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
--------------------------------------------------------------------------------
Level of Evidence
--------------------------------------------------------------------------------
Study Design
--------------------------------------------------------------------------------
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
--------------------------------------------------------------------------------
Hemorrhagic
Complications[double dagger]
--------------------------------------------------------------------------------
Patients With Persistant Thrombocytopenia§
--------------------------------------------------------------------------------
Author
--------------------------------------------------------------------------------
Location
--------------------------------------------------------------------------------
Years
--------------------------------------------------------------------------------
Patients (no.)
--------------------------------------------------------------------------------
Patients Responding With No Therapy*
--------------------------------------------------------------------------------
Patients in Remission at 6 mo[dagger]
--------------------------------------------------------------------------------
ICH
--------------------------------------------------------------------------------
Fatal ICH
--------------------------------------------------------------------------------
Other Deaths
--------------------------------------------------------------------------------
Patients in Remission At Last Follow-up[dagger]
--------------------------------------------------------------------------------
No.
--------------------------------------------------------------------------------
Spontaneous Recovery
--------------------------------------------------------------------------------
Deaths From Hemorrhage
--------------------------------------------------------------------------------
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 glucocorticoid <50,000
--------------------------------------------------------------------------------
Inappropriate
--------------------------------------------------------------------------------
Preoperative Prophylaxis
--------------------------------------------------------------------------------
Platelet Count
--------------------------------------------------------------------------------
Score
--------------------------------------------------------------------------------
IVIg 50,000-100,000 2.1 (C)
Platelet transfusion 10,000-20,000 2.3 (D)
20,000-30,000 1.9 (C)
30,000-50,000 1.4 (B)
50,000-100,000 1.1 (A)
Anti-D 50,000-100,000 1.8 (C)
Oral glucocorticoid 50,000-100,000 2.7 (D)
Parenteral glucocorticoid 50,000-100,000 2.1 (C)
--------------------------------------------------------------------------------
"Appropriateness" and scores are defined in text and Table 2. Doses and regimens
were not specified in the questions to the panel.
--------------------------------------------------------------------------------
Based on opinion, the panel reached consensus on only selected indications for
splenectomy. Assuming that primary treatment (glucocorticoid) has been
unsuccessful and that there are no medical contraindications to the procedure,
the panel considered splenectomy appropriate in the following hypothetical
situations: (1) patients who have had the diagnosis for 6 weeks, have a platelet
count <10,000, and have no bleeding symptoms, (7.5, C), and (2) patients who
have had the diagnosis for 3 months, have experienced a transient or incomplete
response to primary treatment, have a platelet count of <30,000, and are either
bleeding (8.5, B) or not bleeding (7.4, C). The panel reached consensus that
splenectomy is inappropriate in nonbleeding patients who have had the diagnosis
for 6 months and have a platelet count >50,000 and low hemostatic risk (eg, not
engaged in potentially traumatic activities) (1.9, C). The panel also considered
splenectomy inappropriate (1.6 to 2.9, C-D) as initial therapy in patients who
have no bleeding, minor purpura, or even significant mucous membrane bleeding.
Further recommendations regarding the appropriate timing of splenectomy in
patients who do not respond completely to initial glucocorticoid treatment are
presented below.
If an elective splenectomy is planned, the panel considered it appropriate to
provide preoperative prophylaxis with IVIg (7.5 to 7.9, D) or oral
glucocorticoid therapy (7.3 to 7.7, C) in patients with platelet counts <20,000
to reduce the risk of intraoperative and postoperative bleeding (Table 13).
Preoperative prophylaxis that the panel considered inappropriate included
treatment for platelet counts >50,000, using IVIg (2.1, C), oral or parental
glucocorticoid therapy (2.1 to 2.7, C-D), or anti-D (1.8, C). Platelet
transfusions were considered inappropriate as preoperative prophylaxis for
platelet counts >10,000 (1.1 to 2.3, A-D).
The panel endorsed the recommendations of the Advisory Committee on Immunization
Practices that, at least 2 weeks before elective splenectomy, patients should be
immunized with polyvalent pneumococcal vaccine, Hemophilus influenzae b vaccine,
and quadrivalent meningococcal polysaccharide vaccine.84
Other Treatments
Evidence. The treatment options discussed in this section have not been compared
with other treatments (or to no treatment) in controlled trials and have not
been shown to reduce clinically important bleeding or mortality. The order of
discussion does not reflect their relative effectiveness or appropriateness.
Splenic radiation. Two level V studies of 18 patients who had not responded to
at least 1 month of glucocorticoid therapy and in whom splenectomy was
contraindicated reported that four patients achieved sustained (>3 to 12 months)
platelet counts >100,000.164,165 A potential adverse effect of splenic radiation
is the production of adhesions surrounding the spleen, which may complicate
subsequent splenectomy.
Partial splenic embolization. One level V study described 26 patients who had
not completely responded to glucocorticoid therapy who then underwent
angiographically directed gelfoam embolization; seven maintained platelet counts
>100,000 for 9 to 67 months with no additional therapy.166 In this report the
adverse effects of partial splenic embolization included fever, pain, and nausea
in 81% to 100% of patients and perisplenic fluid or pleural effusion in 10% to
19% of patients. Another potential adverse effect is splenic abscess or rupture.
Accessory splenectomy. Eight case series (level V evidence)152,167-173 suggest
that platelet counts are increased in about half of patients, and 10% to 30% of
patients may have sustained, normal platelet counts. During primary splenectomy,
the abdomen is generally inspected for accessory spleens; in the 11 case series
of splenectomy in which the observation and removal of accessory spleens was
mentioned76,138,140,142,146,150,152,155,156,161,174 accessory spleens were
observed in 15% of patients. In a study173 of 65 patients who either failed
splenectomy or relapsed after splenectomy, 12% of patients were found to have an
accessory spleen by radionuclide imaging. No studies have shown that accessory
splenectomy reduces morbidity or mortality. The potential adverse effects of
accessory splenectomy are similar to those of splenectomy.
Azathioprine. Four case series (level V evidence)100,175-178 suggest that about
20% of patients may achieve a normal platelet count, sustained for several
months to years without treatment. An additional one half of patients may
improve their platelet counts but require continuous azathioprine treatment.
Continuous treatment for at least four months appears to be necessary before a
patient is considered unresponsive.178 The potential adverse effects of
azathioprine include reversible leukopenia and a small, but possibly
significant, increase of developing a malignancy179 and in the risk of
developing fetal malformations during pregnancy.180 One study178 of 53 patients
with persistent thrombocytopenia reported that five died from hemorrhage with
severe thrombocytopenia. It is uncertain if the high mortality was caused by
preferential selection of severely affected patients, lack of efficacy, or
worsened thrombocytopenia caused by azathioprine-induced marrow suppression.
Cyclophosphamide. Five case series (level V evidence)100,181-185 suggest that
cyclophosphamide increases platelet counts in 60% to 80% of patients, and 20% to
40% of patients maintain normal platelet counts for 2 to 3 years after
discontinuing treatment. The primary toxicity of cyclophosphamide is reversible
leukopenia. More serious adverse effects have been reported, including alopecia,
teratogenicity, infertility, and urinary bladder hemorrhage and fibrosis.179
Carcinogenicity, including increased risk of myelodysplasia and acute leukemia,
has been suggested in case reports.186,187
Vinca alkaloids. Twelve case series (level V evidence)100,188-198 and a level II
study that compared two methods of vinblastine administration199 suggest that
vinca alkaloids may produce a transient increase in platelet counts lasting 1 to
3 weeks in two-thirds of patients, but a sustained normal platelet count
(requiring no further treatment for at least 3 months) occurs in less than 10%
of patients. The populations in these studies were heterogeneous, including
untreated patients and patients with ITP of short duration, chronic refractory
ITP, and with mild to severe thrombocytopenia. Potential adverse effects of
vinca alkaloids include neutropenia (vinblastine), fever, and
inflammation/thrombophlebitis at the infusion site; neuropathy was reported in
10 of the 13 reports. One death from sepsis during a leukopenic episode was
reported after vinblastine infusion.199 In one study of the infusion of
"vinblastine-loaded" platelets (platelets incubated with vinblastine), 3 of 16
patients had a 30% to 80% decrease in their platelet count within 24 hours of
treatment.192
Danazol. Fourteen case series (level V evidence),200-213 in which about half of
the patients were from a single institution, reported variable rates of response
to danazol, ranging from 10% to 80%. The potential adverse effects of danazol
include weight gain, headaches, hair loss, myalgia, amenorrhea, and liver
dysfunction. Danazol has been a suspected cause of acute thrombocytopenia in
seven patients.213-216 Danazol may be contraindicated in patients with
preexisting liver disease; one case series reported abnormal liver function
tests in 41% of patients.211
Ascorbic acid (vitamin C). Eight case series (level V evidence)217-224 reported
that 15% of patients had increased platelet counts, but other medications were
being taken concurrently. The potential adverse effects of ascorbic acid include
occasional epigastric pain or dyspepsia.
Colchicine. Two case series225,226 report conflicting level V evidence regarding
the effectiveness of colchicine. The principal adverse effect of colchicine is
dose-dependent diarrhea.
Protein A-immunoadsorption. One case series (level V evidence)227 reported that
18 of 72 patients achieved a platelet count >100,000, which was sustained in 16
patients. Earlier publications228,229 included segments of this same patient
population (Guthrie TH, personal communication, August 1995). The potential
adverse effects include fever, chills, nausea, vomiting, and urticaria, which
occur in most patients. Hypotension, serum sickness, and leukocytoclastic
vasculitis with thrombosis have also been reported.227,230,231
FIGURE 3. Length of time panel members would continue initial prednisone
treatment (1 mg/kg) before adding to or changing the regimen in a hypothetical
30-year-old woman who presented initially with a platelet count <10,000. Votes
were stratified to reflect different platelet count responses to treatment. The
figure illustrates that, if the platelet count remains below 10,000, 4 panel
members would add to or change treatment after 1 week, whereas 1 panel member
would not change treatment until 10 weeks.
Plasma exchange. Three case series (level V evidence)232-234 reported that
platelet counts increased to normal for 1 to 4 weeks in 5 of 18 patients with
chronic ITP; no sustained responses were described. Potential adverse effects
include allergic reactions to plasma proteins and a risk for transmissible viral
infections.
2-Chlorodeoxyadenosine. One case series (level V evidence) of seven patients
reported no favorable responses.235
Combination chemotherapy. One case series (level V evidence) of 10 patients236
reported that five patients achieved normal platelet counts that were sustained
for 11 to 126 months. Four patients died, 3 from intracerebral hemorrhage and 1
from a stroke when the platelet count was normal. The potential adverse effects
of combination chemotherapy include marrow suppression with leukopenia and
worsening of thrombocytopenia, and the risks cited above for individual agents,
cyclophosphamide and vinca alkaloids.
Interferon-[alpha] (IFN-[alpha]). Four case series (level V evidence)237-241
reported that 25% of patients achieved platelet counts greater than 100,000 for
1 week to 7 months. The major adverse effects include fever, fatigue, and
myalgias. Some reports241-243 suggest that IFN-[alpha] may worsen
thrombocytopenia.
Cyclosporine A. No published evidence that met panel criteria is available.
Aminocaproic acid. In contrast to other modalities discussed in this section,
aminocaproic acid has not been used to increase the platelet count but rather to
diminish bleeding symptoms. One case series (level V evidence)244 of seven
patients suggested that it helped control bleeding. Its potential adverse
effects include an increased risk of thromboembolism.
Recommendations
To assess opinion on the management of patients who do not respond, or respond
incompletely, to initial treatment with prednisone, the panel ranked selected
treatment options for a hypothetical 30-year-old woman who presents with a
platelet count <10,000 and bleeding symptoms consisting of purpura, menorrhagia,
and epistaxis and who is treated initially with prednisone (1 mg/kg/d).
Depending on the platelet count, most panel members would alter the treatment
plan after 2 to 4 weeks if the patient did not respond (or responded
incompletely) to this dose of prednisone (Fig 3). Most panel members would
recommend elective splenectomy after 4 to 6 weeks of unsuccessful medical
therapy (Fig 4). However, the range of opinions on the panel included one panel
member who recommended splenectomy as early as 2 weeks and another who did not
recommend splenectomy after 10 weeks with no response. Most panel members would
use IVIg at some time during the course of treatment for persistent platelet
counts <30,000. Other preferred options were increased doses of prednisone,
dexamethasone, anti-D, and danazol. If this hypothetical patient responded with
a normal platelet count at 3 weeks, but then relapsed to a platelet count of
10,000 when prednisone was tapered over the following 5 weeks, most panel
members recommended prompt splenectomy, though the range of time was 1 to 10
weeks after the occurrence of the relapse. Three of 11 panel members did not
recommend splenectomy in this situation, but favored a repeat trial of
prednisone or the use of danazol.
FIGURE 4. Length of time after which panel members would recommend splenectomy
after treating a hypothetical 30-year-old woman who presented initially with a
platelet count <10,000. Votes were stratified to reflect different platelet
count responses to treatment. The figure illustrates that, in a patient with
persistent severe thrombocytopenia (platelet count that remains <10,000), most
panel members would recommend splenectomy after 4 to 6 weeks of unsuccessful
medical therapy. Panel member opinions were varied, with one panelist
recommending splenectomy as early as 2 weeks and another not recommending
splenectomy even after 10 weeks of unsuccessful treatment.
The indications for further treatment in patients who are refractory to primary
treatment with glucocorticoids and splenectomy are unclear. There are
insufficient data to develop evidence-based recommendations for when different
treatments should be used, for comparing one treatment with another, or for
assessing which treatments result in more good than harm. Based on opinion, the
panel recommended against further treatment of patients with platelet counts
>30,000 who have failed to respond to splenectomy and have no bleeding symptoms
(2.7, C for platelet count of 30,000 to 50,000; 1.3, B for platelet count
>50,000). Further treatment was recommended (8.9, A) for patients with platelet
counts <30,000 who have active bleeding. In patients who have responded
incompletely to treatment with both prednisone and splenectomy, the preferred
treatment options recommended by the panel are listed in Table 14. Reflecting
the lack of evidence that any single treatment is more effective than another,
there was little panel consensus regarding preferred regimens. TABLE 14
Panel Opinion Regarding Preference for Various Treatment Modalities in an Adult
Patient Who Has Responded Incompletely to Prednisone and Splenectomy
--------------------------------------------------------------------------------
Treatment Options[dagger]
--------------------------------------------------------------------------------
Platelet Count
--------------------------------------------------------------------------------
Bleeding Symptoms*
--------------------------------------------------------------------------------
Higher Preference[double dagger]
--------------------------------------------------------------------------------
Intermediate Preference[double dagger]
--------------------------------------------------------------------------------
Lower Preference[double dagger]
--------------------------------------------------------------------------------
<10,000 Yes IVIg Low-dose glucocorticoid Anti-D
Accessory splenectomy Vinca alkaloids Ascorbic acid
High-dose glucocorticoid Cyclophosphamide Cyclosporine
Danazol Combination chemotherapy Colchicine
Azathioprine Protein A column Interferon
--------------------------------------------------------------------------------
15-25,000 Yes IVIg Low-dose glucocorticoid Anti-D
Accessory splenectomy Danazol Ascorbic acid
High-dose glucocorticoid Vinca alkaloids Cyclosporine
Azathioprine Cyclophosphamide Colchicine
Combination chemotherapy Interferon
Protein A column
--------------------------------------------------------------------------------
<10,000 No IVIg Low-dose glucocorticoid Anti-D
Accessory splenectomy High-dose glucocorticoid Ascorbic acid
Danazol Vinca alkaloids Colchicine
Azathioprine Cyclophosphamide Cyclosporine
Combination chemotherapy Interferon
Protein A column
--------------------------------------------------------------------------------
15-25,000 No (None) High-dose glucocorticoid Ascorbic acid
Accessory splenetomy Vinca alkaloids
Colchicine
Protein A column
Anti-D
Cyclophosphamide
Combination chemotherapy
--------------------------------------------------------------------------------
30-50,000 No (None) (None) High-dose glucocorticoid
Accessory splenectomy
Danazol
Ascorbic acid
Low-dose glucocorticoid
Anti-D
--------------------------------------------------------------------------------
It is assumed that the patient is a 30-year-old otherwise healthy woman who has
responded incompletely to initial therapy consisting of prednisone, 1 mg/kg/d,
and splenectomy. For each clinical situation, the panel was asked to rank in
order their preference among the treatment options listed below. If it was
believed that more than one treatment option should be used concurrently, they
were ranked with the same number. If any treatment options were believed to be
not indicated or inappropriate, they were not selected. This question was
completed by 11 panel members.
*Bleeding symptoms, when indicated, consist only of purpura, intermittent
spontaneous epistaxis, and gingival bleeding.
[dagger]Treatment options are defined as follows: "Low-dose glucocorticoid"
would begin with 1 mg/kg/d of prednisone and would taper to the lowest dose
supporting an acceptable platelet count, with the goal of establishing an
effective dose at which side effects would be tolerable. "High-dose
glucocorticoid" would be dexamethasone, 40 mg/d for 4 days, repeated every 4
weeks for 6 cycles. "IVIg" would be given as needed at a dose of 1 g/kg, or
repeated intermittently at a lower dose, to maintain an acceptable platelet
count. "Anti-D" would be given as needed. "Accessory splenectomy" assumes
radioisotope scanning studies demonstrate a probable accessory spleen. "Vinca
alkaloids" includes vincristine and vinblastine. "Cyclophosphamide" would be
given daily orally or as intermittent intravenous doses. "Combination
chemotherapy" would include cyclophosphamide-vincristine-prednisone (CVP),
CVP-procarbazine, or cyclophosphamide-etoposide-prednisone. Modalities not
selected by any panel members included dapsone, plasma exchange,
6-mercaptopurine, methotrexate, and 2-chlorodeoxyadenosine.
[double dagger]Options ranked as higher preferences received votes from 8-11
panel members, intermediate preference 4-7 panel members, and lower preference
0-3 panel members. Within each preference list, the order was determined using a
score derived by the mean ranking of the treatment option divided by the number
of votes that option received.
--------------------------------------------------------------------------------
ITP in Pregnant Women and Newborns
Diagnosis
Evidence. The diagnosis of ITP is more difficult during pregnancy because the
presentation may closely resemble that of gestational thrombocytopenia (also
termed incidental thrombocytopenia of pregnancy). Gestational thrombocytopenia
is the most common cause of thrombocytopenia during pregnancy, occurring in as
many as 5% of pregnant women at term245,246 and accounting for about 75% of
cases of thrombocytopenia at term.245 Thrombocytopenia associated with
pregnancy-induced hypertension and the HELLP syndrome (an acronym used to
describe hemolysis, elevated liver function tests, and a low platelet count)
accounted for most of the remaining 25% of cases.245 Pregnancy-induced
hypertension, or preeclampsia, occurs in about 10% of pregnancies, principally
after 20 weeks of gestation, and thrombocytopenia may occur in up to 25% of
these patients.245-248 ITP is therefore a relatively uncommon cause of
thrombocytopenia in pregnancy. Gestational thrombocytopenia is characterized by
(1) asymptomatic, mild thrombocytopenia (2) with no past history of
thrombocytopenia (except possibly during a previous pregnancy) (3) that occurs
during late gestation, (4) that is not associated with fetal thrombocytopenia,
and (5) that resolves spontaneously after delivery. Platelet counts are
typically greater than 70,000, with about two thirds being between 130,000 and
150,000. ITP cannot be distinguished from gestational thrombocytopenia with
certainty because the diagnosis of both conditions is based on the observation
of thrombocytopenia with no other apparent cause. Although ITP may compose a
higher percentage of cases when the platelet count is <70,000, or when
thrombocytopenia is discovered earlier in pregnancy, gestational
thrombocytopenia may still be the appropriate diagnosis if the thrombocytopenia
resolves spontaneously after delivery. However severe, refractory
thrombocytopenia presumably due to ITP may also promptly remit after
delivery.249
The differential diagnosis between ITP and gestational thrombocytopenia is
generally of little clinical importance with regard to the mother, because most
cases in which the diagnosis is unclear involve mild thrombocytopenia that does
not threaten maternal health. However, the presence of mild thrombocytopenia may
influence the decision for regional anesthesia at vaginal delivery, though
spinal or epidural hematomas have not been reported in thrombocytopenic women at
delivery.250 The differential diagnosis between ITP and gestational
thrombocytopenia is clinically important with regard to the fetus, because ITP
with even mild thrombocytopenia may harm the fetus, whereas gestational
thrombocytopenia does not.245
Recommendations
Current evidence does not provide a scientific basis for distinguishing ITP from
gestational thrombocytopenia. A thorough history is important because evidence
of previous thrombocytopenia at a time when the patient was not pregnant
suggests the diagnosis of ITP. When no prior platelet counts are available and
other causes of thrombocytopenia are excluded, the diagnosis rests largely on
the severity of thrombocytopenia and the time during gestation when
thrombocytopenia is first discovered.
For example, the panel was given the hypothetical case of a healthy primiparous
woman with no history of thrombocytopenia, no bleeding symptoms or pregnancy
complications and whose history, physical examination, and initial blood counts
and smear are compatible with the diagnosis of ITP. In such a case, the panel
would consider ITP the likely diagnosis if the platelet count was below 50,000
(7.3 to 8.5, B-C for platelet count of 30,000 to 50,000; 8.8 to 9.0, A-B, for
<30,000) at any time during pregnancy. ITP would be considered an unlikely
diagnosis if the platelet count was more than 70,000 in the third trimester or
at term (1.3 to 2.1, B).
The diagnosis of ITP during pregnancy does not require special laboratory
testing. Blood pressure measurement was considered necessary (7.6, D), and
appropriate (8.9, A), to rule out preeclampsia in the evaluation for ITP. Liver
function tests were also considered appropriate (7.5, C). In patients with risk
factors for HIV infection, testing for HIV antibody was considered necessary
(7.5, D) and appropriate (8.9, A). The panel reached consensus that five tests
in particular were unnecessary as part of the routine evaluation of pregnant
women presenting with suspected ITP (Table 7).
Treatment During Pregnancy
Evidence. There are few data to distinguish management of ITP in pregnant women
from that of nonpregnant patients. However, management in the antepartum period
is distinctive because of concerns about the teratogenicity of certain drugs,
the timing of delivery and the requirement for good hemostasis at delivery, and
the risk of neonatal hemorrhage. Some neonates born to mothers with ITP develop
thrombocytopenia, because of placental transfer of anti-platelet antibodies, and
may be at increased risk of intracranial hemorrhage (ICH). Clinically important
intrauterine hemorrhage has not been reported in ITP, in contrast to neonatal
alloimmune thrombocytopenia.245,248 In 30 series published since 1980 that
reported on thrombocytopenia in 656 neonates born to mothers with ITP, the risk
of a newborn having a platelet count <50,000 ranged from 0% to 60%, with a
weighted mean of 13%.245,251-279 One third (28) of the thrombocytopenic infants
had bleeding complications; however, these data are difficult to evaluate
because of inconsistencies in the reported severity of bleeding. Of the 28
infants with bleeding complications, 4 had intracranial hemorrhage and 2 of
these infants died; 2 were premature.252,278,279 Whether any infants had
permanent sequelae is unknown. A review of studies from 1980 to 1990280
concluded that 10% of infants born to women with ITP have a fetal platelet count
<50,000 and 4% have a fetal platelet count <20,000 (Table 15). In this analysis,
studies describing fetal platelet counts obtained before or at birth were
distinguished from studies describing only neonatal platelet counts (see Table
15), which may have been obtained some time after delivery and may therefore
have been lower than the platelet count at birth. Further review of studies of
an additional 552 pregnancies (557 live births) for which only neonatal platelet
counts were reported documented seven infants (1.3%) with intracranial
hemorrhage or death.280 TABLE 15
Fetal Samples To Assess Neonatal Thrombocytopenia and Intracranial Hemorrhage in
Infants Born to Mothers With ITP
--------------------------------------------------------------------------------
Fetal Platelet Counts[dagger]
--------------------------------------------------------------------------------
<50,000 <20,000
Case Series*
--------------------------------------------------------------------------------
No. of Pregnancies/Births
--------------------------------------------------------------------------------
(no. of infants)
--------------------------------------------------------------------------------
No. of Infants With ICH[double dagger] or Death
--------------------------------------------------------------------------------
A. >=10 patients 286/288 29 12 0
10.1% (6.6-13.5%)§ 4.2% (1.9-6.5%)
B. <10 patients 34/34 8 4 0
23.5% (9.2-37.8%) 11.8% (1.0-22.6%)
--------------------------------------------------------------------------------
29 Infants With Platelet Counts <50,000 From Case Series Reporting 10 or More
Patients||
--------------------------------------------------------------------------------
Mode of Delivery
--------------------------------------------------------------------------------
Bleeding Symptoms in the Infant§
--------------------------------------------------------------------------------
Cesarean section 17 9/29 (31%; 7/17 cesarean section, 2/5 vaginal delivery)
Vaginal delivery 5
Not stated 7
--------------------------------------------------------------------------------
*All case series published from January 1980-December 1990 in which a fetal
platelet count was reported were reviewed. Case series were divided between
those reporting 10 or more patients and those reporting <10 patients.
[dagger]Data were examined to determine the timing of the neonatal platelet
count; fetal platelet counts, or platelet counts "at birth," were distinguished
from later counts which may be lower. Platelet counts were accepted as fetal or
"at birth" if they were obtained from cord blood either by prenatal percutaneous
cordocentesis (PUBS) or umbilical vein blood at delivery, or from a fetal scalp
vein confirmed by a neonatal platelet count.
[double dagger]ICH, intracranial hemorrhage.
§95% confidence interval.
||Data insufficient for analysis from reports with <10 patients.
¶Bleeding symptoms included petechiae, purpura, melena, or hematuria.
Adapted with permission from Burrows RF, Kelton JG: Pregnancy in patients with
idiopathic thrombocytopenic purpura: Assessing the risks for the infant at
delivery. Obstetrical & Gynecological Survey, volume 48, number 12, pp 781-788,
1993.280
--------------------------------------------------------------------------------
Maternal or fetal platelet counts have limited utility in predicting the risk of
hemorrhage or in informing decisions about whether cesarean section is
indicated. Cesarean section is often recommended over vaginal delivery on the
assumption that it is less traumatic to the newborn, but there is no direct
evidence of this benefit281,282 (Table 15). The maternal platelet count does not
correlate with the fetal platelet count.245,253,255,258,260-262,265,269,270,274
Fetal platelet count specimens can only be obtained through percutaneous
umbilical blood sampling (PUBS) or fetal scalp vein sampling after cervical
dilation; newborn samples can be obtained at birth by umbilical cord sampling or
capillary blood specimens obtained by heel prick. Each test has its limitations.
Although platelet counts obtained by PUBS within 5 days before delivery appear
to correlate with platelet counts at birth,269,276,283 the procedure should be
performed only by experienced physicians at referral centers, with patients
prepared for immediate cesarean section in the event of fetal complications.
PUBS can induce fetal distress, bleeding, and death; bradycardia is noted in 2%
to 14% of fetuses.269,270,283-286 Fetal scalp vein specimens can only be
obtained after cervical dilation, and accurate platelet counts are obtained in
only one half to two thirds of attempts because of inadequate samples and
platelet clumping.271,287,288 Fetal scalp vein sampling may cause a
cephalohematoma. Platelet levels in fetal scalp vein samples may be more
accurately assessed by examining a stained blood smear.272,289
An important difference between the treatment of ITP in pregnant women and
nonpregnant adults is the potential adverse effects of treatment on the course
of pregnancy and fetal development. Glucocorticoids, for example, are considered
safe in terms of potential teratogenicity but may have other fetal
toxicities.290 In the mother they may exacerbate gestational diabetes mellitus
and postpartum psychiatric disorders.246 IVIg is considered to be safe for the
fetus, having only adverse effects for the mother as described above. Cytotoxic
agents such as cyclophosphamide, vinca alkaloids, and azathioprine are avoided
during pregnancy because of an assumed risk of teratogenicity, although there
are few data regarding the magnitude of the risk.180,291-293 Splenectomy may
increase the risk of preterm labor during the first trimester and can be
technically difficult because of the size of the uterus in the third trimester,
but data regarding the magnitude of risk are lacking.
Recommendations
The special issues in caring for pregnant women with ITP cannot be addressed
through evidence-based recommendations, because there is no evidence that
current testing and treatment options produce a better outcome for the mother or
newborn. Recommendations based on opinion were derived from a questionnaire
completed by nine panel members with expertise in obstetrical and neonatal care
of ITP. In the panel's opinion, women with ITP should not be discouraged from
becoming pregnant if they have platelet counts >50,000 (1.7 to 2.4, B-D), but
they should be discouraged if they have a platelet count <10,000 after
splenectomy and other treatments (8.0, B).
Prenatal care. The panel's opinion was that it is appropriate (but not
necessary) for prenatal care of women with ITP to be managed by an obstetrician
who specializes in high-risk pregnancies (7.4, D) or for such a specialist to
act as a consultant (8.3, C). The panel reached consensus about the following
treatment options during the prenatal period (options for which the panel could
not reach consensus are listed in Table 6).
(1) No treatment. Observation (no specific treatment) was considered appropriate
for women with platelet counts >50,000 (8.3-9.0, A-C) and those with platelet
counts of 30,000 to 50,000 in the first and second trimesters (7.5 B) but
inappropriate in women with platelet counts <10,000 (1.0 to 1.3, A-B) or in
women with platelet counts of 10,000 to 30,000 who are in their second or third
trimester (1.8 to 2.9, B-C) or are bleeding (1.0 to 1.3, A-B).
(2) Glucocorticoids. There was strong disagreement about the appropriateness of
treating pregnant women initially with glucocorticoids (eg, prednisone) when
platelet counts are <10,000. However, the panel agreed that glucocorticoid
therapy is inappropriate when platelet counts exceed 50,000 (1.0, A for
first-second trimester, 2.0, C for third trimester) or when platelet counts of
30,000 to 50,000 occur in the first-second trimester (2.3 to 2.6, D).
(3) IVIg. The panel considered IVIg appropriate initial treatment in the third
trimester for pregnant women with platelet counts <10,000 (7.0 to 7.4, D) or for
women with platelet counts of 10,000 to 30,000 who are bleeding (7.4, D). After
failure of initial glucocorticoid treatment, IVIg was considered appropriate in
any trimester in women with platelet counts <10,000 (8.8 to 9.0, A-B), in women
with platelet counts of 10,000 to 30,000 who are bleeding (8.5 to 8.8, B), and
in asymptomatic women with counts of 10,000 to 30,000 in the third trimester
(8.5, B). However, like glucocorticoids, IVIg was considered inappropriate when
platelet counts exceed 50,000 (1.0 to 1.3, A-B) or when counts of 30,000 to
50,000 occur in the first-second trimester (1.6 to 1.8, B-C).
(4) Splenectomy. Splenectomy was considered appropriate in women in the second
trimester who have failed glucocorticoid and IVIg therapy, have platelet counts
<10,000, and are bleeding (7.3, C), but it was considered inappropriate in
asymptomatic patients with counts >10,000 (1.3 to 2.9, B-D for counts of 10,000
to 50,000; 1.0, A for counts >50,000).
In summary, there was a difference in the panel's approach to treating ITP in
pregnant women and nonpregnant adults (Table 12). The panel agreed that
glucocorticoids were appropriate initial therapy in nonpregnant adults but could
not reach consensus about whether they were more or less appropriate than IVIg
in pregnant women. The wide variation of opinion regarding prednisone and IVIg
as initial treatment reflected a difference in the panel's choice for one agent
or the other. In nonpregnant adults, IVIg was considered appropriate initial
treatment only for severe, life-threatening bleeding, whereas in pregnant women
it was also recommended as initial treatment for women with platelet counts
<10,000 or counts of 10 to 30,000 accompanied by bleeding. The panel also set a
higher threshold for the indications for splenectomy in pregnant women than in
nonpregnant adults, reflecting its concern about the risks to the mother and
fetus.
Antepartum care. Current data provide an inadequate basis for making
evidence-based recommendations on whether and how to predict the risk of
neonatal thrombocytopenia and on the preferred route of delivery as term
approaches. The panel's opinion was that a history of a previous infant with a
platelet count <50,000 at birth (and no evidence of alloimmune thrombocytopenia)
was important information in estimating the risk of fetal thrombocytopenia (8.1,
B). Beyond the history, however, the panel had little enthusiasm for laboratory
testing to predict risks. It considered testing for maternal platelet antibodies
unnecessary (2.3, B). The panel also lacked enthusiasm for performing PUBS (2.0,
B) in women with known ITP and normal platelet counts (and no prior history of
splenectomy), or fetal scalp vein sampling when such women have had prior
splenectomy (2.7, D) (Table 16). In pregnant women without known ITP, the panel
also did not support performing PUBS (1.3 to 2.9, B-C) or fetal scalp vein
sampling (1.7 to 3.0, C-D), even with maternal platelet counts of 40,000 to
75,000 at term. Nonetheless, the panel acknowledged that information obtained
from these tests would influence the preferred route of delivery (see below).
The panel reached consensus about the following potential interventions to
reduce newborn complications (options for which consensus was not reached are
listed in Table 6). TABLE 16
Panel Opinion Regarding the Role of Percutaneous Umbilical Blood Sampling and
Fetal Scalp Vein Platelet Count
--------------------------------------------------------------------------------
Maternal Clinical Features
--------------------------------------------------------------------------------
Platelet Count History
--------------------------------------------------------------------------------
Prior History of ITP
--------------------------------------------------------------------------------
Prior Splenectomy
--------------------------------------------------------------------------------
Recommendations
--------------------------------------------------------------------------------
75,000 at term, normal in 1st trimester No No Not recommended
PUBS (1.3, B)
FPC (1.7, C)}
75,000 in 1st trimester, which remains unchanged on no treatment throughout
pregnancy No No Not recommended
PUBS (2.1, C)
FPC (2.4, D)
40,000 in 3rd trimester, normal in 1st trimester No No Not recommended
PUBS (2.9, C)
FPC (3.0 D)
Normal Yes No Not recommended
PUBS (2.0, B)
(FPC, no consensus)
Normal Yes Yes Not recommended
FPC (2.7, D)
(PUBS, no consensus)
Normal, but previous infant with count of 20,000 at birth Yes Yes (No consensus)
--------------------------------------------------------------------------------
Assumes pregnancy is otherwise uncomplicated and that PUBS procedures are
commonly performed at the hospital. "Recommended" and "Not recommended" = mean
panel score of 7.0-9.0 or 1.0-3.0, respectively, for necessity/appropriateness.
Scores are defined in text and Table 2.
Abbreviations: PUBS, percutaneous umbilical blood sampling; FPC, fetal scalp
vein platelet count.
--------------------------------------------------------------------------------
TABLE 17
Panel Opinion Regarding the Management of Delivery in a Primiparous Woman With
Known ITP
--------------------------------------------------------------------------------
Maternal Platelet Count
--------------------------------------------------------------------------------
Prior Splenectomy
--------------------------------------------------------------------------------
Fetal Platelet Count
--------------------------------------------------------------------------------
Cesarean Section
--------------------------------------------------------------------------------
Vaginal Delivery
--------------------------------------------------------------------------------
Normal No NA Not recommended Recommended
1.0, A 9.0, A
Normal Yes NA Not recommended Recommended
2.1, B 8.0, B
100-150,000 No NA Not recommended Recommended
1.3, B 8.6, B
50-100,000 No NA Not recommended Recommended
1.8, B 8.4, B
<50,000 Yes NA No consensus No consensus
<50,000 No NA Not recommended Recommended
2.6, B 7.6, B
50-100,000 Yes NA Not recommended Recommended
2.9, B 7.3, B
50-100,000 Yes 50,000 (scalp vein) No consensus Recommended
7.0, D
50-100,000 No 50,000 (scalp vein) Not recommended Recommended
2.9, D 7.4, D
Normal Yes <50,000 (PUBS) No consensus No consensus
Normal Yes <20,000 (PUBS) Recommended Not recommended
7.9, B 2.4, B
--------------------------------------------------------------------------------
Assumes no current treatment and an otherwise uncomplicated pregnancy.
"Recommended" and "Not recommended" = mean panel score of 7.0-9.0 or 1.0-3.0,
respectively. Scores are defined in text and Table 2.
Abbreviation: NA, not applicable or not known.
--------------------------------------------------------------------------------
(1) Maternal treatment. Given the hypothetical case of a pregnant woman who had
ITP and a previous infant with a platelet count of 20,000 at birth,
glucocorticoid therapy to increase the fetal platelet count before delivery was
considered unnecessary (2.1, B) and inappropriate (3.0, C). In this case, IVIg
was also considered unnecessary (2.9, C).
(2) Prophylactic platelet transfusions. Platelet transfusions to prevent
maternal bleeding during labor and delivery were considered unnecessary for
women with platelet counts >30,000 and no bleeding symptoms for either vaginal
delivery (1.0, A) or cesarean section (1.0, A for >50,000; 2.9, D for 30 to
50,000). Platelet transfusions were considered to be indicated in women with
platelet counts <10,000 who have minor purpura and who require cesarean section
(7.9, D) and in women with platelet counts <10,000 who have epistaxis or other
mucous membrane bleeding (7.1, D for vaginal delivery; 8.4, B for cesarean
section).
(3) Route of delivery. When asked to define the minimum platelet count required
for vaginal delivery with no anticipated maternal bleeding complications, the
panel's voting range was 10,000 to 50,000, with a mean of 27,000. When asked to
define the minimum platelet count required for cesarian section with no
anticipated maternal bleeding complications, the panel's voting range of 30,000
to 50,000 with a mean of 44,000. Tables 17 and 18 present panel opinions about
the probability of neonatal thrombocytopenia and the appropriateness of vaginal
delivery/cesarean section in a hypothetical primiparous woman and in a
multiparous woman in her second pregnancy, respectively, both with known ITP. In
both instances, cesarean section was considered appropriate (7.9 to 8.1, B) if
the fetal platelet count, as determined by PUBS, is <20,000, but inappropriate
in other circumstances. For example, 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: (1) >100,000 (1.0 to 2.1, A-B), (2) 50,000
to 100,000 (1.6 to 2.9, B), and (3) <50,000 (in primiparous women, only if
splenectomy has not been performed) (2.6, B). TABLE 18
Panel Opinion Regarding the Management of Delivery in a Woman in Her Second
Pregnancy With Known ITP
--------------------------------------------------------------------------------
Maternal Platelet Count
--------------------------------------------------------------------------------
Prior Splenectomy
--------------------------------------------------------------------------------
Platelet Count of Prior Baby
--------------------------------------------------------------------------------
Fetal Platelet Count
--------------------------------------------------------------------------------
Cesarean Section
--------------------------------------------------------------------------------
Vaginal Delivery
--------------------------------------------------------------------------------
Normal No NA NA Not recommended Recommended
1.0, A 9.0, A
Normal Yes NA NA Not recommended Recommended
2.1, B 8.0, B
100-150,000 No NA NA Not recommended Recommended
1.3, B 8.6, B
50-100,000 No NA NA Not recommended Recommended
1.6, B 8.4, B
<50,000 Yes Normal NA Not recommended Recommended
2.0, B 7.9, C
<50,000 No Normal NA Not recommended Recommended
1.6, B 8.3, B
50-100,000 Yes <50,000 NA No consensus No consensus
50-100,000 No <50,000 NA No consensus No consensus
Normal Yes NA 50,000 (PUBS) No consensus No consensus
Normal Yes NA 20,000 (PUBS) Recommended Not recommended
8.1, B 2.4, C
--------------------------------------------------------------------------------
Assumes no current treatment, an otherwise uncomplicated pregnancy, and that the
prior baby was delivered by an uncomplicated vaginal delivery. "Recommended" and
"Not recommended" = mean panel scores of 7.0-9.0 or 1.0-3.0, respectively.
Scores are defined in text and Table 2.
Abbreviation: NA, not applicable or not known.
--------------------------------------------------------------------------------
(4) Neonatology consultation. The panel also addressed the necessity and
appropriateness of having a neonatologist in the labor or delivery room. The
consultation was considered appropriate (7.0, C-D) if there is a history of a
previous infant with a platelet count <20,000 at birth, as well as in a
hypothetical case in which a PUBS platelet count of 40,000 was obtained at 37
weeks. The panel agreed that the consultation was unnecessary (2.5, C) in the
case of a multiparous woman with known ITP, no prior splenectomy, and a normal
platelet count throughout pregnancy (assuming that unfavorable PUBS data or
history on previous infants were unavailable).
Treatment of Newborns
Evidence. There is evidence that neonates born to mothers with ITP can, during
the first week of life, either develop thrombocytopenia or experience further
deterioration of thrombocytopenia noted at birth. A study of 61 neonates born to
50 women with ITP reported that platelet counts decreased in two-thirds of
infants, with most (83%) infants reaching their nadir by day 1 or 2 and 100%
reaching their nadir by day 6.288 Platelet counts stabilized or began to rise by
day 7 in all infants.288 There is little direct evidence of an association
between these transient decreases in platelet counts and the risk of adverse
health outcomes (eg, ICH), nor is there evidence that treating such infants
reduces neonatal morbidity or mortality. However, neonatal thrombocytopenia can
contribute to mortality and neurologic morbidity.294 IVIg has been shown to
increase the platelet count in thrombocytopenic infants born to mothers with ITP
(level V evidence).295 The potential adverse effects of treatment modalities are
reviewed above.
Recommendations. There are no data from which to develop evidence-based
recommendations on newborn care when the mother has ITP. Based on opinion, the
panel considered it both necessary (7.7, C) and appropriate (8.8, B) to obtain
repeat platelet counts on the newborn if the neonatal platelet count at birth
was low (eg, 50,000). Even when newborns have normal platelet counts, the
panel's opinion was that repeat testing should be performed, on average, for 3
to 4 days (range = 0 to 7 days; two panel members voted against any repeat
testing). The panel considered brain imaging (eg, ultrasound) appropriate, even
in the absence of neurologic abnormalities, if the platelet count at birth was
<50,000 (7.3 to 8.1, C); imaging was considered necessary (7.6, D) if the count
was <20,000. If the infant has imaging evidence of ICH, combined treatment with
glucocorticoids and IVIg was considered necessary (7.9, D) and appropriate (8.0,
D) if the platelet count is <20,000. Treating such children with glucocorticoids
alone was considered inappropriate (1.1, A). In newborns without evidence of
ICH, treatment with IVIg alone was considered appropriate (8.0, C) if the
infant's platelet count is <20,000, unnecessary for platelet counts of 20,000 to
50,000 (2.7, D), and unnecessary and inappropriate for counts of 50,000 to
100,000 (2.9, D). Treating the newborn with glucocorticoids alone was considered
unnecessary at any platelet count (1.3 to 3.0, B-D) and inappropriate (2.6, D)
if the platelet count exceeds 50,000. Combined treatment with glucocorticoids
and IVIg was, considered unnecessary (2.0, C) and inappropriate (2.9, D) in
infants with platelet counts exceeding 50,000.
The panel's opinion was that women with ITP should not be discouraged from
breast feeding (1.4, B).
PRIORITIES FOR FUTURE RESEARCH
The evidence-based literature review of ITP provided the opportunity to identify
priorities for research. An important finding of our literature review was the
lack of rigorous clinical trial data on which to base recommendations for the
care of patients with ITP, affecting virtually every decision a clinician
commonly encounters. The panel identified the following research priorities.
(1) There is a need for rigorous prospective studies of the clinical course of
untreated ITP in patients presenting with mild or moderate thrombocytopenia and
no clinically important bleeding. These studies should include long-term
follow-up and should emphasize the clinical outcomes of bleeding and mortality.
(2) There is a need to define clinical features of children presenting with ITP
that may predict which children can be followed without treatment and what
features can reliably predict the risk of intracranial hemorrhage and the
occurrence of chronic ITP.
(3) There is a need to obtain more methodologically rigorous data on the
clinical course of chronic refractory ITP, especially the course of untreated
disease in patients without clinically important bleeding. These natural history
data are especially important for evaluating the efficacy of treatment of
chronic refractory ITP. As noted above, current evidence consists largely of
level V evidence (uncontrolled case series), making it difficult to prove that
treatment is beneficial or to exclude the possibility that some treatments are
more harmful than no treatment.
(4) There is a need for studies to assess the prognostic relation of the
platelet count, at initial presentation and subsequently, to the clinical
outcomes of bleeding and mortality. In practice, the platelet count plays an
important role in decision making despite the lack of definitive data on its
prognostic importance in patients with ITP.
(5) There is a need for randomized clinical trials to evaluate many of the
therapies currently used in ITP. These trials should focus on measuring the
benefits of therapy in terms of the clinical outcomes of bleeding and mortality,
as well as the adverse effects of treatment.
(6) There is a need for data on the costs of treatment regimens.
ACKNOWLEDGMENT
The panel thanks Marcie Byers, Oklahoma City, OK, for her expert assistance
throughout this endeavor.
REFERENCES
Eddy DM: A Manuel for Assessing Health Practices and Designing Practice
Guidelines: The Explicit Approach. Philadelphia, PA, American College of
Physicians, 1991
Woolf SH: Practice guidelines, a new reality in medicine. II. Methods of
developing guidelines. Arch Intern Med 152:946, 1992
Eddy DM: Practice policies: Where do they come from? JAMA 263:1265, 1990
Eddy DM: The challenge. JAMA 263:287, 1990
Field MJ, Lohr KN: Guidelines for Clinical Practice: From Development to Use.
Institute of Medicine Committee on Clinical Practice Guidelines. Washington, DC,
National Academy Press, 1992
Woolf SH: Practice guidelines: A new reality in medicine. I. Recent
developments. Arch Intern Med 150:1811, 1990
Woolf SH: Practice guidelines: A new reality in medicine. III. Impact on patient
care. Arch Intern Med 153:2646, 1993
George JN, El-Harake MA, Aster RH: Thrombocytopenia due to enhanced platelet
destruction by immunologic mechanisms, in Beutler E, Lichtman MA, Coller BS,
Kipps TJ (eds): Williams Hematology. New York, NY, McGraw-Hill, 1995, p 1315
Kurata Y, Miyagawa S, Kosugi S, Kashiwagi H, Honda S, Mizutani H, Tomiyama Y,
Kanakyama Y, Matsuzawa Y: High-titer antinuclear antibodies, anti-SSA/Ro
antibodies and anti-nuclear RNP antibodies in patients with idiopathic
thrombocytopenic purpura. Thromb Haemost 71:184, 1994
Stasi R, Stipa E, Masi M, Oliva F, Sciarra A, Perrotti A, Olivieri M, Zaccari G,
Gandolfo GM, Galli M, Barbui T, Papa G: Prevalence and clinical significance of
elevated antiphospholipid antibodies in patients with idiopathic
thrombocytopenic purpura. Blood 84:4203, 1994
Department of Clinical Epidemiology and Biostatistics MU, Hamilton: How to read
clinical journals. III. To learn the clinical course and prognosis of disease.
Can Med Assoc J 124:869, 1981
Department of Clinical Epidemiology and Biostatistics MU, Hamilton: How to read
clinical journals. To distinguish useful from useless or even harmful therapy.
Can Med Assoc J 124:1156, 1981
Sackett DL: Rules of evidence and clinical recommendation on the use of
antithrombotic drugs. Chest 95:25, 1989 (suppl)
Cook DJ, Guyatt GH, Laupacis A, Sackett DL: Rules of evidence and clinical
recommendations on the use of antithrombotic agents. Chest 102:305S, 1992
Guyett GH, Sackett DL, Cook DJ: User's guide to the medical literature. II. How
to use an article about therapy or prevention. A. Are the results of the study
valid? JAMA 270:2598, 1993
Park RE, Fink A, Brook RH: Physician ratings for appropriate indications for six
medical and surgical procedures. Am J Public Health 76:766, 1986
Brook RH, Chassin M, Fink A, Solomon D: A Method for the Detailed Assessment of
the Appropriateness of Medical Technologies. A RAND Note. N-3376-HHS. Santa
Monica, CA, RAND Corp, 1991
Komrower GM, Watson GH: Prognosis in idiopathic thrombocytopenic purpura of
childhood. Arch Dis Child 29:502, 1954
Choi SI, McClure PD: Idiopathic thrombocytopenic purpura in childhood. Can Med
Assoc J 97:562, 1967
Walker RW, Walker W: Idiopathic thrombocytopenia, initial illness and long term
follow up. Arch Dis Child 59:316, 1984
Ramos MEG, Newman AJ, Gross S: Chronic thrombocytopenia in childhood. Pediatrics
92:584, 1978
Lusher JM, Zuelzer WW: Idiopathic thrombocytopenic purpura in childhood. J
Pediatr 68:971, 1966
Simons SM, Main CA, Yaish HM, Rutzky J: Idiopathic thrombocytopenic purpura in
children. Pediatrics 87:16, 1975
Benham ES, Taft LI: Idiopathic thrombocytopenic purpura in children: Results of
steroid therapy and splenectomy. Aust Paediat J 8:311, 1972
Lammi AT, Lovric VA: Idiopathic thrombocytopenic purpura: An epidemiologic
study. Pediatrics 83:31, 1973
den Ottolander GJ, Gratama JW, deKoning J, Brand A: Long-term follow-up study of
168 patients with immune thrombocytopenia. Scand J Haematol 32:101, 1984
Hoyle C, Darbyshire P, Eden OB: Idiopathic thrombocytopenia in childhood. Scott
Med J 31:174, 1986
Zaki M, Hassanein AA, Khalil AF: Childhood idiopathic thrombocytopenic purpura:
Report of 60 cases from Kuwait. Journal of Tropical Pediatrics 36:10, 1990
Robb LG, Tiedeman K: Idiopathic thrombocytopenic purpura: Predictors of chronic
disease. Arch Dis Child 65:502, 1990
Buchanan GR, Holtkamp CA: Prednisone therapy for children with newly diagnosed
idiopathic thrombocytopenic purpura. A randomized clinical trial. Am J Pediatr
Hematol Oncol 6:355, 1984
Sartorius JA: Steroid treatment of idiopathic thrombocytopenic purpura in
children. Preliminary results of a randomized cooperative study. Am J Pediatr
Hematol Oncol 6:165, 1984
Blanchette VS, Luke B, Andrew M, Sommerville-Nielsen S, Barnard D, De Veber B,
Gent M: A prospective, randomized trial of high-dose intravenous immune globulin
G therapy, oral prednisone therapy, and no therapy in childhood acute immune
thrombocytopenic purpura. J Pediatr 123:989, 1993
Woerner SJ, Abildgaard CF, French BN: Intracranial hemorrhage in children with
idiopathic thrombocytopenic purpura. Pediatrics 67:453, 1981
Imbach P, d'Apuzzo V, Hirt A, Rossi E, Vest M, Barandun S, Baumgartner C, Morell
A, Schoni M, Wagner HP: High-dose intravenous gammaglobulin for idiopathic
thrombocytopenic purpura in childhood. Lancet 1:1228, 1981
Tamary H, Kaplinsky C, Levy I, Cohen IJ, Yaniv I, Stark B, Goshen Y, Zaizov R:
Chronic childhood idiopathic thrombocytopenia purpura: Long-term follow-up. Acta
Paediatr 83:931, 1994
Reid MM: Chronic idiopathic thrombocytopenic purpura: incidence, treatment, and
outcome. Arch Dis Child 72:125, 1995
Halperin DS, Doyle JJ: Is bone marrow examination justified in idiopathic
thrombocytopenic purpura? Am J Dis Child 142:508, 1988
Najean Y, Lecompte T: Genetic thrombocytopenia with autosomal dominant
transmission: A review of 54 cases. Br J Haematol 74:203, 1990
Pearson HA: The spleen and disturbances of splenic function, in Nathan DG, Oski
FA (eds): Hematology of Infancy and Childhood. Philadelphia, PA, Saunders, 1993,
p 1058
Hirsch EO, Dameshek W: "Idiopathic" thrombocytopenia. Review of eighty-nine
cases with particular reference to the differentiation and treatment of acute
(self-limited) and chronic types. Arch Intern Med 88:701, 1951
Lacey JV, Penner JA: Management of idiopathic thrombocytopenic purpura in the
adult. Semin Thromb Hemost 3:160, 1977
Slichter SL, Harker LA: Thrombocytopenia: Mechanisms and management of defects
in platelet production. Clin Haematol 7:523, 1978
Gmur J, Burger J, Schanz U, Fehr J, Schaffner A: Safety of stringent
prophylactic platelet transfusion policy for patients with acute leukemia.
Lancet 338:1223, 1991
Lawrence JB, Yomtovian RA, Dillman C, Masarik SR, Chongkolwatana V, Creger RJ,
Manka A, Hammons T, Lazarus HM: Reliability of automated platelet counts:
Comparison with manual method and utility for prediction of clinical bleeding.
Am J Hematol 48:244, 1995
Schattner E, Bussel J: Mortality in immune thrombocytopenic purpura: Report of
seven cases and consideration of prognostic indicators. Am J Hematol 46:120,
1994
McWilliams NB, Maurer HM: Acute idiopathic thrombocytopenic purpura in children.
Am J Hematol 7:87, 1979
Mazzucconi MG, Francesconi M, Fidani P, Nucci GD, Gandolfo GM, Afeltra A, Masala
C, Prima MD, Rocchi G, Resta S, Mandelli F: Treatment of idiopathic
thrombocytopenic purpura: results of a multicentric protocol. Haematologia
70:329, 1985
Blanchette V, Imbach P, Andrew M, Adams M, McMillan J, Wang E, Milner R, Ali K,
Barnard D, Bernstein M, Chan KW, Esseltine D, DeVeber B, Israels S, Kobrinsky N,
Luke B: Randomised trial of intravenous immunoglobulin G, intravenous anti-D,
and oral prednisone in childhood acute immune thrombocytopenic purpura. Lancet
344:703, 1994
Taub JW, Warrier I, Holtkamp C, Beardsley DS, Lusher JM: Characterization of
autoantibodies against the platelet glycoprotein antigens IIb/IIIa in childhood
idiopathic thrombocytopenia purpura. Am J Hematol 48:104, 1995
Imbach P, Wagner HP, Berchtold W: Intravenous immunoglobulin versus oral
corticosteroids in acute immune thrombocytopenic purpura in childhood. Lancet
2:464, 1985
Bellucci S, Charpak Y, Chastang C, Tobelem G: Low doses v conventional doses of
corticoids in immune thrombocytopenic purpura (ITP): Results of a randomized
clinical trial in 160 children, 223 adults. Blood 71:1165, 1988
Ozsoylu S, Irken G, Karabent A: High-dose intravenous methylprednisolone for
acute childhood idiopathic thrombocytopenic purpura. Eur J Haematol 42:431, 1989
del Principe D, Menichelli A, Mori PG, De Mattia D, Mancuso G, Carnelli V,
Zanesco L, Jankovic M, Calmasini M, Amici A, Miano C, Rosati D, Ciavarella G,
Oddo G, Giulotto P, Masera G, Lanza T: Phase II trial of methylprednisolone
pulse therapy in childhood chronic thrombocytopenia. Acta Haematol 77:226, 1987
van Hoff J, Ritchey AK: Pulse methylprednisolone therapy for acute childhood
idiopathic thrombocytopenic purpura. J Pediatr 113:563, 1988
Albayrak D, Islek I, Kalaycí AG, Gürses N: Acute immune thrombocytopenic
purpura: A comparative study of very high oral doses of methylprednisolone and
intravenously administered immune globulin. J Pediatr 125:1004, 1994
Khalifa AS, Tolba KA, El-Alfy MS, Gadallah M, Ibrahim FH: Idiopathic
thrombocytopenic purpura in Egyptian children. Acta Haematol 90:125, 1993
Ozsoylu S, Sayli TR, Ozturk G: Oral megadose methylprednisolone versus
intravenous immunoglobulin for acute childhood idiopathic thrombocytopenic
purpura. Pediatr Hematol Oncol 10:317, 1993
Saag KG, Koehnke R, Caldwell JR, Brasington R, Burmeister LF, Zimmerman B,
Kohler JA, Furst DE: Low dose long-term corticosteroid therapy in rheumatoid
arthritis: an analysis of serious adverse effects. Am J Med 96:115, 1994
Morris HG, Jorgensen JR, Elrick H, Goldsmith RE: Metabolic effects of human
growth hormone in corticosteroid-treated children. J Clin Invest 47:436, 1968
Bussel JB, Schulman I, Hilgartner MW, Barandun S: Intravenous use of
gammaglobulin in the treatment of chronic immune thrombocytopenic purpura as a
means to defer splenectomy. J Pediatr 103:651, 1983
Bussel JB, Goldman A, Imbach P, Schulman I, Hilgartner MW: Treatment of acute
idiopathic thrombocytopenia of childhood with intravenous infusions of
gammaglobulin. J Pediatr 106:886, 1985
Imholz B, Imbach P, Baumgartner C, Berchtold W, Gaedicke G, Gugler E, Hirt A,
Hitzig W, Mueller-Eckhardt C, Wagner HP: Intravenous immunoglobuklin (i.v. IgG)
for previously treated acute or for chronic idiopathic thrombocytopenic purpura
(ITP) in childhood: A prospective multicenter study. Blut 56:63, 1988
Warrier IA, Lusher JM: Intravenous gammaglobulin (gamimune) for treatment of
chronic idiopathic thrombocytopenic purpura (ITP): A two-year follow-up. Am J
Hematol 23:323, 1986
Bussel JB, Fitzgerald-Pederson J, Feldman C: Alternation of two doses of
intravenous gammaglobulin in the maintenance treatment of patients with immune
thrombocytopenic purpura: More is not always better. Am J Hematol 33:184, 1990
Duhem C, Dicato MA, Ries F: Side-effects of intravenous immune globulins. Clin
Exp Immunol 97:79, 1994 (suppl 1)
Sekul EA, Cupler EJ, Dalakas MC: Aseptic meningitis associated with high-dose
intravenous immunoglobulin therapy: Frequency and risk factors. Ann Intern Med
121:259, 1994
Thomas MJ, Misbah SA, Chapel HM, Jones M, Elrington G, Newsom-Davis J: Hemolysis
after high-dose intravenous Ig. Blood 82:3789, 1993
Centers for Disease Control and Prevention: Outbreak of hepatitis C associated
with intravenous immunoglobulin administration--United States, October 1993-June
1994. MMWR Morb Mortal Wkly Rep 43:505, 1994
Bjoro K, Froland SS, Yun Z, Samdal H, Haaland T: Hepatitis C infection in
patients with primary hypogammaglobulinemia after treatment with contaminated
immune globulin. New Eng J Med 331:1607, 1994
Yu MW, Mason BL, Guo ZP, Tankersley DL, Nedjar S, Mitchell FD, Biswas RM:
Hepatitis C transmission associated with intravenous immunoglobulins. Lancet
345:1173, 1995
Schiano TD, Bellary SV, Black M: Possible transmission of hepatitis C virus
infection with intravenous immunoglobulin. Ann Int Med 122:802, 1995
Becker T, Kuenzlen E, Salama A, Mertens R, Kiefel V, Weib H, Lampert F, Gaedicke
G, Mueller-Eckhardt C: Treatment of childhood idiopathic thrombocytopenic
purpura with Rhesus antibodies (anti-D). Eur J Pediatr 145:166, 1986
Bussel JB, Graziano JN, Kimberly RP, Pahwa S, Aledort LM: Intravenous anti-D
treatment of immune thrombocytopenic purpura: Analysis of efficacy, toxicity,
and mechanism of effect. Blood 77:1884, 1991
Andrew M, Blanchette VS, Adams M, Ali K, Barnard D, Chan KW, DeVeber LB,
Esseltine D, Israels S, Korbrinsky N, Luke B, Milner RA, Woloski BMR, Vegh P: A
multicenter study of the treatment of childhood chronic idiopathic
thrombocytopenic purpura with anti-D. J Pediatr 120:522, 1992
Borgna-Pignatti C, Battisti L, Zecca M, Locatelli F: Treatment of chronic
childhood immune thrombocytopenic purpura with intramuscular anti-D
immunoglobulins. Br J Haematol 88:618, 1994
Brooks PL, O'Shea MJ, Pryor JP: Splenectomy in the treatment of idiopathic
thrombocytopenic purpura. Br J Surg 56:861, 1969
Grosfeld JL, Naffis D, Boles ET Jr, Newton WA Jr: The role of splenectomy in
neonatal idiopathic thrombocytopenic purpura. J Pediatr Surg 5:166, 1970
Zarella JT, Martin LW, Lampkin BC: Emergency splenectomy for idiopathic
thrombocytopenic purpura in children. J Pediatr Surg 13:243, 1978
Davis PW, Williams DA, Shamberger RC: Immune thrombocytopenia: Surgical therapy
and predictors of response. J Pediatr Surg 26:407, 1991
Styrt B: Infection associated with asplenia: Risks, mechanisms, and prevention.
Am J Med 88:5-33N, 1990
Lortan JE: Clinical annotation. Management of asplenic patients. Br J Haematol
84:566, 1993
Schilling RF: Estimating the risk for sepsis after splenectomy in hereditary
spherocytosis. Ann Intern Med 122:187, 1995
Gaston MH, Verter JI, Woods G, Pegelow G, Kellerher J, Presbury G, Zarkowsky H:
Prophylaxis with oral penicillin in children with sickle cell anemia: A
randomized trial. N Engl J Med 314:1593, 1986
Centers for Disease Control and Prevention: Recommendations of the Advisory
Committee on Immunization Practices: Use of vaccines and immune globulins in
persons with altered immunocompetence. MMWR Morbid Mortal Wkly Rep 42:1, 1993
Reiquam CW, Prosper JC: Fresh plasma transfusions in the treatment of acute
thrombocytopenic purpura. J Pediatr 68:880, 1966
Hilgartner MW, Lanzkowsky P, Smith CH: The use of azathioprine in refractory
idiopathic thrombocytopenic purpura in children. Acta Paediatr Scand 59:409,
1970
Weinblatt ME, Kochen J, Ortega J: Danazol for children with immune
thrombocytopenic purpura. Am J Dis Child 142:1317, 1988
Cohn RJ, Schwyzer R, Hesseling PB, Poole JE, Naidoo J, Van Heerden C:
[alpha]-Interferon therapy for severe chronic idiopathic thrombocytopenic
purpura in children. Am J Hematol 43:246, 1993
Guthrie TH, Brannan DP, Prisant LM: Idiopathic thrombocytopenic purpura in the
older adult patient. Am J Med Sci 296:17, 1988
Cortelazzo S, Finazzi G, Buelli M, Molteni A, Viero P, Barbui T: High risk of
severe bleeding in aged patients with chronic idiopathic thrombocytopenic
purpura. Blood 77:31, 1991
Watson-Williams EJ, Macpherson AIS, Davidson S: The treatment of idiopathic
thrombocytopenic purpura. Lancet 2:221, 1958
Carpenter AF, Wintrobe MM, Fuller EA, Haut A, Cartwright GE: Treatment of
idiopathic thrombocytopenic purpura. JAMA 171:1911, 1959
Thompson RL, Moore RA, Hess CE, Wheby MS, Leavell BS: Idiopathic
thrombocytopenic purpura. Arch Intern Med 130:730, 1972
Meyers MC: Results of treatment in 71 patients with idiopathic thrombocytopenic
purpura. Am J Med Sci 242:295, 1961
JiJi RM, Firozvi T, Spurling CL: Chronic idiopathic thrombocytopenic purpura.
Arch Intern Med 132:380, 1973
Picozzi VJ, Roeske WR, Creger WP: Fate of therapy failures in adult idiopathic
thrombocytopenic purpura. Am J Med 69:690, 1980
Ikkala E, Kivilaakso E, Kotilainen M, Hastbacka J: Treatment of idiopathic
thrombocytopenic purpura in adults. Ann Clin Res 10:83, 1978
DiFino SM, Lachant NA, Kirshner JJ, Gottlieb AJ: Adult idiopathic
thrombocytopenic purpura. Clinical findings and response to therapy. Am J Med
69:430, 1980
Jacobs P, Wood L, Dent DM: Results of treatment in immune thrombocytopenia.
Quart J Med 226:153, 1986
Pizzuto J, Ambriz R: Therapeutic experience on 934 adults with idiopathic
thrombocytopenic purpura: multicentric trial of the cooperative Latin American
group on hemostasis and thrombosis. Blood 64:1179, 1984
Kaufman DW, Kelly JP, Johannes CB, Sandler A, Harmon D, Stolley PD, Shapiro S:
Acute thrombocytopenic purpura in relation to the use of drugs. Blood 82:2714,
1993
Doan CA, Bouroncle BA, Wiseman BK: Idiopathic and secondary thrombocytopenic
purpura: Clinical study and evaluation of 381 cases over a period of 28 years.
Ann Intern Med 53:861, 1960
McIntyre OR, Ebaugh FGJ: Palpable spleens in college freshmen. Ann Intern Med
66:301, 1967
Eyster ME, Rabkin CS, Hilgartner MW, Aledort LM, Ragni MV, Sprandio J, White GC,
Eichinger S, De Moerloose P, Andes WA, Cohen AR, Manco-Johnson M, Bray GL,
Schramm W, Hatzakis A, Lederman MM, Kessler CM, Goedert JJ: Human
immunodeficiency virus-related conditions in children and adults with
hemophilia: rates, relationship to CD4 counts, and predictive value. Blood
81:828, 1993
Payne BA, Pierre RV: Pseudothrombocytopenia: A laboratory artifact with
potentially serious consequences. Mayo Clin Proc 59:123, 1984
Savage RA: Pseudoleukocytosis due to EDTA-induced platelet clumping. Am J Clin
Pathol 81:317, 1984
Vicari A, Banfi G, Bonini PA: EDTA-dependent pseudothrombocytopaenia: A 12-month
epidemiological study. Scand J Clin Lab Invest 48:537, 1988
Garcia Suarez J, Calero MA, Ricard MP, Krsnik I, Rus GP, Perera F, Merino JL:
EDTA-dependent pseudothrombocytopenia in ambulatory patients: Clinical
characteristics and role of new automated cell-counting in its detection. Am J
Hematol 39:146, 1992
Najean Y, Lecompte T: Chronic pure thrombocytopenia in elderly patients: An
aspect of the myelodysplastic syndrome. Cancer 64:2506, 1989
von dem Borne AEGK, Vos JJE, Pegels JG, Thomas LLM, van der Lelie H: High dose
intravenous methylprednisolone or high dose intravenous gammaglobulin for
autoimmune thrombocytopenia. Br Med J 296:249, 1988
Godeau B, Zini J-M, Schaeffer A, Bierling P: High-dose methylprednisolone is an
alternative treatment for adults with autoimmune thrombocytopenic purpura
refractory to intravenous immunoglobulins and oral corticosteroids. Am J Hematol
48:282, 1995
Jacobs P, Wood L, Novitzky N: Intravenous gammaglobulin has no advantages over
oral corticosteroids as primary therapy for adults with immune thrombocytopenia:
A prospective randomized clinical trial. Am J Med 97:55, 1994
Laan RFJM, va Riel PLCM, van de Putte LBA, van Erning LJTO, van't Hof MA,
Lemmens JAM: Low-dose prednisone induces rapid reversible axial bone loss in
patients with rheumatoid arthritis. A randomized, controlled study. Ann Intern
Med 119:963, 1993
Bierling P, Farcet JP, Dvedari N, Rochant H: Gamma globulin for idiopathic
thrombocytopenic purpura. N Engl J Med 307:1150, 1982
Newland AC, Treleaven JG, Minchinton RM, Waters AH: High-dose intravenous IgG in
adults with autoimmune thrombocytopenia. Lancet 1:84, 1983
Solal-Celigny P, Bernard JF, Herrera A, Boivin P: Treatment of adult autoimmune
thrombocytopenic purpura with high-dose intravenous plasmin-cleaved
gammaglobulins. Scand J Haematol 31:39, 1983
Abe T, Matsuda J, Kawasugi K, Yoshimura Y, Kinoshita T, Kazama M: Clinical
effects of intravenous immunoglobulin on chronic idiopathic thrombocytopenic
purpura. Blut 47:69, 1983
Kurata Y, Tsubakio T, Yonezawa T, Tarui S: High-dose gammaglobulin therapy for
idiopathic thrombocytopenic purpura in adults. Acta Haematol 69:391, 1983
Carroll RR, Noyes WD, Rosse WF, Kitchens CS: Intravenous immunoglobulin
administration in the treatment of severe chronic immune thrombocytopenic
purpura. Am J Med 76:181, 1984
Oral A, Nusbacher J, Hill JB, Lewis JH: Intravenous gamma globulin in the
treatment of chronic idiopathic thrombocytopenic purpura in adults. Am J Med
187, 1984
Uchino H, Yasunaga K, Akatsuka J: A cooperative clinical trial of high-dose
immunoglobulin therapy in 177 cases of idiopathic thrombocytopenic purpura.
Thromb Haemost 51:182, 1984
Schmidt RE, Budde U, Broschen-Zywietz C, Schafer G, Mueller-Eckhardt C: High
dose gammaglobulin therapy in adults with idiopathic thrombocytopenic purpura
(ITP) clinical effects. Blut 48:19, 1984
Lang JM, Faradji A, Giron C, Bergerat JP, Oberling F: High-dose intravenous IgG
for chronic idiopathic thrombocytopenic purpura in adults. Blut 49:95, 1984
Kurlander R, Coleman RE, Moore J, Gockerman J, Rosse W, Siegal R: Comparison of
the efficacy of a two-day and a five-day schedule for infusing intravenous gamma
globulin in the treatment of immune thrombocytopenic purpura in adults. Amer J
Med 83:17, 1987 (suppl 4A)
Bussel JB, Pham LC, Aledort L, Nachman R: Maintenance treatment of adults with
chronic refractory immune thrombocytopenic purpura using repeated intravenous
infusions of gammaglobulin. Blood 72:121, 1988
Rodeghiero F, Schiavotto C, Castaman G, Vespignani M, Ruggeri M, Dini E: A
follow-up study of 49 adult patients with idiopathic thrombocytopenic purpura
treated with high-dose immunoglobulins and anti-D immunoglobulins. Haematologia
77:248, 1992
Godeau B, Lesage S, Divine M, Wirquin V, Farcet JP, Bierling P: Treatment of
adult chronic autoimmune thrombocytopenic purpura with repeated high-dose
intravenous immunoglobulin. Blood 82:1415, 1993
Tan E, Hajinazarian M, Bay W, Neff J, Mendell JR: Acute renal failure resulting
from intravenous immunoglobulin therapy. Arch Neurol 50:137, 1993
Ruggeri M, Castaman G, De Nardi G, Rodeghiero F: Acute renal failure after
high-dose intravenous immune globulin in a patient with idiopathic
thrombocytopenic purpura. Haematologica 78:338, 1993
Rault R, Piraino B, Johnston JR, Oral A: Pulmonary and renal toxicity of
intravenous immunoglobulin. Clin Nephrol 36:83, 1991
Woodruff RK, Grigg AP, Firkin FC, Smith IL: Fatal thrombotic events during
treatment of autoimmune thrombocytopenia with intravenous immunoglobulin in
elderly patients. Lancet 2:217, 1986
Dalakas MC: High-dose intravenous immunoglobulin and serum viscosity: Risk of
precipitating thromboembolic events. Neurology 44:223, 1994
Salama A, Mueller-Eckhardt C, Kiefel V: Effect of intravenous immunoglobulin in
immune thrombocytopenia. Competitive inhibition of reticuloendothelial system
function by sequestration of autologous red blood cells? Lancet 2:193, 1983
Salama A, Kiefel V, Amberg R, Mueller-Eckhardt C: Treatment of autoimmune
thrombocytopenic purpura with Rhesus antibodies (anti-Rho(D)). Blut 49:29, 1984
Salama A, Kiefel V, Mueller-Eckhardt C: Effect of IgG anti-Rho(D) in adult
patients with chronic autoimmune thrombocytopenia. Am J Hematol 22:241, 1986
Boughton BJ, Chakraverty R, Baglin TP, Simpson A, Galvin G, Rose P, Rohlova B:
The treatment of chronic idiopathic thrombocytopenia with anti-D(Rho)
immunoglobulin: its effectiveness, safety and mechanism of action. Clin Lab
Haematol 10:275, 1988
Whipple AO: Splenectomy as a therapeutic measure in thrombocytopenic purpura
haemorrhagica. Surg Gynecol Obstet 42:329, 1926
Block GE, Evans R, Zajtchuk R: Splenectomy for idiopathic thrombocytopenic
purpura. Arch Surg 92:484, 1966
Wilde RC, Ellis LD, Cooper WM: Splenectomy for chronic idiopathic
thrombocytopenic purpura. Arch Surg 95:344, 1967
Charlesworth D, Torrance HB: Splenectomy in idiopathic thrombocytopenic purpura.
Br J Surg 55:437, 1968
Brennan MF, Rappeport JM, Moloney WC, Wilson RE: Correlation between response to
corticosteroids and splenectomy for adult thrombocytopenic purpura. Am J Surg
129:490, 1975
Schwartz SI, Hoepp LM, Sachs S: Splenectomy for thrombocytopenia. Surgery
88:497, 1980
Ginsberg JS, Brill-Edwards P, Kowalchuk G, Hirsh J: Intermittent compression
units for the postphlebitic syndrome. A pilot study. Arch Intern Med 149:1651,
1989
Escolar G, Cases A, Monteagudo J, Garrido M, Lopez J, Ordinas A, Revert L,
Castillo R: Uremic plasma after infusion of desmopressin (DDAVP) improves the
interaction of normal platelets with vessel subendothelium. J Lab Clin Med
114:36, 1989
Gruenberg JC, Block MA, Van Slyck EJ, Abraham JP: Chronic idiopathic
thrombocytopenic purpura. Effective preoperative preparation and long-term
results of splenectomy. Henry Ford Hosp Med J 30:59, 1982
Musser G, Lazar G, Hocking W, Busuttil RW: Splenectomy for hematologic disease.
The UCLA experience with 306 patients. Ann Surg 200:40, 1984
Salky B, Katsoyannis G, Aufses AH, Jr., Kreel I: Splenectomy for chronic
idiopathic thrombocytopenic purpura. Mount Sinai J Med 51:287, 1984
Rocco MV, Stein RS: Prognostic factors for splenectomy response in adult
idiopathic thrombocytopenic purpura. Southern Med J 77:983, 1984
Boughton BJ, Smith P, Fielding J, Hawker R, Wilson I, Chandler S, Howie A: Size
of spleen rather than amount of platelet sequestration may determine long term
response to splenectomy in adult idiopathic thrombocytopenic purpura. J Clin
Path 38:1172, 1985
Cola B, Tonielli E, Sacco S, Brulatti M, Franchini A: Surgical treatment of
chronic idiopathic thrombocytopenic purpura. Results in 107 cases. Int Surg
71:195, 1986
Coon WW: Splenectomy for idiopathic thrombocytopenic purpura. Surg Gynecol
Obstet 164:225, 1987
Akwari OE, Itani KMF, Coleman RE, Rosse WF: Splenectomy for primary and
recurrent immune thrombocytopenic purpura. Ann Surg 206:529, 1987
Wanachiwanawin W, Visudhiphan S, Piankijagum A, Vatanavicharn S: Serious
complications following treatment of chronic idiopathic thrombocytopenic
purpura. Postgrad Med J 64:426, 1988
Wanachiwanawin W, Piankijagum A, Sindhvananda K, Vathanophas V, Visudhiphan S,
Na-Nakorn S: Emergency splenectomy in adult idiopathic thrombocytopenic purpura.
A report of seven cases. Arch Intern Med 149:217, 1989
Fabris F, Zanatta N, Casonato A, Randi ML, Luzzatto G, Girolami A: Response to
splenectomy in idiopathic thrombocytopenic purpura: prognostic value of the
clinical and laboratory evaluation. Acta Haematol 81:28, 1989
Shaw JHF, Clark MA: Splenectomy for immune thrombocytopenic purpura: Auckland
experience 1979-1987. Aust NZ J Surg 59:123, 1989
Fenaux P, Caulier MT, Hirschauer C, Beuscart R, Goudemand J, Bauters F:
Reevaluation of the prognostic factors for splenectomy in chronic idiopathic
thrombocytopenic purpura (ITP): A report on 181 cases. Eur J Haematol 42:259,
1989
Julia A, Araguas C, Rossello J, Bueno J, Domenech P, Olona M, Guardia R, Petit
J, Flores A: Lack of useful clinical predictors of response to splenectomy in
patients with chronic idiopathic thrombocytopenic purpura. Br J Haematol 76:250,
1990
van Geet C, Hauglustaine D, Vanrusselt M, Vermylen J: Haemostatic effects of
recombinant human erythropoietin in chronic haemodialysis patients. Thromb
Haemost 61:117, 1989
Catovsky D, Fooks J, Richards S: Prognostic factors in chronic lymphocytic
leukaemia: The importance of age, sex and response to treatment in survival. A
report from the MRC CLL 1 trial. Br J Haematol 72:141, 1989
Naouri A, Feghali B, Chabal J, Boulez J, Dechavanne M, Viala JJ, Tissot E:
Results of splenectomy for idiopathic thrombocytopenic purpura. Review of 72
cases. Acta Haematol 89:200, 1993
Rattner DW, Ellman L, Warshaw AL: Portal vein thrombosis after elective
splenectomy: An underappreciated, potentially lethal syndrome. Arch Surg
128:565, 1993
Petit P, Bret PM, Atri M, Hreno A, Casola G, Gianfelice D: Splenic vein
thrombosis after splenectomy: Frequency and role of imaging. Radiology 190:65,
1994
Calverley DC, Jones GW, Kelton JG: Splenic radiation for
corticosteroid-resistant immune thrombocytopenia. Ann Int Med 116:977, 1992
Caulier MT, Darloy F, Rose C, Camier G, Morel P, Bauters F, Fenaux P: Splenic
irradiation for chronic autoimmune thrombocytopenic purpura in patients with
contra-indications to splenectomy. Br J Haematol 91:208, 1995
Miyazaki M, Itoh H, Kaiho T, Ohtawa S, Ambiru S, Hayashi S, Nakajima N, Oh H,
Asai T, Iseki T: Partial splenic embolization for the treatment of chronic
idiopathic thrombocytopenic purpura. Am J Roentgenol 163:123, 1994
Verheyden CN, Beart RW, Clifton MD, Phyliky RL: Accessory splenectomy in
management of recurrent idiopathic thrombocytopenic purpura. Mayo Clin Proc
53:442, 1978
Pawelska S, Konopka L, Zdziechowska H: Recurrence of thrombocytopenia in
patients splenectomized for idiopathic thrombocytopenic purpura. Blut 43:355,
1981
Rudowski WJ: Accessory spleens: clinical significance with particular reference
to the recurrence of idiopathic thrombocytopenic purpura. World J Surg 9:422,
1985
Wallace D, Fromm D, Thomas D: Accessory splenectomy for idiopathic
thrombocytopenic purpura. Surgery 91:134, 1982
Ambriz R, Munoz R, Quintanar E, Sigler L, Aviles A, Pizzuto J: Accessory spleen
compromising response to splenectomy for idiopathic thrombocytopenic purpura.
Radiology 155:793, 1985
Gibson J, Rickard KA, Bautovich G, May J, Kronenberg H: Management of
splenectomy failures in chronic immune thrombocytopenic purpura: role of
accessory splenectomy. Aust N Z J Med 16:695, 1986
Facon T, Caulier MT, Fenaux P, Plantier I, Marchandise X, Ribet M, Jouet JP,
Bauters F: Accessory spleen in recurrent chronic immune thrombocytopenic
purpura. Am J Hematol 41:184, 1992
Chirletti P, Cardi M, Barillari P, Vitale A, Sammartino P, Bolognese A, Caiazzo
R, Ricci M, Muttillo IA, Stipa V: Surgical treatment of immune thrombocytopenic
purpura. World J Surg 16:1001, 1992
Bouroncle BA, Doan CA: Refractory idiopathic thrombocytopenic purpura treated
with azathioprine. N Engl J Med 275:630, 1966
Bouroncle BA, Doan CA: Treatment of refractory idiopathic thrombocytopenic
purpura. JAMA 207:2049, 1969
Sussman LN: Azathioprine in refractory idiopathic thrombocytopenic purpura. JAMA
202:259, 1967
Quiquandon I, Fenaux P, Caulier MT, Pagniez D, Huart JJ, Bauters F:
Re-evaluation of the role of azathioprine in the treatment of adult chronic
idiopathic thrombocytopenic purpura: A report on 53 cases. Br J Haematol 74:223,
1990
Kyle RA, Gertz MA: Second malignancies after chemotherapy, in Perry MC (ed): The
Chemotherapy Sourcebook. Baltimore, MD, Williams and Wilkins, 1992, p 689
Doll DC, Ringenberg QS, Yarbo JW: Antineoplastic agents and pregnancy. Semin
Oncol 16:337, 1989
Laros RK, Penner JA: "Refractory" thrombocytopenic purpura treated successfully
with cyclophosphamide. JAMA 215:445, 1971
Verlin M, Laros RK, Penner JA: Treatment of refractory thrombocytopenic purpura
with cyclophosphamide. Am J Hematol 1:97, 1976
Weinerman B, Maxwell I, Hryniuk W: Intermittent cyclophosphamide treatment of
autoimmune thrombocytopenia. Can Med Assoc J 111:1100, 1974
Srichaikul T, Boonpucknavig S, Archararit N, Chaisiri-pumkeeree W: Chronic
immunologic thrombocytopenic purpura. Results of cyclophosphamide therapy before
splenectomy. Arch Intern Med 140:636, 1980
Reiner A, Gernsheimer T, Slichter SJ: Pulse cyclophosphamide therapy for
refractory autoimmune thrombocytopenic purpura. Blood 85:351, 1995
Smith AG, Prentice AG, Lucie NP, Browning JD, Dagg JH, Rowan RM: Acute
myelogenous leukaemia following cytotoxic therapy: five cases and a review.
Quart J Med 51:227, 1982
Krause JR: Chronic idiopathic thrombocytopenic purpura (ITP): development of
acute nonlymphocytic leukemia subsequent to treatment with cyclophosphamide. Med
Pediatr Oncol 10:61, 1982
Ahn YS, Harrington WJ, Seelman RC, Eytel CS: Vincristine therapy of idiopathic
and secondary thrombocytopenias. N Engl J Med 291:376, 1974
&cmd[;jf51&cmd];
Burton IE, Roberts BE, Child JA, Montgomery DA, Raper CGL: Responses to
vincristine in refractory idiopathic thrombocytopenic purpura. Br Med J 2:918,
1976
Ahn YS, Byrnes JJ, Harrington WJ, Cayer ML, Smith DS, Brunskill DE, Pall LM: The
treatment of idiopathic thrombocytopenia with vinblastine-loaded platelets. N
Engl J Med 298:1101, 1978
Cervantes F, Rozman C, Feliu E, Montserrat E, Diumenjo C, Granena A: Low-dose
vincristine in the treatment of corticosteroid-refractory idiopathic
thrombocytopenic purpura (ITP) in non-splenectomized patients. Postgrad Med J
56:711, 1980
Kelton JG, McDonald JWD, Barr RM, Walker I, Nicholson W, Neame PB, Hamid C, Wong
TY, Hirsh J: The reversible binding of vinblastine to platelets: implications
for therapy. Blood 57:431, 1981
Ahn YS, Harrington WJ, Mylvaganam R, Allen LM, Pall LM: Slow infusion of vinca
alkaloids in the treatment of idiopathic thrombocytopenic purpura. Ann Intern
Med 100:192, 1984
Manoharan A: Slow infusion of vincristine in the treatment of idiopathic
thrombocytopenic purpura. Am J Hematol 21:135, 1986
Simon M, Jouet J, Fenaux P, Pollet J, Walter M, Bauters F: The treatment of
adult idiopathic thrombocytopenic purpura. Infusion of vinblastine in ITP. Eur J
Haematol 39:193, 1987
Linares M, Cervero A, Sanchez M, Garcia S, Miguel-Sosa A, Miguel-Garcia A,
Miguel-Borja JM: Slow infusion of vincristine in the treatment of refractory
thrombocytopenic purpura. Acta Haematol 80:173, 1988
Fenaux P, Quiquandon I, Caulier MT, Simon M, Walter MP, Bauters F: Slow
infusions of vinblastine in the treatment of adult idiopathic thrombocytopenic
purpura: a report on 43 cases. Blut 60:238, 1990
Manoharan A: Targeted-immunosuppression with vincristine infusion in the
treatment of immune thrombocytopenia. Aust NZ J Med 21:405, 1991
Facon T, Caulier MT, Wattel E, Jouet JP, Bauters F, Fenaux P: A randomized trial
comparing vinblastine in slow infusion and by bolus i.v. injection in idiopathic
thrombocytopenic purpura: A report on 42 patients. Br J Haematol 86:678, 1994
Ahn YS, Harrington WJ, Simon SR, Mylvaganam R, Pall LM, So AG: Danazol for the
treatment of idiopathic thrombocytopenic purpura. N Engl J Med 308:1396, 1983
Buelli M, Cortelazzo S, Viero P, Minetti B, Comotti B, Bassan R, Barbui T:
Danazol for the treatment of idiopathic thrombocytopenic purpura. Acta Haematol
74:97, 1985
McVerry BA, Auger M, Bellingham AJ: The use of danazol in the management of
chronic immune thrombocytopenic purpura. Br J Haematol 61:145, 1985
Almagro D: Danazol in idiopathic thrombocytopenic purpura. Acta Haematol 74:120,
1985
Ambriz R, Pizzuto J, Morales M, Chavez G, Guillen C, Aviles A: Therapeutic
effect of danazol on metrorrhagia in patients with idiopathic thrombocytopenic
purpura (ITP). Nouv Rev Fr Hematol 28:275, 1986
Mazzucconi MG, Francesconi M, Falcione E, Ferrari A, Gandolfo GM, Ghiradini A,
Tirindelli MC: Danazol therapy in refractory chronic immune thrombocytopenic
purpura. Acta Haematol 77:45, 1987
Manoharan A: Danazol therapy in patients with immune cytopenias. Aust NZ J Med
17:613, 1987
Schreiber AD, Chien P, Tomaski A, Cines DB: Effect of danazol in immune
thrombocytopenic purpura. N Engl J Med 316:503, 1987
Kotlarek-Haus S, Podolak-Dawidziak M: Danazol in chronic idiopathic
thrombocytopenic purpura resistant to corticosteroids. Folia Haematol 114:768,
1987
Ahn YS, Mylvaganam R, Garcia RO, Kim CI, Palow D, Harrington WJ: Low-dose
danazol therapy in idiopathic thrombocytopenic purpura. Ann Intern Med 107:177,
1987
Nalli G, Sajeva MR, Maffe GC, Ascari E: Danazol therapy for idiopathic
thrombocytopenic purpura (ITP). Haematologia 73:55, 1988
Ahn YS, Rocha R, Mylvaganam R, Garcia R, Duncan R, Harrington WJ: Long-term
danazol therapy in autoimmune thrombocytopenia: unmaintained remission and
age-dependent response in women. Ann Intern Med 111:723, 1989
Edelmann DZ, Knobel B, Virag I, Meytes D: Danazol in non-splenectomized patients
with refractory idiopathic thrombocytopenic purpura. Postgrad Med J 66:827, 1990
Flores A, Carles J, Junca J, Abella E: Danazol therapy in chronic immume
thrombocytopenic purpura. Eur J Haematol 45:109, 1990
Arrowsmith JB, Dreis M: Thrombocytopenia after treatment with Danazol. N Engl J
Med 314:585, 1986
Rabinowe SN, Miller KB: Danazol-induced thrombocytopenia. Br J Haematol 65:383,
1987
Laveder F, Marcolongo R, Zamboni S: Thrombocytopenic purpura following treatment
with danazol. Br J Haematol 90:970, 1995
Brox AG, Howson-Jan K, Fauser AA: Treatment of idiopathic thrombocytopenic
purpura with ascorbate. Br J Haematol 70:341, 1988
Toyama K, Ohyashiki K, Nehashi Y, Ohyashiki JH: Ascorbate for the treatment of
idiopathic thrombocytopenic purpura. Br J Haematol 75:623, 1990
Win N, Matthey F, Davies SC: Ascorbate for the treatment of idiopathic
thrombocytopenic purpura. Br J Haematol 75:626, 1990
Verhoef GEG, Boonen S, Boogaerts MA: Ascorbate for the treatment of refractory
idiopathic thrombocytopenic purpura. Br J Haematol 74:234, 1990
Godeau B, Bierling P: Treatment of chronic autoimmune thrombocytopenic purpura
with ascorbate. Br J Haematol 75:289, 1990
Novitzky N, Wood L, Jacobs P: Treatment of refractory immune thrombocytopenic
purpura with ascorbate. South African Med J 81:44, 1992
Van der Beek-Boter JW, Van Oers MHJ, Von dem Borne AEGK, Klaassen RJL: Ascorbate
for the treatment of ITP. Eur J Haematol 48:61, 1992
Jubelirer SJ: Pilot study of ascorbic acid for the treatment of refractory
immune thrombocytopenic purpura. Am J Hematol 43:44, 1993
Strother SV, Zuckerman KS, LoBuglio AF: Colchicine therapy for refractory
idiopathic thrombocytopenic purpura. Arch Intern Med 144:2198, 1984
Jim RTS: Therapeutic use of colchicine in thrombocytopenia. Hawaii Med J 45:221,
1986
Snyder HW, Cochran SK, Balint JP, Bertram JH, Mittelman A, Guthrie TH, Jones FR:
Experience with protein A-immunoadsorption in treatment-resistant adult immune
thrombocytopenic purpura. Blood 79:2237, 1992
Balint JP Jr, Snyder HW Jr, Cochran SK, Jones FR: Long-term response of immune
thrombocytopenia to extracorporeal immunoadsorption. Lancet 337:1106, 1991
Guthrie TH, Oral A: Immunethromboctyopenia purpura: A pilot study of
staphylococcal protein A immunomodulation in refractory patients. Semin Hematol
26:3, 1989
Kabisch A, Kroll H, Wedi B, Kiefel V, Pralle H, Mueller-Eckhardt C: Severe
adverse effects of protein A immunoadsorption. Lancet 343:116, 1994
Dzik WH, Duncan LM: Case records of the Massachusetts General Hospital. A
55-year-old woman with a skin rash and hemiparesis after staphylococcal protein
A column therapy. N Engl J Med 331:792, 1994
Marder VJ, Nusbacher J, Anderson FW: One-Year follow-up of plasma exchange
therapy in 14 patients with idiopathic thrombocytopenic purpura. Transfusion
21:291, 1981
Blanchette VS, Hogan VA, McCombie NE, Drouin J, Bormanis JD, Taylor R, Rock GA:
Intensive plasma exchange therapy in ten patients with idiopathic
thrombocytopenic purpura. Transfusion 24:388, 1984
Bussel JB, Saal S, Gordon B: Combined plasma exchange and intravenous
gammaglobulin in the treatment of patients with refractory immune
thrombocytopenic purpura. Transfusion 28:38, 1988
Figueroa M, McMillan R: 2-chlorodeoxyadenosine in the treatment of chronic
refractory immune thrombocytopenic purpura. Blood 81:3484, 1993
Figueroa M, Gehlsen J, Hammond D, Ondreyco S, Piro L, Pomeroy T, Williams F,
McMillan R: Combination chemotherapy in refractory immune thrombocytopenic
purpura. N Engl J Med 328:1226, 1993
Proctor SJ, Jackson G, Carey P, Stark A, Finney R, Saunders P, Summerfield G,
Maharaj D, Youart A: Improvement of platelet counts in steroid-unresponsive
idiopathic immune thrombocytopenic purpura after short-course therapy with
recombinant alpha 2b interferon. Blood 74:1894, 1989
Proctor SJ: Alpha interferon therapy in the treatment of idiopathic
thrombocytopenic purpura. Eur J Cancer 27:S63, 1991 (suppl 4)
Bellucci S, Bordessoule D, Coiffier B, Tabah I: Interferon alpha-2b therapy in
adult chronic thrombocytopenic purpura (ITP). Br J Haematol 73:578, 1989
Iannaccaro P, Molica S, Santoro R: Recombinant alpha-2b interferon in refractory
idiopathic immune thrombocytopenia. Eur J Haematol 48:271, 1992
Dubbeld P, Hillen HFP, Schouten HC: Interferon treatment of refractory
idiopathic thrombocytopenic purpura (ITP). Eur J Haematol 52:233, 1994
Matthey F, Ardeman S, Jones L, Newland AC: Bleeding in immune thrombocytopenic
purpura after alpha-interferon. Lancet 335:471, 1990
Hudson JG, Yates P, Scott GL: Further concern over use of alpha-interferon in
immune thrombocytopenic purpura. Br J Haematol 82:630, 1992
Bartholomew JR, Salgia R, Bell WR: Control of bleeding in patients with immune
and nonimmune thrombocytopenia with aminocaproic acid. Arch Intern Med 149:1959,
1989
Burrows RF, Kelton JG: Fetal thrombocytopenia and its relation to maternal
thrombocytopenia. N Engl J Med 329:1463, 1993
Burrows RF, Kelton JG: Platelets and pregnancy. Chapter 4. Current Obstetric
Medicine 2:83, 1993
McCrae KR, Samuels P, Schreiber AD: Pregnancy-associated thrombocytopenia:
Pathogenesis and management. Blood 80:2697, 1992
Ballem PJ: Diagnosis and management of thrombocytopenia in obstetric syndromes,
in Sacher RA, Brecher ME (eds): Obstetric Transfusion Practice. Bethesda, MD,
American Association of Blood Banks, 1993, p 49
Bartholomew JR, Bell WR, Kickler TM, Repke J: Abrupt reversal of gestational
autoimmune thrombocytopenia after delivery. A case report. J Reprod Med 34:234,
1989
Rasmus KT, Rottman RL, Kotelko DM, Wright WC, Stone JJ, Rosenblatt RM:
Unrecognized thrombocytopenia and regional anesthesia in parturients: a
retrospective review. Obstet Gynecol 73:943, 1989
Scott JR, Cruikshank DP, Kochenour NK, Pitkin RM, Warenski JC: Fetal platelet
counts in the obstetric managment of immunologic thrombocytopenic purpura. Am J
Obstet Gynecol 136:495, 1980
Woon KY, Tan KL, Khoo PT: The newborn and maternal idiopathic thrombocytopenic
purpura. J Singapore Paed Soc 23:71, 1981
Aviles A, Conte G, Ambriz R, Sinco A, Pizzuto J: Table 1. Lack of relation
between maternal and neonatal platelet counts. N Engl J Med 305:830, 1981
(abstr)
Karpatkin M, Porges RF, Karpatkin S: Platelet counts in infants of women with
autoimmune thrombocytopenia. Effect of steroid administration to the mother. N
Engl J Med 305:936, 1981
Cines DB, Dusak B, Tomaski A, Mennuit M, Schreiber AD: Immune thrombocytopenic
purpura and pregnancy. N Engl J Med 306:826, 1982
Kelton JG, Inwood MJ, Barr RM, Effer SB, Hunter D, Wilson WL, Ginsburg DA:
Fetus, placenta, and newborn. The prenatal prediction of thrombocytopenia in
infants of mothers with clinically diagnosed immune thrombocytopenia. Am J
Obstet Gynecol 144:449, 1982
Kessler I, Lancet M, Borenstein R, Berrebi A, Mogilner BM: The obstetrical
management of patients with immunologic thrombocytopenic purpura. Int J Gynec
Obstet 20:23, 1982
Logaridis TE, Doran TA, Scott JG, Gare DG, Comtesse C: The effect of maternal
steroid administration on fetal platelet count in immunologic thrombocytopenic
purpura. Management of pregnancy and mode of delivery. Am J Obstet Gynecol
145:147, 1983
Pizzuto J, Aviles A, Niz J: Thrombocytopenia and infant platelet count. Letter
to the editor. Am J Obstet Gynecol 146:994, 1983
Rote NS, Nielsen KG, Neilson VD, Hill HR, Scott JR: Studies by enzyme-linked
immunosorbent assay (ELISA) of antiplatelet antibody and transient neonatal
thrombocytopenic purpura. Am J Reprod Immunol 3:178, 1983
Scott JR, Rote NS, Cruikshank DP: Antiplatelet antibodies and platelet counts in
pregnancies complicated by autoimmune thrombocytopenia purpura. Am J Obstet
Gynecol 145:932, 1983
Laros RK, Kagan R: Route of delivery for patients with immune thrombocytopenia
purpura. Am J Obstet Gynecol 148:901, 1984
Karpatkin M: Clinical and laboratory observations. Corticosteroid therapy in
thrombocytopenic infants of women with autoimmune thrombocytopenia. J Pediatr
105:623, 1984
Wahbeh CJ, Eden RD, Killam AP, Gall SA: Pregnancy and immune thrombocytopenic
purpura. Letter to the editor. Am J Obstet Gynecol 149:238, 1984
Wenske G, Gaedicke G, Heyes H: Idiopathic thrombocytopenic purpura in pregnancy
and neonatal period. Blut 48:377, 1984
Barbui T, Cortelazzo S, Viero P, Buelli M, Casarotto C: Idiopathic
thrombocytopenic purpura and pregnancy. Maternal platelet count and antiplatelet
antibodies do not predict the risk of neonatal thrombocytopenia. La Ricerca Clin
Lab 15:139, 1985
Mazzucconi MG, Francesconi M, Fidani P, Conti L, Martelli MC, Paesano R, Pachi'
A: Pregnancy, delivery and detection of antiplatelet antibodies in women with
idiopathic thrombocytopenic purpura. Haematologica 70:506, 1985
White R: Pregnancy complicated by immune thrombocytopenic purpura. Ir Med J
80:97, 1987
Moise KJ Jr, Carpenter RJ Jr, Cotton DB, Wasserstrum N, Kirshon B, Cano L:
Percutaneous umbilical cord blood sampling in the evaluation of fetal platelet
counts in pregnant patients with autoimmune thrombocytopenia purpura. Obstet
Gynecol 72:346, 1988
Scioscia AL, Grannum AT, Copel JA, Hobbins JC: The use of percutaneous umbilical
blood sampling in immune thrombocytopenic purpura. Am J Obstet Gynecol 159:1066,
1988
Tchernia G: Immune thrombocytopenia purpura and pregnancy. Curr Stud Hematol
Blood Transf 55:81, 1988
Ballem PJ, Buskard N, Wittman BK, Wilson RD, Effer S, Farquharson D: ITP in
pregnancy: Use of the bleeding time as an indicator for treatment. Blut 59:132,
1989
Dan U, Barkai G, David B, Goldenberg M, Kukkia E, Mashiach S: Management of
labor in patients with idiopathic thrombocytopenic purpura. Gynecol Obstet
Invest 27:193, 1989
Burrows RF, Kelton JG: Thrombocytopenia at delivery: A prospective survey of
6715 deliveries. Am J Obstet Gynecol 162:731, 1990
Christiaens GCML, Nieuwenhuis HK, von dem Borne AEGK, Ouwehand WH, Helmerhorst
FM, van Dalen CM, Van der Tweel I: Idiopathic thrombocytopenic purpura in
pregnancy: A randomized trial on the effect of antenatal low dose
corticosteroids on neonatal platelet count. Br J Obstet Gynaecol 97:893, 1990
Kaplan C, Daffos F, Forestier F, Tertian G, Catherine N, Pons JC, Tchernia G:
Fetal platelet counts in thrombocytopenic pregnancy. Lancet 336:979, 1990
Moutet A, Fromont P, Farcet J-P, Rotten D, Bettaieb A, Duédari N, Bierling P:
Pregnancy in women with immune thrombocytopenic purpura. Arch Intern Med
150:2141, 1990
Samuels P, Bussel JB, Braitman LE, Tomaski A, Druzin ML, Mennuti MT, Cines DB:
Estimation of the risk of thrombocytopenia in the offspring of pregnant women
with presumed immune thrombocytopenic purpura. N Engl J Med 323:229, 1990
Sharon R, Tatarsky I: Low fetal morbidity in pregnancy associated with acute and
chronic idiopathic thrombocytopenic purpura. Am J Hematol 46:87, 1994
Burrows RF, Kelton JG: Pregnancy in patients with idiopathic thrombocytopenic
purpura: Assessing the risks for the infant at delivery. Obstet Gynecol Survey
48:781, 1993
Browning J, James D: Immune thrombocytopenia in pregnancy. Fetal Med Rev 2:143,
1990
Cook RL, Miller RC, Katz VL, Cefalo RC: Immune thrombocytopenic purpura in
pregnancy: A reappraisal of management. Obstet Gynecol 78:578, 1991
Garmel SH, Craigo SD, Morin LM, Crowley JM, D'Alton ME: The role of percutaneous
umbilical blood sampling in the management of immune thrombocytopenic purpura.
Prenatal Diagnosis 15:439, 1995
Daffos F, Capella-Pavlovsky M, Forestier F: Fetal blood sampling during
pregnancy with the use of a needle guided by ultrasound: A study of 606
consecutive cases. Am J Obstet Gynecol 153:655, 1985
Pielet BW, Socol ML, MacGregor SN, Ney JA, Dooley SL: Cordocentesis: An
appraisal of risks. Am J Obstet Gynecol 159:1497, 1988
Paidas MJ, Berkowitz RL, Lynch L, Lockwood CJ, Lapinski R, McFarland JG, Bussel
JB: Alloimmune thrombocytopenia: Fetal and neonatal losses related to
cordocentesis. Am J Obstet Gynecol 172:475, 1995
Christiaens GCML, Helmerhorst FM: Validity of intrapartum diagnosis of fetal
thrombocytopenia. Am J Obstet Gynecol 157:864, 1987
Burrows RF, Kelton JG: Low fetal risks in pregnancies associated with idiopathic
thrombocytopenic purpura. Am J Obstet Gynecol 163:1147, 1990
Adams DM, Bussel JB, Druzin ML: Accurate intrapartum estimation of fetal
platelet count by fetal scalp sample smear. Am J Perinatol 11:42, 1994
Rayburn WF: Glucocorticoid therapy for rheumatic diseases: Maternal, fetal, and
breast-feeding considerations. Am J Reprod Immunol 28:138, 1992
Mulvihill JJ, McKeen EA, Rosner F, Zarrabi MH: Pregnancy outcome in cancer
patients. Experience in a large cooperative group. Cancer 60:1143, 1987
Garber JE: Long-term follow-up of children exposed to utero to antieoplastic
agents. Semin Oncol 16:437, 1989
Ostensen M: Treatment with immunosuppressive and disease modifying drugs during
pregnancy and lactation. Am J Reprod Immunol 28:148, 1992
Andrew M, Castle V, Salgal S, Carter C, Kelton JG: Clinical impact of neonatal
thrombocytopenia. J Pediat 110:457, 1987
Ballin A, Andrew M, Ling E, Perlman M, Blanchette V: High-dose intravenous
gammaglobulin therapy for neonatal autoimmune thrombocytopenia. J Pediatr
112:789, 1988
--------------------------------------------------------------------------------
From the Hematology-Oncology Section, the Department of Medicine (J.N.G., Chair,
and G.E.R.) and Biostatistics and Epidemiology (G.E.R.), University of Oklahoma
Health Sciences Center, Oklahoma City; the Department of Family Practice,
Medical College of Virginia, Fairfax Family Practice Center, Fairfax, VA
(S.H.W.); the Department of Medicine, University of Connecticut, Watkins Center
Hematology-Oncology, Manchester, CT (J.S.W., Co-chair); Mount Sinai Medical
School, New York, NY (L.M.A); the Division of Hematology, University of British
Columbia, Vancouver, British Columbia, Canada (P.J.B.); the Department of
Pediatrics, University of Toronto and Hospital for Sick Children, Toronto,
Ontario, Canada (V.S.B.); the Department of Pediatrics, Cornell University
College of Medicine, New York Hospital, New York, NY (J.B.B.); the Department of
Medicine, Pathology and Laboratory Medicine, University of Pennsylvania,
Philadelphia (D.B.C.); the Department of Medicine, Chedoke-McMaster Hospitals,
Hamilton, Ontario, Canada (J.G.K.); the Department of Hematology-Oncology,
Cleveland Clinic, Cleveland, OH (A.E.L.); the Scripps Research Institute, La
Jolla, CA (R.M.); Heartland Hematology-Oncology, Council Bluffs, IA (J.A.O.);
Hematology Clinic, Portland, OR (D.H.R.); and the Department of Pediatrics,
Wayne State University, Children's Hospital of Detroit, Detroit, MI (I.W.).
Submitted November 13, 1995; accepted January 25, 1996.
Supported by The American Society of Hematology.
Adopted by the Executive Committee of The American Society of Hematology at its
annual meeting in Seattle, WA, December 1-5, 1995.
Address reprint requests to James N. George, MD, Chief, Hematology-Oncology
Section, The University of Oklahoma Health Sciences Center, PO Box 26901,
Oklahoma City, OK 73190.
http://www.micro.unsw.edu.au/MICR3051%202001/Blazek,%20Edmonds,%
20Stokes,%20Thomson,%20Thientosapol/ITP.htm
by katrina blazek
What is Idiopathic Thrombocytopenic Purpura?
Idiopathic Thrombocytopenic Purpura (ITP) is an autoimmune disease
that results in low numbers of circulating platelets (1). Destruction
of platelets occurs as a result of autoantibodies attacking the
platelets (1). The mechanism by which production of autoantibodies is
stimulated is unknown (1).
The specificity of the autoantibodies has been linked to a
glycoprotein on the surface of the platelets. For unknown reasons the
glycoproteins become auto-antigenic, thus stimulating the immune
system. Autoantibodies are produced and platelets are destroyed,
primarily by phagocytosis (1).
Studies have determined that the specific glycoproteins that are
auto-antigenic are GPIIb/IIIa and GPIb/IX (1). It has been found that
autoantibodies against one or both of these glycoproteins are present
in 75% of ITP patients (1).
Once the autoantibodies bind to the glycoprotein, platelets are
eliminated from the circulation by either phagocytosis or complement-
nduced lysis. Studies have shown evidence for both these methods of
elimination (2,3).
ITP patients show both low levels of circulating platelets and a
decreased or normal production rate of platelets (4). It would be
expected that low levels of platelets would signal an increase in the
production of platelets. It has been proposed that the autoantibodies
are able to bind to platelet precursors and hence curb production of
platelets. It has been shown that during maturation, megakaryocytes
express GPIIb/GPIIIa and GPIb on their surface (4). Binding of
autoantibodies to megakaryocytes may interfere with their maturation
into platelets or they may destroy the megakaryocytes (4). Destruction
probably occurs in the same way as for mature platelets, by
phagocytosis or complement-induced lysis (4).
There are two forms of Idiopathic Thrombocytopenic Purpura: acute and
chronic.
Acute ITP – occurs predominantly in children (5). In acute ITP, onset
is abrupt and usually follows infection. The type of infection is
commonly viral. The disease is self-limiting with recovery in one or
two months (5). While the child may appear healthy and the condition
not usually severe, there is some cause for concern with the small but
serious risk of cranial hemorrhage (5).
Chronic ITP – In contrast to acute ITP, chronic ITP occurs
predominantly in adults (5). Chronic ITP rarely resolves
spontaneously.
Vaccines linked with ITP
There have been a number of vaccines that have been linked with
causing ITP. These vaccines are discussed below.
Measles-Mumps-Rubella Vaccine (MMR)
ITP is a relatively common childhood disorder with 85% of cases
following viral infection (6). ITP has been shown to follow an acute
infection with measles or rubella as well as after immunisation with
live attenuated measles or rubella viruses (6).
A study in Finland looked at 23 cases of ITP in children following MMR
immunisation (7). It should be kept in mind that this was 23 cases out
of 700,000 immunised children. 22 out of the 23 children recovered
completely within six months (7). In ITP patients that were tested for
anti-platelet immunoglobulin, two thirds were positive which is
consistent with the idea that the vaccine/viruses triggers the
autoimmune response. Complete recovery and minor symptoms indicate
that post-immunisation ITP is not a severe complication. This study
concluded that the MMR vaccination was not unsafe with
regard to ITP due to the relative infrequency of this disease post-immunisation.
Despite the fact that ITP came on quickly, symptoms were mainly
harmless and recovery was complete in six months (7).
Another study also looked at ITP in children and examined these
children's history for recent MMR immunisation (8). This study found
that there was a causal association between MMR and vaccination.
However, the risk was 1 in 24,000 which is relatively low.
Hepatitis B
Several reports have suggested a link between ITP and recombinant
hepatitis B vaccine. One report was a retrospective study of 7 ITP
patients and found that in the three months prior to onset of the
disease all 7 had received one or more injections of recombinant
hepatitis B vaccine (9). In trying to establish a link between the
vaccine and ITP, each patient was examined for other causes of ITP
including pharmalogical, infectious or immune. Despite this, the study
could not rule out the possibility of coincidence in the observation
of ITP after hepatitis B vaccination. This is not entirely unlikely
considering the small number of reports of ITP from a widely used
vaccine (9). The study concluded that an absolute association could
not be determined unless ALL other causes were ruled out which did not
appear to be the case in this study.
Another study looked at cases of ITP in infants under six months of
age after one injection of a recombinant hepatitis B vaccine (10).
However this report looked at only three patients, all of which
recovered. The authors of this article summed it up best when they say
"the complete reversibility of thrombocytopenia in our 3 cases, and in
cases described by others, confirms the benign nature of this
extremely rare complication" (9).
Two letters to the journal Lancet discussed the incidence of ITP
following recombinant hepatitis B vaccination. The first, in 1994,
could only produce 2 cases (11) while the second, in 1995, agreed that
the numbers of ITP patients "should be considered in the light of the
large numbers of vaccination worldwide" (12).
While there are a few reports of ITP following recombinant
hepatitis B vaccination, there are no reports of ITP following
plasma-derived hepatitis B vaccine (9)
Diptheria-Pertussis-Tetanus (DPT)
There is only one report of ITP following DPT vaccination in the
English literature (13). This report only listed two cases and
described adverse reactions to DPT as "benign" (13). Considering the
widespread use of DPT and only two cases of ITP being associated with
it, this vaccine would not be considered unsafe because it causes ITP
Small pox
There is one report of ITP following smallpox vaccination however this
report could also only produce two cases (14). However smallpox
vaccination is rarely used in Australia now and so this has little
relevance to our current day situation.
Postvaccinal Thrombocytopenia: Fact or Myth?
Establishing whether or not there is a link between ITP and certain
vaccines depends largely on the level of passive reporting of such
cases and the ruling out of all other aetiologies. Two journal
articles differ in their opinion of whether current reports of ITP
following vaccination are indicative of the real situation or not. An
article in the Lancet surveyed the histories of children that were
admitted to hospital with different conditions (including ITP) and
looked for recent immunisation (8). They found that the risk of ITP
after MMR was 1 in 24,000 doses (8). However, the previous calculation
was 1 in 130,000
which is a four-fold decrease (8). This latter figure was calculated
as a result of passive reports from doctors. This study concluded that
relying on passive reports was not enough as it gave a low estimation
of the risk involved (8). On the other hand, a letter in Pediatric
Hematology and Oncology points out that many articles
which claim there is a link between MMR and ITP do not show
appropriate documentation on the checks carried out to rule out other
causes (15). The authors of this letter found that two children that
presented with ITP after MMRvaccination were also simultaneously
infected with a parvovirus that
was known to cause thrombocytopenia (15). This article stated that the
association of a short amount of time between vaccination andonset of
disease was not enough to prove a causal link (15).
From the evidence given, it would not be recommended that these
vaccinations be removed from the recommended childhood vaccination
schedule. The risk of developing ITP from these vaccines is very
small, for some even negligible. Also, the mildness of the disease and
complete recover in almost all the cases presented is further proof
that these vaccines should remain in the schedule. The benefits most
certainly out way the risks.
(yeah right.......)
Back to page
