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2000 Part XII: Hemostasis and Thrombosis Chapter 117: Thrombocytopenia 2001

resulting from megakaryocytic hypoplasia. 128–130,132,133 Initial studies indicate that 88 percent reach normal platelet counts or remain stable.
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with recombinant and pegylated TPO molecules showed successful ITP is classified based on the absence or presence of other diseases as
responses in patients with thrombocytopenia, but development of auto- “primary” or ‘”secondary.” “Primary ITP’” denotes the absence of any
antibodies against these molecules restricted their use in clinical set- other identified pathology. All other autoimmune thrombocytopenias
tings. Based on the success of creating erythropoietin receptor agonist are classified as “secondary ITP” (see Table 117–3), and the associated
peptides, a number of screening efforts were undertaken to design small primary disorder is indicated in parenthesis, for example “secondary
peptides or organic molecules that might bind to the TPO receptor and ITP (SLE-associated)” or “secondary ITP (drug-induced).” Heparin-
stimulate thrombopoiesis. One such molecule contains four copies induced thrombocytopenia (HIT) or alloimmune thrombocytopenias
of a 14-amino-acid peptide grafted onto an Ig Fc domain, forming a are not classified as ITP, and maintain their standard classifications. 146
“peptibody” termed romiplostim. This agent, which binds to a region The IWG described three phases of ITP: (1) newly diagnosed ITP
of the TPO receptor that overlaps that bound by authentic TPO, was (within 3 months of diagnosis); (2) persistent ITP (patients who do not
shown to increase platelet counts in patients with ITP who had failed achieve a stable remission between 3 and 12 months after diagnosis);
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other modalities, and was approved by the FDA for this indication and (3) chronic ITP (continuing for more than 12 months). ITP was for-
in 2008. Another small organic thrombopoietic molecule, eltrombopag, merly classified as mild, moderate, and severe depending on the plate-
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was developed almost simultaneously and approved in 2008 by FDA let counts. However, the degree of thrombocytopenia does not always
for the same indications. This agent activates TPO receptor signaling correlate with bleeding. The IWG proposed that the term “severe ITP”
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by binding to the transmembrane domain of the receptor, a site quite only be used for patients with clinically significant bleeding requiring
distinct from the binding site for TPO and romiplostim. Both TPO- additional therapy regardless of platelet count. 146
receptor agonists are currently being evaluated for additional clinical One of the major problems with comparing ITP studies had been
indications in clinical trials. 136 the definition of response to therapy. The IWG proposed the following
Some patients with ITP appear to display a genetic predisposi- terms and criteria for response to ITP treatment: “complete response,
tion. ITP has been documented in monozygotic twins and shown to CR” (platelet count exceeding 100 × 10 /L and no bleeding symptoms),
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be highly prevalent in some families. In addition to contributing to “response, R” (platelet count higher than 30 × 10 /L or at least a two-
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the development of ITP, like in other autoimmune disorders heredity fold increase from the baseline count and no bleeding symptoms), “no
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may also affect the response to ITP therapy. Human leukocyte antigen response, NR” (platelet count below 30 × 10 /L or less than a twofold
(HLA) class I and class II allele frequencies in patients with ITP have increase from the baseline count, or presence of bleeding symptoms).
been studied by several investigators, with inconsistent results. Some “Duration of response” is measured from the time between first mea-
investigators reported an increased frequency of HLA-Aw32, -DRw2, sured CR or R to relapse. “Corticosteroid dependence” is defined as the
and -DRB1 0410. 108,139–141 Investigation has focused on genetic differ- need for ongoing or repeated glucocorticoid use for at least 2 months
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ences associated with dysregulation of immune tolerance and humoral to maintain CR or R. Patients who relapsed after splenectomy (failure
immunity, but results have been inconclusive. For example, genetic to maintain CR or R) and required therapy are classified as “refractory
polymorphisms of cytotoxic T-lymphocyte antigen (CTLA)-4, tumor ITP.” “On-demand therapy” is a term used for therapies employed to
necrosis factor, and Fcγ receptors IIA and IIIA have been suggested to temporarily increase the platelet count in special situations such as
influence the development of ITP and the response to therapy, 141–143 but trauma or surgery. “Adjunctive therapies” are treatments that are not
as yet no strong association has been found. designed to increase platelet counts, but that may decrease bleeding
Accumulating data indicate that the pathophysiology of ITP is symptoms by other means, for example, treatment with oral contracep-
more complex than previously thought, with ITP comprising a heter- tives or antifibrinolytic drugs. 146
ogenous group of disorders with different etiologies and responding to
different treatment modalities. The identification of the different subsets Incidence
of ITP patients will help to better define treatment options. ITP is relatively common, but demographic studies have yielded a wide
range of incidence rates largely because of differences in the age and
Definition and Classification gender distribution of the populations studied and differences in cut-
Although ITP has been recognized for centuries, there is as yet no off platelet counts used to define the disease. ITP can affect males and
consensus on either the definition or management of the disease. In females of any age. In one detailed study, the reported incidence of ITP
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1996, the American Society of Hematology (ASH) published practice was 3.9 per 100,000 per year. Although the overall incidence was higher
guidelines for the diagnosis and management of ITP. In 2003, the Brit- in women than in men, a male predominance was seen in patients
ish Committee for Standards in Haematology published its own guide- younger than 18 years of age and older than 65 years of age. 149
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lines. In spite of these guidelines, the heterogeneity of the definitions
and clinical criteria used in different studies has made it difficult to Clinical Features
interpret the data regarding the incidence, pathogenesis, and treatment ITP is of acute onset in children, often developing after vaccination or
of ITP. In 2008, the International Working Group (IWG) proposed a after a viral illness, and resolves spontaneously in 90 percent of cases. In
standardization of terminology, definitions, and outcome criteria for adults, however, ITP usually is a chronic disease. Table 117–4 highlights
ITP patients. In 2010, an international consensus report on the inves- the differences in ITP in children and adults. Approximately 25 per-
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tigation and management of ITP was published. Shortly thereafter, in cent of adult ITP patients are diagnosed incidentally on routine com-
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2011, ASH updated its 1996 ITP guidelines. 148 plete blood counts. Symptoms and signs of ITP depend not only on the
The IWG definition proposed use of the term “immune throm- platelet count, but also on the nature of coexisting conditions that can
bocytopenia” instead of “idiopathic thrombocytopenic purpura” as the increase the tendency to bleed, such as uremia, trauma, and ingestion
basis for the ITP acronym, because the immune nature of ITP is clear but of drugs that affect platelet function (Table 117–5). Approximately one-
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most ITP patients do not have purpura. A platelet count of 100 × 10 /L third of patients have platelet counts greater than 30 × 10 /L at diag-
was proposed as the threshold level to entertain the diagnosis of ITP, nosis and no significant bleeding. Common bleeding signs include
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because a sustained lower platelet count (100 to 150 × 10 /L) can be seen purpura (ecchymoses and petechiae), epistaxis, menorrhagia, and gin-
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in otherwise healthy individuals, 11,12 and long-term observation of these gival bleeding. Hematuria, hemoptysis, and gastrointestinal bleeding

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