8/13/2019 itp super

1/8

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, anautoantibody directed against the platelet surface develops. The exact antigenic target for mostsuch 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 commoninfection 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 thecourse 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 suddenonset 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 thegums and mucous membranes, particularly with profound thrombocytopenia (platelet count

8/13/2019 itp super

2/8

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 ofearly therapy is to raise the platelet count to >20 10

9/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

8/13/2019 itp super

3/8

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 controlsubjects, 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 asthey do to autologous platelets. Thus, platelet transfusion in ITP is usually contraindicated unlesslife-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 sideeffects are minimal.

2. 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 ofantibody-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.

3. 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.4. 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 ofthrombocytopenia, 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.

Each of these medications may be used to treat exacerbations of ITP, which commonly occurseveral wk after an initial course of therapy.

In the special case of intracranial hemorrhage, multiple modalities should be used, includingplatelet transfusion, IVIG, high-dose corticosteroids, and prompt surgical consultation, with

plans for emergency splenectomy.

8/13/2019 itp super

4/8

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 arebleeding 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 easilycontrolled 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 overwhelmingpostsplenectomy infection caused by encapsulated organisms.

CHRONIC IDIOPATHIC THROMBOCYTOPENIC PURPURA.

Approximately 20% of patients who present with acute ITP have persistent thrombocytopenia

for > 6 moand are said to have chronic ITP. At that time, a careful re-evaluation for associateddisorders 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, autosomalmacrothrombocytopenia, 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 inducingcomplete 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, athrombopoiesis-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 prophylaxisfor a number of yr. Whether penicillin prophylaxis should be lifelong is controversial.

Itp cmdt

Abnormalities of Platelet Number or Function

Thrombocytopenia in the pediatric age range is often immune-mediated (eg, idiopathicthrombocytopenic 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 vonWillebrand disease, and artifactually in automated cytometers (eg, Bernard-Soulier syndrome),

where giant forms may not be enumerated as platelets by automated cell counters.

8/13/2019 itp super

5/8

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 ofchildhood. 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-coatedplatelets 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 acceleratedproduction 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.

8/13/2019 itp super

6/8

Differential Diagnosis

Table 287 lists common causes of thrombocytopenia. ITP is a diagnosis of exclusion. Familyhistory 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 familyhistory of bleeding), if abnormalities other thanpurpuraand 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 Decreased Production

Antibody-

Mediated

Coagulopathy Other Congenital Acquired

Idiopathic

thrombocytopenic

purpura

Disseminated

intravascular

coagulopathy

Hemolytic-uremic

syndrome

Fanconi anemia Aplastic

anemia

Infection Sepsis Thrombotic

thrombocytopenic

purpura

Wiskott-Aldrich

syndrome

Leukemia and

other

malignancies

Immunologic

diseases

Necrotizing

enterocolitis

Hypersplenism Thrombocytopenia

with absent radii

Vitamin B12and folate

deficienciesThrombosis Respiratory distress

syndrome

Cavernous

hemangioma

Wiskott-Aldrich

syndrome

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/ L and mean platelet volume less than 8 fL.

Treatment

General Measures

8/13/2019 itp super

7/8

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 beavoided 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 fromprednisone 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 46hours. 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 maymimic 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 clearanceof 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

8/13/2019 itp super

8/8

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 1year. 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 withthrombotic 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 andH influenzaetype b vaccines at least 2 weeks prior tosplenectomy 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- andadolescent-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

purpuraand 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 purpurain

children. Hematol Oncol Clin North Am 2004;18:1301. [PMID: 15511617]