Immune Thrombocytopenia (ITP) in Children

Epidemiology & Natural History

• In children, the incidence of ITP is markedly higher than in adults, with an estimated 31.6 cases per million person‑years. 1
• Approximately two‑thirds of pediatric patients achieve spontaneous remission within 6 months of diagnosis. 2
• Chronic ITP (duration ≥ 12 months) develops in 20–30 % of children. 3

Definition & Pathophysiology

• ITP is defined by isolated thrombocytopenia (platelet count < 100 × 10⁹/L) without an identifiable underlying cause. 2, 4
• The disease is mediated by auto‑antibodies against platelet glycoproteins GPIIb/IIIa and GPIb/IX, leading to accelerated splenic destruction and impaired megakaryocyte production; T‑cell‑mediated mechanisms also contribute. 2

Classification

• Duration‑based:
  
  • Newly diagnosed – 0–3 months from diagnosis.
  • Persistent – 3–12 months.
  • Chronic – ≥ 12 months. 2, 4
• Etiology‑based:
  
  • Primary ITP – isolated thrombocytopenia with no precipitating factor.
  • Secondary ITP – associated with autoimmune disease, viral infection, Helicobacter pylori (adults), drug exposure, immunodeficiency, or lymphoproliferative syndromes. 2, 5, 1, 6, 4, 7

High‑Risk Bleeding Factors

• Platelet count < 10 × 10⁹/L.
• Active mucosal bleeding (epistaxis, oral bleeding, menorrhagia).
• Concurrent use of antiplatelet agents (e.g., NSAIDs, aspirin).
• Co‑existing coagulopathy or vasculitis (e.g., varicella‑associated ITP). 2, 5, 4, 8

Complications

• Intracranial hemorrhage occurs in 0.1–0.5 % of children with ITP. 5
• Severe mucosal bleeding may require nasal packing, gastrointestinal intervention, or transfusion. 2
• Treatment‑related adverse events include corticosteroid‑induced mood changes, weight gain, hyperglycemia, hypertension, gastritis, infection risk, growth suppression; IVIg can cause headache and aseptic meningitis; anti‑D may cause hemolysis; rituximab increases infection risk; splenectomy predisposes to overwhelming post‑splenectomy infection. 2, 5, 1

Management Strategy

Observation (Watchful Waiting)

• Children with no bleeding or only mild skin manifestations can be observed without pharmacologic therapy, irrespective of platelet count. 1, 6, 8, 9
• Rationale: two‑thirds remit spontaneously within 6 months; treatment does not alter long‑term prognosis; ICH risk is very low; therapies carry significant side‑effects. 2, 5, 4, 8
• Observation protocol includes family education on bleeding precautions, 24‑hour contact information, weekly outpatient review initially, platelet monitoring weekly then every 2–4 weeks, avoidance of high‑risk contact sports, and encouragement of school attendance. 5, 4

First‑Line Pharmacologic Therapy (Indications)

• Initiated for non‑life‑threatening mucosal bleeding, impaired health‑related quality of life, need for invasive procedures, or parental anxiety. 5, 1, 9, 4

Intravenous Immunoglobulin (IVIg)

• Dose: 0.8–1 g/kg as a single infusion.
• > 80 % achieve a platelet response; median time to response 1–2 days (≈ 50 % within 24 h).
• Mechanism: Fc‑receptor blockade, anti‑idiotypic antibodies, complement inhibition.
• Common adverse effects: headache; rare severe events include aseptic meningitis, hemolysis, thrombosis, renal dysfunction. 8, 1, 6, 5

Short‑Course Corticosteroids

• Prednisone 2–4 mg/kg/day (max 60–120 mg) for 5–7 days, then stop or taper; or dexamethasone 0.6 mg/kg/day (max 40 mg) for 4 days.
• 70–80 % achieve a platelet response; response typically within 2–7 days.
• Side‑effects: mood changes, increased appetite, weight gain, hyperglycemia, hypertension, gastritis, infection risk, growth suppression (especially with courses > 7 days, which do not improve outcomes). 8, 5, 1, 2, 9

Anti‑D Immunoglobulin (Rh‑Positive, Non‑Splenectomized)

• Dose: 50–75 µg/kg IV single dose.
• Response rate 50–77 %; ≥ 50 % respond within 24 h.

• Contraindicated in children with anemia from bleeding or evidence of autoimmune hemolysis. 5, 1, 6, 8

• Choice of Agent: IVIg is preferred when a rapid platelet rise is essential (e.g., before urgent procedures or severe mucosal bleeding); corticosteroids or anti‑D are acceptable alternatives when rapid rise is less critical; dexamethasone may achieve a faster response than prednisone. 1, 6, 8

Management of Life‑Threatening Hemorrhage

• Platelet transfusion 10–20 mL/kg (≈ 1 unit per 10 kg).
• IVIg 1 g/kg IV stat.
• Methylprednisolone 30 mg/kg IV daily (max 1 g) for 3 days.
• Tranexamic acid 10 mg/kg IV every 8 h.
• Immediate neurosurgical consultation if intracranial hemorrhage suspected. 2, 5, 6, 4

Second‑Line Therapies (Persistent/Chronic ITP)

• Rituximab: 375 mg/m² IV weekly × 4; B‑cell depletion; 30–60 % achieve sustained remission; response in 4–8 weeks; monitor immunoglobulin levels every 3–6 months. 1, 6, 8, 4
• High‑Dose Dexamethasone Regimens: 0.6 mg/kg/day for 4 days, repeated monthly for 4–6 cycles; response 50–70 %. 4
• Thrombopoietin‑Receptor Agonists:
  
  • Eltrombopag: start 25 mg daily (East Asian) or 50 mg daily (others); titrate by 25 mg q 2 weeks to maintain platelets 50–200 × 10⁹/L; monitor liver function; response 70–80 %.
  • Romiplostim: start 1 µg/kg SC weekly; titrate by 1 µg/kg weekly to target platelets 50–200 × 10⁹/L; response 70–80 %. 9, 4
• Splenectomy: Reserved for chronic ITP refractory to medical therapy after ≥ 12 months; remission in 70–80 % of cases; pre‑operative vaccination (PCV13, PPSV23, MenACWY, MenB, Hib) and lifelong penicillin prophylaxis required; OPSI risk 1–2 % lifetime. 1, 6, 8, 10, 4

Prognosis & Follow‑Up

• Spontaneous remission occurs in 67 % of children within 6 months; chronic disease persists in 20–30 %; overall mortality < 1 % (intracranial hemorrhage 0.1–0.5 %). 2, 3, 5
• Follow‑up schedule: newly diagnosed – weekly CBC initially, then every 2–4 weeks; persistent/chronic – CBC every 1–3 months; monitor bleeding symptoms, treatment side‑effects, quality of life, and immunoglobulin levels in chronic disease. 5, 4

Prevention (Secondary)

• No proven primary prevention.
• Secondary measures: avoid high‑risk contact sports when platelet count < 30 × 10⁹/L; avoid NSAIDs/aspirin; educate families on warning signs of serious bleeding (severe headache, altered mental status, persistent vomiting, severe abdominal pain, hematemesis, melena). 5, 3, 8
• Children with a history of ITP should receive MMR vaccination if unimmunized; benefits outweigh the small recurrence risk. 8

Thrombotic Thrombocytopenic Purpura (TTP) in Children

Pathophysiology

• TTP results from severe ADAMTS13 deficiency (< 10 % activity), causing accumulation of ultra‑large von Willebrand factor multimers that trigger widespread platelet microthrombi, leading to microangiopathic hemolytic anemia, thrombocytopenia, and end‑organ ischemia. 11

Epidemiology

• Global incidence is 2–6 cases per million person‑years; pediatric TTP is rare, with adult incidence markedly higher (incident rate ratio ≈ 31.6 per million). 1

Classification

• Immune‑mediated TTP (iTTP): > 95 % of acquired cases; caused by anti‑ADAMTS13 IgG antibodies; may be triggered by pregnancy, infection, autoimmune disease, or drugs. 11, 4
• Congenital TTP (cTTP): Autosomal recessive ADAMTS13 mutations (≈ 250 reported); presents in infancy/childhood or later with milder phenotype; requires lifelong prophylaxis. 11

Clinical Presentation & Laboratory Findings

• Typical presentation: severe thrombocytopenia (< 30 × 10⁹/L), microangiopathic hemolytic anemia (schistocytes on smear, LDH > 1000 U/L, indirect bilirubin ↑, haptoglobin ↓), neurological symptoms (headache, confusion, seizures, stroke), abdominal pain, renal involvement (hematuria, proteinuria, mild creatinine rise), and fever in some patients. 11, 4
• Expected laboratory abnormalities:
  
  • CBC – severe thrombocytopenia, anemia (Hb ≈ 7–10 g/dL).
  • Peripheral smear – schistocytes (> 1 % RBCs).
  • LDH – markedly elevated (> 10 × ULN).
  • ADAMTS13 activity – < 10 % (send before first plasma exchange).
  • Coagulation studies – generally normal (distinguishes from DIC).
  • Urinalysis – hematuria and proteinuria. 11, 4

Diagnostic Scoring (While Awaiting ADAMTS13)

• PLASMIC score (platelets < 30 × 10⁹/L, hemolysis, no active cancer, no transplant, MCV < 90 fL, INR < 1.5, creatinine < 2 mg/dL) – a score of 6–7 predicts > 90 % probability of ADAMTS13 < 10 %. 11, 3

Immediate Management (Start on Clinical Suspicion)

• Triple therapy (standard of care for iTTP):
• Caplacizumab (adjunct): 10 mg IV bolus before first TPE, then 10 mg SC daily during TPE and for 30 days after the last exchange; accelerates platelet recovery and reduces exacerbations but increases bleeding risk. 11, 6

Supportive Care

• Avoid platelet transfusions except for life‑threatening bleeding.
• Avoid antiplatelet agents (aspirin, NSAIDs) unless specifically indicated.
• RBC transfusion for symptomatic anemia (Hb < 7 g/dL or symptomatic).
• Folic acid 1 mg daily.
• Seizure management if needed; renal replacement therapy for severe AKI. 11, 5, 4

Alternative Regimen (Emerging)

• Caplacizumab + corticosteroids ± rituximab without TPE may be effective in selected patients with less severe disease, but evidence remains limited. 11

Monitoring & Definition of Remission

• Daily: platelet count, hemoglobin, LDH, neurological exam, renal function.
• Weekly (if on caplacizumab): ADAMTS13 activity.
• Remission: platelets > 150 × 10⁹/L for ≥ 2 consecutive days, normalized LDH, no new organ injury, and no TPE for ≥ 30 days.

Relapse Prevention (iTTP)

• Measure ADAMTS13 activity every 3 months during the first year, then every 6 months; if activity falls < 20 %, administer pre‑emptive rituximab (375 mg/m² weekly × 4) to reduce relapse risk.
• Counsel patients to avoid known triggers (infections, quinine, clopidogrel, ticlopidine). 4, 8

Management of Congenital TTP (cTTP)

• Prophylaxis: Recombinant ADAMTS13 (investigational) or fresh‑frozen plasma 10–15 mL/kg IV every 2–4 weeks.
• Acute episodes: FFP 10–20 mL/kg IV (no TPE required unless severe).
• Avoid triggers (infections, surgery, pregnancy) and increase prophylaxis during high‑risk periods. 4, 11

Prognosis & Long‑Term Outcomes

• With modern triple therapy, > 90 % achieve clinical remission; 30‑day mortality ≈ 3.7 %, 6‑month mortality ≈ 7.4 %.
• Relapse occurs in ~16 % of iTTP survivors.
• Neurocognitive deficits affect ~73 % of pediatric survivors, necessitating formal neuropsychological testing.
• Chronic kidney disease may develop from recurrent microvascular injury. 11

Follow‑Up Schedule

• First year post‑remission: ADAMTS13 activity every 3 months, neuropsychological assessment, renal and cardiac monitoring as indicated.
• After first year: ADAMTS13 every 6 months, annual neuropsychological testing in children, surveillance for relapse symptoms.

Prevention (Secondary)

• No proven primary prevention for iTTP.
• Secondary strategies: regular ADAMTS13 monitoring, pre‑emptive rituximab when activity declines, avoidance of infections and high‑risk medications, and multidisciplinary care during pregnancy (close ADAMTS13 surveillance, possible immunosuppression escalation). 4

Pediatric Immune Thrombocytopenia (ITP) and Thrombotic Thrombocytopenic Purpura (TTP): Evidence‑Based Guideline Summary

Pathophysiology

• ITP is an acquired immune‑mediated disorder in which auto‑antibodies target platelet surface glycoproteins, causing accelerated splenic platelet destruction and impaired megakaryocyte production. [@1]
• In TTP, severe ADAMTS13 deficiency (< 10 % activity) leads to accumulation of ultra‑large von Willebrand factor multimers, promoting widespread platelet adhesion, micro‑thrombi formation, and ischemic organ injury. [@3]

Epidemiology

• ITP most frequently presents in children aged 2–10 years. [@1]

Classification

• ITP duration categories:
  
  • Newly diagnosed – diagnosis to 3 months.
  • Persistent – 3–12 months.
  • Chronic – ≥ 12 months. [@1][@2]
• ITP etiology:
  
  • Primary ITP – isolated thrombocytopenia without identifiable cause. [@4]
  • Secondary ITP – associated with autoimmune disease, viral infection, Helicobacter pylori infection, drug exposure, common variable immunodeficiency, or autoimmune lymphoproliferative syndrome. [@4][@5][@1]
• TTP subtypes: immune‑mediated (iTTP) caused by anti‑ADAMTS13 antibodies, and congenital (cTTP) due to ADAMTS13 gene mutations. [@3]

Diagnosis

• ITP diagnosis is clinical, based on isolated thrombocytopenia with normal hemoglobin, white‑cell count, and a peripheral smear showing only reduced platelets. [@1]
• An elevated mean platelet volume supports ITP, reflecting increased young platelets. [@4]
• TTP work‑up requires CBC, reticulocyte count (elevated in hemolysis), indirect bilirubin (elevated), and low haptoglobin; ADAMTS13 activity < 10 % confirms the diagnosis, and detection of an ADAMTS13 inhibitor distinguishes iTTP from cTTP. [@5][@4][@1][@3]
• Treatment must not be delayed while awaiting ADAMTS13 results. [@3]

Management

ITP

• Children with no or only mild skin bleeding should be observed without therapy, irrespective of platelet count. [@4][@5][@8]
• Platelet count alone should not dictate treatment initiation. [@4]
• First‑line therapy for bleeding or high‑risk patients:
  
  • Intravenous immunoglobulin (IVIg) 0.8–1 g/kg as a single dose for rapid platelet rise. [@4][@5]
  • Short‑course corticosteroids (e.g., prednisone 2 mg/kg/day up to 60 mg for 5–7 days, then taper) when IVIg is unavailable or not preferred. [@4]
  • Dexamethasone 0.6 mg/kg/day (max 40 mg) for 4 days as an alternative high‑dose steroid regimen. [@8]
  • Corticosteroid side effects include mood changes, increased appetite, weight gain, hyperglycemia, hypertension, gastritis, and infection risk; monitor blood pressure and glucose during prolonged courses. [@1]
• Life‑threatening hemorrhage warrants platelet transfusion 10–20 mL/kg. [@1]

TTP

• Immediate initiation of therapeutic plasma exchange (TPE), corticosteroids, and rituximab is required on clinical suspicion; do not wait for ADAMTS13 results. [@3]
• TPE should start within 4–8 hours, exchanging 1.0–1.5 plasma volumes (≈ 40–60 mL/kg) per session with fresh‑frozen plasma or VWF‑reduced plasma; continue daily until platelets > 150 × 10⁹/L for ≥ 2 consecutive days and LDH normalizes. [@3]
• Corticosteroid regimen: prednisone 1 mg/kg/day (max 80–100 mg) or dexamethasone 40 mg IV daily for 4 days; taper over 4–6 weeks after remission. [@3][@8]
• Rituximab 375 mg/m² IV weekly for 4 weeks reduces relapse risk and shortens TPE duration. [@3]
• Caplacizumab (10 mg IV loading before first TPE, then 10 mg SC daily during TPE and for 30 days after the last exchange) accelerates platelet normalization but increases bleeding risk; use when available. [@3]
• Platelet transfusions are contraindicated except for life‑threatening bleeding. [@3]
• Avoid antiplatelet agents unless specifically indicated (e.g., acute coronary syndrome). [@4]
• Congenital TTP: recombinant ADAMTS13 is preferred for prophylaxis; if unavailable, give fresh‑frozen plasma 10–15 mL/kg every 2–4 weeks. [@3]

Second‑Line ITP

• Rituximab (375 mg/m² IV weekly × 4) is an option for persistent or chronic ITP with ongoing bleeding despite first‑line therapy. [@5][@8]
• High‑dose dexamethasone 0.6 mg/kg/day for 4 days, repeated monthly for 4–6 cycles, is an alternative second‑line regimen. [@5]
• Thrombopoietin‑receptor agonist romiplostim: start 1 µg/kg subcutaneously weekly, titrate to maintain platelets 50–200 × 10⁹/L. [@1]
• Splenectomy is reserved for chronic ITP (≥ 12 months) refractory to medical therapy; postpone at least 12 months, vaccinate against encapsulated organisms (PCV13, PPSV23, MenACWY, MenB, Hib) ≥ 2 weeks pre‑op, and provide lifelong penicillin prophylaxis post‑op. [@5][@1]

Prognosis & Follow‑Up

• Approximately 67 % of children with ITP achieve spontaneous remission within 6 months; chronic disease (≥ 12 months) occurs in 20–30 %. [@1][@7]
• Severe mucosal bleeding is a common ITP complication; prompt treatment reduces morbidity. [@1]
• In TTP, acute renal impairment (acute kidney injury) occurs in a subset of patients; monitor renal function during acute management. [@5]

Prevention

• No proven primary‑prevention strategies exist for ITP; focus on avoiding high‑risk activities when platelet count < 30 × 10⁹/L, avoiding antiplatelet drugs (e.g., NSAIDs, aspirin), and educating families on warning signs of serious bleeding. [@4][@7]
• For congenital TTP, prophylactic recombinant ADAMTS13 (or regular plasma infusions) and avoidance of known triggers (infections, certain medications) are recommended. [@3]