**3. Diagnosis of chronic ITP**

68 Autoimmune Disorders – Current Concepts and Advances from Bedside to Mechanistic Insights

American Society of Hematology in 2010 (Neunert et al., 2010). In addition, an International Working Group (IWG) of experts on ITP attempted to bring some uniformity to the diagnosis and management of ITP (Rodeghiero et al., 2009). Despite the serious efforts of scientists and specialty societies, the practicing hematologists are still left with many unanswered questions and dilemmas when it comes to treating this benign but challenging

Until recently, adult ITP was considered a disease of young women. However, two recently published studies have shown otherwise (Schoonen et al. 2009, Abrahamson et al., 2009). In these series, the mean ages at presentation were over 50 years, with a slight female predominance (M:F ratio of 1.7:1). In contrary to acute ITP in children, adult ITP is usually insidious in onset, with platelet counts of > 20 x 109/L. The incidence of chronic ITP is 5.8 to

While ITP in children usually pursues an acute and self-limited clinical course that responds well to treatment, ITP in adults tends to present as a chronic relapsing condition. Traditionally, the terms chronic ITP, refractory ITP, and chronic persistent ITP are used interchangeably and are used for chronic phase of the disease. Chronic or refractory ITP was previously defined as immune thrombocytopenia persisting for >3 months, failure to respond to splenectomy, and platelet count of less than 50 x 109/L. The definition has become more confusing since the evolution of splenectomy sparing

The International Working Group (IWG) consensus panel of both adult and pediatric experts in ITP recently provided guidance on terminology, definitions and outcome criteria for this disorder (Proven et al., 2010). Primary ITP, as defined by the IWG, is platelet count less than 100 x 109/L in the absence of other causes or disorders that may be associated with thrombocytopenia. IWG used a higher platelet cutoff than the traditional criterion of 50 x 109/L based on the observation that there might be physiological variations among different racial groups and that the chances of developing persistent thrombocytopenia of less than 100 x 109/L over 10 years of follow-up seemed to be less in patients presenting with a

The IWG also categorizes ITP as newly diagnosed (diagnosis to 3 months), persistent (3 to 12 months from diagnosis) or chronic (lasting for more than 12 months). However, these definitions may not apply to patients with secondary forms of ITP and have not been formally validated. Specifically, "persistent ITP" includes patients not achieving spontaneous remission or not maintaining therapeutic response after stopping treatment between 3 and 12 months from initial diagnosis. The category "chronic ITP" is reserved for

The IWG standardization does not include the degree of thrombocytopenia in classifying the different phases of the disease. The severity of disease varies in patients. Mild, moderate, and severe thrombocytopenia is used commonly in clinical practice. There are no firm guidelines. However, mild thrombocytopenia typically ranges from 50 to 100 x 109/L, moderate thrombocytopenia from 20 to 50 x 109/L, and severe thrombocytopenia under 20 x 109/L. The severity of thrombocytopenia may or may not correlate well with the risk of bleeding. It is well known that the severity and symptoms of ITP in the same patient can

disease.

6.6 per 100,000 in the adult population.

platelet count between 100 and 150 x 109/L.

patients with ITP lasting for more than 12 months.

**2. Definition of chronic ITP** 

modalities of treatment.

Fifty years since the discovery of platelet autoantibodies, there is still no definitive laboratory diagnostic test for ITP. Despite the tremendous advances made in the understanding of the pathophysiology, the diagnosis of ITP remains one of exclusion. An initial complete history and physical examination is essential to identify evidence of bleeding and exclude other etiologies of thrombocytopenia or secondary ITP. Secondary causes of thrombocytopenia include autoimmune disorders as well as exposure to drugs (such as quinine), herbs, foods and other substances. A peripheral smear examination usually helps to exclude other hematological disorders, such as thrombotic thrombocytopenic purpura, leukemia, and pseudothrombocytopenia from platelet aggregation. Testing for hepatitis C and HIV infection is recommended for all patients presenting as ITP (Cines et al., 2005, 2009, 2010).

Glycoprotein-specific assays to detect platelet-associated IgG (PAIgG) autoantibodies lack sufficient sensitivity for them to be of use as a diagnostic tool. Therapeutic response to IVIG is considered by many as confirmatory of ITP, in the absence of identifiable causes of thrombocytopenia. As per American Society of Hematology guidelines, there is insufficient evidence for the utility of routine testing for anti-platelet antiphospholipid and antinuclear antibodies, and thrombopoietin levels. There have been recent reports achieving remission in chronic ITP patients with the eradication of Helicobacter pylori infection. Even though there is insufficient evidence to support routine testing for Helicobacter pylori organisms, patients with gastrointestinal symptoms should be investigated further.

Although 2010 ASH guidelines did not find evidence to support an age threshold for which bone marrow is recommended, most hematologists would favor performing bone marrow examination for patients over 60 years of age to rule out myelodysplasia. This practice is especially useful prior to splenectomy in these older patients who do not show good response to treatment. The diagnosis of ITP should always be reassessed during the course of treatment if any atypical clinical or laboratory abnormalities develop to suggest lupus and other autoimmune or hematological disorder. Table 2 outlines the utility of various diagnostic tests for diagnosing ITP according to current guidelines.

Changing Spectrum of Chronic Immune Thrombocytopenic

cells.

al, 2004).

**4.2 Role of cytotoxic T-cells** 

**4.3 Impaired platelet production** 

and platelet production in ITP.

Purpura: New Face for an Old Disease 71

The initial trigger for the abnormal autoantibody response is unknown. The cause of this loss of self-tolerance probably varies among patients. However, the common pathway appears to involve CD4+ helper T-cells reacting with a specific platelet-associated antigen on the surface of an antigen-presenting cell (such as macrophage, dendritic cell or B-cell). These activated helper T cells produce cytokines that stimulate B-cells to produce specific

The primary site of platelet destruction is the spleen, and to a lesser extent, the liver and bone marrow. In these organs, antibody-sensitized platelets are destroyed by phagocytic

In 30% or more of the ITP patients with no detectable anti-platelet antibody (Harrington, et al., 1953), alternative mechanisms of platelet destruction are likely to play a role. Recent studies suggest that platelet lysis by CD8+ cytotoxic T-cells may be an important pathogenetic pathway in some ITP patients. These T-cells show increased expression of cytotoxic genes, including tumor necrosis factor α, perforin, granzyme A and granzyme B. In addition to causing lysis of platelets, cytotoxic T-cells may damage megakaryocytes in the bone marrow (Olsson et al, 2003). Therefore, downregulation of cytotoxic T-cell response serves as a potentially effective therapeutic target, especially in ITP patients who are

Besides accelerated platelet destruction, abnormal megakaryocytic growth and development are involved in the pathogenesis of ITP. Bone marrow examination under the microscope characteristically reveals normal to increased numbers of megakaryocytes in ITP patients. There may also be a shift to younger forms of megakaryocytes. Despite an apparently adequate number of megakaryocytes, platelet production is impaired. Studies of platelet production have demonstrated decreased or normal turnover in greater than 70% of ITP patients, suggesting an impaired compensatory response of the megakaryocytes to ongoing platelet destruction (Chang et al., 2003; McMillan, et al., 2004). In fact, bone marrow ultrastructural studies have demonstrated abnormalities in 50% to 75% of megakaryocytes in ITP patients. These megakaryocytes show impaired maturation and platelet release, and are unable to adequately compensate for the peripheral platelet destruction (Houwerzijl, et

Produced primarily in the liver, thrombopoietin (TPO) is the hormone responsible for enhancing megakaryocytic maturation and platelet production (Kuter, 2007). When platelet levels are low, free TPO normally increases in the circulation, which then stimulates megakaryocyte proliferation. However, serum levels of TPO fail to increase appropriately in response to thrombocytopenia in ITP patients (Kogusi, et al., 1996). Since TPO binds to both megakaryocytes and platelets, free TPO becomes less available as TPO binds to an increased number of megakaryocytes in the marrow. Furthermore, as platelets to which TPO binds are cleared from the circulation at an increased rate, TPO in turn becomes limited and platelet production is reduced (Kogusi, et al., 1996). These observations involving impaired megakaryocytic growth and relative deficiency of TPO levels have opened new treatment possibilities that involve targeting TPO to stimulate megakaryocytic proliferation

antibodies. These cytokines can also lead to expansion of CD8+ cytotoxic T-cells.

refractory to conventional treatment regimens (Sabnani & Tsang, 2007).


Table 2. Diagnostic tools for chronic ITP
