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2005 106: 2244-2251

Prepublished online June 7, 2005;
doi:10.1182/blood-2004-12-4598

How I treat idiopathic thrombocytopenic purpura (ITP)

Douglas B. Cines and James B. Bussel

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How I treat

How I treat idiopathic thrombocytopenic purpura (ITP)

Douglas B. Cines and James B. Bussel

Introduction
Our goal is to set forth our opinion of the best approach to
managing adults with primary idiopathic (autoimmune) thrombocytopenic purpura (ITP), with emphasis on the word opinion. The
paucity of evidence-based medicine on this topic has been noted.1
Both the American Society of Hematology2 and the British
Committee for Standards in Haematology General Haematology
Task Force3 have issued practice guidelines. These, in large part,
proved to be compendia of opinions from panels of experienced
physicians who concurred on some matters but not on others. We
cite published evidence where we find it compelling and reproducible, but much of what follows rests on our mutual experience
treating patients, both on- and off-study, rather than an encyclopedic, heavily referenced review. Many issues remain unresolved,
expert opinions differ for good reason, and it is likely that our own
approach will change based on emerging data. Comprehensive
reviews on pathogenesis, laboratory testing, secondary ITP, ITP in
children, and treatment are to be found elsewhere.4,5

Who develops ITP?

Until recently, experience from numerous centers over more than a
half-century indicated that the typical adult with ITP is a woman,
generally between 18 and 40 years of age.6 Gender disparity largely
disappears among the elderly.6,7 Two recent publications have questioned this perception. The first was a survey from a single county in
Denmark using International Classification of Disease (ICD) codes at
hospital discharge over a 22-year period. The female-male ratio
was 1.7, the median age at diagnosis was 56 years, and the
incidence of ITP increased with age and increased overall during
the period of study.8 The second was a prospective cohort analysis
of newly presenting adults with platelet counts less than 50 000 109/L
in the Northern Health Region of the United Kingdom. The female-male
ratio was 1.2 and, again, the age-specific incidence was highest among
those older than 60 years.9 Presenting symptoms, severity of
thrombocytopenia, and response to therapy were typical for ITP, so
these data do not simply reflect increased detection of mild cases
based on automated platelet determinations,10 misdiagnosed myelodysplasia (MDS),11 or drug-dependent antibodies.

How we diagnose ITP

ITP remains a diagnosis of exclusion. The essential elements
include an otherwise healthy individual who presents with isolated

From the Departments of Pathology and Laboratory Medicine and Medicine,

University of Pennsylvania School of Medicine, Philadelphia, PA, and
Departments of Pediatrics, Medicine, and Obstetrics and Gynecology, New
York Presbyterian Hospital, Weill Cornell Medical Center, New York, NY.
Submitted December 8, 2004; accepted April 14, 2005. Prepublished online as
Blood First Edition Paper, June 7, 2005; DOI 10.1182/blood-2004-12-4598.
Reprints: Douglas Cines, Departments of Pathology and Laboratory Medicine

2244

thrombocytopenia, an otherwise unremarkable peripheral smear, a

physical examination that only shows evidence of bleeding consistent with the platelet count, and the exclusion of other causes of
thrombocytopenia if grounds for suspicion exist. These include
exposure to drugs, herbs, foods, or other substances (eg, quinine)
associated with thrombocytopenia; pseudothrombocytopenia; giant
platelets; family history consistent with inherited thrombocytopenia; or symptoms/signs suggestive of an underlying disorder that
may cause secondary immune thrombocytopenia. We only perform
bone marrow examinations as a matter of routine in otherwise
typical patients if they are over 60 years of age when the incidence
of MDS becomes significant, in those who do not show a robust
response ( 50 000 109/L) to treatment, and often prior to
splenectomy if not previously performed. Response to treatment,
especially intravenous immune globulin (IVIG) or intravenous
anti-D (IV anti-D), even if transient, is the single best diagnostic
test. Conversely, a poor response to treatment may necessitate
re-evaluation of the diagnosis, including a bone marrow
examination.
Testing for HIV or hepatitis C infection (or both) is indicated in
at-risk populations and the latter may occur more widely than
previously appreciated.12 Remissions induced by eradication of
asymptomatic Haemophilus pylori infection have been reported in
studies from Italy and Japan,13,14 but is not our experience.15 We
neither perform the more sensitive breath testing nor treat empirically at presentation, but consider testing in chronic cases and those
with gastrointestinal symptoms. Approximately 1% of patients
have coexisting immune hemolytic anemia (Evans syndrome) and
a smaller percentage have immune neutropenia, which confer a less
favorable prognosis. Immunoglobulin levels are measured if there
is a history of recurrent infection or allergy, if there is a reaction to
IVIG or prior transfusions, or if there is a concern about common
variable immunodeficiency or IgA deficiency. Clonality and cytogenetics are assessed as part of the bone marrow evaluation.
Disturbances in thyroid function occur with sufficient frequency
that we often measure thyroid-stimulating hormone levels if there
are complaints of persistent fatigue and prior to splenectomy. We
test for antiphospholipid antibodies if there is a history thrombosis,
recurrent or second- or third-trimester gestational failure, or a
prolonged activated partial thromboplastin time.10,16 Up to 5% to
10% of patients eventually meet criteria for systemic lupus
erythematosus or another cause of secondary immune thrombocytopenia.17 Our approach to secondary immune thrombocytopenia,

and Medicine, University of Pennsylvania School of Medicine, 513A

Stellar-Chance, 422 Curie Blvd, Philadelphia, PA 19104; e-mail: dcines@
mail.med.upenn.edu; or James B. Bussel, Departments of Pediatrics,
Medicine, and Obstetrics and Gynecology, New York Presbyterian Hospital,
Weill Cornell Medical Center, 525 E 68th St, Payson 695, New York, NY 10021;
e-mail: jbussel@med.cornell.edu.
2005 by The American Society of Hematology

BLOOD, 1 OCTOBER 2005 VOLUME 106, NUMBER 7

From bloodjournal.hematologylibrary.org by guest on September 1, 2012. For personal use only.

BLOOD, 1 OCTOBER 2005 VOLUME 106, NUMBER 7

including systemic lupus erythematosus, antiphospholipid syndrome, B-cell malignancies (primarily chronic lymphocytic and
large granular leukemias), and HIV infection, among others, has
been reviewed elsewhere.4
We do not rely on measuring antiplatelet antibodies to make or
exclude a diagnosis of ITP. Although some argue that current
methods to detect platelet antigen-specific antibodies are now
sufficiently specific to affirm the diagnosis, antibodies have also
been detected in 10% to 20% of patients with certain causes of
nonimmune thrombocytopenias (eg, chronic liver disease, MDS),
the populations in which testing would be most helpful. These
assays lack sufficient sensitivity to exclude a diagnosis of ITP18-20
and interlaboratory reproducibility is inadequate.21

ITP

2245

events such as viral infection or head trauma, or after inadvertently

taking medications that impair platelet function.27 We would argue
that the goal of therapy must be individualized on the basis of signs
and symptoms, tolerance of treatment, lifestyle, and patient preference. Our usual practice is to maintain a somewhat higher platelet
count initially (eg, 30 000 109/L) while we get to know the
patient, with the goal of establishing a track record of bleeding,
compliance, and risk management that allows us to modify the
threshold for treatment over time.

Treatment at presentation
Principles of management

Who we treat
What is a hemostatic platelet count? Is the platelet count a
reasonable surrogate marker for the risk of serious bleeding? In a
recent 10-year study of 310 patients in whom treatment was
generally used only at platelet counts less than 30 000 109/L,
only one hemorrhagic death occurred.22 In a meta-analysis of 17
studies, the age-adjusted risk of fatal hemorrhage at platelet counts
persistently less than 30 000 109/L was estimated to be 0.4%,
1.2%, and 13% per patient per year for those younger than 40, 40 to
60, and older than 60 years of age, respectively. Predicted 5-year
mortality ranged from 2.2% to 47.8%.23 Similar mortality rates
have been reported by others depending on duration of followup.24-26 Major bleeding, including spontaneous intracerebral hemorrhage (ICH), occurs predominantly in patients with platelet counts
less than 20 000 109/L, generally less than 10 000 109/L.24,27
Thus, a compelling case can be made to treat patients with platelet
counts below 20 000 109/L. Some experts would apply this
reasoning to recommendations for splenectomy,28 although we use
a higher threshold (see Splenectomy).
What is more contentious and requires individualization and
considerable judgment is the wisdom of treating patients with
platelet counts between 20 000 and 50 000 109/L. Although few
otherwise healthy, sedentary individuals die of hemorrhage over a
10-year period if they maintain a stable platelet count more than
20 000 109/L and though we rarely treat patients with platelet
counts more than 30 000 109/L in the absence of extenuating
circumstances that predispose to serious bleeding, no published
follow-up is of sufficient length or size to project risk over a life
span. Our opinion is that it is as unreasonable to apply a one-size
fits all threshold as it would be to attempt to normalize platelet
counts in all patients. Is 20 000 to 30 000 109/L a safe and
appropriate platelet count for the 63-year-old man with angina who
then suddenly requires clopidogrel and aspirin after a coronary
stent is placed? What about the high school student able to afford
college only if awarded a football scholarship, the policeman who
routinely faces physical confrontation, the 28 year-old hard-hat
construction worker, the 19-year-old woman with marked menorrhagia unresponsive to hormonal management, the 26-year-old
who feels completely drained of energy unless her platelet count
approaches 50 000 109/L, or even the extensive traveler. There is
room for disagreement in each of these cases, but they illustrate the types
of issues confronted in real practice.
Although rare, major bleeding has been reported at platelet
counts between 20 000 and 30 000 109/L. Furthermore, counts
may drop suddenly at any time.24 A worrisome number of patients
who developed ICH did so after acute and often unpredictable

Patients typically present with petechiae or purpura that develop

over several days accompanied by platelet counts less than
20 000 109/L, although the onset is often more insidious than
previously appreciated.10 Severe cutaneous bleeding, prolonged
epistaxis, gingival bleeding, overt hematuria, or menorrhagia may
develop at platelet counts less than 10 000 109/L. Spontaneous
or posttraumatic ICH or bleeding at other internal sites is uncommon, but not without precedence,24 at platelet counts between
10 000 and 20 000 109/L. Those with platelet counts between
30 000 and 50 000 109/L may note easy bruising, whereas
platelet counts above 50 000 109/L are usually discovered incidentally. Rarely, do patients present with bleeding disproportionate
to the platelet count because of antibody-induced platelet dysfunction.29 Some patients experience untoward and otherwise unexplained fatigue when their platelet count is low.
Management is predicated primarily on the severity of thrombocytopenia and bleeding. Drugs that interfere with platelet function
are discontinued. Alternatives are substituted for drugs deemed
necessary but potentially causal. The initial goal of treatment is to
attain a hemostatic platelet count ( 30 000 109/L) while minimizing the toxicity of treatment. Figure 1 shows our treatment
algorithm for initial management. The reader is referred elsewhere
for a more comprehensive tabulation of drug doses, expected
response times, and common side effects.30 Therapy is indicated in
all patients who present with bleeding and those with platelet
counts less than 20 000 109/L because fewer than 10% of adults
rapidly attain spontaneous remission. Those with platelet counts
more than 50 000 109/L can almost always be observed, although some (5 of 87 in one series7) require treatment later. In
general, immediate therapy is not required for patients with platelet
counts between 20 000 and 50 000 109/L in the absence of
bleeding or predisposing comorbid conditions such as uncontrolled
hypertension, active peptic ulcer disease, anticoagulation, recent
surgery, or head trauma.2,3 We recommend maintaining platelet
counts above 40 000 to 50 000 109/L for patients requiring
aspirin, nonsteroidal anti-inflammatory drugs, warfarin, or other
antithrombotics.
Hospitalization and emergency therapy

We hospitalize (1) patients with profound mucocutaneous or

internal bleeding and (2) those who present with platelet counts of
less than 20 000 109/L and a history of significant bleeding,
those in whom there is a question about compliance, and in some
cases, those in whom responsiveness to therapy has not been
establishedfor example, when comorbid factors predisposing to
bleeding or complications of therapy are present. All others can be

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2246

BLOOD, 1 OCTOBER 2005 VOLUME 106, NUMBER 7

CINES and BUSSEL

occasion, desmopressin acetate (DDAVP; 0.3 g/kg). We use

-aminocaproic acid or tranexamic acid swish and swallow to help
control oral bleeding, topical thrombin, collagen, and fibrin glue to
manage dental extractions, and progestational agents to manage
menorrhagia.
Initial therapy for nonemergent indications

Figure 1. Therapy of adult ITP before splenectomy. (1) Minimal emergent therapy
includes IV methylprednisolone and IVIG. IV anti-D and platelet transfusions may be
given as needed; repeated or continuous platelet transfusions may be required in
urgent situations; all 3 modalities given prior to transfusions may help preserve their
longevity in the circulation. (2) We generally initiate therapy with prednisone and add
either IV anti-D (in Rh, direct antiglobulin-negative patients) or IVIG as needed for
persistent severe thrombocytopenia with the goal of attaining a platelet count of
greater than 30 000 109/L and cessation of bleeding. Details of therapy and
duration of treatment are discussed in text. (3) Thrombocytopenia recurs in most
adults as corticosteroids are tapered. The treatment modality depends on the severity
of the thrombocytopenia and bleeding, tolerance of treatment, and patient preference
as discussed in Initial therapy for nonemergent indications. We would generally
treat for a minimum of 3 months and a maximum of 12 months, barring evidence of
late improvement, before considering splenectomy. (4) We recommend splenectomy
for those clearly requiring therapy beyond 12 months to maintain a hemostatic
platelet count and sooner in select individuals intolerant of therapy, with active
lifestyles or comorbid risk factors that make higher platelet counts desirable. po
indicates orally; prn, as needed; and q, every.

treated as outpatients. Urgent treatment is initiated with intravenous methylprednisolone (1.0 g/d for 1-3 consecutive days)
combined with IVIG (Figure 1). Before splenectomy in Rh
patients, we have combined IVIG and IV anti-D, which act through
different IgG-Fc receptors,34-36,63 with vincristine and methylprednisolone,37 and platelet transfusions (bolus followed by continuous
infusion as needed) for life- or organ-threatening bleeding or after
head trauma.38 Recombinant factor VIIa may be added in patients
unresponsive to other modalities if an immediate response is
necessary, such as with ICH.39 IVIG is generally well tolerated
other than for a postinfusion headache. Rarely, patients develop
aseptic meningitis, acute renal failure, pulmonary insufficiency,
thrombosis, or hemolysis; dissolving lyophilized preparations in
sterile water to lower osmolarity and slowing the infusion rate may
lessen these risks. Common toxicities of IV anti-D include
fever/chill reactions, which can be ameliorated by pretreatment
with corticosteroids, and extravascular hemolysis; intravascular
hemolysis and disseminated intravascular coordination are rare33,91
and the risk is lessened by avoiding treatment in those with a
positive direct antiglobulin test unless attributable to prior IVIG or
IV anti-D therapy. We also initiate general measures to reduce the
risk of bleeding, including cessation of drugs that impair platelet
function, control of blood pressure, measures to minimize trauma,
and measures to reduce mucosal bleeding, such as -aminocaproic
acid (100 mg/kg loading dose up to a maximum of 5 g given
intravenously over 30-60 minutes followed by up to 5 g every 6
hours intravenously or orally [maximum dose 24 g/day]) and, on

We treat most patients with prednisone (1.0 mg/kg/day) orally as

the initial approach. IV anti-D can be substituted for prednisone in
Rh and direct antiglobulin-negative patients intolerant of corticosteroids or who have contraindications to their use.40,41 Therapy
with prednisone can be supplemented with IVIG (1.0 g/kg/d for 1-2
days), IV anti-D (50-75 g/kg), or IV methylprednisolone (1 g) if
platelet counts remain below 20 000 109/L or if there is another
need for a more rapid response. Rapid lasting responses to
dexamethasone (40 mg orally daily for 4 d/mo) are reported,
although the assertion that this approach increases long-term
response compared with prednisone42 requires longer follow-up
and confirmation. Proton pump inhibitors should be given when
corticosteroids are used for more than a few weeks. We have used
aspirin in patients at risk for thrombosis (even in the absence of
antiphospholipid antibody) whose platelet counts increase rapidly
to more than 600 000 109/L.16
There is no consensus concerning the optimal duration of corticosteroid treatment. Our practice is to continue full doses for 3 to 4 weeks,
until a response is seen or side effects become intolerable.
Response rates vary from 50% to 90% depending on intensity and
duration of therapy, but only 10% to 30% of patients enter stable
remission once therapy is tapered or stopped1,7,25,41,43-46; even those
who enter remission often require additional or alternative therapy,
at least initially.47 We taper prednisone slowly, especially once
doses of 10 mg/d are reached, to avoid adrenal insufficiency.
Failure to respond to prednisone, IV anti-D, and/or IVIG should
prompt the diagnosis to be reconsidered and a bone marrow
evaluation, including cytogenetics and flow cytometry, to be performed.
Persistent ITP

Thrombocytopenia recurs in most patients when corticosteroids are

tapered. We treat patients with persistent ITP with the goal of
maintaining the platelet count more than 20 000 to 30 000 109/L
while avoiding steroid-induced osteoporosis, cataracts, and other
toxicities. The major decision is whether to temporize with medical
therapy or to proceed swiftly to splenectomy. For those in whom
the former is chosen, our preference is to infuse IV anti-D as
needed. In the largest series to date, 25% to 30% of patients showed
responses lasting longer than 1 year.47 Alternatives, including
anti-CD20 (rituximab) or danazol are discussed (see First-line
therapy and Second-line therapy, respectively). For those whose
disease does not abate by 1 year after diagnosis, who do not show a
durable response, or who are intolerant of therapy, we recommend
splenectomy.
Splenectomy

Splenectomy remains the single best option to convert a patient

with ITP into a nonpatient, that is, one who is unlikely to need
frequent monitoring or intervention, and it minimizes interference
with a normal lifestyle. The timing of the procedure depends on

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BLOOD, 1 OCTOBER 2005 VOLUME 106, NUMBER 7

disease severity, responsiveness and side effects of therapy, risk of

trauma and of the procedure, and patient and doctor preference. If
the patient does not wish to temporize, we recommend splenectomy within 3 to 6 months if any therapy (eg, more than 10 mg
prednisone/d) is required to maintain a platelet count greater than
30 000 109/L. In contrast, some experts recommend a far more
protracted period of watchful waiting, with splenectomy reserved
for those with a platelet count consistently less than 20 000
109/L or in the face of difficult-to-control bleeding.28 Although we
might concur with this approach in, for example, a 75-year-old
asymptomatic patient with a platelet count of 18 000 109/L, a
life expectancy of 8 to 12 years, and significant risks from surgery,
we think the benefits of splenectomy outweigh the risks in the
typical active young adult with easy bruising or significant
menorrhagia, a platelet count of 20 000 to 30 000 109/L, and a
life expectancy of 50 to 60 years whose disease shows no signs of
abating. However, long-term effects of the procedure on the
incidence of occlusive cerebrovascular disease remain under study.
Thus, the decision must be individualized, and patients are
increasingly reluctant to have a healthy organ removed unless they
have experienced significant bleeding or morbidity from prior
therapy. Such preferences must be respected. This trend has been
accelerated by evidence that IV anti-D and anti-CD20 may allow
splenectomy to be deferred and possibly avoided.41,47
We use IVIG, IV anti-D, or pulse doses of corticosteroids in
known responders to boost the platelet count prior to splenectomy.
Although splenectomy has been performed safely at exceedingly
low platelet counts, nonresponders may experience bleeding problems after the procedure. Prophylactic platelet transfusions are
rarely warranted and their routine use should be discouraged.
Approximately 85% of patients attain a hemostatic response after
splenectomy and two thirds achieve a durable response (for
reviews, see Kojouri et al48 and Schwartz et al49). Our experience is
consistent with the reported incidence of relapse of 15% to 25%
within 10 years.7,25 In general, responses cannot be predicted
through routinely available measures.48 However, we have
found that patients totally refractory to multiple prior treatments
appear to fare less well, as do the elderly,50 patients with
secondary forms of ITP,51 and perhaps those with an hepatic
platelet sequestration pattern,25,52 although we have no direct
experience on the latter. Mortality rates for open and laparoscopic splenectomy are 1.0% and 0.2%, respectively.48 The
outcomes of the 2 approaches are comparable,53 although the
former hastens recovery and offers better cosmesis. We reserve
splenic irradiation for the rare patient in whom splenectomy is
indicated but hazardous or as a diagnostic test.54
The major known long-term risk of splenectomy is overwhelming bacterial sepsis, which occurs in less than 1% of adults with
uncomplicated ITP.55 We immunize our patients with polyvalent
pneumoccocal, H influenzae type b, and quadrivalent meningococcal polysaccharide vaccines at least 2 weeks prior to splenectomy if
possible,56,57 although our experience is that most patients respond
to vaccination given more than 6 weeks after surgery. We do not
recommend lifelong use of phenoyxmethylpenicillin (250-500 mg
orally twice daily) or erythromycin (500 mg orally twice daily) in
otherwise healthy adults, in contrast to others.3 Revaccination for
pneumococcus is recommended every 5 to 10 years. We suggest
patients wear a MedAlert bracelet. All febrile illnesses demand
careful evaluation and intravenous antibiotics should be provided
urgently at the onset of any systemic illness with fever of 38C
(101F) or higher until bacterial sepsis can be excluded.

ITP

2247

Treatment of chronic ITP

Principles of treatment

Approximately 30% to 40% of patients have platelet counts less

than 50 000 109/L after splenectomy because they did not
respond or they had a relapse, whereas others are unable or
unwilling to undergo the procedure. The goal of therapy in this
setting is to attain a hemostatic platelet count rather than to achieve
cure, while minimizing drug-induced toxicity (Figure 2). Most
patients achieve this goal, although it may take years25,26 and
therapy can be toxic17 if not used judiciously.25,26 There are no
randomized trials to support the effectiveness of any specific
approach.58 We concur with several of the recommendations of the
British Haematology Task Force3 concerning platelet counts for
minor surgery ( 50 000 109/L) and most major surgery
( 80 000 109/L); higher counts are advisable for cardiac bypass
surgery, neurosurgery, and complex orthopedic or plastic surgery.
-Aminocaproic acid can be used as a supplement for oral, nasal,
plastic, and prostate surgery. Alkylating agents should be avoided
or minimized (total dose of cyclophosphamide 2000 mg/m2) in
younger adults and those wishing to have children, whereas other
medications may adversely affect comorbid conditions (eg, corticosteroids and bone density or danazol and prostate disease). Elderly
patients are more likely to have severe bleeding and to suffer
debilitating side effects of therapy.90 It is our practice to look for an
accessory spleen with magnetic resonance imaging or another
sensitive scanning method (eg, heat-damaged red cells) if the
response to splenectomy was durable.49
First-line therapy

We treat symptomatic relapses or severe recurrent thrombocytopenia in the same way as at initial presentation, that is, with
corticosteroids or IVIG or the emergent measures described (see
Hospitalization and emergency therapy) depending on severity,
with the exception that few patients who have undergone splenectomy respond well to IV anti-D.59 Although some patients who
failed to respond to these measures on presentation do so after
splenectomy, it is almost always wise to introduce additional
medications, because few patients can be managed with chronic
low-dose (5-10 mg) or alternate day doses of prednisone or wish to
be bound indefinitely to parenteral therapy with IVIG. However,
we often use these agents initially because the other suggested

Figure 2. Therapy of adult ITP following splenectomy. (1) The goal of therapy in
this population is to maintain a hemostatic platelet count while minimizing druginduced toxicity; select patients may require somewhat higher platelet counts
because of comorbid risk factors as discussed in Treatment of chronic ITP. (2) Our
preference is to use anti-CD20 if not used previously and we consider reuse if a
response was seen prior to splenectomy. Alternatively, we combine danazol with
either azathioprine or mycophenolate mofetil for a minimum of 4 months, if possible,
and use corticosteroids or IVIG (or both) in the interim, as needed. In the future,
thrombopoietic agents currently in clinical trials may be used both before and after
splenectomy. prn indicates as needed.

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2248

CINES and BUSSEL

treatments typically require weeks to months for their effect to

become apparent. Monitoring bone density or prophylactic treatment is indicated to avoid osteoporosis in patients treated chronically ( 6 months) with corticosteroids.
We generally treat patients in whom splenectomy fails with the
anti-CD20 monoclonal antibody, rituximab (375 mg/m2 intravenously every week for 4 weeks). Responses are usually noted
within 4 to 8 weeks after the first infusion but may occur as late as 4
months. A complete or partial remission occurs in 25% to 50% of
patients; many complete responses are durable ( 1 year).60,61 Side
effects are mostly related to the first infusion (fever, chills,
hypotension, bronchospasm, etc). Profound and prolonged peripheral B-cell depletion is universal, but serious infection other than
reactivation of hepatitis B in chronic carriers is rare and generally
seen only in the context of additional immunosuppression. In our
limited experience, patients who responded but had a relapse often
respond to subsequent courses. Optimal dosing for ITP and use in
combination with other modalities is under investigation. The
long-term effect of treatment on immune surveillance is unknown.
Second-line therapy

For patients who do not respond to rituximab, we generally initiate

therapy with at least 2 agents to avoid inducing multiple drug
resistance genes.62 This approach also permits the more problematic agent to be tapered first. We generally choose danazol and
either azathioprine or mycophenolate mofetil. Some patients are
intolerant or unwilling to continue danazol because of mood or
menstrual changes, hirsutism, rash, myalgias, or transaminase
elevations; liver function tests should initially be monitored
monthly and then every 1 to 3 months. Treatment must be
continued for 4 to 6 months to see its full effect. Once a response is
seen, corticosteroids can be tapered and IVIG stopped. Approximately 50% of patients unresponsive to splenectomy but not
refractory to other treatments can be managed using either danazol
alone or combined with low doses of steroids, but in our experience
response rates are higher when danazol is combined with an
immunosuppressant.
Our preference is to use azathioprine (2 mg/kg orally every day
adjusted to avoid severe neutropenia), preferably in combination
with danazol (10-15 mg/kg/d), typically 600-800 mg per day, as the
first approach to chronic immunosuppression because the incidence
of acute and serious side effects is lower than with cyclophosphamide and the frequency of lasting remissions is comparable
(20%-40%).58 However, responses occur more slowly (typically
3-4 months) and this agent, like danazol, is often stopped prematurely. If a response occurs, therapy should be continued at full
doses for at least 12 months and then discontinued gradually.
Should relapse occur, the decision to restart azathioprine must be
balanced against the theoretical risk of complications from longterm use, which appears low based on experience in renal
transplantation. We have less personal experience with the use
of mycophenolate mofetil.63,64 Treatment is begun with 500 mg
orally twice a day and the dose is increased to 1000 to 1500 mg
orally twice a day after 2 weeks. In one study responses lasting 1
to 39 months were noted in 15 of 23 patients with minimal
toxicity64; the response rate in refractory patients is undoubtedly
lower. Once a response is seen, the doses of danazol and the
immunosuppressant can be gradually lowered over a period of
months, but rarely discontinued entirely.65 Danazol alone is
unlikely to work in patients with profound thrombocytopenia
unresponsive to corticosteroids or other measures. Dapsone
(75-100 mg orally daily) provides results similar to danazol,66

BLOOD, 1 OCTOBER 2005 VOLUME 106, NUMBER 7

but should be avoided in patients with glucose-6-phosphate

dehydrogenase deficiency.
An alternative is to use cyclophosphamide either intravenously
(2 or 3 courses of 500-1000 mg/m2 at 3-4week intervals)67 or
orally (1-2 mg/kg daily adjusted to avoid severe neutropenia).
Responses typically require 1 to 3 months. Thrombocytopenia may
worsen initially. If a complete response occurs to oral therapy, we
give full doses for an additional 3 months and then strongly
consider stopping treatment. In the event of relapse, the long-term
risks (eg, secondary malignancy, MDS) must be weighed against
the potential benefits of resuming therapy. Patients should drink at
least 2 L liquids daily to prevent hemorrhagic cystitis, and the
blood count should be monitored weekly. The response to cyclophosphamide or azathioprine in patients who did or did not respond to
the other agent is unknown. We rarely use vinca alkaloids except as
adjunctive therapy because responses are almost always transient
and treatment with vincristine is complicated by peripheral neuropathy. Occasionally, patients can be maintained with periodic doses
of vinblastine. We have seen rare dramatic responses to ex vivo
perfusion of plasma over staphylococcal protein A columns, but its
efficacy is far less than reported and its use is limited by potentially
severe side effects.
Treatment of chronic refractory ITP

Approximately 5% of patients have chronic refractory ITP, defined

as the failure of any modality to keep the platelet count above
20 000 109/L for an appreciable time without unacceptable
toxicity.17,25 Although many patients tolerate extremely low platelet
counts for years without serious bleeding even without treatment,
others suddenly develop ICH or other serious bleeding after
infection or incidental trauma. Options are limited, alternative
therapies are toxic, the minority of patients respond, and morbidity
and mortality are considerable, approaching 10% to 15% in some
series.24-26 We generally reserve the treatments we describe for
patients who are clearly refractory to previously mentioned modalities (ie, splenectomy, danazol, rituximab, or immunosuppressants)
and who have had serious morbidity or have extremely low platelet
counts (eg, less than 10 000 109/L).
If the decision is made to treat, the next step depends in part on
the urgency of the situation. If there is sufficient time, one option is
cyclosporine (1.25-2.5 mg/kg/dose orally every 12 hours, adjusted
based on drug and creatinine levels); in one study, 5 complete and 5
partial remissions were noted in 18 patients who had undergone
splenectomy, but 30% of patients discontinued treatment due to
side effects (hypertension, myalgias, and headaches).68 Highdose cyclophosphamide (1.0-1.5 g/m2 intravenously) given at
4-week intervals may act more rapidly.67 A high fluid intake (3-4
L daily either orally or intravenously during and for at least 3
days after therapy) and frequent blood counts are necessary. The
platelet count may fall before a response is seen and granulocyte
colony-stimulating factor and prophylactic antibiotics may be
needed. Various combinations of chemotherapeutic agents have
been used successfully in small numbers of heavily pretreated
patients.69 In one study, the long-term outcome of 12 patients
(follow-up 35-150 months) included 5 complete and 1 partial
remission.70 Therapy should be stopped if there is no response
after 2 courses and the literature is based on treating responders
with at least 3 or more courses even if the platelet count has
normalized. These recommendations may soon require modification based on the success of thrombopoietic agents (see
Experimental therapy).

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BLOOD, 1 OCTOBER 2005 VOLUME 106, NUMBER 7

Experimental therapy

A new approach is the use of thrombopoietic factors. In one study, 2

of 4 patients developed temporary thrombocytosis after receiving
marrow growth and development factor, a nonglycosylated, truncated form of human thrombopoietin.71 In recently published phase
2 placebo-controlled trials of AMG 531, a molecule that activates
the thrombopoietin receptor, 8 of 12 patients in one study and 7 of 8
in the other showed temporary but substantial increases in platelet
counts at a dose of 3.0 g/kg or higher.72,73 We have used
autologous stem cell transplantation as a measure of last resort in
young patients with recurrent life-threatening bleeding. The largest
reported experience involves 14 patients with refractory ITP who
were more than 6 months after transplantation at the time of
publication.74 Of these, 6 attained stable platelet counts that were
greater than 100 000 109/L and 2 had partial responses (follow-up 9-42 months). There were no procedural deaths, but sepsis
was common and 2 of the 6 complete responders died within a year.
Studies of antitumor necrosis factor receptor and anti
interleukin 2 receptor antagonists are too preliminary to evaluate.

ITP and pregnancy

Women with ITP may consult their physician as to the safety of
becoming pregnant or the diagnosis may be considered for the first
time during pregnancy because years may have passed since a
complete blood count was performed. Several comprehensive
reviews have been published.2,75
ITP occurs in 1 per 1000 to 1 per 10 000 pregnancies,
accounting for approximately 3% of women who are thrombocytopenic at delivery.76 In addition to the differential diagnosis common
to all patients with possible ITP, consideration should be given to
causes of thrombocytopenia confined to or more common during
pregnancy, including pregnancy-induced hypertension and related
conditions such as hemolysis, elevated liver enzymes, and low
platelet count (HELLP), obstetric causes of disseminated intravascular coagulation, microangiopathic hemolytic processes, and
gestational thrombocytopenia, among others (for a review, see
McCrae et al77). The latter, also referred to as incidental or benign
thrombocytopenia of pregnancy, is found in 5% to 8% of healthy
women with an uneventful pregnancy and accounts for at least 75%
of all cases of thrombocytopenia at term.78,92 Thrombocytopenia is
generally mild (platelet counts 70 000 109/L in 95% of cases)
and there seems to be no impact on maternal or fetal health. Platelet
counts generally return to normal within 2 months after delivery.
ITP should be suspected any time during pregnancy if isolated
thrombocytopenia of less than 50 000 109/L is detected, especially during the first 2 trimesters, but the distinction from
gestational thrombocytopenia may occasionally be problematic in
the absence of a prenatal platelet count as both entities are
diagnoses of exclusion.
We rarely, if ever, discourage pregnancy in women with known
ITP, but we explain that maternal and fetal complications may
occur and additional monitoring and therapy may be needed. We
explain that platelet counts commonly fall even during normal
pregnancy, and a woman with ITP may start from a lower baseline.
However, it is also important to point out that precipitous falls are
seen on occasion and demand more intensive therapy with its
attendant complications.
In the absence of symptoms or treatment, we monitor platelet
counts at least monthly through the first 2 trimesters, biweekly in

ITP

2249

the third, weekly as term approaches and more often, if indicated.

Ideally, maternal platelet counts should be maintained above
20 000 109/L throughout pregnancy and above 50 000 109/L
near term to minimize the need for platelet transfusions in the event
an emergency cesarean section is required,2,3,79 but a higher platelet
count may be required for epidural anesthesia. We generally use
corticosteroids as initial therapy, but this can induce or exacerbate
gestational diabetes, bone loss, hypertension, and perhaps abruption and prematurity.80 For this reason, we tend to rely more on
IVIG together with low-dose prednisone (20 mg every day) than in
nonparous patients. We have recently found IV anti-D to be safe
(including for the newborn) and effective, although experience is
limited, caution is indicated, and close monitoring of the fetus with
sonograms and the newborn with hemoglobin and bilirubin determinations is warranted.81 Splenectomy should be avoided if possible,
and deferred to the second trimester when necessary, to avoid
abortion. We do not use danazol, cyclophosphamide, anti-CD20,
vinca alkaloids, and other potentially teratogenic therapy (with the
possible exception of azathioprine for which a registry exists for
renal transplant recipients83). There is limited experience with
chemotherapy for neoplastic diseases in pregnant women that may
be helpful in managing the truly exceptional case (for reviews, see
Koren et al84 and Weisz et al85).
The mode of delivery is based almost entirely on obstetric
considerations.3,76 Postpartum bleeding is uncommon after vaginal
delivery, even in women with severe thrombocytopenia.75,80 Blood
loss during cesarean section varies inversely with platelet counts.
Although we think that a platelet count of 50 000 109/L is
generally sufficient for epidural anesthesia, we find practice
patterns are set by obstetricians and anestheologists.3,86 Criteria for
heparin prophylaxis after cesarean section have been reviewed.3
ITP is not a contraindication to breast-feeding.
Approximately 4% of ITP neonates are born with severe
thrombocytopenia (platelet counts 20 000 109/L), but importantly few have platelet counts that are less than 5000 109/L
unless alloantibodies are also present.87 The severity of neonatal
thrombocytopenia is often most marked 1 to 3 days after birth.
Marked discrepancies between the neonatal and maternal platelet
count are not uncommon. The patient should be informed that no
antenatal maternal measurements reliably predict the neonatal
platelet count, nor does the maternal response to treatment guarantee a favorable neonatal outcome; conversely, women requiring
considerable therapy to manage their platelet count should not
assume their neonate has an inordinate risk of bleeding. Only prior
neonatal outcome provides a useful predictor of neonatal platelet
count in subsequent pregnancies.88 However, 4 of 6 women who
previously delivered severely thrombocytopenic infants treated
with IVIG weekly for the last 6 weeks of pregnancy delivered less
affected neonates (J.B.B., unpublished data, 2005). The risk of ICH
is estimated to be less than 1%, which we think is less than that of
percutaneous umbilical vein sampling in severely thrombocytopenic fetuses.3,76 We are not aware of evidence that the risk of ICH
can be reduced by cesarean section.89 We measure cord platelet
counts in all newborns and serial platelet counts should be obtained
during the first week postpartum because the onset of severe
thrombocytopenia may be delayed. Sonography, computed tomography scanning, or magnetic resonance imaging of the head should
be performed in all neonates born with platelet counts less than
50 000 109/L even in the absence of symptoms; finding a silent
ICH demands immediate management and has implications for
subsequent pregnancies.

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2250

CINES and BUSSEL

BLOOD, 1 OCTOBER 2005 VOLUME 106, NUMBER 7

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