**1. Introduction**

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

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Characterized by low platelet counts, immune thrombocytopenic purpura (ITP) has been discovered to be an acquired autoimmune disorder since the mid-1900s (Evans et al., 1951). In the 21st century, the modern generation would shudder at Harrington and Hollingsworth's experiment they performed to search for the pathogenesis of ITP. By injecting themselves with 500 ml of blood from a patient from low platelet counts, they developed the same bleeding disorder and were able to reproduce the disease in themselves (Harrington et al., 1951). Since that experiment, the pathogenesis and the therapeutic options of ITP have evolved by leaps and bounds. The traditional model of ITP is that of pathologic destruction of platelets by antiplatelet antibody. For many decades, this model of autoimmune thrombocytopenic purpura has shaped our understanding of the disorder and our therapeutic management of ITP (Buchanan et al, 1977, Hou et al. 1995, Fujisawa K et al. 1992). Recent studies have broadened our perspective beyond humoral dysregulation to include the cellular immune system and abnormalities of megakaryocytes as well (Olsson, et al., 2003, Ballem et al., 1987, McMillan et al., 2004). These recent findings have opened the door for new treatment possibilities for ITP.

In contrast to a more predictable clinical course of acute ITP, the pathogenesis, natural history and management of chronic ITP are significantly more diverse and rapidly evolving. The established treatment practices for chronic ITP have also undergone a major change. After a long period of standard treatment approach using steroids, splenectomy, and immunosuppressive therapy, a breakthrough came with the use of B-cell depletion therapy (Cines and McMillan, 2005). The availability of monoclonal antibody, rituximab, has led hematologists to reconsider the role of splenectomy in the frontline management of chronic ITP (Arnold et al., 2007). A new era has begun with the development of thrombopoietinmimetic agents that stimulate megakaryocytes to grow and produce platelets (Nurden et al., 2009).

Since chronic ITP remains a heterogeneous disorder; there is no consensus on the definite diagnostic criteria and management. In 1996, the American Society of Hematology published a landmark paper recommending guidelines to assist clinicians in the management of ITP (George et al., 1996). Since then, there have been tremendous advances in the management of both adult and pediatric ITP. These guidelines were updated by the

Changing Spectrum of Chronic Immune Thrombocytopenic

Table 1. Commonly used definitions in ITP

presenting as ITP (Cines et al., 2005, 2009, 2010).

**3. Diagnosis of chronic ITP** 

define ITP.

Purpura: New Face for an Old Disease 69

vary from time to time. Table 1 summarizes the different terminologies commonly used to

Newly diagnosed ITP From initial diagnosis to 3 months Persistent ITP From 3-12 months of initial diagnosis Chronic ITP ITP lasting for greater than 12 months Mild Thrombocytopenia Platelet count between 50-100 x 109/L Moderate Thrombocytopenia Platelet count between 20-50 x 109/L Severe thrombocytopenia Platelet count below 20 x 109/L

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

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,

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

patients with gastrointestinal symptoms should be investigated further.

diagnostic tests for diagnosing ITP according to current guidelines.

Primary ITP Platelet count less than 100 x 109/L in the absence

of other causes of thrombocytopenia

**Category Definition** 

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 disease.

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 6.6 per 100,000 in the adult population.
