Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis

INTRODUCTION — Immune thrombocytopenia (ITP) of childhood is characterized by isolated thrombocytopenia (platelet count <100,000/microL with normal white blood cell count, hemoglobin, and blood smear). The cause of ITP remains unknown in most cases, but it can be triggered by a viral or environmental trigger or it may be secondary to an underlying immunologic defect [1-3]. ITP was previously known as idiopathic thrombocytopenic purpura or immune thrombocytopenic purpura. The current term Immune ThrombocytoPenia preserves the widely-recognized acronym "ITP," while acknowledging the immune-mediated mechanism of the disorder and that patients may have little or no signs of purpura or bleeding [1].

The clinical features and diagnosis of ITP in children will be reviewed here. The initial treatment of newly diagnosed ITP and management of chronic ITP in children are discussed separately. (See "Immune thrombocytopenia (ITP) in children: Initial management" and "Immune thrombocytopenia (ITP) in children: Management of chronic disease".)

TERMINOLOGY — The following terms are used throughout this topic:

●Primary ITP – ITP in the absence of other causes or disorders that may be associated with the thrombocytopenia is known as primary ITP and is the main focus of this topic review.

●Secondary ITP – Secondary ITP refers to immune-mediated thrombocytopenia with an underlying cause, including drug-induced or associated with systemic illness, such as systemic lupus erythematosus (SLE), infection (eg, HIV), immune deficiency (eg, common variable immunodeficiency [CVID] or autoimmune lymphoproliferative syndrome [ALPS]), and other causes. Secondary causes of immune-mediated thrombocytopenia are outlined briefly below. (See 'Differential diagnosis' below.)

Primary ITP is categorized into three phases, depending on duration [1]:

●Newly diagnosed ITP – ITP within three months from diagnosis (ie, from the first low platelet count)

●Persistent ITP – ITP between 3 and 12 months after diagnosis

●Chronic ITP – ITP lasting for more than 12 months

PATHOGENESIS — In ITP, autoantibodies (usually immunoglobulin G) are directed against platelet membrane antigens, such as the glycoprotein (GP) IIb/IIIa complex [4,5]. Antibodies may be directed against other targets such as GP Ib/IX, GP Ia/IIa, and GP VI. The antibody-coated platelets have a shortened half-life because of accelerated clearance by tissue macrophages, predominantly those in the spleen. In addition, the same antibodies may inhibit platelet production. The net effect is a decrease, often substantial, in the platelet count.

Approximately 60 percent of children with ITP have detectable antiplatelet antibodies. In patients without detectable antibodies, the mechanism is uncertain but is presumed to be immune-mediated. Thus, measurement of antiplatelet antibodies is generally not helpful in diagnosing ITP, because the test is neither sensitive nor specific. (See 'No role for antiplatelet antibody testing' below.)

In a subset of patients with ITP, whether or not antibodies are demonstrable, an alternative immunologic mechanism of T cell-mediated cytotoxicity may cause thrombocytopenia. These cytotoxic T cells may act upon megakaryocytes in the bone marrow rather than circulating platelets. It is not known how often this occurs, nor whether cytotoxic T cells play a role in the typical patient with ITP, nor whether their primary role involves platelet destruction during passage through the spleen or in the marrow.

Mechanisms rupturing self-tolerance appear to play a role as well. These mechanisms involve regulatory T cells (Tregs) and B cells (eg, checkpoint disruptions).

Our understanding of the pathogenesis of ITP is based largely on studies in adult patients; there is less information available specifically on ITP in children. The pathogenesis of ITP is discussed in greater detail separately. (See "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis", section on 'Pathogenesis'.)

EPIDEMIOLOGY — ITP is one of the most common causes of symptomatic thrombocytopenia in children. The annual incidence of ITP is estimated to be between 1 and 6.4 cases per 100,000 children [3,6]. This figure is probably an underestimate because it is based primarily upon patients that develop symptomatic thrombocytopenia, particularly those who require hospitalization.

Children with ITP can present at any age, but there is a peak in incidence between two and five years and a smaller peak in adolescence. In a prospective population-based study from the five Nordic countries (Sweden, Finland, Norway, Denmark, and Iceland) between 1998 and 2000, the annual incidence of ITP was 4.8 per 100,000 children younger than 15 years of age [7]. One-half of the patients were between one and four years of age, and approximately 80 percent were younger than eight years of age.

In childhood ITP, there is a slight predominance of boys to girls, especially in infants. This was best illustrated in the largest case series of children with ITP from the registry of the Intercontinental Childhood ITP Study Group that included >2000 infants and children from 3 months to 16 years old. In infants between 3 and 12 months of age, the male-to-female ratio was 1.7:1 [8]. The male predominance was minimal in older children, such that the overall male-to-female ratio in this pediatric cohort was 1.2:1 [9]. By contrast, there is a female predominance of ITP in adolescents and younger adults (eg, 18 to 45 years of age). One hypothesis to explain the female predominance in adolescents is that higher levels of estrogen may promote autoimmunity. (See "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis", section on 'Epidemiology'.)

Seasonal fluctuations have been reported, with a peak incidence of ITP occurring in the spring and early summer in temperate climates [7,9]. This observation supports the notion that viral triggers are an important cause of ITP; however, the finding has not always been consistent. An association with allergic diseases (eg, allergic rhinitis and atopic dermatitis) has also been reported [10].

CLINICAL FEATURES — ITP typically presents with the sudden appearance of a petechial rash (picture 1), bruising, and/or bleeding in an otherwise healthy child. Thrombocytopenia is occasionally detected incidentally if a complete blood count (CBC) with platelets is performed for another reason (eg, preoperatively or on a routine check-up).

Preceding illness or vaccination — Approximately 60 percent of children with newly diagnosed ITP have a history of a preceding viral illness within the past month [7,8]. Numerous viruses have been identified as triggers of ITP, including Epstein-Barr virus, influenza, varicella zoster virus, and HIV [11]. ITP occurring in association with coronavirus disease 2019 (COVID-19) has been described [12].

There is a very small increased risk of developing ITP in the six weeks following a measles, mumps, and rubella (MMR) vaccination. MMR-associated ITP is rare, occurring in approximately 2.6 cases per 100,000 doses of vaccine. (See "Measles, mumps, and rubella immunization in infants, children, and adolescents", section on 'Adverse effects'.)

Early childhood vaccines other than MMR do not appear to be associated with increased risk of ITP [13]. There have been case reports of ITP following administration of varicella, hepatitis A, pneumococcus, and tetanus-diphtheria-acellular pertussis vaccines in older children [13]. However, because of the small number of exposed cases and potential confounding, the association of ITP with these vaccines has not been confirmed.

Vaccine-associated thrombocytopenia secondary to COVID-19 vaccination is very rare, as discussed separately. (See "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)".)

Lack of systemic signs and symptoms — Other than mucocutaneous bleeding, patients usually appear well and systemic symptoms are generally absent. The history should carefully explore systemic symptoms (eg, fever, anorexia, bone or joint pain, weight loss, gastrointestinal [GI] symptoms, headaches), exposure to thrombocytopenia-inducing drugs (table 1), prior history of bleeding, and family history of bleeding since these findings are generally absent in children with ITP at onset of their disease. Occasionally, children will have a history of bruising or bleeding stretching back one to six months, during which it appears that the ITP was already active. On physical examination, there is no significant enlargement of lymph nodes, liver, or spleen, although the spleen may be mildly enlarged in as many as 10 percent of cases.

If any of these features are present, including mild splenomegaly, other causes of thrombocytopenia should be carefully considered and appropriate testing pursued. (See 'Differential diagnosis' below and 'Further evaluation' below.)

Bleeding symptoms

Grading of severity — Bleeding signs and symptoms in children with ITP can range from none or minimal (eg, several small groups of petechiae or small bruises) to severe and life-threatening (eg, intracranial hemorrhage [ICH] or severe GI or genitourinary bleeding) [14]. The Buchanan and Adix bleeding score is commonly used to objectively characterize bleeding symptoms in patients with ITP (table 2).

Most patients who present for medical attention have signs of cutaneous bleeding (eg, petechiae (picture 1), purpura, and ecchymoses); serious hemorrhage is fortunately very infrequent.

Mucocutaneous bleeding — At presentation, more than one-half of affected children have only cutaneous bleeding (also referred to as "dry" purpura), including petechiae (picture 1), purpura, and ecchymoses [7].

Mucosal bleeding (also referred to as "wet" bleeding) may be present in as many as 40 percent of children with newly diagnosed ITP and typically involves the nasal passages as well as buccal and gingival surfaces (as shown in panel B (picture 2)). Less often, mucosal bleeding may arise from the GI, genitourinary, or vaginal tracts. Conjunctival or retinal hemorrhages are infrequently seen [15].

The severity of presenting symptoms is generally commensurate with the degree of thrombocytopenia, but many children have minimal bleeding even when platelet counts are very low. In one large cohort study, mucosal bleeding was more common with platelet counts <10,000/microL compared with ≥15,000/microL (51 versus 19 percent) [7].

In a large registry study of children with newly diagnosed ITP, the following bleeding manifestations were reported [15]:

●Cutaneous (petechiae, purpura, or bruising) – 86 percent

●Oral – 19 percent

●Nasal – 20 percent

●No bleeding – 9 percent

●Menstrual, GI, or urinary bleeding – <3 percent

Serious hemorrhage — Serious bleeding (defined as epistaxis >5 to 15 minutes duration, GI bleeding, other severe mucosal bleeding requiring hospital admission, and/or blood transfusions) develops in approximately 3 percent of children with ITP [7,16-18]. ICH occurs in approximately 0.5 percent.

Factors associated with increased risk of serious bleeding include [16]:

●Severe thrombocytopenia (defined as platelet count <10,000/microL or <20,000/microL, depending on the study). In most studies, nearly all severe bleeding events occurred in children with very low platelet counts; however, most patients with platelet counts in this range do not experience severe bleeding events. (See "Immune thrombocytopenia (ITP) in children: Initial management", section on 'Bleeding complications'.)

●Previous "wet" purpura bleeding.

●Trauma, especially to the head.

●Exposure to antiplatelet medications (eg, aspirin, ibuprofen, other nonsteroidal antiinflammatory drugs) and anticoagulants (eg, heparin, warfarin).

Intracranial hemorrhage — ICH is the most serious consequence of thrombocytopenia but is fortunately a rare complication of ITP in children, with reported rates ranging from 0.1 to 0.8 percent [7,8,15,16,18-20]. This was illustrated in reports of the Intercontinental Childhood ITP Study Group registry, which reported 10 cases of ICH among 1784 patients (0.6 percent) [15], and from the Nordic registry, which reported no case of ICH among 501 patients during the first six months after diagnosis [18]. A systematic review of 51 prospective clinical trials including 1965 children with ITP found that ICH occurred in 0.4 percent (95% CI 0.1-0.9) [16]. More than 90 percent of ICHs in children with ITP are intraparenchymal and supratentorial [21].

Children presenting with signs and symptoms concerning for ICH (eg, headache, persistent vomiting, altered mental status, seizures, focal neurologic findings, recent head trauma) require urgent evaluation (including neuroimaging) and treatment. The threshold for obtaining neuroimaging in children with ITP is substantially lower than for the general pediatric population, especially if the platelet count is <10,000 to 20,000. (See "Immune thrombocytopenia (ITP) in children: Initial management", section on 'Life-threatening bleeding'.)

Risk factors for ICH are the same as for severe bleeding in general (ie, very low platelet count, head trauma, exposure to antiplatelet medications, and signs of excessive bleeding [eg, wet purpura in the mouth, hematuria, prolonged epistaxis, GI bleeding, or other pronounced mucosal bleeding]) (see 'Serious hemorrhage' above). Children who present with these risk factors should be carefully assessed for signs or symptoms of ICH since the urgency and degree of treatment will be altered by presence of ICH. (See "Immune thrombocytopenia (ITP) in children: Initial management", section on 'Life-threatening bleeding'.)

Laboratory findings — Thrombocytopenia usually is the only abnormality detected. Other CBC parameters are generally normal, although there may be exceptions (table 3).

●Platelet count – A platelet count of <100,000/microL is used to define thrombocytopenia in ITP [1]. However, in most case series, the presenting platelet count is <30,000/microL [9,18], probably because patients with mild disease are less likely to have bleeding, and may never come to medical attention. Approximately 80 percent of children with ITP have platelet counts <20,000/microL at presentation, and approximately 45 percent of children have platelet counts <10,000/microL [8,15]. Platelet counts in children are generally somewhat lower than in adults with ITP. If possible, it is helpful to determine if the patient has had a previously normal platelet count to exclude an inherited thrombocytopenia. (See "Causes of thrombocytopenia in children", section on 'Inherited platelet disorders'.)

●Other CBC findings – The white blood cell count and differential, hemoglobin concentration, and other red cell indices are generally normal. If a reticulocyte count is obtained, it should be normal as well. Anemia is occasionally seen in children with considerable ITP-related bleeding (eg, epistaxis or heavy menstrual bleeding). If ongoing for weeks, anemia in this setting is typically microcytic reflecting iron deficiency. Anemia without microcytosis should prompt consideration of other causes (eg, aplastic anemia, leukemia, Evans syndrome). The white blood cell count may be low or high if there has been an ongoing or recent infection. (See 'Differential diagnosis' below.)

●Peripheral blood smear – On examination of the peripheral blood smear, the white or red blood cells should generally appear normal. Exceptions to this include patients with postinfectious ITP, in whom activated "atypical" lymphocytes may be seen (picture 3). Patients with iron deficiency anemia from excessive ITP-related bleeding may have microcytic hypochromic red cells (picture 4).

Platelets appear decreased in number but are usually normal or increased in size, particularly if symptoms have been present for several days or longer.

Findings on peripheral smear that should prompt further evaluation include (see 'Differential diagnosis' below and 'Further evaluation' below):

•Early white blood cell forms (eg, blasts) (picture 5), suggesting leukemia or lymphoma

•Polychromasia (picture 6), reticulocytosis (picture 7), and/or spherocytes (picture 8), suggesting hemolytic anemia

•Schistocytes (picture 9), suggesting microangiopathic hemolytic anemia

•Predominantly very large (giant) platelets (picture 10) or predominantly small platelets, suggesting an inherited thrombocytopenia syndrome (table 4A)

The approach to evaluating the peripheral blood smear is reviewed separately. (See "Evaluation of the peripheral blood smear".)

●Bone marrow examination – Bone marrow examination (aspirate and biopsy) is not routinely necessary for children with ITP unless atypical features are present, as discussed below. (See 'Indications for bone marrow examination' below.)

In patients with ITP, the bone marrow should be appropriately cellular and the erythroid and myeloid precursors should be normal in number and appearance. The megakaryocytes are typically normal or increased in number and may appear large and/or immature [22].

EVALUATION

Initial evaluation — Initial laboratory testing for patients with suspected ITP includes the following (table 3) [23]:

●Complete blood count (CBC), including platelet count, white blood cell differential, and red blood cell indices

●Examination of the peripheral blood smear

In addition, many experts (including the author of this topic review) obtain the following tests at the time of initial presentation:

●Reticulocyte count

●Direct antiglobulin test

●Serum immunoglobulin levels

The latter investigates the possibility of underlying common variable immunodeficiency (CVID) [2]. (See 'Differential diagnosis' below and "Common variable immunodeficiency in children".)

In some cases, it may be reasonable to include additional tests in the initial laboratory panel (eg, antiphospholipid antinuclear antibodies in adolescent females).

Further evaluation — Consensus is lacking as to the extent of evaluation required for the child with suspected ITP. For children with systemic signs and symptoms or other abnormalities in the CBC or peripheral blood smear, we suggest further investigation to evaluate for other possible causes of thrombocytopenia (table 5) [2]. The diagnostic evaluation should be performed in consultation with a pediatric hematologist-oncologist.

Findings suggestive of other diagnoses — Additional testing should be performed according to the reason for concern (see 'Differential diagnosis' below):

●Systemic signs and symptoms – Systemic signs and symptoms are typically absent in ITP, with the possible exception of fatigue. Thus, other diagnoses should be considered in children who have systemic signs and symptoms (fevers, weight loss, joint pain, refusal to walk). These findings may indicate the presence of a malignancy, autoimmune disorder, chronic infection, or immune deficiency.

•Malignancy – Signs and symptoms concerning for malignancy include lymph node enlargement, splenomegaly, bone or joint pain (especially if bilateral and out of proportion to findings on examination), fevers, weight loss, neutropenia, leukocytosis, or marked anemia. Although a single finding in isolation does not always require evaluation for malignancy, a combination of multiple findings (eg, pancytopenia; bone pain and lymphadenopathy) is worrisome and generally warrants evaluation for malignancy. In addition, certain findings are worrisome even as isolated findings (eg, blasts on the peripheral blood smear) and require prompt evaluation and consultation.

If there is sufficient clinical concern, evaluation for possible malignancy should be performed, including bone marrow aspirate and biopsy and other blood tests and imaging studies as appropriate. (See 'Indications for bone marrow examination' below and "Overview of common presenting signs and symptoms of childhood cancer".)

•Systemic illness or recurrent infection – Testing may also be warranted to evaluate the following:

-Systemic lupus erythematosus (SLE) and other autoimmune disorders if there is evidence of kidney disease, joint disease, antiphospholipid antibodies, or other compatible findings. (See "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis" and "Diagnosis of antiphospholipid syndrome" and "Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis".)

-HIV, hepatitis C, cytomegalovirus, Epstein-Barr virus, Helicobacter pylori, and possibly malaria (depending on travel history and exposure). The evaluation for these is discussed separately. (See "Screening and diagnostic testing for HIV infection" and "Hepatitis C virus infection in children" and "Overview of cytomegalovirus infections in children" and "Laboratory tools for diagnosis of malaria".)

-Immune deficiency, especially CVID, Wiskott-Aldrich syndrome, and DiGeorge syndrome. (See "Common variable immunodeficiency in children" and "Wiskott-Aldrich syndrome" and "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis".)

●Anemia – If there is evidence of hemolysis (eg, jaundice, elevated reticulocyte count, abnormalities on peripheral smear [spherocytes, polychromasia, schistocytes]), evaluation for an autoimmune hemolytic anemia (AIHA), thrombotic thrombocytopenic purpura (TTP), and hemolytic uremic syndrome (HUS; including atypical inherited forms) should be performed. The evaluation for AIHA in children is reviewed in detail separately. (See "Autoimmune hemolytic anemia (AIHA) in children: Classification, clinical features, and diagnosis", section on 'Initial laboratory evaluation'.)

•Evans syndrome – ITP associated with AIHA indicates a diagnosis of Evans syndrome. If there is evidence of hemolysis and the direct antiglobulin test is strongly positive (confirming Evans syndrome), testing for other autoimmune and immunodeficiency disorders, including autoimmune lymphoproliferative syndrome (ALPS), SLE, CVID, DiGeorge syndrome, and other immunodeficiency disorders, should be pursued. (See "Autoimmune hemolytic anemia (AIHA) in children: Classification, clinical features, and diagnosis", section on 'Evans syndrome' and "Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis".)

•HUS – Hemolytic anemia and thrombocytopenia following a recent history of diarrhea and gastroenteritis warrants testing of renal function (blood urea nitrogen, creatinine, and urinalysis) and screening for Shiga toxin-producing bacteria to evaluate for HUS. (See "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children".)

•TTP – Inherited or acquired causes of TTP or other thrombotic microangiopathies should be considered; acquired TTP is typically a disorder of adolescents. TTP can result in life-threatening complications, and delay in diagnosis and treatment may have serious consequences. In a young patient with hemolysis and thrombocytopenia in whom onset at birth or soon after cannot be excluded, hereditary TTP should be considered. Very rarely, young children may develop acquired (autoimmune) TTP. (See "Hereditary thrombotic thrombocytopenic purpura (hTTP)" and "Diagnosis of immune TTP" and "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

•Non-hemolytic anemia in the absence of bleeding – In children with ITP who present with concomitant non-hemolytic anemia (ie, low reticulocyte count) that cannot be explained by bleeding, bone marrow aspirate and biopsy are warranted to evaluate for malignancy and inherited or acquired bone marrow failure syndromes. Inherited bone marrow failure syndromes may have associated physical findings (eg, short stature, hyper- or hypopigmented skin lesions, and thumb and/or radial abnormalities in Fanconi anemia). (See "Clinical manifestations and diagnosis of Fanconi anemia", section on 'Clinical features' and "Treatment of acquired aplastic anemia in children and adolescents" and "Overview of common presenting signs and symptoms of childhood cancer".)

●Excessive bleeding – In patients with excessive bleeding (ie, greater than expected based on platelet count and/or recurrent severe mucosal bleeding), coagulation studies should be performed, including prothrombin time, activated partial thromboplastin time, fibrinogen, and D-dimer. In addition, screening for von Willebrand disease type 2B should be pursued since it is associated with low platelets. Evaluation of platelet function can be considered, though it may need to be deferred until the platelet count has recovered. (See "Approach to the child with bleeding symptoms", section on 'Initial laboratory evaluation'.)

●Concern for inherited thrombocytopenia – Evaluation for an inherited thrombocytopenia (table 4A-B) may be warranted in any of the following scenarios:

•Review of the medical record reveals that the patient has had prior low platelet counts (especially if there has never been a documented normal platelet count)

•There is a family history of thrombocytopenia or any syndromic features consistent with an inherited thrombocytopenic syndrome (table 4A-B)

•Patient fails to respond to ITP treatment (if given) (see "Immune thrombocytopenia (ITP) in children: Management of chronic disease", section on 'Evaluation')

Inherited platelet disorders are discussed in greater detail separately. (See "Causes of thrombocytopenia in children", section on 'Inherited platelet disorders'.)

Indications for bone marrow examination — Bone marrow examination is not routinely necessary for children with a typical presentation of ITP [2,4,23]. It is performed in selected patients to exclude other causes of thrombocytopenia, such as malignancy or marrow failure. Based on the available data, treatment with glucocorticoids is not considered an indication for bone marrow examination if the child otherwise has typical features of ITP [2,4]; however, expert opinion varies and some centers choose to perform a bone marrow examination for all patients before initiating steroid treatment [24]. Other factors that may impact this decision include the experience of the clinician, likelihood of repeated follow-up, and how the findings of the bone marrow examination will alter management.

We generally perform bone marrow examination in the following patients [2,23]:

●Patients with atypical clinical or laboratory features at presentation that suggest malignancy or bone marrow failure as discussed above (eg, especially lymph node enlargement, splenomegaly, bone or joint pain, fevers, weight loss, neutropenia, leukocytosis, atypical lymphocytes, or marked anemia). (See 'Findings suggestive of other diagnoses' above.)

●Patients who are refractory to treatment (ie, insufficient or no response to standard treatments such as glucocorticoids, intravenous immune globulin [IVIG], and/or anti-D immune globulin). Our practice differs from the 2011 guidelines from the American Society of Hematology, which state that bone marrow examination is not necessary in children who fail IVIG [23]. This issue was not addressed in the 2019 American Society of Hematology guidelines [25]. (See "Immune thrombocytopenia (ITP) in children: Initial management", section on 'First-line therapies'.)

●Patients who develop new findings during follow-up that are not consistent with ITP (eg, subsequent clinical findings of lymph node enlargement; organomegaly; bone or joint pain; fevers; or new laboratory findings of neutropenia, leukocytosis, or anemia without bleeding) or who stop responding to ITP therapies that had previously been effective.

●Patients in whom treatment with a thrombopoietin receptor agonist is being contemplated. (See "Immune thrombocytopenia (ITP) in children: Management of chronic disease", section on 'Thrombopoietin receptor agonists'.)

●For the rare patient who has inadequate or transient response to ITP treatment and is planned to undergo splenectomy, we suggest performing bone marrow examination prior to surgery if it has not been performed previously. In the modern era, splenectomy is rarely performed for management of ITP in children and, when it is used, it is typically done only after the patient has failed multiple other therapies [26]. Thus, most children will have undergone bone marrow evaluation prior to undergoing splenectomy.

●The rare patient with ITP that has not resolved by 12 months but who has never required treatment and thus cannot be labeled as "refractory to treatment." Bone marrow examination may be warranted in such patients to exclude other causes of persistent thrombocytopenia since most children with mild ITP have recovery of platelet counts within a year.

For children without any atypical features or findings, the likelihood of finding an alternative diagnosis on bone marrow examination appears to be low. In a single-center retrospective study of 484 children who underwent bone marrow aspiration to confirm a provisional diagnosis of ITP, none of those with typical hematologic features of ITP (ie, normal white blood cell count and hemoglobin) had evidence of leukemic changes or bone marrow failure, though one patient was later diagnosed with aplastic anemia [27]. Among children with nonspecific, "atypical" hematologic findings (n = 152), 7 percent were found to have a diagnosis other than ITP, divided evenly between leukemia and bone marrow failure. All of the children who were found to have other diagnoses had clinical and/or laboratory findings at presentation that were suggestive of an alternative diagnosis (eg, anemia, leukopenia, leukocytosis).

Similar findings were noted in another retrospective review of 127 children with presumed ITP in whom bone marrow examination was performed [28]. Only five patients (3.9 percent) had a diagnosis other than ITP. As in the previous study, all presented with clinical and/or laboratory findings that were atypical for ITP. Leukemia was not diagnosed in any patient.

In addition, childhood leukemia presenting as isolated thrombocytopenia has not been reported in the centralized leukemia study registries, with the exception of a single patient with Down syndrome who presented with isolated thrombocytopenia and was found to have acute leukemia; however, this patient also had marked splenomegaly.

Immature platelet fraction — The immature platelet fraction (IPF) is an automated laboratory test used for quantifying platelet production and turnover. The IPF assay uses nucleic acid-specific dyes to detect young platelets that contain residual RNA (reticulated platelets). It is increasingly available on automated blood cell counters. (See "Automated complete blood count (CBC)", section on 'Reticulated platelets and immature platelet fraction (IPF)'.)

The utility of the IPF in evaluating children with suspected ITP is unclear. Some experts have suggested that IPF might be useful in cases where the diagnosis of ITP is uncertain, particularly to help distinguish ITP from bone marrow failure states, including leukemia and acquired or inherited aplastic anemia. In our experience, if the diagnosis of ITP is uncertain, bone marrow examination is the most reliable and established method for excluding a diagnosis of leukemia or aplastic anemia. However, the IPF may be helpful when used in conjunction with other tests. (See 'Indications for bone marrow examination' above.)

Several studies have shown that IPF values are elevated in ITP and seem to be higher than in bone marrow failure states [29-33]. However, whether IPF can reliably distinguish between ITP and leukemia or bone marrow failure remains uncertain. Some studies have suggested that IPF has prognostic value since high IPF appears to be associated with better platelet function and lower bleeding risk [31,33,34].

Additional clinical studies are needed to determine the role of IPF measurement in the evaluation of children with ITP.

No role for antiplatelet antibody testing — Testing for antibodies to specific platelet glycoproteins (GPs; such as GP Ib/IX) is not recommended for patients with suspected ITP [2,4,23,35,36]. The presence of these antibodies does not exclude thrombocytopenia due to other causes, nor does the absence of antibodies eliminate the diagnosis of ITP. (See "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis", section on 'Antiplatelet antibody testing'.)

DIAGNOSIS — ITP is largely a clinical diagnosis made in well-appearing patients with mucocutaneous bleeding without other systemic signs or symptoms and with laboratory confirmation of isolated thrombocytopenia. ITP is a diagnosis of exclusion, so other causes of thrombocytopenia must be ruled out. In most cases, the diagnosis can be established based upon the clinical presentation and results of the initial laboratory evaluation (table 3); however, in patients with atypical findings, additional evaluation is warranted. (See 'Further evaluation' above.)

For children with a typical presentation of ITP (sudden onset of a petechial rash or bruising in an otherwise well-appearing child), a presumptive diagnosis of ITP may be established based upon all of the following criteria [1,4]:

●Platelet count <100,000/microL.

●Otherwise normal complete blood count (CBC) with normal differential white count, hemoglobin, and reticulocyte count.

●No abnormalities on the peripheral blood smear. In particular, there should be no evidence of hemolysis or blasts (atypical lymphocytes from viral activation are acceptable although flow cytometry may be required to distinguish them from leukemic blasts). (See "Approach to the child with lymphocytosis or lymphocytopenia", section on 'Blood lymphocyte morphology'.)

●No findings on history and physical examination to suggest another cause of thrombocytopenia. Children <1 or >10 years old should be scrutinized more closely for any atypical features. Findings that suggest a diagnosis other than ITP include:

•Systemic symptoms (eg, fever, anorexia, bone or joint pain, headaches, or weight loss)

•History of clinically significant systemic disease

•Enlargement of lymph nodes, liver, or spleen

•Abnormal thumbs or forearms and/or hyper- or hypopigmented skin lesions (suggestive of Fanconi anemia)

•Longstanding history of thrombocytopenia or atypical bleeding

•Family history of thrombocytopenia or bleeding of unknown etiology

In addition, an unequivocal response to standard ITP treatments (eg, intravenous immune globulin [IVIG] and anti-D immune globulin), even if the response is transient, helps to confirm the diagnosis. However, many patients do not require such treatments.(See "Immune thrombocytopenia (ITP) in children: Initial management".)

Distinguishing primary from secondary ITP may be difficult.

DIFFERENTIAL DIAGNOSIS — The diagnosis of ITP is generally straightforward in healthy-appearing children with a typical presentation (ie, sudden onset of a petechial rash or bruising with isolated thrombocytopenia on laboratory evaluation). However, in some cases, other causes of thrombocytopenia must be excluded (table 5). (See "Causes of thrombocytopenia in children".)

Alternative diagnostic considerations include the following [2,22,37]:

●Leukemia – Most childhood leukemia is due to acute lymphoblastic leukemia (ALL). Children with ALL usually have other clinical and laboratory findings that distinguish ALL from ITP. These include systemic symptoms (eg, fever, bone and joint pain, or weight loss), hepatosplenomegaly, lymphadenopathy, leukocytosis, and significant anemia (hemoglobin <10 g/dL). The thrombocytopenia in ITP typically is more severe than in ALL. Examination of the peripheral blood smear may demonstrate blast cells on the peripheral blood smear, but these may be difficult to distinguish from atypical lymphocytes that may be present in a postviral case of ITP. If there is concern for leukemia, flow cytometry and bone marrow examination (aspirate and biopsy) should be performed. (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children".)

●Active infection – Ongoing viral infections, such as infectious mononucleosis (Epstein-Barr virus), cytomegalovirus, hepatitis C, and HIV-1, can cause thrombocytopenia. These disorders may be differentiated from ITP by the presence of systemic signs and symptoms and by performing specific viral testing [38]. (See "Clinical manifestations and treatment of Epstein-Barr virus infection", section on 'Primary EBV infection in infants and children' and "Overview of cytomegalovirus infections in children" and "Hepatitis C virus infection in children" and "Pediatric HIV infection: Classification, clinical manifestations, and outcome".)

●Autoimmune hemolytic anemia (AIHA) – An AIHA that occurs in combination with thrombocytopenia is known as Evans syndrome. A hemolytic process is suggested by the anemia, jaundice, elevated reticulocyte count, and spherocytes and polychromasia on the peripheral smear. The diagnosis of AIHA is established by a positive direct antiglobulin test (formerly called the Coombs test). If AIHA is diagnosed, testing for an underlying autoimmune disease or immunodeficiency, including autoimmune lymphoproliferative syndrome (ALPS) and common variable immunodeficiency (CVID), is important, as discussed immediately below. (See "Autoimmune hemolytic anemia (AIHA) in children: Classification, clinical features, and diagnosis".)

●Systemic autoimmune disease – Immune-mediated thrombocytopenia may be the presenting manifestation of an autoimmune disease, such as systemic lupus erythematosus (SLE) or ALPS. Autoimmune diseases are more common in adolescent females.

•The most common initial symptoms of SLE are the gradual onset of fever, malaise, and general deterioration over several months, with or without a malar rash; joint stiffness consistent with mild arthritis may be the first sign. Laboratory findings include the presence of autoantibodies, such as antinuclear antibodies and antiphospholipid antibodies. (See "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis".)

•ALPS has been thought to typically present with chronic lymphadenopathy and/or splenomegaly. However, it is now recognized that approximately one-quarter of children presenting with Evans syndrome (even without lymphadenopathy or splenomegaly) may actually have ALPS [39,40]. The signature screening laboratory abnormality is increased numbers of alpha/beta double-negative T cells detected by flow cytometric immunophenotyping with triple color flow. (See "Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis".)

●Immunodeficiency syndromes – Approximately 20 to 25 percent of patients with CVID have associated autoimmune hematologic disorders, including ITP, AIHA, or Evans syndrome [41]. Thus, patients with ITP and recurrent infections should be evaluated for CVID and other immunodeficiency syndromes by measuring serum immunoglobulin levels. In our practice, we measure immunoglobulin levels in all children with ITP because patients with CVID, especially those with autoimmune disease, do not always have a notable history of infections [2]. (See "Common variable immunodeficiency in children".)

Wiskott-Aldrich syndrome should be considered in boys with eczema, small platelet size, bleeding out of proportion to the platelet count, family history, and/or lack of response to ITP treatments. DiGeorge syndrome should be considered in patients with hypocalcemia and cardiac anomalies. (See "Wiskott-Aldrich syndrome" and "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis".)

●Inherited disorders causing thrombocytopenia – Isolated thrombocytopenia may be a presenting finding in certain rare inherited diseases, some of which may also feature impaired platelet function (table 4A-B). Some of these syndromes are associated with other abnormalities (eg, immunodeficiency, renal disease, sensorineural hearing loss, risk of malignancy). Historical platelet counts from children and their parents and ascertainment of the duration of bleeding symptoms can help distinguish between congenital and acquired causes. Inherited platelet disorders are discussed in greater detail separately. (See "Causes of thrombocytopenia in children", section on 'Inherited platelet disorders'.)

●Drug exposure – Drugs commonly associated with thrombocytopenia include heparin, quinidine, phenytoin, sulfonamides, valproate, and vancomycin; others are summarized in the table (table 1). This possibility is explored by a history of exposure to such drugs, including whether the drugs are present in the household and might have been accidentally ingested by the child. In a child on such a medication, it should be changed to an equivalent medication if possible, to see if the "ITP" resolves. (See "Drug-induced immune thrombocytopenia".)

●Bone marrow failure syndromes – In acquired bone marrow failure syndromes (eg, aplastic anemia), a low platelet count is almost always associated with other significant changes in the peripheral blood, such as anemia, macrocytosis, low reticulocyte count, and/or leukopenia/neutropenia. There may also be syndromic features. The diagnosis is established by bone marrow examination including a biopsy and molecular testing and/or by genomic testing. (See "Treatment of acquired aplastic anemia in children and adolescents".)

●Hemolytic uremic syndrome (HUS) – HUS is characterized by hemolytic anemia, thrombocytopenia, and acute kidney injury. Patients may have a history of gastrointestinal (GI) symptoms (bloody diarrhea, abdominal pain, and vomiting) occurring approximately one week prior to the presentation of HUS with transient resolution. HUS is distinguished from ITP on the basis of the clinical history, presence of microangiopathic hemolytic anemia (with fragmented erythrocytes [schistocytes] on peripheral smear (picture 9)), and abnormal renal function (ie, oliguria, elevated blood urea nitrogen and creatinine). (See "Overview of hemolytic uremic syndrome in children".)

●Thrombotic thrombocytopenic purpura (TTP) – TTP is characterized by severe microangiopathic hemolytic anemia (with schistocytes on the peripheral smear (picture 9)), thrombocytopenia, and neurologic abnormalities (confusion, somnolence, headache). Renal insufficiency also may be present, often with gross or microscopic blood in the urine and typically a very high lactate dehydrogenase. TTP is associated with absent or reduced ADAMTS13 activity: It can be hereditary or acquired. Graver systemic illness suggests that ITP is not the diagnosis. (See "Diagnosis of immune TTP", section on 'Clinical and laboratory findings' and "Hereditary thrombotic thrombocytopenic purpura (hTTP)".)

●Disseminated intravascular coagulation (DIC) – DIC is characterized by thrombocytopenia and a clinical picture of hemorrhage and thrombosis with end-organ damage in the setting of an underlying condition such as sepsis, trauma, or malignancy. The diagnosis of DIC is suggested by abnormal coagulation studies (prothrombin time and activated partial thromboplastin time), evidence of increased thrombin generation (ie, low fibrinogen), increased fibrinolysis (eg, elevated D-dimer), and the presence of microangiopathic changes on the peripheral blood smear (eg, schistocytes (picture 9)). Patients with DIC are usually considerably sicker than those with ITP, and often bleed out of proportion to their already very low platelet counts. (See "Disseminated intravascular coagulation in infants and children".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Immune thrombocytopenia (ITP) and other platelet disorders".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword[s] of interest.)

●Basics topic (see "Patient education: Immune thrombocytopenia (ITP) (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Clinical presentation

•Physical findings – Childhood immune thrombocytopenia (ITP) typically presents with the sudden appearance of a petechial rash, bruising, and/or bleeding in an otherwise healthy-appearing child, with a peak in the three- to five-year-old age range. (See 'Clinical features' above.)

•Preceding viral illness or vaccination – Many children with ITP have a history of preceding viral illness. ITP may also infrequently occur following measles, mumps, and rubella (MMR) vaccination. (See 'Preceding illness or vaccination' above.)

•Absence of systemic symptoms – Other than mucocutaneous bleeding, patients with ITP usually appear and feel well. Systemic symptoms (eg, fever, anorexia, bone or joint pain, weight loss, or any other sign or symptom suggestive of an underlying serious illness), exposure to thrombocytopenia-inducing drugs (table 1), prior history of bleeding, and family history of bleeding are all generally absent in children with ITP at onset of their disease. On physical examination, there is no significant enlargement of lymph nodes, liver, or spleen. If any of these features are present, other causes of thrombocytopenia should be considered. (See 'Lack of systemic signs and symptoms' above and 'Further evaluation' above.)

●Bleeding severity – Bleeding symptoms in children with ITP can range from none or minimal (eg, few petechiae or small bruises) to, rarely, severe and life-threatening (eg, intracranial hemorrhage [ICH], severe gastrointestinal [GI] bleeding) (table 2). Patients with platelet counts <10,000/microL are more likely to have mucosal bleeding and ICH. (See 'Bleeding symptoms' above.)

•Mucocutaneous bleeding – Most patients have signs of cutaneous bleeding (petechiae (picture 2), purpura, and ecchymoses). Approximately 40 percent of patients also have mucosal bleeding (involving the nasal passages, oral cavity, and genitourinary and GI tracts). (See 'Mucocutaneous bleeding' above.)

•Serious and life-threatening hemorrhage – Serious hemorrhage requiring hospitalization and/or blood transfusion occurs in approximately 3 percent of children with ITP. ICH is the most severe consequence of ITP and occurs in <1 percent of patients. (See 'Serious hemorrhage' above and 'Intracranial hemorrhage' above.)

●Evaluation

•Initial laboratory tests – We suggest the following initial laboratory tests for the evaluation for patients with suspected ITP (table 3) (see 'Initial evaluation' above):

-Complete blood count (CBC) with differential and red blood cell indices

-Examination of the peripheral blood smear

-Reticulocyte count

-Blood type and direct antiglobulin test

-Immunoglobulin levels

In some cases, it may be reasonable to include additional tests in the initial laboratory panel (eg, antiphospholipid antinuclear antibodies in adolescent females).

•Additional evaluation – Evaluation for other causes of thrombocytopenia should be carried out if there are findings that are inconsistent with ITP (eg, abnormal white blood cell count or abnormalities on physical examination or on peripheral blood smear). (See 'Further evaluation' above.)

A bone marrow examination is not routinely required in children with a typical presentation (ie, sudden onset of a petechial rash or bruising in an otherwise well-appearing child) and characteristic laboratory findings of ITP (ie, isolated thrombocytopenia). Indications for bone marrow aspiration and biopsy include atypical clinical or laboratory features at presentation, new findings that emerge during follow-up that are not consistent with ITP, or failure to respond to ITP treatment (if given). (See 'Indications for bone marrow examination' above.)

●Diagnosis – ITP is largely a clinical diagnosis. For children with a typical presentation of ITP (ie, sudden onset of a petechial rash or bruising in an otherwise well-appearing child), the diagnosis of ITP is based upon the following criteria (see 'Diagnosis' above):

•Platelet count <100,000/microL

•Otherwise normal CBC with normal differential white count, hemoglobin, and reticulocyte count

•No abnormalities on the peripheral blood smear, particularly no evidence of hemolysis or blasts

•No findings on history and physical examination to suggest another cause of thrombocytopenia

●Differential diagnosis – Other causes of thrombocytopenia in children include malignancy, infection, autoimmune disorders, immunodeficiency syndromes, drug-induced thrombocytopenia, bone marrow failure, microangiopathic hemolytic anemias (eg, hemolytic uremic syndrome [HUS], thrombotic thrombocytopenic purpura, disseminated intravascular coagulation [DIC]), and inherited thrombocytopenias (table 5). (See 'Differential diagnosis' above and "Causes of thrombocytopenia in children" and "Approach to the child with unexplained thrombocytopenia".)