OVERVIEW: What every practitioner needs to know

Are you sure your patient has idiopathic thrombocytopenic purpura? What are the typical findings for this disease?

Primary childhood ITP (Idiopathic or Immune Thrombocytopenic Purpura) is an immune-mediated disorder characterized by severe thrombocytopenia usually without a known cause. The typical child with ITP will be previously healthy except possibly for a history of a viral illness in the last few months, have the sudden (in the last few days or weeks) onset of mucocutaneous bleeding, and be found to have isolated often profound thrombocytopenia on the complete blood count. Secondary ITP is defined as thrombocytopenia associated with other disorders. This chapter will focus on primary childhood ITP.

The majority (70%) of children with ITP will be between the ages of 1 and 10 years. Although ITP has been documented in infants between the ages of 3 and 12 months and in adolescents, there should be heightened concern for secondary causes of thrombocytopenia in these age groups.

Most notable in primary childhood ITP is the LACK of any additional historical or physical findings other than bleeding. Epistaxis is a common presenting feature and hematuria is rare. With rare exception there are no symptoms to suggest an acute infection, such as fever or malaise. Children with ITP will not complain of bone or joint pain. Indeed, children with this disorder feel perfectly well and wonder why they have to be at the doctor’s office.

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There is usually no history of medication ingestion. No family members are known to have thrombocytopenia or mild bleeding symptoms. Physical examination is often characterized by impressive, diffuse petechiae and purpura. Oral purpura may be mild to severe, but lymphadenopathy and splenomegaly are absent.

While most children with primary ITP will recover in 6 weeks to 6 months, approximately 10-15% will subsequently develop chronic ITP. Chronic ITP is defined as persistent thrombocytopenia for greater than 12 months. Certain clinical characteristics at diagnosis of primary ITP have been found to be predictors of chronic ITP: insidious onset, no preceding infection or vaccination, age > 11years at presentation, higher platelet count (>20 x 109/L) at presentation, and female gender. Conversely, children < 10 years old presenting with abrupt onset (< 2 week of bleeding symptoms) usually have resolution of ITP within 3-6 months and have a lower risk of developing chronic ITP.

Acute infection and thrombocytopenia

While many children with ITP have a history of a transient viral illness within the preceding month, a few children will present during acute varicella or Epstein Barr infection. Isolated thrombocytopenia has been reported as the initial presentation of HIV infection in children. Often in these cases there are none of the typical signs and symptoms of HIV and response to ITP treatment is usually good, frequently with sustained remissions. H. pylori infection has been diagnosed in adults with ITP especially in endemic areas. However, there has not been a proven connection between H. pylori infection and ITP in children.

Thrombocytopenia can be seen at the time of many other acute infections from both viral and bacterial pathogens. However, this “thrombocytopenia with infection” should be differentiated from childhood ITP. The thrombocytopenia seen with these acute infections is usually not as severe as seen in ITP, so bleeding tends to not be a prominent symptom. The platelet count returns to normal as the acute infection resolves, unlike the more prolonged course in ITP.

ITP can be seen after immunizations, especially measles-mumps-rubella with an estimated risk of ITP at approximately 1 in 25,000 doses. ITP is unlikely after other immunizations.

What other disease/condition shares some of these symptoms?

While the differential diagnosis of thrombocytopenia in a child is extensive, with the classic presentation of childhood ITP essentially no other disorder will present the same way. One exception is the rare disorder amegakaryocytic thrombocytopenia. Children with this disorder are usually younger, do not respond to typical ITP therapy, and evolve into aplastic anemia. A number of studies have been published which have shown that leukemia does not present with the features of typical ITP.

Atypical presentation suggesting other diseases/conditions:

If any component of the history, physical exam, or laboratory picture is atypical, it is imperative to search for other disorders that can mimic ITP or are secondary causes of ITP.

Atypical History:

If the clinical history of bleeding does not correlate with the platelet count (e.g., minimal bruising or bleeding in a child reported to have a platelet count of 5 x 109/L), it is important to insure that the platelet count is accurate and not pseudo-thrombocytopenia. Pseudo-thrombocytopenia can result from clumping of platelets, so the platelet count is spuriously low. Be particularly watchful for this problem when there was difficulty obtaining the venous sample. Careful examination of the blood smear and repeat testing may be necessary.

Thrombocytopenia in a child with a history of recurrent infections should alert one to the diagnosis of Wiskott Aldrich syndrome (or the less severe X-linked thrombocytopenia), common variable immunodeficiency, or leukemia (especially if associated with additional physical or laboratory abnormalities).

A history of bone pain (or refusal to walk in the toddler) would suggest leukemia.

A rash and joint pain especially in a teenage girl would suggest the diagnosis of systemic lupus erythematosis. Thrombocytopenia has very rarely been reported with other auto-immune diseases such as inflammatory bowel disease and juvenile idiopathic arthritis, both of which usually present with thrombocytosis.

Fever and infection are infrequently presenting features of ITP as addressed above.

An infant or toddler with Down Syndrome presenting with isolated thrombocytopenia, even if there are no atypical findings otherwise, cannot be presumed to have ITP, since myelodysplastic syndrome and acute myelogenous leukemia will often present with isolated thrombocytopenia in these children.

If there is a family history of mild to moderate bleeding, this should raise the possibility of an inherited thrombocytopenia. While very uncommon, the list is long, including Wiskott Aldrich syndrome, X-linked thrombocytopenia, familial thrombocytopenias, the macrothrombocytopenias, gray platelet syndrome, von Willebrand disease Type IIB, and platelet-type pseudo-von Willebrand disease. A history of bruising and other bleeding symptoms that are chronic rather than the typical acute presentation would be consistent with one of the inherited thrombocytopenias or alternatively chronic ITP.

Atypical Physical Examination:

Children with ITP are generally well-appearing, so a child that appears sick should lead to a complete evaluation for an underlying cause, such as infection or leukemia. Extensive vascular anomalies (not simple hemangiomas) would suggest thrombocytopenia as part of the Kassabach-Meritt syndrome. Diffuse and often impressive lymphadenopathy can be seen with leukemia/lymphoma and autoimmune lymphoproliferative syndrome (ALPS). Splenomegaly is also a typical finding in ALPS and leukemia. The combination of thrombocytopenia and splenomegaly would also suggest hypersplenism from liver disease and/or portal hypertension.

Atypical Laboratory Findings:

See below.

What caused this disease to develop at this time?

ITP in the majority of children is a result of the formation of autoantibodies or immune complexes resulting from exposure to viruses or possibly toxins. These platelet IgG antibodies have specificity for platelet antigens, such as glycoproteins IIB/IIIa and Ib/IX. When antibody-coated platelets traverse the spleen, they bind to the splenic Fc receptors on macrophages which remove the platelets from circulation. Subsequently, platelet antigen-specific T-cell clones proliferate and drive the B-cells producing autoantibodies. There is evidence that platelet dysfunction (irrespective of platelet count) may correlate with severity of bleeding symptoms.

Studies in adults with ITP have revealed evidence of antibody suppression of megakaryocytic production of platelets, although similar studies have not been reported in children. It is not clear why any particular child gets ITP. While a viral illness is presumed to commonly precede ITP, no one agent or group of agents have been proven to routinely cause ITP. Even with endemics of viral illness in the community only the occasional child will develop ITP. A tendency for families of children with ITP to have allergic disorders has been reported, but a family history of acute ITP is so rare that there is little to no evidence that there is a genetic predisposition to the disorder.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The important laboratory studies to confirm the diagnosis are a complete blood count (CBC) and review of the peripheral smear by a pediatric hematologist or hematopathologist. With a history and physical examination typical of childhood ITP, no other studies are necessary.

The CBC should reveal a very low platelet count, usually below 20 x 109/L, a normal white blood count and differential, and a normal hemoglobin, unless there has been significant bleeding. Review of the smear should document the low platelet count and occasional large platelets can be seen. Atypical lymphocytes may be present if there has been a recent viral illness or evidence of infectious mononucleosis.

There has been considerable controversy in the past about the need for examination of the bone marrow to confirm a diagnosis of ITP, especially if there is consideration of using corticosteroids for treatment. The major concern has been that the diagnosis of leukemia will be missed. However, a retrospective study of over 2000 children with leukemia found no instances of isolated thrombocytopenia without additional abnormal findings to suggest the diagnosis of leukemia. In another study of bone marrow aspirations in over 300 children with typical ITP presentation, there were no cases of leukemia and one with aplastic anemia. However, in children who present with atypical features, especially if there is adenopathy and splenomegaly or multiple cytopenias, a bone marrow examination is mandatory.

Additional laboratory studies to consider

A direct antiglobulin test (Coombs test) may be indicated if anemia that can’t be explained by blood loss is present. The combination of autoimmune thrombocytopenia and autoimmune anemia is termed Evans syndrome. This diagnosis is important to make since the natural history of children with Evans syndrome is quite different (more prolonged and often more severe) than children with ITP. Also, if the use of anti-D immunoglobulin (WinRho) is being considered as treatment, blood group Rh (D) type as well as Coombs test are mandatory, since WinRho is not effective in patients who are Rh negative and contraindicated in the presence of autoimmune hemolytic anemia.

Teenagers, especially girls and those with an atypical presentation, may have underlying systemic lupus erythematosis. Consideration should be given to not only performing a Coombs test, but also screening for collagen vascular disease. A battery of studies that may be considered include creatinine, liver function tests, antinuclear antibody, double-stranded DNA, antiphospholipid lipid, and C3.

Quantitative immunoglobulins should be obtained in a child with a history of recurrent infections to rule out common variable immune deficiency.

Laboratory studies not indicated

Coagulation studies – PT, PTT, fibrinogen – are not indicated in the child with typical ITP. Routine testing for anti-platelet antibodies, anti-phospholipid antibodies, anti-nuclear antibody, or thrombopoietin level is not recommended.

Atypical laboratory findings suggesting other diseases/conditions

Whenever there are two or especially three abnormal cell lines on the CBC, the diagnosis of leukemia, other marrow infiltrative process, or aplastic anemia must be entertained. Leukemia can present with either a low or high white blood count with or without the presence of blasts on peripheral smear. If there is anemia out of proportion to the amount of bleeding, a reticulocyte count should be performed. A low reticulocyte count would suggest lack of production as seen in leukemia and aplastic anemia. A high reticulocyte count could be associated with a concomitant hemolytic anemia, as seen in Evans syndrome.

Thrombocytopenia plus microangiopathic hemolytic anemia are classically seen together in patients with hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. Children with these disorders are usually quite sick and differentiation from typical ITP is not problematic.

Platelet size may be a hint that ITP is not the correct diagnosis. There are a number of inherited syndromes with usually mild to moderate thrombocytopenia and either small or large platelets. Small platelets are seen in Wiskott Aldrich syndrome and X-linked thrombocytopenia. Giant platelets (as large as red blood cells) are seen in the MYH9 syndromes of macrothrombocytopenia: May-Hegglin anomaly, Fechtner syndrome, Epstein syndrome, and Sebastian syndrome. Besides the finding of huge platelets in the MYH9 syndromes, Dohle-like inclusions can be seen in the neutrophils. Large platelets can also be seen in Bernard-Soulier syndrome and the gray platelet syndrome.

Would imaging studies be helpful? If so, which ones?

Imaging studies are not of value in the routine diagnosis or management of ITP. They may be indicated in patients with atypical presentations.

If you are able to confirm that the patient has idiopathic thrombocytopenic purpura, what treatment should be initiated?

  • Supportive Care:

    Routine management for all patients with ITP includes education regarding the disease, avoiding platelet “poisons” such as aspirin, ibuprofen, or other medications, and age-dependent counseling regarding activities. Information about ITP that should be emphasized include:

    ITP is usually a self-limited disease that has no curative therapy

    most children will recover within 6 weeks to 6 months

    serious bleeding is uncommon (in most studies <10%) and life-threatening bleeding such as intracranial hemorrhage is rare (0.1-0.8%), but can be devastating

    a small fraction (10-15%) of patients will develop chronic ITP, defined as ITP lasting more than 12 months

    children should be able to have a normal life style, including return to school, with some exceptions

    physical activities that would pose risk for significant trauma should be avoided, e.g., contact sports, certain physical education activities, etc. A discussion with school officials is recommended

    any significant injury, especially head injury, warrants immediate attention by the primary physician

    any new bleeding (e.g. prolonged epistaxis, oral bleeding, hematuria, but NOT simple bruising) warrants immediate attention

    while pharmacologic treatment is available that is effective in increasing the platelet count (discussed below), it is usually short-lived (i.e. 2-4 weeks)

  • Initial Pharmacologic Therapy:

    Initiation of pharmacologic treatment is not required in all patients and is case dependent.

    There is controversy regarding whether a platelet count alone should prompt treatment. Many pediatric hematologists have used a platelet count of < 10 x 109/L as an indication to treat, especially, for example, in a rambunctious toddler. However, recent evidence-based practice guidelines have been published by the American Society of Hematology which recommend that children with minimal to no bleeding (bruising or petechiae only) be treated with supportive care only regardless of the platelet count. There is accumulating evidence that this approach is being more widely practiced and is safe.

    For the child who has significant bleeding, such as severe epistaxis, GI bleeding or menorrhagia, pharmacologic therapy is warranted. (For life threatening bleeding, see below.) Oral bleeding (“wet purpura”) has historically been considered to be a risk factor for more serious bleeding such as intracranial hemorrhage, although there are insufficient data to prove this. Nonetheless, wet purpura is often cited as an indication for pharmacologic intervention. There are few, primarily retrospective studies addressing potential risk factors for life-threatening bleeding. One retrospective, controlled study identified hematuria and history of head trauma, as significant risk factors (in addition to severe thrombocytopenia) for the development of intracranial hemorrhage. Consideration of pharmacologic treatment for children with these findings is warranted. Other factors, such as the social situation, availability of follow-up, etc. may also impact the decision to treat.

    If one decides to intervene with drug therapy, the following are accepted options:

    Corticosteroids. Prednisone or prednisilone at 2mg/kg/day has been used in the treatment of ITP for decades. Randomized trials have shown that this “low dose” therapy has limited benefit in rapidly increasing the platelet count, although platelet counts rise faster than placebo. “High dose” prednisone or methylprednisolone at different doses has shown a rapid increase of the platelet count within 24-72 hours. Doses from 4 mg/kg to 30 mg/kg of oral and IV corticosteroid have been used with rapid response of the platelet count into a “safe” range (> 20 x 109/L) within 2-4 days. The author’s experience with 4/mg/kg/day of oral prednisone for 4 days has proven effective and well tolerated. Corticosteroids should not be used in the rare circumstance of ITP with active varicella infection.

    Intravenous immunoglobulin G. Blockade of splenic Fc receptors is believed to be the mechanism for the rapid rise in the platelet count seen after administration of intravenous immunoglobulin G (IVIG) in ITP. IVIG was initially studied at 400mg/kg/day for 5 days then subsequently 0.8 -1 gm/kg/day for 1-2 days and has proven to be highly effectively in increasing the platelet count within 24 – 48 hours in the vast majority of children. A recent meta-analysis showed that IVIG was more effective than corticosteroids in increasing the platelet count to > 20 x 109/L at 48 hours, although there were no differences in clinically relevant outcomes. High dose IVIG is frequently associated with side effects.

    Intravenous anti-D. Patients who are Rh+ would be eligible to receive treatment with IV anti-D. It is presumed that antibody-coated red cells from this small dose of IV anti-D compete with antibody-coated platelets for splenic binding sites, thus allowing longer platelet survival. Doses of 50 – 75 ugm/kg have both been found to effectively and rapidly increase the platelet count. A dose of 75 ugm/kg of anti-D has been found in one study to be equally effective as 0.8 gm/kg of IVIG in increasing the platelet count to > 20 x 109/L 24 hours after treatment. Since IV anti-D is associated with infusional toxicity such as fever and chills, it is common practice to give acetaminophen and small dose of corticosteroids prior to the infusion. IV anti-D is contraindicated in patients who have a positive antiglobulin (Coombs) test or have infectious mononucleosis and should be used with caution in those with a hemoglobin < 10 gm/dL. Although IV anti-D is considered to be in general a safe treatment for ITP, severe intravascular hemolysis associated with renal failure and death has been reported. A recent Black Box Warning which recommends close monitoring for 8 hours in a healthcare setting has limited the flexibility and utility of this treatment option.

Table I. Comparison of treatment options for ITP

   Supportive Care  Corticosteriods “Low Dose”  Corticosteroids “High Dose”  IVIG IV anti-D
 Dose  N.A.  2 mg/kg/day  > 4 mg/kg/d  0.8-1 gm/kg  50-75 ugm/kg
 Cost  None  Low  Low  High  High
 Onset  N.A.  Slow  Rapid  Very Rapid  Very Rapid
 Side Effects  None  Minimal/Moderate  Minimal/Moderate  Moderate/Severe  Moderate/Severe

  • Subsequent Pharmacologic Therapy

    Children who receive Supportive Care only as initial management should be considered for pharmacologic therapy if there is new onset of significant bleeding, such as a prolonged nose bleed, GI bleeding, menorrhagia, or significant trauma, especially head trauma.

    For children who receive drug treatment and have a good response, a fall in the platelet count would be expected in 2-4 weeks. It is important to advise families to anticipate this drop in platelets. The platelet count often does not fall to the initial low platelet count level and subsequent treatment is not necessary. Indications for subsequent therapy should be similar to initial therapy.

Treatment of life-threatening bleeding

Treatment of life-threatening bleeding is designed to increase the platelet count as rapidly as possible. Recommendations for treatment are based almost exclusively on case reports. One emergency management strategy would be the following:

Immediate infusion of 30 mg/kg (maximum dose 1 gram) of IV methylprednisolone over 30 minutes, followed immediately by,

Platelet infusion at age/weight appropriate dose (increased dose may be required), followed by or concomitant with,

IVIG 1 gm/kg;

Repeat administration of these treatments may be necessary and will depend on initial rise and duration of platelet response to therapy.

Additional therapy that has been used in the emergency setting includes recombinant Factor VIIa, antithrombolytics, and splenectomy.

(Note: This is the only setting when platelet infusion should be considered, since usually antiplatelet antibodies destroy transfused platelets immediately.)

Treatment of chronic ITP

Chronic ITP is defined as ITP lasting for more than 12 months. Although chronic ITP has previously been defined as ITP lasting for more than 6 months, at least a third of children with thrombocytopenia at 6 months will eventually have a spontaneous remission.

There are many children with chronic ITP who have mild to moderate thrombocytopenia (platelet count > 20 x 109/L ) and require no intervention. Treatment can be considered for the small group of children who have platelet counts below 20 x 109/L, who have symptomatic bleeding, or who have significant impact on their quality of life by thrombocytopenia.

Clinical guidelines from the American Society of Hematology recommend for children or adolescents who have significant ongoing bleeding despite treatment with IVIG, anti-D, or conventional doses of corticosteroids consideration of the following drugs: (1) rituximab (375 mg/m2 x 4 weekly doses) or (2) high dose dexamethasone (0.6 mg/kg/day for 4 days every 4 weeks). Both of these agents have be found in small studies to have an approximately 25% response rate. In a systematic review of rituximab in children with chronic ITP, the pooled response rate was 68%. The five-year estimate of persistent response is 26%. In small studies, high dose dexamethasone has been found to have initial response rates of 50-80%, but limited sustained responses.

Side effects are frequent with both therapies. Cases of progressive multifocal leukoencephalopathy following rituximab have been reported in adults, most with primary hematological malignancies, but have not been reported in children.

Thrombopoietin receptor agonists eltrombopag and romiplostim have proven efficacy in adults with chronic ITP. Recent studies in children document similar efficacy.

– Eltrombopag has been approved for use in children by the FDA. It has the advantage of daily oral administration. 40 – 62% of patients receiving eltrombopag in two randomized, placebo-controlled trials achieved a platelet count > 50 x 109/L. In a follow-up study, 80% achieved a platelet count >50 x 109/L at least once. The drug was well tolerated with minimal safety concerns.

– Romiplostim is given as a weekly subcutaneous injection. Although not approved by the FDA at this time, preliminary studies have shown a good response rate (15 of 17 patients achieved platelet counts > 50 x 109/L) without significant toxicity.

Many other single agent treatments have been attempted with only a modicum of success. Data are insufficient to recommend treatment with danzol, interferon, azathioprine, cyclosporine, mycophenolate mofetil, anti-CD52 monoclonal antibody or combination therapies. One exception to this long list of minimally effective agents may be dapsone. In a recent retrospective study dapsone (2 mg/kg/day) given over 3 months yielded a very high response rate of 66%. Additional, ideally prospective studies are needed to confirm these excellent results.

Splenectomy has been found in most studies to have the highest and most sustained responses in the treatment of chronic ITP in children. However, there is a reluctance to utilize splenectomy because of the “hoped for” spontaneous remission and concerns for risk of post-splenectomy infection or other complications. With appropriate pre-splenectomy immunization, with or without post-splenectomy antibiotic prophylaxis, the risk of post-splenectomy sepsis is very low. Splenectomy should be considered for children and adolescents with chronic ITP who have persistent or recurrent bleeding or where there is a significant impact on quality of life, especially if standard therapies have failed.

What are the adverse effects associated with each treatment option?

The adverse effects of the treatments for primary ITP are as follows:

Supportive Care

The main problem with providing only supportive care to the child with ITP is high parental (and often physician) anxiety. While data would suggest that it is both safe and reasonable to not treat the non-bleeding child with pharmacologic agents, parents often wish to have the risk of a serious hemorrhage removed by giving drugs that increase the platelet count even though the reprieve from anxiety is only temporary.

The counseling skills of the physician are critical during the first few days following the diagnosis to emphasize the facts regarding the expected course as noted above – reassuring the parents and at the same time finding the correct balance to not underemphasize the potential risks. Side effects from pharmacologic therapy, which can be severe, should be emphasized. Finally, at least during the first few weeks following the diagnosis, frequent (at least weekly) visits are important, as is the ability to contact a knowledgeable care provider at any time.

Corticosteroids

Side effects of corticosteroids depend on the dose and duration of treatment. Short term (3-4 days) high dose (4 mg/kg/day po to 30 mg/kg/day IV [max. 1 gm.]) treatment is associated with few side effects. These include transient mood changes (especially in teenagers), glucosuria, and dyspepsia (Prophylactic H2-antagonists are recommended). The longer corticosteroid treatment is given the more likely are the many toxicities of this class of drugs, including emotional changes, such as anger, anxiety, and mood swings, insomnia, hypertension, hyperglycemia, increase in appetite, weight gain, dyspepsia, peptic ulcers, immunosuppression with risk of opportunistic infection, avascular necrosis, osteoporosis, cataracts, growth suppression, and adrenal insufficiency.

IV anti-D

The side effects that can be expected with IV anti-D include hemolysis and infusional toxicity, such as fever, chills, nausea/vomiting, headache. Rarely, severe intravascular hemolysis with renal failure and death has been reported. A recent Black Box Warning recommends close monitoring for 8 hours in a healthcare setting. Components of the monitoring including clinical observation for signs of hemolysis, such as back pain, fever, shaking chills, discolored urine, as well as urine dipsticks for hemoglobin at baseline, 2, 4, and 8 hours after administration.

Intravenous immunoglobulin G

Common side effects associated with IVIG include infusional toxicities such as fever, chills, tachycardia, hypotension, especially if given too quickly, and headaches. Headaches are common and severe headaches have been associated with aseptic meningitis. Severe headache occurring while the patient is still thrombocytopenic often leads to head CT scan to rule out intracranial hemorrhage.

Other toxicities include transient neutropenia, hemolytic anemia, renal insufficiency, thrombosis, and gastrointestinal symptoms. Some preparations of IVIG contain small amounts of IgA and should not be given to patients with IgA deficiency, since anaphylactoid reactions have been reported in this situation. IgA-depleted IVIG preparations are available.

What causes this disease and how frequent is it?

Primary ITP of childhood is estimated to have an incidence of approximately 5 per 100,000 or about 3,850 new cases per year. The majority of children are between the ages of 1 and 10 years. Incidence appears to be highest in ages 1 -5 years, then 6-10 years, followed by 1-14 years. There may be a slight male predominance – the opposite of ITP in adults. The disorder occurs most often in the late winter and spring coinciding with the highest incidence of viral infections in children.

What is the evidence?

Cines, DB, Blanchette, VS. “Immune thrombocytopenic purpura”. N Eng J Med. vol. 346. 2002. pp. 995-1008. (Review of pathophysiology of ITP.)

Heitinik-Polle, KMJ, Nijsten, J, Boonacker, CWB. “Clinical and laboratory predictors of chronic immune thrombocytopenia n children: a systematic review and meta-analysis”. Blood. vol. 124. 2014. pp. 3295-3307. (Predictors of chronic ITP identified in a systematic review of 54 studies.)

Lowe, EJ, Buchanan, GR. “Idiopathic thrombocytopenic purpura diagnosed during the second decade of life”. J Pediartr. vol. 141. 2002. pp. 253-258. (Retrospective study of large number of patients in the adolescent age group demonstrating overlap of features of childhood and adult ITP.)

Drachman, JG. “Inherited thrombocytopenia: when a low platelet count does not mean ITP”. Blood. vol. 103. 2004. pp. 390-398. (Review of differential diagnosis of thrombocytopenia.)

Frelinger, AL, Grace, RF, Gerrits, AJ. “Platelet function tests, independent of platelet count, are associated with bleeding severity in ITP”. Blood. vol. 126. 2015. pp. 873-879. (Study demonstrating the degree of platelet dysfunction is associated with severity of bleeding independent of the platelet count.)

Wang, WC. “Evans syndrome in childhood: pathophysiology, clinical course, and treatment”. Am J Pediatr Hematol Oncol. vol. 10. 1988. pp. 330-338. (Review of natural history of Evans syndrome.)

Dubansky, AS, Boyett, JM, Faletta, J. “Isolated thrombocytopenia in children with acute lymphoblastic leukemia: A rare event in a Pediatric Oncology Group Study”. Pediatrics. vol. 84. 1989. pp. 1068-1071. (Retrospective review of 2,239 children with acute lymphoblastic leukemia which showed that none had thrombocytopenia without other signs or symptoms of leukemia at diagnosis.)

Calpin, C, Dick, P, Poon, A. “Is bone marrow aspiration needed in acute childhood idiopathic thrombocytopenic purpura to rule out leukemia”. Archives in Pediatr Adolescent Med. vol. 152. 1998. pp. 345-247. (Retrospective study of 332 children and adolescents with typical ITP. No cases of leukemia and one case of aplasia were found.)

Aladjidi, N, Fernandes, H, Leblanc, T. “Evans syndrome in children: long-term outcome in a prospective French national observational cohort”. Front. Pediatr. vol. 3. 2015. pp. 1-8. (Prospective study of natural history of Evans syndrome emphasizing the associated immune manifestations, long-term complications, and treatment toxicity,)

Neunert, C, Lim, W, Crowther, M. “Clinical guideline update on "Immune thrombocytopenia: an evidence based practice guideline developed by the American Society of Hematology"”. Blood. vol. 117. 2011. pp. 4190-207. (The most authoritative guideline on diagnosis and treatment of both childhood and adult ITP. Experts in the field without conflicts of interest based recommendations on high quality scientific studies.)

Rohmer, B, Valla, FV, Baleydier, F. “Newly diagnosed immune thrombocytopenic purpura in childhood: Successful implementation of a limited intervention strategy in the setting of pediatric emergency care”. J Pediatr. vol. 166. 2015. pp. 480-482. (Report of outcome of limited intervention strategy based on clinical bleeding irrespective of the platelet count.)

Kuhne, T, Buchanan, GR, Zimmerman, S. “A prospective comparative study of 2540 infants and children with newly diagnosed idiopathic thrombocytopenic purpura (ITP) from the Intercontinental Childhood ITP Study Group”. J Pediat. vol. 143. 2003. pp. 605-608. (A registry study which noted 3 episodes of intracranial hemorrhage (0.17%) in newly diagnosed patients followed for 6 months.)

Neunert, CE, Buchanan, GR, Imbach, P. “Severe hemorrhage in children with newly diagnosed immune thrombocytopenic purpura”. Blood. vol. 112. 2008. pp. 4003-4008. (Prospective study of 505 children with platelet count < 20 x 109/L and no or mild bleeding at diagnosis. Three children developed severe bleeding (0.6%) and none had intracranial hemorrhage. Interpretation of the study is compromised by the fact that half of the children received some type of treatment.)

Psaila, B, Petrovic, A, Page, LK. “Intracranial hemorrhage (ICH) in children with immune thrombocytopenia (ITP): study of 40 cases”. Blood. vol. 114. 2009. pp. 4777-4683. (National survey identified 40 children with ICH and 2 controls per case. One of the largest studies of its kind. Lack of treatment information and reporting bias limit conclusions.)

Buchanan, GR, Holtkamp, CA. “Prednisone therapy for children with newly diagnosed idiopathic thrombocytopenic purpura. A randomized clinical trial”. Am J Pediatr Hematol Onco. vol. 6. 1984. pp. 355-61. (Randomized study showing only modest benefit of 2 mg/kg/day of prednisone versus placebo.)

van Hoff, J, Ritchey, AK. “Pulse methylprednisolone therapy for acute childhood idiopathic thrombocytopenic purpura”. J Pediatr. vol. 113. 1988. pp. 563-566. (Prospective study showing rapid response to high dose IV corticosteroid therapy (30 mg/kg) with minimal side effects. Limited by small sample size.)

Jaybose, S, Patel, P, Inamdar, S. “Use of intravenous methylprednisolone in acute idiopathic thrombocytopenic purpura”. Am J Pediatr Hematol Oncol. vol. 9. 1987. pp. 133-135. (Prospective study with 5 mg/kg/day of corticosteroids with similar results to van Hoff study.)

Carcao, MD, Ziprusky, A, Butchart, S. “Short-course oral prednisone therapy in children presenting with acute immune thrombocytopenic purpura (ITP)”. Acts Paediatr Suppl. vol. 424. 1998. pp. 71-74. (Study of 25 children receiving 4 mg/kg/day x 4 days of oral prednisone showed 83% with platelet count > 20 x 109/L within 48 hours.)

Scaradavou, A, Woo, B, Woloski, BMR. “Intravenous anti-D treatment of immune thrombocytopenic purpura: Experience in 272 patients”. Blood. vol. 89. 1997. pp. 2689-2700. (Large study of adults and children reporting on efficacy and safety of anti-D which showed that children responded the best with a good safety profile.)

Blanchette, VS, Imbach, P, Andrew, M. “Randomised trial of intravenous immunoglobulin G, intravenous anti-D and oral prednisone in childhood acute immune thrombocytopenic purpura”. Lancet. vol. 344. 1994. pp. 703-707. (Randomized clinical trial which showed that IVIG at 0.8 gm/kg x 1 was equivalent to 1 gm/kg x 2.)

Beck, CE, Nathan, PC, Parkin, PC. “Corticosteroids versus intravenous immune globulin for the treatment of acute immune thrombocytopenic purpura in children: A systematic review and meta-analysis of randomized controlled trials”. J Pediatr. vol. 147. 2005. pp. 521-527. (High quality scientific review which showed that IVIG was more effective than corticosteroids in increasing the platelet count to > 20 x 109/L at 48 hours, although there were no differences in clinically relevant outcomes.)

Tarantino, MD, Young, G, Bertolone, SJ. “Single dose of anti-D immune globulin at 75 mcg/kg is as effective as intravenous immune globulin at rapidly raising the platelet count in newly diagnosed immune thrombocytopenic purpura in children”. J Pediatr. vol. 148. 2006. pp. 489-494. (Randomized trial that showed that IV anti-D at 75 mcg/kg was as effective as IVIG 0.8 gm/kg and more effective than 50 mcg/kg of anti-D, albeit with increased side effects.)

O’Brien, SH, Ritchey, AK, Smith, KJ. “A cost-utility analysis of treatment for acute childhood idiopathic thrombocytopenic purpura (ITP)”. Pediatr Blood Cancer. vol. 48. 2007. pp. 173-180. (Decision analytic model comparing IVIG, IV anti-D, and high-dose prednisone which demonstrated that a brief course of high-dose prednisone is an inexpensive and effective stategy for the treatment of ITP.)

HedlundTreutiger, I, Henter, J-I, Elinder, G. “Randomized study of IVIg and high-dose dexamethasone therapy for children with chronic idiopathic thrombocytopenic purpura”. J Pediatr Hematol Oncol. vol. 25. 2003. pp. 139-144. (Prospective randomized trial of small number of patients demonstrating 25% response to dexamethasone even after failure of IVIG.)

Liang, Y, Zhang, L, Gao, J. “Rituximab for children with immune thrombocytopenia: A systematic review”. PLos ONE. vol. 7. 2012. -1. (Systematic review of 14 studies (323 children) treated with rituximab for chronic ITP.)

Carson, KR, Evens, AM, Richey, EA. “Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 case from the Research on Adverse Drug Events and Reports project”. Blood. vol. 113. 2009. pp. 4834-4840. (No children with PML reported in this review.)

Bussel, JB, de Miguel, PG, Despotovic, JM. “Eltrombopag for the treatment of children with persistent and chronic immune thrombocytopenia (PETIT): a randomised, multicentre, placebo-controlled study”. Lancet Haematol. vol. 2. 2015. pp. e315-25.

Grainger, JD, Locatelli, Chotsampancharoen, T. “Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial”. Lancet. vol. 386. 2015. pp. 1649-1658. (2 randomized, placebo-controlled trials of eltrombopag in childhood chronic ITP demonstrating the superiority of eltrombopag.)

Bussel, JB, Buchanan, GR, Nugent, DJ. “A randomized double-blind study of romplostim to determine its safety and efficacy in children with immune thrombocytopenia”. Blood. vol. 118. 2011. pp. 28-36. (A small randomized study demonstrating the superiority of romiplostim over placebo.)

Kuhne, T, Blanchette, V, Buchanan, GR. “Splenectomy in children with idiopathic thrombocytopenic purpura: A prospective study of 134 children from the Intercontinental Childhood ITP Study Group”. Pediatr Blood Cancer. vol. 49. 2007. pp. 829-834. (An international registry study of 134 patients splenectomized for chronic ITP. 86% of patients had a complete platelet response and 80% had sustained response at 1 year post-splenectomy.)

Fogarty, P, Segal, J. “The epidemiology of immune thrombocytopenic purpura”. Curr Opin Hematol. vol. 14. 2007. pp. 515-519. (Review of studies of pediatric and adult ITP.)

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