Idiopathic Thrombocytopenic Purpura (ITP)

Definition & Pathophysiology

• Incidence: ~100 persons per million annually; 50% are children
• The term "idiopathic" reflects that no specific underlying cause is identified in primary ITP

Classification

• Bimodal age distribution: 1-5 years and >60 years
• Adult form is more common in females; childhood form is equally distributed between sexes
• Associated conditions in adults: SLE, CLL, Hodgkin's disease

Clinical Features

• Mucocutaneous bleeding: petechiae (pinpoint skin hemorrhages), ecchymoses (purpuric patches) on skin and mucous membranes
• Spontaneous bleeding from mucous membranes - epistaxis is common
• Menorrhagia in women; prolonged bleeding from minor wounds
• Positive tourniquet test
• Spleen: palpable in < 10% of patients - gross splenic enlargement should raise suspicion for an alternative diagnosis
• Hemorrhage from urinary/GI tract and hemarthrosis are rare
• Intracranial hemorrhage: uncommon, but the most frequent cause of death

Bleeding Risk by Platelet Count

Investigations

• Platelet count: reduced, usually < 60 × 10⁹/L; diagnosis of exclusion
• Peripheral blood smear: isolated thrombocytopenia, normal red cell and white cell morphology (no schistocytes - this distinguishes from TTP)
• Coagulation studies (PT, aPTT): normal - this is key
• Bleeding time: not helpful for diagnosis
• Bone marrow aspiration: plentiful megakaryocytes (normal to increased), confirming peripheral destruction rather than underproduction
• Antiplatelet antibody testing: not routinely recommended due to low sensitivity/specificity

Differential Diagnosis

• In vitro platelet clumping (EDTA-dependent agglutinins)
• Giant platelets miscounted as WBCs

• Pregnancy (gestational thrombocytopenia, preeclampsia, HELLP)
• Drug-induced (heparin, quinidine, sulfonamides, GPIIb/IIIa inhibitors, linezolid, vancomycin)
• Viral infections: HIV, HCV, EBV
• Helicobacter pylori infection
• Hypersplenism (chronic liver disease)
• Alcohol, vitamin B12/folate/copper deficiency
• Rheumatologic disorders (SLE, RA)

• Myelodysplastic syndrome
• Congenital thrombocytopenias
• Thrombotic thrombocytopenic purpura (TTP) / HUS
• Chronic disseminated intravascular coagulation (DIC)
• Lymphoproliferative disorders (CLL, NHL)

Treatment

Observation (No Treatment)

• Asymptomatic patients with platelet count > 30,000/mm³ may be observed
• Platelet counts > 50,000/mm³ are rarely associated with clinical problems, even with invasive procedures
• Children with acute ITP: >70-80% achieve spontaneous complete remission regardless of therapy

First-Line: Corticosteroids

• Prednisone 0.5-2 mg/kg/day OR dexamethasone 50 mg/day for 4 days
• Response (platelets > 50,000/mm³) seen in up to two-thirds of patients within 1-3 weeks
• ~50-75% of patients are responders; complete response in ~25%
• Steroid therapy should not be prolonged

First-Line (Acute/Severe): Intravenous Immunoglobulin (IVIG)

• Indications: acute bleeding, preparation for surgery/splenectomy, pregnancy, platelet count < 20,000/mm³
• Raises platelet count within 3 days
• Also increases efficacy of platelet transfusions

Second-Line Therapies

TPO Receptor Agonists (Katzung Pharmacology):

• Romiplostim (Nplate) - subcutaneous injection; approved for chronic ITP failing steroids, IVIG, or splenectomy
• Eltrombopag (Promacta) - oral; also approved for thrombocytopenia in hepatitis C
• Avatrombopag (Doptelet) - oral; also used for thrombocytopenia in chronic liver disease before procedures

Fostamatinib:

• Oral tyrosine kinase (SYK) inhibitor; decreases signaling through Fc and B cell receptors, reducing antibody-mediated platelet destruction
• A 2024 meta-analysis confirmed efficacy in refractory ITP [PMID: 38856778]

Splenectomy

1. Life-threatening bleeding
2. Patient's desire to avoid long-term therapies and cost
3. Failure of medical therapies (after waiting 12-24 months)

• Response rate: ~80% immediate improvement; durable long-term remission in ~60-66%
• Platelet count improvement expected within 10 days postoperatively
• Good prognosis markers: platelets ≥ 150,000/mm³ by postop day 3 or ≥ 500,000/mm³ by postop day 10
• Preferred approach: laparoscopic splenectomy (minimally invasive, fewer complications)
• Must search for accessory spleen (at hilum, pancreatic tail, gastrosplenic/splenorenal ligaments, omentum, mesentery) - a missed accessory spleen is a leading cause of treatment failure
• In children: splenectomy is controversial; avoided when possible due to high spontaneous remission rates
• In pregnant women (2nd trimester) failing steroids and IVIG with platelets < 10,000 (no symptoms) or < 30,000 (with bleeding): splenectomy is the treatment of choice

• Target platelet count 30-50 × 10⁹/L before surgery (use medical therapy, not platelet transfusions, to achieve this)
• Vaccinate against Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type B before splenectomy (ideally 2 weeks prior)

• Short-term: subphrenic infection, pleural effusion, febrile illness
• Long-term: Overwhelming post-splenectomy infection (OPSI) - mainly S. pneumoniae, N. meningitidis, H. influenzae; sepsis rate 2%, mortality 1%
• Thrombosis: 3-4x increased risk of venous and arterial thrombosis post-splenectomy; LMWH recommended perioperatively

Summary Algorithm

ITP Diagnosed
     |
Platelet > 30,000, asymptomatic → Observe
     |
Platelet < 30,000 OR symptomatic
     ↓
1st Line: Corticosteroids ± IVIG (if acute bleeding)
     |
Refractory / Dependent / > 12 months
     ↓
2nd Line: Rituximab or TPO-RAs (eltrombopag, romiplostim)
     |              OR
     ↓
Splenectomy (if chronic > 12-24 months, failed medical therapy)

Recent Evidence (2024-2025)

• A 2025 network meta-analysis (PMID: 40196346) comparing TPO receptor agonists in adults confirms their efficacy and safety; comparative effectiveness data now informs individualized selection.
• A 2025 pediatric systematic review (PMID: 40547032) comparing rhTPO, romiplostim, and eltrombopag in children found all three effective, supporting medical management over splenectomy in this group.
• A 2024 meta-analysis of fostamatinib (PMID: 38856778) confirmed efficacy and safety for refractory ITP, supporting its use as a third-line option.