Immune thrombocytopenia (ITP), formerly known as idiopathic thrombocytopenic purpura, is an autoimmune disorder characterized by a low platelet count and increased risk of mucocutaneous bleeding. During the last decade its management has changed, with the advent of new medications and with increased awareness of treatment side effects. This article will focus on the pathophysiology, diagnosis, and management of ITP in adults.
A SLIGHT FEMALE PREDOMINANCE UNTIL AGE 65
The estimated age-adjusted prevalence of ITP in the United States is 9.5 to 23.6 cases per 100,000.1 In a recent study in the United Kingdom, the incidence was 4.4 per 100,000 patient-years among women and 3.4 among men.2 A slight female predominance was seen until age 65; thereafter, the incidence rates in men and women were about equal.
INCREASED PLATELET DESTRUCTION AND DECREASED PRODUCTION
ITP is a complex immune process in which cellular and humoral immunity are involved in the destruction of platelets3 as well as impaired platelet production. Several theories have emerged in the last decade to explain this autoimmune process.
Autoantibodies form against platelets
The triggering event for antibody initiation in ITP is unknown.3 Autoantibodies (mostly immunoglobulin G [IgG] but sometimes IgM and IgA) are produced against the platelet membrane glycoprotein GPIIb-IIIa. The antibody-coated platelets are rapidly cleared by the reticuloendothelial system in the spleen and liver, in a process mediated by Fc-receptor expression on macrophages and dendritic cells. Autoantibodies may also affect platelet production by inhibiting megakaryocyte maturation and inducing apoptosis.4,5
Patients with ITP also have CD4+ T cells that are autoreactive to GPIIb-IIIa and that stimulate B-cell clones to produce antiplatelet antibodies. Although autoreactive T cells are present in healthy individuals, they appear to be activated in patients with ITP by exposure to fragments of GPIIb-IIIa rather than native GPIIb-IIIa proteins.6 Activated macrophages internalize antibody-coated platelets and degrade GPIIb-IIIa and other glycoproteins to form “cryptic” epitopes that are expressed on the macrophage surface as novel peptides that induce further proliferation of CD4+ T-cell clones. Epitope spread thereby sustains a continuous loop that amplifies the production of GPIIb-IIIa antibodies.7
Defective T-regulatory cells appear to be critical to the pathogenesis of ITP by breaking self-tolerance, allowing the autoimmune process to progress.8 This, together with several other immune mechanisms such as molecular mimicry, abnormal cytokine profile, and B-cell abnormalities, may lead to enhanced platelet clearance.9
In addition to destroying platelets, antibodies may impair platelet production.10 Good evidence for platelets being underproduced in patients with ITP is that treating with thrombopoietin agonists results in increased platelet counts.
A DIAGNOSIS OF EXCLUSION
ITP is defined as isolated thrombocytopenia with no clinically apparent associated conditions or other causes of thrombocytopenia.11 No diagnostic criteria currently exist, and the diagnosis is established only after excluding other causes of thrombocytopenia.
A recent report12 from an international working group established a platelet count threshold of less than 100 × 109/L for diagnosing ITP, down from the previous threshold of 150 × 109/L. The panel also recommended using the term “immune” rather than “idiopathic” thrombocytopenia, emphasizing the role of underlying immune mechanisms. The term “purpura” was removed, because many patients have no or minimal signs of bleeding at the time of diagnosis.12
The 2011 American Society of Hematology’s evidenced-based guidelines for the treatment of ITP present the most recent authoritative diagnostic and therapeutic recommendations.13
ITP is considered to be primary if it occurs in isolation, and secondary if it is associated with an underlying disorder. It is further classified according to its duration since diagnosis: newly diagnosed (< 3 months), persistent (3−12 months), and chronic (> 12 months).
In adults, ITP tends to be chronic, presenting with a more indolent course than in childhood, and unlike childhood ITP, infrequently following a viral infection.
Clinical features associated with ITP are related to thrombocytopenia: petechiae (pinpoint microvascular hemorrhages that do not blanch with pressure), purpura (appearing like large bruises), epistaxis (nosebleeds), menorrhagia, gum bleeding, and other types of mucocutaneous bleeding. Other common clinical features include fatigue, impaired quality of life, and treatment-related side effects (eg, infection).14
A low platelet count may be the sole initial manifestation. The patient’s history, physical examination, blood counts, and findings on blood smear are essential to rule out other diagnoses. Few diagnostic tests are useful in the initial evaluation (Table 1). Abnormalities in the blood count or blood smear may be further investigated with bone marrow biopsy but is not required if the patient has typical features of ITP, regardless of age.
Because there are no specific criteria for diagnosing ITP, other causes of thrombocytopenia must be excluded. The differential diagnosis can be further classified as ITP due to other underlying disease (ie, secondary ITP) vs nonautoimmune causes that are frequently encountered in clinical practice.