Thrombopoietin Receptor Agonist Research Articles

Thrombopoietin receptor agonists use and risk of thrombotic events in patients with immune thrombocytopenic purpura: A systematic review and meta‑analysis of randomized controlled trials.

Thrombopoietin receptor agonists (TPO-RAs) have a role in second-line immune thrombocytopenic purpura (ITP) treatment, binding to and activating thrombopoietin receptors on megakaryocyte membranes in the bone marrow. This promotes megakaryocyte maturation and increases platelet production. Despite a 2-6% incidence of thrombotic events during TPO-RA treatment, it remains uncertain whether TPO-RAs elevate thrombosis rates. A comprehensive search of electronic databases was conducted using the relevant search criteria. To assess the risk of bias, the included studies were assessed using the revised Cochrane Risk of Bias Assessment Tool 2.0, and a meta-analysis was performed using RevMan 5.4.1. A total of 1,698 patients with ITP were included from randomized controlled trials (RCTs). There were 26 thromboembolic events in the TPO-RAs group and 4 in the control group. However, there was no significant difference in the incidence of thrombotic events between the two groups [odds ratio (OR)=1.76, 95% confidence interval (CI): 0.78-4.00, P=0.18], even if the duration of treatment was >12 weeks (OR=2.46, 95% CI: 0.81-7.43, P=0.11). Subgroup analysis showed that none of the four drugs significantly increased the incidence of thrombotic events (romiplostim: OR=0.92, 95% CI: 0.14-6.13, P=0.93; eltrombopag: OR=2.32, 95% CI: 0.64-8.47, P=0.20; avatrombopag: OR=4.15, 95% CI: 0.20-85.23, P=0.36; and hetrombopag: OR=0.76, 95% CI: 0.03-18.76, P=0.87). There was also no significant difference in the results of the double-blinded placebo-controlled RCTs (OR=1.21, 95% CI: 0.41-3.58, P=0.73). Compared to patients with ITP who did not receive TPO-RA treatment, those receiving TPO-RA treatment did not exhibit a significantly increased risk of thrombotic events.

Current trends in the treatment of aplastic anemia

Aplastic anemia is a syndrome characterized by reduced hematopoietic stem cells, bone marrow hypoplasia, and pancytopenia, and is often considered a T-cell-mediated autoimmune disease. It is predominantly treated with hematopoietic stem cell transplantation and immunosuppressive therapy with anti-human thymocyte immunoglobulin (ATG) and cyclosporine. Only rabbit ATG was previously available in Japan, but equine ATG was recently approved for use in 2023. Thrombopoietin receptor agonists available in Japan are oral eltrombopag and injectable romiplostim. In hematopoietic stem cell transplantation for aplastic anemia, a conditioning regimen of reduced-dose cyclophosphamide and fludarabine has been used to reduce cardiotoxicity. Human leukocyte antigen haploidentical stem cell transplants have also been developed, and their use in patients without a donor is increasingly reported. Future advancements in novel drugs and transplantation therapies could revolutionize the management of aplastic anemia.

Avatrombopag for the salvage treatment of platelet transfusion refractoriness.

Platelet transfusion refractoriness (PTR) is a life-threatening and intractable condition in hematological patients. Thrombopoietin receptor agonists such as avatrombopag promote platelet production and modulate immune intolerance. However, its application in PTR has not been extensively studied. We aimed to compare the platelet response (PR) as well as bleeding events and mortality rate between the best available therapies (BATs) and avatrombopag (Ava) treatments in refractory PTR patients. A total of 71 refractory PTR patients were enrolled at Nanfang Hospital. Intravenous immunoglobulin, steroids, and human leucocyte antigen-matched platelet transfusions were administered to 30 patients in the BATs group. The Ava group included 41 patients. Data of refractory PTR patients were retrospectively collected. The primary endpoint was PR (defined as an increase of platelet count to ⩾50 × 109/L without platelet transfusion support for 7 consecutive days). Secondary endpoints included platelet-transfusion independence rate, cumulative platelet transfusion units, World Health Organization bleeding grades, adverse events, overall survival (OS), and bleeding event-free survival (EFS). There were 75.6% and 13.3% refractory PTR patients who reached PR within 3 months in Ava and BATs groups. The median platelet counts were significantly higher in Ava group from day 7. Platelet-transfusion independence rate in Ava was higher than BATs group. The median cumulative platelet transfusion unit in Ava was lower than that of BATs group. The OS and bleeding events-free EFS rate of Ava group improved within 3 months as compared to BATs group. Cox proportional hazards regression analysis revealed that Ava therapy was a protective factor for the OS and EFS. No primary disease progression or termination of avatrombopag was observed due to intolerability. Our study suggests that avatrombopag is an effective and safe treatment option for refractory PTR patients.

Efficacy and safety of avatrombopag in combination with immunosuppressive therapy in treatment-naïve and relapsed/refractory severe aplastic anaemia: protocol for the DIAAMOND-Ava-FIRST and DIAAMOND-Ava-NEXT Bayesian Optimal Phase II trials

IntroductionImmunosuppressive therapy (IST) with antithymocyte globulin (ATG) and ciclosporin is standard of care for patients with severe aplastic anaemia (sAA) not eligible or suitable for allogeneic stem cell transplant. While...

Rectifying the impairment of immune thrombocytopenia plasmas through photobiomodulation

<p>Immune thrombocytopenia (ITP) is an autoimmune hemorrhage disorder. The first-line treatment of this disorder is corticosteroids, followed by thrombopoietin (TPO) receptor agonists such as Nplate, and/or splenectomy. Yet, the extended usage of corticosteroids or the expensive Nplate, coupled with the implications of splenectomy, raises concerns due to the array of associated side effects and an escalated vulnerability to subsequent complications. The current investigation shows that while anti-platelet antibodies and ITP plasmas hinder megakaryocyte differentiation and maturation and impair proplatelet and platelet formation in ex vivo culture of umbilical cord human CD34+ stem cells (cHSCs), low-level laser (LLL) treatment or photobiomodulation (PBM) effectively mitigates these detrimental impacts. PBM reinstated megakaryocyte differentiation and maturation, bolstering proplatelet and platelet formation in the presence of auto-platelet antibodies or ITP plasmas. The mitigating effects of PBM appear to pivot on its capacity to uphold cellular mitochondrial functionality and rectify the mitochondrial impairments engendered by anti-platelet antibodies or ITP plasmas. These findings underscore the potential of PBM as a safe and cost-efficient alternative for the management of a specific subset of ITP patients.</p>

Rectifying the impairment of immune thrombocytopenia plasmas through photobiomodulation

<p>Immune thrombocytopenia (ITP) is an autoimmune hemorrhage disorder. The first-line treatment of this disorder is corticosteroids, followed by thrombopoietin (TPO) receptor agonists such as Nplate, and/or splenectomy. Yet, the extended usage of corticosteroids or the expensive Nplate, coupled with the implications of splenectomy, raises concerns due to the array of associated side effects and an escalated vulnerability to subsequent complications. The current investigation shows that while anti-platelet antibodies and ITP plasmas hinder megakaryocyte differentiation and maturation and impair proplatelet and platelet formation in ex vivo culture of umbilical cord human CD34+ stem cells (cHSCs), low-level laser (LLL) treatment or photobiomodulation (PBM) effectively mitigates these detrimental impacts. PBM reinstated megakaryocyte differentiation and maturation, bolstering proplatelet and platelet formation in the presence of auto-platelet antibodies or ITP plasmas. The mitigating effects of PBM appear to pivot on its capacity to uphold cellular mitochondrial functionality and rectify the mitochondrial impairments engendered by anti-platelet antibodies or ITP plasmas. These findings underscore the potential of PBM as a safe and cost-efficient alternative for the management of a specific subset of ITP patients.</p>

Clinical and economic effectiveness of thrombopoietin receptor agonists in the treatment of primary immune thrombocytopenia in the Moscow region

Clinical and economic effectiveness of thrombopoietin receptor agonists in the treatment of primary immune thrombocytopenia in the Moscow region

Knowledge map of thrombopoietin receptor agonists: A bibliometric analysis

BackgroundThrombopoietin receptor agonists (TPO-RAs) have been widely used to treat thrombocytopenia, however, a scientometric profile of TPO-RAs research is lacking. Methods: This study uses VOSviewer, CiteSpace, and R software to provide an overview of current research, highlight study hotspots, and predict future research directions of TPO-RAs. Results: One thousand seven hundred and nineteen relevant studies from 1993 to 2022 with 43962 citations were identified from the Web of Science Core Collection. Over three decades, the USA has been leading TPO-RAs publications. Industries and academic institutions have been actively involved in TPO-RAs research, with funding provided by pharmaceutical companies and public funding bodies. The most productive and cited journals are British Journal of Hematology and Blood, respectively. When author keywords were categorised into three clusters, i.e., cluster 1 (immune thrombocytopenic purpura (ITP)), cluster 2 (avatrombopag, lusutrombopag, and thrombocytopenia), and cluster 3 (TPO-RAs for ITP and off-label drug use), ITP was found to be the current research hotspot, while oral TPO-RAs and licensed or unlicensed drug indications of thrombocytopenic diseases require further investigation. Conclusion: This study has generated the knowledge map of TPO-RAs, which provides a dynamic roadmap for future research in this field.

Role of thrombopoietin receptor agonists in chemotherapy-induced thrombocytopenia: A meta-analysis.

Chemotherapy-induced thrombocytopenia (CIT) is a significant challenge in cancer treatment, often leading to dose reductions and reduced number of cycles. The limited effectiveness of platelet transfusions in managing CIT highlights the need for alternative treatments. Thrombopoietin receptor agonists (TPO-RA), including romiplostim, eltrombopag and avatrombopag, have shown potential in increasing platelet counts in CIT patients, necessitating a comprehensive analysis of their efficacy. This meta-analysis followed the Preferred Reporting Items for Systemic Reviews and Meta-analysis guidelines, searching Ovid databases up to 5 October 2023. The primary metric of interest was platelet count changes post-TPO-RA administration in CIT patients. From the initial 867 studies obtained, 7 studies were selected based on the inclusion criteria. The analysis included 348 patients. A significant association was found between TPO-RA administration and platelet count increase, with a combined-effect increase of 69.52 ± 2.24 × 109/l. Subgroup analysis based on Romiplostim use suggested an increase of approximately 70.11 ± 39.07 × 109/l, while non-Romiplostim TPO-RAs showcased an increase of about 68.09 ± 82.58 × 109/l. The meta-analysis demonstrates the effectiveness of TPO-RAs in managing CIT. Further research comparing platelet increases across standardised TPO-RA regimens is recommended to refine treatment strategies. This analysis provides valuable insights for clinicians in tailoring CIT treatment using TPO-RAs.

Guidelines for the diagnosis and management of idiopathic thrombocytopenic purpura

Introduction. Primary immune thrombocytopenia (ITP) is an autoimmune disease caused by the production of antibodies to the membrane structures of platelets and their precursors — megakaryocytes, which causes not only increased destruction of platelets, but also inadequate thrombocytopoiesis, characterized by isolated thrombocytopenia below 100.0×109/L and the presence/absence of hemorrhagic syndrome of varying severity.Aim: to present modern recommendations for the diagnosis and treatment of ITPBasic information. The recommendations are based on the experience of Russian and international experts, the leadership of the international working group on the study of primary immune thrombocytopenia, and recommendations of the European and American Societies of Hematology using new data on the development and course of ITP. Approaches to the treatment of the disease using new drugs from the group of thrombopoietin receptor agonists are present

Thrombopoietin-receptor agonists for adult patients with immune thrombocytopenia: a narrative review and an approach for managing patients fasting intermittently.

Thrombopoietin-receptor agonist (TPO-RAs) currently represent the state of art for treating immune thrombocytopenia. Their different molecular structures contribute to the difference in their pharmacodynamics and pharmacokinetics. This narrative review aims to provide an overview of the current TPO-RAs approved for primary immune thrombocytopenia (romiplostim, eltrombopag, avatrombopag) and the effect of intermittent fasting in adult patients receiving TPO-RAs. Literature was searched with no limits on date or language, using various combinations of keywords. Data on the pharmacokinetics, pharmacodynamics, efficacy, and safety of TPO-RAs and the effect of intermittent fasting were summarized. Switching between TPO-RAs is a useful strategy to tackle some associated limitations. Romiplostim and avatrombopag have an advantage over eltrombopag as they do not require any dietary restrictions. In cases where romiplostim and avatrombopag are unavailable, patients should be educated on the appropriate administration, possible interactions, and dietary restrictions before initiating eltrombopag.

Clinical and pathological features of clonal cytopenia of undetermined significance presenting with isolated thrombocytopenia (CCUS-IT).

Clonal cytopenia of undetermined significance (CCUS) is defined as somatic mutations of myeloid malignancy-associated genes in the blood or bone marrow with one or more persistent unexplained cytopenias that do not meet diagnostic criteria for a defined myeloid neoplasm. CCUS with isolated thrombocytopenia (CCUS-IT) is rare. This is a retrospective case series of patients with prolonged isolated thrombocytopenia, a pathogenic mutation on a myeloid molecular panel, and a bone marrow biopsy with morphologic atypia below the WHO-defined diagnostic threshold for dysplasia. Five male patients were identified with a median age at CCUS-IT diagnosis of 61 years (56-74). Median duration of thrombocytopenia prior to CCUS-IT diagnosis was 4 years (3-12), and median platelet count at CCUS-IT diagnosis was 41 × 103 /μL (26-80). All patients had megakaryocytic hyperplasia and megakaryocytes with hyperchromasia and high nuclear-cytoplasmic ratio. Pathogenic SRSF2 mutations were identified in all 5 patients with median variant allele frequency of 36% (28%-50%). Three patients were treated with IVIg and/or steroids with no response; one of three responded to thrombopoietin receptor agonists. Three patients progressed to MDS and one to AML. We describe the clinicopathological features of CCUS-IT which can mimic immune thrombocytopenia.

Glucocorticosteroid-induced complications in patients with idiopathic thrombocytopenic purpura

Glucocorticosteroids (GCS) are the first-line treatment for idiopathic thrombocytopenic purpura (ITP). Despite their high efficacy in patients with newly diagnosed ITP, an adequate level of platelets remains after GCS withdrawal in only less than 20 % of patients. Additionally, GCS use is associated with an increased risk of different adverse reactions, including serious and life-threatening ones. Thrombopoietin receptor agonists represent a relatively new class of drugs for treating ITP as a second-line therapy. This paper reviews the risks of GCS pharmacotherapy, as well as the evidence supporting the use of thrombopoietin receptor agonists as both first-line and second-line treatment for patients with ITP.

Real-world evidence confirms thrombopoietin receptor agonists are safe and effective for all stages of immune thrombocytopenia.

Real-world evidence confirms thrombopoietin receptor agonists are safe and effective for all stages of immune thrombocytopenia.

Abstract B030: Intracerebral and intraventricular hemorrhage due to severe thrombocytopenia: A rare case of Evans syndrome

Abstract Introduction: Evans syndrome (ES) is a rare autoimmune disorder characterized by the development of autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and/or immune neutropenia (AIN) without an identifiable cause. It is believed to involve immune system dysregulation, leading to the destruction of red blood cells, platelets, and neutrophils. Case Presentation: A 68-year-old male with a history of coronary artery disease, hypertension, diabetes, and atrial fibrillation presented with abdominal pain and diarrhea. Laboratory tests revealed a platelet count of 3k, suggesting ITP. Initial treatment with dexamethasone and platelet transfusion provided limited improvement. A bone marrow biopsy showed mildly hypercellular bone marrow with trilineage hematopoiesis. However, the patient's condition rapidly deteriorated, and he returned to the emergency department with severe symptoms, including headache, gum bleeding, and lower extremity petechiae. A CT scan revealed a large intraparenchymal hematoma with intraventricular hemorrhage, highlighting the risk of life-threatening bleeding in ES patients. Discussion: The patient was managed with platelet transfusions, high-dose steroids, and intravenous immunoglobulin (IVIG), which provided temporary relief but failed to maintain stable platelet levels. Further investigations revealed a positive antinuclear antibody (ANA), suggesting an underlying rheumatological condition and confirming the diagnosis of secondary ES. This finding necessitated the exploration of treatment options. Of interest is Romiplostim (Promacta), a thrombopoietin receptor agonist, which has shown promise in increasing platelet counts and reducing bleeding episodes in refractory ITP. Considering the positive ANA and the suspected rheumatological etiology, Romiplostim may serve as a viable long-term treatment option to stabilize platelet levels and mitigate bleeding risks in this case. Conclusion: This case highlights the complexity of Evans syndrome and emphasizes the need to promptly recognize and manage life-threatening bleeding complications, particularly in older patients. The presence of a positive ANA suggests an underlying rheumatological condition, necessitating comprehensive evaluation, and tailored therapeutic approaches. Although further research is needed to understand the pathogenesis and optimal management strategies for ES, Romiplostim holds promise as a potential treatment for patients with secondary ES who are unresponsive to conventional therapies. Citation Format: Kiersten R. Patterson, Aliya M. Khan, Raj Patel. Intracerebral and intraventricular hemorrhage due to severe thrombocytopenia: A rare case of Evans syndrome [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B030.

Development and Validation of a UV Spectroscopic Method to Estimate Eltrombopag Olamine along with Bulk and In-house Formulation

The current UV Spectroscopic method developed involving ethanol as a solvent is simple, fast, specific, precise, and sensitive for the estimation of Eltrombopag Olamine in bulk in day-to-day analysis. As per the ICH Q2 (R1) guideline, the method was validated. Eltrombopag Olamine is a drug used to treat thrombocytopenia (a low blood platelet count) in adults and youngsters with chronic immune idiopathic thrombocytopenic purpura that didn't get well with different treatments. Eltrombopag Olamine is additionally accustomed to treating severe aplastic anemia. It’s conjointly being studied within the treatment of different conditions and kinds of cancer. Eltrombopag Olamine binds to the thrombopoietin receptor, which causes the bone marrow to create more platelets. It’s class of thrombopoietin receptor agonists, also known as Promacta. Eltrombopag is also recently approved (2012) for the treatment of thrombocytopenia in a patient with chronic hepatitis C to start and sustain interferon-based therapy. The solvent used in the entire method development and validation was ethanol. The maximum wavelength of absorption was found to be 423nm. Beer’s law was obeyed in the concentration range of 5 to 30ug/ml with a correlation coefficient of 0.9966. The method was precise with an RSD of less than 2%, the LOD, and LOQ were found to be 6.18ug/ml and 18.7ug/ml respectively, % recovery of the drug is 98 to 100%. The method was validated for linearity, precision, accuracy, and robustness and all parameters were found to be satisfactory which proves that this method can be used for routine analysis of Eltrombopag Olamine.

VAYHIT3: An Open-Label, Single-Arm, Phase II Trial to Evaluate the Efficacy and Safety of Ianalumab in Patients with Primary Immune Thrombocytopenia (ITP) Previously Treated with at Least 1 Corticosteroid and 1 Thrombopoietin Receptor Agonist (TPO-RA)

Background: In patients with ITP, autoreactive B cells mediate the production of autoantibodies that target platelets and megakaryocytes, resulting in an increased rate of platelet destruction and decreased platelet production. B-cell activating factor (BAFF) regulates the differentiation, proliferation and survival of B cells via interactions with the BAFF receptor (BAFF-R). Patients with ITP have elevated serum BAFF levels, which positively correlate with increased disease activity. Ianalumab is a novel, fully human immunoglobulin G1 monoclonal antibody that targets BAFF-R and has a unique dual mechanism of action: direct B-cell depletion mediated by antibody-dependent cellular cytotoxicity and inhibition of B-cell differentiation, proliferation and survival via blockade of BAFF-R-mediated signaling. Following first-line corticosteroids, TPO-RAs are a standard second-line treatment for ITP; however, patients often require chronic TPO-RA treatment and endure potential side effects with increased costs. For patients who previously received corticosteroids and a TPO-RA, the choice of subsequent therapy (eg a different TPO-RA, rituximab, fostamatinib, mycophenolate mofetil, splenectomy) is not well defined. Thus, in patients with ITP requiring additional lines of therapy, there is an unmet need for new, well-tolerated therapies with disease-modifying potential that can safely induce high response rates after a short therapeutic course and maintain durable responses after treatment discontinuation. Trial design: VAYHIT3 (NCT05885555) is a multicenter, open-label, single-arm, Phase II trial enrolling approximately 40 adult patients with primary ITP who have previously received at least 1 corticosteroid and 1 TPO-RA. Additional prior therapies are allowed. Eligible patients must have lost response, had an insufficient response, had no response or been intolerant to their last ITP therapy. Along with a platelet count of <30 G/L, patients must be assessed by the investigator as needing treatment. Exclusion criteria include a neutrophil count of <1000/mm 3 and prior splenectomy. All patients will receive intravenous ianalumab every 4 weeks (Figure). Patients may receive concomitant therapy with a corticosteroid or TPO-RA if clinically indicated, which may be tapered. The primary efficacy analysis will occur after all patients have been followed up until Week 25 Day 1 or discontinued the study earlier. All patients with a platelet count of ≥30 G/L in the absence of a rescue therapy in the last 4 weeks or new ITP therapy at Week 25 Day 1 visit will continue efficacy monitoring until they have a platelet count of <30 G/L, start a new ITP therapy or require a rescue therapy. Safety will be monitored in all patients for up to 2 years after the last dose of ianalumab. Endpoints: The primary endpoint is confirmed response, defined as a platelet count of ≥50 G/L for 2 or more consecutive assessments at least 7 days apart between Week 1 Day 1 and Week 25 Day 1 visits and in the absence of both a rescue therapy for ≥4 weeks prior to the assessment of platelet count and the receipt of a new ITP therapy. Secondary endpoints include time to confirmed response, time to loss of response, quality and stability of response, proportions of patients experiencing bleeding events and requiring rescue therapies, changes in B cell and immunoglobulin levels, and pharmacokinetics, immunogenicity and safety of ianalumab. Exploratory biomarker assessments are also included to expand upon the understanding of ianalumab pharmacodynamics and exposure-response in patients with ITP. Conclusions: VAYHIT3 will evaluate the ability of a short therapeutic course of ianalumab to induce durable responses in patients who have received 2 or more prior lines of therapy, including at least 1 corticosteroid and 1 TPO-RA, for whom significant unmet needs exist. Current status: VAYHIT3 is recruiting. Ianalumab is also being investigated in 2 ongoing, randomized, double-blind, Phase III ITP trials: VAYHIT1 (NCT05653349) is assessing ianalumab versus placebo in addition to first-line corticosteroids, and VAYHIT2 (NCT05653219) is assessing ianalumab versus placebo in addition to eltrombopag in patients who failed first-line corticosteroid treatment.

Short-Term Efficacy of Combination Therapy with Recombinant Human Thrombopoietin (rh-TPO) and Thrombopoietin Receptor Agonists (TPO-Ra) in Patients with Severe Immune Thrombocytopenia

Introduction: Bleeding manifestations in patients with immune thrombocytopenia (ITP) range from mild skin bruises to lifethreatening intracranial hemorrhage. When the risk of bleeding is becoming high or life-threatening bleeding events occurs, we often use a combination of therapies to rapidly raise platelets to the safe range, including platelet transfusions, high-dose glucocorticoid, and intravenous immunoglobulins. Recombinant human thrombopoietin (rh-TPO) and thrombopoietin receptor agonists (TPO-Ra) are two kinds of thrombopoietic drugs commonly used in China. In patients with severe ITP refractory to glucocorticoids, we lack experience with the use of rh-TPO and TPO-Ra in this emergency situation. Patients and methods： We included ITP patients with platelets <10*10 9/L and bleeding symptoms requiring treatment, who were refractory to glucocorticoids and used thrombopoietic drugs. The bleeding score was calculated with reference to the Chinese guidelines for adult ITP. The patients were divided into three groups according to the medication used: rh-TPO group(rh-TPO 30000IU Qd), TPO-Ra group(Eltrombopag 25mg-75mg/d or Avatrombopag 2.5mg-7.5mg/d or Hetrombopagolamine 20mg-60mg/d), and rh-TPO+TPO-Ra group(combination of two drugs at the same dosage). The platelet count should be rechecked every 1-2 days during the treatment. Platelet transfusion and hemostatic drugs can be used as needed. According to the standardized and international criteria, and taking into account the characteristics of this study, platelet counts were classified as short-term Complete Response(sCR), short-term Response(sR), and short-term No Response (sNR), based on the highest value of platelet counts from the start of treatment to the time of hospital discharge, short-term Overall Response(sOR)=sCR+sR. The three groups were compared the effective time(defined as the time to first sCR/sR after treatment) , peak platelet count after treatment, time to peak platelet count after treatment and other short-term efficacy indicators. Results Nineteen patients were include in this study, with 68.4% (13/19) was female. The median age was 58 years [range 17-79]. 15.8%(3/19) were newly diagnosed with ITP, 10.5%(2/19) had persistent ITP, and 73.7%(14/19) had chronic ITP. All patients were treated with glucocorticoids prior to this treatment, but they had a poor response. The median platelet count was 3*10 9/L [range 1-9] and the median bleeding score was 4 [range 2-9] before treatment. The common bleeding sites were skin ecchymosis and oral mucous membrane hemorrhage in 100%(19/19)and 47.3%(9/19), respectively. Severe bleeding symptoms were the manifestation in 3 cases: including 2 heavy menstrual flow and 1 hemoptysis and gastrointestinal. 100%(19/19) achieved a sOR and 31.6%(6/19) achieved a sCR. The median bleeding score was 0[0-2] after treatment and none had active bleeding symptoms. Platelet transfusion and hemostatic drugs were administered to all patients. Further details are provided in Table 1. Among 19 patients, 7(36.8%) used rh-TPO alone, 6(31.6%) TPO-Ra alone and 6(31.6%) used rh-TPO+TPO-Ra. There was no statistically significant difference in Clinical characteristics, including ages, gender, platelet counts and bleeding score among the three groups of patients before treatment (P=0.727, 0.594, 0.719, 0.299). In terms of treatment efficacy, we were unable to perform a statistical analysis of sOR rates because all three groups reached 100%. The sCR and the peak platelet count after treatment of rhTPO+TPO-Ra group was higher than the other two groups, 28.6%(2/7), 16.7%(1/6) and 50%(3/6) of patients achieved sCR respectively, the peak platelet counts after treatment in the three groups were 62*10 9/L, 72*10 9/L, 79.5*10 9/L respectively in this treatment, but there was no statistically significant difference (P=0.425，0.924). In addition, the effective time and time to peak platelet count after treatment of the three group are also no statistically significant difference(p=0.692,0.505). Further details are provided in Table 2. Conclusion This retrospective study suggests that the patients with severe ITP who were refractory to glucocorticoids, the use of rh-TPO and TPO-Ra may rapidly increase to safe ranges, but the combination is not necessary.

Platelet-Derived TGF-β1 Induces Functional Reprogramming of Myeloid-Derived Suppressor Cells in Immune Thrombocytopenia

Introduction: Immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by isolated thrombocytopenia and varying degrees of bleeding symptoms. Platelets are anucleate cytoplasmic cell fragments that play dual physiological roles as both cellular mediators of thrombosis and immune modulatory cells. Platelets are the largest storage pool of TGF-β1, a crucial enforcer of immune homeostasis and tolerance. Studies have shown that TGF-β1 released by platelets contributes to the pathogenesis of pulmonary arterial hypertension and cervical carcinoma. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immature myeloid cells with potent immunosuppressive functions. Our previous studies have shown that MDSCs are impaired in number and function in patients with ITP. The objective of this study was to elucidate the underlying molecular mechanisms of MDSCs reprogramming by platelet-derived TGF-β1. Methods: A transwell assay was used to determine the impact of platelets on MDSCs induced from peripheral blood mononuclear cells (PBMCs) of ITP patients and healthy controls. The percentage of circulating MDSCs in ITP patients was detected before and after administration of thrombopoietin receptor agonists (TPO-RAs). Besides, anti-CD61 immune-sensitized splenocytes were transferred into SCID mice to establish an active murine model of ITP. Subsequently, MDSCs from TPO-RA-treated ITP mice were transplanted as cell therapy to rescue treatment-free ITP mice. In specific, adeno-associated viral (AAV) vectors efficiently infected MDSCs to enable cell-specific Smad2/3 knock-down. Finally, platelet specific TGF-β1-deficient mice were used to validate the effect of platelet-derived TGF-β1 on MDSCs. Results: TGF-β1 levels in the supernatant of MDSCs co-cultured with platelets of high concentration was significantly higher than that in MDSCs co-cultured with platelets of low concentration or alone. FACS analysis showed that platelet mass enhanced the inhibitory effects of MDSCs on the proliferation of CD4 + T cells, which could be offset by TGF-β1 inhibitor (TGF-βi). Besides, TPO-RAs treatment induced significantly increased percentage of circulating MDSCs in responders with chronic ITP. Likewise, TPO-RA significantly expanded MDSC population in active ITP murine models. Furthermore, after receiving donor MDSCs from TPO-RA-treated ITP mice, arrested differentiation of plasma cells, reduced Fas ligand expression on cytotoxic T cells, and re-balanced T cell subsets were found in the recipient mice, indicating augmented inhibitory functions of MDSCs. Mechanistically, transcriptome analysis confirmed the participation of TGF-β/Smad pathway in donor MDSCs from TPO-RA-treated ITP mice, which was offset by Smad2/3 knockdown. Finally, by constructing ITP models using Pf4 cre-Tgfb1 fl/fl and Pf4 cre+Tgfb1fl/fl mice, we found that TGF-β1 inhibition and platelet TGF-β1-deficence, both, could counteract the elevated platelet count and MDSCs percentage, as well as improved immunosuppressive capacity of MDSCs trigged by TPO-RA modulation. Conclusion: To sum up, it was demonstrated that platelet TGF-β1 induced the expansion and functional reprogramming of MDSCs via TGF-β/Smad pathway. These data indicate that platelet recovery not only serves as an endpoint of remission, but also paves the way for tolerance induction in immune-mediated thrombocytopenia. Our exploratory study deciphered immunological changes induced by TPO-RAs and helped to identify molecular mechanisms responsible for long-term remission after TPO-RA discontinuation.

Real-World Evidence of Avatrombopag for the Treatment of Immune Thrombocytopenia Intolerant or Ineffective to Eltrombopag/Hetrombopag

Abstract Objectives: Thrombopoietin receptor agonists (TPO-RA) have dramatically changed the treatment landscape for immune thrombocytopenia (ITP). Although avatrombopag has been confirmed to achieve platelet response for chronic ITP in clinical trials, and it has no hepatotoxicity unlike eltrombopag or hetrombopag, there is still a lack of real-world research on the application of avatrombopag in Chinese ITP patients. Here, we aimed to evaluate the effect and safety of avatrombopag in ITP treatment in a real-world clinical practice. Methods: In this retrospective analysis, we enrolled consecutive cohorts of 50 adult ITP patients who received avatrombopag in two centers from January 2021 to March 2023. The median duration of follow-up of these patients was 16.5 months (range from 3.8 to 25.4 months). Results: The median age of patients was 44 years when they received the treatment of avatrombopag, and 42% of them were males. Most patients (n=45) had a persistent (3-12 months) or chronic course (more than 12 months) of ITP. The patients in our study were heavily treated, who received a median of 4 kinds of ITP treatment prior to avatrombopag. The baseline TPO levels was 88.1 (110.2±84.5) pg/ml. Based on the reasons for choosing avatrombopag, these patients were divided into eltrombopag/hetrombopag intolerance group (IG, n=14) and eltrombopag/hetrombopag unresponsive group (UG, n=36). The reasons for choosing avatrombopag in IG included active hepatitis B (n=4), hepatic insufficiency before using TPO-RA (n= 6), autoimmune hepatitis (n=1), hepatic lesion after using eltrombopag (n=2), and myelofibrosis after using eltrombopag (n=1). Compared with UG, more patients had a history of liver disease (active Hepatitis B and autoimmune liver diseases, P=0.003). The median platelet count before avatrombopag was 9 × 10 9/L. The median duration of avatrombopag treatment was 12 weeks and the median weekly dose of avatrombopag was 140 mg. Among the total cohort, platelet response (platelet count ≥30 × 10 9 /L) was achieved in 44/50 (88%) and complete platelet response (platelet count ≥100 × 10 9 /L) was seen in 35/50 patients (70%) after using avatrombopag. The median time of platelets rising above 30 × 10 9 /L was 7 days, while it was 8 days when platelet count exceeded 50 × 10 9 /L. Nearly half patients (47%) were able to discontinue more than 1 concomitant ITP medication after avatrombopag treatment. Besides, most patients (74%) in our study tapered off or withdrew steroids. There were no significant differences in baseline platelet count, 30-day response rate, the maximum effective dose of avatrombopag and duration of avatrombopag between IG and UG. So far, 19 patients achieved platelet response were still taking avatrombopag, and 58% of them maintained platelet count above 100× 10 9 /L. Meanwhile, 31 patients discontinued avatrombopag.The reasons for withdrawal of drug included adverse events (n=2), sustained remission in ITP (n=8), no/lose response to avatrombopag (n=10), and unablity to afford the cost consistently (n=11). Avatrombopag was well tolerated in most patients, even those suffered from hepatic insufficiency and/or myelofibrosis after other TPO-RA. However, two cases had thrombosis and two patients reported mild fatigue. Conclusion: In the ITP population, avatrombopag was effective and safe, especially for those intolerant or ineffective to eltrombopag/hetrombopag. However, most patients with ITP were not able to afford the long-term usage of avatrombopag in China.