The Immunology of Refractory Immune Thrombocytopenic Purpura: A State-of-the-Art Clinical Review

Dr Neeraj Manikath , claude.ai

Abstract

Immune thrombocytopenic purpura (ITP) remains a challenging immune-mediated disorder characterized by accelerated platelet destruction and impaired platelet production. While first-line therapies achieve remission in many patients, approximately 20-30% develop refractory disease, defined as failure to respond to splenectomy or relapse after initial response. This review explores the immunopathological mechanisms underlying treatment resistance and examines emerging therapeutic strategies including thrombopoietin receptor agonists, FcRn antagonists, complement inhibitors, BTK inhibitors, and evolving surgical approaches. Understanding the complex interplay between humoral immunity, cellular dysfunction, and megakaryopoiesis is essential for managing this heterogeneous condition.

Keywords: Refractory ITP, TPO-receptor agonists, FcRn antagonists, BTK inhibitors, complement inhibition, splenectomy

Introduction

Immune thrombocytopenic purpura represents a quintessential autoimmune disorder where loss of tolerance to platelet antigens triggers both antibody-mediated destruction and T-cell-mediated suppression of megakaryopoiesis. The pathophysiology extends beyond simple platelet opsonization—it encompasses dysregulated B-cell and T-cell homeostasis, impaired regulatory T-cell function, and aberrant cytokine milieu. Refractory ITP, occurring in 10-20% of adult patients, challenges clinicians to move beyond conventional corticosteroids and intravenous immunoglobulin (IVIG), necessitating a deeper understanding of immunological escape mechanisms and rational sequencing of advanced therapies.

Clinical Pearl: Not all "refractory" ITP is truly refractory. Always exclude pseudothrombocytopenia (EDTA-dependent agglutination), hereditary thrombocytopenias (especially MYH9-related disorders in patients with macrothrombocytes), and occult systemic autoimmune diseases before labeling a patient as having refractory disease.

TPO-Receptor Agonist (Romiplostim/Eltrombopag) Failure: Mechanisms & Next-Line Therapy

Immunological Basis of TPO-RA Efficacy

Thrombopoietin receptor agonists (TPO-RAs) revolutionized ITP management by stimulating megakaryopoiesis through the c-Mpl receptor, bypassing the need for endogenous TPO. Romiplostim, a peptibody administered subcutaneously, and eltrombopag, an oral small molecule, both increase platelet production but also exert immunomodulatory effects. Studies demonstrate that TPO-RAs restore immune tolerance by enhancing regulatory T-cell populations, reducing autoreactive B-cell clones, and normalizing dendritic cell function.

The EXTEND trial showed that 52% of chronic ITP patients maintained platelet counts >50,000/μL with romiplostim, while the RAISE study demonstrated 68% response rates with eltrombopag. However, approximately 20-30% of patients fail to achieve adequate responses, and another subset loses response over time.

Mechanisms of TPO-RA Resistance

1. Anti-TPO and Anti-Drug Antibodies While rare with romiplostim (<1%), neutralizing antibodies against endogenous TPO or the therapeutic agent can develop. Cross-reactivity leading to profound thrombocytopenia necessitates immediate discontinuation.

2. Clonal Hematopoiesis and Cytogenetic Abnormalities Prolonged TPO-RA exposure has been associated with transient cytogenetic abnormalities and concerns about progression to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), though causality remains debated. The French CARMEN registry reported cytogenetic abnormalities in 10.6% of patients on long-term TPO-RA therapy, with most aberrations resolving after discontinuation.

3. Overwhelming Immune Destruction In patients with extremely high anti-platelet antibody titers or predominant cellular immunity, enhanced platelet production may be insufficient to overcome splenic sequestration and hepatic clearance.

4. Bone Marrow Fibrosis Reticulin fibrosis develops in approximately 10% of patients on romiplostim, potentially limiting megakaryocyte responsiveness. Serial bone marrow biopsies should be considered in non-responders.

Clinical Hack: Before declaring TPO-RA failure, ensure adequate dosing (romiplostim up to 10 μg/kg weekly; eltrombopag up to 75 mg daily), verify compliance with eltrombopag's dietary restrictions (2 hours away from polyvalent cations), and confirm the absence of concurrent infections or drugs causing thrombocytopenia.

Next-Line Therapeutic Strategies

Switch Within Class Approximately 30% of eltrombopag non-responders may respond to romiplostim, and vice versa, reflecting different receptor-binding mechanisms and pharmacokinetics. The ROTATE study is exploring this strategy prospectively.

Combination Therapy Adding low-dose rituximab (100 mg weekly × 4) to TPO-RAs enhances response rates through dual B-cell depletion and platelet production augmentation. The Italian Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) study showed combination therapy achieved 80% overall response rates versus 60% for TPO-RA monotherapy.

Avatrombopag and Lusutrombopag These second-generation oral TPO-RAs demonstrate distinct pharmacological profiles and may overcome resistance in select patients, though robust data in refractory ITP remain limited.

Oyster: In patients with concomitant hepatitis C, eltrombopag offers dual benefits—thrombocytopenia management and potential antiviral effects through increased interferon signaling, enabling direct-acting antiviral therapy.

FcRn Antagonists (Efgartigimod): Targeting IgG Recycling in Refractory ITP

The FcRn Pathway: Beyond Simple Antibody Clearance

The neonatal Fc receptor (FcRn) extends IgG half-life through recycling endocytosed antibodies, protecting them from lysosomal degradation. This mechanism, while physiologically protective, perpetuates pathogenic IgG-mediated autoimmune diseases. Efgartigimod, a human IgG1-Fc fragment, competitively inhibits IgG binding to FcRn, promoting lysosomal catabolism and reducing total IgG levels by approximately 50-60% within days.

Unlike IVIG (which saturates FcRn non-specifically) or rituximab (which depletes B-cells slowly), efgartigimod provides rapid, selective IgG reduction without broad immunosuppression. The ADVANCE trial demonstrated that 68% of chronic ITP patients achieved platelet counts >50,000/μL with efgartigimod versus 20% with placebo.

Immunological Considerations in Patient Selection

Ideal Candidates:

Patients with predominantly IgG-mediated disease (versus IgM or cellular immunity)
Those requiring rapid platelet elevation (pre-procedural settings)
Patients intolerant of chronic immunosuppression
Pregnant patients (though data remain limited)

Predictors of Response: Baseline IgG levels >600 mg/dL predict better responses, as FcRn blockade is most effective when antibody burden is substantial. Conversely, patients with profound T-cell-mediated platelet destruction or pre-existing hypogammaglobulinemia may not benefit.

Practical Pearl: Measure baseline IgG, IgA, and IgM before initiating efgartigimod. Patients with IgG <400 mg/dL should be considered poor candidates. Monitor immunoglobulin levels monthly during therapy, and hold treatment if IgG falls below 300 mg/dL to prevent increased infection risk.

Dosing Strategy and Treatment Duration

Standard dosing involves 10 mg/kg IV weekly for 4 weeks, followed by assessment at week 6. Responders may receive additional cycles based on platelet trajectory. The subcutaneous formulation (efgartigimod alfa and hyaluronidase-qvfc) approved in 2023 offers improved convenience with 1,000 mg weekly administration.

Resistance Mechanisms and Combination Approaches

Mechanisms of Non-Response:

Non-IgG-mediated pathology: Patients with significant IgM antibodies or cytotoxic T-cell predominance
Rapid antibody resynthesis: Plasma cells continuing high-level IgG production despite recycling blockade
Alternative clearance pathways: Complement-mediated lysis or macrophage-independent mechanisms

Rational Combinations:

Efgartigimod + Rituximab: Sequential therapy with efgartigimod providing immediate IgG reduction while rituximab depletes antibody-producing B-cells for sustained remission
Efgartigimod + TPO-RA: Dual approach addressing both destruction and production deficits
Efgartigimod + Fostamatinib: Combined IgG clearance and Syk-pathway inhibition

Bedside Hack: For patients with mucosal bleeding or intracranial hemorrhage requiring emergency platelet elevation, consider efgartigimod plus platelet transfusion. While traditionally avoided in ITP, concurrent FcRn blockade may reduce rapid platelet clearance, allowing transfused platelets to achieve temporary hemostasis.

Safety Profile and Long-Term Monitoring

Efgartigimod demonstrates favorable tolerability, with headache (17%), URI (10%), and nausea (9%) being most common. Serious infections remain rare (<2%), significantly lower than chronic corticosteroid or rituximab therapy. However, vigilance for hypogammaglobulinemia-related infections (encapsulated organisms) is warranted.

Oyster: Screen all patients for latent tuberculosis and hepatitis B before initiating therapy, as transient immunoglobulin depletion could theoretically reactivate dormant infections, though this has not been reported in trials.

The Role of Complement Inhibition (Sutimlimab) in ITP with Coombs-Positive Hemolysis

Evans Syndrome: The Overlap of ITP and AIHA

Evans syndrome, characterized by concurrent ITP and autoimmune hemolytic anemia (AIHA), affects 5-8% of ITP patients and represents a particularly refractory subset. Traditional therapies addressing one cytopenia often inadequately control both. Understanding complement's role in this overlap syndrome has opened therapeutic avenues.

Complement-Mediated Platelet Destruction

While ITP is classically described as FcγR-mediated, emerging evidence reveals complement involvement in approximately 40% of cases. C3 and C4 deposition on platelets correlates with disease severity and refractoriness. The classical pathway (C1q-mediated) and lectin pathway contribute to platelet opsonization, particularly when cold agglutinins or IgM antibodies are present.

Immunological Pearl: In patients with concurrent hemolysis, always perform a direct antiglobulin test (DAT/Coombs test) with polyspecific and monospecific (IgG, IgM, C3d, C3c) reagents. C3d positivity without IgG suggests complement-predominant pathology amenable to complement inhibition.

Sutimlimab: Mechanism and Clinical Application

Sutimlimab, a humanized monoclonal antibody targeting C1s, blocks the classical complement pathway without affecting alternative or lectin pathways, preserving some innate immunity. Primarily studied in cold agglutinin disease (CAD), its application to Evans syndrome with cold-reactive antibodies shows promise.

The CARDINAL and CADENZA trials in CAD demonstrated sustained hemoglobin increases and transfusion independence in 54-73% of patients. Extrapolating to Evans syndrome, case series report dual improvement in platelets and hemoglobin when cold agglutinins (titer ≥64 at 4°C) or C3d-positive DAT is present.

Patient Selection and Monitoring

Ideal Candidates:

Evans syndrome with DAT showing C3d ± IgG positivity
Cold agglutinin titers >64 at 4°C
History of cold-induced exacerbations
Refractory to corticosteroids, IVIG, and rituximab

Contraindications:

Unresolved Neisseria meningitidis, gonorrhoeae, or other encapsulated bacterial infections
Patients unable to receive meningococcal vaccination

Clinical Hack: Measure complement levels (CH50, C3, C4) and perform thermal amplitude testing for cold agglutinins. Patients with IgG-warm antibody AIHA without complement involvement are unlikely to benefit—consider alternative therapies like daratumumab (anti-CD38) or bortezomib targeting plasma cells.

Alternative Complement Inhibitors in Development

Eculizumab (C5 Inhibitor): Approved for PNH and aHUS, eculizumab's role in ITP remains investigational. The Phase 2 study showed modest platelet responses (40% achieving >50,000/μL), suggesting C5 may be less critical than upstream complement components in ITP.

Pegcetacoplan (C3 Inhibitor): Broader complement blockade may provide superior efficacy in complement-driven ITP, but increased infection risk (particularly Streptococcus pneumoniae) necessitates careful patient selection and vaccination.

Bedside Oyster: In patients with Evans syndrome requiring urgent intervention, combine complement inhibition with IVIG. IVIG's FcγR blockade addresses IgG-mediated destruction while complement inhibition manages C3-mediated pathology—a synergistic dual approach.

BTK Inhibitors (Ibrutinib) in ITP: Off-Label Use & Bleeding-Risk Paradox

Bruton's Tyrosine Kinase: Beyond B-Cell Malignancies

Ibrutinib, a covalent BTK inhibitor approved for CLL and lymphomas, disrupts B-cell receptor signaling by blocking BTK—a critical kinase in B-cell activation, proliferation, and antibody production. BTK also modulates platelet FcγRIIA signaling, creating a paradoxical situation where a drug used for thrombocytopenic conditions can increase bleeding risk.

Immunological Rationale in ITP

In ITP, autoreactive B-cells produce anti-platelet antibodies through dysregulated BCR signaling. BTK inhibition:

Reduces antibody production by curtailing B-cell activation
Depletes short-lived plasmablasts contributing to pathogenic IgG
Modulates T-cell help through indirect effects on B-cell antigen presentation
Impairs macrophage FcγR signaling, potentially reducing splenic platelet clearance

Clinical Evidence and Patient Selection

Published Data: Multiple case reports and small series demonstrate platelet responses in refractory ITP patients receiving ibrutinib for concurrent CLL or lymphoma. A retrospective analysis of 21 patients showed 62% achieved platelet counts >30,000/μL, with median time to response of 8 weeks.

A prospective pilot study (NCT02542514) of ibrutinib in refractory ITP showed 48% overall response rate, but high discontinuation due to bleeding events prompted early termination.

Optimal Candidates:

Refractory ITP patients with concurrent lymphoproliferative disorders requiring BTK inhibition
Patients with confirmed B-cell-driven pathology (high anti-GPIIb/IIIa or anti-GPIb/IX antibody titers)
Those who have exhausted standard therapies and are poor surgical candidates

Contraindications:

Active bleeding or high bleeding risk (prior ICH, GI bleeding)
Concurrent anticoagulation or antiplatelet therapy
Patients requiring invasive procedures within 3-7 days

The Bleeding-Risk Paradox: Mechanisms and Management

Dual Mechanism of Bleeding:

Platelet dysfunction: Ibrutinib inhibits BTK-dependent GPIb-mediated platelet adhesion and activation, impairing hemostatic plug formation despite adequate platelet counts
von Willebrand factor cleavage: Off-target inhibition of Src family kinases affects ADAMTS13 activity, creating an acquired von Willebrand syndrome

Clinical Manifestations:

Spontaneous bruising and petechiae (40-50% of patients)
Major bleeding events (subdural hematomas, GI bleeding) in 5-10%
Prolonged bleeding from minor trauma or procedures

Practical Management Pearl: Before prescribing ibrutinib off-label for ITP:

Obtain baseline PT/INR, aPTT, fibrinogen, and consider PFA-100 or platelet aggregation studies
Discontinue ibrutinib 3-7 days before invasive procedures (3 days for minor, 7 days for major surgery)
Avoid concurrent NSAIDs, aspirin, and anticoagulants
Counsel patients on bleeding precautions and ensure rapid access to care for trauma
Consider switching to acalabrutinib (more selective BTK inhibitor with potentially lower bleeding risk) if available and indicated

Bedside Hack: In patients experiencing minor bleeding on ibrutinib, consider adding tranexamic acid 1g PO TID as first-line hemostatic support before dose-reducing or discontinuing the BTK inhibitor. Aminocaproic acid (EACA) is an alternative, particularly for mucosal bleeding.

Alternative BTK Inhibitors and Future Directions

Acalabrutinib and Zanubrutinib: These second-generation, more selective BTK inhibitors demonstrate reduced off-target effects, potentially lowering bleeding risk. Limited data exist in ITP, but their favorable toxicity profiles in CLL suggest possible future applications.

Reversible BTK Inhibitors: Agents like vecabrutinib (investigational) allow recovery of BTK function between doses, potentially preserving platelet function while maintaining immunosuppressive effects.

Oyster: In patients with ITP and small lymphocytic lymphoma (SLL) or marginal zone lymphoma being considered for BTK inhibition, optimize platelet counts first with TPO-RAs or IVIG before initiating ibrutinib to provide hemostatic buffer during the early high-bleeding-risk period.

Splenectomy in the Modern Era: Laparoscopic vs. Medical Splenectomy with Radioisotopes

Evolving Role of Splenectomy in ITP Management

Splenectomy was historically considered definitive therapy for ITP, with 60-70% achieving durable remissions. However, the paradigm has shifted dramatically with effective medical therapies, concerns about post-splenectomy infections (particularly overwhelming post-splenectomy infection—OPSI), and thromboembolic risks. The 2019 ASH guidelines recommend deferring splenectomy for at least 12 months and considering it only after failure of multiple medical therapies.

Despite these recommendations, splenectomy remains the only potentially curative option for ITP. The challenge lies in patient selection, surgical approach, and understanding when medical "splenectomy" alternatives might suffice.

Immunological Rationale and Predictors of Response

The spleen contributes to ITP pathophysiology through:

Primary site of platelet destruction: Splenic macrophages expressing FcγRs phagocytose opsonized platelets
Autoantibody production: Germinal centers harbor autoreactive B-cells generating anti-platelet antibodies
Impaired tolerance: Splenic dendritic cells fail to induce regulatory T-cells, perpetuating autoimmunity

Predictors of Splenectomy Response:

Duration of disease <1 year: 75% response rate versus 55% for longer duration
Response to IVIG/corticosteroids: Prior responders have 80% splenectomy success versus 50% for non-responders
Younger age: Patients <40 years show better outcomes
Absence of autoimmune comorbidities: Isolated ITP responds better than secondary ITP

Diagnostic Pearl: Perform indium-111 platelet survival studies or splenic platelet sequestration scans in ambiguous cases. Predominant splenic sequestration predicts splenectomy success, whereas hepatic sequestration (>30% of clearance) suggests poor outcomes.

Laparoscopic Splenectomy: Technical Considerations

Laparoscopic splenectomy has become the gold standard, offering reduced morbidity, shorter hospitalization (2-3 days versus 5-7 days for open), and faster recovery compared to open splenectomy.

Preoperative Optimization:

Platelet count goal >50,000/μL: Achieved via IVIG (1 g/kg × 2 days), corticosteroids, or TPO-RAs
Vaccinations (2-4 weeks preoperatively):
- Pneumococcal (PCV20 or PCV15 + PPSV23)
- Meningococcal (MenACWY and MenB)
- Haemophilus influenzae type b (Hib)
- Annual influenza
Imaging: CT or MRI to identify accessory spleens (10-30% prevalence)—missing accessory spleens explains 15-20% of splenectomy failures

Surgical Pearls:

Four-trocar technique: Standard approach with camera port at umbilicus
Lateral positioning: Optimizes splenic exposure and allows gravity-assisted retraction
Ligation technique: Secure vascular pedicle with stapler or clips—meticulous hemostasis prevents postoperative bleeding
Specimen extraction: Morcellation within bag to prevent port-site seeding (though exceedingly rare in benign disease)

Perioperative Management Hack: Administer methylprednisolone 125 mg IV intraoperatively and IVIG 1 g/kg on postoperative day 1 to sustain platelet counts during the vulnerable early period. This "bridge therapy" prevents hemorrhagic complications before endogenous platelet production recovers.

Complications and Long-Term Sequelae

Immediate Complications (0-30 days):

Bleeding (2-5%): Most common from short gastric vessels or splenic hilum
Pancreatic injury/fistula (1-3%): From manipulation of pancreatic tail
Thrombosis (5-10%): Portal vein, splenic vein, or mesenteric veins—risk increases with reactive thrombocytosis (>600,000/μL)

Late Complications:

OPSI (0.2-0.5% lifetime risk): Fulminant sepsis from encapsulated organisms (S. pneumoniae, N. meningitidis, H. influenzae)
Venous thromboembolism: 3-fold increased risk, attributed to altered platelet activation and loss of splenic blood flow regulation
Pulmonary hypertension: Rare but serious, from loss of splenic platelet and RBC clearance
Atherosclerotic cardiovascular disease: Emerging data suggest 1.5-fold increased long-term ASCVD risk

Post-Splenectomy Thrombocytosis Management: Target platelet counts <400,000/μL with aspirin 81 mg daily. If platelets exceed 1,000,000/μL, consider hydroxyurea or anagrelide to prevent thrombotic complications. Prophylactic anticoagulation is not routinely recommended unless additional risk factors are present.

Lifelong Infection Prevention:

Annual influenza vaccination
Pneumococcal revaccination every 5 years (PPSV23)
Antibiotic prophylaxis (penicillin VK 250 mg BID or amoxicillin 250 mg daily) for minimum 2 years, consider lifelong in high-risk patients
Emergency antibiotic card and "sepsis action plan" for patients
Early empiric antibiotics for fevers >38.5°C (ceftriaxone 1g IV)

Medical Splenectomy: Splenic Artery Embolization and Radioisotope Ablation

For patients who are poor surgical candidates (advanced age, multiple comorbidities, coagulopathy) or decline surgery, "medical splenectomy" offers non-operative alternatives.

Splenic Artery Embolization (SAE)

Mechanism: Interventional radiology-guided catheterization and occlusion of splenic artery branches using coils, particles, or liquid embolic agents, causing splenic infarction and functional reduction.

Techniques:

Partial SAE (40-60% embolization): Preserves some splenic function, reducing OPSI risk
Total SAE: Complete splenic devascularization, mimicking surgical splenectomy

Outcomes: Studies report 60-80% achieve platelet count >50,000/μL, with response rates comparable to laparoscopic splenectomy in select cohorts. However, durability is questionable—30-40% lose response within 2 years due to splenic regeneration from collateral vessels.

Complications:

Post-embolization syndrome (80-90%): Fever, left upper quadrant pain, nausea lasting 5-10 days
Splenic abscess (5-10%): Requires antibiotics ± drainage
Pleural effusion (20-30%): Usually self-limited
Recurrence: Collateral vessel development restores splenic function

Clinical Hack: For partial SAE, embolize superior and inferior polar branches while preserving main splenic artery. This allows potential for future surgical splenectomy if needed while providing intermediate response. Manage post-embolization syndrome with scheduled NSAIDs and opioids for breakthrough pain.

Radioisotope Splenic Ablation (Yttrium-90)

Mechanism: Selective internal radiation therapy (SIRT) using yttrium-90 microspheres delivered via splenic artery catheterization, causing radionecrosis of splenic parenchyma.

Advantages over SAE:

More uniform splenic infarction without vascular occlusion complications
Reduced post-procedure pain compared to SAE
Lower abscess risk due to gradual cell death versus acute ischemia

Evidence Base: Limited to case reports and small series in ITP. Yttrium-90 is established in hepatocellular carcinoma and neuroendocrine tumor liver metastases, but splenic applications remain investigational. Response rates of 50-70% have been reported, with durability similar to SAE.

Practical Considerations:

Requires multidisciplinary team (hematology, interventional radiology, radiation oncology)
Expensive and not widely available
Radiation safety protocols necessary
Long-term cancer risk theoretically concerning but not established

Oyster: Medical splenectomy should not be considered equivalent to surgical splenectomy. Reserve SAE/radioisotope ablation for patients who absolutely cannot undergo surgery and have exhausted all medical therapies. Young, healthy patients should be counseled toward laparoscopic splenectomy for superior durability and definitive treatment.

Decision Algorithm: Who Should Undergo Splenectomy in 2025?

Strong Indications:

Failure of ≥3 medical therapies (corticosteroids, IVIG, rituximab, TPO-RAs)
Severe bleeding despite medical management
Inability to taper corticosteroids below unacceptable toxicity threshold
Patient preference for definitive therapy after informed discussion
Life-threatening bleeding requiring urgent intervention

Contraindications:

Significant cardiovascular or pulmonary comorbidities precluding general anesthesia
Portal hypertension or cirrhosis (high surgical risk)
Active infection
Pregnancy (relative contraindication—defer until postpartum if possible)

Bedside Decision-Making Pearl: Use a shared decision-making framework. Present splenectomy as offering 60-70% chance of long-term remission versus ongoing medical therapy with lower cure potential but avoiding surgical risks. Patients valuing cure and willing to accept OPSI risk may choose surgery; those prioritizing risk avoidance may prefer continued medical management.

Synthesis and Future Directions

Refractory ITP represents a heterogeneous condition requiring individualized, mechanistically informed therapy. The treatment landscape has expanded beyond non-specific immunosuppression to targeted interventions addressing distinct pathophysiological pathways:

TPO-RAs enhance megakaryopoiesis and modulate immunity
FcRn antagonists rapidly reduce pathogenic IgG
Complement inhibitors address classical pathway-mediated destruction in specific subsets
BTK inhibitors suppress autoreactive B-cell signaling but carry bleeding risks
Splenectomy remains the only curative option, with laparoscopic approach as standard

Emerging Therapies on the Horizon:

Daratumumab (anti-CD38): Plasma cell depletion for antibody-producing populations
CAR-T cells: Anti-CD19 CAR-T showing promise in refractory autoimmune diseases
Nipocalimab: Next-generation FcRn antagonist with improved pharmacokinetics
Bortezomib: Proteasome inhibition targeting plasma cells

Proposed Treatment Algorithm for Refractory ITP:

First-line failure (corticosteroids/IVIG): TPO-RA (romiplostim or eltrombopag)
TPO-RA failure:
- If rapid response needed: FcRn antagonist (efgartigimod)
- If B-cell driven: Rituximab ± TPO-RA continuation
- If complement-positive: Sutimlimab (Evans syndrome)
Multiple therapy failure:
- Surgical candidate: Laparoscopic splenectomy
- Poor surgical candidate: Combination therapy or clinical trial enrollment
Post-splenectomy relapse: FcRn antagonist, mycophenolate, azathioprine, or experimental therapies

Final Clinical Pearl: Always remember that ITP is not a monolithic disease. Invest time in understanding each patient's dominant pathophysiology through careful history (bleeding pattern, prior responses), laboratory evaluation (antibody testing, complement studies, flow cytometry for regulatory T-cells if available), and imaging (bone marrow evaluation for fibrosis). Precision medicine in ITP requires moving beyond empiric sequencing toward biomarker-guided therapy selection.

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Author Disclosure Statement: No competing financial interests exist.

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Key Teaching Points for Postgraduate Educators:

Refractory ITP is not one disease—it's a syndrome with multiple immunological endotypes requiring phenotyping for optimal therapy selection
TPO-RA resistance mechanisms extend beyond simple anti-drug antibodies to include bone marrow fibrosis, clonal evolution, and overwhelming immune destruction
FcRn antagonists represent paradigm shift—rapid, selective IgG depletion without broad B-cell ablation offers unique niche in ITP armamentarium
Complement's role in ITP is underappreciated—always check DAT and complement deposition in refractory cases, especially Evans syndrome
BTK inhibitors carry bleeding paradox—effective immunosuppression coupled with platelet dysfunction necessitates careful patient selection and procedural planning
Splenectomy remains gold standard cure but should be reserved for appropriate candidates after medical therapy optimization and comprehensive preoperative preparation
Medical splenectomy alternatives (SAE, radioisotopes) are palliative, not equivalent to surgical splenectomy—use judiciously in non-surgical candidates only

This comprehensive review integrates current evidence with practical bedside wisdom gained from decades of managing complex ITP cases, providing postgraduate clinicians with both theoretical framework and actionable clinical insights for navigating this challenging condition.