Diagnosis and management of typical, newly diagnosed primary immune thrombocytopenia (ITP) of childhood

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The problem

Newly diagnosed primary immune thrombocytopenia (ITP) typically occurs in healthy children and is characterized by immune-mediated destruction of otherwise normal platelets. The cause of ITP is not usually known, but the condition can be triggered by a viral infection or other immune phenomenon. ITP affects approximately 5 in 100,000 children per year, most commonly between age 2 to 5 years ^[1]. Typical natural history is self-resolution within 6 months, which occurs in 75% to 80% of cases ^[2], with some of the remaining children resolving within a year of diagnosis ^[3]. Most children present with mild bruising and petechiae, but approximately 3% present with more serious bleeding from the nose, mucosa or gastrointestinal tract ^[4]. The most serious complication of ITP is intracranial hemorrhage, which occurs in approximately 0.17% to 0.6% of cases ^[1][5][6].

Typical ITP can be diagnosed based on classic features of the patient’s history, physical examination and laboratory investigation. Specific ‘red flags’ should signal alternate diagnoses and warrant a hematology consultation (Table 1). By definition, the platelet count in typical ITP is <100 x 10⁹/L, but most cases have a platelet count of <20 x 10⁹/L. In children with typical features of ITP and no red flags, a bone marrow examination to rule out leukemia is not necessary ^[2][7]. Secondary causes of ITP include drug-induced, systemic lupus erythematosus and infections or immune-deficiencies, and malignancy needs to be considered if red flags are present. These causes need investigation in children who do not present typically.

Table 1: ‘Red flags’ for alternate diagnoses

History

Constitutional symptoms (fevers, weight loss, night sweats) Bone pain Recurrent thrombocytopenia Poor treatment response

Physical examination

Lymphadenopathy Hepatomegaly Splenomegaly Child is “unwell” Signs of chronic disease

Investigations

Low Hb (unless mildly low and explained by bleeding history) High mean corpuscular volume (MCV) Abnormal white blood cell (WBC) and/or neutrophil count Abnormal cellular morphology on smear

How best to manage cases of typical ITP in children remains unclear. Pharmacological treatments increase the platelet count to reduce bleeding or perceived bleeding risk. They are not curative, however, and side effects as well as potential requirement for hospitalization must be considered. While ITP guidelines in the U.K. ^[8] have recommended only treating children with significant bleeding symptoms, this practice has not traditionally been followed in North America ^[1][6].

Management options include observation without specific treatment or active therapy with corticosteroids, intravenous immunoglobulin (IVIG) or with anti-D immunoglobulin (anti-D) for Rh-positive children. Whether early treatment affects the risk for life-threatening bleeding complications or for developing chronic ITP is unclear ^{[4][5][9][10]}.

This practice point summarizes the most recent recommendations from the American Society of Hematology ^[2] and new information from recent studies ^[1][6]. Guidance for decision-making is offered ^[11] with the goal of decreasing variable practice among health care providers and enhancing patient-centred management of this common childhood condition. Treatment advice applies to children aged 90 days through 17 years who have typical, newly diagnosed primary ITP (up to 3 months post-diagnosis). This practice point does not address persistent, chronic or secondary ITP ^[12].

New research and guidance

In 2011, the American Society of Hematology (ASH) released a clinical practice guideline on the evaluation and management of ITP ^[2]. For typical ITP, the guideline suggested an approach aimed at achieving a platelet count associated with adequate hemostasis (i.e., with no active bleeding, specifically no epistaxis, menorrhagia or blood in stools), rather than attaining an absolute number, while involving the patient and family in treatment decisions. Most children with no bleeding or only mild bleeding (petechiae and/or bruising; an estimated 77% of cases) can be managed using observation alone, regardless of platelet count. This recommendation aligned with international guidelines ^[13], and was based both on the relative rarity of significant bleeding and lack of evidence that treatment decreases risk for severe bleeding or for developing chronic ITP ^{[4][5][9][10]}. The recommendation to move away from platelet count as a surrogate marker for hemostasis and toward observation as the preferred management option marked a shift from previous practice in North America.

Before publication of the 2011 guidelines, children hospitalized for typical, newly diagnosed ITP in the United States usually received IVIG treatment (i.e., in approximately 78% of cases) ^[6]. One recent study indicated poor uptake of the guidelines. Out of 4,937 children with ITP, the number receiving pharmacological treatment increased post-guideline (94.1% versus 92.9%). Of note, only 14% of these children had documented significant bleeding ^[1]. The tendency to actively treat ITP in the United States contrasts with practice patterns in the U.K., where platelet-raising treatment is used in only 16% of cases ^[14].

Recommendations

For children without active bleeding (described clinically in Table 2), strongly consider observation as the first-line approach, with oral corticosteroids or IVIG as second-line options. Involve the family in management decisions and consider multiple factors, including the individual’s bleeding risk (e.g., activity level), logistics (e.g., household distance from hospital) and social issues (e.g., reliability of follow-up). Shared decision-making should incorporate each family’s values and preferences.

For children with moderate bleeding, active therapy continues to be recommended. Treatment options include a single dose of IVIG (0.8 g/kg to 1.0 g/kg) or a short course of corticosteroids ^[15]. Intravenous anti-D immune globulin (anti-D) can only be used in Rh-positive children and is generally not considered as first-line therapy due to rare but serious adverse effects ^[2].

For children with severe bleeding (e.g., prolonged epistaxis, gastrointestinal bleeding or ICH; an estimated 3% of total cases), immediate treatment in hospital with intravenous steroids and IVIG is indicated. Tranexamic acid may help as an adjunct therapy at a dose of 25 mg/kg/dose orally, 3 to 4 times per day (maximum 1500 mg per dose), or 10 mg/kg/dose IV every 8 hours ^[16]. Tranexamic acid should only be used in discussion with a hematologist, and needs to be discontinued if the platelet count is expected to rise, as thrombotic events may occur. Platelet transfusion is generally contraindicated except for acute, life-threatening bleeds or in children requiring immediate surgery.

Shared decision-making in children with ITP ^[11]

The relative rarity of severe bleeding with ITP makes it unlikely that future trials will fully establish the risks and benefits of active treatment or alleviate the decisional conflict that exists among providers and families considering treatment options. Decisions remain preference-sensitive because the benefits of any single option do not clearly outweigh potential risks. This uncertainty provides an ideal opportunity for SDM, with discussions among patients, parents and health care providers considering two or more clinically reasonable options and paying explicit attention to family values and preferences. Risk adversity, the desire for inpatient versus outpatient management, and the risks and benefits of each option (e.g., degree of comfort with blood products or corticosteroid side effects, and observation versus active therapy) should be considered. Older children’s personal goals relating to their participation in or return to regular activities after an episode should also be accounted for. Clear, unbiased communication, preferably using educational resources to inform families concerning the pros and cons of management options (Table 3), is essential for effective SDM.

Initial non-responders or early relapse

When pharmacotherapy is used, the goal is to raise platelet counts to a level where hemodynamic stability is achieved. Some experts continue to use a quantitative threshold (i.e., a platelet count >10 or 20 x 10⁹/L) to reduce risk for serious bleeding. For children who do not respond initially, further treatment may involve switching to a different modality (e.g., from IVIG to corticosteroids or vice-versa). Approximately one-third of children who respond to treatment initially, regardless of type, will relapse, with platelet counts falling below 20 x 10⁹/L within 2 to 6 weeks. Retreatment decisions should be based on similar criteria to those initially considered, with modality depending on tolerance of and response to previous treatment agents.

Supportive care and monitoring

All follow-up visits should include a physical examination, checking the platelet count and anticipatory guidance around bleeding signs. Appointments should be regularly scheduled until platelet counts have recovered, with frequency of follow-up depending on the clinical scenario and platelet count. When platelet counts remain low or there is evidence of bleeding, patients must avoid contact sports and activities that may cause injuries, especially to the head. Medications and complementary medicines with anti-platelet activity (e.g., non-steroidal anti-inflammatories and some herbal products) must also be avoided. Dentists and doctors should be reminded of the condition at each visit. Collaboration among community physicians, emergency department staff, hematologists and hospitalist paediatricians is encouraged to build uniformity in evidence-based best practice.

TABLE 2: Classification of bleeding and management options
Severity [2] Proportion of cases [4]	No or mild bleeding (77%)	Moderate bleeding (20%)	Severe bleeding (3%)
Clinical description	No bleeding; or (at most) bruising, petechiae or occasional, mild epistaxis No or very little interference with daily living May include non-oozing petechiae on oral mucosa or resolved mild epistaxis	More severe skin manifestations, with some mucosal lesions and more troublesome epistaxis or menorrhagia	Bleeding episodes (epistaxis, melena, menorrhagia and/or intracranial hemorrhage) requiring hospital admission
Management options	Observation Corticosteroids (e.g., prednisone) IVIG	Corticosteroids (e.g., prednisone) IVIG	Non life-threatening (see Moderate bleeding) Life-threatening: IV methylprednisolone + IVIG + platelet transfusion +/- tranexamic acid
Data drawn from references [2][4] IVIG Intravenous immunoglobulin IV intravenous

TABLE 3: Comparison of therapeutic options
	Observation*	Glucocorticoids	IVIG
Dose	N/A	Oral prednisone or dexamethasone (steroids may be given IV) Dose regimes vary: prednisone 4 mg/kg/day orally (divided twice to four times daily) for 4 days (to a maximum 150 mg/day) [15] without taper, versus 2 mg/kg/day orally  for 1 to 2 weeks, with tapering dose No evidence to support a longer versus brief course [4]	0.8 g/kg to 1 g/kg Single dose Consider measuring baseline IG levels for children <1 year of age or when an immune deficiency is suspected
Side-effects and disadvantages	Longer period of activity restriction [2] Anxiety while awaiting platelet recovery [2]	Mood changes Increased appetite, weight Gastritis (consider use of stomach protectant) Hypertension (with a longer course) Poor taste may affect tolerance	Headache (aseptic meningitis) Nausea, vomiting Fever Rash Hemolysis (rare) Requires IV placement and (at minimum) a one-day stay in hospital
Cost	Outpatient management No medication cost	Outpatient management No IV required Inexpensive	Hospital admission Expensive
Action	75% to 80% will improve within 6 months [2] Will take longer for platelet count to rise	Effective in up to 72% to 88% of cases [2] Increase in platelets, usually within 48 h	Effective in >80% of cases [2] Increase in platelets usually within 24 h; peak response at 2 to 7 days [2] Should be used if more rapid increase is required [10]
*Only recommended in cases with no or mild bleeding
Data drawn from reference [2][4][10][15]  IVIG Intravenous immunoglobulin IV intravenous N/A not applicable

Recommended resources

SickKids Hospital (updated December 2012). Immune thrombocytopenia (ITP): What happens after diagnosis: http://www.aboutkidshealth.ca/En/HealthAZ/ConditionsandDiseases/blooddisorders/Pages/ITP-what-happens-after-diagnosis.aspx

Centre hospitalier universitaire Sainte-Justine, Services d’hématologie et de pédiatrie (July 2013 version).  Protocole de prise en charge des thrombopénies immunes aiguës, nouvellement diagnostiquées, au CHU Sainte-Justine: http://www.urgencehsj.ca/wp-content/uploads/thrombop%C3%A9nie.pdf

Acknowledgements

This practice point was reviewed by the Community Paediatrics Committee and the Emergency Medicine and Hospital Paediatrics Sections of the Canadian Paediatric Society. It was also reviewed by representatives of the Canadian Paediatric Thrombosis and Hemostasis Network, with our thanks.

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CANADIAN PAEDIATIC SOCIETY ACUTE CARE COMMITTEE

Members: Carolyn Beck MD, Laurel Chauvin-Kimoff MD (Chair), Kimberly Dow MD (Board Representative), Catherine Farrell MD (past member), Jeremy Friedman MD (past member), Evelyne D. Trottier MD, Kristina Krmpotic MD, Kyle McKenzie MD

Liaisons: Kevin Chan MD, CPS Paediatric Emergency Medicine Section; Marie-Joëlle Doré-Bergeron MD, CPS Hospital Paediatrics Section

Principal authors: Jeremy N Friedman MD, Carolyn E Beck MD

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References

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Disclaimer: The recommendations in this position statement do not indicate an exclusive course of treatment or procedure to be followed. Variations, taking into account individual circumstances, may be appropriate. Internet addresses are current at time of publication.