Professional Documents
Culture Documents
How I treat
Introduction
Our goal is to set forth our opinion of the best approach to thrombocytopenia, an otherwise unremarkable peripheral smear, a
managing adults with primary idiopathic (autoimmune) thrombocy- physical examination that only shows evidence of bleeding consis-
topenic purpura (ITP), with emphasis on the word opinion. The tent with the platelet count, and the exclusion of other causes of
paucity of evidence-based medicine on this topic has been noted.1 thrombocytopenia if grounds for suspicion exist. These include
Both the American Society of Hematology2 and the British exposure to drugs, herbs, foods, or other substances (eg, quinine)
Committee for Standards in Haematology General Haematology associated with thrombocytopenia; pseudothrombocytopenia; giant
Task Force3 have issued practice guidelines. These, in large part, platelets; family history consistent with inherited thrombocytope-
proved to be compendia of opinions from panels of experienced nia; or symptoms/signs suggestive of an underlying disorder that
physicians who concurred on some matters but not on others. We may cause secondary immune thrombocytopenia. We only perform
cite published evidence where we find it compelling and reproduc- bone marrow examinations as a matter of routine in otherwise
ible, but much of what follows rests on our mutual experience typical patients if they are over 60 years of age when the incidence
treating patients, both on- and off-study, rather than an encyclope-
of MDS becomes significant, in those who do not show a robust
dic, heavily referenced review. Many issues remain unresolved,
response ( 50 000 109/L) to treatment, and often prior to
expert opinions differ for good reason, and it is likely that our own
splenectomy if not previously performed. Response to treatment,
approach will change based on emerging data. Comprehensive
especially intravenous immune globulin (IVIG) or intravenous
reviews on pathogenesis, laboratory testing, secondary ITP, ITP in
children, and treatment are to be found elsewhere.4,5 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.
Who develops ITP?
Testing for HIV or hepatitis C infection (or both) is indicated in
Until recently, experience from numerous centers over more than a at-risk populations and the latter may occur more widely than
half-century indicated that the typical adult with ITP is a woman, previously appreciated.12 Remissions induced by eradication of
generally between 18 and 40 years of age.6 Gender disparity largely asymptomatic Haemophilus pylori infection have been reported in
disappears among the elderly.6,7 Two recent publications have ques- studies from Italy and Japan,13,14 but is not our experience.15 We
tioned this perception. The first was a survey from a single county in neither perform the more sensitive breath testing nor treat empiri-
Denmark using International Classification of Disease (ICD) codes at cally at presentation, but consider testing in chronic cases and those
hospital discharge over a 22-year period. The female-male ratio with gastrointestinal symptoms. Approximately 1% of patients
was 1.7, the median age at diagnosis was 56 years, and the have coexisting immune hemolytic anemia (Evans syndrome) and
incidence of ITP increased with age and increased overall during a smaller percentage have immune neutropenia, which confer a less
the period of study.8 The second was a prospective cohort analysis favorable prognosis. Immunoglobulin levels are measured if there
of newly presenting adults with platelet counts less than 50 000 109/L is a history of recurrent infection or allergy, if there is a reaction to
in the Northern Health Region of the United Kingdom. The female-male IVIG or prior transfusions, or if there is a concern about common
ratio was 1.2 and, again, the age-specific incidence was highest among variable immunodeficiency or IgA deficiency. Clonality and cytoge-
those older than 60 years.9 Presenting symptoms, severity of netics are assessed as part of the bone marrow evaluation.
thrombocytopenia, and response to therapy were typical for ITP, so Disturbances in thyroid function occur with sufficient frequency
these data do not simply reflect increased detection of mild cases
that we often measure thyroid-stimulating hormone levels if there
based on automated platelet determinations,10 misdiagnosed myelo-
are complaints of persistent fatigue and prior to splenectomy. We
dysplasia (MDS),11 or drug-dependent antibodies.
test for antiphospholipid antibodies if there is a history thrombosis,
recurrent or second- or third-trimester gestational failure, or a
How we diagnose ITP prolonged activated partial thromboplastin time.10,16 Up to 5% to
10% of patients eventually meet criteria for systemic lupus
ITP remains a diagnosis of exclusion. The essential elements erythematosus or another cause of secondary immune thrombocy-
include an otherwise healthy individual who presents with isolated topenia.17 Our approach to secondary immune thrombocytopenia,
From the Departments of Pathology and Laboratory Medicine and Medicine, and Medicine, University of Pennsylvania School of Medicine, 513A
University of Pennsylvania School of Medicine, Philadelphia, PA, and Stellar-Chance, 422 Curie Blvd, Philadelphia, PA 19104; e-mail: dcines@
Departments of Pediatrics, Medicine, and Obstetrics and Gynecology, New mail.med.upenn.edu; or James B. Bussel, Departments of Pediatrics,
York Presbyterian Hospital, Weill Cornell Medical Center, New York, NY. Medicine, and Obstetrics and Gynecology, New York Presbyterian Hospital,
Weill Cornell Medical Center, 525 E 68th St, Payson 695, New York, NY 10021;
Submitted December 8, 2004; accepted April 14, 2005. Prepublished online as
e-mail: jbussel@med.cornell.edu.
Blood First Edition Paper, June 7, 2005; DOI 10.1182/blood-2004-12-4598.
Reprints: Douglas Cines, Departments of Pathology and Laboratory Medicine 2005 by The American Society of Hematology
including systemic lupus erythematosus, antiphospholipid syn- events such as viral infection or head trauma, or after inadvertently
drome, B-cell malignancies (primarily chronic lymphocytic and taking medications that impair platelet function.27 We would argue
large granular leukemias), and HIV infection, among others, has that the goal of therapy must be individualized on the basis of signs
been reviewed elsewhere.4 and symptoms, tolerance of treatment, lifestyle, and patient prefer-
We do not rely on measuring antiplatelet antibodies to make or ence. Our usual practice is to maintain a somewhat higher platelet
exclude a diagnosis of ITP. Although some argue that current count initially (eg, 30 000 109/L) while we get to know the
methods to detect platelet antigen-specific antibodies are now patient, with the goal of establishing a track record of bleeding,
sufficiently specific to affirm the diagnosis, antibodies have also compliance, and risk management that allows us to modify the
been detected in 10% to 20% of patients with certain causes of threshold for treatment over time.
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 Treatment at presentation
Principles of management
Who we treat Patients typically present with petechiae or purpura that develop
over several days accompanied by platelet counts less than
What is a hemostatic platelet count? Is the platelet count a 20 000 109/L, although the onset is often more insidious than
reasonable surrogate marker for the risk of serious bleeding? In a previously appreciated.10 Severe cutaneous bleeding, prolonged
recent 10-year study of 310 patients in whom treatment was epistaxis, gingival bleeding, overt hematuria, or menorrhagia may
generally used only at platelet counts less than 30 000 109/L, develop at platelet counts less than 10 000 109/L. Spontaneous
only one hemorrhagic death occurred.22 In a meta-analysis of 17 or posttraumatic ICH or bleeding at other internal sites is uncom-
studies, the age-adjusted risk of fatal hemorrhage at platelet counts mon, but not without precedence,24 at platelet counts between
persistently less than 30 000 109/L was estimated to be 0.4%, 10 000 and 20 000 109/L. Those with platelet counts between
1.2%, and 13% per patient per year for those younger than 40, 40 to 30 000 and 50 000 109/L may note easy bruising, whereas
60, and older than 60 years of age, respectively. Predicted 5-year platelet counts above 50 000 109/L are usually discovered inci-
mortality ranged from 2.2% to 47.8%.23 Similar mortality rates dentally. Rarely, do patients present with bleeding disproportionate
have been reported by others depending on duration of follow- to the platelet count because of antibody-induced platelet dysfunc-
up.24-26 Major bleeding, including spontaneous intracerebral hemor- tion.29 Some patients experience untoward and otherwise unex-
rhage (ICH), occurs predominantly in patients with platelet counts plained fatigue when their platelet count is low.
less than 20 000 109/L, generally less than 10 000 109/L.24,27 Management is predicated primarily on the severity of thrombo-
Thus, a compelling case can be made to treat patients with platelet cytopenia and bleeding. Drugs that interfere with platelet function
counts below 20 000 109/L. Some experts would apply this are discontinued. Alternatives are substituted for drugs deemed
reasoning to recommendations for splenectomy,28 although we use necessary but potentially causal. The initial goal of treatment is to
a higher threshold (see Splenectomy). attain a hemostatic platelet count ( 30 000 109/L) while mini-
What is more contentious and requires individualization and mizing the toxicity of treatment. Figure 1 shows our treatment
considerable judgment is the wisdom of treating patients with
algorithm for initial management. The reader is referred elsewhere
platelet counts between 20 000 and 50 000 109/L. Although few
for a more comprehensive tabulation of drug doses, expected
otherwise healthy, sedentary individuals die of hemorrhage over a
response times, and common side effects.30 Therapy is indicated in
10-year period if they maintain a stable platelet count more than
all patients who present with bleeding and those with platelet
20 000 109/L and though we rarely treat patients with platelet
counts less than 20 000 109/L because fewer than 10% of adults
counts more than 30 000 109/L in the absence of extenuating
rapidly attain spontaneous remission. Those with platelet counts
circumstances that predispose to serious bleeding, no published
more than 50 000 109/L can almost always be observed, al-
follow-up is of sufficient length or size to project risk over a life
though some (5 of 87 in one series7) require treatment later. In
span. Our opinion is that it is as unreasonable to apply a one-size
general, immediate therapy is not required for patients with platelet
fits all threshold as it would be to attempt to normalize platelet
counts between 20 000 and 50 000 109/L in the absence of
counts in all patients. Is 20 000 to 30 000 109/L a safe and
bleeding or predisposing comorbid conditions such as uncontrolled
appropriate platelet count for the 63-year-old man with angina who
hypertension, active peptic ulcer disease, anticoagulation, recent
then suddenly requires clopidogrel and aspirin after a coronary
stent is placed? What about the high school student able to afford surgery, or head trauma.2,3 We recommend maintaining platelet
college only if awarded a football scholarship, the policeman who counts above 40 000 to 50 000 109/L for patients requiring
routinely faces physical confrontation, the 28 year-old hard-hat aspirin, nonsteroidal anti-inflammatory drugs, warfarin, or other
construction worker, the 19-year-old woman with marked menor- antithrombotics.
rhagia unresponsive to hormonal management, the 26-year-old Hospitalization and emergency therapy
who feels completely drained of energy unless her platelet count
approaches 50 000 109/L, or even the extensive traveler. There is We hospitalize (1) patients with profound mucocutaneous or
room for disagreement in each of these cases, but they illustrate the types internal bleeding and (2) those who present with platelet counts of
of issues confronted in real practice. less than 20 000 109/L and a history of significant bleeding,
Although rare, major bleeding has been reported at platelet those in whom there is a question about compliance, and in some
counts between 20 000 and 30 000 109/L. Furthermore, counts cases, those in whom responsiveness to therapy has not been
may drop suddenly at any time.24 A worrisome number of patients establishedfor example, when comorbid factors predisposing to
who developed ICH did so after acute and often unpredictable bleeding or complications of therapy are present. All others can be
From www.bloodjournal.org by guest on November 17, 2016. For personal use only.
2246 CINES and BUSSEL BLOOD, 1 OCTOBER 2005 VOLUME 106, NUMBER 7
2248 CINES and BUSSEL BLOOD, 1 OCTOBER 2005 VOLUME 106, NUMBER 7
treatments typically require weeks to months for their effect to but should be avoided in patients with glucose-6-phosphate
become apparent. Monitoring bone density or prophylactic treat- dehydrogenase deficiency.
ment is indicated to avoid osteoporosis in patients treated chroni- An alternative is to use cyclophosphamide either intravenously
cally ( 6 months) with corticosteroids. (2 or 3 courses of 500-1000 mg/m2 at 3-4week intervals)67 or
We generally treat patients in whom splenectomy fails with the orally (1-2 mg/kg daily adjusted to avoid severe neutropenia).
anti-CD20 monoclonal antibody, rituximab (375 mg/m2 intrave- Responses typically require 1 to 3 months. Thrombocytopenia may
nously every week for 4 weeks). Responses are usually noted worsen initially. If a complete response occurs to oral therapy, we
within 4 to 8 weeks after the first infusion but may occur as late as 4 give full doses for an additional 3 months and then strongly
months. A complete or partial remission occurs in 25% to 50% of consider stopping treatment. In the event of relapse, the long-term
patients; many complete responses are durable ( 1 year).60,61 Side risks (eg, secondary malignancy, MDS) must be weighed against
effects are mostly related to the first infusion (fever, chills, the potential benefits of resuming therapy. Patients should drink at
hypotension, bronchospasm, etc). Profound and prolonged periph- least 2 L liquids daily to prevent hemorrhagic cystitis, and the
eral B-cell depletion is universal, but serious infection other than blood count should be monitored weekly. The response to cyclophos-
reactivation of hepatitis B in chronic carriers is rare and generally phamide or azathioprine in patients who did or did not respond to
seen only in the context of additional immunosuppression. In our the other agent is unknown. We rarely use vinca alkaloids except as
limited experience, patients who responded but had a relapse often adjunctive therapy because responses are almost always transient
respond to subsequent courses. Optimal dosing for ITP and use in and treatment with vincristine is complicated by peripheral neurop-
combination with other modalities is under investigation. The athy. Occasionally, patients can be maintained with periodic doses
long-term effect of treatment on immune surveillance is unknown. of vinblastine. We have seen rare dramatic responses to ex vivo
Second-line therapy perfusion of plasma over staphylococcal protein A columns, but its
efficacy is far less than reported and its use is limited by potentially
For patients who do not respond to rituximab, we generally initiate severe side effects.
therapy with at least 2 agents to avoid inducing multiple drug
resistance genes.62 This approach also permits the more problem- Treatment of chronic refractory ITP
atic agent to be tapered first. We generally choose danazol and Approximately 5% of patients have chronic refractory ITP, defined
either azathioprine or mycophenolate mofetil. Some patients are as the failure of any modality to keep the platelet count above
intolerant or unwilling to continue danazol because of mood or
20 000 109/L for an appreciable time without unacceptable
menstrual changes, hirsutism, rash, myalgias, or transaminase
toxicity.17,25 Although many patients tolerate extremely low platelet
elevations; liver function tests should initially be monitored
counts for years without serious bleeding even without treatment,
monthly and then every 1 to 3 months. Treatment must be
others suddenly develop ICH or other serious bleeding after
continued for 4 to 6 months to see its full effect. Once a response is
infection or incidental trauma. Options are limited, alternative
seen, corticosteroids can be tapered and IVIG stopped. Approxi-
therapies are toxic, the minority of patients respond, and morbidity
mately 50% of patients unresponsive to splenectomy but not
and mortality are considerable, approaching 10% to 15% in some
refractory to other treatments can be managed using either danazol
series.24-26 We generally reserve the treatments we describe for
alone or combined with low doses of steroids, but in our experience
patients who are clearly refractory to previously mentioned modali-
response rates are higher when danazol is combined with an
ties (ie, splenectomy, danazol, rituximab, or immunosuppressants)
immunosuppressant.
and who have had serious morbidity or have extremely low platelet
Our preference is to use azathioprine (2 mg/kg orally every day
adjusted to avoid severe neutropenia), preferably in combination counts (eg, less than 10 000 109/L).
with danazol (10-15 mg/kg/d), typically 600-800 mg per day, as the If the decision is made to treat, the next step depends in part on
first approach to chronic immunosuppression because the incidence the urgency of the situation. If there is sufficient time, one option is
of acute and serious side effects is lower than with cyclophospha- cyclosporine (1.25-2.5 mg/kg/dose orally every 12 hours, adjusted
mide and the frequency of lasting remissions is comparable based on drug and creatinine levels); in one study, 5 complete and 5
(20%-40%).58 However, responses occur more slowly (typically partial remissions were noted in 18 patients who had undergone
3-4 months) and this agent, like danazol, is often stopped prema- splenectomy, but 30% of patients discontinued treatment due to
turely. If a response occurs, therapy should be continued at full side effects (hypertension, myalgias, and headaches).68 High-
doses for at least 12 months and then discontinued gradually. dose cyclophosphamide (1.0-1.5 g/m2 intravenously) given at
Should relapse occur, the decision to restart azathioprine must be 4-week intervals may act more rapidly.67 A high fluid intake (3-4
balanced against the theoretical risk of complications from long- L daily either orally or intravenously during and for at least 3
term use, which appears low based on experience in renal days after therapy) and frequent blood counts are necessary. The
transplantation. We have less personal experience with the use platelet count may fall before a response is seen and granulocyte
of mycophenolate mofetil.63,64 Treatment is begun with 500 mg colony-stimulating factor and prophylactic antibiotics may be
orally twice a day and the dose is increased to 1000 to 1500 mg needed. Various combinations of chemotherapeutic agents have
orally twice a day after 2 weeks. In one study responses lasting 1 been used successfully in small numbers of heavily pretreated
to 39 months were noted in 15 of 23 patients with minimal patients.69 In one study, the long-term outcome of 12 patients
toxicity64; the response rate in refractory patients is undoubtedly (follow-up 35-150 months) included 5 complete and 1 partial
lower. Once a response is seen, the doses of danazol and the remission.70 Therapy should be stopped if there is no response
immunosuppressant can be gradually lowered over a period of after 2 courses and the literature is based on treating responders
months, but rarely discontinued entirely.65 Danazol alone is with at least 3 or more courses even if the platelet count has
unlikely to work in patients with profound thrombocytopenia normalized. These recommendations may soon require modifica-
unresponsive to corticosteroids or other measures. Dapsone tion based on the success of thrombopoietic agents (see
(75-100 mg orally daily) provides results similar to danazol,66 Experimental therapy).
From www.bloodjournal.org by guest on November 17, 2016. For personal use only.
Experimental therapy the third, weekly as term approaches and more often, if indicated.
Ideally, maternal platelet counts should be maintained above
A new approach is the use of thrombopoietic factors. In one study, 2
20 000 109/L throughout pregnancy and above 50 000 109/L
of 4 patients developed temporary thrombocytosis after receiving
near term to minimize the need for platelet transfusions in the event
marrow growth and development factor, a nonglycosylated, trun-
an emergency cesarean section is required,2,3,79 but a higher platelet
cated form of human thrombopoietin.71 In recently published phase
count may be required for epidural anesthesia. We generally use
2 placebo-controlled trials of AMG 531, a molecule that activates
corticosteroids as initial therapy, but this can induce or exacerbate
the thrombopoietin receptor, 8 of 12 patients in one study and 7 of 8
gestational diabetes, bone loss, hypertension, and perhaps abrup-
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 tion and prematurity.80 For this reason, we tend to rely more on
autologous stem cell transplantation as a measure of last resort in IVIG together with low-dose prednisone (20 mg every day) than in
young patients with recurrent life-threatening bleeding. The largest nonparous patients. We have recently found IV anti-D to be safe
reported experience involves 14 patients with refractory ITP who (including for the newborn) and effective, although experience is
were more than 6 months after transplantation at the time of limited, caution is indicated, and close monitoring of the fetus with
publication.74 Of these, 6 attained stable platelet counts that were sonograms and the newborn with hemoglobin and bilirubin determi-
greater than 100 000 109/L and 2 had partial responses (fol- nations is warranted.81 Splenectomy should be avoided if possible,
low-up 9-42 months). There were no procedural deaths, but sepsis and deferred to the second trimester when necessary, to avoid
was common and 2 of the 6 complete responders died within a year. abortion. We do not use danazol, cyclophosphamide, anti-CD20,
Studies of antitumor necrosis factor receptor and anti vinca alkaloids, and other potentially teratogenic therapy (with the
interleukin 2 receptor antagonists are too preliminary to evaluate. 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
ITP and pregnancy Koren et al84 and Weisz et al85).
The mode of delivery is based almost entirely on obstetric
Women with ITP may consult their physician as to the safety of considerations.3,76 Postpartum bleeding is uncommon after vaginal
becoming pregnant or the diagnosis may be considered for the first delivery, even in women with severe thrombocytopenia.75,80 Blood
time during pregnancy because years may have passed since a loss during cesarean section varies inversely with platelet counts.
complete blood count was performed. Several comprehensive Although we think that a platelet count of 50 000 109/L is
reviews have been published.2,75 generally sufficient for epidural anesthesia, we find practice
ITP occurs in 1 per 1000 to 1 per 10 000 pregnancies, patterns are set by obstetricians and anestheologists.3,86 Criteria for
accounting for approximately 3% of women who are thrombocyto- heparin prophylaxis after cesarean section have been reviewed.3
penic at delivery.76 In addition to the differential diagnosis common ITP is not a contraindication to breast-feeding.
to all patients with possible ITP, consideration should be given to Approximately 4% of ITP neonates are born with severe
causes of thrombocytopenia confined to or more common during thrombocytopenia (platelet counts 20 000 109/L), but impor-
pregnancy, including pregnancy-induced hypertension and related
tantly few have platelet counts that are less than 5000 109/L
conditions such as hemolysis, elevated liver enzymes, and low
unless alloantibodies are also present.87 The severity of neonatal
platelet count (HELLP), obstetric causes of disseminated intravas-
thrombocytopenia is often most marked 1 to 3 days after birth.
cular coagulation, microangiopathic hemolytic processes, and
Marked discrepancies between the neonatal and maternal platelet
gestational thrombocytopenia, among others (for a review, see
count are not uncommon. The patient should be informed that no
McCrae et al77). The latter, also referred to as incidental or benign
antenatal maternal measurements reliably predict the neonatal
thrombocytopenia of pregnancy, is found in 5% to 8% of healthy
platelet count, nor does the maternal response to treatment guaran-
women with an uneventful pregnancy and accounts for at least 75%
tee a favorable neonatal outcome; conversely, women requiring
of all cases of thrombocytopenia at term.78,92 Thrombocytopenia is
generally mild (platelet counts 70 000 109/L in 95% of cases) considerable therapy to manage their platelet count should not
and there seems to be no impact on maternal or fetal health. Platelet assume their neonate has an inordinate risk of bleeding. Only prior
counts generally return to normal within 2 months after delivery. neonatal outcome provides a useful predictor of neonatal platelet
ITP should be suspected any time during pregnancy if isolated count in subsequent pregnancies.88 However, 4 of 6 women who
thrombocytopenia of less than 50 000 109/L is detected, espe- previously delivered severely thrombocytopenic infants treated
cially during the first 2 trimesters, but the distinction from with IVIG weekly for the last 6 weeks of pregnancy delivered less
gestational thrombocytopenia may occasionally be problematic in affected neonates (J.B.B., unpublished data, 2005). The risk of ICH
the absence of a prenatal platelet count as both entities are is estimated to be less than 1%, which we think is less than that of
diagnoses of exclusion. percutaneous umbilical vein sampling in severely thrombocytope-
We rarely, if ever, discourage pregnancy in women with known nic fetuses.3,76 We are not aware of evidence that the risk of ICH
ITP, but we explain that maternal and fetal complications may can be reduced by cesarean section.89 We measure cord platelet
occur and additional monitoring and therapy may be needed. We counts in all newborns and serial platelet counts should be obtained
explain that platelet counts commonly fall even during normal during the first week postpartum because the onset of severe
pregnancy, and a woman with ITP may start from a lower baseline. thrombocytopenia may be delayed. Sonography, computed tomog-
However, it is also important to point out that precipitous falls are raphy scanning, or magnetic resonance imaging of the head should
seen on occasion and demand more intensive therapy with its be performed in all neonates born with platelet counts less than
attendant complications. 50 000 109/L even in the absence of symptoms; finding a silent
In the absence of symptoms or treatment, we monitor platelet ICH demands immediate management and has implications for
counts at least monthly through the first 2 trimesters, biweekly in subsequent pregnancies.
From www.bloodjournal.org by guest on November 17, 2016. For personal use only.
2250 CINES and BUSSEL BLOOD, 1 OCTOBER 2005 VOLUME 106, NUMBER 7
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