Key Points
Two Types: Acute and Chronic
Diagnosis: Established by excluding known causes of thrombocytopenia
Treatment: Depends on the platelet count and the presence and severity of bleeding.
When therapy is indicated, the primary treatment options for the newly diagnosed patient are:
Corticosteroids
Intravenous immunoglobulin
Intravenous anti-D Ig
Foundation
Definition
Immune thrombocytopenia purpura (ITP) of childhood is an acquired immune-mediated, and usually self-limiting, condition of low platelet counts.
Persistent ITP refers to ITP lasting between 3–12 months from diagnosis, which includes
Patients not achieving spontaneous remission or
Patients not maintaining their response after stopping treatment between 3–12 months from diagnosis
Chronic ITP is reserved for patients with ITP lasting >6 months.
Epidemiology
Incidence
Estimated at 4–8 cases per 100,000 children annually
The rate is probably higher because of subclinical cases.
Age
Most common in children 2–10 years of age
Peak incidence at 2–4 years of age
Sex
In children, both sexes are equally affected.
Female predominance over male (2.3:1) is seen during adolescence and adulthood.
Etiology
ITP is caused by antibodies (mostly immunoglobulin G [IgG]) directed against antigens normally present on platelet membranes such as glycoproteins IIb/IIa and Ib/IX.
The antibody-coated platelets are then recognized and destroyed by reticuloendothelial cells found mostly in the spleen.
Risk Factors
History of a preceding infection, subsequently resolved
Elicited in the majority of patients
>70% of cases occur after viral infections.
In some cases, ITP is seen after measles-mumps-rubella immunization.
Diagnosis
Signs and Symptoms
Typically, there is sudden onset of petechiae, purpura, and ecchymosis in the absence of other signs of illness.
Mucosal (nose, mouth, and gingival surfaces) bleeding may be present.
Usually, there are no significant abnormalities on history and physical examination.
No other systemic symptoms, such as fever, weight loss, bone pain, or joint pain
No significant enlargement of lymph nodes, liver, or spleen
If any of these symptoms or physical findings is present, the case is not typical of ITP and other diagnoses should be considered.
Differential Diagnosis
Infections with Epstein-Barr virus, hepatitis C virus, and HIVcan be ruled out by
History
Physical examination
Liver enzymes/function tests and viral studies, if needed
Drugs such as heparin and sulfonamides can be ruled out by history.
Other autoimmune diseases, such as systemic lupus erythematosus
May be difficult to diagnose
Are more likely to affect teenagers and adults than younger children
Common variable immunodeficiency and autoimmune lymphoproliferative syndrome should be considered in cases of multiple autoimmune cytopenias.
Acute leukemiaor bone marrow failure
Acquired aplastic anemia
Low platelet count is usually associated with other significant changes in peripheral blood, such as
Macrocytic anemia
Leukopenia
Neutropenia
Destructive thrombocytopenias, such as thrombotic thrombocytopenic purpura (TTP) and disseminated intravascular coagulation(DIC)
Patients with these conditions present with other clinical and laboratory abnormalities and are usually sicker than ITP patients.
Inherited thrombocytopenia
Although thrombocytopenia in most children is either autoimmune or drug related, keep this category in mind.
Elicit a family history of thrombocytopenia, especially parent-child or maternal uncle–nephew.
Diagnostic features on peripheral smear that may point to inherited thrombocytopenia
Abnormal size of platelets (either small or giant)
Absence of platelet α-granules (gray platelets)
Döhle-like bodies
Microcytosis
Clinical features that suggest inherited thrombocytopenia
Bleeding out of proportion to the platelet count
Onset of thrombocytopenia early in life
Associated features, such as
Absent radii
High-frequency hearing loss
Cataracts
History of a stable level of thrombocytopenia for years
Type 2B von Willebrand diseaseresults in increased spontaneous binding of the high-molecular-weight von Willebrand factor (VWF) multimers to platelets.
Can lead to increased clearance of platelets from circulation, resulting in variable thrombocytopenia
Usually of autosomal dominant inheritance, so important to obtain family history regarding mucocutaneous bleeding
If suspected, VWF studies including multimer analysis should be done in consultation with a hematologist.
Diagnostic Approach
ITP is a diagnosis of exclusion after considering other causes of isolated thrombocytopenia.
For patient with mucocutaneous signs of bleeding who is otherwise healthy, a reasonable workup includes
Complete blood count
Peripheral blood smear
Reticulocyte count
Blood typing
Complete blood count
Thrombocytopenia is usually the only laboratory abnormality.
Platelet count is usually < 20,000/mcL.
Peripheral blood smear
Will reveal morphologically normal leukocytes and erythrocytes
Large, freshly produced platelets are usually seen.
These young reticulated platelets contain messenger RNA and are metabolically active.
May explain why ITP patients do not bleed as severely as those with bone marrow failure and similarly low platelet counts
If other abnormalities are seen, obtaining additional tests may be indicated, such as
Viral antibodies (HIV, cytomegalovirus, Epstein-Barr virus, varicella, rubeola, mumps, or parvovirus, depending on the clinical picture)
Tests for rheumatologic and other hematologic conditions (eg, leukemia, bone marrow failure)
Reticulocyte count
Helpful when diagnosis of ITP is not straightforward (ie, in cases in which associated mild anemiaexists, which is not rare)
Blood typing
Determination of Rh status, which determines whether a patient is treatable with anti-D antibodies
Both reticulocyte count and blood typing are not strictly needed for evaluation.
However, drawing blood to keep aside for reticulocyte count and blood typing is preferable to performing multiple traumatic blood draws on a thrombocytopenic child.
Platelet antibodies tests
Although ITP is caused by platelet antibodies, these tests are sensitive but not specific.
Not indicated for the diagnosis of acute ITP in children
Assessment of bleeding time
Bleeding time is prolonged in ITP, but this test is unnecessary, traumatic, and inaccurate in children.
Tests for prothrombin time and activated partial thromboplastin time are unnecessary.
Results are typically normal in these patients.
Diagnostic Procedures
Bone marrow biopsy
Performed in the past by many pediatric hematologists to rule out acute lymphocytic leukemiafor fear of partially treating and thus masking a leukemic process
Now, typically performed when patients have clinical or laboratory features atypical of ITP at presentation that suggest an alternate diagnosis, such as acute leukemiaor a bone marrow failure syndrome
Also indicated for patients in whom ITP is initially diagnosed but who do not respond to treatment
Timing of bone marrow evaluation is an individualized decision.
Most likely time is between 7–14 days after treatment begins, but response is poor
May be considered
In patients who have an atypical clinical course
In patients in whom splenectomy is contemplated for additional confirmation of diagnosis
To rule out a malignant process
Bone marrow in ITP
Is cellular, with normal erythroid and myeloid precursors
Usually shows increased numbers of megakaryocytes
Management
Treatment Approach
Early treatment does not alter the natural course and does not affect the development of chronic ITP.
The same principles of treatment of acute ITP apply to a certain extent to management of chronic ITP.
Most ITP cases in children can be managed on an outpatient basis.
Consensus is that treatment is indicated for the patient with overt bleeding.
Treatment and management recommendations for patients who have different clinical manifestations remain a subject of debate.
Current therapy recommendations are based on expert consensus opinions.
American Society of Hematology guidelines
Children with ITP and platelet counts >30,000/mcL
Require no treatment if they have few or no symptoms, as is usually the case
Patients with platelet counts between 10,000 and 30,000/mcL
Treatment recommendations are based on the presence and severity of associated bleeding symptoms or the risk of bleeding.
The lower the platelet count, the more likely the patient is to receive treatment, even if symptoms are relatively mild.
Children who should be treated
Other important factors in treatment decision include
Child’s age
Child’s degree of activity
Social variables, such as reliability of caregivers and ease of access to emergency medical care
When therapy is indicated, the primary treatment options for the newly diagnosed patient are
Corticosteroids
Intravenous immunoglobulin (IVIG)
Intravenous anti-D Ig
Platelet transfusions
Ineffective because the transfused platelets are rapidly destroyed
Chronic ITP: the chance of spontaneous remission is still significant during this period, making deferral of more aggressive therapeutic approaches reasonable.
Other options include splenectomy, immunosuppressive therapy, rituximab, and thrombopoietin (TPO) receptor agonists.
General useful advice to families with an affected child includes
Avoid activities associated with increased likelihood of trauma, such as contact sports.
Make sure the child uses a helmet when riding a bicycle.
Avoid medications that interfere with platelet function, such as aspirin and nonsteroidal anti-inflammatory drugs.
Specific Treatments
Corticosteroids
Used for many years in all age groups
Reduce the risk of symptoms, most likely by reducing reticuloendothelial system phagocytosis of antibody-coated platelets
Most pediatric hematologists use prednisone for 2–3 weeks.
Shorter courses at higher doses are also effective.
Intravenous or oral methylprednisolone up to 3–7 days and dexamethasone for 4 days every 4 weeks have been given.
Most patients respond to steroids.
Response is faster with higher doses (seen after 72 hours of starting treatment).
Platelets usually decrease after steroids are discontinued if the titer of platelet antibodies remains elevated.
A second course of treatment may be necessary
If bleeding develops
If the platelet count decreases to < 10,000/mcL
Side effects of brief courses of corticosteroids include
Behavioral changes
Increased appetite
Hyperglycemia
Weight gain
Side effects are more pronounced at higher doses.
Caution should be taken when using steroids in the setting of active infection, especially with varicellainfection.
IVIG
Compared with patients receiving steroids
Rapid improvement in platelet count is seen, usually within 24 hours.
Probably interferes with Fc receptor activity, resulting in prolonged survival of antibody-coated platelets
Other mechanisms of action include
Regulatory properties of anti-idiotypic antibodies in IVIG
Effects on cytokine synthesis and on receptors for cytokines and complement
One intriguing proposal for mechanism of action
Concentration-dependent elimination of IgG is a known phenomenon and IVIG administration causes acceleration of the rate of IgG catabolism.
Such a process would eliminate individual IgG molecules in direct proportion to their relative concentration in plasma.
Thus elimination of antiplatelet antibodies is accelerated.
Far more expensive than steroids
Side effects
Anti-Rho (D) Ig
Binds to the D-antigen in Rh-positive individuals; the antibody-coated red cells block the Fc receptor of reticuloendothelial cells
Results in rapid increase in platelet count, usually in 1–2 days
A single dose of 50–75 mcg/kg is most commonly used.
Achieves a more rapid increase in platelet count that is similar to that seen with IVIG therapy
An average decrease in the hemoglobin level of ~1.3 g is seen as a result of the mild hemolysis of the patient’s Rho (D)-positive red cells.
Should be used with caution in children with preexisting anemia
Should probably be given only to children with a hemoglobin level >10 g/dL
With increased use, there have been a few cases of patients developing increased hemolysis leading to severe anemia, acute renal insufficiency, DIC, and multisystem organ failure.
It should always be used with caution.
It is recommended that patients treated with anti-Rho (D) receive intravenous fluids and be observed for the development of hematuriaand hemoglobinuria for at least 8 hours.
Signs and symptoms of intravascular hemolysis include back pain, shaking chills, fever, and discolored urine or hematuria.
Absence of the signs and symptoms of intravascular hemolysis within 8 hours does not indicate that intravascular hemolysis cannot occur subsequently.
Thrombopoietin receptor agonists
A number of studies with TPO receptor agonists have shown encouraging results in adults.
Some children have been successfully treated, and new information about safety and response is emerging.
Ongoing Care
Follow-up
Patients should have blood counts done once or twice weekly.
Blood counts should be less frequent when the platelet count is
Stable
>30,000 cells/mcL
Increasing with time
Complications
Hemorrage
~15–20% of pediatric patients will develop moderate or major hemorrhagic problems.
Intracranial hemorrhage
Intracranial hemorrhage (ICH) is rare; it occurs in 0.1–1% of acute ITP.
The most serious complication and most likely cause of death in ITP
Recognizing which patients are more likely to develop ICH is difficult.
A literature review of 62 reported pediatric and adolescent cases of ICH in the setting of ITP showed
Median time from the diagnosis of ITP to ICH was 32 days (range, 0 days–8 years).
72% of cases occurred ≤6 months of diagnosis.
Platelet count was < 10,000/mcL in 71.4% of the cases.
Treatments before the ICH was primarily steroids but also included IVIG, splenectomy, and others.
A significant number of patients developed ICH despite having already initiated steroid treatment.
Many patients have other risk factors, including
Preceding head injury
Other preceding mucocutaneous bleeding
Prior aspirin treatment
Management is an emergency that requires
Immediate imaging (computed tomography) to determine location and extent of the bleeding
Immediate consultation with
Pediatric intensivist
Hematologist
Neurosurgeon
General surgeon
Treatment includes
Administration of IVIG, steroids, continuous platelet transfusions to rapidly increase the platelet count
Surgical intervention, if needed, including
Craniotomy (especially with posterior fossa hemorrhages that are more likely to cause herniation or brainstem compression)
Splenectomy
Chronic ITP
Defined as persistence of thrombocytopenia lasting for >6 months from the time of diagnosis
~10% of patients with typical ITP develop chronic thrombocytopenia.
In a prospective Dutch study, variables that predicted development of chronic disease included
Platelet count >10,000/mcL at the onset
Absence of infection shortly before the onset of the disease
The 232I/T Fc gamma receptor IIB genotype
In another meta-analysis, female gender and older age (>11 years) at presentation, among other variables, correlated with increased likelihood of developing chronic ITP.
Given sufficient time (even years), a significant proportion of such patients will improve or remit.
Management should focus on
Minimizing risk for bleeding
Maintaining a safe platelet count
Many patients will require no treatment
If treatment is needed
Periodic short courses of steroids may be given.
In case of long-term need for steroids, alternate-day dosing may be effective in preventing bleeding while reducing side effects.
IVIG or anti-Rho(D) Ig has also been used, but these measures are only temporary.
Splenectomy
Effective in improving the platelet count and reducing the associated risk of bleeding in 60–90% of children
A small but real risk remains of overwhelming postsplenectomy sepsis, which may be life threatening.
Usually delayed until the child is >5 years because the risk of overwhelming sepsis decreases with age.
American Society of Hematology guidelines recommend waiting until ≥12 months after diagnosis, if possible.
Platelet counts following splenectomy
Generally monitored indefinitely
Any drop in platelet counts or increase in symptoms should prompt assessment for the presence of an accessory spleen.
If not previously done, bone marrow biopsy is recommended for patients being considered for splenectomy.
Presplenectomy immunizations and subsequent penicillin prophylaxis are necessary.
Rituximab for refractory chronic ITP
A chimeric murine-human anti-CD20 monoclonal antibody
Acts by destroying B-lymphocytes by activating complement-dependent and an antibody-dependent cellular toxicity
Therefore, mechanism of action is a slow but effective decrease in production of antibodies.
In a study of 24 patients 2–19 years of age who received 375 mg/m 2of rituximab in 4 weekly doses
63% achieved complete remission for 4–30 months (platelet count of >150,000/mcL).
Although long-term remissions have been documented, use of rituximab in ITP is relatively recent.
Long-term follow-up may be needed for accurate prognostication.
Use may be associated with
Infusion-related reactions
Development of transient hypogammaglobulinemia
Prognosis
Treatment does not alter the course (ie, the incidence of patients who go on to develop chronic ITP).
It does shorten the duration of thrombocytopenia in some patients.
For typical cases of childhood ITP
80% of patients will have platelet counts return to normal ≤2 months of presentation, with or without therapy.
Another 10% will recover normal platelet levels in the next few months.
~10% will go on to have chronic thrombocytopenia (>6 months’ duration).
~25% of children will have a relapse after initial treatment.
10% have chronic ITP.
10% have recurrence but resolution ≤6 months.
5% have ITP recurrences and remissions throughout their lives.
Immune thrombocytopenia in the neonate
Most neonatal thrombocytopenia is not immune in nature but is caused by
Sepsis
Congenital infections
Drugs
Asphyxia
Necrotizing enterocolitis
2 conditions occur when immune thrombocytopenia is seen in neonates.
Neonatal alloimmune thrombocytopenia (NAIT)
A condition in which the mother develops antiplatelet antibodies directed against specific antigens found on fetal platelets but lacking on hers
Associated 20% risk of ICH
Treatment usually involves administration of maternal washed platelets and IVIG.
Importance of detection and accurate diagnosis of NAIT is in the ability to prevent complications in future pregnancies by
Treating the mother with IVIG and steroids
Performing in utero blood sampling and intervening in case of thrombocytopenia
Hematologist and high-risk fetal-maternal specialist should be involved in management.
Another less serious condition is that resulting from passive transfer of maternal platelet autoantibodies in a mother with ITP.
Only 4% of babies born to mothers with ITP have platelet counts < 20,000/mcL.
The risk of ICH is low (< 1%), and no proof exists that cesarean delivery alters that risk.
Usually resolves within a few weeks as the antibodies are used up
Physicians may choose to treat the babies with IVIG in case the platelet count decreases to < 30,000/mcL.
Maternal ITP is not a contraindication to breastfeeding.
When to Admit
Significant bleeding
Severe anemia
Significant concern for possible traumatic injury
Any neurologic change in the setting of thrombocytopenia
When to Refer
History of feveror bone pain
Hepatomegaly, splenomegaly, significant lymphadenopathy
Family history of thrombocytopenia
Platelet count < 20,000/mcL
Abnormal leukocyte count on peripheral smear or associated anemia
Lack of response to initial therapy
All children with refractory ITP
