Clinical manifestations and diagnosis of immune (idiopathic) thrombocytopenic purpura in adults

Author
James N George, MD Section Editor
Lawrence LK Leung, MD Deputy Editor
Stephen A Landaw, MD, PhD
Last literature review version 18.2: May 2010 | This topic last updated: May 18, 2010 (More)
INTRODUCTION — Immune thrombocytopenic purpura (also called idiopathic
thrombocytopenic purpura, immune thrombocytopenia, ITP) is an acquired disorder. There are
only two criteria required in order to make this diagnosis [1-5]:
 • Isolated thrombocytopenia is present. The rest of the complete blood count, including an
examination of the peripheral blood smear, is entirely normal, unless other coincidental
abnormalities are present, such as iron deficiency.
 • Clinically apparent associated conditions (eg, systemic lupus erythematosus, antiphospholipid
syndrome, chronic lymphocytic leukemia) are not present. Patients with these associated
conditions are described as having "secondary immune thrombocytopenia" [6]. Also, drugs,
including herbal remedies and quinine-containing beverages that may cause thrombocytopenia
are NOT apparent etiologies.
The clinical manifestations, diagnosis, and differential diagnosis of ITP will be reviewed here.
The treatment and prognosis of this disorder and the clinical manifestations, diagnosis,
treatment, and prognosis of childhood ITP are discussed separately. (See "Treatment and
prognosis of immune (idiopathic) thrombocytopenic purpura in adults" and "Clinical
manifestations and diagnosis of immune (idiopathic) thrombocytopenic purpura in children".)
PATHOGENESIS — The pathogenesis of ITP is related to a combination of increased platelet
destruction along with inhibition of megakaryocyte platelet production via the production of
specific IgG autoantibodies by the patient's B cells, most often directed against platelet
membrane glycoproteins such as GPIIb/IIIa [2,7-9].
Inciting events — The etiology of ITP is unclear, but is thought to include genetic as well as
acquired factors [6,10,11].
• Some cases of ITP are associated with a preceding viral infection. It is possible that resulting
anti-viral antibodies cross-react with platelet glycoproteins. Infection with HIV, HCV, CMV [12],
and VZV may be associated with such antibodies therefore cause secondary ITP. (See 'Onset
after infection' below.)
 • Alterations in the immune response might induce loss of peripheral tolerance and promote the
development of self-reactive antibodies. (See 'B- and T-cell responses in ITP' below.)
• Abnormalities in the immune system may predispose to the development of autoimmune
thrombocytopenia. Examples include the antiphospholipid syndrome, systemic lupus
erythematosus, Evans syndrome, post-hematopoietic cell transplantation ITP, and the
secondary ITP seen in patients with chronic lymphocytic leukemia and other low-grade
lymphoproliferative disorders, especially those treated with purine analogs, and the autoimmune
lymphoproliferative syndrome [6]. (See appropriate topic reviews).
Although ITP has been reported in association with nonhematologic malignancies, especially
breast cancer, the association is likely coincidental [13-16].
B- and T-cell responses in ITP — B cell autoimmune IgG responses in ITP appear to be driven
by CD4+ helper T cells reacting to platelet membrane glycoprotein epitopes [17], possibly
involving CD40:CD40L co-stimulation processes [18], with splenic macrophages as the major
antigen-presenting cells [19,20]. (See "The humoral immune response", section on 'Activation
signals' and "Megakaryocyte biology and the production of platelets", section on 'Immune
thrombocytopenic purpura'.)
The following pathogenic loop has been suggested to explain this process [19,20]
 • Membrane GPIIb/IIIa and/or GPIb/IX of phagocytosed platelets are processed, and their
digested peptides are presented by macrophages to autoreactive HLA-restricted CD4+ T-cells.
 • These T-cells become activated when T-cell receptors recognize the HLA-DR antigenic
peptide complex on the antigen-presenting macrophages.
 • The activated T-cells secrete IL-6 and upregulate CD154 expression, exerting helper activity
on autoreactive antibody-producing B-cells. The latter are restricted B-cell clones that undergo
proliferation and somatic mutation under antigenic pressure.
 • The autoantibodies thus produced bind to platelets, and the opsonized platelets are
phagocytosed mainly by splenic macrophages, perhaps aided by complement activation [21],
thus completing the loop. The autoantibodies can also bind to megakaryocytes, decreasing
overall platelet production.
The importance of interactions between B- and T-cells in ITP was illustrated in a study which
evaluated T-cell subset changes in 30 patients with chronic ITP and elevated levels of platelet-
associated immunoglobulin, who were treated with the B-cell depleting antibody rituximab [22].
Pre-treatment abnormalities in the T-cell compartment of these patients reverted in responders
to rituximab, whereas they remained unchanged in nonresponders. This study suggests that
depletion of B-cells may reduce co-stimulation of pathogenic T-cell clones in the responders.
Alternative mechanisms involving T-cells, including T-cell-mediated cytotoxicity and defects in
the number and/or function of regulatory T-cells (Tregs) have also been postulated [23-31]. The
latter mechanism is supported by a study showing a reduced number and defective suppressive
capacity of Tregs in ITP patients compared with controls, and restored Treg numbers and
regulatory function, especially in responders, following treatment with rituximab [30]
Antibodies are not demonstrable in all patients with ITP and assays for antiplatelet antibodies
have not yet proven to be important for management decisions [2,3,32,33]. (See
"Megakaryocyte biology and the production of platelets", section on 'Immune thrombocytopenic
purpura'.)
INCIDENCE — ITP is a common acquired bleeding disorder. The incidence of ITP in children is
greater than the incidence among adults (figure 1). In children, the incidence of ITP in boys and
girls is similar [34]. (See "Clinical manifestations and diagnosis of immune (idiopathic)
thrombocytopenic purpura in children".)
A Denmark survey from 1973 to 1995 estimated the annual incidence of ITP among adults to be
22 per million per year, using a platelet count cut-off of 50,000/microL [35]. The incidence rate
rose during the study period, due primarily to increased recognition of asymptomatic patients
[35].However, this incidence estimate primarily includes symptomatic patients. This is an
important issue since, in two large case series, 18 percent [36] and 29 percent [37] of adults
were discovered to have ITP when they had no bleeding symptoms. Therefore, the total
incidence of ITP among adults is likely to be greater than 22 per million per year. This was
shown in a UK population-based study of patients all diagnosed with ITP from 1990 through
2005. The crude ITP incidence for this period was 39 and 44 per million per year for men and
women, respectively [38].Because ITP in adults is typically a chronic disease, the prevalence
exceeds the incidence. In one estimate of the prevalence of ITP in the US, the estimate was
approximately 100 per million per year, with age cohorts ranging from 41 to 160 per million per
year, with the highest values seen in the oldest age cohort [39].Many reports have suggested
that, among adults with ITP, approximately 70 percent are women and 72 percent of these
women are less than 40 years of age. However, the Denmark survey reported a sex difference
in the incidence of ITP only for those <60 years of age [35], while a total lack of sex difference
was noted in a population-based cohort from the Northern Health Region of England of newly-
presenting adults with ITP and platelet counts <50,000/microL [37]. The overall incidence of ITP
in the latter study was 16 per million per year, with no difference between males and females in
any age group, and with the highest age-specific incidence in those >60 years of age.The
findings in the Danish and English series may be due to differences in methodology, as both
surveys identified all patients who met criteria for ITP, rather than those presenting with
symptoms. Thus, the traditional teaching that ITP is primarily a disease of young females will
have to be modified. This was shown in the UK study in which the highest incidence of ITP was
found in subjects >75 years of age [38]. The incidence of ITP was greater in females in the age
range from 18 to 64 years, while it was greater in males for those <18 as well as >65 years of
age.All published reports on the incidence of ITP have been critically reviewed, comparing the
strengths and weakness of their methodology [40].
CLINICAL MANIFESTATIONS AND ASSOCIATIONS — There is marked interpatient variability
in the clinical presentation of ITP. Although the onset of ITP may be acute and abrupt, it is more
often insidious. Similarly, bleeding in symptomatic patients can range from petechiae and easy
bruising to a severe bleeding diathesis. In addition, the clinical laboratory routine of reporting a
platelet count with all requests for blood counts, which began with the introduction of automated
cell counters, has resulted in the discovery of asymptomatic, mild thrombocytopenia, thereby
enlarging the clinical spectrum of ITP.The clinical manifestations of ITP are limited to those
related to excessive bleeding caused by thrombocytopenia. The bleeding manifestations of
thrombocytopenia are described as mucocutaneous, to distinguish them from the delayed,
slowly evolving visceral hematomas characteristic of coagulation disorders such as hemophilia
(see below). Thus, in patients with thrombocytopenia due to ITP:
 • Petechiae, purpura, and easy bruising are expected.
 • Epistaxis, gingival bleeding, and menorrhagia are common.
 • Overt gastrointestinal bleeding and gross hematuria are rare.
 • Intracranial hemorrhage, a potentially fatal bleeding complication, is so uncommon that there
is no reliable estimate of its frequency.
The clinical manifestations of thrombocytopenia also vary with age. Older patients may have
more severe bleeding manifestations, such as gastrointestinal bleeding and possibly intracranial
hemorrhage because of comorbidities such as hypertension [41,42].
Onset after infection — Children with ITP typically present with an acute, sudden clinical onset,
usually associated with a history of infection in the several weeks preceding the illness [43-46].
In one series, for example, infection in the three weeks prior to the onset of ITP was seen in 84
percent of cases [43,44].How infection, viral or bacterial, might promote the development or
worsening of ITP is uncertain, although a number of mechanisms have been postulated:
• Virus-specific antibodies may crossreact with normal platelet antigens, and contribute to
increased platelet clearance [45].
 • Helicobacter pylori infection has been associated with ITP in some reports. Experimental
observations, including the induction of platelet aggregation by certain strains of H. pylori, and
cross-reactivity between platelet-associated IgG and H. pylori cytotoxin-associated gene A
(CagA) protein may explain this association. (See "Chronic refractory immune (idiopathic)
thrombocytopenic purpura in adults", section on 'Helicobacter pylori infection'.)
• Molecular mimicry between HIV proteins and platelet GPIIb/IIIa may be important in the
pathogenesis of primary HIV-associated thrombocytopenia. (See "Hematologic manifestations
of HIV infection: Thrombocytopenia and coagulation abnormalities", section on 'Reduced
platelet survival'.)
 • A number of autoimmune phenomena have been noted following infection with the hepatitis C
virus, including immune thrombocytopenia and autoimmune hemolytic anemia [47]. Molecular
mimicry between HCV core envelope protein 1 and platelet GP IIb/IIIa has been implicated in
the genesis of HCV-associated thrombocytopenia [48]. (See "Extrahepatic manifestations of
hepatitis C virus infection", section on 'Autoimmune disorders'.)
 • Bacterial products, such as lipopolysaccharides, when attached to the surface of platelets in
the presence of antiplatelet antibodies, can significantly increase platelet phagocytosis [49].
Drug-associated immune thrombocytopenia — A number of drugs have been associated with
the development of autoimmune disorders, such as pure red cell aplasia, autoimmune hemolytic
anemia, and immune thrombocytopenic purpura. Two of these are discussed below.
Alemtuzumab — Use of the monoclonal anti-CD52 antibody alemtuzumab in several treatment
settings (eg, chronic lymphocytic leukemia, organ transplantation, multiple sclerosis) has been
associated with the development of autoimmune disorders (eg, autoimmune hemolytic anemia,
pure red cell aplasia), including ITP [50-53]. The mechanism involved may be related to the
ability of this agent to cause severe immune dysregulation. (See "Treatment of relapsed or
refractory chronic lymphocytic leukemia", section on 'Alemtuzumab' and "Treatment of
relapsing-remitting multiple sclerosis in adults", section on 'Alemtuzumab'.)
Purine analogs — Use of purine analogs in patients with low-grade lymphoma has been
associated with an increased incidence of autoimmune hemolytic anemia and immune
thrombocytopenic purpura. This subject is discussed separately. (See "Autoimmune
complications following purine analog therapy", section on 'Autoimmune thrombocytopenia'.)
Comparison with vasculitic purpura — The defining characteristics of petechiae and purpura in
thrombocytopenic patients are that they are asymptomatic and not palpable. This is an
important clinical distinction from patients with vasculitis, such as Henoch-Schönlein purpura or
drug hypersensitivity. In vasculitic purpura, the patient experiences a prodrome of stinging or
burning. On examination, vasculitic purpura has a palpable, papular character. (See "Clinical
manifestations and diagnosis of Henoch-Schönlein purpura".)Thrombocytopenic purpura and
vasculitic purpura also have a different pattern of distribution. Thrombocytopenic purpura is
consistently localized to dependent portions of the body. As a result, petechiae are most dense
on the feet and ankles, fewer are present on the legs, and only scattered petechiae occur
elsewhere on the body. Areas with firm subcutaneous tissue, such as the soles of the feet, are
protected from petechiae, while areas with minimal subcutaneous support, such as the oral
mucosa and conjunctivae, may have large bullous appearing hemorrhages (picture 1). In
contrast, vasculitic purpura may occur in symmetrical patches without regard for a dependent
distribution (picture 2).
Comparison with coagulation disorders — The clinical manifestations of ITP are distinct from the
bleeding abnormalities that occur with a coagulation disorder. Patients with hemophilia, for
example, do not have petechiae or purpura because their platelet function is normal. The most
common manifestation of hemophilia is the delayed formation of a hematoma following trauma,
as in a muscle or joint space. In comparison, muscle hematomas and hemarthroses rarely occur
in patients with ITP (table 1). (See "Approach to the adult patient with a bleeding diathesis",
section on 'Clinical manifestations'.)
Correlation between bleeding and the platelet count — There are few data that describe the risk
of clinically important bleeding at different levels of thrombocytopenia. Furthermore, the
correlation between bleeding symptoms and the platelet count may be in part related to the
etiology of the thrombocytopenia.Because the pathogenesis of ITP involves accelerated platelet
destruction by autoantibodies, with a compensatory increase in platelet production in some
patients, circulating platelets in patients with ITP are younger and have greater hemostatic
effectiveness [54]. As a result, bleeding manifestations in patients with ITP are less severe at
equivalent platelet counts than in patients with thrombocytopenia due to marrow aplasia or
chemotherapy-induced marrow suppression.There are more direct observations on patients with
chemotherapy-induced marrow suppression to determine the appropriate platelet count
threshold that requires platelet transfusion support. These data indicate that clinically important
bleeding rarely occurs with platelet counts above 10,000/microL, unless the patient is febrile or
has a serious systemic illness [55].There is suggestive evidence that a similar threshold exists
in ITP. Clinically important bleeding does not appear to occur in these patients unless the
platelet count is less than 10,000/microL; even at this level, most patients do not have serious
bleeding episodes (figure 2) [56]. These observations suggest that treatment of ITP may be
unnecessary unless the platelet count is less than 10,000/microL. However the standard of
practice for adults with ITP is that treatment is generally initiated when the platelet count is less
than 30,000 to 50,000/microL because the course of the disease and risks for bleeding cannot
be predicted at the time of the initial diagnosis. (See "Treatment and prognosis of immune
(idiopathic) thrombocytopenic purpura in adults".)Acquired platelet function
abnormality — When bleeding in ITP appears to be more severe than would be suggested by
the platelet count alone, the patient may (rarely) have an autoantibody that inhibits the function
of platelet glycoprotein (GP) IIb/IIIa, resulting in abnormal platelet aggregation (ie, acquired
Glanzmann thrombasthenia) in addition to the underlying thrombocytopenia [57]. (See
"Congenital and acquired disorders of platelet function", section on 'Acquired Glanzmann
thrombasthenia'.)
DIAGNOSIS — There is no "gold standard" test that can establish the diagnosis of ITP. The
diagnosis is, in part, one of exclusion, requiring that other causes of thrombocytopenia be ruled
out (table 2). Few diagnostic studies other than the history, physical examination, complete
blood count, and examination of the blood smear are necessary.Overall approaches to the
patient with thrombocytopenia are presented separately. (See "Evaluation and management of
thrombocytopenia by primary care physicians" and "Approach to the adult patient with
thrombocytopenia".)
Peripheral smear — Examination of the blood smear may provide evidence for other causes of
thrombocytopenia, such as the presence of schistocytes in patients with thrombotic
thrombocytopenic purpura-hemolytic uremic syndrome (picture 3). (See "Approach to the adult
patient with thrombocytopenia", section on 'CBC and peripheral smear' and "Diagnosis of
thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults".)Examination of the
peripheral blood smear is essential to exclude "pseudothrombocytopenia" due to the artifact of
platelet agglutination induced by the standard blood count anticoagulant, EDTA (picture 4).
EDTA-dependent agglutinins are present in approximately 0.1 percent of people in the general
population [58-61]. This phenomenon is thought to result from a "naturally occurring" platelet
autoantibody directed against a normally concealed epitope on the platelet membrane
glycoprotein (GP) IIb/IIIa, which becomes exposed by EDTA-induced dissociation of GP IIb/IIIa
[62]. This subject is discussed separately. (See "Approach to the adult patient with
thrombocytopenia", section on 'Pseudothrombocytopenia'.)It is important for each clinical
laboratory to have an established procedure for responding to artifactually low platelet counts
caused by these agglutinins. An appropriate procedure is to report that an artifact due to platelet
clumping is present, rather than the actual platelet count, which could be misinterpreted as true
thrombocytopenia.Three other artifacts can affect platelet counting:
• Cold-dependent platelet agglutinins and autoantibodies may induce "rosetting" of platelets
around neutrophils and/or monocytes, resulting in pseudothrombocytopenia.
 • Giant platelets that can occur in certain congenital thrombocytopenic disorders (picture 5) may
not be recognized as platelets by some automated instruments used for blood counts, resulting
in pseudothrombocytopenia. (See "Automated hematology instrumentation", section on 'Platelet
counting' and "Automated hematology instrumentation", section on 'The optical platelet count'.)
 • Cryoglobulin particles may be counted as platelets, artifactually elevating the platelet count in
patients who have cryoglobulinemia [63]. (See "Approach to the patient with thrombocytosis",
section on 'Spurious thrombocytosis'.)
Making a presumptive diagnosis — A presumptive diagnosis of ITP is made when the history
(eg, lack of ingestion of a drug, beverage, food, or herbal remedy that can cause
thrombocytopenia, such as quinine, including quinine in beverages such as tonic water, a
sulfonamide such as sulfamethoxazole, or heparin [64]), physical examination, complete blood
count, and examination of the peripheral blood smear do not suggest other etiologies for the
patient's isolated thrombocytopenia. (See "Drug-induced thrombocytopenia", section on 'Initial
approach'.)The only recommended further tests in such patients are [1,65]:
 • Testing for HIV and HCV in patients with appropriate risk factors
• Thyroid function testing to exclude the infrequent presence of occult hyperthyroidism or
hypothyroidism before elective splenectomy is performed
 • Bone marrow aspiration/biopsy in patients over 60 years of age to rule out myelodysplastic
syndrome [66,67]. Bone marrow studies should also be performed in patients responding poorly
to therapy and/or prior to splenectomy in order to reevaluate/reconfirm the initial diagnosis of
ITP.
For patients with presumed ITP, severe thrombocytopenia, and/or clinical bleeding, urgent
hematologic consultation is most appropriate. For asymptomatic patients with modest degrees
of thrombocytopenia, consultation is less urgent, but should be pursued in order to establish a
baseline, should treatment be required in the future.
Antiplatelet antibody testing — The American Society of Hematology ITP Practice Guideline did
not recommend antiplatelet antibody studies in patients thought to have ITP [1], and there is still
no evidence that antiplatelet antibody studies are important for the diagnosis of ITP. This
recommendation is different from the common practice of many physicians, but is consistent
with the absence of data that platelet antibody testing affects management decisions [2]. The
lack of clinical value of antiplatelet antibody testing reflects limitations of laboratory
methodology. The absence of detectable antiplatelet antibodies does not imply the absence of
autoantibodies as the underlying pathogenesis of ITP.
The lack of value of antibody testing can be illustrated by the following observations:
 • A small study compared patients with ITP to patients initially suspected of having ITP in whom
an alternative diagnosis was subsequently made [68]. Commonly used commercial tests for
both platelet-bound IgG and serum platelet-bindable IgG had no predictive value.
 • A larger series included 90 patients with a clinical diagnosis of ITP and 160 patients with a
clinical diagnosis of incidental thrombocytopenia of pregnancy (gestational thrombocytopenia);
four laboratories with expertise in platelet antibody testing were involved and eight different
assays for antiplatelet antibodies were used [69]. There was no difference between these two
groups with six of the tests; a seventh test had a statistically significant distinction, but the
difference was clinically unimportant because there was almost complete overlap among
individual patients.
• A subset of 40 patients in the preceding study had a statistically significant distinction when
glycoprotein-specific antiplatelet antibodies were assayed [69]. In another report, however, there
were variable results with platelet glycoprotein-specific antiplatelet antibody tests when the
same samples from patients with ITP were studied in eight different laboratories [70].
 • In reviews of four prospective studies, antiplatelet antibody tests were positive in 49 to 66
percent of patients with ITP, but were also positive in 7 to 28 percent of patients with apparently
nonimmune etiologies (eg, gestational thrombocytopenia, myelodysplastic syndrome,
familial/congenital thrombocytopenia) [57,71].
• Two studies of newer techniques demonstrated only 53 to 55 percent sensitivity for making the
diagnosis of ITP and 82 to 84 percent specificity [71,72].
These data provide support for the concept that thrombocytopenia in ITP is mediated by
autoantibodies, but the frequency of false negative and false positive results limits the value of
these tests for making clinical decisions [65].
Results of platelet antibody testing in ITP are also different from the standard practice in
autoimmune hemolytic anemia, which is defined by the presence of a positive antibody test (ie,
direct antiglobulin test [DAT], direct Coombs test). In many cases of ITP, what is being
measured is "platelet-associated IgG", which may reflect plasma IgG acquired by platelet
pincytosis rather than antiplatelet antibodies [73].At this time, platelet antibody tests are not
necessary for management decisions in patients with suspected ITP. Specifically, currently
available tests do not distinguish ITP from secondary thrombocytopenic purpura, and a negative
test does not rule out the diagnosis of ITP [2,68,71,72,74,75].
Clinically apparent associated conditions — Patients with thrombocytopenia and a clinically
apparent associated condition causing the thrombocytopenia may have a disorder comparable
to ITP. However, these patients can be distinguished from those with ITP because the clinical
course is often dominated by the associated condition. Examples include:
 • Chronic lymphocytic leukemia and other lymphoproliferative disorders. (See "Autoimmune
complications following purine analog therapy" and "Overview of the complications of chronic
lymphocytic leukemia".)
 • Thrombocytopenia associated with HIV infection. (See "Hematologic manifestations of HIV
infection: Thrombocytopenia and coagulation abnormalities", section on 'Thrombocytopenia'.)
• Systemic lupus erythematosus and other autoimmune disorders. Approximately 3 to 15
percent of patients with apparently isolated ITP go on to develop systemic lupus erythematosus
(SLE). In one series of 115 patients who underwent splenectomy for ITP, 14 (12.5 percent)
subsequently developed SLE [76]. (See "Hematologic manifestations of systemic lupus
erythematosus in adults", section on 'Thrombocytopenia'.)
In the definition of ITP, the emphasis on excluding only clinically apparent associated conditions
is important, because patients with typical ITP often have isolated abnormalities on serologic
tests without symptoms of a systemic disorder. As an example, up to 40 percent of otherwise
typical patients with ITP have positive tests for antinuclear antibodies [77] or antiphospholipid
antibodies [78-81].ITP and other autoimmune phenomena (eg, autoimmune hemolytic anemia,
pernicious anemia) are often seen in patients with common variable immunodeficiency (CVI)
[82]. The diagnosis of ITP may be made before, at the time of, or following the diagnosis of CVI
[83]. Testing for immunoglobulin levels has been suggested as a way to determine which
patients with ITP also suffer from CVI. Treatment of ITP with agents resulting in further
immunosuppression is relatively contraindicated when these conditions co-exist. (See "Clinical
manifestations and epidemiology of common variable immunodeficiency", section on
'Autoimmune disease'.)
The presence of antinuclear antibodies does not appear to affect the overall clinical course of
these patients, but antiphospholipid antibodies are associated with a high incidence of
thrombosis and/or fetal loss over the subsequent five years [84]. Patients should be alerted
about this increased risk. (See "Clinical manifestations of the antiphospholipid syndrome",
section on 'Hematologic manifestations' and "Treatment of the antiphospholipid syndrome",
section on 'Prophylaxis'.)
Bone marrow aspiration and biopsy — In the typical patient with ITP, overall bone marrow
cellularity is normal, with normal erythropoiesis and myelopoiesis. Megakaryocytes are present
in normal to increased numbers. In some patients, a shift towards younger megakaryocytes with
lesser degrees of nuclear polyploidy and less evidence of platelet production may be noted.
(See "Megakaryocyte biology and the production of platelets", section on 'Immune
thrombocytopenic purpura'.)Bone marrow examination is not required in most patients with
isolated thrombocytopenia and suspected ITP [1,3,85]. However, it should be performed in
patients over the age of 60, because of concern for the presence of myelodysplasia [86]. (See
"Clinical manifestations and diagnosis of the myelodysplastic syndromes", section on
'Thrombocytopenia' and 'Myelodysplasia' below.) Marrow examination is also of critical
importance in making a diagnosis of the rare condition, acquired pure megakaryocytic aplasia
(amegakaryocytic thrombocytopenia), in which megakaryocytes are either severely reduced in
number, or absent (see 'Differential diagnosis' below and "Recombinant hematopoietic growth
factors in inherited bone marrow failure syndromes", section on 'Amegakaryocytic
thrombocytopenia').
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of ITP in which patients develop
thrombocytopenia without other cytopenias is listed in the table (table 2).
TTP-HUS and DIC — Serious consequences result if thrombocytopenia as part of thrombotic
thrombocytopenia purpura-hemolytic uremic syndrome (TTP-HUS) or chronic disseminated
intravascular coagulation (DIC) is mistaken for ITP. These syndromes have other associated
hematologic and clinical abnormalities, such as the presence of fragmented red cells
(schistocytes) in TTP-HUS or abnormalities of coagulation in DIC, which should make their
diagnosis quickly apparent.
However, in some patients with TTP-HUS, only thrombocytopenia and anemia are present and
the anemia may be attributed to bleeding due to the thrombocytopenia [87]. (See "Causes of
thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults" and "Clinical
features, diagnosis, and treatment of disseminated intravascular coagulation in adults".)
Gestational thrombocytopenia — A common cause of thrombocytopenia is incidental
thrombocytopenia of pregnancy (also termed gestational thrombocytopenia) which occurs in
approximately 5 percent of women near the end of an otherwise uncomplicated pregnancy [88].
(See "Thrombocytopenia in pregnancy", section on 'Gestational thrombocytopenia'.)
The diagnostic criteria for gestational thrombocytopenia include [1]:
 • Asymptomatic, mild thrombocytopenia (platelet count typically >70,000/microL)
 • No past history of thrombocytopenia (except possibly during a previous pregnancy)
• Occurrence during late gestation
 • Absence of fetal thrombocytopenia
 • Spontaneous resolution following delivery
The diagnosis of incidental thrombocytopenia of pregnancy, as with the diagnosis of ITP,
requires the exclusion of other causes of thrombocytopenia. Thus, these two disorders may be
impossible to accurately distinguish prior to delivery. As noted above, antiplatelet antibody
testing does not reliably distinguish between these disorders [69]. This diagnostic dilemma may
have important management implications related to the risk of fetal thrombocytopenia:
thrombocytopenia does not occur in infants born to mothers with gestational thrombocytopenia,
but may occur in up to 15 percent of infants born to mothers with ITP [88]. (See "Treatment and
prognosis of immune (idiopathic) thrombocytopenic purpura in adults".)
Drugs — Drug-induced thrombocytopenia, including acute thrombocytopenia caused by
quinine-containing beverages, foods, and herbal remedies, cannot be initially distinguished from
ITP. The diagnosis of drug-induced disease requires resolution of the thrombocytopenia upon
cessation of the implicated drug, typically within five days (table 3) [64,89]. Drug-induced
thrombocytopenia, rather than ITP, should always be suspected in patients with recurrent, acute
episodes of severe, symptomatic thrombocytopenia.
Although drug-dependent antibodies can be documented by laboratory assays [90,91], these
assays are not routinely available in clinical laboratories and therefore cannot contribute to initial
management decisions. Furthermore, tests for drug-dependent antibodies may be negative in
patients with drug-induced thrombocytopenia. As examples:
• The test may not be sufficiently sensitive to detect the drug dependent antibody.
• The antibody may only react with a metabolite of the drug. This may be seen in patients with
thrombocytopenia caused by acetaminophen, naproxen, and ibuprofen. (See "Drug-induced
thrombocytopenia", for a more complete discussion of this subject).
A systematic review of published case reports of drug-induced thrombocytopenia presented a
comprehensive database on the level of clinical evidence supporting a causal relationship of the
drug to thrombocytopenia [64]. This database, updated through October 2008, is available at
<www.ouhsc.edu/platelets>.
Infection — Viral and bacterial infections commonly cause thrombocytopenia, which may be
acute (eg, rubella, infectious mononucleosis, ehrlichiosis, hepatitis) or chronic and persistent
(eg, HIV infection, HCV infection) [92]. (See "Hematologic manifestations of HIV infection:
Thrombocytopenia and coagulation abnormalities", section on 'Thrombocytopenia' and
"Extrahepatic manifestations of hepatitis C virus infection", section on 'Autoimmune
thrombocytopenic purpura and hemolytic anemia'.)
Hypersplenism — Hypersplenism due to portal hypertension caused by chronic liver disease is
characteristically associated with mild thrombocytopenia secondary to increased pooling of
platelets in the splenic sinusoids [93]. Diminished production of thrombopoietin may play a
contributory role [94]. Other signs of portal hypertension are typically present and the spleen is
usually palpable; however, these signs are not apparent in some patients. (See "Extrinsic
nonimmune hemolytic anemia due to mechanical damage: Fragmentation hemolysis and
hypersplenism", section on 'Extravascular nonimmune hemolysis due to hypersplenism'.)
Myelodysplasia — Myelodysplasia (MDS) in elderly patients may present initially with pure
thrombocytopenia [66,67]. This constitutes the rationale noted above for examination of the
bone marrow in elderly patients with suspected ITP.This was shown in a retrospective study of
interphase FISH analysis for del(20q) on thawed frozen bone marrow cell pellets from 23 adult
patients with ITP. These patients had bone marrow examination performed mostly because of
age >60 and/or failure to respond to ITP therapy, including splenectomy. While bone marrow
morphology, cellularity, and karyotype were normal in all of the cases, del(20q) was present in
12 (52 percent) [86,95]. (See "Clinical manifestations and diagnosis of the myelodysplastic
syndromes", section on 'Thrombocytopenia'.)
Congenital thrombocytopenias — Congenital, familial thrombocytopenia should be considered
in patients with persistent thrombocytopenia unaffected by treatment [96-98]. Although some
reports suggest that the platelets in patients with ITP are larger than normal, truly giant platelets
approaching the diameter of red blood cells do not occur in ITP. Their presence on the
peripheral smear or automated cell counters strongly suggests the presence of congenital,
familial thrombocytopenia (picture 5).
As an example, in a study of 35 patients with inherited macrothrombocytopenias and 56 with
ITP, a mean platelet volume >12.4 fL had a sensitivity and specificity of 83 and 89 percent,
respectively, in separating the former from the latter [99].
Among children, congenital thrombocytopenias are often initially misdiagnosed as ITP. Some of
these are discussed elsewhere in the program. (See "Approach to the adult patient with
thrombocytopenia", section on 'Abnormal platelet morphology' and "Congenital and acquired
disorders of platelet function", section on 'Inherited disorders of platelet function'.)
The most common of these and their typical clinical characteristics include:
• von Willebrand disease type 2B, with greater than expected bleeding for the degree of
thrombocytopenia. (See "Clinical presentation and diagnosis of von Willebrand disease", section
on 'Type 2B'.)
 • Wiskott-Aldrich syndrome and its variant, X-linked thrombocytopenia, with small platelets and
recurrent infections. (See "Wiskott-Aldrich syndrome".)
• Alport syndrome (hereditary nephritis) variants, with giant platelets, renal failure, and hearing
loss [100]. (See "Genetics, pathogenesis, and pathology of hereditary nephritis (Alport
syndrome)".)
 • May-Hegglin anomaly, with giant platelets and Döhle bodies in granulocytes, and other
manifestations of MYH9 gene mutations (the gene encoding the nonmuscle myosin heavy chain
IIA) [101]. (See "Approach to the adult patient with thrombocytopenia", section on 'May-Hegglin
anomaly'.)
• Fanconi syndrome, with short stature, anemia, and neutropenia. (See "Inherited aplastic
anemia in children", section on 'Fanconi anemia'.)
• Bernard-Soulier syndrome, with giant platelets and greater than expected bleeding for the
degree of thrombocytopenia. (See "Approach to the adult patient with thrombocytopenia",
section on 'Bernard-Soulier syndrome'.)
• Thrombocytopenia with absent radius (TAR) syndrome, with skeletal abnormalities. (See
"Neonatal thrombocytopenia", section on 'Thrombocytopenia-absent radius syndrome'.)
Acquired pure megakaryocytic aplasia — Patients with the rare disorder acquired pure
megakaryocytic aplasia (acquired amegakaryocytic thrombocytopenia) are clinically
indistinguishable from patients with ITP, except for the absence of bone marrow
megakaryocytes. (See "Recombinant hematopoietic growth factors in inherited bone marrow
failure syndromes", section on 'Amegakaryocytic thrombocytopenia'.)
ADDITIONAL INFORMATION — Additional information concerning thrombocytopenic
conditions (ie, drug-induced, ITP, TTP-HUS, and thrombocytopenia in pregnancy) can be found
on a database maintained by Dr. James N. George at the University of Oklahoma Health
Sciences Center. This database is updated regularly and is available at
<www.ouhsc.edu/platelets>.
SUMMARY AND RECOMMENDATIONS
Making the diagnosis — There is no "gold standard" test that can establish the diagnosis of ITP.
The diagnosis is in part one of exclusion, requiring that other causes of thrombocytopenia be
ruled out (table 2).
A presumptive diagnosis of ITP is made when the history (eg, lack of ingestion of a drug that
can cause thrombocytopenia), physical examination, complete blood count, and examination of
the peripheral blood smear do not suggest other etiologies for the patient's
isolated thrombocytopenia.
Recommended testing — Few diagnostic studies other than the history, physical examination,
complete blood count, and examination of the blood smear are necessary. The only
recommended further tests in such patients include [1]:
 • HIV and HCV testing in patients at risk for these infections
• Bone marrow aspiration in patients over 60 years of age to rule out one of the myelodysplastic
syndromes (see 'Myelodysplasia' above)
When to obtain hematologic consultation
• For patients with presumed ITP, severe thrombocytopenia, and/or clinical bleeding, urgent
hematologic consultation is most appropriate.
 • For asymptomatic patients with modest degrees of thrombocytopenia, consultation is less
urgent, but should be pursued in order to establish a clinical and laboratory baseline, should
treatment be required in the future. (See "Treatment and prognosis of immune (idiopathic)
thrombocytopenic purpura in adults", section on 'General therapeutic principles'.)

Treatment and prognosis of immune (idiopathic) thrombocytopenic purpura in adults

Author
James N George, MD Section Editor
Lawrence LK Leung, MD Deputy Editor
Stephen A Landaw, MD, PhD
Last literature review version 18.2: May 2010 | This topic last updated: June 9, 2010 (More)
INTRODUCTION — Immune (idiopathic) thrombocytopenic purpura (ITP) is an acquired
disorder. Only two criteria are required for its diagnosis [1-5]:
 • Thrombocytopenia, with an otherwise normal complete blood count and white blood cell
differential, including a normal peripheral blood smear (except when coincidental abnormalities
are also present, such as concomitant iron deficiency).
 • No clinically apparent associated condition(s) or medications (including herbal preparations,
quinine-containing beverages) that may cause thrombocytopenia are present.
The pathogenesis of ITP is presumed to be related to increased platelet destruction along with
inhibition of platelet production via the production of specific autoantibodies. However, such
antibodies are not easily demonstrable in all patients, and assays for antiplatelet antibodies
have not been important for management decisions. (See "Clinical manifestations and diagnosis
of immune (idiopathic) thrombocytopenic purpura in adults", section on 'Pathogenesis'.)
The initial treatment and prognosis of ITP in adults will be reviewed here. The approach is
compatible with guidelines for ITP issued by the British Committee for Standards in
Haematology General Haematology Task Force in 2003 [1], and an international consensus
report in 2009 [2].
Treatment of chronic, refractory ITP, the clinical manifestations, diagnosis, and differential
diagnosis of ITP in adults, and issues related to ITP in children are discussed separately. (See
"Chronic refractory immune (idiopathic) thrombocytopenic purpura in adults" and "Clinical
manifestations and diagnosis of immune (idiopathic) thrombocytopenic purpura in adults" and
"Clinical manifestations and diagnosis of immune (idiopathic) thrombocytopenic purpura in
children".)
GENERAL THERAPEUTIC PRINCIPLES — Major bleeding is rare in patients with ITP,
primarily occurring in those with platelet counts below 10,000/microL (figure 1) [6]. The goal for
treatment of ITP is to provide a safe platelet count to prevent major bleeding, rather than
returning the platelet count to normal [3,5]. This involves the following critical concepts (see
'Patient selection' below:
 • Adults with severe thrombocytopenia (ie, a platelet count below 30,000/microL) at the time of
diagnosis are always treated even if they are asymptomatic or have only minor bleeding
symptoms, because the course of the disease and the risk for future bleeding cannot be known.
• Avoid unnecessary treatment of asymptomatic patients with mild to moderate
thrombocytopenia (ie, a platelet count greater than 30,000 to 50,000/microL).
• The efficacy of continued therapy is uncertain among asymptomatic patients with chronic
severe thrombocytopenia who have had no or only a partial response to treatment. Such
patients often report that the morbidity from side effects of therapy exceeds any problems
caused by their ITP [7].
Natural history — An understanding of the natural history of untreated ITP, which differs
between children and adults, provides part of the rationale for deciding which patients should be
treated. Many children receive no specific therapy, since 70 to 80 percent have a spontaneous
complete remission of the disease within six months. (See "Clinical manifestations and
diagnosis of immune (idiopathic) thrombocytopenic purpura in children".)
Spontaneous remissions are unusual in adults, occurring in 9 percent in one series [8]. The
necessity for treatment in adults varies with the severity of the thrombocytopenia:
 • Adults with severe thrombocytopenia (platelet count below 30,000/microL) at the time of
diagnosis are treated, most often with glucocorticoids. However, most do not maintain a normal
platelet count after glucocorticoids are discontinued [8,9]. (See 'Initial treatment' below.)
• Most adults presenting with platelet counts greater than 30,000 to 50,000/microL have a stable
and benign course without treatment [8,10-12]. Data from case series suggest that 15 percent
or less of such patients develop more severe thrombocytopenia and require treatment during
three to seven years of follow-up [8,10,11].
The frequency of spontaneous remissions in adults after a prolonged duration of ITP is less
clear. The incidence of major bleeding and death from bleeding is also unknown, although these
events are thought to be rare. The absence of firm data on these important clinical outcomes
impairs all management decisions. The following observations suggest that ITP may be a more
benign disease than previously thought, and may be best approached by a conservative
treatment program in the majority of patients [8,11,12].
In a report of 208 adults with ITP who were followed for a median of 92 months, the following
findings were noted [8]:
 • 42 percent had a platelet count above 50,000/microL and were not treated; these patients had
a spontaneous remission rate of 9 percent. Fifteen percent of patients had a subsequent fall in
platelet count to less than 50,000/microL and were treated with prednisone.
 • At last follow-up in 95 treated patients, 43 were in complete remission without therapy and 52
were still being treated.
• Five deaths were attributable to thrombocytopenia.
A second series evaluated long-term morbidity and mortality in 152 patients who were followed
for a median duration of 9.5 years [11]:
 • The long-term mortality risk was equal to that in the general population.
• Six patients died of ITP-related causes: two from disease-related causes (eg, intracranial
hemorrhage); and four from complications of treatment (eg, infection related to
immunosuppressive therapy or previous splenectomy).
• Morbidity from splenectomy in 78 patients was 26 percent (eg, postoperative complications
resulting in prolonged hospitalization or readmission).
These data suggest caution in the therapeutic approach to ITP, reserving aggressive treatment
for patients with severe and symptomatic thrombocytopenia.
INITIAL TREATMENT — There are few prospective, controlled trials concerning the
effectiveness of different therapies for ITP on long-term outcomes [2,3]. Nevertheless, since
spontaneous remissions are unusual in adults with ITP, treatment to increase the platelet count
is always initiated in patients with a platelet count below 30,000/microL, which is severe enough
to constitute a risk for bleeding.
Some adults who present with an abrupt onset of purpura and severe thrombocytopenia have a
self-limited course, possibly caused by an inapparent infection or an adverse drug reaction. In a
cohort study from England, for example, 28 of 343 patients (8 percent) initially registered as
having ITP were subsequently determined to have had drug-induced thrombocytopenia [12].
Quinine was the most commonly implicated agent (13 patients). Three patients had
splenectomy before the drug-induced etiology was recognized.
Patient selection — The above observations reinforce the importance of appropriate patient
selection for treatment of the ITP:
• All patients with severe thrombocytopenia (platelet count less than 30,000/microL) should be
treated because they are at risk of bleeding. This is especially true in the patient with
comorbidities (eg, older patient, hypertension), in whom the bleeding might be fatal.
 • Patients with mild to moderate asymptomatic thrombocytopenia that is discovered incidentally
on a routine blood count should not be treated.
 • As noted above, among patients with initial platelet counts above 30,000 to 50,000/microL,
fewer than 15 percent of untreated patients develop more severe thrombocytopenia that require
treatment after three to seven years of follow-up [8,10,11]. These data suggest that such
patients require careful follow-up but no specific initial therapy [1,13].
 • When treatment is given, it should be limited in duration unless symptomatic
thrombocytopenia persists.
Asymptomatic patients with even lower platelet counts may be carefully followed without specific
treatment, since experience in patients who have ITP [6], aplastic anemia [14], and
thrombocytopenia due to chemotherapy-induced marrow suppression [15] suggests that major
bleeding does not occur unless the platelet count is <10,000/microL (figure 1).
An additional consideration for assessing the relative benefits and risks of initial treatment is the
patient's lifestyle. What may be a safe platelet count for a sedentary, older patient could be a
potential risk for a physically active, younger patient [13]. However, older patients may be more
at risk for bleeding because of associated conditions (eg, peptic ulcer disease, hypertension,
cerebrovascular disease) [10,16], disorders requiring treatment with antiplatelet agents or
anticoagulants (eg, coronary heart disease), or the need for surgery or other invasive
procedures.
The decision to treat or not to treat is complex, and there are no data to guide management
decisions. Factors that should be taken into account include:
• Presence or absence of severe or life-threatening bleeding
• Risks for trauma from the patient's age, occupation, and lifestyle
• Medical conditions and medications increasing the risk of thrombocytopenia, bleeding, and/or
infection, especially if myelosuppressive or immunosuppressive agents are to be employed
Accordingly, the decision to treat should be a shared one between the clinician and the patient.
Patients may be bothered by side effects of treatment much more than their physician
appreciates. On the other hand, physicians may be more concerned about the risk for bleeding
than their patients [7].
A scheme for the sequence of treatment divides treatment into three sequential steps (algorithm
1).
Glucocorticoids — The goal of initial glucocorticoid treatment is not to "cure" the ITP, but to
support the platelet count in a safe range with minimal and tolerable side effects until a
spontaneous remission occurs, or until more definitive management establishes a durable
remission.
Prednisone — In adults, a standard practice for many decades has been to initiate treatment
with oral prednisone, 1 mg/kg given as a single daily dose. Most adults with ITP respond to
prednisone treatment within two weeks, with the majority responding within the first week. The
duration of initial prednisone treatment is determined by the platelet count response. If the
platelet count recovers promptly to normal, the prednisone dose is tapered and discontinued;
there is no standard regimen for tapering the prednisone dose. Some hematologists feel that a
very gradual tapering schedule increases the chance for a durable remission; others feel that a
more rapid tapering schedule is better, in order to diminish glucocorticoid side effects and to
determine if further treatment is actually required. A reasonable course is to taper and
discontinue prednisone over four to six weeks after achieving a normal platelet count. This
schedule includes the time period during which most spontaneous remissions might otherwise
occur. (See "Glucocorticoid withdrawal".) Patients with persistent symptomatic and severe
thrombocytopenia (usually described as a platelet count <10,000/microL) after two weeks of
prednisone should be considered for additional treatment; patients with severe bleeding may
require additional treatment immediately. Most adults who initially respond to glucocorticoids will
have a recurrence of thrombocytopenia when the dose is tapered and discontinued, indicating
the need for further treatment. In one series, for example, 39 percent of prednisone-treated
patients had a complete remission; however, only one-half of these patients had a sustained
complete remission lasting more than six months after maintenance therapy was discontinued
[8].
If thrombocytopenia recurs, prednisone may be temporarily resumed until a decision for more
definitive treatment is made. Long-term glucocorticoid treatment is not appropriate, as the
consequences may be severe. The risk for glucocorticoid-induced osteoporosis is a particular
concern, especially in women and older patients. It is generally recommended that patients
treated with prednisone for more than three months should receive calcium and vitamin
D supplementation, along with monitoring of bone mineral density. (See "Major side effects of
systemic glucocorticoids" and "Prevention and treatment of glucocorticoid-induced
osteoporosis".)
High-dose dexamethasone — The role of high-dose dexamethasone for initial treatment of ITP
in adults is being actively investigated. A number of non-randomized studies have suggested
the utility of this agent when given in a dose of 40 mg per day (either orally or intravenously) for
4 to 8 consecutive days, given for 1 to 6 cycles of 14 to 28 days in length [9,17,18]. Two of the
largest of these studies are discussed below. A brief course of high-dose dexamethasone (40
mg/day orally for four consecutive days) was given to 157 consecutive patients with either a
platelet count <20,000/microL or a count <50,000/microL with clinically significant bleeding [9].
Response criteria for this study included an initial platelet count increase of ≥30,000/microL, a
platelet count >50,000/microL by day 10, and cessation of bleeding. Lack of response was
defined as a platelet count increase of <30,000/microL, or a platelet count of ≤50,000/microL by
day 10. If the platelet count subsequently dropped to <30,000/microL within the first six months,
a second four-day course of dexamethasone was given, followed by 15 mg/day PO of
prednisone, with gradual tapering. Those patients not responding to the first or second courses
of dexamethasone were offered other treatments.
The following results were noted [9]:
 • There was an initial response in 106 of the 125 eligible patients (85 percent). Platelet counts
increased more than 20,000/microL by the third day of treatment, with a mean count of
101,000/microL at one week (range: 50,000 to 260,000).
• Fifty-three of the 106 responding patients (50 percent) had a sustained platelet count
≥50,000/microL after a single course of dexamethasone, and required no further treatment
during two to five years of follow-up.
 • The remaining 53 patients had a relapse (as defined above) at a median time of 45 days
(range: 14 to 129 days). All responded to a second four-day course of dexamethasone.
 • A platelet count <90,000/microL on day 10 was associated with a relapse rate of 70 percent,
while those with a count >120,000/microL on day 10 had a relapse rate of less than 20 percent.
 • Treatment was well tolerated; discontinuation of treatment because of intolerable side effects
was not required in any patient.
In a multicenter trial, 95 patients with severe ITP (median platelet count 10,000/microL, range
1000 to 35,000) were given high-dose dexamethasone in a dose of 40 mg/day (either orally or
intravenously) for 4 consecutive days; treatment was repeated every 14 days for 4 cycles [18].
Complete (ie, platelet count ≥150,000/microL), partial (ie, platelet count 50,000 to
149,000/microL), and minimal (ie, platelet count 31,000 to 49,000/microL) responses were seen
in 64, 20, and 1 percent of patients, respectively. Overall response rates after one, two, three, or
four treatment cycles were obtained in 70, 76, 89, and 86 percent, respectively, suggesting that
maximum benefit was attained after three cycles.
Overall relapse-free survival was 81 percent at 15 months, and was 87 versus 65 percent for
those attaining a complete or a partial/minimal response, respectively. Treatment was well
tolerated.
A small (36 patients) randomized trial found a significantly greater platelet count response at 5
days for high-dose dexamethasone over conventional dose prednisolone (60 mg/day) [19].
Confirmation of these results in a larger randomized trial setting (ie, three cycles of high-dose
dexamethasone versus standard prednisone treatment at 1 mg/kg per day) is planned in a
subsequent trial. This will be required before high-dose dexamethasone can be recommended
as initial treatment for severe or symptomatic ITP, especially since a prior study demonstrating
successful use of this protocol in patients with relapsed/resistant ITP could not be confirmed in
follow-up studies [20].
Advantages of this regimen are the short and defined duration of treatment, compared with the
indefinite duration of daily oral prednisone treatment [21].
High-dose methylprednisolone — High-dose methylprednisolone (HDMP) has generally been
used in children and in adults resistant to conventional doses of prednisone. However, one
study evaluated the efficacy of HDMP as first-line therapy for 21 adults with severe
thrombocytopenia and severe or persistent mucosal or vaginal bleeding. Results were
compared with 36 patients with a less severe presentation who were treated with conventional
doses of prednisone [22]. HDMP was given in a dose of 30 mg/kg intravenously over the course
of one hour initially and tapered every third day to 1 mg/kg once daily. Patients treated with
HDMP responded more rapidly (4.7 versus 8.4 days) and had a higher response rate (80 versus
53 percent) despite presenting with more severe clinical disease. Three of the 12
nonresponders to conventional doses of prednisone responded to a subsequent course of
HDMP. There was no difference between the two groups in the frequency of complete or
persistent remission. Further studies are required to assess the utility of this approach, which
employed a high dose of this agent not usually employed in adults. (See 'Methylprednisolone
versus IVIG' below and 'Emergency treatment of life-threatening bleeding' below.)
Intravenous immunoglobulin — The platelet count can be temporarily supported by the use of
intravenous immune globulin (IVIG) or by anti-Rh(D) (Rho(D) immune globulin, anti-D,
WinRho™) in patients whose red cells are Rh(D) positive and who have not had a splenectomy.
Both of these agents increase the platelet count in most patients with ITP within several days,
with an effect that may last for several weeks [3,23,24]. (See "Intravenous immune globulin in
hematologic disorders", section on Idiopathic thrombocytopenic purpura.)
A prospective, multicenter trial randomly assigned 35 consecutive adult patients with ITP (mean
platelet count 26,000/microL) to receive IVIG at an initial total dose of either 0.5 or 1.0 g/kg over
a period of 4 to 12 hours on day 1 [25]. Non-responders received additional IVIG in divided
doses on days 4 and 5 to reach a total intravenous dose of 2.0 g/kg. Results of this study
included the following:
 • Responses (an increase in platelet count to ≥80,000/microL to at least twice the initial platelet
count) to the lower (0.5) and higher (1.0) IVIG doses were seen in 6 and 28 percent on day 2,
24 and 61 percent on day 3, and 24 and 67 percent on day 4, respectively.
 • Eleven of the 13 non-responders to the 0.5 g/kg dose, and two of the six non-responders to
the 1.0 g/kg dose, responded by day 8 to a total dose of 2.0 g/kg, for an overall response rate of
78 percent.
• Transient and reversible intolerance to IVIG was seen in two patients in the low dose group,
and consisted of hypertension and headache in one, and chills, vomiting, and hypotension in the
other.
Anti-D is effective only in Rh-positive patients in whom the immunoglobulin binds to the
erythrocyte D antigen, and is also apparently effective only in patients who have not had
splenectomy. Immune-mediated clearance of the sensitized erythrocytes occupies the Fc
gamma receptors in the reticuloendothelial system, minimizing removal of antibody-coated
platelets [26-28]. Accordingly a modest amount of hemolysis is expected with the use of this
agent, although more severe degrees of hemolysis have been reported following use of this
agent (see below) [29,30]. The response rate to anti-D in one series was 70 percent, with the
increase in platelet count lasting more than 21 days in 50 percent of the responders [24].
 Standard intravenous regimens for these products are [31]:
 • IVIG — 1 g/kg per day, given for one to two days
 • Anti-D — 50 to 75 mcg/kg per day, given once
Neither modality is expected to induce a long-term remission. However, these agents may be
valuable in a patient with life-threatening bleeding, or in preparing for splenectomy or other
surgical procedures (see 'Emergency treatment of life-threatening bleeding' below and
'Splenectomy' below).
Side effects — IVIG and anti-D can cause mild alloimmune hemolysis and IVIG may also cause
headache, nausea, and vomiting, symptoms that may cause concern for the possible
occurrence of intracranial hemorrhage [32]. Some sucrose-containing products may also be
associated with acute renal failure [33].
If an Rh(D)-positive patient who received anti-D requires a red cell transfusion, Rh(D)-negative
red cells should be used, to avoid worsening ongoing hemolysis. Caution should also be
exercised if the patient receives platelets from an Rh(D)-positive donor, since these
preparations may contain significant quantities of red cells. Additional information on these
topics can be obtained from the revised package insert and the Food and Drug Administration
website [34].
Intravascular hemolysis from anti-D — Unpublished data from anti-D clinical trials for the
treatment of ITP have revealed an estimated incidence of intravascular hemolysis of 0.7 percent
[35,36]. Signs and symptoms consistent with intravascular hemolysis, including back pain,
shaking chills, and/or hemoglobinuria, occurred within four hours of anti-D administration.
Severe complications included anemia, requiring transfusion and ending fatally in one case,
acute onset or exacerbation of renal insufficiency, requiring dialysis in two cases [37], and six
cases of disseminated intravascular coagulation (DIC) associated with acute hemoglobinemia or
hemoglobinuria, five of which were fatal [38]. Estimates for the risk of development of
intravascular hemolysis or DIC are less than 1/1000 and 1/10,000, respectively.
The etiology of intravascular hemolysis following anti-D administration is unknown [39]. No risk
factors associated with this adverse event have been identified, including age, gender, renal
function prior to treatment, hemoglobin concentration, concomitantly administered packed red
cells, or dose. Some of the patients in whom DIC occurred had tolerated previous doses of the
drug. A "black box" warning indicates that patients receiving anti-D should be monitored for
hemoglobinuria/hematuria/renal function during the 8 hours following use of this agent, and that
this agent not be used in patients with evidence of, or at high risk for, hemolysis (eg,
reticulocytosis, positive Coombs test) [40,41].
Methylprednisolone versus IVIG — The relative efficacy of high-dose intravenous
methylprednisolone (MP, 15 mg/kg per day on days 1 to 3) versus IVIG (0.7 g/kg per day on
days 1 to 3) was studied in a prospective randomized trial in 122 patients with previously
untreated severe acute ITP (ie, platelet count ≤20,000/microL) [42]. In a second randomization,
patients received either placebo or oral prednisone (1 mg/kg per day) on days 4 to 21. Major
study results included:
 • The percent of patients with a platelet count >50,000/microL on days 2 and 5 was slightly
greater for those receiving IVIG (7 and 79 percent, respectively) than for those receiving MP (2
and 60 percent).
• Use of prednisone was significantly more effective than placebo for all short-term study
endpoints (eg, days with platelet count >50,000/microL, highest platelet count, platelet count at
21 days, and time to relapse).
 • The remission rate at one year was not affected by the initial treatment (IVIG versus MP); use
of prednisone did not prevent progression to chronic ITP.
SECOND-LINE MANAGEMENT AFTER FAILURE OF INITIAL THERAPY
Overview — Second-line management should be reserved for patients with persistent
symptomatic thrombocytopenia following treatment with glucocorticoids, typically those with
platelet counts <30,000/microL. As the risks of treatment with second-line agents are greater
than those seen with initial glucocorticoid treatment, the indications for treatment with second-
line agents must become more stringent. A current issue is the choice between splenectomy
and rituximab as the next treatment for patients who have severe and symptomatic
thrombocytopenia following failure of initial glucocorticoid treatment.
 • Splenectomy has been the traditional second-line treatment for many years in adults with ITP;
it remains the most effective treatment for ITP with the highest rate of complete and durable
remissions [43].
• Rituximab may induce a lower frequency of durable remissions than splenectomy, but for
some patients avoidance of surgery may be the preferred choice.
A review of available treatments for ITP has suggested that many other modalities (eg,
thrombopoietin (TPO)-receptor agonists) may be considered as "second-line treatments";
however these additional modalities are uncommonly used, may be less effective, and have
more risk than either splenectomy or rituximab [2]. As an example, TPO-receptor agonists
support the platelet count but do not induce remissions in ITP; therefore they are more
appropriately considered for patients who require platelet count support after splenectomy and
rituximab have failed to result in the attainment of a safe platelet count. (See "Chronic refractory
immune (idiopathic) thrombocytopenic purpura in adults", section on Thrombopoiesis-
stimulating agents for a more complete discussion of the risks and benefits of these agents.)
Anti-D following glucocorticoid failure — Twenty-seven Rh(D)+ patients with a diagnosis of ITP
within the prior 1 to 12 months, who had failed initial treatment with glucocorticoids (26 patients)
or other treatments, and who had platelet counts ≤30,000/microL, received intermittent
treatment with anti-D at an intravenous dose of 50 to 75 microg/kg whenever their platelet count
was ≤30,000/microL [44]. Initial results suggested that most patients responded to anti-D; in
some patients splenectomy may have been avoided or delayed.
However, in a subsequent randomized, controlled clinical trial comparing standard treatment
(glucocorticoids, splenectomy) to treatment with anti-D for initial management of patients with
ITP, splenectomy was delayed but the overall frequency of splenectomy was not diminished
[45].
Splenectomy — Splenectomy appears to work in ITP via two separate mechanisms. (See
"Approach to the adult patient with splenomegaly and other splenic disorders", section on
'Normal splenic function'.)
• Splenectomy removes the major site where antibody-coated platelets are trapped and
destroyed [46].
• As the spleen contains about 25 percent of the total lymphoid mass of the body, splenectomy
may contribute to a decrease in anti-platelet antibody production.
There are more than 70 years of experience with splenectomy, beginning when it was the only
effective treatment, prior to the introduction of glucocorticoids in 1950. A systematic review of
splenectomy for ITP reported data from 47 case series describing results with 15 or more adult
patients [43]. Patient outcomes were consistent across many years and many different
countries. Sixty-six percent of 2623 patients achieved a complete remission, defined by a
normal platelet count with no subsequent treatment. An additional 22 percent had a partial
response, defined by a platelet count over 50,000/microL, with or without treatment [43].
Follow-up after splenectomy in these 47 case series varied from 1 to 153 months (median: 29
months) and demonstrated that the percent of patients remaining in complete remission was not
related to the duration of follow-up (figure 2) [43].
These data suggest that in most of the two-thirds of patients who achieve a complete remission
following splenectomy, the remission is durable.
Indications and results — Important considerations affecting the decision for splenectomy
include:
 • The severity of bleeding or thrombocytopenia and the assumed risk for major bleeding.
Splenectomy is not appropriate for patients with mild or moderate thrombocytopenia and minor
bleeding.
 • The patient's lifestyle related to risk for bleeding.
 • The duration of ITP. Since ITP can remit spontaneously in a small percent of patients,
splenectomy is usually deferred for four to six weeks after diagnosis. A 2010 review has
suggested that splenectomy be deferred for six months after diagnosis [2]. However, many
patients with persistent severe and symptomatic thrombocytopenia in spite of initial
glucocorticoid treatment will require consideration of splenectomy much sooner than six months.
 • The probability that splenectomy will provide a complete remission from ITP. The best
estimate for a complete remission following splenectomy is 66 percent [43]. Some studies, both
in adults and children, have suggested that splenic sequestration of radiolabeled platelets
[47] or a response to IVIG [48,49] may predict a favorable response to splenectomy; however,
the data are not consistent and study of the sequestration of radiolabeled platelets remains an
investigational procedure [43,50-54].
The only clinical parameter that predicts a favorable response to splenectomy is patient age;
younger patients respond better [3,43,47,55]. However, a specific age cut-off for this
observation could not be determined in our literature review [43].
• The potential risks from the surgical procedure. In a healthy, young, thin patient, splenectomy
is a low risk procedure. Surgical risk is increased in older or obese patients with other medical
problems.
 • The morbidity and mortality from splenectomy appear to be less with laparoscopic techniques
than with standard laparotomy [56-59]. One case series reported that 26 percent of 78 patients
undergoing splenectomy by standard laparotomy suffered postoperative complications, resulting
in prolonged hospitalization or readmission [11]. In the author's review of over 3000 such
procedures, morbidity was 9.6 versus 12.9 percent and mortality 0.2 versus 1.0 percent for
laparoscopic and laparotomy splenectomies, respectively [43]. Patients who achieve a complete
remission following splenectomy typically do so within the first two weeks after surgery; some
may have an immediate post-operative "surge" in their platelet counts [58]. This prompt
response is consistent with the concept that the spleen is the major site of destruction of
antibody-sensitized platelets, and is supported by studies of infusion of plasma from patients
with ITP into normal volunteers [46]. Infusion of such plasma caused thrombocytopenia in
normal subjects, while in splenectomized subjects much larger doses were required to induce
thrombocytopenia [46]. A longer-term benefit of splenectomy is this procedure's removal of the
major site of autoantibody production.
Complications — The risks of splenectomy include those of the surgical procedure plus
increased susceptibility to serious infection. With respect to surgical risk, patients should have a
platelet count >50,000/microL when undergoing splenectomy, usually after response to
treatment with glucocorticoids, IVIG, anti-D, and/or platelet transfusions. However, some
patients with ITP undergo splenectomy with more severe thrombocytopenia (ie, platelet counts
<50,000/microL) and have only negligible bleeding [60]. The risk of overwhelming infection
throughout the patient's lifetime post-splenectomy is very small, with an estimated mortality of
0.73 per 1000 patient-years [61]. However, the rare occurrences of overwhelming and rapidly
fatal sepsis in splenectomized patients are dramatic [62]. Patients should be immunized at least
two weeks prior to splenectomy for Streptococcus pneumoniae, Hemophilus influenzae b, and
Neisseria meningitidis [3]. Since many adults with ITP will be considered for splenectomy, an
appropriate routine is to immunize all adults at the time of diagnosis, before extensive
immunosuppressive treatment has been given. (See "Prevention of sepsis in the asplenic
patient".)
Rituximab — Rituximab is another second-line treatment to be considered after failure of initial
glucocorticoid treatment, and has at least short-term effectiveness in about 40 percent of
patients with ITP [63]. This was shown in a prospective multicenter phase II trial involving 60
patients who were considered to be candidates for splenectomy, had ITP for ≥6 months and a
platelet count <30,000/microL, and were treated with four weekly intravenous injections of
rituximab (375 mg/m2 per dose) [64]. The following findings were noted:
• Good responses (ie, a platelet count ≥50,000/microL with at least a doubling of the initial
platelet count at one or two years after the first rituximab dose) were seen in 24 patients (40
percent) at one year and in 20 patients (33 percent) at two years.
 • At two years, 24 patients (40 percent) had sustained platelet counts ≥30,000/microL without
treatment.
 • Sixteen patients (27 percent) experienced transient side effects; rituximab treatment was
discontinued in only one.
 • Among the 36 nonresponders, 25 underwent splenectomy. Splenectomy resulted in good
responses (as defined above) in 15 (60 percent) at a median follow-up of 18 months.
A multicenter phase III trial investigated the efficacy of combined treatment with rituximab and
dexamethasone in previously untreated adult ITP patients. In this randomized study, 103
patients with a platelet count ≤20,000/microL received 40 mg/day of dexamethasone for four
consecutive days with or without rituximab (375 mg/m2 weekly for 4 weeks, starting on day 7).
Results in 101 evaluable patients included [65]:
• At six months, 63, 53, and 43 percent of the 49 patients treated with dexamethasone plus
rituximab achieved platelet counts >50,000, >100,000, or >150,000/microL, respectively. The
corresponding figures for the 52 patients treated with dexamethasone alone were 36, 33, and
25 percent, respectively.
• Patients randomly assigned to treatment with dexamethasone alone who failed to achieve
platelet counts >50,000/microL were eligible to receive "salvage" therapy with dexamethasone
plus rituximab. Of the 27 patients so treated, 56, 44, and 37 percent achieved platelet counts
>50,000, >100,000, or >150,000/microL, respectively.
• At a median follow-up of 20 months, the rates of relapse (ie, a platelet count <50,000/microL)
were 23, 26, and 14 percent for those treated with dexamethasone alone, dexamethasone plus
rituximab, or "salvage" therapy, respectively.
 • Grades 3 or 4 adverse events were more common in those treated with dexamethasone plus
rituximab (10 versus 2 percent for the dexamethasone alone arm).
The authors concluded that the regimen of dexamethasone plus rituximab provides an option for
second-line therapy, especially in those not responding to glucocorticoids, and could serve as
an alternative to splenectomy. Although previously untreated patients were selected for this
study to avoid potential bias from prior treatments, the authors recommend this regimen only as
second-line therapy. No trial has directly compared rituximab to splenectomy in patients with
ITP unresponsive to glucocorticoids or other first-line agents, nor has any trial compared
different regiments of rituximab. The regimen of 375 mg/m2/week for 4 weeks was adapted
because it was the standard dose for patients with lymphoma. A much lower dose, 100
mg/week for 4 weeks appeared to have similar efficacy for inducing remissions in ITP in one
series of 28 patients [66]. While rituximab-associated side effects may be fewer than the
surgical complications of splenectomy, the response rates appear to be less than with
splenectomy, both for the percent of patients achieving a complete remission as well as for the
duration of remission [43,63,67,68]. However long-term complications are rare with both
rituximab and splenectomy and their frequency may be similar. Progressive multifocal
leukoencephalopathy is the most critical long-term adverse effect of rituximab, but it has been
reported in only one patient treated for ITP [69]. However, as noted in the above study,
treatment with rituximab did not seem to lower the response rate to splenectomy should it be
required later due to rituximab failure [64]. Rituximab has also been documented to be effective
in both adults and children who have failed to respond to splenectomy [70-78]. Major responses
(ie, platelet counts >50,000/microL) have been seen in approximately 50 percent, with complete
remissions (ie, platelet counts >150,000/microL) in about one-third. (See "Treatment and
prognosis of immune (idiopathic) thrombocytopenic purpura in children", section on 'Treatment
of refractory chronic ITP'.)
• In two reports, 16 of 18 patients achieving complete remission maintained that status at a
median observation period of 72 weeks [74] and 17 of 31 patients with responses lasting more
than one year maintained that response for a total of five years [76].
• In a third report in 26 patients with relapsed or refractory ITP and active, symptomatic disease,
complete and partial responses to rituximab were seen in 14 and 4 subjects, respectively [79].
Nine of the 18 responding patients relapsed after a median of 21 months (range: 8 to 66
months).
Two systematic reviews of case series describing rituximab treatment of five or more patients
with chronic refractory ITP have documented a short-term 30 to 43 percent rate of complete
remission with this agent [63,80]. This remission rate is similar to that noted in a prospective
cohort study of children with chronic ITP; 11 of 30 children (37 percent) responded with a
sustained platelet count >100,000/microL for at least 4 consecutive weeks [81]. The durability of
these responses is uncertain; the systematic review mentioned above noted that the median
follow-up of patients in the available series was only 9.5 months [63].
None of the studies included in one of the systematic reviews of rituximab employed a control
group and the quality of such data was considered to be poor [63]. The finding of significant
toxicity of rituximab in this review, including death in 2.9 percent of cases, suggests caution in
its use. Although many of the deaths may have been related to long courses of complex
treatment regimens for patients with advanced disease, some of the nine reported deaths may
have been attributable to toxicity of rituximab [63]. Rituximab might be preferred by those
patients who are not good candidates for surgery or who wish to avoid surgery. However,
accumulating experience shows that rituxan response may be less durable than the response to
splenectomy. The use of rituximab as initial second-line treatment after failure of steroids may
not avoid surgery, but may only prolong the period before the more definitive splenectomy is
done. Although rituximab has been studied in combination with dexamethasone in previously
untreated patients, it is not recommended for initial treatment.
Thrombopoiesis-stimulating agents — Thrombopoiesis- stimulating agents (TPO mimetics) are
approved by the United States FDA for use in ITP in adults "with insufficient response to
corticosteroids, immunoglobulins, or splenectomy", and have been advocated for second-line
treatment of ITP in a 2010 review [2]. The basis for this recommendation is that these agents
are the only treatments for ITP with efficacy supported by randomized clinical trials, although
they are also the only treatments for ITP that have been extensively evaluated by randomized
clinical trials as a required part of their approval process. (See "Chronic refractory immune
(idiopathic) thrombocytopenic purpura in adults", section on 'Thrombopoiesis-stimulating
agents'.) We do not recommend the use of thrombopoiesis-stimulating agents as second-line
treatment until other treatments to achieve a durable remission have failed. Thrombopoiesis-
stimulating agents are expensive, only support an increased platelet count as long as they are
continued, do not induce a remission, and their long-term side effects are not fully known. Our
recommendation is similar to that of the European medicines evaluation agency (EMEA), which
has approved these agents for "splenectomized adults who are refractory to other treatments."
CHRONIC REFRACTORY ITP — Approximately 10 percent of all adult patients diagnosed with
ITP do not respond adequately to combinations of the above therapeutic measures (eg,
glucocorticoids, IVIG, splenectomy) and go on to have chronic, symptomatic thrombocytopenia
[82]. The management of such patients (chronic refractory ITP) is discussed separately. (See
"Chronic refractory immune (idiopathic) thrombocytopenic purpura in adults".)
EMERGENCY TREATMENT OF LIFE-THREATENING BLEEDING — Although rare,
intracerebral bleeding, severe gastrointestinal bleeding, and death from bleeding can occur in
ITP [8]. Life-threatening bleeding may be seen at any age and at any time during the course of
this disease, but appears to be more common in older patients [10,16]. In one report, for
example, the rates of severe hemorrhagic complications in patients >60 or <40 years of age
were 10.4 and 0.4 percent per patient per year, respectively [10]. Similar rates of 13.0 and 0.4
percent per patient per year, respectively, were noted in a meta-analysis of 17 studies, involving
1817 patients with ITP and platelet counts <30,000/microL [83].
Therapeutic options — After conventional critical care measures are underway, the important
modalities that can be employed in a hemorrhagic emergency include:
 • Platelet transfusions
• IVIG (1 g/kg, repeated the following day if the platelet count remains <50,000/microL)
 • Pulse methylprednisolone (1 g intravenously, repeated daily for three doses)
• Recombinant human factor VIIa
Platelet transfusions — Although patients with ITP may have rapid destruction of circulating
platelets, clinical experience with platelet transfusion demonstrates that many patients have
higher platelet count increments that last for durations longer than anticipated [84,85]. In one
report, for example, 13 of 31 (42 percent) platelet transfusions raised the platelet count to
>20,000/microL; next day platelet counts remained elevated in five of the seven responders
[84]. Even if the platelet response is limited, transfused platelets, alone or in conjunction with the
use of IVIG, may provide critical temporary hemostatic support [86]. (See "Clinical and
laboratory aspects of platelet transfusion therapy", section on 'Immune thrombocytopenia'.)
Factor VIIa — If critical bleeding continues after initial management with platelet transfusions,
IVIG, and methylprednisolone, intravenous recombinant human factor VIIa may be effective [87-
90]. (See "Therapeutic uses of recombinant coagulation factor VIIa", section on 'Off-label
experience'.)
ITP DURING PREGNANCY AND NEONATAL THROMBOCYTOPENIA — Platelet
autoantibodies in pregnant patients with ITP can cross the placenta and produce
thrombocytopenia in the infant. Issues related to the treatment of the pregnant patient with ITP
and her newborn are discussed separately, but are briefly reviewed here. (See
"Thrombocytopenia in pregnancy", section on 'ITP during pregnancy and delivery'.)
The following observations have been made with respect to the incidence of and risk factors for
neonatal thrombocytopenia:
• The incidence of fetal thrombocytopenia with platelet counts <50,000/microL or
<20,000/microL is approximately 10 to 15 percent and 5 percent, respectively [91-98].
 • The platelet count of the mother often does not correlate with the fetal platelet count;
treatment of the mother with IVIG or glucocorticoids does not alter the incidence of fetal
thrombocytopenia [92,93].
 • The only characteristics that have correlated with an increased incidence of fetal
thrombocytopenia are prior splenectomy (a surrogate for more severe ITP), thrombocytopenia in
the first or preceding sibling, and marked thrombocytopenia at some point during the pregnancy
[94,95,98,99]. In one series of 64 pregnant women with chronic ITP, the incidence of severe
neonatal thrombocytopenia (<50,000/microL) was 57 percent in mothers with prior splenectomy
and a gestational platelet count less than 50,000/microL and zero in mothers who had neither of
these two findings [98].
 • Infants' platelet counts are typically lowest several days AFTER delivery [93]; therefore, daily
monitoring of platelet counts is essential. (See "Neonatal thrombocytopenia", section on
'Autoimmune thrombocytopenia'.)
 • The incidence of neonatal intracerebral hemorrhage is <1 percent; there are no differences in
the rate of fetal complications with cesarean delivery compared with vaginal delivery [95-97]. A
fetal loss rate of approximately 1 to 2 percent appears to be neither preventable nor treatable
[100,101].
We do not recommend modification of maternal management based upon expectations of
neonatal thrombocytopenia. There is also no evidence that maternal platelet count or fetal scalp
vein platelet count should be used to determine the mode of delivery [3]. Management of the
mother is related to maintaining a platelet count that is considered safe for providing hemostasis
during delivery, typically above 25,000 to 50,000/microL [3]. (See "Thrombocytopenia in
pregnancy".)
LONG-TERM OUTCOMES — As with many aspects of ITP, there are better data for ITP in
children than in adults. Case series with long follow-up in children support a conservative
approach to treatment, since most children eventually achieve a spontaneous remission from
ITP if they are followed for 10 to 20 years [102]. Appreciation of this benign outcome has
markedly diminished the frequency of splenectomy in children to <1 percent [103]. (See
"Treatment and prognosis of immune (idiopathic) thrombocytopenic purpura in children", section
on 'Outcome'.) There are few comparable long-term outcome studies among adults. Patients
with chronic refractory ITP may drift away from their physicians after a series of unsuccessful
treatments and may either continue to do well in spite of persistent thrombocytopenia or their
thrombocytopenia may eventually resolve. (See 'Natural history' above and "Chronic refractory
immune (idiopathic) thrombocytopenic purpura in adults", section on 'Treatment goals'.)Four
studies are of relevance in this regard:
• In one study, 115 patients with ITP who presented from 1974 to 1994 with platelet counts
<30,000/microL were followed for a median of 11 years [11]. At the time of last follow-up, 91
patients (79 percent) had normal platelet counts or platelet counts >50,000/microL and required
no treatment; 20 patients (17 percent) had no response to treatment or required continued
treatment; 4 patients (4 percent) died - one from bleeding and 3 from infectious complications of
treatment.
 • In a second study, 191 patients who presented from 1993 to 1999 with platelet counts
<30,000/microL were followed for a median of 5 years [12]. Of these, 178 patients (93 percent)
had normal platelet counts or platelet counts >50,000/microL and required no treatment; 7
patients (4 percent) had no response to treatment or required continued treatment; 3 patients (3
percent) died - two from bleeding (but each had reasons other than thrombocytopenia for
bleeding) and one from infectious complications of splenectomy.
 • A small study involved 15 patients with splenectomy failure or postsplenectomy recurrence
[104]. Nine of the 15 received treatment with immunosuppressive agents, with 5 responses.
However, in 8 of the 15 patients, normal or "safe" platelet counts were achieved in a subsequent
3 to 12 year period, during which time they received no treatment.
• Similar results were reported in a single institutional experience in which 105 patients with
chronic refractory ITP were followed for a median of 9 years [105]. Stable complete or partial
remissions were attained in 71 percent; two-thirds of the patients were able to discontinue
treatment. The median time to remission after initial splenectomy failure was 46 months (range:
1 to 437 months).
Mortality — The mortality of ITP in published case series ranges from 0.3 to 5 percent,
consistent with the estimated frequency of intracranial hemorrhage [8,10-12,106,107]. There
are, however, several reasons to believe that reports with the higher mortality rates are not
relevant to current practice:
• The above estimates come from relatively small series of patients potentially biased by more
severe events.
• Many of these series were reported prior to the availability of modern treatment and supportive
care, such as intensive care units, platelet transfusions, and IVIG or anti-D.
• The practice of obtaining routine platelet counts has led to the identification of many
asymptomatic patients, shifting the overall clinical spectrum of ITP towards that of decreased
severity.
Thus, the life-long incidence of major bleeding and death from bleeding in patients with ITP is
most likely substantially <1 percent. If this estimate is true, then the indications for aggressive
management with immunosuppressive regimens should be restricted to patients with severe
thrombocytopenia and clinically important bleeding [11]. This recommendation is strengthened
by the observation that, in a series of 105 patients with chronic refractory ITP, of the 17 ITP-
related deaths, 6 were associated with the treatment given, rather than the disease itself [105].
ADDITIONAL INFORMATION — Additional information concerning thrombocytopenic
conditions (ie, drug-induced, ITP, TTP-HUS, and thrombocytopenia in pregnancy) can be found
on the following website maintained and updated by Dr. James N. George at the University of
Oklahoma Health Sciences Center: <www.ouhsc.edu/platelets> [108].
SUMMARY AND RECOMMENDATIONS
Overall treatment goal — The goal for treatment of ITP is to provide a safe platelet count to
prevent major bleeding, rather than correcting the underlying disease. A critical concept is to
avoid unnecessary treatment of asymptomatic patients with mild to moderate thrombocytopenia.
(See 'General therapeutic principles' above.)
Who should be treated — Only some patients with ITP should be treated. These include the
following patient groups. (See 'Patient selection' above.)
• We recommend treatment of patients with moderate or severe thrombocytopenia and bleeding
symptoms (Grade 1C). Such treatment should be limited in duration unless symptomatic
thrombocytopenia persists.
• We suggest that patients with a platelet count less than 30,000/microL and no bleeding should
be treated, because they are at risk of bleeding (Grade 2C).
• We recommend against treatment of patients with mild, asymptomatic thrombocytopenia,
discovered incidentally on a routine blood count (Grade 1C).
Initial treatment — If treatment is indicated, as above, we recommend the use of glucocorticoids
as a single agent as initial therapy in preference to observation or supportive care (eg,
transfusions), intravenous immunoglobulin, splenectomy, rituximab, or immunosuppressive
agents (Grade 1B).
Glucocorticoid choices include either prednisone (1 mg/kg per day orally) or dexamethasone (40
mg/day orally for 4 days, repeated every 14 to 28 days as needed). The use of prednisone is
the regimen employed by most hematologists. (See 'Glucocorticoids' above.)
Initial glucocorticoid failure — Additional treatment should be given to patients with persistent,
symptomatic, and severe thrombocytopenia (ie, a platelet count <10,000/microL) either after two
to three weeks of treatment with glucocorticoids, or following their withdrawal. Therapeutic
choices for these patients include:
• Continuation or reinstitution of glucocorticoids for a limited duration
 • Intravenous immunoglobulin or anti-D immunoglobulin in RhD-positive individuals to achieve
temporary responses
 • Splenectomy or rituximab in an attempt to achieve durable responses.
In patients who fail treatment with glucocorticoids or require ongoing glucocorticoids to maintain
an adequate platelet count, we suggest splenectomy (Grade 2C). This is based primarily on the
apparent higher long-term success with splenectomy compared with alternative options.
Rituximab is an option for patients who refuse splenectomy. (See 'Rituximab' above.)
If splenectomy is being considered, it should be deferred for at least four to six weeks after initial
diagnosis, unless the patient has severe and symptomatic thrombocytopenia unresponsive to
initial treatment with glucocorticoids. We prefer the laparoscopic approach to open splenectomy
because of its lower morbidity and mortality. (See 'Splenectomy' above.)
Continued treatment failure — Patients with persistent and severe thrombocytopenia
(≤20,000/microL) after treatment with prednisone, splenectomy, and rituximab, who have a
continuing requirement for therapies to increase and/or sustain the platelet count, are
considered to have chronic refractory ITP. Management of such patients is challenging and is
discussed separately. (See "Chronic refractory immune (idiopathic) thrombocytopenic purpura in
adults".)
Life-threatening bleeding — Life-threatening bleeding requires immediate intervention. After
conventional critical care measures are underway, emergent platelet transfusion should be
initiated. This should be combined with other rapidly-acting interventions (eg, intravenous pulse
methylprednisolone, intravenous immunoglobulin, splenectomy).
Intravenous recombinant human factor VIIa is an option if all other treatments have failed to
control the bleeding. (See 'Emergency treatment of life-threatening bleeding' above.)
Approach to the adult patient with thrombocytopenia

Authors
Stephen A Landaw, MD, PhD
James N George, MD Section Editor
Lawrence LK Leung, MD Deputy Editor
Stephen A Landaw, MD, PhD
Last literature review version 18.2: May 2010 | This topic last updated: March 23, 2010 (More)

INTRODUCTION — The clinician is frequently faced by a patient presenting with a low platelet

count, the cause of which is not immediately apparent. This topic will provide a structure through
which the cause(s) of such thrombocytopenia can be assessed. A related topic describes the
most common outpatient and inpatient presentations of adults with newly recognized
isolated thrombocytopenia (ie, patients in whom the remainder of the blood count is normal, and
who may or may not have signs of systemic disease) and provides a general guideline for the
evaluation and management of thrombocytopenic patients in the office and hospital settings.
(See "Evaluation and management of thrombocytopenia by primary care physicians".)
Other issues related to thrombocytopenia are presented separately:
 • Thrombocytopenia in pregnancy. (See "Thrombocytopenia in pregnancy".)
• Evaluation of the patient with a bleeding diathesis. (See "Approach to the adult patient with a
bleeding diathesis".)

DEFINITIONS — The normal platelet count in adults ranges from 150,000 to 450,000/microL,

with mean values of 237,000 and 266,000/microL in males and females, respectively [1].
Thrombocytopenia is defined as a platelet count less than 150,000/microL (150 x 10(9)/L),
keeping in mind that 2.5 percent of the normal population will have a platelet count lower than
this. A recent fall in the platelet count by one-half, while still in the normal range, may herald
severe clinical problems (see below), and requires active follow-up. However, thrombocytopenia
is not usually detected clinically (see below) until the platelet count has fallen to levels
significantly below 100,000/microL.
Variation of the platelet count in a given individual is limited; differences in the absolute platelet
count greater than 70 to 90,000/microL will occur by chance less than 1 percent of the time [1].
As an example, even if the patient's platelet count is within the normal range, if the count has
recently fallen 50 percent or more from a prior value, this should immediately raise the
possibility of heparin-induced thrombocytopenia in any patient begun on heparin therapy within
the preceding 5 to 10 days. If confirmed, this constitutes a medical emergency, requiring
appropriate urgent action. (See "Heparin-induced thrombocytopenia".)
Surgical bleeding due solely to a reduction in the number of platelets does not generally occur
until the platelet count is less than 50,000/microL, and clinical or spontaneous bleeding does not
occur until the platelet count is less than 10,000 to 20,000/microL. In a study of patients with
idiopathic thrombocytopenic purpura, for example, minimal bleeding after trauma was
uncommon unless the platelet count was less than 60,000/microL, whereas self-limited
bleeding, spontaneous bleeding requiring special attention (eg, nasal packing for epistaxis), and
severe life threatening bleeding did not occur until platelet counts were <40,000, <12,000, and
<6000/microL, respectively [2].

OVERVIEW OF PLATELET KINETICS — Platelets are produced in the bone marrow from

megakaryocytes which are derived from more primitive precursors (picture 1). The
megakaryocyte produces platelets by cytoplasmic shedding directly into bone marrow sinusoids
(picture 2). It has been estimated that about 1000 to 5000 platelets are produced by each
megakaryocyte. In normal individuals, platelet production is approximately 35,000 to
50,000/microL of whole blood per day [3,4]; this value can be increased up to eight-fold during
times of increased demand [4]. (See "Megakaryocyte biology and the production of platelets".)
Platelets survive in the circulation for 8 to 10 days, after which they are removed from the
circulation by cells of the monocyte-macrophage system, perhaps as a result of programmed
apoptosis [5]. In normal individuals, approximately one-third of the total platelet mass is found in
the spleen, in equilibrium with the circulating pool of platelets [6]. (See 'Distributional
thrombocytopenia caused by splenomegaly' below.)

Young versus old platelets — The youngest platelets in the circulation are larger and appear to
be more hemostatically active.
Two observations are of interest in this regard:
 • Thrombocytopenic patients with idiopathic thrombocytopenic purpura (ITP) do not usually
have serious bleeding, suggesting that the small numbers of young platelets in these patients
are more hemostatically active than mixed age platelets in normal subjects. Patients with ITP
also appear to have less bleeding than patients with similar severities of thrombocytopenia
caused by marrow failure, such as subjects with thrombocytopenia following chemotherapy,
who also have a population of platelets of mixed age.
 • Aged platelets in dogs are less responsive to thrombin [7] and collagen [8] than younger
platelets.

Reticulated platelets — The youngest platelets in the circulation contain RNA and have been
called reticulated platelets; they are analagous to the young, RNA-containing red cells
(reticulocytes). This property allows them to be specifically analyzed by automated
instrumentation. The clinical usefulness of analyzing for this young platelet fraction is currently
being evaluated (figure 1). (See "Automated hematology instrumentation", section on
'Reticulated platelets' and "Platelet function testing", section on 'Reticulated platelets'.)
As an example, the percent of reticulated platelets was determined in three groups of patients,
with the following results [9]:
 • Normal subjects — 1.3 percent (95% CI 1.1-1.5)
• Thrombocytopenia with "normal or decreased thrombopoietic activity" — 7.5 percent (95% CI
5.3-9.7)
 • Thrombocytopenia with "increased platelet turnover" — 30 percent (95% CI 25-35)
However, these data cannot be fully interpreted, as no information (eg, clinical or platelet kinetic
data) was supplied to independently determine platelet turnover.
MECHANISMS OF THROMBOCYTOPENIA — Analogous to the red blood cell system, the
major mechanisms for a reduced platelet count are decreased production and increased
destruction. Two additional mechanisms include dilutional or distributional thrombocytopenia.
However, before the evaluation of the mechanism of thrombocytopenia is considered, it is
imperative to validate the platelet count to exclude the possibility of spurious or
pseudothrombocytopenia and be certain that actual thrombocytopenia exists.

Pseudothrombocytopenia — The platelet count can be falsely low in a number of clinical

situations:
 • If anticoagulation of the blood sample is inadequate, the resulting thrombin-induced platelet
clumps can be counted as leukocytes by automated cell counters. In these circumstances, the
WBC count is rarely increased by more than 10 percent and there is usually an associated
spurious thrombocytopenia [10].
 • Approximately 0.1 percent of normal subjects have EDTA- dependent agglutinins which can
lead to platelet clumping and spurious thrombocytopenia and spurious leukocytosis. This is
thought to result from a "naturally occurring" platelet autoantibody directed against a normally
concealed epitope on the platelet membrane glycoprotein (GP) IIb/IIIa, which becomes exposed
by EDTA-induced dissociation of GP IIb/IIIa [11-17]. Pseudothrombocytopenia then occurs
because EDTA is the anticoagulant employed in the tubes used for routine complete blood
counts.
 • Pseudothrombocytopenia can also occur after the administration of the murine monoclonal
antibody abciximab, which is directed against the GP IIb/IIIa receptor [18]. (See "Drug-induced
thrombocytopenia", section on 'Glycoprotein IIb/IIIa inhibitors'.)
EDTA-induced platelet clumping can be diagnosed by examination of the peripheral smear
(picture 3). This is an established routine for laboratory technologists, but sometimes the
physician only receives the report of the falsely low platelet count number, without the note
about clumping or a repeat count in a non-EDTA anticoagulant.
If platelet clumping is observed, the platelet count is repeated using heparin or sodium citrate as
an anticoagulant. If citrate is used, one should remember to correct the platelet count for dilution
caused by the amount of citrate solution used; no such correction is needed for heparin.
Alternatively, one can use freshly-shed non-anticoagulated blood pipetted directly into platelet
counting diluent fluid.
Decreased platelet production — Platelet production by the bone marrow can be impaired when
the marrow is suppressed or damaged. In almost all disorders caused by marrow suppression
or damage, white cell and red cell production are also affected. Examples include:
 • After viral infections (eg, rubella, mumps, varicella, parvovirus, hepatitis C, and Epstein-Barr
virus). Decreased platelet counts also regularly occur in children receiving live attenuated
measles vaccination, but the thrombocytopenia is rarely clinically important [19]. However, when
viral infections occur in a patient who already has marrow suppression from another etiology,
such as chemotherapy, the ensuing thrombocytopenia may be severe.
• Certain infectious agents are capable of damaging megakaryocytes directly, such as the
human immunodeficiency virus. (See "Hematologic manifestations of HIV infection:
Thrombocytopenia and coagulation abnormalities", section on 'Ineffective platelet production'.)
• Following chemotherapy or radiation therapy to sites of platelet production (eg, total nodal
irradiation).
• In cases of congenital or acquired bone marrow aplasia or hypoplasia, such as Fanconi
anemia, acquired pure megakaryocytic aplasia, and thrombocytopenia with absent radius (TAR)
syndrome. Although congenital thrombocytopenias are more commonly diagnosed in children,
many conditions are mild and not recognized until an adult has a routine blood count including a
platelet count. (See "Aplastic anemia: Pathogenesis; clinical manifestations; and diagnosis" and
"Recombinant hematopoietic growth factors in inherited bone marrow failure syndromes",
section on 'Amegakaryocytic thrombocytopenia'.)
• Direct alcohol toxicity. (See "Alcohol abuse and hematologic disorders".)
• Vitamin B12 and folic acid deficiency. (See "Etiology and clinical manifestations of vitamin B12
and folic acid deficiency".)

Increased platelet destruction — Increased platelet destruction is seen in a number of

conditions, including:
 • Idiopathic thrombocytopenic purpura (ITP) and systemic lupus erythematosus, in which the
mechanism in many cases is presumed to be due to the presence of autoimmune anti-platelet
antibodies. However, ineffective platelet production may also contribute to thrombocytopenia in
patients with ITP [20]. This observation has led to the develop of new treatments for ITP that
stimulate platelet production. (See "Clinical manifestations and diagnosis of immune (idiopathic)
thrombocytopenic purpura in adults", section on 'Pathogenesis' and "Hematologic
manifestations of systemic lupus erythematosus in adults", section on 'Thrombocytopenia' and
"Chronic refractory immune (idiopathic) thrombocytopenic purpura in adults", section on
'Thrombopoiesis-stimulating agents'.)
 • Alloimmune destruction (posttransfusion, neonatal, post- transplantation [21,22])
• Disseminated intravascular coagulation (DIC, (table 1)
 • Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) (see "Causes
of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults")
 • The antiphospholipid syndrome (see "Clinical manifestations of the antiphospholipid
syndrome")
 • The HELLP syndrome (hemolytic anemia, elevated liver function tests, and low platelet count)
in pregnant women (see "HELLP syndrome")
• Certain drugs, most notably heparin, quinine, quinidine, and valproic acid (see below) (see
"Heparin-induced thrombocytopenia" and "Drug-induced thrombocytopenia")
• Following certain infections (eg, infectious mononucleosis, cytomegalovirus)
• Patients infected with HIV have a high incidence of thrombocytopenia, which bears a similarity
to ITP (see "Hematologic manifestations of HIV infection: Thrombocytopenia and coagulation
abnormalities", section on 'Primary HIV-associated thrombocytopenia')
• Physical destruction of platelets during cardiopulmonary bypass, within giant cavernous
hemangiomata (Kasabach-Merritt syndrome), occasionally in large aortic aneurysms, and rarely
in intravascular or intracardiac metastatic lesions [23].

Dilutional thrombocytopenia — Patients who have had massive blood loss and transfusional
support with packed RBC will have dilutional thrombocytopenia due to absence of viable
platelets in packed RBC products. The usual platelet count in patients receiving 15 or 20 red
blood cell units in 24 hours is 47,000 to 100,000/microL and 25,000 to 61,000/microL,
respectively [24,25]. This problem can be obviated by giving platelet concentrates to patients
receiving more than 20 units of packed RBC in a 24 hour period.

Distributional thrombocytopenia caused by splenomegaly — Normally, about one-third of

circulating platelets are sequestered in the spleen, where they are in equilibrium with circulating
platelets. Splenic sequestration of platelets can be increased to as high as 90 percent in
patients with congestive splenomegaly due to portal hypertension (figure 2), although total
platelet mass and overall platelet survival remain relatively normal [6]. Thus, patients with
cirrhosis, portal hypertension, and splenomegaly may have significant degrees of "apparent"
thrombocytopenia (with or without leukopenia and anemia), but rarely have clinical bleeding,
since their total available platelet mass is usually normal.

CLINICAL PRESENTATION — Patients with thrombocytopenia may be asymptomatic and

thrombocytopenia may be first detected on a routine complete blood count. The symptomatic
presentation of thrombocytopenia is bleeding, characteristically mucosal and cutaneous.
Mucosal bleeding may be manifest as epistaxis and gingival bleeding, and large bullous
hemorrhages may appear on the buccal mucosa due to the lack of vessel protection afforded by
the submucosal tissue. Bleeding into the skin is manifested as petechiae or superficial
ecchymoses. (See "Clinical manifestations and diagnosis of immune (idiopathic)
thrombocytopenic purpura in adults".)

Menorrhagia (menstrual flow that does not taper after more than three days) and metrorrhagia
(uterine bleeding between periods) are also common and there may be persistent, profuse
bleeding from superficial cuts. Patients with thrombocytopenia tend to bleed immediately after
vascular trauma; they do not experience the delayed bleeding that is characteristic of patients
with coagulation disorders such as hemophilia. Posttraumatic or postoperative surgical bleeding
usually responds to local measures, but may persist for hours or days after small injuries.
Bleeding into the central nervous system rarely occurs; when it does there is often preceding
trauma, but it is the most common cause of death due to thrombocytopenia. The pattern of
bleeding in patients with thrombocytopenia (and in patients with disordered platelet function)
differs from that seen in patients with coagulation disorders such as hemophilia, in that the latter
group has delayed bleeding that begins several hours or a day after trauma, because normal
platelet function can provide temporary hemostasis. Patients with coagulation disorders also
have deep bleeding (into tissues, muscles, and joints), minimal bleeding after minor cuts, more
delayed bleeding, more postsurgical bleeding, and tend not to have petechiae (table 2).

Petechiae — Petechiae are pinhead sized, red, flat, discrete lesions often occurring in crops in
dependent areas (picture 4); they are most dense on the feet and ankles, where the hydrostatic
pressure on the small superficial vessels is greatest, and fewer are present on the legs.
Petechiae are not found on the sole of the foot where the vessels are protected by the strong
subcutaneous tissue. Petechiae are due to the presence of red cells which have extravasated
from capillaries; they are nontender and do not blanch under pressure. They are asymptomatic
and not palpable, and should be distinguished from small telangiectasias, angiomas, and
vasculitic purpura (picture 5).

Purpura — Purpura is a purplish discoloration of the skin due to the presence of confluent

petechiae. Two types of purpura are generally recognized:
• Dry purpura is the term used when the only bleeding is in the skin, as in frame A of the picture
(picture 4).
 • Wet purpura is the term used when there is extensive mucous membrane bleeding, as in
frame B of the picture (picture 4).
It is generally felt that the presence of wet purpura is the more serious, and is a prognostic sign
for potentially life-threatening hemorrhage.

Ecchymoses — Ecchymoses are nontender areas of bleeding into the skin, usually associated
with multiple colors, due to the presence of extravasated blood (red, purple) plus the colors due
to breakdown of heme pigment by skin macrophages (green, orange, yellow). Ecchymotic
lesions characteristically are small, multiple, and superficial. They usually develop without
noticeable trauma and do not spread into deeper tissues.

INITIAL APPROACH — There is no substitute for an accurate history and physical examination.

However, a platelet count that does not make sense within the context of the clinical picture
should be repeated before extensive evaluation is undertaken. For extremely low platelet counts
in symptomatic patients, such re-testing should be performed immediately; for asymptomatic
patients with modest reductions in platelet count (eg, 75,000 to 100,000/microL), testing may be
repeated in one to two weeks, provided that the patient is advised to immediately report any
changes in clinical status during this interval.
If, after initial evaluation and retesting, the cause of the thrombocytopenia is not apparent,
hematologic consultation is warranted.
The general history — Certain conditions associated with thrombocytopenia are obvious and
can be immediately recognized by the clinician:
• Recent viral or rickettsial infection
• Previously diagnosed hematologic disease (eg, acute and chronic leukemias, chronic
myeloproliferative or myelodysplastic diseases)
• Nonhematologic diseases known to decrease platelet counts (eg, eclampsia, sepsis, DIC,
anaphylactic shock, hypothermia, massive transfusions)
 • A positive family history of bleeding and/or thrombocytopenia
 • Recent live virus vaccination
• Poor nutritional status, especially in the elderly and alcoholics
 • Pregnancy, especially late in the third trimester or at onset of labor (see below), but also with
a prior history of ITP or TTP-HUS, or with preeclampsia or eclampsia (see "Thrombocytopenia
in pregnancy").
• Recent organ transplantation from a donor sensitized to platelet alloantigens [21]
 • Recent transfusion of a platelet-containing product in an allosensitized recipient (see
"Immunologic blood transfusion reactions", section on 'Posttransfusion purpura')
Medications — It is critical to review the list of ALL medications taken by the patient which might
be associated with the development of thrombocytopenia (table 3A-C). This list should also
include any over-the-counter and herbal products, quinine containing beverages, aspirin and
non-steroidal antiinflammatory agents. (See "Drug-induced thrombocytopenia" and 'Drug
ingestion' below.)

Recent travel — Fever and thrombocytopenia in an adult or child with a history of recent travel
may indicate infection; malaria or dengue virus infection are common causes [26,27]. Other
infections which may be associated with recent travel and thrombocytopenia include
leptospirosis, meningococcemia, rat-bite fever, rickettsial infections, hantavirus, and other viral
hemorrhagic fevers (eg, Ebola, Lassa fever). (See "Clinical presentation and diagnosis of
dengue virus infections", section on 'Laboratory findings' and "Evaluation of fever in the
returning traveler", section on 'Differential diagnosis'.)

The bleeding history — Patients with a suspected bleeding disorder should be questioned about
past bleeding problems, a history of iron-responsive anemia, bleeding outcomes with surgical
procedures and tooth extractions, history of transfusion, character of menses, and dietary habits
or antibiotic use which might predispose to deficiencies of vitamin K, vitamin B12, and folic acid.
(See "Approach to the adult patient with a bleeding diathesis", section on 'Patient history' and
"Preoperative assessment of hemostasis", section on 'Patient questionnaires'.)

Drug ingestion — Medications may cause thrombocytopenia via induction of peripheral platelet

destruction or production of bone marrow aplasia or hypoplasia. Some drugs can also
exacerbate an underlying platelet disorder. Examples include the platelet dysfunction induced
by aspirin and many other antiinflammatory drugs; and the co-ingestion of drugs that potentiate
the anticoagulant effects of warfarin. (See "Nonselective NSAIDs: Overview of adverse effects".)
The timing of onset of clinical bleeding or first recognition of the thrombocytopenia with use of
medications should be explored in depth, since it may focus attention on the most likely
agent(s). Explicit questions about over-the-counter medicines, medicines taken irregularly or not
prescribed by a physician (eg, medicines prescribed for a friend or a family member but taken
by the patient), and herbal remedies are required, because patients are often reluctant to report
their use of these medicines. It is good practice to review each of the patient's medications for
the possibility of drug-induced thrombocytopenia, especially if the drug has been recently
introduced and/or its side effects are not generally known.
The spectrum of drugs reported as causing drug-induced thrombocytopenia is broadening and
changing progressively, reflecting changes in drug consumption. A complete list and analysis of
all published reports of drug-induced thrombocytopenia is available [28]. (See "Drug-induced
thrombocytopenia", for a continuously updated table of drugs causing thrombocytopenia).
As an example, the list of thrombocytopenia-inducing agents in Denmark contains 110 different
drugs (excluding cytotoxic drugs); 20 percent of reported cases concerned drugs not previously
listed, and 25 percent were caused by drugs which appeared on the list only sporadically [29].
Some of the most commonly cited agents causing thrombocytopenia include:
 • Heparin (see "Heparin-induced thrombocytopenia")
• Valproic acid
• Gold salts (see "Major side effects of gold")
• Quinine and quinidine
• Trimethoprim-sulfamethoxazole and other sulfonamides
• Interferons
• Measles-mumps-rubella vaccine
 • Glycoprotein IIb/IIIa inhibitors (eg, abciximab)

Hospitalized patients often do not know what medications have been prescribed. In addition to
reviewing the hospital chart for active medications and nursing notes and bedside flow sheets
concerning the use of heparin flushes of vascular access lines, it may be important to review
anesthesia records. In many medical centers, anesthesiologists give medications directly to the
patient without the need for entering a medication order. Important medicines may also be
contained in materials used in surgery, such as vancomycin mixed into joint replacement
cement [30].
Thrombocytopenia in the ICU patient — The most common cause of thrombocytopenia
developing for the first time in a patient in an intensive care unit (ICU) setting is sepsis,
accounting for one-half of the cases [31]. However, many ICU patients have more than one
cause of thrombocytopenia. The following conditions are likely contributors to this picture:
 • Infection, sepsis, septic shock
• Use of heparin
• Disseminated intravascular coagulation (DIC)
• Massive blood transfusion
• Post-transfusion purpura
• Cardiopulmonary resuscitation
• Cardiopulmonary bypass
• Adult respiratory distress syndrome
 • Pulmonary embolism
 • Use of intravascular catheters
• Solid organ allograft rejection
 • Use of drugs associated with thrombocytopenia (eg, antibiotics, chemotherapy, antiplatelet
agents such as abciximab)

In one study, evolution of DIC, cardiopulmonary resuscitation as the admission category, and
signs of organ failure at admission were independently associated with the development of
thrombocytopenia, while septic shock, a higher APACHE II score, and a ≥30 percent decrease
in platelet counts were significant risk factors for ICU death [32].

The physical examination — There are a number of critical areas which must be examined.
These include, but are not limited to:
 • Examination of the ocular fundus for evidence of bleeding, since CNS bleeding is the most
common cause of death in the thrombocytopenic patient
 • Examination for lymphadenopathy, hepatosplenomegaly, and other masses which might
suggest the presence of a disseminated disorder
 • Examination of the stool for occult blood.
Examination of the skin — Since bleeding into the skin is one of the most common findings in
thrombocytopenia, this part of the examination should be the most detailed. Sites of bleeding
should be noted, especially in the dependent parts of the body. This is normally the feet and
ankles in ambulatory patients, as in panel A of the picture (picture 4), but may be the presacral
area in bedridden patients. Sites of indwelling catheters and drains, areas of previous trauma,
incision sites, and exit sites of venous access devices should be carefully examined.

It is good practice to outline areas of bleeding with a marking pen, or to mark out involved and
uninvolved skin areas and serially note changes in the number of petechiae or bleeding pattern
within those sites, in order to obtain insight into the patient's progress. As noted above, the sites
and timing of bleeding with thrombocytopenia differ from those in coagulation disorders (table
2).

CBC AND PERIPHERAL SMEAR — Laboratory examination should start with the complete
blood count (CBC). The "gold standard" for evaluation of thrombocytopenia of any cause is
examination of a peripheral smear prepared from a freshly-shed sample of non- anticoagulated
blood. The importance of a careful examination of the peripheral smear for estimation of platelet
numbers, morphology, presence or absence of platelet clumping, as well as evaluation of
associated white and red blood cell changes cannot be overemphasized.
It is especially important to use the CBC and blood smear to help rule in or out thrombotic
thrombocytopenic purpura and acute leukemia as expeditiously as possible, since inordinate
delay in making these diagnoses and initiating appropriate treatment may prove fatal.

Pseudothrombocytopenia and artifacts — It is critical to confirm that the reported

thrombocytopenia is true and not a falsely low platelet count due to artifact, or represents blood
taken from a different individual.
A spuriously low platelet count owing to inadequate sample anticoagulation or to EDTA-induced
platelet clumping can be confirmed by evaluation of the peripheral smear (preferably prepared
from freshly-shed non-anticoagulated blood) for the presence of platelet clumps (picture 3).
Repeat blood sampling and the use of an alternate anticoagulant, such as heparin or sodium
citrate, helps to make this diagnosis. (See 'Pseudothrombocytopenia' above.)
The following findings can give clues to the genesis of the thrombocytopenia [33]:

Abnormal platelet morphology — There are a number of congenital thrombocytopenic disorders.

These can often be diagnosed following examination of the peripheral smear by virtue of
alterations in platelet size, abnormal platelet granules, and/or neutrophilic inclusions [34]. Many
of these patients have been initially (and erroneously) diagnosed as having immune
thrombocytopenic purpura (ITP)

May-Hegglin anomaly — The May-Hegglin anomaly is an autosomal dominant trait

characterized by giant platelets, mild to moderate thrombocytopenia, and leukocyte inclusions.
Platelets are large (30 to 80 fL, normal: 7 to 10 fL) and some may be larger than red cells [35-
38]. Because of their large size, the platelets may not be recognized by the laboratory particle
counter; therefore the reported platelet count may be falsely low. Inclusions in neutrophils,
eosinophils, and some monocytes resemble Döhle bodies seen in infection.

The disorder has been linked to mutations of the non-muscle myosin heavy chain gene, MYH9,
found on chromosome 22q [39,40]. Unlike the Fechtner and Epstein syndromes, disorders also
associated with mutations of the MYH9 gene, nephritis, deafness, and cataracts (Alport
manifestations) are not seen in patients with the May-Hegglin anomaly [41].
Most patients are asymptomatic, discovered incidentally (eg, at the time of a routine blood
count), and require no specific treatment. The bleeding tendency, if present, is usually mild, but
severe hemorrhages have been reported. Case reports suggest that infusions of DDAVP or
platelets have been effective in controlling or preventing operative bleeding [42-46]. Similarly,
use of antifibrinolytic agents or recombinant human factor VIIa may be transiently helpful [41].

Alport syndrome — The major findings in Alport syndrome (also called hereditary nephritis)
include hematuria, progressive renal failure, and, in many families, deafness and ocular
abnormalities (eg, cataracts). A few families have large platelets (20 to 27 fL),
thrombocytopenia, and leukocyte inclusions resembling those seen in the May-Hegglin anomaly
[36] (picture 6). Platelet function is normal.
Related conditions, which vary according to the presence or absence of nephritis, neutrophilic
inclusions, cataracts, and deafness have also been described (eg, Sebastian platelet syndrome,
Fechtner syndrome, Epstein syndrome) [34]. These conditions are associated with mutations in
the MYH9 gene.

Bernard-Soulier syndrome — The Bernard-Soulier syndrome is an autosomal recessive

disorder presenting with mild thrombocytopenia, circulating "giant" platelets, marked platelet
dysfunction, and bleeding. The bleeding is disproportionately more severe than suggested by
the thrombocytopenia, and is explained by the absence of the platelet glycoprotein (GP) Ib-IX-V,
a receptor for von Willebrand factor. Most patients with autosomal dominant
macrothrombocytopenia share clinical and molecular features with heterozygous Bernard-
Soulier syndrome [47]. (See "Congenital and acquired disorders of platelet function", section on
'Giant platelet disorders'.)

Wiskott-Aldrich syndrome — The Wiskott-Aldrich syndrome is a rare X-linked disorder which

presents as a clinical triad of immunodeficiency, eczema, and moderate to severe
thrombocytopenia with small (3 to 5 fL) platelets. Some male subjects with mutations of the
Wiskott-Aldrich Syndrome Protein (WASP) gene may have only thrombocytopenia (which may
be intermittent [48]) and small platelets, without immunodeficiency or eczema, a condition
termed X-linked (congenital) thrombocytopenia [49]. (See "Severe combined immunodeficiency
(SCID): An overview" and "Wiskott-Aldrich syndrome", section on 'Platelets'.)

Other inherited thrombocytopenic disorders — These disorders, which are uncommon, some of

which are associated with giant platelets, are discussed separately. (See "Congenital and
acquired disorders of platelet function", section on 'Giant platelet disorders'.)
Decreased platelet production — Findings that suggest reduced production of platelets as the
cause for the patient's thrombocytopenia include:
• Circulating blast cells, indicating the presence of acute leukemia (picture 7)
• A leukoerythroblastic blood picture (teardrop RBCs, nucleated RBCs, and early myeloid forms
in the blood) suggests marrow invasion with tumor, fibrosis, or granulomatous infection, such as
tuberculosis (picture 8A-B)
 • Other cytopenias, with or without macrocytosis, monocytosis, or decreased neutrophil
lobulation (Pelger-Huet anomaly) (picture 9), suggest the presence of a myelodysplastic state
• Oval macrocytic RBCs along with hypersegmentation of neutrophils suggest vitamin B12 or
folic acid deficiency (picture 10A-B)
 • Platelets that are normal sized or small, in contrast to large sized platelets, suggest a reduced
bone marrow response to need [50].

Increased peripheral destruction — Findings that suggest increased peripheral destruction of

platelets as the cause of thrombocytopenia include:
• Microangiopathic blood picture, with fragmented RBCs, hemolytic anemia, and increased
serum concentration of lactate dehydrogenase, as in disseminated intravascular coagulation
(DIC) or thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) (picture
11)
 • Large platelets (megathrombocytes) on the peripheral smear without significant bleeding
suggest the presence of young, hemostatically active platelets in response to peripheral
destruction [50].
 • Associated autoimmune disease, especially in a young women (see "Hematologic
manifestations of systemic lupus erythematosus in adults")
 • Underlying lymphoproliferative disease (eg, chronic lymphocytic leukemia or Hodgkin's
disease) especially when a leukoerythroblastic blood picture is absent (see above)

BONE MARROW EXAMINATION — Bone marrow aspiration and biopsy is indicated in virtually

all patients with thrombocytopenia severe enough to constitute a risk for major bleeding. The
only valid exclusion to this requirement is the patient less than 60 years of age with
isolated thrombocytopenia whose physical examination, complete blood count, and examination
of the peripheral blood smear do not suggest other etiologies for the thrombocytopenia and
therefore have a clinical diagnosis of ITP. In patients over 60 years of age, isolated
thrombocytopenia may be the initial abnormality of myelodysplasia, and therefore a bone
marrow examination is appropriate in this group. (See 'Diagnosis of ITP' below.)
Although the information outlined in the above section is generally reliable in determining
whether thrombocytopenia is due to decreased production or to increased peripheral
destruction, this question can be answered in a definitive manner only through examination of
the bone marrow. The following items need the most careful attention:
 • The presence of normal to increased numbers of megakaryocytes indicates that the patient's
thrombocytopenia is due, at least in part, to increased peripheral destruction. While the
presence of younger, less polypoid megakaryocytes and fewer mature, platelet-producing
megakaryocytes is commonly reported in idiopathic thrombocytopenic purpura, this finding is
difficult to quantitate.
 • Decreased numbers of megakaryocytes on the bone marrow biopsy, along with overall
decreased or absent cellularity (picture 12 and picture 13), is consistent with thrombocytopenia
due to decreased bone marrow production, as in aplastic anemia. (See "Aplastic anemia:
Pathogenesis; clinical manifestations; and diagnosis".)
 • In a hypercellular marrow, the presence of megaloblastic changes in the red cell and
granulocytic series suggests vitamin B12 or folic acid deficiency (picture 14), while the presence
of dysplastic changes in the red cell, granulocytic, and megakaryocytic lineages suggests a
myelodysplastic disorder (picture 15 and picture 16). (See "Clinical manifestations and
diagnosis of the myelodysplastic syndromes".)
 • The presence of granulomata, increased reticulin or collagen fibrosis (picture 17 and picture
18), or infiltration with malignant cells (picture 19) establishes the diagnosis of marrow invasion,
especially when a leukoerythroblastic blood picture is also present (see above).
 • In rare cases, severe reduction or absence of megakaryocytes with no other abnormalities (ie,
acquired amegakaryocytic thrombocytopenia, acquired pure megakaryocytic aplasia), may be
due to the presence of an autoantibody directed against the thrombopoietin receptor, most often
reported in patients with systemic lupus erythematosus. (See "Recombinant hematopoietic
growth factors in inherited bone marrow failure syndromes", section on 'Amegakaryocytic
thrombocytopenia'.)

DIAGNOSIS OF GESTATIONAL THROMBOCYTOPENIA — Incidental thrombocytopenia of

pregnancy, also termed gestational thrombocytopenia, is defined by the following five criteria:
 • Mild and asymptomatic thrombocytopenia
 • No past history of thrombocytopenia (except possibly during a previous pregnancy)
• Occurrence during late gestation
 • No association with fetal thrombocytopenia
 • Spontaneous resolution after delivery

Platelet counts are typically greater than 70,000/microL, with about two-thirds being 130,000 to
150,000/microL. The frequency of gestational thrombocytopenia in the largest series of
consecutive women admitted for labor and delivery is 5 percent. Neonatal thrombocytopenia did
not occur in infants born to mothers with gestational thrombocytopenia (except in one infant with
congenital myelodysplasia). Gestational thrombocytopenia is considered to be benign and any
change from routine obstetrical care is discouraged. (See "Thrombocytopenia in pregnancy".)

DIAGNOSIS OF ITP — There is no "gold standard" test that can establish the diagnosis of ITP,
and testing for antiplatelet antibodies is not generally recommended. (See "Clinical
manifestations and diagnosis of immune (idiopathic) thrombocytopenic purpura in adults".) The
diagnosis based almost entirely on exclusion of other causes of thrombocytopenia (table 4).
Few diagnostic studies other than the history, physical examination, complete blood count, and
examination of the blood smear are necessary.

A presumptive diagnosis of ITP is made when the history (eg, lack of ingestion of a drug that
can cause thrombocytopenia), physical examination, complete blood count, and examination of
the peripheral blood smear do not suggest other etiologies for the isolated thrombocytopenia.
The only recommended further tests in such patients are:
 • HIV testing in patients with risk factors for HIV infection
• Bone marrow aspiration to rule out myelodysplastic syndrome, especially in patients >60 years
of age

RECOMMENDATIONS — While thrombocytopenia can be caused by a myriad of conditions

including systemic disease, infection, drugs, and primary hematologic disorders, a number of
salient points will help the physician in determining its cause:
 • Thrombocytopenia is defined as a platelet count less than 150,000/microL (150 x 10(9)/L),
keeping in mind that 2.5 percent of the normal population will have a platelet count lower than
this. A fall in platelet count to levels less than 150,000/microL may herald severe clinical
problems, and requires active follow-up, although thrombocytopenia is not usually detected
clinically until the platelet count has fallen to levels significantly below 100,000/microL.
 • The importance of a careful examination of the peripheral smear for estimation of platelet
numbers, morphology, presence or absence of platelet clumping, as well as evaluation for red
and white blood cell abnormalities cannot be overemphasized
 • Findings that suggest reduced production of platelets as the cause for the patient's
thrombocytopenia include the presence of small platelets, malignant cells, a leukoerythroblastic
blood picture, leukopenia, anemia, and/or large (macrocytic) red cells
 • Large platelets (megathrombocytes) on the peripheral smear without significant bleeding
suggest the presence of young, hemostatically active platelets in response to peripheral
destruction. However, very large platelets, approaching the size of red cells, suggest a
congenital thrombocytopenia.
• Other findings that suggest increased peripheral destruction of platelets as the cause of
thrombocytopenia include the presence of fragmented red cells, hemolytic anemia, and an
increased serum concentration of lactate dehydrogenase
• A presumptive diagnosis of idiopathic thrombocytopenic purpura (ITP) is made when the
history (eg, lack of ingestion of a drug that can cause thrombocytopenia), physical examination,
complete blood count, and examination of the peripheral blood smear do not suggest other
etiologies for the isolated thrombocytopenia
 • Bone marrow aspiration and biopsy is indicated in virtually all patients with UNEXPLAINED
thrombocytopenia severe enough to constitute a risk for major bleeding. The only valid
exclusion to this requirement is the patient less than 60 years of age with a presumptive
diagnosis of ITP (see above).

Management issues — Management issues for patients with thrombocytopenia, including

activity restrictions, indications for treatment, and management of invasive procedures, are
discussed separately. (See "Evaluation and management of thrombocytopenia by primary care
physicians", section on 'Patient management'.)