Nelson ITP

484.1 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. 4841 ]. 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. RBCantibody 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 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.

2.

3.

4.

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.
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Abnormalities of Platelet Number or Function Thrombocytopenia in the pediatric age range is often immune-mediated (eg, idiopathic thrombocytopenic purpura, neonatal auto- or alloimmune thrombocytopenia, heparin-induced thrombocytopenia), but is also caused by consumptive coagulopathy (eg, DIC, Kasabach-Merritt syndrome), acute leukemias, rare disorders such as Wiskott-Aldrich syndrome and type IIb von Willebrand disease, and artifactually in automated cytometers (eg, Bernard-Soulier syndrome), where giant forms may not be enumerated as platelets by automated cell counters.

Idiopathic Thrombocytopenic Purpura Essentials of Diagnosis & Typical Features

Otherwise healthy child. Decreased platelet count. Petechiae, ecchymoses.

General Considerations Acute idiopathic thrombocytopenic purpura (ITP) is the most common bleeding disorder of childhood. It occurs most frequently in children aged 25 years and often follows infection with viruses, such as rubella, varicella, measles, parvovirus, influenza, or EBV. Most patients recover spontaneously within a few months. Chronic ITP (> 6 months' duration) occurs in 1020% of affected patients. The thrombocytopenia results from clearance of circulating IgM- or IgG-coated platelets by the reticuloendothelial system. The spleen plays a predominant role in the disease by forming the platelet cross-reactive antibodies and sequestering the antibody-bound platelets. Clinical Findings Symptoms and Signs Onset of ITP is usually acute, with the appearance of multiple petechiae and ecchymoses. Epistaxis is also common at presentation. No other physical findings are usually present. Rarely, concurrent infection with EBV or CMV may cause hepatosplenomegaly or lymphadenopathy, simulating acute leukemia. Laboratory Findings Blood The platelet count is markedly reduced (usually < 50,000/ L and often < 10,000/ L), and platelets frequently are of larger size on peripheral blood smear, suggesting accelerated production of new platelets. The white blood count and differential are normal, and the hemoglobin concentration is preserved unless hemorrhage has been significant. Bone Marrow The number of megakaryocytes is increased. Erythroid and myeloid cellularity is normal. Other Laboratory Tests Platelet-associated IgG or IgM, or both, may be demonstrated on the patient's platelets or in the serum. PT and aPTT are normal.

Differential Diagnosis Table 287 lists common causes of thrombocytopenia. ITP is a diagnosis of exclusion. Family history or the finding of predominantly giant platelets on the peripheral blood smear is helpful in determining whether thrombocytopenia is hereditary. Bone marrow examination should be performed if the history is atypical (ie, the child is not otherwise healthy, or if there is a family history of bleeding), if abnormalities other than purpura and petechiae are present on physical examination, or if other cell lines are affected on the CBC. The importance of performing a bone marrow examination prior to using corticosteroids in the treatment for ITP is controversial. Table 287. Common Causes of Thrombocytopenia.

Increased Turnover AntibodyMediated Idiopathic thrombocytopenic purpura Infection Coagulopathy Disseminated intravascular coagulopathy Sepsis Other Hemolytic-uremic syndrome Thrombotic thrombocytopenic purpura Hypersplenism Respiratory distress syndrome Wiskott-Aldrich syndrome

Decreased Production Congenital Fanconi anemia Acquired Aplastic anemia Leukemia and other malignancies Vitamin B12 and folate deficiencies

Wiskott-Aldrich syndrome Thrombocytopenia with absent radii

Immunologic diseases

Necrotizing enterocolitis Thrombosis Cavernous hemangioma

Metabolic disorders Osteopetrosis

Complications Severe hemorrhage and bleeding into vital organs are the feared complications of ITP. Intracranial hemorrhage is the most serious (but rarely seen) complication, occurring in less than 1% of affected children. The most important risk factors for hemorrhage are a platelet count less than 10,000/ Treatment General Measures L and mean platelet volume less than 8 fL.

Treatment is optional in most children in the absence of bleeding. Aspirin and other medications that compromise platelet function should be avoided. Bleeding precautions (eg, restriction from physical contact activities, use of helmets, etc) should be observed. Platelet transfusion should be avoided except in circumstances of life-threatening bleeding, in which case emergent splenectomy is to be pursued. In this setting, administration of corticosteroids and IVIG is also advisable. Corticosteroids Patients with clinically significant but nonlife-threatening bleeding (ie, epistaxis, hematuria, and hematochezia) and those with a platelet count of less than 10,000/ L may benefit from prednisone at 24 mg/kg orally per day for 35 days, decreasing to 12 mg/kg/d for a total of 14 days. The dosage is then tapered and stopped. No further prednisone is given regardless of the platelet count unless significant bleeding recurs, at which time prednisone is administered in the smallest dose that achieves resolution of bleeding episodes (usually 2.55 mg twice daily). Follow-up continues until the steroid can again be discontinued, spontaneous remission occurs, or other therapeutic measures are instituted. Intravenous Immunoglobulin (IVIG) IVIG is the treatment of choice for severe, acute bleeding, and may also be used as an alternative or adjunct to corticosteroid treatment in both acute and chronic ITP of childhood. IVIG may be effective even when the patient is resistant to corticosteroids; responses are prompt and may last for several weeks. Most patients receive 1 g/kg/d for 13 days. Infusion time is typically 46 hours. Platelets may be given simultaneously during life-threatening hemorrhage but are rapidly destroyed. Adverse effects of IVIG are common, including transient neurologic complications (eg, headache, nausea, and aseptic meningitis) in one third of patients. These symptoms may mimic those of intracranial hemorrhage and necessitate radiologic evaluation of the brain. A transient decrease in neutrophil number may also be seen. Anti-Rho(D) Immunoglobulin This polyclonal immunoglobulin binds to the D antigen on red blood cells. The splenic clearance of anti-Dcoated red cells interferes with removal of antibody-coated platelets, resulting in improvement in thrombocytopenia. This approach is effective only in Rh(+) patients with a functional spleen. The time required for platelet increase is slightly longer than with IVIG. However, approximately 80% of Rh(+) children with acute or chronic ITP respond well. Significant hemolysis may occur transiently with an average hemoglobin concentration decrease of 0.8 g/dL. However, severe hemolysis occurs in 5% of treated children, and clinical and laboratory evaluation approximately 5 days following administration is warranted in all patients. Rho(D) immunoglobulin is less expensive and infused more rapidly than IVIG, but is more expensive than corticosteroids. Splenectomy

Most children with chronic ITP have platelet counts greater than 30,000/

L. Up to 70% of

such children spontaneously recover with a platelet count greater than 100,000/ L within 1 year. For the remainder, corticosteroids, IVIG, and anti-D immunoglobulin are typically effective treatment for acute bleeding. Splenectomy produces a response in 7090%, but it should be considered only after persistence of significant thrombocytopenia for at least 1 year. Preoperative treatment with corticosteroids, IVIG, or anti-D immunoglobulin is usually indicated. Postoperatively, the platelet count may rise to 1 million/ L, but is not often associated with thrombotic complications in the pediatric age group. The risk of overwhelming infection (predominantly with encapsulated organisms) is increased after splenectomy, particularly in the young child. Therefore, the procedure should be postponed, if possible, until age 5 years. Administration of pneumococcal and H influenzae type b vaccines at least 2 weeks prior to splenectomy is recommended. Meningococcal vaccine, although controversial, may be considered. Penicillin prophylaxis should be started postoperatively and continued for 13 years. Rituximab (Anti-CD20 Monoclonal Antibody) The efficacy of treating childhood chronic ITP in several series and a phase I/II trial has been demonstrated; remission was observed in 40%. Because of significant adverse events, this therapy may be reserved for refractory cases with significant bleeding. Prognosis Ninety percent of children with ITP will have a spontaneous remission. Features associated with the development of chronic ITP include female gender, age greater than 10 years at presentation, insidious onset of bruising, and the presence of other autoantibodies. Older child- and adolescent-onset ITP is associated with an increased risk of chronic autoimmune diseases. Appropriate screening by history and laboratory studies (eg, antinuclear antibody) is warranted. Franchini M: Rituximab for the treatment of childhood chronic idiopathic thrombocytopenic purpura and hemophilia with inhibitors. Pediatr Blood Cancer 2007;49:6. [PMID: 17311349] Imbach P: Childhood ITP: 12 months follow-up data from the prospective registry I of the Intercontinental Childhood ITP Study Group (ICIS). Pediatr Blood Cancer 2006;46:351. [PMID: 16086422] Tarantino MD: The pros and cons of drug therapy for immune thrombocytopenic purpura in children. Hematol Oncol Clin North Am 2004;18:1301. [PMID: 15511617]