Immune thrombocytopenia: Evolving mechanistic understanding and clinical development of new therapies

ABSTRACT

Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by isolated thrombocytopenia resulting from increased platelet destruction, impaired platelet production, or both. Once viewed primarily as a benign, antibody-mediated condition, ITP is now recognized as a heterogeneous immune dysregulation syndrome involving autoreactive lymphocytes, innate immune activation, complement engagement, and megakaryocytic dysfunction. Although corticosteroids, intravenous immunoglobulin, anti-D immunoglobulin, rituximab, splenectomy, and thrombopoietin receptor agonists have constituted the therapeutic foundation for decades, these approaches remain limited by transient responses, toxicity, and insufficient disease modification. Advances in immunopathology have catalyzed the development of targeted therapeutics designed to interrupt discrete mechanisms underlying platelet destruction or impaired thrombopoiesis. Bruton tyrosine kinase (BTK) inhibitors (rilzabrutinib and orelabrutinib) modulate B-cell activation and macrophage effector pathways; spleen tyrosine kinase inhibitors (fostamatinib) block Fcγ receptor-mediated phagocytosis, neonatal Fc receptor inhibitors (efgartigimod and rozanolixizumab) accelerate IgG catabolism and rapidly reduce pathogenic autoantibody burden; and complement inhibition (sutimlimab) provides a rational strategy for patients in whom classical pathway activation contributes to refractory disease. Collectively, these agents represent the most significant expansion of the ITP treatment landscape in decades, offering steroid-sparing options and enabling more durable, individualized disease control. As ITP management transitions toward mechanism-based, biomarker-informed approaches, understanding the immunologic underpinnings of emerging therapies will be essential for optimizing treatment sequencing, improving long-term outcomes, and advancing personalized care for patients with this complex autoimmune disorder.

INTRODUCTION

Immune thrombocytopenia (ITP) is an acquired autoimmune disorder diagnosed by isolated thrombocytopenia and exclusion from other identifiable causes, and caused by increased platelet destruction, impaired platelet production, or a combination of both [1,2]. The pathogenesis is multifactorial, engaging various elements of the immune system and leading to peripheral platelet destruction as well as impaired megakaryopoiesis, ultimately diminishing platelet production in the bone marrow [1]. Although historically classified as a benign hematologic condition, ITP is now recognized as a heterogeneous immune dysregulation syndrome with variable clinical trajectories, ranging from transient, self-limited thrombocytopenia to chronic, treatment-refractory disease requiring long-term therapy [3]. The estimated annual incidence in adults is approximately 2–4/100,000 persons, with a slight female predominance and increasing prevalence in older populations [4]. Despite generally favorable overall survival, ITP imposes a substantial burden through bleeding episodes, treatment-related complications, impaired quality of life, and the psychological stress of unpredictable disease activity [5].

Local data regarding the epidemiology and clinical characteristics of ITP remain insufficient in Taiwan, and only a limited number of reports have been published. Population-based studies from Taiwan provide valuable real-world insights into the epidemiology and clinical characteristics of ITP. Using the National Health Insurance Research Database, Hung et al. identified 4,855 incident ITP cases between 2006 and 2013 and reported age-specific incidence rates of 4.0, 2.0, and 5.4 per 100,000 person-years in individuals aged <15, 15–59, and ≥60 years, respectively. A male predominance was observed in children, whereas adult patients showed a female predominance [6]. Consistent findings were reported by Wu et al., who observed an overall ITP incidence of 2.59 per 100,000 person-years and demonstrated strong associations between ITP and hepatitis B, hepatitis C, Helicobacter pylori infection, tuberculosis, and thyroid disorders [7]. Overall, Taiwanese data suggest comparable ITP incidence to Western populations but distinct geographic patterns in secondary causes and treatment-related complications.

For decades, treatment options were largely limited to corticosteroids, intravenous immunoglobulin (IVIG), anti-D immunoglobulin, rituximab, splenectomy, and thrombopoietin receptor agonists (TPO-RAs). A summary of the currently available therapeutic options is provided in Table 1. We also provide a summary of pathophysiology and currently available therapeutic options for ITP in Figure 1. Although effective for many patients, these therapies continue to encounter substantial limitations and unmet clinical needs [27]. In this context, an expanding array of mechanistically rational therapies has emerged, designed to target discrete immunologic components of ITP pathogenesis. These include neonatal Fc receptor (FcRn) inhibitors that accelerate pathogenic IgG clearance [28], spleen tyrosine kinase (Syk) inhibitors that block Fcγ receptor-mediated macrophage phagocytosis [29], BTK inhibitors that suppress B-cell activation and macrophage signaling [30], and complement inhibitors that disrupt classical or terminal pathway activation [31]. Collectively, these therapies represent the most significant expansion in ITP treatment options in decades. As ITP management enters a new era driven by biomarker-guided and mechanism-based strategies, understanding the scientific foundation of novel therapies will be essential for optimizing patient outcomes.

Table 1.

Summary of the currently available therapeutic options for immune thrombocytopenia

Drugs/Treatment	FDA approval	Mechanism of action	Route	Key clinical phase study	Suggested dose	Response rate	Common side effects	Reference
Corticosteroids	Traditional therapy	Suppresses immune responses and reduces antiplatelet antibody production	IV, oral	Multiple clinical studies	Prednisone (0.5–2.0 mg/kg daily) or Dexamethasone (40 mg daily for 4 days)	Initial response 70%–80%; long-term sustained response <20%–30%	Weight gain, hyperglycemia, mood changes, infection risk	[8,9,10]
IVIG	-	Blocks Fc receptors and reduces platelet destruction	IV	Phase III	1–2 g/kg given as one bolus dose or over 4 to 5 days	Rapid response 60%–80% (short duration)	Headache, renal impairment, hemolysis	[11,12]
Anti-D (Rho[D] immune globulin)	1995	Clears Rh⁺ RBCs to reduce splenic platelet phagocytosis	IV	Multiple clinical studies	50 µg/kg as a single injection	60%–70% (Rh⁺, nonsplenectomized patients only)	Hemolysis, renal failure	[13,14]
Rituximab	Off-label	B-cell depletion → decreases autoantibody production	IV	Phase II–III	375 mg/m2, or 100 mg/m2 weekly for 4 weeks	Initial response 40%–60%; sustained response 20%–25% at 1–2 years	Fever, infection, hypogammaglobulinemia	[15,16,17,18]
Splenectomy	-	Removes the primary site of platelet destruction	Surgery	Multiple clinical studies	-	Long-term response ~60%–70%	Infection risk, thrombosis, lifelong vaccination requirement	[19,20]
TPO-RAs
Eltrombopag	2008	Oral TPO-RA → enhances megakaryocyte and platelet production	Oral	RAISE (Phase III)/EXTEND (Phase 2/3)	25–75 mg once daily	60%–70% respond	Liver dysfunction, thrombosis, hypertension	[21,22,23]
Romiplostim	2008	TPO receptor agonist → increases platelet production	SC	Phase III	1–10 µg/kg weekly	Durable response ~40%–50%	Bone marrow fibrosis, thrombosis risk	[24,25]
Avatrombopag	2019	Oral TPO-RA; not affected by food or iron	Oral	Phase III	20–40 mg once daily	~65% response rate	Headache, fatigue, thrombosis	[26]

IVIG: Intravenous immunoglobulin, FDA: Food and Drug Administration, IV: Intravenous, RBCs: Red blood cells, TPO-RAs: Thrombopoietin receptor agonists, SC: Subcutaneous

Figure 1.

Pathophysiology and targeted therapies for immune thrombocytopenia

CURRENT GUIDELINES AND UNMET NEEDS

Corticosteroids remain the recommended first-line treatment for newly diagnosed adult ITP, with the American Society of Hematology (ASH) favoring a short course of prednisone (≤6 weeks) or dexamethasone pulses [32]. While steroids yield initial responses in 70%–80% of patients, only 20%–30% achieve sustained remission [33]. Prolonged steroid exposure is strongly discouraged due to well-documented toxicities, including weight gain, mood alteration, metabolic complications, infection risk, and profound quality-of-life impairment [34]. IVIG is recommended for patients with active bleeding or requiring a rapid platelet increase. However, its short duration of effect, high cost, logistic burden, and global shortages limit its use [35]. Anti-D immune globulin is infrequently used because of safety concerns and is currently not available in Taiwan. Despite guideline recommendations, corticosteroids yield high initial response rates but poor long-term remission and substantial toxicity [8]. IVIG provides rapid but transient platelet increases and is resource-intensive [35]. Real-world practice shows that many patients are exposed to excessive or prolonged steroid courses, driven by limited access to second-line therapies or delayed referral to hematology. This highlights a critical unmet need: effective steroid-sparing strategies that induce early remission without compromising safety.

Guidelines provide several preferred second-line options but lack a specific sequencing strategy due to limited comparative trials [32]. Commonly recommended therapies include: rituximab, splenectomy, and TPO-RAs. Rituximab is recommended as a second-line option, particularly for patients seeking treatment-free remission. The initial overall platelet response rate is approximately 40%–60%, with sustained responses of 20%–25% at 1–2 years. Clinical responses typically begin 4–8 weeks after treatment; however, relapse is common, most often occurring within 12–24 months [36]. Yet its efficacy appears lower in contemporary cohorts than in early trials, and concerns remain about long-term immunosuppression, hypogammaglobulinemia, and infection risk [16].

While historically curative, splenectomy is now less favored and generally delayed until at least 12 months postdiagnosis [33]. This hesitancy stems from risks of severe infection, thrombosis, and unclear long-term advantages over modern drugs [32]. However, it remains an important option for selected patients [37].

The advent of TPO-RAs represented a significant paradigm shift, introducing a targeted approach to stimulate platelet production and enabling durable responses in patients who had long been considered refractory to conventional therapies [38]. TPO-RAs are strongly endorsed due to high response rates, sustained platelet increases, and favorable safety profiles. They are now the most commonly used second-line therapy in many countries [39]. However, TPO-RAs are not universally effective and do not directly address immune dysregulation. Guidelines also note uncertainty about their disease-modifying potential and the optimal timing for tapering or discontinuation. Most patients require prolonged therapy, and platelet counts typically decline after discontinuation. Safety concerns include an increased risk of thromboembolic events as well as hepatotoxicity, most notably with eltrombopag. Long-term therapy may induce reversible bone marrow reticulin fibrosis, necessitating periodic monitoring [40]. Practical limitations include the potential for significant platelet count fluctuations requiring frequent dose adjustments and the high financial cost associated with chronic treatment.

Conventional immunosuppressive agents, including azathioprine, mycophenolate mofetil (MMF), and cyclosporine, have long been used as second- or third-line therapies for ITP, particularly in patients with relapsed or steroid-refractory disease. Despite the emergence of TPO-RA, these immunosuppressants remain clinically relevant, especially in regions where access to newer agents is limited or cost-prohibitive.

Taiwanese real-world data provide important insights into the effectiveness of azathioprine. Chang et al. conducted a single-institution retrospective study [41]. Among patients who relapsed or were refractory to steroids, azathioprine was the most frequently used second-line therapy, administered to nearly half of patients, with an overall response rate of 71.4%. These outcomes were comparable to those observed with splenectomy and support the continued use of azathioprine as an effective and accessible treatment option in Taiwan. Beyond Taiwan, a recent large retrospective study from Canada evaluated azathioprine with relapsed or refractory ITP, including individuals previously treated with TPO-RAs or splenectomy [42]. The overall response rate was 47.8%, with a sustained response rate exceeding 75% at 6 months among responders.

MMF is an immunosuppressive agent that inhibits inosine monophosphate dehydrogenase, leading to suppression of T-and B-lymphocyte proliferation. Several retrospective studies and small prospective series have demonstrated that MMF can achieve platelet responses in approximately 40%–70% of patients with chronic or refractory ITP, with a median time to response of 4–8 weeks [43,44]. In a study published by Bradbury et al., the addition of MMF to glucocorticoid therapy as first-line treatment for ITP resulted in a higher response rate (91.5%), although it was associated with a modest decrease in quality of life [45].

Cyclosporine is a calcineurin inhibitor that suppresses T-cell activation by blocking interleukin-2 transcription and downstream immune signaling. Several small prospective studies and retrospective series have reported platelet response rates of approximately 50%–70% in patients with chronic or refractory ITP, with responses typically observed within 4-8 weeks of treatment [46,47]. However, cyclosporine use is limited by its safety profile, requiring close monitoring for nephrotoxicity, hypertension, infections, and metabolic adverse effects. Overall, conventional immunosuppressive agents remain the useful alternative agents for ITP when newer targeted therapies are unavailable, contraindicated, or ineffective.

The modern management of ITP has evolved substantially over the past decade, guided by updated professional society recommendations and the introduction of multiple targeted therapies. Current international guidelines – including those from the ASH [32], the International Consensus Report [48], and the Japanese ITP management guidelines [49] – provide evidence-based frameworks for diagnosis and treatment. Despite their utility, these guidelines were developed before the widespread clinical availability of many emerging agents, resulting in a gap between rapidly advancing therapeutic science and formal recommendations. Moreover, none of these therapies directly addresses the complex mechanistic heterogeneity of ITP, leading to highly variable treatment responses and a persistent population of patients with chronic refractory disease. Current guidelines lack mechanistic biomarkers or disease endotypes, forcing clinicians to select therapies empirically.

Beyond platelet count endpoints, health-related quality of life (HRQoL) and cumulative treatment burden are increasingly recognized as critical outcomes in ITP management [50]. Repeated or prolonged corticosteroid exposure remains a major driver of impaired HRQoL due to well-documented physical, metabolic, neuropsychiatric, and sleep-related adverse effects, as well as increased infection risk [51]. Many patients report that steroid-related toxicity and relapse anxiety outweigh bleeding symptoms as determinants of daily functioning and treatment dissatisfaction. In this context, the emergence of targeted, steroid-sparing therapies offers an important opportunity to shift ITP management toward sustained disease control with fewer systemic effects [51]. Oral small-molecule agents and infrequently administered biologics may reduce the need for recurrent rescue therapy, hospital visits, and dose cycling, thereby lowering overall treatment burden and improving adherence [52]. Rapid-acting agents that provide predictable platelet responses can also alleviate uncertainty around procedures, work, and travel, which are common patient-reported stressors. As such, incorporation of HRQoL metrics, patient-reported outcomes, and steroid exposure-free response as complementary endpoints in future trials will be essential to fully capture the real-world value of novel ITP therapies.

Furthermore, they exclude emerging therapeutic classes – such as FcRn inhibitors, Syk inhibitors, complement inhibitors, and BTK inhibitors – that are now entering clinical practice or late-stage clinical development.

NEW PERSPECTIVES ON THE PATHOPHYSIOLOGY OF IMMUNE THROMBOCYTOPENIA

ITP is a heterogeneous autoimmune disorder. Historically, ITP was considered primarily an antibody-mediated disease driven by antiplatelet IgG and Fcγ receptor-dependent clearance [53]. However, advances in immunology and platelet biology have revealed a far more intricate network of immune dysregulation involving humoral, cellular, innate, and stromal components. Contemporary models emphasize that ITP arises from a combination of loss of immune tolerance, aberrant effector immune responses, disrupted megakaryopoiesis, and complement-driven amplification, ultimately producing a nonredundant and self-perpetuating cascade of thrombocytopenia [54]. The new perspectives included:

1. Autoantibody-mediated platelet destruction: Autoreactive B cells produce IgG autoantibodies against platelet glycoproteins, leading to opsonization and Fcγ receptor–mediated clearance by splenic macrophages and, secondarily, hepatic Kupffer cells. Immune complexes amplify phagocytosis and local inflammation, whereas antibody specificity may shape disease severity; for instance, anti-GPIb/IX antibodies are often linked to complement activation and treatment resistance [55,56].

2. Impaired thrombopoiesis: Although platelet destruction is central to ITP, impaired platelet production is now recognized as equally important. Antiplatelet antibodies and cytotoxic T cells can directly damage megakaryocytes. Inflammatory cytokines disrupt the marrow niche, suppress megakaryocyte maturation, and blunt TPO responsiveness [57].

3. T-cell dysregulation: T-cell abnormalities form a core component of ITP pathogenesis. Patients exhibit a shift toward Th1-and Th17-predominant immunity, characterized by increased IFN-γ and IL-17 secretion. Regulatory T cells (Tregs) are numerically reduced and functionally impaired, diminishing peripheral tolerance and enabling sustained autoreactivity [58].

4. Innate immune activation and complement pathways: Growing evidence indicates that innate immune mechanisms – particularly complement activation – significantly amplify platelet destruction in ITP. Platelets in severe or refractory cases often exhibit C3b or C4d deposition, promoting clearance through complement receptors on macrophages and neutrophils. Complement fragments further create a proinflammatory milieu that enhances vascular permeability and phagocytic activity. In some patients, complement activation synergizes with autoantibodies to accelerate platelet loss, helping explain treatment resistance and supporting the rationale for complement-targeted therapies [59].

5. FcRn-mediated IgG recycling and autoantibody persistence: The FcRn regulates IgG homeostasis by preventing lysosomal degradation and prolonging IgG survival. In ITP, this pathway preserves pathogenic antiplatelet antibodies, allowing sustained opsonization and platelet clearance. FcRn blockade accelerates IgG catabolism, rapidly reducing autoantibody levels and limiting antibody-mediated destruction, making FcRn inhibitors a targeted approach to a core driver of chronic autoimmunity in ITP [60].

6. Intracellular signaling pathways in phagocytosis and autoimmunity: Advances in molecular immunology have identified critical intracellular signaling pathways that govern phagocytosis and autoreactive B-cell activation, including Syk, which is essential for Fcγ receptor-mediated phagocytosis, and bruton’s tyrosine kinase (BTK) supports B-cell receptor (BCR) signaling, promoting survival and proliferation of autoreactive B cells [61].

Below, I will introduce the new therapeutic agents for ITP that have entered clinical use or are currently being evaluated in clinical trials. The summary is shown in Table 2. We also provide a summary of pathophysiology and new therapeutic agents for ITP in Figure 1.

Table 2.

New therapeutic agents for immune thrombocytopenia

Drugs/treatment	FDA approval	Mechanism of Action	Route	Key clinical phase study	Suggested dose	Response rate	Common side effects	Reference
BTK inhibition (BTK inhibitors)
Rilzabrutinib	2025	Reversible covalent BTK inhibitor Inhibits B-cell and Fc receptor signaling → reduces platelet destruction	Oral	Phase 3 (LUNA 3)	400 mg twice daily	Any platelet response ~60%–70%; durable response ~20%–30%	Gastrointestinal discomfort, headache	[62,63,64,65]
Orelabrutinib	Not yet approved	Irreversible highly selective BTK inhibitor	Oral	Phase 2	30–50 mg once daily	Response rates 36.4%	Infections, fatigue, diarrhea, nausea, skin rashes, and liver enzyme changes	[66]
Syk inhibitors
Fostamatinib	2018	Syk inhibitor → blocks macrophage-mediated platelet clearance	Oral	Phase 3 (FIT1 and FIT2)	100–150 mg twice daily	Overall platelet response was 43%; Median time to response was 15 days	Diarrhea, hypertension, and elevations in liver enzymes	[67,68,69,70]
Neonatal Fc receptor blockade or antagonist (FcRn Inhibitors)
Efgartigimod	Not yet approved	Reduces IgG levels and decreases antiplatelet antibodies	IV	Phase 3 (ADVANCE IV trial)	5–10 mg/kg/dose weekly for 4 weeks	51% achieved platelet counts ≥50×109/L; Median time to response was 8–10 days	Headache, hematuria, and petechiae	[28,71]
Rozanolixizumab	Not yet approved	Humanized monoclonal antibody designed to bind and inhibit FcRn	SC	Phase 3	Single doses (15–20 mg/kg)	Increases to ≥50 k/µL were seen by Day 8 in over 45%	Headache, pyrexia and nausea	[72]
Complement blockade
Sutimlimab	Not yet approved	Selectively inhibits C1s, a key protease in the classical complement pathway	IV	Phase 1/2	Biweekly doses (6.5 g if <75 kg, 7.5 g if ≥75 kg)	42% of participants achieved durable platelet responses	Headache and mild infusion reactions	[59]

BTK: Bruton tyrosine kinase, Syk: Spleen tyrosine kinase, FcRn: Neonatal Fc receptor, IV: Intravenous, SC: Subcutaneous, FDA: Food and Drug Administration

BRUTON TYROSINE KINASE INHIBITION

BTK is a central signaling molecule in the B-cell receptor (BCR) pathway and a key mediator of Fcγ receptor–dependent macrophage activation [73]. In ITP, BTK contributes simultaneously to the upstream production of pathogenic autoantibodies and to the downstream phagocytic clearance of antibody-opsonized platelets [61]. These dual biological roles make BTK inhibition an attractive therapeutic strategy, as it can modulate both autoreactive B-cell activity and macrophage-mediated platelet destruction.

BTK plays a central role in immune processes, driving ITP pathogenesis. In B cells, BTK amplifies BCR signaling, promoting autoreactive B-cell expansion, plasma-cell differentiation, and class switching to IgG1 and IgG3, thereby sustaining the production of autoantibodies against platelet glycoproteins such as GPIIb/IIIa, GPIb/IX, and GPVI [74]. In macrophages, BTK acts downstream of Fcγ receptor engagement by IgG-opsonized platelets, facilitating phagocytosis, immune-complex processing, and cytokine production, including TNF-α and IL-6. These functions position BTK as a key mediator of effector-phase platelet destruction in addition to its role in humoral autoimmunity [75].

Rilzabrutinib: The first Bruton’s tyrosine kinase inhibitor designed for autoimmune use

Rilzabrutinib is a reversible covalent BTK inhibitor specifically designed to modulate immune activity while avoiding the bleeding and cardiac toxicities commonly observed with irreversible BTK inhibitors used in oncology [76]. Its mechanism of action involves noncovalent yet durable binding to BTK, enabling potent and sustained inhibition without prolonged off-target kinase suppression. Through this mechanism, rilzabrutinib effectively suppresses autoreactive B-cell signaling and attenuates Fcγ receptor-mediated macrophage phagocytosis, leading to a rapid rise in platelet counts. Notably, unlike irreversible agents such as ibrutinib or acalabrutinib, rilzabrutinib does not impair platelet function in vitro, a key advantage for patients with thrombocytopenia [63].

Rilzabrutinib has shown promising results across multiple phase studies for ITP, with a successful Phase 3 LUNA 3 trial leading to its FDA approval for ITP in August 2025. This trial evaluated oral rilzabrutinib in previously treated adults with persistent or chronic ITP. 64% of the patients receiving rilzabrutinib achieved a platelet response during the first 12 weeks and were eligible to continue treatment [64,65].

Most treatment-emergent adverse events were mild and included headache, gastrointestinal discomfort, and fatigue. Notably, no atrial fibrillation, major cardiac events, or significant bleeding complications were reported, and infection rates remained low without meaningful laboratory abnormalities. BTK inhibitors represent an important addition to the therapeutic landscape of ITP. Rilzabrutinib – the most clinically advanced agent – has demonstrated rapid, durable responses with an excellent safety profile, even in heavily pretreated patients.

Orelabrutinib: Second-generation Bruton’s tyrosine kinase inhibitor

Orelabrutinib is an irreversible, highly selective BTK inhibitor with reduced off-target kinase binding. Early-phase studies in ITP suggest good tolerability and promising platelet responses, with response rates of approximately 36.4% in patients who were refractory to, relapsed after, or intolerant of first-line therapies, including glucocorticoids or IVIG. However, additional data are needed to confirm its efficacy and safety [66].

SPLEEN TYROSINE KINASE INHIBITORS

Syk is a central signaling molecule in Fcγ receptor-mediated phagocytosis, serving as a critical downstream effector in macrophage-driven platelet clearance [77]. In ITP, platelet-bound IgG autoantibodies engage Fcγ receptors on splenic, hepatic, and bone marrow macrophages, triggering Syk activation and subsequent engulfment of opsonized platelets [78]. This pathway plays a central role in many patients with chronic or refractory ITP, making Syk inhibition an attractive therapeutic strategy that directly targets antibody-mediated destruction without requiring B-cell depletion or broad immunosuppression. Following Fcγ receptor engagement, Syk activation drives critical downstream processes, including actin cytoskeleton remodeling that enables phagocytosis, inflammatory cytokine release, augmentation of immune complex processing, and amplification of autoimmune signaling pathways [79]. In ITP, autoreactive IgG bound to platelet glycoproteins forms immune complexes that are rapidly cleared by Syk-dependent phagocytic activity. Blocking Syk disrupts this signaling cascade and reduces platelet destruction, regardless of the specific autoantibody involved. Unlike therapies targeting IgG production by rituximab or IgG recycling by FcRn inhibitors, Syk inhibition acts at the effector phase of the autoimmune reaction, making it particularly helpful in patients with antibody-mediated phagocytic clearance [78].

Fostamatinib: The first FDA-approved spleen tyrosine kinase inhibitor for immune thrombocytopenia

Fostamatinib is an oral prodrug rapidly converted to the active metabolite R406, a potent ATP-competitive inhibitor of Syk. It was approved by the U.S. FDA in 2018 for adult chronic ITP, based on robust safety and efficacy data from multiple clinical studies [67]. Fostamatinib inhibits Syk phosphorylation and downstream recruitment of signaling molecules necessary for phagocytosis. This prevents macrophage-mediated internalization of IgG-opsonized platelets and reduces circulating inflammatory mediators. Unlike steroids or IVIG, which act through broad immunomodulation, fostamatinib selectively impairs the final common pathway of antibody-mediated platelet clearance [67].

The pivotal Phase III trials FIT1 and FIT2 enrolled adults with chronic, heavily pretreated ITP (median 3 prior therapies, many of whom failed TPO-RAs and rituximab) [67]. Stable platelet response with more than 50 × 10⁹/L could reach 18%, and the overall platelet response was 43%. Median time to response was 15 days, with some responses seen as early as 7 days, and bleeding events were substantially reduced, especially mucosal bleeding. Long-term studies demonstrated durable responses, with maintained platelet counts for 1–2 years and no evidence of cumulative toxicity [68]. The most common adverse events included diarrhea, hypertension, and elevations in liver enzymes. No increased risk of malignancy or immunosuppressive complications has been observed.

These results highlight that fostamatinib is particularly effective in the difficult-to-treat population that has failed multiple prior therapies, including TPO-RAs and immunosuppressive regimens. Next-generation Syk inhibitors may offer further improvements in potency and tolerability. As evidence accumulates, Syk inhibition will likely become an integral component of individualized, mechanism-driven ITP management.

NEONATAL FC RECEPTOR BLOCKADE OR ANTAGONIST

FcRn has emerged as a central therapeutic target in ITP, driven by its key role in regulating IgG homeostasis and the persistence of pathogenic autoantibodies [80]. FcRn is responsible for the recycling and prolonged half-life of IgG by binding IgG molecules in acidic endosomes and returning them to the circulation rather than allowing degradation. FcRn inhibitors represent one of the most promising and rapidly advancing therapeutic classes in ITP, offering a mechanism-based strategy to reduce IgG-mediated platelet destruction without broad immunosuppression [81]. In ITP, the majority of pathogenic autoantibodies that target platelet glycoproteins (GPIIb/IIIa, GPIb/IX, GPVI) are IgG class, meaning that FcRn activity directly contributes to the maintenance of the autoimmune process. Unlike rituximab, FcRn inhibitors do not deplete B cells or plasma cells; instead, they modulate the circulating autoantibody burden with minimal effect on IgM or cellular immunity [82]. This makes FcRn blockade an attractive option for patients who require rapid IgG reduction or who are at high risk for complications associated with traditional immunosuppressive therapy.

Efgartigimod: A first-in-class neonatal Fc receptor blocker

Efgartigimod, a humanized Fc fragment engineered for high-affinity FcRn binding, was the first FcRn inhibitor to demonstrate clinical efficacy in ITP [71]. It competitively inhibits the interaction between endogenous IgG and FcRn, leading to dose-dependent reductions in total IgG and pathogenic autoantibodies. The Phase II study of efgartigimod enrolled adults with persistent or chronic ITP who had failed at least one prior therapy. Platelet responses occurring within 1–2 weeks, and response rates were 46% for any platelet count response. Significant improvement in bleeding scores was reported [71]. The Phase III ADVANCE IV trial further validated these findings. 51% achieved platelet counts at least 50 × 10⁹/L, and median time to response was 8–10 days [28]. Efgartigimod’s rapid onset and good tolerability make it particularly attractive for patients with symptomatic thrombocytopenia requiring early improvement, or as a steroid-sparing approach after first-line therapy.

Rozanolixizumab: A subcutaneous neonatal Fc receptor inhibitor

Rozanolixizumab is a humanized monoclonal antibody designed to bind and inhibit FcRn in a dose-dependent manner. It is administered subcutaneously, offering convenience compared with intravenous agents. Primary ITP is an antiplatelet-antibody-mediated disorder with accelerated platelet clearance and decreased platelet production. In phase 3 studies, significant increases to at least 50 k/μL were seen by Day 8 in over 45% of treated patients [72]. The most frequent treatment-emergent adverse events overall were headache, pyrexia, and nausea, as seen previously.

Nipocalimab

Nipocalimab (M281), a high-affinity FcRn blocker, is being evaluated in several IgG-mediated autoimmune diseases [83]. While ITP-specific data remain in the early phases, further studies are needed.

COMPLEMENT BLOCKADE

Complement activation has historically been underrecognized in ITP, but a growing body of evidence indicates that the complement system plays a key pathogenic role in a subset of patients [31]. Complement-mediated platelet clearance, amplification of antibody-driven immune responses, and proinflammatory signaling contribute to severe or refractory disease in a manner not fully addressed by conventional therapies. Complement inhibitors – well established in other hematologic conditions such as paroxysmal nocturnal hemoglobinuria [84] and cold agglutinin disease [85] – are now being explored as targeted treatments for ITP.

The complement system comprises three activation pathways – classical, alternative, and lectin – that converge at C3 activation and formation of the membrane attack complex. In ITP, complement activation is typically initiated through the classical pathway. This process begins when IgG or IgM autoantibodies bind to platelet glycoproteins, followed by the complement component C1q binds to antibody-coated platelets. Subsequent activation of C4 and C2 leads to the formation of the C3 convertase, C3b deposition promotes opsonization, and then downstream activation may form C5a (proinflammatory) [31]. Platelets that acquire C3b or C4d become targets for rapid clearance by macrophages in the spleen and liver. In addition, complement fragments potentiate immune activation, enhancing B-cell and macrophage responses, thus sustaining the autoimmune cycle.

Sutimlimab: C1s inhibition

Sutimlimab is a humanized monoclonal antibody that selectively inhibits C1s, a key protease in the classical complement pathway. It was FDA-approved for cold agglutinin disease and has subsequently been investigated in ITP [59]. By blocking C1s, sutimlimab prevents activation of the classical pathway at its earliest stage, thereby reducing C4 and C3 activation, preventing complement-mediated opsonization, and minimizing pro-inflammatory downstream signaling. In a phase 1 study (NCT03275454) evaluating the safety, efficacy, pharmacokinetics, and pharmacodynamics of biweekly sutimlimab in patients with chronic or refractory ITP, 42% of participants achieved durable platelet responses. The mean platelet count declined to baseline values during washout and rose again with retreatment, indicating a clear pharmacodynamic effect. Consequently, C1s inhibition may represent a safe and promising therapeutic strategy for chronic or refractory ITP [59]. Headache and mild infusion reactions are the most common adverse events, and low rates of infection with no thrombotic signal have been detected. However, vaccination against encapsulated bacteria is still recommended. Sutimlimab treatment is well-tolerated with no new safety signals, although additional patients and further studies are needed to confirm these findings.

Eculizumab and ravulizumab, which inhibit terminal C5, and pegcetacoplan, a C3 inhibitor, may have potential roles in the treatment of ITP, but they remain under investigation. However, complete complement blockade may impair host defense, and the overall benefit–risk balance in ITP remains uncertain.

SPECIAL ISSUES OF NOVEL AGENTS

Although novel agents have demonstrated efficacy in the treatment of ITP, their use still requires careful consideration of patient-specific factors, including age, thrombotic risk, underlying disease associations, and pregnancy status.

In older adults, treatment decisions are often complicated by comorbidities, polypharmacy, and increased vulnerability to treatment-related toxicity. Prolonged corticosteroid exposure is particularly problematic in this population due to risks of osteoporosis, diabetes, infection, and neuropsychiatric adverse effects [86]. Steroid-sparing agents, such as FcRn inhibitors, Syk inhibitors, and BTK inhibitors, may therefore be especially attractive in elderly patients by providing effective platelet responses with more favorable long-term tolerability profiles; however, additional studies are needed to further evaluate their efficacy and safety in this population. Oral small-molecule therapies may further reduce treatment burden and improve adherence in this group.

Patients with high thrombotic risk – including those with cardiovascular disease, antiphospholipid antibodies, or prior thrombosis – represent another clinically challenging population. While TPO-RAs are effective, their association with increased platelet production and potential thrombotic risk necessitates caution in selected patients. One real-world study provided evidence suggesting that TPO-RAs are associated with a higher incidence of thromboembolic events, particularly venous thrombosis [87]. In the LUNA 3 trial for rilzabrutinib, only one patient with multiple risk factors experienced a Grade 3 peripheral embolism [65]. In a clinical study of Fostamatinib, one patient had deep venous thrombosis, and one patient with acute myocardial infarction was reported only [69,70]. Regarding long-term safety, interim analyses from the open-label ADVANCE study demonstrated that prolonged efgartigimod treatment maintained a favorable safety profile, with no newly identified drug-related thrombotic risk [88]. In this setting, therapies that reduce immune-mediated platelet destruction without directly stimulating thrombopoiesis may offer safer alternatives, although long-term thrombotic safety data remain limited.

In secondary ITP, where thrombocytopenia occurs in association with autoimmune disease, infection, malignancy, or immune-modulating therapies, the underlying immune dysregulation is often more complex. Targeted agents that modulate specific immune pathways – such as BTK inhibitors affecting B-cell and macrophage activation [89], or FcRn inhibitors reducing pathogenic IgG levels [90] – may be particularly relevant in these patients. Their use may complement or, in selected cases, reduce reliance on broad immunosuppression, although evidence from dedicated secondary ITP cohorts is still emerging.

Management of pregnancy-associated ITP remains especially constrained by fetal safety considerations. Current treatment options are largely limited to corticosteroids and IVIG. While most novel agents lack sufficient safety data to support routine use during pregnancy, their development highlights important future directions.

Collectively, consideration of these specific clinical scenarios underscores the importance of personalized, context-dependent use of novel ITP therapies and highlights areas where further real-world and population-specific studies are urgently needed.

EMERGING BIOLOGICS AND NEXT-GENERATION THERAPEUTIC TARGETS

The rapid expansion of targeted therapy in ITP has driven interest in emerging biologics and next-generation immunomodulators aimed at addressing unmet needs in refractory or mechanistically distinct disease. These agents – targeting autoantibodies, cytotoxic immune responses, regulatory T-cell dysfunction, plasma-cell persistence, and impaired megakaryopoiesis – represent the next wave of precision ITP therapy.

While the expanding repertoire of targeted therapies represents a major advance in ITP management, real-world implementation will be influenced by access, cost, and healthcare resource constraints. Newer biologics and small-molecule inhibitors are often associated with higher direct drug costs and variable reimbursement across healthcare systems, which may limit timely availability, particularly outside medical centers. Conversely, these agents may reduce indirect costs by decreasing steroid-related complications, hospitalizations for bleeding or rescue therapy, and the need for repeated infusions or prolonged inpatient care [91]. Oral formulations and infrequently dosed biologics may also lessen clinic visit burden and improve treatment continuity [92]. As these therapies progress through clinical development and post-marketing use, formal health-economic analyses and real-world utilization studies will be essential to define their cost-effectiveness, optimal positioning, and equitable integration into routine ITP care.

CONCLUSION

ITP is entering a transformative era as deeper insights into its heterogeneous immunopathology enable the development of mechanism-based therapies. Targeted agents – including FcRn, Syk, BTK, and complement inhibitors – now offer more precise, steroid-sparing options that align with dominant disease pathways and provide meaningful alternatives for refractory patients. Yet optimal treatment sequencing, biomarker integration, and long-term durability remain unmet needs. The future of ITP management will rely on personalized, endotype-driven strategies that match therapy to underlying biology, incorporate rational combinations, and prioritize patient-centered goals such as steroid avoidance, rapid rescue, and sustained off-therapy remission. In Taiwan, treatments recommended by the ASH guidelines – including corticosteroids, TPO-RAs, and rituximab – are all currently available; however, newer therapeutic agents have not yet been approved. It is hoped that these novel treatments will become available in Taiwan in the near future, thereby providing patients with ITP with a broader range of therapeutic options.

Data availability statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.