should not form the basis for definitive decisions on
health care policy. Indications for which the panel could not reach consensus
(scores of 3.1 to 6.9) are generally not listed in the text; thus,
recommendations frequently address only the "extremes" of inappropriate and
appropriate practice and do not comment on intermediate clinical scenarios that
may be common. The fact that the panel did not reach consensus regarding these
indications does not necessarily signal the appropriateness or inappropriateness
of clinicians' decisions to administer tests or treatments in these settings.
This practice guideline describes a range of approaches to the diagnosis and
management of ITP. Its recommendations are not intended to serve as inflexible
rules, and they are not inclusive of all proper methods of care or other methods
of care that may achieve similar results. Adherence to the guideline will not
ensure a successful outcome in every case. The ultimate judgment regarding the
care of a particular patient should be made by the physician in light of the
clinical data and circumstances presented by the patient and the diagnostic and
treatment options available.
Peer Review
Before the final panel meeting, the report was independently reviewed by eight
private practice and university-based hematologists with expertise in adult
and/or pediatric ITP (Drs Neil Abramson, Jacksonville, FL; Barbara Alving,
Washington, DC; Diana Beardsley, New Haven, CT; Jack Levin, San Francisco, CA;
Joan Parkhurst, Oklahoma City, OK; Graham Pineo, Calgary, Alberta, Canada; Gary
Ratkin, St Louis, MO; Samuel Silver, Ann Arbor, MI).
RESULTS
ITP In Children
Clinical Course
A critical issue in caring for children with ITP is determining which patients
require treatment, either at the time of diagnosis or in the management of
chronic disease. To make informed management decisions, prognostic information
is needed to predict (1) how platelet counts will respond, with or without
therapy, (2) likely health outcomes without treatment, and (3) whether early
response to intervention reduces the incidence of adverse outcomes.
Evidence. There have been no large prospective studies which assembled an
inception cohort of children with ITP and followed the clinical course of
untreated patients to document the incidence of clinically important bleeding
and mortality. Data on the clinical course of untreated ITP in children come
from two types of evidence: (1) case series in which selected children with ITP
were not treated and were followed to document the incidence of spontaneous
remission, clinically important bleeding, and mortality, and (2) data from
untreated control groups in relatively small, brief randomized clinical trials
evaluating the effectiveness of alternative treatments. The case-series data are
summarized in Table 3.18-29
The best data on untreated disease come from two series in which about 75% of
patients were not treated initially.22,25 Most patients had platelet counts
<50,000 at presentation, and in one of the reports22 most had platelet counts
<20,000. Of the 221 untreated children, 2 (0.9%) had fatal bleeding associated
with the acute presentation, and 191 (87%) had a complete remission from ITP.
The platelet count normalized in 2 to 8 weeks, with one half to two thirds of
the patients recovering within 4 weeks.22,25
There are limitations to the inferences that can be drawn from these data.
First, 25% of the inception cohort in each series were selected for treatment.
If clinicians treated patients with the most serious clinical presentations,
then the clinical course in the remaining patients may underestimate the
frequency of important bleeding and mortality, and may overestimate the rate of
spontaneous remission. However, even if it is assumed that patients selected for
treatment would not have had a spontaneous remission, then the "least frequency"
estimate of the probability of complete spontaneous remission is 191 of 298
(64%). Second, 7% to 14% of patients were lost to follow-up, some of whom may
have suffered a relapse of ITP, with bleeding complications or death. In the
remaining series in Table 3, the children selected to be followed without
treatment represented only 10% to 56% of the inception cohort; patients with
more severe clinical presentations were generally treated. Thus, the untreated
patients in Table 3 may represent a select population with mild to moderate
symptoms who may have a more favorable prognosis than the average child with ITP.
TABLE 3
Clinical Course of ITP Children
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Hemorrhagic
Complications[double dagger]
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Patients With Persistant Thrombocytopenia§
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Author
--------------------------------------------------------------------------------
Location
--------------------------------------------------------------------------------
Years
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Patients (no.)
--------------------------------------------------------------------------------
Patients Responding With No Therapy*
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Patients in Remission at 6 mo[dagger]
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ICH
--------------------------------------------------------------------------------
Fatal ICH
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Other Deaths
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Patients in Remission At Last Follow-up[dagger]
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No.
--------------------------------------------------------------------------------
Spontaneous Recovery
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Deaths From Hemorrhage
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Komrower and Watson18 UK 1948-1953 43 18/24 25|| 4 3 3¶ 31 9 2 0
Choi and McClure19 Canada 1950-1964 239 20/25 105/161 1 1 0 120/128 18 5 0
Walker and Walker20 UK 1950-1980 177 51/63 138 1 0 1# 162 15 5 0
Ramos et al21 US 1952-1977 150 -- 135 0 0 0 143 13 6 0
Lusher and Zuelzer22 US 1956-1964 146 101/109 129/142** 1 1 0 135/142 -- -- --
Simons et al23 US 1956-1973 84 19/20 50 1 2 0 58 -- -- --
Benham and Taft14 Australia 1958-1966 132 13/15 97** 2 0 0 116 26 10 0
Lamm and Lovric25 Australia -- 152 91/112 116 1 1 0 147 29 23 1
den Ottolander et al26 Netherlands -- 77 23/35 38/75 1 1 0 60 -- -- --
Hoyle et al17 UK 1962-1982 136 35/41 97/132 1 1 0 117/132 16 9 0
Zaki et al28 Kuwait 1981-1986 60 18/23 41 0 0 0 44 16 2 0
Robb and Tiedeman29 Australia 1968-1987 297 -- 236/289 3 3 0 163 37 4 2
Summary 1,693 389/467 1,207/1,597 16 13 4 1,396/1,574 179 66 (37%) 3
(83%) (76%) (0.9%) (0.7%) (0.2%) (89%) (2%)
--------------------------------------------------------------------------------
Abbreviation: ICH, intracranial hemorrhage.
In these series, the upper age limit ranged from 12 to 16 years old.
*The numerator is the number of patients with a complete response, typically
defined as a normal platelet count without relapse; the denominator is the total
number of patients managed without specific initial therapy. The response rate
for untreated patients is greater than the overall response at 6 mo because of
selection of patients with good prognostic features for no treatment.
[dagger]A different denominator from the original number of patients indicates
that some patients were not followed long enough to be included in the estimate.
[double dagger]Note that 6 of the total 17 deaths occurred in the first (and
smallest) study of patients before 1953 Komrower and Watson.18 Omitting this
study, the frequency of fatal intracranial hemorrhage is 9/1,650 (0.5%) and the
overall mortality is 10/1,650 (0.6%). Eight of the fatal ICH occurred acutely,
within 5 wk of diagnosis; the other 5 occurred between 1 to 2 years after
diagnosis. All 4 of the other hemorrhagic deaths occurred acutely within 5 wk.
§Persistant thrombocytopenia was defined as >6 mo after diagnosis, except for
Lusher and Zuelzer22 and Benham and Taft,34 who defined persistant
thrombocytopenia as >12 mo after diagnosis.
||Includes 7 patients who had splenectomy <6 mo after diagnosis. No patients
were treated with glucocorticoids in this study.
¶Described only as "uncontrollable bleeding."
#Death due to hemorrhage (not ICH) and presumed sepsis 2 wk after diagnosis.
**The distinction of acute v chronic ITP is determined at 12 mo rather than 6 mo
in these two reports, and these are the data for remission at 12 mo.
--------------------------------------------------------------------------------
Further information about clinical course in children presenting with severe
thrombocytopenia is provided by the control groups of prospective randomized
studies.30-32 In one illustrative study32 53 patients, each of whom had platelet
counts <20,000 and purpuric symptoms, were randomly assigned to treatment (IVIg
or oral prednisone) or no treatment. Among the 16 children who received no
treatment, platelet counts increased to >20,000 in a median of 4 days (range, 1
to 132 days) and to >50,000 in a median of 16 days (range, 2 to 132 days).
Chronic ITP (defined as a platelet count <150,000 for more than 6 months)
occurred in 3 of the 16 patients (19%, 95% confidence interval, 4% to 46%).
Only limited observational data are available regarding the complications of
intracranial hemorrhage. In a review of 14 children with intracranial
hemorrhage, Woerner et al33 reported that 4 died and 2 others may have had
neurologic sequelae. Of the 30 children with intracranial hemorrhage described
in this report33 and the references in Table 3, 12 (40%) occurred within the
first 12 days after diagnosis, including 2 patients with a history of head
trauma. The intracranial hemorrhages in the other 18 patients occurred between 1
month and 5 years after diagnosis, typically after glucocorticoids and
splenectomy failed to induce a remission. At least 24 of these 30 patients were
reported before 1981, when IVIg therapy was initially described.34
Unlike ITP in adults, persistent thrombocytopenia is uncommon in children. In
the 12 case series in Table 3, 10 defined chronic disease as 6 months of
thrombocytopenia and 2 studies defined it as 12 months.22,24 In the 12 series,
ITP resolved in 1,207 (76%) of the 1,597 children who were followed for these
time periods. Features of the presenting illness that were associated with an
increased risk of chronic persistent thrombocytopenia included a history of
purpura for more than 2 to 4 weeks before diagnosis,23-25,29 female sex,21-23,28
age over 10 years,23,28 and a higher platelet count at presentation.22 The fate
of children with chronic ITP is uncertain, although about one third appear to
have spontaneous remissions several months to many years after diagnosis.35,36
Diagnosis
Few clinical studies have evaluated the sensitivity and specificity of the
diagnostic tests used for children with suspected ITP, because in the absence of
a "gold-standard" test for ITP the diagnosis is based only on the presence of
thrombocytopenia with no other apparent cause. Other etiologies are uncommon: in
a study of 127 consecutive children with suspected ITP who had bone marrow
aspirations, other causes of thrombocytopenia were identified in only 5 (4%)
children, all of whom had atypical presenting features.37 Therefore, in the
absence of additional scientific evidence on the accuracy or effectiveness of
diagnostic tests for ITP, the panel's recommendations regarding the history,
physical examination, laboratory tests, and special procedures are based
entirely on opinion.
Directed history and physical examination. By definition, the diagnosis of ITP
cannot be made without a compatible history and physical examination that
excludes other causes of thrombocytopenia. The most likely alternate causes vary
with the age of the child. For example, many case series exclude infants less
than 4 to 6 months old in part because neonatal alloimmune or autoimmune
thrombocytopenia cannot be ruled out at this age. The most important elements of
the history and physical examination identified by the panel are presented in
Table 4. The maternal and birth history are especially relevant when evaluating
infants. The presence of congenital anomalies in the patient or family members
may be a clue for congenital thrombocytopenia, an important consideration in
children with persistent thrombocytopenia.38 TABLE 4
Principal Elements of the History and Physical Examination in a Child With
Suspected ITP
--------------------------------------------------------------------------------
History
Bleeding symptoms
Type of bleeding
Severity of bleeding
Duration of bleeding
Hemostasis with prior invasive procedures
Systemic symptoms, especially of recent (within 6 wk) viral illness or exposure
to viruses such as varicella, or recurrent infections suggesting
immunodeficiency; symptoms of an autoimmune disorder
Recent live virus immunization
Medications, including heparin, quinidine/quinine, and sulfonamides, which may
cause thrombocytopenia, and aspirin, which may exacerbate bleeding
Risk factors for HIV infection, including maternal HIV status
Family history of thrombocytopenia or hematologic disorder
In an infant <6 mo old, include perinatal and maternal history
Comorbid conditions, which may increase the risk of bleeding
Lifestyle, including vigorous and potentially traumatic activities
Physical examination
Bleeding signs
Type of bleeding (including retinal hemorrhages)
Severity of bleeding
Liver, spleen, and lymph nodes
Evidence for infection
Presence of dysmorphic features suggestive of congenital disorder, including
skeletal anomalies, auditory acuity
Specific Congenital Syndromes to Exclude
Fanconi syndrome
Thrombocytopenia-absent radius
Wiskott-Aldrich syndrome
Alport syndrome (and its variants)
Bernard-Soulier syndrome
May-Hegglin anomaly
Gray platelet syndrome
--------------------------------------------------------------------------------
Although the essential elements of the physical examination of children and
adults with ITP are generally the same, one difference may be the presence of
splenomegaly, which may be slightly more common in children, especially in
infants. Data from six case series suggest that the spleen may be palpable in
12% of children with ITP.18,19,22,24,25,27 However, this may reflect the greater
incidence of palpable spleens in children in general, which is estimated to be
about 10%.39
Complete blood count with examination of the peripheral blood smear. A complete
blood count and an examination of the peripheral blood smear are essential in
ITP. The principal features of the examination of the blood smear that were
identified by the panel are the same for children and adults (Table 5). Although
most patients with ITP present with platelet-related bleeding, the condition may
be first detected by the incidental discovery of thrombocytopenia on routine
blood counts. Because ITP is defined by a low platelet count without another
apparent cause, the clinician must know the normal values for the laboratory.
Aside from thrombocytopenia, the blood counts of patients with ITP should be
normal or otherwise readily explained by a coincident disorder (eg, thalassemia
minor). The presence of platelet clumps suggests pseudothrombocytopenia (see
Adult section, below). Anemia, if present, may be caused by bleeding or iron
deficiency resulting from chronic thrombocytopenia, but this is uncommon in
children. White blood cell morphology should be normal, although some children
with ITP may have atypical lymphocytes or eosinophilia.22,25,40
Other laboratory data. Recommendations regarding other laboratory tests were
derived from opinion by a questionnaire completed by six panel members (see text
above). The recommendations assume that the history, physical examination, and
initial blood counts and smear are compatible with the diagnosis of ITP and do
not include atypical findings that are uncommon in ITP or suggest other disease
etiologies. For example, a direct antiglobulin test, which the panel did not
recommend for patients with a typical presentation of ITP, may be appropriate if
the peripheral smear shows red blood cell polychromatophilia with poikilocytosis
and spherocytes. Indications for which the panel did not reach consensus (score
of 3.1-6.9) are not listed in the text but are summarized in Table 6. TABLE 5
The Peripheral Blood Smear in ITP
--------------------------------------------------------------------------------
Consistent with the diagnosis of ITP
1. Thrombocytopenia. Platelets are normal in size or may appear larger than
normal, but consistently giant platelets (approaching the size of red blood
cells) should be absent.
2. Normal red blood cell morphology.
3. Normal white blood morphology.
Not consistent with the diagnosis of ITP
1. Predominant giant platelets.
2. Red blood cell poikilocytosis, schistocytes, polychromatophilia (unless
response to bleeding), macrocytes, nucleated red blood cells.
3. Leukocytosis or leukopenia, with immature or abnormal cells (although
atypical lymphocytes and eosinophilia may occur in children with ITP).
--------------------------------------------------------------------------------
TABLE 6
Indications for Which the Necessity/Appropriateness of Routine Testing Is
Uncertain (Based on Opinion of Panel)
--------------------------------------------------------------------------------
Tests of Uncertain Appropriateness (meean panel scores 3.01-6.99)
--------------------------------------------------------------------------------
Indications
--------------------------------------------------------------------------------
Children
--------------------------------------------------------------------------------
Adults
--------------------------------------------------------------------------------
To establish the diagnosis in all patients at presentation ANA (a), direct
antiglobulin (a), HIV (a), bone marrow (a), platelet antigen-specific antibody,
mean platelet volume, reticulocyte count ANA, direct antiglobulin, lupus
anticoagulant/APLA (a), chemistry profile, coagulation studies, chest x-ray (a),
HIV, bone marrow, mean platelet volume, reticulocyte count (a), thyroid
function, urinalysis (a)
To establish the diagnosis before splenectomy ANA, direct antiglobulin, lupus
anticoagulant/APLA, abdominal CT/ultrasound (a), serum immunoglobulins (a),
platelet antigen-specific antibody ANA, direct antiglobulin, lupus
anticoagulant/APLA, serum complement, abdominal CT/ultrasound, bone marrow (n),
chest x-ray, platelet antigen-specific antibody, platelet survival, thyroid
function
To establish the diagnosis in patients who fail to respond to primary treatment
(eg, glucocorticoid) and splenectomy ANA, direct antiglobulin, lupus
anticoagulant/APLA (a), abdominal CT/ultrasound (a), serum immunoglobulins,
platelet-associated IgG, platelet antigen-specific antibody, platelet survival,
thyroid function ANA, direct antiglobulin, lupus anticoagulant/APLA, serum
complement, abdominal CT/ultrasound, chest x-ray, platelet-associated IgG,
platelet antigen-specific antibody, platelet survival, thyroid function
Other tests of uncertain appropriateness: ANA, to establish the diagnosis in
pregnant and nonpregnant women; lupus anticoagulant/APLA, to establish the
diagnosis in women at presentation (a) and pregnant women; abdominal
CT/ultrasound, for suspected splenomegaly on physical examination in children
(n) and adults; HIV, in adult patients with no risk factors for HIV infection;
thyroid function, to rule out thyroid disease in all patients at presentation
(a) and before elective splenectomy (n).
--------------------------------------------------------------------------------
Tests that the panel considered unnecessary/inappropriate for routine evaluation
of all patients (mean scores, 1.0-3.0) are listed in Table 7. Tests which the
panel considered appropriate/unnecessary (mean scores, 7.0-9.0) are described in
the text. Listed here are the specific clinical scenarios for which the panel
assigned a mean panel score of 3.01-6.99, not reaching consensus on whether the
test is appropriate/necessary. (a) = appropriateness uncertain, but testing is
not necessary, (n) = necessity uncertain, but testing is appropriate.
--------------------------------------------------------------------------------
The panel reached consensus that six diagnostic tests were unnecessary in the
routine evaluation of children presenting with suspected ITP, and that an
additional 12 tests were both unnecessary and inappropriate (Table 7).
Recommendations that diagnostic tests are "inappropriate" refer to performing
them on all patients at presentation. Testing for HIV antibody was considered
necessary (8.7, B), and appropriate (9.0, A), in patients with risk factors for
HIV infection. An abdominal CT scan or ultrasound examination was considered
appropriate (8.2, B) in patients with suspected splenomegaly on initial physical
examination. Bone marrow aspiration was considered both appropriate and
necessary to establish the diagnosis in patients with persistent
thrombocytopenia (> 6 to 12 months) (7.0, D) and in patients unresponsive to
IVIg (8.2, B). However, the panel concluded that it is neither necessary (1.3,
B) nor appropriate (2.7, C) to perform a bone marrow aspiration to establish the
diagnosis of ITP before initiating IVIg therapy. The test is also unnecessary
(3.0, C) to establish the diagnosis in patients who require more than an initial
course of IVIg or to allay parental anxiety. TABLE 7
Tests That Are Unnecessary/Inappropriate to Establish the Diagnosis of ITP in
All Patients at Presentation (Based on Opinion of Panel)
--------------------------------------------------------------------------------
Unnecessary, But May be Appropriate (Mean Panel Score for Necessity, Consensus
Code)
--------------------------------------------------------------------------------
Unnecessary and Inappropriate (Mean Panel Score for Appropriateness, Consensus
Code)
--------------------------------------------------------------------------------
Children
Platelet antigen-specific antibody (1.3, B)
Mean platelet volume (1.8, B)
Bone marrow (2.0, B)
HIV test (2.0, B)
Antinuclear antibody (2.0, C)
Direct antiglobulin test (2.5, C) Platelet survival study (1.0, A)
Chest x-ray (1.0, A)
Abdominal CT or ultrasound (1.0, A)
Coagulation studies (1.2, A)
Serum complement level (1.7, C)
Lupus anticoagulant/APLA (2.0, C)
Bleeding time (2.0, C)
Platelet-associated IgG (2.2, C)
Thyroid function tests (2.3, D)
Serum chemistry profile* (2.7, D)
Urinalysis (2.8, D)
Serum immunoglobulin level (3.0, D)
--------------------------------------------------------------------------------
Adults
Lupus anticoagulant/APLA (1.8, B)
Platelet antigen-specific antibody (1.7, C)
Direct antiglobulin test (2.1, B)
Chest x-ray (2.1, C)
Mean platelet volume (2.4, D)
Reticulocyte count (2.6, D)
Urinalysis (2.6, C)
Thyroid function tests (2.9, D) Bleeding time (1.7, C)
Platelet survival study (2.4, C)
Serum complement (2.6, D)
Abdominal CT/ultrasound (2.6, D)
Platelet-associated IgG assay (3.0, D)
--------------------------------------------------------------------------------
Pregnant women
Platelet antibody (1.4, B)
Serum fibrin D-dimer (2.4, D)
PT/PTT (2.6, C)
Lupus anticoagulant/APLA (2.9, D)
Uric acid (2.9, D) None
--------------------------------------------------------------------------------
Tests of uncertain appropriateness/necessity are listed in Table 6.
*Including LDH, BUN, creatinine, and liver function tests.
--------------------------------------------------------------------------------
The panel also reached consensus regarding testing in the following specific
clinical situations:
(1) To establish the diagnosis before splenectomy: Tests that the panel
considered unnecessary for this purpose included platelet antigen-specific
antibody assay (2.0, C), abdominal CT scan or ultrasound (2.0, C), and serum Ig
level (3.0, D). Tests that the panel considered unnecessary and inappropriate
included (scores are for appropriateness): serum complement level (1.8, C),
chest x-ray (2.5, C), thyroid function studies (2.5, D), platelet survival study
(2.5, D), and platelet-associated IgG assay (2.7, C).
(2) To establish the diagnosis in patients who have failed to respond to
glucocorticoid therapy, IVIg, and splenectomy: Tests that the panel considered
unnecessary for this purpose included platelet-associated IgG assay (1.2, A),
platelet antigen-specific antibody assay (2.0, C), abdominal CT scan or
ultrasound (2.8, C), platelet survival study (2.8, D), lupus anticoagulant or
antiphospholipid antibody (3.0, C), and thyroid function testing (3.0, D). Tests
that the panel considered unnecessary and inappropriate included chest x-ray
(2.2, C) and serum complement level (2.5, D) (scores are for appropriateness).
Treatment
Essentially all evidence regarding the efficacy of treatment of ITP is indirect,
inferred by measuring a surrogate outcome, platelet count, rather than a health
outcome such as bleeding or mortality. The panel accepted the platelet count as
a useful surrogate outcome, because numerous studies of thrombocytopenia show a
correlation between platelet counts and clinically important bleeding.41-44 The
limitations of this assumption are highlighted by several factors. First, the
association between platelet count and clinically important bleeding has been
demonstrated principally in patients with thrombocytopenia with conditions other
than ITP. Second, the platelet count may not reflect beneficial or potential
harmful effects of treatment that are independent of an effect on platelets.
Even an effect on the platelet count is difficult to validate convincingly based
on currently available data, because evidence of treatment efficacy consists
largely of reports from uncontrolled case series (level V evidence, the weakest
category, Table 1). Without an internal control group for comparison, such
studies are unable to clarify whether the favorable results were due to the
treatment under study or would have occurred even without treatment (or with
another treatment). Although the potential adverse effects of certain treatments
for ITP are known, a valid framework for the systematic comparison of benefits
and harms is lacking, making it difficult to determine when a treatment results
in more harm than good. Given these gaps in the evidence, treatment
recommendations in this report rely largely on opinion.
Hospitalization
Evidence. There have been no studies to evaluate the effectiveness of
hospitalizing children with ITP.
Recommendations. In the absence of evidence, the opinion of the panel was that
hospitalization is appropriate for a child with severe, life-threatening
bleeding, regardless of the platelet count (9.0, A), and for a child with a
platelet count of <20,000 and mucous membrane bleeding that may require clinical
intervention (8.2, C). Hospitalization is inappropriate for a child with a
platelet count of 20,000 to 30,000 who is asymptomatic (2.8, D) or for a child
with a platelet count >30,000 who is either asymptomatic or has only minor
purpura (1.0 to 1.5, B) (Table 8). Indications for hospitalization under
intermediate conditions are less clear. Hospitalization may also be appropriate
for children with platelet counts <20,000 who may be inaccessible or
noncompliant (8.2, B) or whose parents request hospitalization (7.0 to 7.4, B).
Emergency Treatment
Evidence. Although there are no published data on the efficacy of different
treatments for the management of children with urgent, life-threatening
bleeding, evidence regarding the morbidity and mortality associated with severe
hemorrhage from thrombocytopenia is extensive.18,33,45
Recommendations. The opinion of the panel was that the serious consequences of
severe, life-threatening bleeding justify the use of several regimens. Assuming
that conventional critical care measures are already underway, there was strong
agreement (9.0, A) among panel members that appropriate interventions include
platelet transfusions, high-dose parenteral glucocorticoid (eg, 30 mg/kg
methylprednisolone daily for 3 days), and IVIg, either alone or in combination
with glucocorticoids. See more detailed discussion of these treatments below.
Observation (No Specific Initial Treatment)
Evidence. Evidence about the outcomes of not treating ITP is derived from
studies of the clinical course of untreated cases (see "Clinical Course"). Two
level I studies31,32 and many level V studies suggest that 30% to 70% of
children recover from severe thrombocytopenia, achieving platelet counts of
50,000 to 100,000 within 3 weeks without specific treatment. Level I evidence
indicates that platelet count recovery is more rapid with either IVIg or
glucocorticoid therapy than with no specific treatment30-32,46-48 (see Table 9),
but it remains uncertain if this effect on platelet count influences morbidity
or mortality. Moreover, the data come from children with severe thrombocytopenia
at presentation; no comparable studies have been performed on children with less
severe thrombocytopenia. Although it may seem intuitive that less severe
thrombocytopenia would provide an even weaker indication for intervention, there
is some evidence that children with higher platelet counts may have a greater
risk of chronic, persistent thrombocytopenia.22,49 However, there is no evidence
that the risk of developing chronic ITP is lowered by treatment.
Recommendations. Current evidence is inadequate to recommend which groups of
children with ITP can be safely managed without therapy. The opinion of the
panel was that it was appropriate to withhold specific treatment for
asymptomatic children with platelet counts of 20,000 to 30,000 (7.0, C), and
more strongly for children with platelet counts >30,000 who are asymptomatic or
who have only minor purpura (8.3 to 9.0, A-C) (Table 8, Fig 2). The panel
acknowledges that some pediatric hematologists who were not represented on the
panel do not recommend specific treatment for children presenting with severe
thrombocytopenia (platelet counts <20,000); these hematologists believe that
careful observation is sufficient and preferable. The panel believed that
withholding specific treatment was inappropriate for children with a platelet
count <50,000 who present with significant mucous membrane bleeding (1.0, A for
platelet count <30,000; 2.0, B for platelet count of 30,000 to 50,000). Not
treating children with severe life-threatening bleeding was considered
inappropriate (1.0, A) at any platelet count. Although the panel considered it
appropriate (7.7 to 8.7, B-C) to withhold treatment at the parents' request for
children with platelet counts >30,000, it was considered inappropriate (2.8, D)
to do so if the platelet count was <10,000.
Glucocorticoid Therapy
Evidence. Level I and II studies of the efficacy of glucocorticoids are
summarized in Table 9. Randomized clinical trials (level I and II) have shown
that glucocorticoids increase the platelet count more quickly than when no
specific treatment is administered. For example, the median time to achieve a
platelet count of >50,000 was 4 days with prednisone treatment (4 mg/kg/d for 7
days, then tapered) versus 16 days in untreated children.32 The efficacy of
glucocorticoids has only been demonstrated in terms of platelet recovery time
and not in terms of morbidity or mortality. All relevant data come from children
with acute ITP of recent onset. There have been no randomized controlled studies
of glucocorticoid treatment in children with chronic thrombocytopenia.
Three general cateories of regimens for glucocorticoids have been evaluated: (1)
1 to 2 mg/kg/d or 60 mg/m2/d of oral prednisone for approximately 21
days27,30,31,46,47,50-52 (level I, II, and V evidence); (2) 4 mg/kg/d of oral
prednisone for 7 days then tapered32,48 (level I evidence); and (3) 10 to 30
mg/kg/d of oral or IV methylprednisolone for several days52-57 (level II, III, V
evidence). Because ITP in children is typically self-limited, the duration of
treatment was limited in many studies to 21 days. Initial reports used 2
mg/kg/d, comparable to the adult dose, but more recent studies have used 4
mg/kg/d, which is well-tolerated because the duration of treatment is short. In
recent studies,32,48 the dose of 4 mg/kg/d was continued for only 7 days and the
dose was then tapered and discontinued on day 21. Several studies using very
high doses (10 to 50 mg/kg/d of methylprednisolone for 3 to 7 days) suggest that
platelet count recovery is as rapid as that seen with IVIg,52,55-57 but similar
findings have also been reported with a dose of 4 mg/kg/d for the first 7
days.32,48
The potential adverse effects of glucocorticoid therapy include all of the signs
and symptoms of hypercortisolism in Cushing syndrome, including facial swelling,
weight gain, hyperglycemia, hypertension, cataracts, and behavioral
abnormalities.58 The toxicities of glucocorticoids are dose and duration
dependent. Glucocorticoid therapy may increase the risk of growth retardation in
children.59
Recommendations. There is level I evidence that children with acute ITP and
severe thrombocytopenia experience more rapid recovery of platelets if given
glucocorticoids, but it is unknown if this influences morbidity or mortality.
There is also inadequate evidence of the efficacy of glucocorticoids in other
patient categories (less severe thrombocytopenia, chronic ITP) to develop
definitive recommendations based on the data. The opinion of the panel was that
in patients with platelet counts <50,000 it is appropriate (7.0 to 8.4, B-D) to
treat severe, life-threatening bleeding initially with high-dose oral (eg,
prednisone, 4 to 8 mg/kg/d) or parenteral (eg, methylprednisolone, 30 mg/kg/d)
glucocorticoid. High doses of oral glucocorticoid are also appropriate as
initial therapy for children with mucous membrane bleeding and platelet counts
<20,000 (7.6, C) and for those with minor purpura and platelet counts <10,000
(7.0, D). The panel considered glucocorticoids inappropriate (1.0 to 2.2, A-C)
as initial therapy for children with platelet counts >30,000 and no symptoms or
only minor purpura (Table 8). Treatment for the sole purpose of determining
responsiveness or confirming the diagnosis was considered inappropriate for
high-dose parenteral glucocorticoids in patients with platelet counts >10,000,
for conventional-dose oral glucocorticoids in patients with platelet counts
>20,000, and for high-dose oral glucocorticoids in patients with platelet counts
>30,000 (1.0 to 2.8, A-D). When oral glucocorticoids are used, level I studies
suggest that the regimens of 1.5 or 2 mg/kg/d for 14 to 21 days,30,46,47 60
mg/m2/d for 21 days,31 or 4 mg/kg/d for 7 days, followed by a tapering dose
until day 21,32,48 are more effective than no treatment. These regimens have not
been compared with each other, and some may be more effective than others in
rapidly reaching a platelet count that may reduce the risk of serious
hemorrhage. TABLE 8
Panel Opinion Regarding Initial Treatment Options in Children
--------------------------------------------------------------------------------
Treatment Options
--------------------------------------------------------------------------------
Platelet Count <20,000
--------------------------------------------------------------------------------
Appropriate
(mean panel scores 7-9)
--------------------------------------------------------------------------------
Appropriateness Uncertain
(mean panel scores, 3.1-6.9)
--------------------------------------------------------------------------------
Inappropriate
(mean panel scores, 1-3)
--------------------------------------------------------------------------------
Asymptomatic No treatment*, hospitalization, conventional-dose oral
glucocorticoid,[dagger] high-dose oral glucocorticoid,[double dagger] high-dose
parenteral glucocorticoid,§ IVIg (1 g/kg × 1 d), IVIg (total dose of 2 g/kg
given over 2-5 d), anti-D||
Minor purpura IVIg (1 g/kg × 1 d), (7.2, D)[dagger]
High-dose oral glucocorticoid, (7.0, D)¶ Hospitalization, conventional-dose oral
glucocorticoid, high-dose parenteral glucocorticoid, IVIg (total dose of 2 g/kg
given over 2-5 d), anti-D No treatment (2.5 D)Ÿ
Mucous membrane bleeding that may require clinical intervention IVIg (1 g/kg × 1
d) (8.3, B)
Hospitalization, (8.2, C)
IVIg (total dose of 2 g/kg given over 2-5 d), (7.8, B)
High-dose oral glucocorticoid, (7.6, C) Conventional-dose oral glucocorticoid,
high-dose parenteral glucocorticoid, anti-D No treatment (1.0 A)
Severe, life threatening bleeding Hospitalization (9.0, A)
IVIg (1 g/kg × 1 d) (8.8, A-B)
High-dose parenteral glucocorticoid (8.0-8.4, B-C)
IVIg (total dose of 2 g/kg given over 2-5 d), (7.8, C)
High-dose oral glucocorticoid (7.0-7.4, C-D) Conventional-dose oral
glucocorticoid therapy, anti-D No treatment (1.0, A)
--------------------------------------------------------------------------------
Platelet Count 20-30 × 103
--------------------------------------------------------------------------------
Appropriate
(mean panel scores 7-9)
--------------------------------------------------------------------------------
Appropriateness Uncertain
(mean panel scores, 3.1-6.9)
--------------------------------------------------------------------------------
Inappropriate
(mean panel scores, 1-3)
--------------------------------------------------------------------------------
Asymptomatic No treatment (7.0, C) Conventional-dose oral glucocorticoid,
high-dose oral glucocorticoid, IVIg (1 g/kg × 1 d), IVIg (total dose of 2 g/kg
given over 2-5 d), anti-D High-dose parenteral glucocorticoid, (2.6, C)
Hospitalization (2.8, D)
Minor purpura No treatment, hospitalization, conventional-dose oral
glucocorticoid, high-dose oral glucocorticoid, IVIg (1 g/kg × 1 d), IVIg (total
dose of 2 g/kg given over 2-5 d), anti-D High-dose parenteral glucocorticoid,
(2.6, C)
Mucous membrane bleeding that may require clinical intervention Hospitalization,
conventional-dose oral glucocorticoid, high-dose oral glucocorticoid, high-dose
parenteral glucocorticoid, IVIg (1 g/kg × 1 d, IVIg (total dose of 2 g/kg given
over 2-5 d), anti-D No treatment (1.0, A)
Severe, life-threatening bleeding Hospitalization (9.0 A)
IVIg (1 g/kg × 1 d) (8.5, B)
IVIg (total dose of 2 g/kg given over 2-5 d) (8.2, C)
High-dose parenteral glucocorticoid (7.6, C)
High-dose oral glucocorticoid (7.4, C) Conventional-dose oral glucocorticoid,
anti-D No treatment (1.0, A)
Platelet count 30-50 × 104 Appropriate
(mean panel scores 7-9) Appropriateness Uncertain
(mean panel scores, 3.1-6.9) Inappropriate
(mean panel scores, 1-3)
--------------------------------------------------------------------------------
Platelet Count 30-50 × 104
--------------------------------------------------------------------------------
Appropriate
(mean panel scores 7-9)
--------------------------------------------------------------------------------
Appropriateness Uncertain
(mean panel scores, 3.1-6.9)
--------------------------------------------------------------------------------
Inappropriate
(mean panel scores, 1-3)
--------------------------------------------------------------------------------
Asymptomatic No treatment (9.0, A) IVIg (total dose of 2 g/kg given over 2-5 d),
(1.0, A)
IVIg (1 g/kg × 1 d) (1.2, A)
Anti-D (1.2, A)
High-dose parenteral glucocorticoid (1.2, B)
Hospitalization (1.5, B)
High-dose oral glucocorticoid (2.0, C)
Conventional-dose oral glucocorticoid (2.0, C)
Minor purpura No treatment (8.3, C) IVIg (total dose of 2 g/kg given over 2-5 d)
(1.0, A)
IVIg (1 g/kg × d) (1.2, A)
Anti-D (1.2, A)
High-dose parenteral glucocorticoid (1.2, B)
Hospitalization (1.5, B)
High-dose oral glucocorticoid (2.2, C)
Conventional-dose oral glucocorticoid (2.2, C)
Mucous membrane bleeding that may require clinical intervention Hospitalization,
conventional-dose oral glucocorticoid, high-dose oral glucocorticoid, IVIg (1
g/kg × 1 d), IVIg (total dose of 2 g/kg given over 2-5 d) No treatment (2.0, B)
High-dose parenteral glucocorticoid (2.8, D)
Anti-D (3.0, D)
Severe, life-threatening bleeding Hospitalization (9.0, A)
IVIg (1 g/kg × 1 d) (8.0, C)
High-dose oral glucocorticoid (7.4, C)
IVIg (total dose of 2 g/kg given over 2-5 d) (7.3, D)
High-dose parenteral glucocorticoid (7.0, D) Conventional-dose oral
glucocorticoid No treatment (1.0, A)
Anti-D (3.0, D)
--------------------------------------------------------------------------------
"Appropriate" and "Not appropriate" = mean panel score of 7.0-9.0 or 1.0-3.0,
respectively. "Appropriate" = treatment may or may not be necessary, but
performing it is not wrong, "Inappropriate" = treatment should not be performed.
Mean panel score is graded on a scale of "1" to "9" with "1" representing low
appropriateness and "9" representing high appropriateness. Letter codes
following panel scores reflect strength of agreement, the panel consensus
(defined by standard deviation) around the mean panel score. "A" = complete or
virtual unanimity, "B" = strong agreement, "C" = moderate agreement, "D" =
moderate disagreement, "E" = strong disagreement (see Table 4).
*"No treatment" implies careful observation. In patients with major risk factors
for bleeding (eg, elevated blood pressure, ulcer disease, vigorous lifestyle),
not treating is considered inappropriate in all patients if the platelet count
is 20-30 × 105 (2.3 C), 10-20 × 105 (1.3, B) or <10 × 105 (1.0, A). Not treating
patients less than 3 years of age is also considered inappropriate if the
platelet count is 10-20 × 105 (1.6, B) or less than 10 × 105 (2.4, B).
[dagger]Eg, 1-2 mg/kg/d of prednisone.
[double dagger]Eg, 4-8 mg/kg/d of prednisone.
§Eq, 30 mg/kg/d of methylprednisolone.
||Anti-D given intravenously.
¶These recommendations were made only for patients with platelet counts <10,000.
--------------------------------------------------------------------------------
IVIg
Evidence. Clinical trials of IVIg therapy for ITP are summarized in Table 9. One
level I study has shown that initial IVIg treatment of children with acute ITP
increases the platelet count more rapidly than no specific treatment and than
glucocorticoid therapy.32 Five level V studies34,60-63 suggest that IVIg will
increase the platelet count substantially in a majority of patients, although
some do not respond. Less than 10% of patients with chronic ITP have sustained,
normal platelet counts without further treatment; in others thrombocytopenia
recurs in several weeks to several months. No controlled data clarify whether
these occasional prolonged responses without further treatment are different
from those that would be observed in untreated children. Repeated treatments
with IVIg may sustain platelet counts at a level of >20,000 to 30,000 and be
useful to avoid splenectomy. For both acute and chronic ITP, there is no
evidence that treatment with IVIg diminishes mortality or morbidity.
The first reported IVIg regimen was 0.4 g/kg daily for 5 consecutive days.
Subsequent studies suggested that 1 g/kg for 1 day64 or 0.4 g/kg/d for 2 days50
may be sufficient in most responding patients. Recently, a randomized trial
showed that a single dose of 0.8 g/kg achieves the same results as the former
regimen with less cost and possibly fewer side effects.48 TABLE 9
Clinical Trial Evidence: Effectiveness of Glucocorticoids, IVIg, and Anti-D in
Initial Treatment of ITP in Children
--------------------------------------------------------------------------------
Study Population
--------------------------------------------------------------------------------
Outcome
--------------------------------------------------------------------------------
Authors
--------------------------------------------------------------------------------
N
--------------------------------------------------------------------------------
Age
--------------------------------------------------------------------------------
Follow-up
--------------------------------------------------------------------------------
Randomized Treatment Arms
--------------------------------------------------------------------------------
Outcome Measure
--------------------------------------------------------------------------------
Platelet Count
--------------------------------------------------------------------------------
Bleeding Symptoms
--------------------------------------------------------------------------------
Adverse Effects
--------------------------------------------------------------------------------
Deaths
--------------------------------------------------------------------------------
Evidence Level
--------------------------------------------------------------------------------
McWilliams and Maurer46 27 6 yr (mean) NR Prednisone (2 mg/kg/d × 21 d)
No treatment Median time to platelet count of 150K 21 d
60 d (P <= .03) NR*
NR NR*
NR 0
0 I
Sartorius31 93 6 mo-16 yr >6 mo Prednisone (60 mg/m2/d × 21 d, then tapered)
Placebo Proportion with platelet count >30K and >100K, and with negative
Rumpel-Leede test Prednisone > placebo (P < .01) Prednisone < placebo (by
Rumpel-Leede test (P < .01) NR 0
0 I
Buchanan and Holtkamp30 27 <11 yr 28 d Prednisone (2 mg/kg/d × 14 d, then taper
to d 21)
Placebo Platelet count, bleeding time, clinical bleeding score at d 0-28
Prednisone > placebo (P < .05) only at d 7 Prednisone < placebo (P < .05) only
at d 7 (bleeding time and clinical score) Increased appetite, weight gain 0
0 I
Imbach et al50 94 <16 yr 1 yr Prednisone (60 mg/m2/d × 21 d, follow-up protocol
for poor response/remissions) Proportion with platelet count >100K 77% NR 77%
with weight gain or acne 0 II
IVIg (0.4 g/kg/d × 5 d, follow-up protocol for poor response/remissions) 83% (no
difference) NR 22% with headache, fever, vomiting, vertigo 1 died on day 6,
excluded from analysis
Mazzucconi et al47 61 2-12 yr >6 mo Prednisone (0.5 mg/kg/d × 1 mo or until
platelet normalization) Proportion with platelet count >150K 62% NR NR NR I
Prednisone (1.5 mg/kg/d × 1 mo or until platelet normalization) 81% (P < .05) NR
NR NR
Belluci et al51 160 <15 yr >12 mo Prednisone (0.25 mg/kg/d × 3 wk)
Prednisone (1 mg/kg/d × 3 wk) Proportion with platelet count >100K for >3 mo 71%
77% (no difference) NR
NR NR
NR 0
0 II
Khalifa et al56 30 2 mo-15 yr >6 mo Methylprednisolone (IV, 10 mg/kg/d × 5 d)
Prednisone (2 mg/kg/d × 4 wk)
IVIg (0.4 g/kg/d × 5d) Mean platelet count on days 1-14 Methylprednisolone =
IVIg > prednisone (P < .001) NR
NR
NR NR
NR
NR 0
0
0 I
Ozsoyle et al57 20 2 mo-11 yr >6 mo Methylprednisolone (po. 30 mg/kg/d × 3 d,
then 20 mg/kg/d × 4 d)
IVIg (0.4 g/kg/d × 5 d) Proportion with platelet count >150K in 3 d, 6 mo 60%,
90% (no difference)
60%, 75% None
NR NR
NR 0
0 II
Blanchette et al32 53 7 mo-14 yr 180 d Prednisone (4 mg/kg/d × 7 d, then tapered
to d 21) Median time to platelet count >20K, >50K 2 d, 4 d NR Weight gain,
behavioral change 0 I
IVIg (1 g/kg/d × 2 d)
No therapy 1 d, 2 d (P < .01 v prednisone)
4 d, 16 d (P < 0.1 v either treatment) NR 75% with nausea, vomiting, headache,
fever 0
Blanchette et al48 146 6 mo-18 yr 6-32 mo Prednisone (4 mg/kg/d × 7 d then
tapered to d 21)) Median time to platelet count >20k, >50K 2 d, 3 d NR None 0 I
IVIg (1 g/kg/d × 2 d)
IVIg (0.8 g/kg once) 2 d, 2 d
1 d, 2 d (P < .05 v prednisone) NR
NR 16-18% with fever, nausea, vomiting, headache 0
0
Anti-D (25 µg/kg/d × 2 d) 2 d, 2.5 d (P < .05 v both IVIg regimens) NR 24% with
hemoglobin <10 g/dL 0
Albayrak et al55 57 2 mo-17 yr 6 mo Methylprednisolone (po, 30 mg/kg/d × 7 d)
Mean platelet count on days 0-30 Mean >100K by d 4. No difference among groups
NR Increased appetite and Cushingoid appearance 0 II
Methylprednisolone (po, 50 mg/kg/d × 7 d) 1 ICH Increased appetite and
Cushingoid appearance 0
IVIg (0.5 g/kg/d × 5 d) NR 1 pt with aseptic meningitis; 2 with headache,
vomiting 0
--------------------------------------------------------------------------------
*NR, Not reported.
--------------------------------------------------------------------------------
Adverse effects of IVIg are common (15% to 75%) but generally mild, including
headache, backache, nausea, and fever.32,65 Aseptic meningitis may occur.66 Rare
reported complications include alloimmune hemolysis67 and hepatitis C
infection.68-71 No hepatitis C has been reported with viral inactivated
products. Other complications have been reported in adults (see below).
Recommendations. There is level I evidence that children with acute, previously
untreated ITP experience more rapid recovery of platelets with IVIg than with
glucocorticoids or no specific therapy, but it is unclear whether this
enhancement of platelet recovery influences bleeding or mortality or if there
are circumstances in which the disadvantages of IVIg might outweigh its
benefits. There is inadequate evidence regarding the efficacy of IVIg in other
patient categories to develop definitive recommendations based on data. The
opinion of the panel was that, regardless of the platelet count, it is
appropriate (7.3 to 8.8, A-D) to treat severe, life-threatening bleeding
initially with IVIg. IVIg was also considered appropriate as initial therapy for
children with platelet counts <10,000 and minor purpura (1 g/kg for 1 day, 7.2,
D) and for children with platelet counts <20,000 and mucous membrane bleeding
(7.8 to 8.3, B). In all categories, a dose of 1 g/kg administered on 1 day
received higher panel ratings (7.2 to 8.8, A-D) than a total dose of 2.0 g
administered over 2 to 5 days (6.4 to 8.2, B-D). IVIg was considered appropriate
initial treatment in children with platelet counts below 20,000 in whom
inaccessibility or noncompliance is a concern (7.6 to 8.7, B-C). The panel
considered IVIg inappropriate (1.0 to 1.2, A) in children with platelet counts
>30,000 who are asymptomatic or have only minor purpura (Table 8).
Anti-Rh(D)
Evidence. One level I trial48 (Table 9) compared anti-Rh(D) to IVIg and
glucocorticoid as initial therapy in patients with acute ITP and platelet counts
<20,000 at presentation. The time required to increase platelet counts to
>20,000 and >50,000 was slightly longer with anti-Rh(D) than with glucocorticoid
or IVIg therapy. There are no level I or II data comparing anti-Rh(D) treatment
to no treatment, nor is there evidence regarding the effectiveness of anti-Rh(D)
in reducing mortality or morbidity from bleeding. Four level V studies72-75
suggest that anti-Rh(D) may increase the platelet count in about 80% of children
with acute and chronic ITP, and that repeated treatments may postpone the need
for splenectomy, but the responses are generally transient, lasting a median
time of 5 weeks.
The only clinically important adverse effect of anti-Rh(D) appears to be
alloimmune hemolysis. All Rh(D)+ patients develop a positive direct antiglobulin
test after treatment, accompanied by a transient (1 to 2 weeks) decrease in
hemoglobin concentration of about 0.5 to 2 g/dL. Although in two studies 4% to
24% of patients had a hemoglobin concentration of <10 g/dL after 7 to 14
days,48,74 red blood cell transfusion was not required.
Recommendations. There is level I evidence indicating that anti-Rh(D) increases
the platelet count less rapidly than IVIg or glucocorticoids in children with
acute, severe thrombocytopenia (platelet count <20,000). Based on opinion, the
panel considered initial treatment with anti-Rh(D) inappropriate (1.0 to 3.0,
A-D) for children presenting with platelet counts >30,000 (Table 8). The use of
anti-Rh(D) in chronic ITP was not addressed in the panel survey.
Splenectomy
Evidence. Compared to adults, children with ITP are less likely to undergo
splenectomy. Sixteen case series (level V evidence)18-29,76-79 describe outcomes
from splenectomy over the past 40 years. In most instances, splenectomy was
performed in children in whom thrombocytopenia had persisted for more than 1
year and who had clinically important bleeding. In some case series, children
underwent splenectomy earlier in the course of their illness because of
uncontrollable hemorrhage that was unresponsive to glucocorticoid therapy.
Splenectomy is less frequent in more recent case series.36 These data
consistently show that most children (72% of the 271 children undergoing
elective splenectomy in the 16 case series) achieve a complete remission from
ITP after splenectomy. An effect of splenectomy on morbidity or mortality has
not been shown directly. There are few data on accessory splenectomy in
children; it is discussed under Adult Treatment below.
The potential adverse effects of splenectomy include the operative and
postoperative complications of bleeding and infection. An important concern for
late morbidity and mortality after splenectomy is the long-term risk of fatal
bacterial infection, particularly in children less than 5 years old, in whom the
risk may be 1 death per 300 to 1,000 patient-years.80-82 However, most of these
observations involved splenectomy for other diseases and predated the current
practice of presplenectomy immunization and the administration of
postsplenectomy prophylactic penicillin. Prophylactic penicillin has been shown
to reduce the risk of infection in children with sickle cell anemia,83 and this
observation may be generalizable to other asplenic children.
Recommendations. Although all available evidence is level V, the consistency of
observations, the frequency of complete responses to splenectomy, and similar
observations in larger samples of adult patients with chronic ITP suggest that
splenectomy is an effective therapy. However, there are inadequate data to make
evidence-based recommendations on the appropriate indications and timing for
splenectomy, on when the harms of splenectomy might outweigh its potential
benefits, or on appropriate preoperative management. Many of the case series
predated the use of IVIg and anti-Rh(D) therapy, which can provide intermittent
support for children with recurrent, symptomatic thrombocytopenia and thereby
postpone or avoid the need for splenectomy. The occurrence of spontaneous
complete remissions in some children with chronic ITP may also lessen the need
for this procedure.
The panel reached consensus on only selected indications for splenectomy, such
as persistence of disease 12 months after diagnosis with bleeding symptoms and a
platelet count of <10,000 (7.5 to 9.0, A-C for ages 3 to 12 years) or of 10,000
to 30,000 with bleeding symptoms (7.6 to 7.9, B for ages 8 and 12), but it
considered only certain scenarios. These scenarios assume that primary treatment
(glucocorticoid, IVIg, and/or anti-D) was only transiently successful and that
there are no medical contraindications to the surgery. The panel had strong
disagreement (5.0, E) about the appropriateness of emergency splenectomy in the
case of urgent, life-threatening bleeding in which conventional critical care
measures are already underway.
If an elective splenectomy is planned, preoperative prophylaxis that the panel
considered appropriate to reduce the risk of intraoperative and postoperative
bleeding included (1) IVIg (8.8, A), parental glucocorticoid (7.2, D), and
anti-D (7.2, D) therapy for platelet counts <10,000 and (2) IVIg therapy for
platelet counts of 10,000 to 20,000 (8.5, B) or 20,000 to 30,000 (7.7, B).
Indications that were considered inappropriate for preoperative prophylaxis
included IVIg for platelet counts >50,000 (2.6, D), platelet transfusion for
platelet counts of 20,000 to 30,000 (2.3, D) or >30,000 (1.0, A), anti-D for
platelet counts >50,000 (1.0, A), oral glucocorticoid therapy for platelet
counts >50,000 (2.6, D), and parenteral glucocorticoid therapy for platelet
counts of 30,000 to 50,000 (2.2, C) or >50,000 (1.0, A).
The panel endorsed the recommendations of the Advisory Committee on Immunization
Practices that, at least 2 weeks before elective splenectomy, children should be
immunized with Hemophilus influenzae type b vaccine and, if over 2 years of age,
with polyvalent pneumococcal vaccine and quadrivalent meningococcal
polysaccharide vaccine.84
Other Treatments
Evidence. Only four level V case series have evaluated other treatment
modalities (plasma infusion, azathioprine, danazol, and interferon) for ITP in
children.85-88 The modalities are described in the subsequent section on
treatment of adults.
Recommendations. There is insufficient evidence to make recommendations about
alternative treatment modalities when ITP symptoms persist after primary
treatment and splenectomy, or to assess when the benefits of such treatments
outweigh their potential harms. Furthermore, the data on the clinical course of
ITP in children do not clarify whether further treatment is even necessary under
these circumstances. Based on opinion, the panel did not recommend further
treatment of children with platelet counts >30,000 who have failed to respond to
splenectomy and have no bleeding symptoms (2.0, B for platelet count of
30,000-50,000; 1.0, A for platelet count >50,000). Further treatment was
recommended (9.0, A) for children with platelet counts <30,000 who have active
bleeding. The panel considered many treatments (and no treatment) to be
reasonable options, reflecting the lack of evidence that any single treatment is
better than another.
ITP in Adults
Clinical Course
An understanding of the clinical course of ITP in adults is essential to make
informed management decisions, to know which patients require treatment either
at the time of diagnosis or in the management of chronic disease, and to
estimate morbidity and mortality, with and without treatment.
Evidence. ITP in adults is typically a chronic disease. However, the clinical
course of untreated disease is uncertain, because, in contrast to children,
patients with symptomatic thrombocytopenia are generally treated initially with
glucocorticoids. Despite this bias, which would tend to underestimate the
severity of untreated disease, the data suggest that the course of ITP is more
serious in adults than in children, with an estimated rate of fatal hemorrhage
of 5%, due mainly to intracranial hemorrhage (Table 10). Most data on fatal
hemorrhages were collected in previous decades, when platelet transfusions and
IVIg were unavailable and supportive care for critical complications was less
effective. Thus, current mortality rates may be less than 5%. At equivalent
platelet counts, hemorrhagic complications may be more common in older
patients.89,90 There are no long-term follow-up data on outcomes in adults with
incidentally discovered asymptomatic thrombocytopenia. In addition, the relative
incidence of symptomatic versus incidentally discovered thrombocytopenia is
unknown. TABLE 10
Clinical Course of ITP: Adults
--------------------------------------------------------------------------------
Hemorrhagic Complications[dagger]
--------------------------------------------------------------------------------
Patients With Persistant Thrombocytopenia§
--------------------------------------------------------------------------------
Author
--------------------------------------------------------------------------------
Location
--------------------------------------------------------------------------------
Years
--------------------------------------------------------------------------------
Patients (no.)
--------------------------------------------------------------------------------
Patients With Complete Remission on No Therapy*
--------------------------------------------------------------------------------
ICH
--------------------------------------------------------------------------------
Other
--------------------------------------------------------------------------------
Other Deaths
--------------------------------------------------------------------------------
Patients in Complete Remission* at Last Follow-up[double dagger]
--------------------------------------------------------------------------------
No.
--------------------------------------------------------------------------------
Spontaneous Recovery
--------------------------------------------------------------------------------
Deaths From Hemorrhage
--------------------------------------------------------------------------------
Watson-Williams et al91 Scotland 1928-1957 78 12/26|| 4 1 0 46/62 (74)¶ -- -- --
Carpenter et al92 US 1945-1959 46# 0/12 2 0 0 20/35 (57) -- -- --
Thompson et al93 US 1945-1970 66 3 -- -- 4 37/62 (60) -- -- --
Meyers94 US 1950-1961 71 0 2 0 2 56/57 (84) 15 0 2
Jiji et al95 US 1951-1972 91 0 -- -- 5 53/86 (64) -- -- --
Picozzi et al96 US 1959-1969 38 0 0 0 0 25/36 (69) 16 8 0
Ikkala et al97 Finland 1966-1973 41 1 -- 2 1 27/38 (71) 14 0 0
DiFino et al98 US 1971-1979 62 0 0 3 3 34/51 (67) 18 0 3
Jacobs et al99/ South Africa 1971-1981 148 1 1 1 0 78/146 (53) 18 0 0
den Ottolander et al26 Netherlands -- 69 1 -- -- -- 39/69 (57) -- -- --
Pizzuto and Ambriz100 Central and South America# -- 934 9 27** -- 19** 577/887
(65) 384 14 20
Cortelazzo et al90 Italy 1982-1989 117 --[dagger][dagger] -- -- 1 33/67 (49) --
-- --
Summary 1,761 27 36 7 35 1,027/1,606 (64%) 465 22 (5%) 25 (5%)
--------------------------------------------------------------------------------
Abbreviation: ICH, intracranial hemorrhage.
*Complete remission is defined as a normal platelet count on no therapy
continuing to the time of the last observation. In almost all patients there was
no opportunity to observe a spontaneous remission because steroids were begun at
the time of diagnosis. In the first two series, a substantial number of patients
were untreated when, before 1950, splenectomy was the only effective modality.
[dagger]Acute hemorrhagic deaths are arbitrarily defined as occurring within 6
mo of diagnosis. Other hemorrhagic deaths occurred after 6 mo, or the time was
not specified--and it was unclear even if all of these were due to hemorrhage
from ITP.
[double dagger]The number of patients is less than the original series by deaths
and patients lost to follow-up. This estimate is largely dependent on the
duration of follow-up, which was variable.
§Patients who failed to achieve a complete response to glucocorticoid,
splenectomy, and subsequent therapy. In contrast to children, persistence is
defined as lack of response to treatment rather than by an arbitrary time.
||This group contained 3 children less than 12 years old, and it was not stated
if they were among the patients whose ITP resolved.
¶Numbers in parentheses are percentages.
#This study was a collaborative effort of 10 institutions.
**This report stated that 27 of the total of 46 hemorrhagic deaths were due to
ICH, 9 due to gastrointestinal or pulmonary bleeding, and 10 due to "massive"
purpura, but these etiologies were not distinguished according to time from
diagnosis.
[dagger][dagger]49 patients with platelet counts over 30,000/µl and no bleeding
symptoms were not treated and apparently had no major hemorrhagic complications.
Whether any complete remissions occurred is not stated. These patients are not
included in the estimate of patients in complete remission at last follow-up.
--------------------------------------------------------------------------------
Table 10 presents 12 case series from 12 countries with patient observations
spanning 61 years.26,90-100 The data show that spontaneous remission of chronic
ITP occurs infrequently; approximately 5% of patients had an apparent
spontaneous recovery after failing to respond completely to glucocorticoid,
splenectomy, and any subsequent therapy. In the earliest series,91 which
occurred before the introduction of glucocorticoid therapy when splenectomy was
considered the only effective treatment, 26 of the 78 patients had no therapy:
10 of the 26 had an insidious onset of symptoms, and only 1 patient had a
remission, after 3 years of persistent thrombocytopenia; the other 16 patients
had an acute onset of symptoms, and 11 had a complete recovery within 3 months.
In contrast, a subsequent series involving 46 patients reported no complete
remissions in the 12 untreated patients.92 In another series,96 spontaneous
remission occurred in 8 of 16 patients with persistent ITP. Other series in
Table 10 reported rare patients who recovered spontaneously. These data are
difficult to interpret because of small sample sizes, distant past observations,
and uncertain diagnoses of ITP. Unlike children, essentially all adult patients
received glucocorticoid therapy and half underwent splenectomy. Despite
treatment, 36% of patients had persistent thrombocytopenia at the time of last
follow-up.
Diagnosis
History and physical examination. The history and physical examination are aimed
at detecting alternative causes of thrombocytopenia. The most important elements
of the history and physical examination identified by the panel are presented in
Table 11. The primary objective of the history is to assess the type of bleeding
and to distinguish platelet-related mucocutaneous bleeding from delayed visceral
hematomas, which are characteristic of coagulation disorders. TABLE 11
Principal Elements of the History and Physical Examination in an Adult Suspected
of Having ITP
--------------------------------------------------------------------------------
History
Bleeding symptoms
Type of bleeding
Severity of bleeding
Duration of bleeding
Hemostasis with prior surgeries, pregnancies
Systemic symptoms, including weight loss, fever, headache, and symptoms of
autoimmune disorders such as arthralgias, skin rash, alopecia, and venous
thrombosis
Risk factors for HIV infection
Pregnancy status
Medications, including heparin, alcohol, quinidine/quinine, and sulfonamides,
which may cause thrombocytopenia, and aspirin, which may exacerbate bleeding
Transfusion history
Family history of thrombocytopenia, including bleeding symptoms and symptoms of
autoimmune disorders
Comorbid conditions which may increase the risk of bleeding, such as
gastrointestinal disease, central nervous system disease, urologic disease
Lifestyle, including vigorous and potentially traumatic activities
Physical Examination
Bleeding signs
Type of bleeding (including retinal hemorrhages)
Severity of bleeding
Liver, spleen, and lymph nodes; jaundice and other stigmata of liver disease
Evidence for infection, particularly bacteremia or HIV infection
Evidence for autoimmune disease, such as arthritis, goiter, nephritis, or
cutaneous vasculitis
Evidence for thrombosis
Neurologic function
Skeletal anomalies
--------------------------------------------------------------------------------
Drug-induced thrombocytopenia must always be considered and may be difficult to
exclude. Drugs most commonly associated with thrombocytopenia include quinidine
and quinine-containing medications among nonhospitalized patients, and heparin
among hospitalized patients. A case-control study101 also reported an
association with sulfonamides, sulfonylureas, dipyridamole, and salicylates.
Alcohol also causes thrombocytopenia, as well as chronic liver disease that can
lead to congestive splenomegaly and increased platelet pooling. Finally, the
history should consider the patient's lifestyle, which may influence the goals
of treatment. A sedentary individual, for example, may tolerate a lower platelet
count than a patient whose profession or hobbies involve a high level of
exertion or potential trauma.
Physical examination is principally directed at assessing the type and severity
of bleeding and at excluding other causes of thrombocytopenia. Splenomegaly, for
example, provides evidence against ITP. A large study102 reported that less than
3% of ITP patients had splenomegaly. This corresponds with the observation that
about 3% of healthy young adults have palpable spleens.103 Signs of liver
disease or lymphadenopathy may suggest lymphoproliferative, autoimmune, or
infectious diseases. Acute and severe thrombocytopenia may be a manifestation of
bacteremia or viral infection; HIV infection is commonly associated with
thrombocytopenia.104 Acute anemia, neurologic, or renal abnormalities may
suggest thrombotic thrombocytopenic purpura. Neurologic function and funduscopic
examination also provide a baseline in the event of subsequent central nervous
system bleeding. Additionally, hearing impairment and skeletal anomalies may
suggest disorders associated with congenital thrombocytopenia.38
Complete blood count with examination of a peripheral blood smear. A complete
blood count and examination of a peripheral blood smear are essential in
diagnosing ITP. Incidentally detected thrombocytopenia on a routine blood count
is often the first clue to the diagnosis. The evaluation of a low platelet count
should distinguish between true thrombocytopenia and pseudothrombocytopenia,
which occurs in about 0.1% of adults,105-108 most commonly due to innocent
platelet agglutinins that cause platelet clumping in the presence of the
anticoagulant EDTA. In each patient, thrombocytopenia must be confirmed by
direct examination of the peripheral blood smear. The principal elements of the
blood smear examination for ITP are described above for children and in Table 5.
Particularly in older patients, evidence for myelodysplasia should be carefully
evaluated, including the presence of the Pelger-Huet anomaly, nucleated red
blood cells, schistocytes, and immature granulocytes.109 Other peripheral blood
smear abnormalities may suggest the presence of a viral infection, megaloblastic
hematopoiesis, or microangiopathic disorders.
Other laboratory data. Recommendations regarding other laboratory tests were
derived from opinion by a questionnaire completed by 11 panel members. The
recommendations assume that the history, physical examination, and initial blood
counts and smear were compatible with the diagnosis of ITP and do not include
atypical findings that are uncommon in ITP or suggest other disease etiologies.
If aytpical findings are present, then additional diagnostic evaluation may be
necessary. Indications for which the panel could not reach consensus are not
listed here but are summarized in Table 6.
The panel reached consensus that 8 tests were unnecessary as part of the routine
evaluation of adults presenting with suspected ITP, and that an additional 5
tests were both unnecessary and inappropriate (Table 7). Testing for HIV
antibody was considered necessary (8.6, B), as well as appropriate (8.8, B), in
patients with risk factors for HIV infection. There was no consensus on the
appropriateness or necessity of a bone marrow aspirate/biopsy to establish the
diagnosis in all adult patients at presentation (Fig 1). Bone marrow examination
was considered appropriate to establish the diagnosis in patients over age 60
(7.8, C) and in patients considering splenectomy (7.5, D). The test was
considered unnecessary (2.7, C) to establish the diagnosis for medicolegal
protection. Thyroid function testing was considered appropriate (7.0, C) to rule
out occult hyperthyroidism or hypothyroidism only before an elective
splenectomy. The panel also reached consensus regarding testing in the following
situations:
(1) To establish the diagnosis before splenectomy: Tests that the panel
considered unnecessary for this purpose included platelet antigen specific
antibody assay (1.7, C), serum complement level (1.8, C), platelet survival
study (1.9, C), and direct antiglobulin test (2.6, C). The panel considered
platelet associated IgG assay both unnecessary and inappropriate (3.0, D).
(2) To establish the diagnosis in patients who have failed to respond to
glucocorticoid therapy and splenectomy: Tests that the panel considered
unnecessary for this purpose included platelet-associated IgG assay (1.7, B),
platelet-antigen specific antibody assay (1.8, C), serum complement level (2.0,
C), platelet survival study (2.4, D), and direct antiglobulin test (2.9, D).
Treatment
As with children, inferences regarding the effectiveness of treating ITP in
adults were based on the surrogate outcome measure of the platelet count (see
above).
Hospitalization
Evidence. There have been no studies to evaluate the effectiveness of
hospitalizing adults with ITP.
Recommendations. The opinion of the panel was that hospitalization is
appropriate for patients with severe, life-threatening bleeding, regardless of
the platelet count (8.8, B), as well as for patients with platelet counts
<20,000 who have significant mucous membrane bleeding (8.1, C) or who are
inaccessible or noncompliant (8.2-8.6, B-C). Hospitalization was considered
inappropriate (1.1 to 2.2, A-C) for patients with platelet counts >20,000 who
are either asymptomatic or have only minor purpura. Indications for
hospitalization under intermediate conditions are less clear (Table 12).
Emergency Treatment
Evidence. There have been no studies to evaluate the effectiveness of different
regimens for the emergency treatment of severe bleeding.
Recommendations. Although evidence for the effectiveness of treatment regimens
is lacking, the opinion of the panel is that the serious consequences of severe,
life-threatening bleeding justify the use several regimens. Assuming that
conventional critical care measures are already underway, the opinion of the
panel was that appropriate interventions include high-dose parenteral
glucocorticoid therapy (1 g of methylprednisolone daily for 3 days) and IVIg,
either alone or in combination (9.0, A), and platelet transfusions (7.5, D). See
further discussion of individual treatments below.
Observation (No Specific Initial Treatment)
Evidence. The only evidence regarding the outcomes of not treating adults with
ITP is a level V, prospective study of selected patients with platelet counts
>30,000 and no symptomatic bleeding (49 of 117 total patients with ITP).90 No
adverse events were reported among these 49 patients during a mean follow-up
period of 30 months. Other data suggest that spontaneous, serious bleeding is
rare (<5% of patients) with platelet counts >10,000, and is reported in about
40% of patients with platelet counts <10,000.41 Clinically important bleeding
with trauma rarely occurs at platelet counts >50,000.41
Recommendations. Current evidence is inadequate to state with certainty which
groups of patients with ITP can be safely managed without therapy. The opinion
of the panel was that not providing specific initial treatment was appropriate
(7.0 to 7.8, C-D) in patients who have platelet counts >50,000 and are either
asymptomatic or have only minor purpura. The panel believed that withholding
treatment was inappropriate for patients with a platelet count <20,000,
regardless of their symptoms (1.2 to 1.8, B), and for patients with a platelet
count <50,000 who present with significant mucous membrane bleeding (1.0, A for
platelet count <20,000; 1.2 to 2.0, B for platelet count of 20,000 to 50,000) or
who have risk factors for bleeding, such as hypertension, peptic ulcer disease,
or vigorous lifestyle (1.0 to 1.1, A for platelet count <20,000; 1.6, B for
platelet count of 20,000 to 30,000; 2.9, C for platelet count of 30,000 to
50,000). Not treating severe life-threatening bleeding was considered
inappropriate (1.0, A for platelet count <50,000). The panel considered it
inappropriate (1.6 to 1.9, B-C) to withhold treatment at the patient's request
if the platelet count was <20,000. Patient inaccessibility or noncompliance was
considered an inappropriate reason not to treat patients with platelet counts of
20,000 to 30,000 (2.3, C) or <20,000 (1.2 to 1.3, B).
Glucocorticoid Therapy
Evidence. Glucocorticoids have been the standard initial treatment for adults
with moderate to severe thrombocytopenia and symptomatic purpura since their
introduction in 1950. Uncontrolled data regarding the efficacy of glucocorticoid
treatment are summarized in the 12 case series in Table 10. Of these patients,
82% were treated initially with glucocorticoid preparations. The experience of
these patients, which are all reported in level V studies, suggests that most
increase their platelet count initially. Although it has been suggested that
very high doses of glucocorticoid may result in a more rapid increase of the
platelet count,110,111 two level II studies suggested equal efficacy in adults
of different regimens of low-dose prednisone (0.5 mg/kg v 1.5 mg/kg47 and 0.25
mg/kg v 1.0 mg/kg.51 Fewer (3% to 50%) patients maintain normal platelet counts
once therapy is discontinued, although there is an unexplained, extreme
variation in reported remission rates among the level V studies. No randomized
controlled studies have compared glucocorticoid with no treatment, and there is
no evidence of an effect of glucocorticoid treatment on morbidity or mortality.
A randomized trial involving 40 patients (level II) compared glucocorticoid
therapy to IVIg and both in combination as initial treatment and demonstrated no
difference in response, although this study is too small to make definitive
conclusions.112
The potential adverse effects of glucocorticoids include all of the signs and
symptoms of hypercortisolism in Cushing syndrome, including facial swelling,
weight gain, hyperglycemia, hypertension, weight gain, cataracts, and behavioral
abnormalities.58 Perhaps the greatest risk is the development of osteoporosis;
although there are no data in patients with ITP, an objective decrease in bone
density has been documented in patients with rheumatoid arthritis after the
equivalent of only 10 mg of prednisone daily for 20 weeks.113 The toxicities of
glucocorticoids are dose and duration dependent.
Recommendations. There is consistent level V evidence that glucocorticoids can
achieve early responses, most of which are transient. Although this suggests a
role for initial glucocorticoid therapy in symptomatic patients, there are
otherwise few data from which to develop evidence-based recommendations on
specific indications. Based on opinion, the panel concluded that glucocorticoid
therapy (prednisone, 1 to 2 mg/kg/d) was appropriate initial treatment in
patients with platelet counts <30,000, including asymptomatic patients (6.8 to
8.6, C), patients with minor purpura (7.7 to 8.6, C), and those with significant
mucous membrane or vaginal bleeding (8.5 to 8.6, B-C) (Table 12). Glucocorticoid
therapy was also considered appropriate for patients with platelet counts of
30,000 to 50,000 if clinically important bleeding was present (7.3, C) and for
patients with severe, life-threatening bleeding, regardless of the platelet
count (7.1 to 7.8, C-D). The recommended duration of glucocorticoid treatment is
addressed below. Glucocorticoid therapy was considered inappropriate initial
treatment when the platelet count is >50,000 and the patient is either
asymptomatic (2.2, C) or has only minor purpura (3.0, D). TABLE 12
Panel Opinion Regarding Initial Treatment Options in Adults
--------------------------------------------------------------------------------
Treatment Options
--------------------------------------------------------------------------------
Platelet Count <20,000
--------------------------------------------------------------------------------
Appropriate
(mean panel scores, 7-9)
--------------------------------------------------------------------------------
Appropriateness Uncertain
(mean panel scores, 3.1-6.9)
--------------------------------------------------------------------------------
Inappropriate
(mean panel scores, 1-3)
--------------------------------------------------------------------------------
Asymptomatic Prednisone* (8.6, C) Hospitalization, IVIg[dagger] No
treatment[double dagger] (1.4-1.8, B)
Splenectomy (2-5, D)
Minor purpura Prednisone (8.6, C) Hospitalization, IVIg No treatment (1.2-1.5,
B)
Splenectomy (2.5, D)
Mucous membrane or vaginal bleeding that may require clinical intervention
Prednisone (8.5-8.6, B-C)
Hospitalization (8.1, C) IVIg No treatment (1.0, A)
Splenectomy (2.9, D)
Severe, life threatening bleeding Hospitalization (8.8, B)
IVIg (8.5, C)
Prednisone (7.6, D) Splenectomy No treatment (1.0, A)
--------------------------------------------------------------------------------
Platelet Count 20-30 × 103
--------------------------------------------------------------------------------
Appropriate
(mean panel scores, 7-9)
--------------------------------------------------------------------------------
Appropriateness Uncertain
(mean panel scores, 3.1-6.9)
--------------------------------------------------------------------------------
Inappropriate
(mean panel scores, 1-3)
--------------------------------------------------------------------------------
Asymptomatic Prednisone, IVIg No treatment§
Hospitalization (1.8, B)
Splenectomy (2.5, D)
Minor purpura Prednisone (7.7, C) IVIg No treatment§
Hospitalization (2.2, C)
Splenectomy (2.5, D)
Mucous membrane or vaginal bleeding that may require clinical intervention
Prednisone (8.5, B) Hospitalization, IVIg No treatment (1.2, B)
Splenectomy (2.5, D)
Severe, life-threatening bleeding Hospitalization (8.8, B)
IVIg (8.0, D)
Prednisone (1-2 mg/kg/d) (7.8, D) Splenectomy No treatment (1.0, A)
--------------------------------------------------------------------------------
Platelet Count 30-50 × 103
--------------------------------------------------------------------------------
Appropriate
(mean panel scores, 7-9)
--------------------------------------------------------------------------------
Appropriateness Uncertain
(mean panel scores, 3.1-6.9)
--------------------------------------------------------------------------------
Inappropriate
(mean panel scores, 1-3)
--------------------------------------------------------------------------------
Asymptomatic Prednisone No treatment||
Hospitalization (1.2, B)
IVIg (1.6, B)
Splenectomy (2.1, D)
Minor purpura Prednisone No treatment||
Hospitalization (1.3, B)
IVIg (2.2, C)
Splenectomy (2.4, D)
Mucous membrane or vaginal bleeding that may require clinical intervention
Prednisone (7.3, C) Hospitalization, IVIg No treatment (2.0, B)
Splenectomy (2.4, D)
Severe, life-threatending bleeding Hospitalization (8.8, B)
Prednisone (7.8, C)
IVIg (7.0, D) No treatment (1.0, A)
Splenectomy (2.7, D)
--------------------------------------------------------------------------------
"Appropriate" and "Not appropriate" = mean panel score of 7.0-9.0 or 1.0-3.0,
respectively, "Appropriate" = treatment may or may not be necessary, but
performing is not wrong. "Inappropriate" = treatment should not be performed.
Mean panel score is graded on a scale of "1" to "9", with "1" representing low
appropriateness and "9" representing high appropriateness. Letter codes
following panel scores reflects strength of agreement, the panel consensus
(defined by standard deviation) around the mean panel score. "A" = complete or
virtual unanimity, "B" = strong agreement, "C" = moderate agreement, "D" =
moderate disagreement, "E" strong disagreement (see Table 4).
*Prednisone dose, 1-2 mg/kg/d.
[dagger]IVIg regimen, 1-2 g/kg given over 1-5 days.
[double dagger]"No treatment" implies careful observation.
§Not treating patients with a platelet count of 20-30 × 105 is inappropriate for
patients age 60 or older (2.7, D) or for patients who have major risk factors
for bleeding (eg, elevated blood pressure, ulcer disease, vigorous lifestyle)
(1.6, B). For all other patients, appropriateness is uncertain.
||Not treating patients with a platelet count of 30-50 × 105 is inappropriate
for patients who have major risk factors for bleeding (eg, elevated blood
pressure, ulcer disease, vigorous lifestyle) (2.9, C). For all other patients,
appropriateness is uncertain.
--------------------------------------------------------------------------------
IVIg
Evidence. IVIg has been studied more in children than in adults, in whom it is
used primarily for patients who are unresponsive to glucocorticoids and other
therapies. Relevant data come largely from case series,64,114-126 level V
evidence, most of which describe patients with severe, chronic thrombocytopenia
who were observed for a short duration after IVIg treatment. Most, but not all,
patients in these series experienced an increased platelet count with IVIg.
Among patients with chronic ITP (usually defined in these series as >3 to 4
months), platelet counts increased in about 75% of patients and reached normal
levels in about half of patients. In more than 75% of patients who initially
responded, the platelet count returned to pretreatment levels, usually within 3
to 4 weeks. In one study,125 patients were given subsequent infusions of IVIg to
maintain platelet counts above 20,000; about one third of the patients who
required repeated infusions ultimately became refractory to IVIg but an equal
number appeared to have long-term responses. No studies have compared IVIg to no
treatment or measured the effects of IVIg on morbidity or mortality. As noted
earlier, one randomized study112 did not detect a difference in outcomes among
patients treated initially with IVIg, prednisone, or the combination of IVIg and
prednisone.
The dose of IVIg has been the subject of several studies. As in children, the
original dose of IVIg was 0.4 g/kg/d administered on 5 consecutive days.
Subsequently, the same total dose was administered as 1 g/kg/d on 2 consecutive
days.64 One randomized study127 showed no difference in the response of patients
with chronic ITP to 1 g/kg given once or on 2 consecutive days (level II trial).
For "maintenance therapy," a higher dose (1 g/kg v 0.5 g/kg as a single
infusion) was found to yield a greater platelet count response, but the same
frequency of treatments was necessary to maintain a platelet count >20,000.64
The adverse effects of IVIg are common (15% to 75%) but generally mild,
including headache, backache, nausea, and fever.32,65 Aseptic meningitis may
occur.66 Rare reported complications include alloimmune hemolysis67 and
hepatitis C infection.68-71 No hepatitis C has been reported with viral
inactivated products. Cases of renal failure,128,129 pulmonary insufficiency,130
and thrombosis, including stroke and myocardial infarction,131,132 have been
reported as complications of IVIg treatment.
Recommendations. There is no evidence regarding the efficacy of IVIg as initial
treatment and only level V evidence that it can achieve temporary improvements
of platelet counts in patients who are refractory to initial treatment. Further,
a benefit of IVIg in terms of morbidity or mortality remains uncertain.
Therefore, evidence-based recommendations regarding appropriate indications are
not possible at this time. Based on opinion, the panel concluded that IVIg was
appropriate initial treatment only for patients with platelet counts <50,000 who
have severe, life-threatening bleeding (7.0 to 8.5, C-D). The panel believed
that IVIg was inappropriate initial treatment for patients with platelet counts
of 30,000 to 100,000 who were asymptomatic (1.1 to 1.6, A-B) or who had only
minor purpura, (1.3 to 2.2, B-C). There was strong disagreement (category E)
among the panel about the appropriateness of IVIg as initial therapy for
patients with platelet counts <20,000 who are asymptomatic or have only minor
purpura, or for patients with risk factors for bleeding, such as hypertension,
peptic ulcer disease, or a vigorous lifestyle.
Anti-(Rh) D
Evidence. Five level V studies of anti Rh(D) in adults, suggest that it can
transiently increase platelet counts, usually lasting for 2 to 3 weeks, in about
half of unsplenectomized patients; response rates in splenectomized patients
were less.126,133-136 Evidence regarding its effect on morbidity or mortality is
lacking.
The only clinically important adverse effect of anti-Rh(D) appears to be
alloimmune hemolysis. All Rh (D)+ patients develop a positive direct
antiglobulin test after treatment, accompanied by a transient (1 to 2 weeks)
decrease in hemoglobin concentration of about 0.5 to 2 g/dL. Although in two
studies 4% to 24% of patients had a hemoglobin concentration of <10 g/dL after 7
to 14 days,48,74 red blood cell transfusion was not required.
Recommendations. There is insufficient evidence to make recommendations
regarding anti-Rh (D) treatment in adults. The opinion of the panel on anti-Rh
(D) treatment of adults was not assessed.
Splenectomy
Evidence. Splenectomy was the first effective treatment for ITP137 and was an
established therapeutic modality long before glucocorticoid therapy was
introduced in 1950. Thirty-six case series describe the results of splenectomy,
but all provide only level V evidence.26,76,90-100,102,138-161 Moreover, the
relevance of early studies to current clinical practice may be limited, because
splenectomy was often performed as initial therapy and because early series
often combined the results of children and adults. Not surprisingly, therefore,
early studies reported better long-term results. In most recent case series
restricted to adults, splenectomy was performed in patients who were either
unresponsive to initial glucocorticoid therapy or in those for whom continued
glucocorticoid therapy was required to maintain a safe platelet count. Most
studies suggest that approximately two thirds of patients achieve and sustain a
normal platelet count after splenectomy and require no additional therapy. Most
other patients experience a lesser increase or only transient normalization of
platelet counts, with approximately half of the relapses occurring within 6
months of splenectomy.158 Over 80% of platelet responses occur within several
days; responses may occur after 10 days but are uncommon.102,158 There is some
evidence that the rate and magnitude of platelet recovery may have prognostic
value. Durable platelet responses has been correlated with platelet counts
>150,000 on the first155 or third postoperative day158 or >500,000 on the 10th
postoperative day.157 No preoperative clinical parameters appear to have similar
prognostic value; studies of the predictive value of an initial response to
glucocorticoid therapy have yielded conflicting results. As in other aspects of
ITP, younger patients appear to respond better to splenectomy than older
patients.155,157,158 No studies have specifically reported on morbidity or
mortality after splenectomy.
Some evidence is available regarding the adverse effects of splenectomy in
adults. Even in the face of severe thrombocytopenia, the immediate risks of
clinically important intraoperative and postoperative hemorrhage appear small,
approximately 1% in the 36 cited case series. Operative mortality rates were
less than 1%, an impressive figure because these data include reports before the
advent of platelet transfusions, IVIg, and effective antibiotics to manage
postoperative infections. Most operative deaths occur in older patients with
coexisting illnesses.45 Postoperative morbidity may be related to the extent of
previous glucocorticoid therapy.102 Splenic or portal vein thrombosis may occur
after splenectomy.162,163 Postsplenectomy patients have a small but
significantly increased susceptibility to fatal bacterial infection, although
this appears to be less important in adults than in children. The estimated risk
of fatal bacterial infection in splenectomized adults is about 1 per 1,500
patient-years,80,82 but these estimates are from the era before immunization for
Strep pneumoniae and were determined in patients splenectomized for other
diseases.
Recommendations. Although all available evidence is level V, the efficacy of
splenectomy is supported by the consistent incidence of sustained normalization
of platelet counts in patients who had previously been refractory to
glucocorticoid therapy for several weeks or years. However, there are inadequate
data to make evidence-based recommendations on the appropriate indications and
timing for splenectomy, on when the benefits of splenectomy outweigh its
potential harms, and on appropriate preoperative management. TABLE 13
Panel Opinion Regarding Preoperative Prophylaxis Against Bleeding Before
Elective Splenectomy in Adults
--------------------------------------------------------------------------------
--------------------------------------------------------------------------------
Appropriate
--------------------------------------------------------------------------------
Preoperative Prophylaxis
--------------------------------------------------------------------------------
Platelet Count
--------------------------------------------------------------------------------
Score
--------------------------------------------------------------------------------
IVIg <10,000 7.9 (D)
10,000-20,000 7.5 (D)
Oral glucocorticoid <10,000 7.7 (C)
10,000-20,000 7.3 (C)
--------------------------------------------------------------------------------
Appropriateness Uncertain
--------------------------------------------------------------------------------
Preoperative Prophylaxis
--------------------------------------------------------------------------------
Platelet Count
--------------------------------------------------------------------------------
IVIg 20,000-50,000
Platelet transfusion <10,000
Anti-D <50,000
Oral glucocorticoid 20,000-50,000
Parenteral gl |
