Immune Thrombocytopenia: Treatment, Pathophysiology & Novel Therapies
- Immune thrombocytopenia (ITP) is a chronic autoimmune disorder associated with platelet destruction and increased bleeding risk, considerable economic burden, and impairment of health-related quality of life.
- 2026;32:S3-S11.For author data and disclosures, see end of text.
- Immune thrombocytopenia (ITP) is an autoimmune platelet disorder characterized by a low platelet count, increased incidence of bleeding, and heightened risk of thrombosis.1,2 ITP is also associated with...
This supplement was supported by Sanofi.
ABSTRACT
Table of Contents
- ABSTRACT
- Introduction
- The Underlying Pathophysiology of ITP
- Current Therapeutic Landscape and Unmet Needs
- Treatment choice should be individualized based on factors such as bleeding severity, response duration, comorbidities, TE risk, adherence, and patient preferences.2,5 The ASH guidelines emphasize shared decision-making,encouraging clinicians to tailor treatment based on not only age and clinical presentation but also individual patient values,preferences,and support network.2 As new therapies become available, this approach supports the importance of individualizing treatment according to each patientS specific risk profile.5 Common comorbid conditions in ITP-such as cardiovascular disease (CVD), diabetes mellitus (DM), and prior venous TE (VTE)-may lead to further thrombosis and complicate therapeutic decisions especially when patients are on anticoagulants or antiplatelet therapy.2,28,29
- Patient-Centered Considerations in ITP Management
- Persistent Challenges and Inadequate Responses
- Spotlight on BTK Pathway and Emerging Science
- Understanding Immune Thrombocytopenia (ITP)
Immune thrombocytopenia (ITP) is a chronic autoimmune disorder associated with platelet destruction and increased bleeding risk, considerable economic burden, and impairment of health-related quality of life. the pathophysiology of ITP involves increased platelet destruction and impaired platelet production due to a multifactorial breakdown of immune tolerance driven by dysregulated B and T cells. Advances in understanding ITP pathophysiology have led to the growth of new immune-modulating therapies, such as Bruton tyrosine kinase (BTK) inhibitors.Rilzabrutinib (Wayrilz; Sanofi) is an oral BTK inhibitor recently approved for treatment of adult patients with persistent or chronic ITP who have had an insufficient response to a previous treatment. Rilzabrutinib targets several aspects of ITP disease pathophysiology by modulating multiple immune pathways. Approval was based on results from a phase 3 trial (LUNA 3 [NCT04562766]), in which patients with ITP who received rilzabrutinib demonstrated a rapid, durable platelet response and improvements in fatigue and bleeding with a tolerable safety profile.
Am J Manag Care. 2026;32:S3-S11.
For author data and disclosures, see end of text.
Introduction
Immune thrombocytopenia (ITP) is an autoimmune platelet disorder characterized by a low platelet count, increased incidence of bleeding, and heightened risk of thrombosis.1,2 ITP is also associated with significant health-related quality of life (HRQOL) impacts such as fatigue, impaired physical and cognitive functioning, and anxiety.2,3 Existing therapies exert a high treatment burden in the form of adverse events (AEs) and platelet count fluctuations, and a subset of patients experiance persistent disease that underscores the high unmet need for new and improved therapies for ITP.4-7 Current therapies for ITP managements do not target the underlying immune dysregulation and cannot address its broad clinical manifestations.8 Complex immune dysregulation leading to autoimmunity and systemic inflammation is increasingly being recognized to underlie the pathophysiology of ITP, and the role of targeting these dysfunctional pathways is currently being investigated.9,10 The bruton tyrosine kinase (BTK) inhibitor rilzabrutinib (Wayrilz; Sanofi) recently received FDA approval for the treatment of adults with persistent or chronic ITP who had an insufficient response to a prior treatment.11,12 B“`html
ITP is a heterogeneous autoimmune disorder characterized by a decreased platelet count and a risk of bleeding.1 The incidence of ITP is estimated to be 1.2 to 6.8 per 100,000 adults per year.2 ITP is diagnosed by excluding other causes of thrombocytopenia and confirming the presence of isolated thrombocytopenia with a platelet count of <100 × 109/L.3 The diagnosis is further supported by the exclusion of other causes of thrombocytopenia, such as drug-induced thrombocytopenia, infections, and systemic diseases.4
Clinical manifestations of ITP range from mild to severe,with bleeding being the primary concern. The severity of bleeding is correlated with the degree of thrombocytopenia, but there is significant variability among patients.5 The clinical course of ITP is also variable, with some patients experiencing spontaneous remission, while others require long-term treatment to maintain a safe platelet count.6
The pathophysiology of ITP is complex and involves both immune-mediated platelet destruction and impaired platelet production.7 Autoantibodies against platelet glycoproteins, such as GPIIb/IIIa and GPIb/IX, are commonly found in patients with ITP and contribute to platelet clearance by the reticuloendothelial system.8-10 However, the presence of autoantibodies does not always correlate with disease severity or response to treatment.11
In addition to autoantibodies, T cells play a critical role in the pathogenesis of ITP.12 CD4+ T helper cells promote B cell activation and autoantibody production, while CD8+ cytotoxic T cells can directly kill platelets.13 Dysregulation of T cell subsets and impaired T cell tolerance contribute to the chronic nature of ITP.
ITP is classified based on the duration of symptoms (Figure 2
Symptoms of ITP are typically characterized by episodes of non-life-threatening bleeding.5 Presentation of bleeding includes petechiae and purpura frequently enough in the lower extremities, epistaxis, heavy menstrual bleeding (HMB), gingival and gastrointestinal (GI) bleeding, and intracranial hemorrhage.5,16,18 These can be seen in approximately 60% of patients with ITP,19 while severe bleeding occurs in approximately 10% of adult patients with primary ITP.20 Other symptoms of ITP such as fatigue, anxiety concerning unstable platelet counts, depression, and cognitive impairment considerably impact patient QOL.3,21,22
The Underlying Pathophysiology of ITP
In normal physiology, platelet production is driven by thrombopoietin (TPO), a glycoprotein hormone and growth factor that helps to regulate megakaryocyte (MK) proliferation, maturation, and subsequent platelet formation.23,24 The pathophysiology of ITP involves a multifactorial breakdown of immune tolerance that results in increased platelet destruction and impaired platelet production that are driven by dysregulated B and T cells (
As many as 30% to 40% of patients with ITP lack detectable autoantibodies, even though whether this results from a lack of robustness in antibody testing or the existence of purely T cell-mediated forms of ITP remains unknown.23
Immune-Cell Dysregulation and Cytokine Imbalance
T-cell and cytokine abnormalities also contribute to the autoimmune pathophysiology of ITP.1 Regulatory T cells (Tregs) play a vital role in the maintenance of self-tolerance; their reduction in ITP is thought to be a critical component of the pathophysiology of the disease,23 and unbalanced T helper cell 1 (Th1), Th17, and Th22 subsets contribute to sustained immune activation. Cytotoxic CD8+ T cells play a dual role in ITP, directly lysing platelets and inhibiting thrombopoiesis in the bone marrow. Dendritic cells demonstrate enhanced self-antigen presentation in ITP; this dysfunction promotes the autoreactive response of immune cells to platelets.23
Bone Marrow Impairment and Megakaryocyte Dysfunction
Autoreactivity renders the bone marrow microenvironment dysfunctional in ITP, exacerbating thrombopoiesis defects. Autoantibodies against MKs can increase apoptosis or impair MK maturation, leading to reduced platelet production despite normal TPO levels. Mesenchymal stem cells (MSCs) are also impacted; these cells normally sustain MK maturation and platelet formation but become apoptotic in ITP. Further, MSCs lose their immunosuppressive functions in ITP and fail to regulate T-cell activity.23
Current Therapeutic Landscape and Unmet Needs
the current goal of ITP treatment is to stop active bleeding and prevent future bleeding.1 The treatment of ITP follows 3 main mechanistic pathways: reducing antiplatelet antibody production, inhibiting platelet clearance, and increasing platelet production Table.
Treatment options like corticosteroids, IVIg, and splenectomy carry heightened risks in these populations that may outweigh disease-related morbidity.28 Use of TPO-RAs requires careful consideration of adherence, drug interactions, and thrombotic risk, notably in patients with comorbidities or polypharmacy.28 These findings reinforce the importance of aligning ITP treatment decisions with each patient’s evolving risk profile and comorbidity burden rather than relying solely on platelet count or bleeding history.29
Patient-Centered Considerations in ITP Management
Research continues to highlight the role of systemic inflammation in the clinical etiology of fatigue, depression, anxiety, and other QOL issues commonly impacting patients with ITP.2,30 Inflammation has been increasingly recognized as a contributing factor in ITP, with patients showing elevated levels of inflammatory markers such as TNF-α, IL-6, NLRP3-related cytokines (IL-18 and IL-1β), and IFN-γ.27,31,32 This systemic inflammatory state may further influence disease progression and symptom burden.32
The impact of ITP reaches beyond hematologic parameters, affecting multiple aspects of daily life.1 Patients report substantial effects on their physical and emotional well-being, with fatigue emerging as a major burden.3 The Immune Thrombocytopenia World Impact Survey (I-WISh), which included 1507 patients with ITP and 472 health care providers (HCPs), furnished valuable insights into these challenges. the survey, conducted across 13 countries, involved factors including disease symptoms, HRQOL, emotional and financial impact, treatment experiences, and patient-physician relationships. Some 49% of patients surveyed reported reducing, or seriously considering a reduction in, their working hours due to their ITP, and 11% of patients had to stop working becuase of their disease. Further,among those employed at the time of the survey,36% believed that ITP negatively impacted their work productivity.3
In the same study, physicians provided perspectives on symptom management and treatment patterns, reinforcing the need for a comprehensive approach to care.3 A discrepancy was identified between patient-reported fatigue at diagnosis and HCP recognition of fatigue.Fifty percent of patients reported fatigue, while HCPs reported that only 38% of their patients were fatigued. Patients in this study also reported anxiety about their ITP management,with 63% worried about fluctuating platelet counts,63% fearing disease progression,41% being concerned about mortality,and 39% believing their HCPs underestimated their symptoms.These findings suggest that fatigue and anxiety are significant symptoms for many patients with ITP, although they may be underrecognized or underestimated by HCPs.3
ITP is known to cause HMB in premenopausa
2010 to 2016 data from 2 US private health care claims databases to estimate the incidence, health care use, and costs of newly diagnosed ITP. This study found an annual incidence of ITP to be 6.1 per 100,000 persons. ITP was more common in females (6.7/100,000 persons) than males (5.5 per 100,000 persons) and was highest in neonates, infants, and children aged 0 to 4 years (8.1/100,000 per 100,000) and in adults 65 years or older (13.7/100,000 persons). Patients averaged 0.33 hospitalizations (95% CI, 0.32-0.35) and 15.3 ambulatory visits (95% CI, 15.1-15.6) in the first year, with mean health care costs of $21,290 per patient. Hospitalizations peaked in the 3 months following diagnosis and were twice as frequent in children. While per-patient expenditures for ITP-related hospitalizations were comparable across age groups, the cost of ambulatory care was much lower for the youngest age group (age 0-4 years, $4321) surveyed compared with costs for the oldest age group (age ≥ 65 years, $13,712). New annual cases of ITP were estimated at nearly 20,000 in the United States, with total first-year health care expenditures exceeding $400 million. This study’s reliance on claims data represents a significant limitation, as these data cannot capture undiagnosed cases; they may include individuals misdiagnosed with ITP.36
Another retrospective analysis examined US hospital data from 2006 to 2012 that detailed ITP-related hospitalizations, revealing that there were 296,870 ITP-associated hospitalizations over the study period.37 these hospitalizations were most commonly attributed to coagulation disorders, followed by splenectomy, septicemia, GI hemorrhage, intracranial hemorrhage, and epistaxis.37 The average length of stay for an ITP-related hospitalization was 6 days, which was 28% longer than the national average for hospital stays. The average cost per ITP-related hospitalization, adjusted to 2024 dollars, was $22,428, which was 48% higher than the average US per-hospitalization cost. these findings highlight the substantial health care burden associated with ITP hospitalizations, which may increase as the US population continues to age.37
Persistent Challenges and Inadequate Responses
The management of ITP remains complex due to diagnostic challenges, treatment limitations, and the need for individualized care.Diagnosis requires extensive testing to exclude secondary causes, and the variable clinical presentation of the disease complicates early detection. First-line corticosteroids are effective for some patients but are often limited by AEs and inconsistent long-term responses. Second-line treatments, including TPO-RAs and rituximab, lack standardized selection criteria, and splenectomy is less favored due to potential long-term complications. Significant challenges in treating ITP remain, including disease that is persistent despite multiple lines of therapy, management of bleeding and thrombotic risks, and steroid overuse contributing to fatigue and metabolic issues.15
Spotlight on BTK Pathway and Emerging Science
BTK, a critical enzyme in the B-cell receptor signaling pathway, is essential for autoantibody production, cytokine release, and cell proliferation.9 BTK is involved in maturation of B cells, production of antibodies, and regulation of the innate inflammatory machinery, including NLRP3 inflammasome and FcγR-mediated signaling pathways in macrophages.8 These multimodal effects of BTK in immune-mediated diseases make it a key target in ITP.
At least a doubling from baseline in the absence of rescue therapy during the first 12 weeks) were allowed to continue double-blinded treatment through week 24 of the trial; nonresponders could either drop out of the study or enter the 28-week open-label period and receive 400 mg of rilzabrutinib twice daily while remaining blinded to their initial treatment.
The primary efficacy end point of the trial was durable platelet response (defined as platelet counts ≥ 50 × 103/μL for two-thirds or more of ≥ 8 weekly platelet measurements during the last 12 weeks of the trial without rescue therapy). At least 2 of these platelet counts of at least 50 × 103/μL had to be taken during the final 6 weeks of the 24-week blinded treatment period. Secondary end points included the number of weeks with a platelet count of at least 50 × 103/μL or at least 30 × 103/μL to less than 50 × 103/μL and at least doubled from baseline in the absence of rescue therapy, the number of weeks with a platelet count of at least 30 × 103/μL and at least doubled from baseline in the absence of rescue therapy, change from baseline at week 13 on the ITP patient Assessment Questionnaire (ITQ-PAQ) item 10 (a measure of physical fatigue scored from 0 to 100, with higher score indicating better HRQOL) and change from baseline at week 25 in the idiopathic thrombocytopenic purpura bleeding scale (IBLS). The IBLS is scored from 0 (none) to 2 (marked bleeding) based on assessment of 11 sites on the body.
At baseline,the median patient age was 47 and 46 years in the rilzabrutinib and placebo arms,respectively. The median duration of ITP was 8.1 years in the rilzabrutinib arm and 6.2 years in the placebo arm. A baseline platelet count of less than 15 × 103/μL was seen in 49% and 46% of the patients in the rilzabrutinib and placebo arms, respectively. Additionally, 43% of patients in the rilzabrutinib arm and 52% of patients in the placebo arm had at least 5 unique prior therapies; in both arms, 28% of patients had prior splenectomy. Moreover, 40% of patients in the rilzabrutinib arm were treated with rilzabrutinib monotherapy.
A platelet response in the first 12 weeks of the study was achieved by 85 (64%) and 22 (32%) of patients given rilzabrutinib or placebo, respectively; these patients were eligible to continue the double-blind period.The primary end point of durable response was met in 31 (23%) versus none (0%) of patients who received rilzabrutinib versus placebo, respectively (P < .0001), and it was identical for both durable response definitions used in the study.
All prespecified secondary efficacy end points were statistically significant for rilzabrutinib versus placebo. In the absence of rescue therapy, the least squares mean difference (SE) in number of weeks with a platelet response for rilzabrutinib versus placebo was 6.46 (0.78) (P < .0001). Patients who received rilzabrutinib also dem
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- Arnold M, et al. Thrombopoietin receptor agonists for immune thrombocytopenia: systematic review and meta-analysis. BMJ. 2016;353:i1483.doi:10.1136/bmj.i1483
- Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;116(9):1881-1892. doi:10.1182/blood-2010-03-280183
- Neunert C, Terrell DR, Aster RH, et al. American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;117(16):3289-3307.doi:10.1182/blood-2011-03-318683
- Stasi R, Sarpatwari A, El-Kassar O, et al. Demographics, clinical characteristics, and prior treatment patterns of patients with chronic immune thrombocytopenia: findings from the I-WISh study. Adv Ther. 2018;35(11):1738-1748.doi:10.1007/s12325-018-0733-z
- Cooper N, Kruse A, Kruse C, et al. Immune thrombocytopenia (ITP) World Impact Survey (I-WISh): impact of ITP on health-related quality of life. Am J Hematol. 2021;96(2):199-207.doi:10.1002/ajh.26036
- Kuter DJ, Efraim M, Mayer J, et al. Rilzabrutinib, an oral BTK inhibitor, in immune thrombocytopenia. N Engl J Med. 2022;386(15):1421-1431. doi:10.1056/NEJMoa2110297
- Singh A, Uzun G, Bakchoul T. Primary immune thrombocytopenia: novel insights into pathophysiology and disease management. J Clin Med. 2021;10(4):789. doi:10.3390/jcm10040789
- gonzález-Porras JR,Godeau B,Carpenedo M. Switching thrombopoietin receptor agonist treatments in patients with primary immune thrombocytopenia. Ther Adv Hematol. 2019;10:2040620719837906. doi:10.1177/2040620719837906
- Cantoni S, Carpenedo M, Mazzucconi MG, et al. Alternate use of thrombopoietin receptor agonists in adult primary immune thrombocytopenia patients: a retrospective collaborative survey from italian hematology centers. Am J Hematol. 2018;93(1):58-64. doi:10.1002/ajh.24935
- Kuter DJ, Ghanima W. Evaluating rilzabrutinib in the treatment of immune thrombocytopenia. Immunotherapy. 2025;17(11):767-782. doi:10.1080/1750743X.2025.2545170
- Zhu S, gokhale S, Jung J, et al. Multifaceted immunomodulatory effects of the BTK inhibitors ibrutinib and acalabrutinib on different immune cell subsets – beyond B lymphocytes.Front Cell Dev Biol. 2021;9:727531. doi:10.3389/fcell.2021.727531
- Kuter DJ,bussel JB,Ghanima W,et al. Rilzabrutinib versus placebo in adults and adolescents with persistent or chronic immune thrombocytopenia: LUNA 3 phase III study. Ther Adv Hematol.
Understanding Immune Thrombocytopenia (ITP)
Immune thrombocytopenia (ITP) is an autoimmune disorder where the body’s immune system attacks and destroys platelets, leading to a low platelet count and increased risk of bleeding.
What is ITP and how Does it Develop?
ITP occurs when the immune system mistakenly identifies platelets as foreign and produces antibodies against them. These antibodies attach to the platelets, marking them for destruction by the spleen. This process results in thrombocytopenia – a lower-than-normal platelet count. The exact cause of ITP is frequently enough unknown, but it can be triggered by viral infections, vaccinations, or certain medications.
Key Research Findings on ITP
- Investigation and Management: A 2010 study in Blood provided a detailed overview of the investigation and management of ITP, outlining diagnostic approaches and treatment strategies. (Provan D, et al. Blood. 2010;115(2):168-186. doi:10.1182/blood-2009-06-225565)
- Fatigue and ITP: Research published in the British Journal of haematology in 2015 highlighted the significant impact of fatigue on individuals with ITP, even when platelet counts are stable. (Hill QA, Newland AC. Br J Haematol. 2015;170(2):141-149. doi:10.1111/bjh.13385)
- NLRP3 Expression: A 2016 study in Immunological Research found elevated expression of NLRP3, a protein involved in inflammation, in patients with ITP, suggesting a potential role for inflammation in the disease process. (Qiao J, et al. Immunol Res. 2016;64(2):431-437. doi:10.1007/s12026-015-8686-5)
- ITP in the Elderly: A 2018 article in the European Journal of Internal Medicine addressed the specific challenges of managing ITP in elderly patients, considering their increased risk of comorbidities and bleeding. (Lucchini E, et al. Eur J Intern Med. 2018;58:70-76. doi:10.1016/j.ejim.2018.09.005)
- thrombotic Risk: Research indicates a paradoxical risk of thrombosis (blood clots) in some ITP patients, prompting investigation into the complex interplay between inflammation, platelet function, and coagulation. (Saldanha A, et al. )
Further research continues to refine our understanding of ITP and improve treatment options.