Idiopathic Thrombocytopenic Purpura The most common cause of acute onset of thrombocytopenia in an otherwise well child is (autoimmune) idiopathic

thrombocytopenic purpura (ITP). ETIOLOGY. In a small number of children, 14 wk after exposure to a common viral infection, an autoantibody directed against the platelet surface develops. The exact antigenic target for most such antibodies in most cases of acute ITP remains undetermined. After binding of the antibody to the platelet surface, circulating antibody-coated platelets are recognized by the Fc receptor on the splenic macrophages, ingested, and destroyed. A recent history of viral illness is described in 5065% of cases of childhood ITP. The reason why some children respond to a common infection with an autoimmune disease remains unknown. Most common infectious viruses have been described in association with ITP, including Epstein-Barr virus (see Chapter 251 ) and HIV (see Chapter 273 ). Epstein-Barr virusrelated ITP is usually of short duration and follows the course of infectious mononucleosis. HIV-associated ITP is usually chronic. CLINICAL MANIFESTATIONS. The classic presentation of ITP is that of a previously healthy 14 yr old child who has sudden onset of generalized petechiae and purpura. The parents often state that the child was fine yesterday and now is covered with bruises and purple dots. Often there is bleeding from the gums and mucous membranes, particularly with profound thrombocytopenia (platelet count <10 109/L). There is a history of a preceding viral infection 14 wk before the onset of thrombocytopenia. Findings on physical examination are normal, other than the finding of petechiae and purpura. Splenomegaly is rare, as is lymphadenopathy or pallor. An easy to use classification system has been proposed from the U.K. to characterize the severity of bleeding in ITP on the basis of symptoms and signs, but not platelet count: 1. 2. 3. 4. No symptoms Mild symptoms: bruising and petechiae, occasional minor epistaxis, very little interference with daily living Moderate: more severe skin and mucosal lesions, more troublesome epistaxis and menorrhagia Severe: bleeding episodesmenorrhagia, epistaxis, melenarequiring transfusion or hospitalization, symptoms interfering seriously with the quality of life

The presence of abnormal findings, such as hepatosplenomegaly or remarkable lymphadenopathy, suggests other diagnoses (leukemia). When the onset is insidious, especially in an adolescent, chronic ITP or the possibility that thrombocytopenia is a manifestation of a systemic illness, such as systemic lupus erythematosus (SLE), is more likely. In 7080% of children who present with acute ITP, spontaneous resolution occurs within 6 mo. Therapy does not appear to affect the natural history of the illness. Fewer than 1% of patients have intracranial hemorrhage. Those who favor interventional therapy argue that the objective of early therapy is to raise the platelet count to >20 109/L and prevent the rare development of intracranial hemorrhage. Approximately 20% of children who present with acute ITP go on to have chronic ITP.

LABORATORY FINDINGS. Severe thrombocytopenia (platelet count <20 109/L) is common, and platelet size is normal or increased, reflective of increased platelet turnover. In acute ITP, the hemoglobin value, white blood cell (WBC) count, and differential count should be normal. Hemoglobin may be decreased if there have been profuse nosebleeds or menorrhagia. Bone marrow examination shows normal granulocytic and erythrocytic series, with characteristically normal or increased numbers of megakaryocytes. Some of the megakaryocytes may appear to be immature and are reflective of increased platelet turnover. Indications for bone marrow aspiration include an abnormal WBC count or differential or unexplained anemia as well as findings suggestive of bone marrow disease on history and physical examination.

Other laboratory tests should be done as indicated by the history and physical examination. In adolescents with new-onset ITP, an antinuclear antibody test should be done to evaluate for SLE. HIV studies should be done in at-risk populations, especially sexually active teens. Platelet antibody testing is seldom useful in acute ITP. A Coombs test should be done if there is unexplained anemia to rule out Evans syndrome (autoimmune hemolytic anemia and thrombocytopenia) [see Chapter 464 ] or before instituting therapy with IV anti-D.

DIFFERENTIAL DIAGNOSIS. The well-appearing child with moderate to severe thrombocytopenia, an otherwise normal complete blood cell count (CBC), and normal findings on physical examination has a limited differential diagnosis that includes exposure to medication that induces drug-dependent antibodies, splenic sequestration due to previously unappreciated portal hypertension, and rarely, early aplastic processes, such as Fanconi anemia (see Chapter 468 ). Other than congenital syndromes, such as amegakaryocytic thrombocytopenia and thrombocytopenia-absent radius (TAR) syndrome, most marrow processes that interfere with platelet production also cause abnormal synthesis of red blood cells (RBCs) and WBCs and therefore manifest diverse abnormalities on the CBC. Disorders that cause increased platelet destruction on a nonimmune basis are usually serious systemic illnesses with obvious clinical findings (e.g., hemolytic-uremic syndrome [HUS], disseminated intravascular coagulation [DIC]) [see Table 484-1 and Fig. 484-1 ]. Isolated enlargement of the spleen suggests the potential for hypersplenism owing to either liver disease or portal vein thrombosis. Autoimmune thrombocytopenia may be an initial manifestation of SLE, HIV infection, or rarely, lymphoma. Wiskott-Aldrich syndrome (WAS; see Chapter 125.2 ) must be considered in young males found to have low platelet counts, particularly if there is a history of eczema and recurrent infection. TREATMENT. There are no data showing that treatment affects either short- or long-term clinical outcome of ITP. Many patients with new-onset ITP have mild symptoms, with findings limited to petechiae and purpura on the skin, despite severe thrombocytopenia. Compared with untreated control subjects, treatment appears to be capable of inducing a more rapid rise in platelet count to the theoretically safe level of >20 109/L, although there are no data indicating that early therapy prevents intracranial hemorrhage. Antiplatelet antibodies bind to transfused platelets as well as they do to autologous platelets. Thus, platelet transfusion in ITP is usually contraindicated unless life-threatening bleeding is present. Initial approaches to the management of ITP include the following: 1. No therapy other than education and counseling of the family and patient for patients with minimal, mild, and moderate symptoms, as defined earlier. This approach emphasizes the usually benign nature of ITP and avoids the therapeutic roller coaster that ensues once interventional therapy is begun. This approach is far less costly, and side effects are minimal. Intravenous immunoglobulin (IVIG). IVIG at a dose of 0.81.0 g/kg/day for 12 days induces a rapid rise in platelet count (usually>20 109/L) in 95% of patients within 48 hr. IVIG appears to induce a response by downregulating Fc-mediated phagocytosis of antibody-coated platelets. IVIG therapy is both expensive and time-consuming to administer. Additionally, after infusion, there is a high frequency of headaches and vomiting, suggestive of IVIG-induced aseptic meningitis. Intravenous anti-D therapy. For Rh positive patients, IV anti-D at a dose of 5075g/kg causes a rise in platelet count to>20 109/L in 8090% of patients within 4872 hr. When given to Rh positive individuals, IV anti-D induces mild hemolytic anemia. RBC-antibody complexes bind to macrophage Fc receptors and interfere with platelet destruction, thereby causing a rise in platelet count. IV anti-D is ineffective in Rh negative patients. Prednisone. Corticosteroid therapy has been used for many years to treat acute and chronic ITP in adults and children. Doses of prednisone of 14 mg/kg/24 hr appear to induce a more rapid rise in platelet count than in untreated patients with ITP. Whether bone marrow examination should be performed to rule out other causes of thrombocytopenia, especially acute lymphoblastic leukemia, before institution of prednisone therapy in acute ITP is controversial. Corticosteroid therapy is usually continued for 23 wk or until a rise in

2.

3.

4.

platelet count to>20 109/L has been achieved, with a rapid taper to avoid the long-term side effects of corticosteroid therapy, especially growth failure, diabetes mellitus, and osteoporosis. Each of these medications may be used to treat exacerbations of ITP, which commonly occur several wk after an initial course of therapy. In the special case of intracranial hemorrhage, multiple modalities should be used, including platelet transfusion, IVIG, high-dose corticosteroids, and prompt surgical consultation, with plans for emergency splenectomy. Currently, there is no consensus regarding the management of acute childhood ITP. The American Society of Hematology has published treatment guidelines for adults with ITP, but there is significant disagreement within the field. The only consensus is that patients who are bleeding significantly should be treated, and these may represent only 5% of children with ITP. Intracranial hemorrhage remains rare, and there are no data showing that treatment actually reduces its incidence. The role of splenectomy in ITP should be reserved for 1 of 2 circumstances. The older child (> 4 yr) with severe ITP that has lasted >1 yr (chronic ITP) and whose symptoms are not easily controlled with therapy is a candidate for splenectomy. Splenectomy must also be considered when life-threatening hemorrhage (intracranial hemorrhage) complicates acute ITP, if the platelet count cannot be corrected rapidly with transfusion of platelets and administration of IVIG and corticosteroids. Splenectomy is associated with a lifelong risk of overwhelming postsplenectomy infection caused by encapsulated organisms.

CHRONIC IDIOPATHIC THROMBOCYTOPENIC PURPURA. Approximately 20% of patients who present with acute ITP have persistent thrombocytopenia for > 6 mo and are said to have chronic ITP. At that time, a careful re-evaluation for associated disorders should be performed, especially for autoimmune disease, such as SLE; chronic infectious disorders, such as HIV; and nonimmune causes of chronic thrombocytopenia, such as type 2B and platelet-type von Willebrand disease, X-linked thrombocytopenia, autoimmune lymphoproliferative syndrome, common variable immunodeficiency syndrome, autosomal macrothrombocytopenia, and WAS (also X-linked). Therapy should be aimed at controlling symptoms and preventing serious bleeding. In ITP, the spleen is the primary site of both antiplatelet antibody synthesis and platelet destruction. Splenectomy is successful in inducing complete remission in 6488% of children with chronic ITP. This must be balanced against the lifelong risk of overwhelming postsplenectomy infection. This decision is often affected by lifestyle issues as well as the ease with which the child can be managed using medical therapy, such as IVIG, corticosteroids, IV anti-D, or rituximab (see Chapter 464 ). AMG 531, a thrombopoiesis-stimulating protein, has had some success in treating adults with chronic immune thrombocytopenia. Before splenectomy, the child should receive pneumococcal and meningococcal vaccines, and after splenectomy, he or she should receive penicillin prophylaxis for a number of yr. Whether penicillin prophylaxis should be lifelong is controversial.