Newly diagnosed ITP
Resolution within 3 months of diagnosis
Persistent ITP
Resolution 3–12 months from diagnosis; includes patients not reaching spontaneous remission or not maintaining complete response off therapy
Chronic ITP
Lasting more than 12 months
6 Onset of ITP Children
7 Clinical and Laboratory Characteristics
Bleeding symptoms are mainly bruising and mucocutaneous bleedings such as petechiae (diameter of 0.5–3 mm, no blanching under pressure, not palpable) or ecchymosis (flat, rounded, or irregular red, blue, purplish, or yellow-green patch larger than petechiae), oral or nasal bleeding, hematuria, or hypermenorrhea. Rarely, organ bleeding such as gastrointestinal or intracranial bleeding occurs [25]. Patients are often noticed incidentally during laboratory examinations performed for unrelated diseases. ITP in children is more frequent in males, whereas adult ITP more involves females. Severe bleeding is rare and is found in children with a platelet count less than 20 × 109/L [4, 26, 27]. Predictors of bleeding due to ITP in children include female sex, older age at presentation (age ≥11 years), absence of preceding infection or vaccination, insidious onset, higher platelet count at presentation, presence of antinuclear antibodies, and treatment with a combination of methylprednisolone and intravenous immunoglobulin. Furthermore, children with mucosal bleeding at diagnosis or treatment with intravenous immunoglobulin alone develop chronic ITP less often [7].
8 Bleeding Assessment Tools (BATs) for ITP in Children
The bleeding risk and severity of ITP have usually been evaluated based on peripheral platelet counts and bleeding symptoms. However, objective evaluation of the degree or severity of bleeding symptoms is not easy. Various BATs have been proposed for ITP in children and adults [25, 28–32]. More recently, a new standard in bleeding assessment for ITP in children and adults (ITP-BAT bleeding scale, version 1.0) has been reported from the IWG.
The ITP-BAT bleeding scale is made up of three major bleeding domains of the skin (S), visible mucosae (M), and organs (O), with a gradation of severity (SMOG index). The gradation of severity for each domain is further classified on the site of bleeding with gradings ranging from 0 to 3 or 4 according to the spread of the hemorrhagic area, need for medical intervention and red blood cell transfusion, and reductions in levels of blood hemoglobin. For example, a SMOG index of S2 M2 O3 could represent findings of subcutaneous hematoma (S2), epistaxis (M2), and menorrhagia (O3). Considering the lifelong potential functional impairment caused by intracranial bleeding, the IWG recommends that all cases of intracranial bleeding be reported, irrespective of grade, such as S grade 2 M grade 2 O grade 3 (intracranial grade 2; post trauma, requiring hospitalization). However, the value of summing up the worst grades for all manifestations in each domain is currently uncertain, and interpretation remains ambiguous [25].
9 Diagnosis of ITP in Children
Information about the family and medical history before onset are important. The characteristics of bleeding symptoms and physical and laboratory examinations are crucial for differential diagnosis. The Japanese Society of Pediatric Hematology/Oncology proposed diagnostic criteria for pediatric ITP (Table 2) [33]. However, no gold standards exist for ITP diagnosis, and exclusion of other thrombocytopenic disorders remains central to the diagnosis. Bone marrow examination is usually unnecessary in children and adolescents with typical features of ITP, but when abnormal physical symptoms (such as abnormal rash, recurrent fever, or joint pain), lymphadenopathy, splenomegaly, abnormal cell counts, abnormal morphology of red or white blood cells, and poor response to medical treatments such as immunoglobulin and corticosteroids are present, bone marrow evaluation may be needed to rule out other disorders. In recent years, measurement of plasma levels of TPO, TPO receptor protein, and immature platelets (reticulo-platelets), which may indicate platelet production in the bone marrow, has been developed as complementary inspection methods [8].
Table 2
Diagnostic criteria for ITP children according to the Committee on Platelets of the Society of Japanese Pediatric Hematology/Oncology
1. Bleeding symptoms present | |
Bleeding symptoms as mainly purpura (petechia or ecchymosis) and also oral bleeding, epistaxis, melena, hematuria, hypermenorrhagia | |
Joint bleeding does not usually occur. Although patient would be unaware of a bleeding symptom, patient is admitted to clinic after identification of thrombocytopenia | |
2. Laboratory findings | |
a. Peripheral blood examinations • Decreased platelets: <100 × 109/L. It should be noted that attention to false thrombocytopenia is required when performing automatic blood cell counting • Numbers and morphological features of both red and white blood cells are normal. However, as for bleeding tendency or iron-deficiency anemia, a mild increase or decrease of white blood cells may also be observed. | |
b. Bone marrow • Numbers of megakaryocytes are normal or increased: Many megakaryocytes lack platelet production • Numbers or morphological features of both red blood cells and granulocyte lineages are normal: Granulocyte/erythroid (G/E) ratio overall; production of both lineages is present Bone marrow examination is not routinely conducted for diagnosis of ITP Bone marrow examination is considered at the presence of abnormal numbers and morphological feature of red and/or white blood cells, at disputable diagnosis of ITP, with the considerable use of corticosteroids or absence of desirable response to administration of large amounts of gamma globulin | |
3. Exclusion of various diseases that can cause thrombocytopeniaa | |
4. ITP diagnosis can be made if the characteristic features of points 1–3 are presentb | |
5. Criteria of ITP phase | |
a. Acute phase: Recovery from thrombocytopenia within 6 months from estimated onset or diagnosis b. Chronic phase: Thrombocytopenia prolonged for 6 months or more from estimated onset or diagnosis preceding virus infection often indicates acute-phase ITP |
10 Differential Diagnoses
A diagnosis of ITP is reached by excluding underlying disorders with thrombocytopenia caused by platelet destruction and/or production and congenital thrombocytopenia. Diagnosis of congenital thrombocytopenia is not easy and is usually achieved based on platelet size and morphology in peripheral blood specimens, clinical manifestations of hemorrhagic and nonhemorrhagic symptoms, and results of platelet-function tests such as platelet aggregation tests using three different inducers adenine diphosphate (ADP), collagen and ristocetin, platelet-membrane glycoprotein analysis, flow-cytometric analysis with specific-labeled antiplatelet antibodies, electron microscopic analysis, or genetic analysis. A recent distinction algorithm using platelet size for congenital thrombocytopenia is shown in Table 3 [34, 35].
Table 3
Classification of congenital thrombocytopenia by platelet size
Platelet size | Mode of inheritance | Gene | Remarks |
---|---|---|---|
Small (MPV: <5 fLa) | |||
Wiskott-Aldrich syndromea | X, AR | WAS, WIPF1 | Immunodeficiency, eczema, thrombocytopenia |
X-linked thrombocytopenia | X | WAS | Thrombocytopenia (mild eczema, susceptibility to infection) |
Normal (MPV: 7.2–11.7 fL, 3–4 μm in diameterb) | |||
Congenital amegakaryocytic thrombocytopenia | XR | MPL | Reduced megakaryocytes, transition to bone marrow failure |
Congenital thrombocytopenia with radioulnar synostosis | XD | HOXA11 | Radioulnar fusion, transition to bone marrow failure |
Thrombocytopenia with absent radii syndrome | XR | RBM8A | Radial defect, normalization of platelet count with age |
Familial platelet disorder with propensity to myeloid malignancy | XD | RUNX1 (AML1) | Transition to AML/MDS |
Autosomal-dominant thrombocytopenia, thrombocytopenia 2 | XD | ANKRD26 | Reduction of GP1a and α granules, transition to acute leukemia |
Cytochrome C mutation | XD | CYCS (G41S mutation) | Apoptosis of megakaryocytes |
Large (more than twice normal platelets, ≥8 μm in diameter) | |||
MYH9 disorders | AD | MYH-9 | |
May-Hegglin syndrome | Clear white blood cell inclusions | ||
Sebastian syndrome | Somewhat ambiguous white blood cell inclusion bodies | ||
Fechtner syndrome | Combined with glomerulonephritis and deafnessc | ||
Epstein syndrome | Combined with glomerulonephritis and deafness, leukocyte inclusion bodies difficult to recognize | ||
Bernard-Soulier syndrome | AR | GP1BA, GP1BB, GP9 | Lack of ristocetin-induced platelet aggregation |
DiGeorge/velocardiofacial syndrome | AD | 22q 11.2 del (GP1BB) | Contiguous gene syndrome |
α-Actinin abnormality | AD | ACTN1
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