Immune Thrombocytopenia

• Immune thrombocytopenia (ITP) of childhood is an acquired immune-mediated, and usually self-limiting, condition of low platelet counts (< 100,00/μL).

• Newly diagnosed ITP refers to ITP up to 3 months after diagnosis.

• 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 >12 months.

• Primary ITP is thrombocytopenia without a known cause and secondary ITP is thrombocytopenia secondary to a known cause such as lupus.

• Incidence

  • Estimated at 5–10 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 1-5 years of age.

• Sex

  • In children, both sexes are equally affected.

  • Female predominance over male (2.3:1) is seen during adolescence and adulthood.

• 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.

• 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.

  • The best estimate of absolute risk is 1 in 24,000 doses

  • Usually occurs within 6 weeks of vaccination

  • This number is considerably less than ITP that occurs after natural infections with measles, mumps, or rubella.

• 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 are present, the case is not typical of ITP and other diagnoses should be considered.

The following conditions can cause thrombocytopenia

• Infections with Epstein-Barr virus, hepatitis C virus, and HIV can 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 should be considered in cases of multiple infections.

• Acute leukemia or bone marrow failure

  • Children with leukemia usually have symptoms and abnormal physical findings not seen in ITP.

    • Hepatosplenomegaly

    • Lymphadenopathy

    • Leukocytosis (white blood cell count >10,000/mcL)

    • Significant anemia (hemoglobin count < 10/dL)

• 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 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

    • Intellectual disability

    • Renal failure

    • High-frequency hearing loss

    • Cataracts

    • History of a stable level of thrombocytopenia for years

• Type 2B von Willebrand disease results 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.

• 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 anemia exists, 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.

• Bone marrow biopsy

  • Performed in the past by many pediatric hematologists to rule out acute lymphocytic leukemia for 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 leukemia or 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

• 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.

• Indications for inpatient therapy include:

  • Severe bleeding such as hematuria, blood in stool, or intracranial bleeding

  • Uncertainty about the diagnosis

  • Those with social concerns

  • Those who live far from the hospital

  • Those for whom follow-up cannot be guaranteed

• American Society of Hematology guidelines (2019) recommend:

  • No treatment if the child has few or no symptoms, as is usually the case

• 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.

• 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 patients respond to steroids.

  • Prednisone (4 mg/kg per day; maximum, 120 mg daily, for 4-7 days) or dexamethasone (0.6 mg/kg per day; maximum, 40 mg per day for 4 days)

  • 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

  • Sleep disturbance

  • 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 varicella infection.

• Recommended dose: 0.8 to 1.0 g/kg.

• 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

  • Chills

  • Fever

  • Headache

  • Nausea and vomiting

  • Tend to be more pronounced in older patients

  • Neutropenia (absolute neutrophil count < 1500/mcL) develops in ~30% of patients.

• 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 hematuria and 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.

• 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.

• 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

• ~15–20% of pediatric patients will develop moderate or major hemorrhagic problems.

• 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 were 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

    • Arteriovenous malformations

• 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

• Defined as persistence of thrombocytopenia lasting for >12 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/m² of 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

• 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 (>12 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.

• 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.

• Significant bleeding

• Severe anemia

• Significant concern for possible traumatic injury

• Any neurologic change in the setting of thrombocytopenia

• History of fever or bone pain

• Hepatomegaly, splenomegaly, significant lymphadenopathy

• Family history of thrombocytopenia

• Abnormal leukocyte count on peripheral smear or associated anemia

• Lack of response to initial therapy

• All children with refractory ITP