Platelet disorders

PLATELET DISORDERS

Immune Thrombocytopenia
Adam Cuker1 and Douglas B. Cines1
1Departments

of Medicine and of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA

Immune thrombocytopenia (ITP) comprises a heterogeneous group of disorders characterized by autoimmunemediated platelet destruction and impairment of thrombopoiesis. ITP may occur in the absence ofan evident predisposing etiology (primary ITP) or secondary to a growing list of associated conditions (secondary ITP), and must be differentiated from other causes of thrombocytopenia. This review focuses on primary ITP in adults. The traditional goal of therapy in this population is to achieve a hemostatic platelet count of 30 109/L or above for most patients while minimizing treatment-relatedmorbidity. This approach has been called into question by the recent advent of well-tolerated and effective agents for the management of ITP, including pulse-dose dexamethasone, rituximab, and the thrombopoietin receptor agonists. Recent studies suggest the potential for aggressive therapy at the time of diagnosis to alter the natural history of ITP and point to the importance of quality-of-lifeconsiderations in therapeutic decision making.

Introduction
Immune thrombocytopenia (ITP) is an autoimmune syndrome involving antibody- and cell-mediated destruction of platelets and suppression of platelet production that may predispose to bleeding.1 Recent recommendations from an international working group suggest that ITP be used to designate all cases of immune-mediated thrombocytopenia,whether occurring as a component of another clinically evident disorder or drug exposure (secondary ITP) or in the absence of a clear predisposing etiology (primary ITP).2,3 The international working group also recommends that a platelet count below 100 109/L, rather than 150 109/L, be required for diagnosis. This threshold is based on observational evidence that fewer than 10% of otherwise healthyindividuals with a stable platelet count between 100 and 150 109/L develop more severe unexplained ITP over the ensuing 10 years.4 This review focuses on primary ITP in the adult population, but includes certain aspects of secondary forms and pediatric ITP where pertinent. The management of ITP in pregnancy is discussed elsewhere in this issue (see “Thrombocytopenia in Pregnancy”).

Etiology
Theunderlying defects leading to autoantibody production are unknown. Heritability is uncommon,8 although predisposing polymorphisms in cytokines and Fc receptors have been described. A Th1/Th0 cytokine profile,9 a reduction in suppressor T-regulatory cells,10 and an increase in B-cell-activating factor11 may predispose to emergence of autoantibodies in response to exogenous antigens.12 Molecularmimicry appears to play a role in the development of self-reactive platelet antibodies after vaccination and certain viral infections. For example, antibodies to microbial (viral and bacterial) antigens that cross-react with platelets, often an epitope within glycoprotein IIIa, have been identified in patients who develop ITP in association with HIV, hepatitis C virus, and Helicobacter pyloriinfection.13–15 In support of this postulated mechanism, microbial reduction/eradication leads to remission in a substantial fraction of infected patients, although questions remain regarding how platelet-reactive autoantibodies develop and, in the case of H. pylori, why there appears to be marked variations in response rates among patients from different parts of the world.16 The mechanisms leading toautoantibody production may differ in secondary forms of ITP associated with immunosuppression or immune dysregulation.1

Incidence and Demographics
Estimates of the incidence of adult-onset ITP range from approximately 1.6 to 3.9 per 100,000 persons per year, with a prevalence ranging from 9.5 to 23.6 per 100,000 persons, based on diagnostic codes in the UK health registry5,6; estimates based...