Idiopathic Thrombocytopenic Purpura in Adults
Drew Provan, MD, FRCP, FRCPath, and Adrian Newland, MA, FRCP, FRCPath
Summary: Immune thrombocytopenic purpura (ITP) is an organ-
specific autoimmune disorder in which platelets opsonized by anti-
platelet antibodies are destroyed by the reticuloendothelial system.
As a result the peripheral blood platelet count is low; if sufficiently
severe, it may lead to bruising and mucocutaneous bleeding. The dis-
order may occur in adults and in children; in the former the disease
affects primarily females, whereas the childhood type affects the
sexes equally. For most individuals the disorder is minor, requiring
little treatment, but patients with more severe forms of the disease
require therapy to elevate the platelet count to a safe level to prevent
serious bleeding. Therapies include corticosteroids, intravenous im-
munoglobulin, splenectomy, and immunosuppressive agents. Be-
cause there have been few trials in ITP, there is little evidence to guide
treatment, and all the treatments may have adverse effects in terms of
morbidity and mortality. The American Society of Hematology and
British Committee for Standards in Haematology guidelines provide
a framework for management but nonetheless are based on little evi-
dence. In this paper the authors review the management of ITP in
adults, children, and pregnant women and highlight some of the novel
therapies being explored in this disorder, in addition to some of the
ongoing laboratory research exploring the mechanisms underlying
the disease.
Key Words: immune thrombocytopenic purpura, therapy, diagnosis,
adults, pregnancy
(J Pediatr Hematol Oncol 2003;25:S34–S38)
I diopathic thrombocytopenic purpura (ITP) is an autoim-
mune disorder in which there is a reduced platelet count
(<150 × 109/L) due to autoantibody or immune complexes
binding to platelet surface antigen(s). This leads to premature
platelet destruction by the reticuloendothelial system and in
particular the spleen.1,2
The existence of the immune character of ITP has been
known for many years.3 It is clear from the literature that both
the investigation and management of patients with ITP vary
widely and are seldom evidence-based. This is largely because
Received for publication July 3, 2003; accepted July 14, 2003.
From the Department of Haematology, Bart’s and the London School of Medi-
cine and Dentistry, Queen Mary, University of London, London, United
Kingdom.
Reprints: Drew Provan, Department of Haematology, Barts and the London
School of Medicine and Dentistry, Whitechapel Road, London E1 1BB,
U.K. (e-mail: a.b.provan@qmul.ac.uk).
Copyright © 2003 by Lippincott Williams & Wilkins
S34 J Pediatr Hematol Oncol • Volume 25, Supplement 1, December 2003
there has been a lack of clinical trials in this disorder. In keep-
ing with the American Society of Hematology (ASH) guide-
lines, treatment regimens are based largely on expert opinion.4
This is true also for the recently published British Society for
Hematology/British Committee for Standards in Hematology
U.K. ITP guidelines.5 The diagnosis of ITP remains clinical
and one of exclusion. No clinical or laboratory parameters can
establish the diagnosis of ITP with accuracy. There is also a
lack of natural history data, although this is being addressed by
various studies.6–8
Here we briefly review the nature of adult ITP before
discussing treatment options for adults and pregnant women,
based largely on the U.K. ITP guidelines.5
DIAGNOSTIC APPROACH
Adult chronic ITP has an incidence of 58 to 66 new cases
per million population per year (5.8–6.6 per 100,000) in the
United States,9 with a similar incidence in the United King-
dom. Chronic ITP affects predominantly women in the child-
bearing years, with a female-to-male ratio of 3:1.10 Adult ITP
differs from the typically acute form of ITP that occurs in
childhood. In adults, ITP usually has a subtle onset, with no
prodromal illness. Symptoms and signs are variable, ranging
from the common asymptomatic patient with mild bruising or
mucosal bleeding to florid hemorrhage, the most serious of
which is intracranial. Most serious bleeding occurs in patients
with platelet counts below 10 × 109/L, but even most of these
patients suffer little serious bleeding.11
An important component of patient management is ac-
curate diagnosis, ensuring that the patient has idiopathic rather
than a secondary form of ITP. For this reason a full history
must be obtained before examining the patient. In the history
one should ask about the type of bleeding, attempting to dis-
tinguish platelet-type mucocutaneous bleeding from coagula-
tion-type bleeding and assessing the severity, extent, and du-
ration of bleeding. Is there a history of bleeding with previous
surgery, dentistry, or trauma? The history should be used to
determine the presence of other medical disorders that may
give rise to thrombocytopenia, recent transfusion, a history of
excess alcohol consumption, or a family history of thrombo-
cytopenia. Drug ingestion may give to rise to bleeding and/or
thrombocytopenia, as may HIV infection, other autoimmune
disorders, and malignancy (e.g., lymphoid neoplasms). The
examination should be used to assess the type, severity, and
extent of bleeding and to exclude conditions that might cause
J Pediatr Hematol Oncol • Volume 25, Supplement 1, December 2003 ITP in Adults

nonimmune thrombocytopenia (e.g., severe infection, TTP). TABLE 1. Recommendation for “Safe” Platelet Counts
The presence of splenomegaly should be noted; if present it in Adults
probably indicates a diagnosis other than ITP, since ITP is not
typically associated with splenic enlargement. Dentistry (fillings) ⱖ10 × 109/L
Extractions ⱖ30 × 109/L
LABORATORY INVESTIGATIONS Regional dental block ⱖ30 × 109/L
These are kept fairly simple and comprise a repeat com- Minor surgery ⱖ50 × 109/L
plete blood count (CBC) to confirm the thrombocytopenia Major surgery ⱖ80 × 109/L
and a blood film examination looking for pseudo-thrombo- Obstetrics See text
cytopenia (EDTA-dependent platelet agglutination).12 The Evidence level IV
blood film may also determine the presence of myelodyspla-
sia, other hematologic malignancies, and red cell fragmenta-
tion syndromes.
Other investigations add little to the diagnosis of ITP. In Pooled normal human immunoglobulin is effective in 75% of
particular, assays for antiplatelet antibodies are expensive and patients, but the responses are transient and 3 to 4 weeks fol-
do not alter management. For this reason they should not be lowing IVIG treatment platelet counts drift back to pretreat-
part of the standard ITP workup. Bone marrow aspiration is ment levels,4,17 with little evidence of a lasting effect. The
contentious, but we agree with the ASH panel4 that a bone mechanism of action of IVIG is believed to involve blockade
marrow aspiration is unnecessary in typical ITP but should be of reticuloendothelial Fc receptors and other effectors of anti-
done if the patient is older than 60 years, has atypical features, body-dependent cytotoxicity.18 In addition there are anti-
or has a poor response to first-line therapy, or if splenectomy is idiotype antibodies in IVIG that block autoantibody binding to
being considered.5,13 circulating platelets and immune suppression.19,20

MANAGEMENT Second-Line Therapy

The requirement for treatment varies from patient to pa- Methylprednisolone is a useful second-line treatment,
tient and is dictated by factors such as clinical status (asymp- especially when the platelet count must be elevated quickly, in
tomatic, bruising, bleeding, or planned intervention likely to combination with intravenous cyclophosphamide and/or IVIG
induce bleeding in a patient with ITP who is thrombocytope-
nic). Severe bleeding is a major concern in thrombocytopenic
patients, but recent data from several case series show that the TABLE 2. Therapies for Adults with ITP
rate of fatal hemorrhage is 0.0162 to 0.0389 cases per patient-
year at risk (the time at risk is defined as the time when the Standard treatment Oral corticosteroids (e.g.,
prednis(ol)one)
platelet count is <30 × 109/L).7 In their recent review Portielje IVIG
et al6 found that more than half the patients died of infection Splenectomy
caused by immunosuppressive therapy rather than from bleed- Refractory disease Oral dexamethasone
ing. These findings tend to favor a policy of using therapy only Danazol
when required, thus minimizing the risks of infection through Dapsone
immunosuppression and reserving treatment for those who ac- Combination chemotherapy
Cyclosporin A
tually require it. Azathioprine
One of the most common concerns is whether a patient’s
Faster acting (e.g., for rapid
platelet count is “safe” enough for him or her to undergo spe- elevation of platelet count)
cific procedures. After reviewing the literature we attempted to Anti-D
design a list of “safe” platelet counts that we hope will be use- IV methylprednisolone
ful to clinicians, but an audit of the U.K. guidelines will be High-dose IVIg
Vinca alkaloids
required to determine whether these figures are clinically use-
IV cyclophosphamide
ful (Table 1).
Experimental therapies Rituximab
Campath-1H
First-Line Therapy Mycophenolate mofetil
There are no large randomized studies comparing no Anti-CD40 ligand
treatment versus therapy with corticosteroids or IVIG (Table Not recommended Protein A columns
2). There is usually no indication for therapy in adults who IFN␣
Autologous stem cell
have no symptoms or signs, or in whom the platelet count is
transplantation
greater than 30 × 109/L (grade C recommendation; Table 3).14–16

© 2003 Lippincott Williams & Wilkins S35

Provan and Newland J Pediatr Hematol Oncol • Volume 25, Supplement 1, December 2003

TABLE 3. Classification of Grades of Recommendations with ITP who undergo splenectomy will achieve a normal
platelet count, which is often lasting. Even patients who do not
A Requires at least one randomized Evidence levels Ia, Ib have a complete response can still expect some improvement
controlled trial as part of a in platelet counts.4
body of literature of overall
good quality and consistency A number of predictive variables indicating a likely re-
addressing specific sponse to splenectomy have been assessed, such as response to
recommendation oral steroids or to high-dose IVIG.21,22 Indium-labeled autolo-
B Requires the availability of Evidence levels IIa, gous platelet scanning appears to be the most sensitive predic-
well-conducted clinical studies IIb, III tor of response to splenectomy to date.23 Najean et al showed
but no randomized clinical in 528 patients that when platelet destruction is splenic, 96% of
trials on the topic of
recommendation patients ages 5 to 30 and 91% of those older than 30 can expect
C Requires evidence obtained from Evidence level IV to obtain a remission; if platelet destruction is hepatic or mixed
expert committee reports or splenic and hepatic, 92% of patients failed to normalize their
opinions and/or clinical platelet counts or had incomplete responses to splenectomy.23
experiences of respected Indium scanning is therefore worthwhile if the facilities are
authorities. Indicates an available.
absence of directly applicable
clinical studies of good quality
Failure of First- and Second-Line Therapies
Campath-1H24 and rituximab25 may be of value in pa-
tients who have no response to other therapies but need to in-
crease their platelet count (e.g., active bleeding). Mycopheno-
(evidence level IIa; Table 4). Because of the relatively frequent late mofetil appears to be effective in some patients with severe
incidence of accessory splenic tissue, this should be sought in refractory ITP, but larger studies are required to confirm its
those failing to respond to splenectomy, although removal sel- efficacy and safety.26 In terms of the risk/benefit ratio, we
dom has any major benefit. Agents such as high-dose IVIG, would not recommend treatment with interferon-␣, protein A
vinca alkaloids, anti-D, danazol, azathioprine, and cyclosporin columns, plasmapheresis, or liposomal doxorubicin.5
are worth considering in nonurgent or “semi-urgent” cases
where the platelet count needs to be elevated. Emergency Treatment
Splenectomy has been shown to be an effective mode of For rapid elevation of the platelet count in emergencies,
treatment in ITP.1,19 The procedure is not “curative” since transfusion of random donor platelets is appropriate. When a
platelet opsonization still occurs, but the lifespan of antibody- higher platelet count is required but there is less urgency, IVIG
coated platelets is longer since there is less destruction of the and/or intravenous methylprednisolone and/or intravenous cy-
platelets by splenic macrophages. Around 66% of patients clophosphamide may be useful (evidence level IV).

Suspected ITP in Pregnancy

TABLE 4. Classification of Evidence Levels
Ia Evidence obtained from meta-analysis of randomized
controlled trials
Ib Evidence obtained from at least one randomized
controlled trial
IIa Evidence obtained from at least one well-designed
controlled study without randomization
IIb Evidence obtained from at least one other type of
well-designed quasi-experimental study*
III Evidence obtained from well-designed nonexperimental
descriptive studies, such as comparative studies,
correlated studies, and case studies
IV Evidence obtained from expert committee reports or
opinions and/or clinical experience of respected
authorities
*Refers to a situation in which implementation of an intervention is out-
side the control of the investigators, but an opportunity exists to evaluate its
effect.
As in nonpregnant patients, the diagnosis of ITP is one of
exclusion. Benign gestational thrombocytopenia is 100 times
more common, but because there are no definitive diagnostic
tests, it may be impossible to distinguish these conditions until
a nonpregnant platelet count is available.27 All women with
platelet counts below 100 × 109/L should be screened for clini-
cal or laboratory evidence of preeclampsia, coagulopathy, or
autoimmune disease.
Asymptomatic women with platelet counts above 20 ×
109/L do not need treatment until delivery is imminent.28
Platelet counts above 50 × 109/L are safe for normal vaginal
delivery in patients with otherwise normal coagulation.28
Platelet counts above 80 × 109/l are safe for cesarean section
and spinal or epidural anesthesia in patients with otherwise
normal coagulation. In women who need treatment, both oral
corticosteroids27,28 and IVIG27 appear to have a similar re-
sponse rate to the use of these agents in nonpregnant patients.
The decision must take into account maternal clinical factors

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J Pediatr Hematol Oncol • Volume 25, Supplement 1, December 2003
and preference in addition to the expense, availability, and (re-
mote) risks of microbial transmission by IVIG. There are no
convincing data on the effect (beneficial or otherwise) of cor-
ticosteroids or IVIG on the fetal/neonatal platelet count (all
grade C evidence). Severe refractory ITP may respond to high-
dose IV methylprednisolone with or without IVIG or azathio-
prine. If essential, splenectomy may be performed (ideally in
the second trimester); the laparoscopic route may have clinical
advantages similar to those seen in nonpregnant patients.
The mode of delivery in women with ITP should be de-
cided by primarily obstetric indications.27–29 There is no evi-
dence to support the routine use of cesarean section (grade B
evidence). Women undergoing operative delivery should be
considered for thromboprophylaxis according to their indi-
vidual clinical risk factors. Standard prophylactic doses of
UFH or LMW heparin should be used if the maternal platelet
count is above 100 × 109/l (grade C evidence).
The risk of clinically dangerous thrombocytopenia in the
neonate is very low but cannot be predicted by clinical or labo-
ratory parameters in the mother.27,28,30–32 Attempts to measure
the fetal platelet count by cordocentesis or fetal scalp blood
sampling are not recommended as they carry more risks than
potential clinical benefits (grade B evidence). Because of the
risk of hemorrhagic complications in the neonate, the applica-
tion of scalp electrodes for monitoring in labor and fetal blood
sampling should be avoided. The use of vacuum extraction is
contraindicated, and complicated instrumental delivery (e.g.,
rotational forceps) should be avoided if possible (grade C evi-
dence).
Cord platelet counts should be measured in all neonates
of mothers with ITP, and those with subnormal levels should
be monitored clinically and with daily counts until after the
nadir, which usually occurs on day 2 to 5 after delivery (grade
C evidence).27 Treatment of the thrombocytopenic neonate
should be reserved for those with clinical evidence of hemor-
rhage or a platelet count below 20 × 109/L, when there is usu-
ally a prompt response to IVIG (1 g/kg). Life-threatening hem-
orrhage should be treated with immediate platelet transfusion
and IVIG (grade C evidence).
ONGOING RESEARCH
Although we have much greater understanding of the
immune system in health and disease, the cause of autoim-
mune disease is largely unknown. Genetic studies carried out
in a variety of autoimmune disorders point to possible linkage
between single nucleotide polymorphisms (SniPs) and up- or
downregulation of cytokines or their receptors.33 A number of
studies have shown an association between the presence of cy-
tokine polymorphisms and development of autoimmune dis-
eases. These include multiple sclerosis,34 Graves’ disease,35
insulin-dependent diabetes mellitus,36 systemic lupus erythe-
matosus,37 rheumatoid arthritis,38 and many others. Cytokine
protein levels have been shown to be abnormal in ITP, but to
© 2003 Lippincott Williams & Wilkins
ITP in Adults
date this has not been correlated with genetic polymorphisms
within the genes themselves. We are examining cytokine poly-
morphisms in adults with ITP and trying to determine whether
we can link specific polymorphisms with disease chronicity,
response to splenectomy or IVIG, and overall outcome (good-
or bad-prognosis disease). Data at present are limited, and our
findings suggest there is little correlation between ITP subtype
and HLA,39 but there does appear to be an association with the
polymorphism within the IL-6 promoter region.40 Larger num-
bers of patients are being studied, and the results will be pub-
lished in due course.
CONCLUSIONS
ITP is a disorder in which self-reacting antibodies cause
premature platelet destruction. The diagnosis remains clinical
and requires few investigations in “typical” cases. Treatment
should be reserved for those requiring it and should not be dic-
tated solely by the platelet count. Studies show that there is
major morbidity and mortality associated with treatment, so
inappropriate treatment should be avoided. Standard therapies
are moderately effective, but studies are required to assess op-
timal treatment with conventional drugs and novel agents that
may offer lower toxicity. In addition, newer therapies may be
more targeted in their actions. It is hoped that genetic studies
might enable therapies to be tailored to each patient’s needs
and may help explain the underlying cause of ITP.
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