Basics
Description
- Idiopathic or immune thrombocytopenic purpura (ITP) is an autoimmune syndrome characterized by the following:
- Isolated thrombocytopenia (platelet count formally <100,000/mm3, typically <20,000/mm3)
- Shortened platelet survival
- Platelet autoantibodies
- Increased number of megakaryocytes in the bone marrow
- Primary ITP implies absence of other causes for thrombocytopenia; secondary ITP indicates another diagnosis associated with autoimmune thrombocytopenia.
- Phases of ITP
- Newly diagnosed (acute) ITP: within 3 months of initial diagnosis
- Persistent ITP: transient improvement or continued thrombocytopenia for 3-12 months
- Chronic ITP: persistent thrombocytopenia >12 months after initial presentation
Epidemiology
- Most common acquired platelet disorder in childhood
- Often follows viral syndrome by a few weeks; this may be associated with higher likelihood of spontaneous recovery.
- Males and females are equally affected in childhood ITP (mild male predominance in younger children; female-to-male ratio is 3:1 in adult and chronic ITP).
- Median age at diagnosis is 4 years. Children <1 year or >10 years are more likely to develop chronic ITP.
- >70% of childhood ITP resolves within 6-12 months.
- Risk of severe bleeding is <5% and of intracranial bleeding is ~0.5%.
Incidence
Incidence is 1-10/100,000 children per year (<15 years of age).
Pathophysiology
- Thrombocytopenia due to increased destruction of antibody-coated platelets in the reticuloendothelial system, particularly the spleen
- Hypothesized that antibodies generated in response to foreign antigen or drug cross-react with platelet membrane glycoproteins (most commonly IIb/IIIa and Ib/IX)
- Other mechanisms of immune dysregulation have been implicated, including possible inhibition of thrombocytopoiesis, limiting ability to compensate for destruction.
- Typical bone marrow aspirate shows increased numbers of immature megakaryocytes.
Commonly Associated Conditions
- In younger children, primary ITP is the most common presentation of ITP.
- Secondary ITP is seen with autoimmune disorders (e.g., systemic lupus erythematosus [SLE], autoimmune lymphoproliferative syndrome [ALPS]).
- HIV
Diagnosis
History
- Presents with unusual bruising (with minor or no trauma, or in uncommon locations such as torso, neck, face), petechiae, epistaxis, prolonged bleeding with minor trauma, gingival bleeding, hematuria, or hematochezia
- Acute onset in an otherwise well child
- Not associated with pallor, fatigue, weight loss, or persistent fevers
- A majority of cases are preceded by a viral infection 1-3 weeks before onset (particularly varicella; also Epstein-Barr virus, cytomegalovirus).
- Associated with recent MMR in younger children; possibly hepatitis A vaccine, Tdap in older children
- Ascertain history of other autoimmune diseases (e.g., rheumatologic disorders, thyroid disease, hemolytic anemia).
- Obtain medication history, focusing on drugs with antiplatelet effects or associated with thrombocytopenia (e.g., valproate, heparin).
- Family history is usually negative for bleeding disorders. Ask about family autoimmune disease.
- Screen for bleeding, headache, abdominal or back pain, and any focal neurologic change.
Physical Exam
- Clusters of petechiae or large or purple bruises readily apparent on skin or mucosae
- Hematomas or persistent slow bleeding on mucosal surfaces or from minor trauma
- Absence of lymphadenopathy (LAD), hepatosplenomegaly (HSM), masses, bone pain
- Screen for nonobvious bleeding (neurologic and funduscopic exam, abdominal or muscular tenderness); these events are rare.
Diagnostic Tests & Interpretation
Lab
- Thrombocytopenia (typically <20,000/mm3) with normal WBC and hemoglobin (or mild anemia in proportion to amount of blood loss)
- Mean platelet volume may be increased.
- Peripheral blood smear will be otherwise normal, with no red cell fragmentation, no spherocytes, and no blasts. Review also rules out pseudothrombocytopenia from platelet aggregation.
- Prothrombin time/INR and partial thromboplastin time are normal. Bleeding time will be prolonged, but testing is unnecessary.
- Direct antiglobulin (Coombs) test to exclude coexisting autoimmune hemolysis (Evans syndrome)
- Limited role for antinuclear antibody (ANA) and other immunologic tests in subset of patients at higher risk for other autoimmune disease
- HIV testing if risk factors are identified
- Bone marrow aspirate is needed only if unexplained anemia, abnormal WBC, blasts on peripheral smear, organomegaly, jaundice, or lymphadenopathy is present. It is safe to perform with a low platelet count.
- There is controversy over whether to obtain a marrow aspirate before giving corticosteroids and little evidence to support it.
- Marrow shows normal to increased numbers of megakaryocytes with otherwise normal morphology and cellularity.
- Assays for platelet-associated antibodies (either direct or indirect) are not sensitive and are not routinely indicated.
- Demonstration of platelet-associated IgG may be useful in more complicated patients in whom chronic ITP is a possible diagnosis.
Imaging
As indicated by symptoms, particularly abdominal pain, headache, vision, or focal neurologic change
Differential Diagnosis
- Consider malignancy if persistent fever, weight loss, adenopathy, bone pain, or organomegaly is present (mild splenomegaly seen in 5-10% of patients with ITP).
- Other destructive thrombocytopenias
- Secondary ITP: infection, drug induced, posttransfusion purpura, autoimmune hemolytic anemia (when coexistent with ITP is called Evans syndrome), lymphoproliferative disorders, SLE
- Nonimmunologic: microangiopathic hemolytic anemia (including TTP, HUS), disseminated intravascular coagulation (DIC), Kasabach-Merritt syndrome (hemangioma), cardiac defects (left ventricular outflow obstruction, prosthetic heart valves), malignant hypertension
- Impaired or ineffective production
- Marrow-infiltrative processes (leukemias, other tumor metastases, myelofibrosis, osteopetrosis, storage diseases)
- Drug- or radiation-induced thrombocytopenia or aplastic anemia, nutritional deficiency states (iron, folate, vitamin B12)
- Infection-associated suppression: typically viral (e.g., hepatitis, Epstein-Barr virus, HIV, parvovirus B19), also severe or neonatal sepsis
- Congenital disorders: thrombocytopenia absent radii (TAR) syndrome, dyskeratosis congenita, Fanconi anemia, trisomies 13 and 18, Bernard-Soulier syndrome, Wiskott-Aldrich syndrome, May-Hegglin anomaly, other inherited thrombocytopenias (X linked or autosomal dominant), metabolic disorders (e.g., methylmalonic acidemia)
Treatment
- Because severe hemorrhage is rare and ITP resolves spontaneously in 90% of pediatric cases, most patients without severe bleeding will not require treatment.
- Treatment slows antibody-mediated platelet clearance and raises platelet counts acutely but does not alter the long-term course.
- Patients with a platelet count <10,000/mm3 are at higher risk for bleeding, but platelet count alone is not an indication for treatment.
- Active toddlers or children at risk for trauma may require treatment when platelet count is <20,000-30,000/mm3.
- Observation alone is acceptable for older children without serious bleeding and with adequate supervision and assured follow-up; may be preferable to repeated treatment in clinically well children with chronic ITP
Medication
First Line
- IVIG: 94-97% will have an increase in platelet count >20,000/mm3 by 72 hours. The usual dose is 0.8-1 g/kg. Response typically peaks after 1 week and lasts 3-4 weeks.
- Advantages: faster time to platelet increase (24 hours), helps confirm diagnosis
- Disadvantages: high cost, long infusion time, allergic reactions; 10-30% have evidence of aseptic meningitis with severe headache and stiff neck; headache, nausea, vomiting, or fever more common
- Scheduled acetaminophen and diphenhydramine for 24 hours after infusion may reduce acute side effects.
- Subcutaneous administration has been used successfully as an alternative to IV.
- Corticosteroids: 80% respond with platelet counts >20,000/mm3 by 72 hours (faster with high-dose pulse therapy). Oral prednisone at 2 mg/kg/24 h tapered over 1-4 weeks is typical.
- Advantages: ease of dosing, low cost, often longer duration of response
- Disadvantages: short-term side effects: mood changes, increased appetite and weight gain, hypertension, insulin resistance. Long-term side effects with chronic use: adrenal suppression, osteopenia, growth delay
- Anti-Rh D immunoglobulin-WinRho-SDF (patient must be Rh[+], nonsplenectomized, and not have hemolysis or hemorrhage): 80% respond with platelet counts >20,000/mm3 after 72 hours. Dose is 50-75 mcg/kg IV over 3-5 minutes. If hemoglobin (Hb) <10 mg/dL, give 25-40 mcg/kg. 1 mcg = 5 IU of drug. Response lasts ~5 weeks.
- Advantages: less expensive than IVIG but more costly than steroids; lower rate of allergic side effects (10%) than with IVIG and does not cause aseptic meningitis; amenable to outpatient administration
- Disadvantages: fever/chills, mild hemolysis (Hb decrease of 1-3 g/dL) in all patients; rare reports of catastrophic hemolysis; subcutaneous route may ameliorate risk.
- Any of these therapies may be repeated if responsive patient later develops recurrent thrombocytopenia.
Second Line
- Rituximab (anti-CD20 monoclonal antibody) induces response in many refractory patients (after median 5 weeks), but duration is often limited (median 12 months).
- Thrombopoietin receptor agonists (e.g., eltrombopag, romiplostim) have been shown in trials to improve platelet counts and bleeding risk in patients with chronic ITP. Cost, concerns about adverse effects including myelofibrosis and thrombosis, and paucity of long-term follow-up data limit use.
- Cytotoxic drugs (e.g., vincristine) or immunosuppression (e.g., cyclosporine A or mycophenolate mofetil) is effective in some patients refractory to other therapy and splenectomy.
Additional Therapies
General Measures
- Platelet transfusions are generally ineffective because transfused platelets are rapidly destroyed. Role is limited to emergent support for critical hemorrhage.
- Avoid medications that affect platelet function, such as aspirin, ibuprofen, most other NSAIDs, and anticoagulants.
- Educate parents about signs and symptoms of intracranial hemorrhage and GI bleeding.
- Avoid activities with significant fall, collision, or other trauma risk while thrombocytopenic.
Surgery/Other Procedures
Splenectomy: 70-80% respond with complete remission. No reliable presurgical predictors of response have been found; generally deferred until >12 months from diagnosis to allow for spontaneous remission or medical response
- Advantages: response in patients refractory to medical therapy
- Disadvantages: surgical morbidity; risk of sepsis with encapsulated organisms (immunize preoperatively against Haemophilus influenzae, pneumococcus, and meningococcus and consider penicillin prophylaxis)
Inpatient Considerations
Initial Stabilization
Life-threatening hemorrhage: The goal is to stop bleeding rapidly. Platelet transfusion, IVIG, and steroids (after emergent marrow exam, if indicated) should be given concomitantly.
Ongoing Care
Follow-up Recommendations
Patient Monitoring
- Platelet count twice weekly when <20,000/mm3, weekly when <50,000/mm3 or after treatment, except in stable chronic ITP. Increase interval if no symptoms and platelet count >50,000/mm3.
- Platelet counts may fall transiently with intercurrent illnesses prior to resolution of ITP.
- Discontinue monitoring when no symptoms and normal platelet count for >3 months.
Prognosis
- Acute ITP: In 3 months, 60% of children will have a platelet count >100,000/mm3; at 1 year from diagnosis, 90%. Recurrence is rare.
- Chronic ITP: Platelet count tends to be higher, at 40,000-80,000/mm3. Remissions can occur many years after diagnosis (predicted spontaneous remission rate 61% after 15 years).
- Not yet possible to prospectively distinguish patients with self-limited ITP from those who will persist with chronic ITP
- Patients with chronic ITP should be periodically reevaluated for secondary ITP.
Complications
- The incidence of significant bleeding-related morbidity and mortality is low (<5%).
- Intracranial hemorrhage is rare (<0.5%).
- May occur without prior trauma
- Retinal hemorrhage is rare.
- Mucosal bleeding from nose, gums, lower GI tract, or kidneys is not uncommon. Hematemesis and melena are rare.
- Significant menorrhagia may occur.
Additional Reading
- Eberl W, Dickerhoff R, Pediatric Committee of Society of Thrombosis and Hemostasis Research. Newly diagnosed immune thrombozytopenia-German guideline concerning initial diagnosis and therapy. Klin Padiatr. 2012;224(3):207-210. [View Abstract]
- Kime C, Klima J, Rose MJ, et al. Patterns of inpatient care for newly diagnosed immune thrombocytopenia in US children's hospitals. Pediatrics. 2013;131(5):880-885. [View Abstract]
- Neunert CE, Buchanan GR, Imbach P, et al. Bleeding manifestations and management of children with persistent and chronic immune thrombocytopenia: data from the Intercontinental Cooperative ITP Study Group (ICIS). Blood. 2013;121(22):4457-4462. [View Abstract]
- Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;117(16):4190-4207. [View Abstract]
Codes
ICD09
- 287.31 Immune thrombocytopenic purpura
- 287.32 Evans' syndrome
- 287.3 Primary thrombocytopenia
ICD10
- D69.3 Immune thrombocytopenic purpura
- D69.41 Evans syndrome
SNOMED
- 32273002 Idiopathic thrombocytopenic purpura (disorder)
- 75331009 Evans syndrome (disorder)