Immune thrombocytopenia (ITP)

Definition and epidemiology

• Definition: isolated thrombocytopenia (platelet count <100K) due to immune-mediated platelet destruction and impaired production. Diagnosis of exclusion.
• Epidemiology: prevalence ~9.5 to 23.6 per 100,000 persons (adult incidence ~3 per 100,000/year). Twice as common in females when young; F = M in patients >65 y and in children. Bimodal age distribution.
• Phases: newly diagnosed (<3 months, most common in children, usually self-limited, often post-infectious antibody cross-reactivity), persistent (3 to 12 months), chronic (>12 months). Persistent and chronic are the most common patterns in adults. Relapsing ITP (episodes separated by off-therapy remission) is the second-most common adult pattern.
• Severity: severe ITP = bleeding requiring treatment; refractory ITP = fails ≥2 lines including splenectomy. Can be primary or secondary.
• Historical pearl: Harrington (1950) infused blood from an ITP patient into himself and became thrombocytopenic with seizure, recovering by day 5; healthy volunteers reproduced the effect, establishing a circulating platelet-destroying (antibody) factor.

Pathogenesis

• Antibody-mediated platelet destruction: IgG autoantibodies against GPIIb/IIIa (same target as in Glanzmann) → Fc-mediated clearance by splenic macrophages.
• Impaired megakaryopoiesis: anti-GPIb-V-IX antibodies on megakaryocytes impair platelet production.
• T-cell dysregulation: Treg deficiency, Th17 expansion.

Clinical features

• Mucocutaneous bleeding: petechiae, purpura, epistaxis, gingival bleeding, menorrhagia, hematuria, melena. Severe: GI bleed, hemoptysis, intracranial hemorrhage (rare, <1%).
• Bleeding risk correlates with platelet count but is variable. Significant spontaneous bleeding usually plt <20K; intracranial bleeding usually <10K plus risk factors.
• No splenomegaly typically. If splenomegaly is present, consider alternative diagnoses (lymphoma, MDS, MPN).

Diagnostic workup

• CBC + smear: isolated thrombocytopenia with normal RBC and WBC morphology (may have anemia if bleeding). MCV may be elevated (reticulocytosis or other cause). Rule out pseudothrombocytopenia (EDTA-induced clumping, repeat in citrate).
• Peripheral smear: verify low count, exclude schistocytes (TMA), blasts (leukemia/MDS), atypical lymphocytes.
• Workup for secondary ITP: test HCV and HIV in ALL patients; H. pylori: test in patients from high-prevalence (endemic) regions regardless of GI symptoms; not routine in low-prevalence settings; hepatitis B (before rituximab); CMP, ANA, IgG/IgA/IgM levels (CVID can mimic), TSH.
• Bone marrow biopsy: not routine. Indicated for atypical features, additional cytopenias, splenomegaly, abnormal smear, refractory disease, or non-response (age alone is not an indication; consider in older adults only to exclude MDS).
• Anti-platelet antibody testing: NOT routinely recommended (low sensitivity cannot exclude ITP; GP-specific direct assays are highly specific but insensitive).
• ITP is paradoxically associated with thrombosis (see ITP and VTE).

Differential diagnosis (rule out)

• Decreased production: liver disease (↓ thrombopoietin), infection (HCV, HIV; H. pylori is bacterial and causes secondary ITP via increased destruction), marrow damage/replacement (drugs, alcohol, thiazides), congenital defects, ineffective production (B12/folate deficiency).
• Increased destruction, non-immune/mechanical: DIC, TTP, HELLP.
• Increased destruction, immune: ITP, HIT, SLE.
• Splenic sequestration (hypersplenism, eg, cirrhosis with portal hypertension): contributes less than previously believed; in liver disease, reduced hepatic thrombopoietin synthesis is a major additional mechanism.
• Pseudothrombocytopenia (EDTA artifact): repeat in citrate; clumps on smear; no clinical significance.
• DIC: ↓ plt + ↓ fibrinogen + ↑ PT/INR + ↑ aPTT + ↑ D-dimer + ↑ LDH + MAHA (sepsis, malignancy, trauma).
• TTP: thrombocytopenia + MAHA + neuro, plus/minus renal, plus/minus fever; ADAMTS13 <10%; plasma exchange emergency.
• HIT: type II, plt fall 5 to 14 d post-heparin, paradoxical thrombosis; stop heparin, start argatroban; 4Ts + anti-PF4/heparin.
• Drug-induced: heparin, vancomycin, linezolid, sulfa, quinine; recovers after discontinuation.
• Infections: HIV, HCV, CMV; treat infection, platelets recover.
• Lymphoproliferative malignancy / MDS / hypersplenism / MAHA: as above; marrow biopsy or underlying-disease treatment.

Treatment: when to treat

• Goal: achieve normal hemostasis, NOT a normal platelet count.
• Treat if: plt <30K, clinically significant (more than minor mucocutaneous) bleeding, or pre-procedural need; minor bleeding with adequate counts can be observed. Consider comorbidities, anticoagulant/antiplatelet use, procedures, and age.
• Plt 30 to 100K without bleeding: observation is reasonable (especially chronic stable ITP).
• Children: observe regardless of platelet count if no or minor bleeding.
• Pre-procedural targets: ≥50K most procedures; ≥80 to 100K for neuraxial anesthesia (≥70K acceptable in obstetrics), ophthalmologic, neurosurgery.
• Do NOT treat with steroids longer than 6 weeks.

First-line therapy

• Corticosteroids: prednisone 0.5 to 2.0 mg/kg/day, or dexamethasone 40 mg/day × 4 days. Children: 2 to 4 mg/kg/day divided BID for 5 to 7 days. Time to response 3 to 4 days. Meta-analysis (Mithoowani, Lancet Haematol 2016): prednisone equals high-dose dexamethasone for OR/CR at 6 months, but dexamethasone gives a faster rise (response 79% vs 59% at 14 days) with fewer reported toxicities than prednisone.
• IVIG: 0.8 to 1.0 g/kg IV × 1 dose (up to 2 g/kg max). Time to response 24 to 48 h (preferred with acute bleeding). Works by Fc interaction between platelets and macrophages (temporary reduction in destruction). Black box warning: thrombosis, renal failure; also infusion reaction, aseptic meningitis.
• Anti-D immunoglobulin (WinRho): for Rh-positive, non-splenectomized patients. In the spleen, antibody competes between antibody-coated RBCs and antibody-coated platelets → hemolysis spares platelets (not useful post-splenectomy). Dose 50 to 75 mcg/kg IV × 1; time to response 24 to 48 h. Black box warning: fatal intravascular hemolysis (expect a mean Hgb drop of ~1 to 2 g/dL; label mean maximum 1.7 g/dL at 50 mcg/kg). Contraindicated if Rh-negative, post-splenectomy, or AIHA.

Second-line therapy (persistent / chronic)

• TPO receptor agonists (TPO-RAs): increase platelet production via MPL receptor on megakaryocytes (JAK/STAT), prevent megakaryocyte apoptosis, mobilize stem cells. Goal plt >50K; overall platelet response ~60 to 90% (durable off-drug response much lower). Most lose response after stopping (transient rebound thrombocytopenia possible), but ~10 to 30% achieve sustained treatment-free remission; no cross-resistance reported; some sustained remissions (immune tolerance). Adverse effects: thromboembolic events, hepatotoxicity; marrow reticulin (EXTEND: moderate-to-marked fibrosis in only 2 of 117, no progressive-fibrosis signal). Dose titration by platelet response:
  • Romiplostim (Nplate): SC, start 1 mcg/kg weekly; if plt <50K increase by 1 mcg/kg/week; if >200 to ≤400K for 2 consecutive weeks decrease by 1 mcg/kg/week; if >400K hold then reduce.
  • Eltrombopag (Promacta): oral 50 mg daily (25 mg if East/Southeast-Asian ancestry or hepatic impairment); titrate by 25 mg; ~10% reversible hepatotoxicity. Empty-stomach, avoid cations.
  • Avatrombopag (Doptelet): oral 20 mg daily, taken with food; no cation restriction.
  • Lusutrombopag and avatrombopag: short pre-procedural course in chronic liver disease to raise platelets (ADAPT-1/2, L-PLUS 1/2); no excess VTE, unlike eltrombopag (ELEVATE stopped early for portal vein thrombosis).
• Rituximab (Rituxan): anti-CD20; 375 mg/m² IV weekly × 4. ORR 50 to 70% (remission induction); long-term remission ~30% at 1 year, ~20% at 5 years. Adverse effects in ~41%: serum sickness, hypersensitivity, infection, hypogammaglobulinemia. No surgery and no chronic daily drug, but only a minority (~20% at 5 y) have durable remission; trade-off vs TPO-RA and splenectomy.
• Splenectomy: removes the site of destruction; response in 7 to 10 days, ORR ~90%, long-term remission ~60 to 70%. Vaccinate against encapsulated organisms (pneumococcus, Hib (single adult dose), meningococcus (MenACWY booster q5y, MenB per schedule)); lifelong fever precautions and antibiotic prophylaxis; perioperative thrombotic risk. Delay at least 1 year (spontaneous resolution possible); increasingly late-line in the modern era.

Sequencing (persistent and chronic)

• Adults: shared decision; ASH 2019 conditionally suggests TPO-RA over rituximab and rituximab over splenectomy. At 3 to 12 months use TPO-RA (preferred) or rituximab; at >12 months use TPO-RA (preferred), rituximab, or splenectomy weighing: rituximab (no chronic drug/surgery but durable remission in only ~20% at 5 y), TPO-RA (durable while on daily drug), splenectomy (durable, no daily drug, but surgery + vaccination).
• Children: TPO-RA first, then rituximab, then splenectomy.

Third-line / refractory agents

• Rilzabrutinib (Wayrilz): reversible covalent BTK inhibitor; FDA Aug 2025 for chronic/persistent ITP after ≥1 prior therapy (adults only). LUNA 3 (Kuter, Blood 2025): durable platelet response 23% vs 0% placebo; median time to first response ~15 d. Oral, well tolerated, no myelosuppression; positions between TPO-RA and rituximab.
• Fostamatinib (Tavalisse): Syk inhibitor, subsequent-line (not first-line) indicated for chronic ITP with insufficient response to prior therapy (Syk drives macrophage Fc-mediated phagocytosis), FDA approved 2018; 100 mg BID increasing to 150 mg BID. Phase 3 OR 43% vs 14% placebo; ~78% in second-line use (better if less refractory); durable response ~18%. Key adverse effect: diarrhea (limits use), plus HTN, N/V, dizziness, transaminitis (manage with dose reduction/interruption).
• Efgartigimod (Vyvgart): neonatal Fc receptor (FcRn) blocker → reduces IgG recycling and lowers pathogenic IgG. NOT FDA-approved for ITP (approved for ITP in Japan only; US ADVANCE NEXT results expected 2027); ADVANCE IV: ~22% vs 5% sustained plt >50K, ORR ~50% vs ~20%.
• Combinations: TPO-RA plus immunosuppressive (eltrombopag + rituximab or + dexamethasone).

Acute severe bleeding

• Combine modalities: IVIG 1 g/kg + IV methylprednisolone 1 g/day × 3 days + platelet transfusion + TXA; target plt >50K to stop bleeding; add anti-D if Rh-positive and non-splenectomized.
• Recombinant factor VIIa is NOT recommended for ITP bleeding (unproven efficacy, thrombosis risk); prioritize IV corticosteroids + IVIG + platelet transfusion + TXA.
• Emergency splenectomy for refractory life-threatening bleeding (very rare).

Thrombocytopenia in pregnancy

• ITP therapy in pregnancy: first-line corticosteroids, IVIG, or combination. Refractory: anti-D (WinRho), splenectomy (rare, best in 2nd trimester), azathioprine, high-dose methylprednisolone + IVIG. Therapy to the mother does not affect the fetal platelet count.
• Generally avoided in pregnancy (limited data): vinca alkaloids, danazol, cyclophosphamide/mycophenolate (teratogenic). Rituximab and TPO-RAs are not absolute contraindications: rituximab for very severe refractory disease (neonatal B-cell depletion risk), selected TPO-RAs as late-pregnancy rescue after other therapies fail. Azathioprine and cyclosporine are compatible.
• Delivery: mode by obstetric indication. Epidural/neuraxial: reasonable at platelets ≥70K (SOAP 2021; hematoma risk very low); 50 to 70K individualized.

Neonatal thrombocytopenia: autoimmune vs alloimmune

• Neonatal autoimmune (transplacental maternal ITP IgG): can occur even if the mother is in remission; no correlation between maternal and neonatal counts; nadir at ~3 to 4 days of age (may be undetectable at birth); most recover by day 7 but can persist weeks. Treat clinical bleeding with IVIG 1 g/kg × 1 to 2 doses.
• Neonatal alloimmune thrombocytopenia (NAIT): different mechanism, maternal antibody to fetal HPA-1a (or other) inherited from father; severe thrombocytopenia possible even in a first pregnancy; risk of intracranial hemorrhage. Treat with HPA-matched (antigen-negative) platelets and IVIG.

ITP and VTE

• Patients with ITP have a ~2-fold increased risk of VTE, from traditional risk factors plus ITP-related factors (splenectomy, TPO-RA use).
• Management: aggressive ITP control plus anticoagulation. The CARMEN (French) study showed minor bleeding risk with aspirin; an aspirin threshold of ~30 to 50K platelets is used.

Special situations

• H. pylori-associated ITP: eradication can resolve thrombocytopenia (~30 to 50% in endemic areas).
• HIV-associated ITP: ART often resolves it; IVIG/steroids if active bleeding.
• HCV-associated ITP: treat HCV (DAAs) to raise platelets.
• Evans syndrome = AIHA + ITP; treat both (steroids + rituximab; consider mycophenolate).

High yield

• Diagnosis of exclusion: isolated thrombocytopenia; test HCV and HIV in all; bone marrow biopsy NOT routine.
• Treat if plt <30K, bleeding, or pre-procedural; goal is hemostasis, not a normal count.
• Dexamethasone 40 mg × 4 d gives faster response than prednisone; IVIG for rapid rise.
• Anti-D (WinRho): only for Rh-positive, non-splenectomized; causes hemolysis; contraindicated if Rh-negative, post-splenectomy, or AIHA.
• TPO-RAs: preferred 2nd line for chronic ITP; most relapse off drug (~10 to 30% treatment-free remission); avatrombopag is taken with food and has no cation restriction.
• Rituximab: durable response in ~30% at 1 year.
• Fostamatinib (Syk) and efgartigimod (FcRn; ITP approval in Japan only, not US) and rilzabrutinib (BTK, Aug 2025) are newer oral/biologic options.
• Splenectomy: ORR ~90%, durable ~60 to 70%; delay ≥1 year; vaccinate first.
• Azathioprine and cyclosporine are the third-line agents compatible with pregnancy.
• Avoid platelet transfusion in TTP; acceptable in ITP for severe bleeding.
• Pregnancy ITP: IVIG/steroids; TPO-RAs and rituximab generally avoided (refractory rescue only).
• Neonatal: autoimmune (maternal ITP, no count correlation) vs alloimmune NAIT (HPA-1a, can be severe in first pregnancy).
• ITP raises VTE risk ~2-fold; aspirin threshold ~30 to 50K.