Patients with immune thrombocytopenic purpura (ITP) usually express thyroid antigen-specific antibodies. The purpose of this study was to explore the causal relationship between Hashimoto's thyroiditis (HT) and ITP.

A two-sample Mendelian randomization (TSMR) analysis was applied to investigate the potential causal relationship between HT and ITP in European population. Five complementary methods including inverse variance weighted (IVW), Mendelian Randomization-Egger (MR-Egger), weighted median, and weighted mode were performed in our study. Risk genes of HT and ITP were selected through Mendelian randomization (MR), and the common risk genes were further analysed by bioinformatics methods to explore the common pathogenesis of the two diseases.

The MR analysis revealed a potential causal relationship between HT and risk of ITP [odds ratio (OR) = 1.22; 95% confidence interval (CI) 1.01, 1.49; P = 0.046]. Gene eQTL data were obtained from the IEU database. HT and ITP were respectively treated as outcome variables for MR analysis, and a total of 32 common risk genes were selected, including 12 high-risk genes and 20 low-risk genes. Functional analysis including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) analysis revealed that risk genes were closely related to antigen processing and presentation, and played a crucial role in the process of various viral and bacterial infections.

Our study demonstrated that HT may increase the risk of ITP, and revealed the role of their common risk genes in the development of the two diseases.

Thrombopoietin receptor agonists-romiplostim, eltrombopag and avatrombopag-are commonly used as second-line treatments for immune thrombocytopenia (ITP).

A Markov model was developed to estimate the cost effectiveness of the three TPO-RAs in adults with insufficient response to previous treatment from the perspective of the UK National Health Service (NHS). The model considered the effects of bleeding events, concomitant ITP medications, rescue therapies and treatment related adverse events over a lifetime horizon. Model inputs for effectiveness were based on a network meta-analysis and other published literature on ITP management. Other model inputs included costs (e.g., drug acquisition and administration) and healthcare resource utilisation.

Avatrombopag was associated with higher quality-adjusted life-years (QALYs) (10.979) than romiplostim (10.628) and eltrombopag (10.085), producing incremental QALYs of -0.351 and -0.894, respectively. Avatrombopag was associated with lower total costs (GBP £319,334) compared with romiplostim (GBP 406,361 [cost saving of GBP 87,027]) and higher total costs compared with eltrombopag (GBP 313,987 [incremental cost of GBP 5347]). Avatrombopag therefore dominated romiplostim (more effective and less expensive) and was cost-effective versus eltrombopag (incremental cost-effectiveness ratio of GBP 5982 per QALY).

Avatrombopag is a cost-effective treatment compared with romiplostim and eltrombopag for the second-line treatment of adults with ITP from the perspective of the UK NHS.

Immune thrombocytopenia (ITP) is characterized by impaired platelet production and increased platelet destruction. Zanubrutinib is a highly selective next-generation Bruton tyrosine kinase (BTK) inhibitor that may reduce autoantibody production and reduce macrophage Fcγ receptor-mediated platelet destruction. In this single-arm, phase II study, we aimed to assess the efficacy and safety of zanubrutinib in corticosteroid-resistant or relapsed ITP. All patients received 80 mg zanubrutinib once daily for 6 weeks followed by a 20-week safety follow-up period. The primary endpoint was overall response (OR), defined as at least two consecutive platelet counts of at least 30 × 109/L, at least a 2-fold increase in the baseline count, the absence of bleeding, and no need for rescue therapy at 4 weeks. The trial was registered with ClinicalTrials.gov, number NCT05279872. Between January 1, 2022 and October 30, 2022, 20 patients were enrolled. The median platelet count was 19 (10-25) × 109/L at the time of enrollment. Participants had received a median of 4 (3-6) different therapies for ITP. Eleven (55%, 95% CI: 31.5%-76.9%) patients achieved an OR to the intervention. Two (10%) patients achieved a complete response. At the 6-month follow-up, a sustained response was achieved in seven (35.0%, 95% CI: 15.4%-59.2%) patients. There were no grade 4 or worse adverse events or treatment-related deaths. The most common adverse events were upper respiratory tract infection (in 25% of the patients). Zanubrutinib showed an encouraging response rate and tolerability, supporting its therapeutic potential for the treatment of ITP. Trial Registration: ClinicalTrials.gov identifier: NCT05279872.

This study aimed to compare the efficacy and safety of thrombopoietin receptor agonists (TPO-RA) in the treatment of immune thrombocytopenia (ITP) in adults. A systematic review was conducted using network meta-analysis and a disproportionality analysis based on the FDA Adverse Event Reporting System (FAERS) database to evaluate hemorrhagic and thrombotic events of clinical concern. Our network meta-analysis included 14 randomized controlled trials (RCTs) involving 1,454 patients. The results indicated that, in terms of efficacy, romiplostim [odds ratio (OR), 0.04; 95% confidence interval (CI), 0 to 0.68] was the most effective, followed by avatrombopag, hetrombopag, and eltrombopag. Regarding safety, there were no significant differences in the safety profiles of the four TPO-RA compared to placebo. According to the surface under the cumulative ranking curve (SUCRA), avatrombopag exhibited the highest safety ranking at 23.8%. Within the FAERS database, we identified 982 cases of TPO-RA-related hemorrhagic and thrombotic events. The highest number of preferred terms (PTs) associated with romiplostim was 26, followed by 18 for eltrombopag and 7 for avatrombopag. The findings of this study suggest that romiplostim exhibits significant efficacy, whereas avatrombopag presents a superior safety profile. In the context of clinical second-line treatment, the selection of the most suitable TPO-RA should be guided by the specific circumstances of each patient. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/#recordDetails.

Primary immune thrombocytopenia is an autoimmune bleeding disorder characterized by variable immune-mediated platelet destruction. These patients have reported thrombotic complications, both venous and arterial, in addition to bleeding. Splenectomy and thrombopoietin receptor agonists are recommended for patients who do not respond to steroids or immunosuppressive treatments. Chronic thromboembolic pulmonary hypertension is a rare disease that results from a persistent, organized thromboembolic obstruction of the pulmonary arteries due to an incompletely resolved pulmonary embolism.

We report two cases of chronic thromboembolic pulmonary hypertension induced by a thrombotic mechanism after treatment with splenectomy and Eltrombopag, a thrombopoietin receptor agonist, for refractory primary immune thrombocytopenia. Consequently, the patients were referred for surgical pulmonary thromboendarterectomy therapy as suggested.

In older patients, those with a history of thrombotic manifestations, or those with high-risk factors, clinicians should evaluate and monitor the risk of thrombotic events and chronic thromboembolic pulmonary hypertension when treating primary immune thrombocytopenia with splenectomy and Eltrombopag.

Thrombocytopenia is a common clinical problem in cancer patients undergoing high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HSCT). It can occur as prolonged isolated thrombocytopenia (PIT) or secondary failure of platelet recovery (SFPR) and may cause potentially fatal bleeding. However, data on the treatment of post-transplant thrombocytopenia is still lacking.

We reported our practices involving 15 pediatric patients who received eltrombopag (ELT) treatment for PIT and SFPR after autologous HSCT.

The overall response was 78.5% (11/14), with 1 patient excluded due to noncompliance. The 12 surviving patients' median follow up was 699 days (range: 167 to 2250 d).

Our study indicates the efficacy and safety of ELT for treating PIT and SFPR after autologous HSCT in pediatric patients. However, more studies are needed to confirm these findings in children.

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.

Eltrombopag (EPAG) is an oral thrombopoietin receptor agonist analog with the potential risk to induce liver injury. This prospective registry study evaluated the prevalence and severity of hepatic injury in Chinese patients with severe aplastic anemia undergoing low-dose EPAG treatment (75 mg/day) in the context of standard immunosuppressive therapy (IST). The incidence of acute drug-induced liver injury was slightly higher in the IST + EPAG group than in the IST group at the 1st and 2nd month, but no statistically significant difference was observed: 10% vs 5% (p = 0.400), 9% vs 8% (p = 1.000). At the 1st month, the incidences of alanine aminotransferase, aspartate aminotransferase, and total bilirubin increased of grade 3 or higher in the IST + EPAG and the IST groups, were 5% vs 3% (p = 0.228), 2% vs 1% (p = 1.000), 2% vs 1% (p = 1.000), respectively. The logistic analysis indicated that serum ferritin level was associated with severe liver injury events. There was a slight increase in the incidence of severe hepatic injury events in the patients with SAA treated by EPAG, but it was insignificant.

Predominantly antibody deficiencies have an estimated prevalence of >1 in 25 000. Their classical phenotype entails the association of autoimmune manifestations with increased susceptibility to infections. Up to 8% of these patients ultimately develop immune thrombocytopenic purpura (ITP). Reducing the risk for infections and considering nonimmunosuppressive treatments, such as thrombopoietin receptor agonists (TPO-RAs), are important considerations for these patients. This nationwide retrospective case series assessed the outcomes and safety of TPO-RAs as treatment for ITP in adults diagnosed with predominantly antibody deficiencies. Response and complete response to treatment were defined as platelet count reaching 30 × 109/L and 100 × 109/L, respectively. We analyzed data from 28 patients. The median follow-up time after introduction of the first TPO-RAs was 33 months (range, 2 weeks to 10.6 years). After 6 weeks of follow-up, response was achieved in 24 of the 28 patients (85.7%), and among those, 21 patients (75%) displayed a complete response. At the last available follow-up visit, only 7 patients (25%) needed second-line therapies for ITP, and among those, only 5 patients (17.9%) received immunosuppressants. Only 3 patients (10.7%) reported laboratory-confirmed hepatobiliary adverse events of light or mild severity and 3 patients (10.7%) reported thrombotic events. In conclusion, TPO-RAs seemed to be an effective and safe option of treatment in these case series. Our results suggest that eltrombopag or romiplostim should be considered as second-line therapy for ITP related to predominantly antibody deficiencies.

Thrombopoietin (TPO) is a plasma glycoprotein that binds its receptor on megakaryocytes (MKs) and MK progenitors, resulting in enhanced platelet production. The mechanism by which TPO is secreted from hepatocytes remains poorly understood. Lectin mannose-binding 1 (LMAN1) and multiple coagulation factor deficiency 2 (MCFD2) form a complex at the endoplasmic reticulum membrane, recruiting cargo proteins into COPII vesicles for secretion. In this study, we showed that LMAN1-deficient mice (with complete germline LMAN1 deficiency) exhibited mild thrombocytopenia, whereas the platelet count was entirely normal in mice with approximately 7% Lman1 expression. Surprisingly, mice deleted for Mcfd2 did not exhibit thrombocytopenia. Analysis of peripheral blood from LMAN1-deficient mice demonstrated normal platelet size and normal morphology of dense and alpha granules. LMAN1-deficient mice exhibited a trend toward reduced MK and MK progenitors in the bone marrow. We next showed that hepatocyte-specific but not hematopoietic Lman1 deletion results in thrombocytopenia, with plasma TPO level reduced in LMAN1-deficient mice, despite normal Tpo mRNA levels in LMAN1-deficient livers. TPO and LMAN1 interacted by coimmunoprecipitation in a heterologous cell line, and TPO accumulated intracellularly in LMAN1-deleted cells. Together, these studies verified the hepatocyte as the cell of origin for TPO production in vivo and were consistent with LMAN1 as the endoplasmic reticulum cargo receptor that mediates the efficient secretion of TPO. To our knowledge, TPO is the first example of an LMAN1-dependent cargo that is independent of MCFD2.

The management of immune thrombocytopenia (ITP) is continuously evolving with the development and introduction of newer therapies and a better understanding of the disease. Corticosteroids still represent the cornerstone of first-line treatment. Patients who fail to achieve remission with a short course of corticosteroids require subsequent therapy. Most guidelines recommend starting with either a thrombopoietin receptor agonist (TPO-RA), rituximab, or fostamatinib since these agents have been investigated in randomized trials and have well-characterized efficacy and safety profiles. Patients' involvement to reach a shared decision regarding choice of therapy is essential as these treatments have different modes of administration and mechanisms of action. Less than 10% will fail to respond to and/or be intolerant of multiple second-line therapeutic options and thus be considered to have refractory ITP and require a third-line therapeutic option. Such patients may require drugs with different targets or a combination of drugs with different mechanisms of action. Combining a TPO-RA and an immunomodulatory agent may be an appropriate approach at this stage. Many studies have been conducted during the last 2 decades investigating the efficacy and safety of combinations strategies for first and later lines of therapies. Yet none of these are recommended by current guidelines or have gained wide acceptance and consensus.

ABSTRACTImmune thrombocytopenia (ITP), an autoimmune disease characterized by low platelet counts and increased bleeding risk, can impair health-related quality of life (HRQoL), impacting patients' daily lives and mental health. A number of patient-reported outcome (PRO) measures (both generic and specific to ITP) can be used to understand the impact of ITP on HRQoL and generate evidence to guide disease management. As well-developed PRO tools could help in HRQoL assessment, their optimization could help to solidify a patient-centric approach to ITP management. Shared decision-making is a collaborative process between a patient and their healthcare professional in making decisions about care. Treatment decisions based on this shared process between physician and patient are recommended by clinical guidelines. The goal of this narrative review is to discuss treatment decisions with regards to patient-centric ITP management, with a focus on the impact of PRO measures and the process of shared decision-making in practice.

Thrombopoietin receptor agonists are used in addition to steroids for idiopathic thrombocytopenic purpura. A 55-year-old male with idiopathic thrombocytopenic purpura, treated with eltrombopag, developed a rapid decline in renal function following the increase in eltrombopag dose. Renal biopsy showed glomerular endothelial disorder and platelet thrombus, which suggested eltrombopag-induced renal-limited thrombotic microangiopathy. He was treated with steroids; however, his renal function did not improve, and hemodialysis was initiated. During the treatment, acute myocardial infarction and arteriovenous fistula obstruction occurred. After that, he was subsequently diagnosed with antiphospholipid antibody syndrome. Eltrombopag can cause thrombotic microangiopathy and, in some cases, result in renal failure. Patients with idiopathic thrombocytopenic purpura coexisted with antiphospholipid antibody syndrome are at increased risk of thrombosis with thrombopoietin agonists and require careful follow-up.

Due to the limited real-world research on the application of avatrombopag (AVA) for immune thrombocytopenia (ITP) in China, we evaluated the effectiveness and safety of AVA in clinical practice. We included 121 adult ITP patients treated with AVA across three medical centres. Based on the reasons for choosing AVA, these patients were divided into eltrombopag (ELT)/hetrombopag (HET) intolerance group (IG), and ELT/HET unresponsive group (UG). Compared with UG, more patients in IG had a history of liver disease and received fewer treatments before AVA. Amongst all patients, 83% had platelet response (≥30 × 109/L) after AVA and 62% achieved complete response (≥100 × 109/L, CR). Sixty-two percent in IG and 56% in UG were able to discontinue more than one concomitant ITP medication. A total of 17 patients underwent multiple switches of thrombopoietin receptor agonists (TPO-RAs), resulting in an 88% platelet response rate. Sixty-three patients discontinued AVA, 27% were due to unaffordability. AVA was well tolerated in most patients. In the ITP population, AVA proved effective and safe, particularly in patients intolerant or unresponsive to ELT/HET. Patients benefited from TPO-RAs switches, particularly those undergoing multiple switches. However, many patients struggled with the long-term financial burden of AVA.

Eltrombopag, a nonpeptide thrombopoietin receptor agonist, is primarily used for treating immune thrombocytopenic purpura. The aim of this study was to investigate the pharmacokinetic profile and food-drug interaction of test and reference eltrombopag olamine tablets among healthy Chinese volunteers. An open, randomized, single-dose, 2-period crossover design was employed, involving fasting and fed conditions with a 10-day washout period. Ninety-six healthy volunteers received a single oral dose of 25 mg of the 2 eltrombopag formulations, with 48 participants in each group: fasting volunteers and those consuming a high-fat, low-calcium meal. Plasma eltrombopag concentrations were analyzed using liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters were derived from the concentration-time profiles. The geometric mean ratios, with 90% confidence intervals, for the maximum plasma concentration, area under the concentration-time curve from time 0 to the last measurable concentration, and area under the concentration-time curve from time 0 to infinity fell within the bioequivalence acceptance criteria (80%-125%) under both fasting and fed conditions, indicating bioequivalence between the test and reference formulations. Administration of eltrombopag with a high-fat, low-calcium diet reduced the net systemic exposure by approximately 40%. Adverse events were recorded, and no serious adverse events were observed in either fasting or fed conditions. In conclusion, eltrombopag is well tolerated and exhibits a favorable safety profile in the Chinese population. The achievement of bioequivalence under fasting and fed conditions supports the demonstration of biosimilarity between the test and reference formulations.

Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder, leading to an increased bruising and bleeding tendency. Eltrombopag, a thrombopoietin receptor agonist, is an effective treatment option even in elderly patients with ITP. In this report, we present a case of recurrent thrombosis, presenting as acute myocardial infarction and cerebral infarction, in a very elderly patient with dementia, atrial fibrillation, and ITP on eltrombopag treatment. Multiple comorbidities with thrombosis and bleeding risks posed a therapeutic dilemma. Conditions unique to the elderly, such as cognitive impairment or frailty, led to a delayed diagnosis. This case gives an insight into how to manage a practical therapeutic problem in such a case. Physicians need to understand conditions unique to the elderly, such as cognitive impairment, frailty, or quality of life that influence treatment goals. These efforts can help provide health benefits while minimizing treatment risks, especially in elderly patients with multiple comorbidities.

Thrombopoietin receptor agonists (TPO-Ras; romiplostim/eltrombopag/avatrombopag) have demonstrated high efficacy rates (59-88%) and a good safety profile in clinical trials with adult patients with immune thrombocytopenia (ITP). Similar efficacy and safety results have been observed with romiplostim and eltrombopag in paediatric cohorts. Continuous treatment with TPO-RAs has shown durable responses with long-term use, up to 3 years. The effect of TPO-RAs was generally considered transient, as platelet counts tended to drop to baseline values after a short period of time (about 2 weeks), unless treatment was maintained. Several groups have reported successful discontinuation of TPO-RAs without the need for concomitant treatments. This is referred to as sustained remission off treatment (SROT). Both short- and medium-term treatment with TPO-RAs may reduce costs to our healthcare systems and, more importantly, may reduce the potential side effects that may be associated with continuous TPO-RA treatment. The issue of tapering and discontinuation of TPO-RAs in paediatric patients with ITP has received little attention to date. Given that paediatric ITP has much higher rates of spontaneous remission than ITP in adults, we consider that the possibility of SROT of TPO-RAs in paediatric patients with ITP is a neglected but very relevant issue in this subtype of the disease.

Hematopoietic cell transplantation (HCT) is a well-established procedure that has become a therapeutic mainstay for various hematological conditions. Prolonged thrombocytopenia following HCT is associated with a significant risk of morbidity and mortality, yet no universally recognized treatment protocol exists for such a complication. First-generation thrombopoietin receptor (TpoR) agonists as well as second-generation agents are known for their role in enhancing platelet production, and their use is expanding across various thrombocytopenic conditions. Therefore, we conducted this comprehensive review of the literature to provide an updated evaluation of the use of TpoR agonists and explore their efficacy and safety in the treatment of extended post-HCT thrombocytopenia. The literature search was conducted using PubMed database from 1996 through December 2023, using a predefined strategy with medical subject headings terms. We identified 64 reports on the utility of TpoR agonists, five of them were randomized controlled trials and the rest were retrospective observational studies and case series, with a total number of 1730 patients. Second-generation TpoR agonists appear more convenient than subcutaneous recombinant human thrombopoietin (rhTpo) as they can be orally administered and exhibit similar efficacy in platelet recovery, as indicated by recent trial results. Among these agents, avatrombopag, unlike eltrombopag, does not require any dietary restrictions, which could be more favorable for patients. However, eltrombopag remains the most extensively studied agent. TpoR agonists had promising effects in the treatment of post-HCT thrombocytopenia with a good safety profile so far, highlighting the potential benefit of their use.

Despite diverse therapeutic options for immune thrombocytopaenia (ITP), drug efficacy and selection challenges persist. This study systematically identified potential indicators in ITP patients and followed up on subsequent treatment. We initially analysed 61 variables and identified 12, 14, and 10 candidates for discriminating responders from non-responders in glucocorticoid (N = 215), thrombopoietin receptor agonists (TPO-RAs) (N = 224), and rituximab (N = 67) treatments, respectively. Patients were randomly assigned to training or testing datasets and employing five machine learning (ML) models, with eXtreme Gradient Boosting (XGBoost) area under the curve (AUC = 0.89), Decision Tree (DT) (AUC = 0.80) and Artificial Neural Network (ANN) (AUC = 0.79) selected. Cross-validated with logistic regression and ML finalised five variables (baseline platelet, IP-10, TNF-α, Treg, B cell) for glucocorticoid, eight variables (baseline platelet, TGF-β1, MCP-1, IL-21, Th1, Treg, MK number, TPO) for TPO-RAs, and three variables (IL-12, Breg, MAIPA-) for rituximab to establish the predictive model. Spearman correlation and receiver operating characteristic curve analysis in validation datasets demonstrated strong correlations between response fractions and scores in all treatments. Scoring thresholds SGlu ≥ 3 (AUC = 0.911, 95% CI, 0.865-0.956), STPO-RAs ≥ 5 (AUC = 0.964, 95% CI 0.934-0.994), and SRitu = 3 (AUC = 0.964, 95% CI 0.915-1.000) indicated ineffectiveness in glucocorticoid, TPO-RAs, and rituximab therapy, respectively. Regression analysis and ML established a tentative and preliminary predictive scoring model for advancing individualised treatment.

Immune thrombocytopenia is caused by autoantibodies against surface antigens on platelets. Since only about 50 % of cases will allow the identification of glycoprotein-specific antibodies, ITP remains a diagnosis of exclusion. Apart from EDTA-induced pseudo thrombocytopenia, other diseases like secondary thrombocytopenia due to medication, a large number of other disease and hereditary thrombocytopenias must be taken into account. The first-line therapy of ITP includes corticosteroids and intravenous immunoglobulins. The second line consists of thrombopoietin receptor agonists, rituximab, or splenectomy. For further lines of therapy, Fostamatinib and non-steroidal immunosuppressives are available.

Sovleplenib, a novel spleen tyrosine kinase (SYK) inhibitor, showed promising safety and activity in patients with primary immune thrombocytopenia in a phase 1b/2 trial. We aimed to evaluate the efficacy and safety of sovleplenib in patients with chronic primary immune thrombocytopenia.

This randomised, double-blind, placebo-controlled, phase 3 trial (ESLIM-01) was done in 34 clinical centres in China. Eligible patients, aged 18-75 years, had chronic primary immune thrombocytopenia, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and received one or more previous treatments. Patients were randomly assigned (2:1) to receive oral sovleplenib or placebo, 300 mg once daily, for 24 weeks. Randomisation was stratified by baseline platelet counts, previous splenectomy, and concomitant treatment for anti-immune thrombocytopenia at baseline. The primary endpoint was durable response rate (proportion of patients with a platelet count of ≥50 × 109/L on at least four of six scheduled visits between weeks 14 and 24, not affected by rescue treatment) assessed by intention-to-treat. The trial is registered with ClinicalTrials.gov, NCT05029635, and the extension, open-label phase is ongoing.

Between Sept 29, 2021, and Dec 31, 2022, 188 patients were randomly assigned to receive sovleplenib (n=126) or placebo (n=62). 124 (66%) were female, 64 (34%) were male, and all were of Asian ethnicity. Median previous lines of immune thrombocytopenia therapy were 4·0, and 134 (71%) of 188 patients had received previous thrombopoietin or thrombopoietin receptor agonist. The primary endpoint was met; durable response rate was 48% (61/126) with sovleplenib compared with zero with placebo (difference 48% [95% CI 40-57]; p<0·0001). The median time to response was 8 days with sovleplenib compared with 30 days with placebo. 125 (99%) of 126 patients in the sovleplenib group and 53 (85%) of 62 in the placebo group reported treatment-emergent adverse events (TEAEs), and most events were mild or moderate. Frequent TEAEs of grade 3 or higher for sovleplenib versus placebo were platelet count decreased (7% [9/126] vs 10% [6/62]), neutrophil count decreased (3% [4/126] vs 0% [0/62]), and hypertension (3% [4/126] vs 0% [0/62]). Incidences of serious TEAEs were 21% (26/126) in the sovleplenib group and 18% (11/62) in the placebo group. There were no deaths in the study.

Sovleplenib showed a clinically meaningful sustained platelet response in patients with chronic primary immune thrombocytopenia, with a tolerable safety profile and improvement in quality of life. Sovleplenib could be a potential treatment option for patients with immune thrombocytopenia who received one or more previous therapy.

HUTCHMED and Science and Technology Commission of Shanghai Municipality.

Background and Objectives: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by the autoantibody-mediated destruction of platelets. The treatment of ITP aims to maintain a sufficient platelet count to prevent bleeding. First-line treatment options include corticosteroids and intravenous immunoglobulin (IVIg), while second-line treatments include splenectomy, rituximab and other immunosuppressive agents, and thrombopoietin (TPO) receptor agonists. This study aims to discuss the treatment methods and results from 100 patients with ITP at the Muğla Training and Research Hospital through a pharmacological approach. Materials and Methods: Demographic characteristics, clinical findings, bone marrow aspiration and biopsy results, and treatments and treatment responses at the time of diagnosis of the 100 patients with ITP who were treated and followed up in the period 2015-2023 were evaluated retrospectively. Results: In the third month after treatment, the overall response percentage was 100% in patients who received steroids only and 88% in patients who received IVIg treatment alone or in combination with steroids (p > 0.05). The most preferred second-line treatments were splenectomy (41%), eltrombopag (26%), and rituximab (10%). Bone marrow biopsy was performed in 54% of patients, where 35.1% showed increased megakaryocytes, 44.4% adequate megakaryocytes, and 14.8% decreased megakaryocytes. It is noted that eltrombopag and rituximab, in particular, yield higher complete remission rates than immunosuppressive drugs. Conclusions: Considering the side effects of immunosuppressive medications, IVIg, splenectomy, and steroid therapy, the use of new agents such as eltrombopag, which are easily tolerated and have a lower risk of side effects, is expected to increase.

Platelet α-granules are rich in transforming growth factor β1 (TGF-β1), which is associated with myeloid-derived suppressor cell (MDSC) biology. Responders to thrombopoietin receptor agonists (TPO-RAs) revealed a parallel increase in the number of both platelets and MDSCs. Here, anti-CD61 immune-sensitized splenocytes were transferred into severe combined immunodeficient mice to establish an active murine model of immune thrombocytopenia (ITP). Subsequently, we demonstrated that TPO-RAs augmented the inhibitory activities of MDSCs by arresting plasma cells differentiation, reducing Fas ligand expression on cytotoxic T cells, and rebalancing T-cell subsets. Mechanistically, transcriptome analysis confirmed the participation of TGF-β/Smad pathways in TPO-RA-corrected MDSCs, which was offset by Smad2/3 knockdown. In platelet TGF-β1-deficient mice, TPO-RA-induced amplification and enhanced suppressive capacity of MDSCs was waived. Furthermore, our retrospective data revealed that patients with ITP achieving complete platelet response showed superior long-term outcomes compared with those who only reach partial response. In conclusion, we demonstrate that platelet TGF-β1 induces the expansion and functional reprogramming of MDSCs via the TGF-β/Smad pathway. These data indicate that platelet recovery not only serves as an end point of treatment response but also paves the way for immune homeostasis in immune-mediated thrombocytopenia.

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by an isolated decrease in platelet count and an increased risk of bleeding. The pathogenesis is complex, affecting multiple components of the immune system and causing both peripheral destruction of platelets and inadequate production in the bone marrow. In this article, we review the treatment of ITP from a historical perspective, discussing first line and second line treatments, and management of refractory disease.

Few studies have reported the real-world use of both romiplostim and eltrombopag in immune thrombocytopenia (ITP). TRAIT was a retrospective observational study aimed to evaluate the platelet responses and adverse effects associated with the use of these thrombopoietin receptor agonists (TPO-RAs) in adult patients with ITP in the United Kingdom. Of 267 patients (median age at diagnosis, 48 years) with ITP (primary ITP [n = 218], secondary ITP [n = 49]) included in the study, 112 (42%) received eltrombopag and 155 (58%) received romiplostim as the first prescribed TPO-RA. A platelet count ≥30 × 109/L was achieved in 89% of patients with the first TPO-RA treatments, while 68% achieved a platelet count ≥100 × 109/L. Treatment-free response (TFR; platelet count ≥30 × 109/L, 3 months after discontinuing treatment) was achieved by 18% of the total patients. Overall, 61 patients (23%) switched TPO-RAs, most of whom achieved platelet counts ≥30 × 109/L with the second TPO-RA (23/25 who switched from eltrombopag to romiplostim [92%]; 28/36 who switched from romiplostim to eltrombopag [78%]). TFR was associated with secondary ITP, early TPO-RA initiation after diagnosis, the presence of comorbidity and no prior splenectomy or treatment with steroids or mycophenolate mofetil. Both TPO-RAs had similar efficacy and safety profiles to those reported in clinical studies.

Avatrombopag (AVA) is a novel thrombopoietin receptor agonist (TPO-RA) that has been recently approved as a second-line therapy for immune thrombocytopenia (ITP) in adults; however, its safety and efficacy data in children are lacking. Here, we demonstrated the efficacy and safety of AVA as second-line therapy in children with ITP. A multicentre, retrospective, observational study was conducted in children with persistent or chronic ITP who did not respond to or relapsed from previous treatment and were treated with AVA for at least 12 weeks between August 2020 and December 2022. The outcomes were the responses (defined as achieving a platelet count ≥30 × 109/L, twofold increase in platelet count from baseline and absence of bleeding), including rapid response within 4 weeks, sustained response at weeks 12 and 24, bleeding control and adverse events (AEs). Thirty-four (18 males) patients with a mean age of 6.3 (range: 1.9-15.3) years were enrolled. The median number of previous treatment types was four (range: 1-6), and 41.2% patients switched from other TPO-RAs. Within 4 weeks, overall response (OR) was achieved in 79.4% patients and complete response (CR, defined as a platelet count ≥100 × 109/L and the absence of bleeding) in 67.7% patients with a median response time of 7 (range: 1-27) days. At 12 weeks, OR was achieved in 88.2%, CR in 76.5% and sustained response in 44% of patients. At 24 weeks, 22/34 (64.7%) patients who achieved a response and were followed up for 24 weeks were evaluated; 12/22 (54.55%) achieved a sustained response. During AVA therapy, median platelet counts increased by week 1 and were maintained throughout the treatment period. The proportion of patients with grade 1-3 bleeding decreased from 52.95% at baseline to 2.94% at 12 weeks, while concomitant ITP medications decreased from 36.47% at baseline to 8.82% at 12 weeks, with only 9 (26.47%) patients receiving rescue therapy 23 times within 12 weeks. There were 61.8% patients with 59 AEs: 29.8% with Common Terminology Criteria for Adverse Events grade 1 and the rest with grade 2. These findings show that AVA could achieve a rapid and sustained response in children with persistent or chronic ITP as a second-line treatment, with good clinical bleeding control and reduction of concomitant ITP therapy, without significant AEs.

Immune thrombocytopenia (ITP) management with co-existing acute coronary syndrome (ACS) remains challenging as it requires a clinically relevant balance between the risk and outcomes of thrombosis and the risk of bleeding. However, the literature evaluating the treatment approaches in this high-risk population is scarce.

In this review, we aimed to summarize the available literature on the safety of ITP first- and second-line therapies to provide a practical guide on the management of ITP co-existing with ACS. We recommend holding antithrombotic therapy, including antiplatelet agents and anticoagulation, in severe thrombocytopenia with a platelet count < 30 × 109/L and using a single antiplatelet agent when the platelet count falls between 30 and 50 × 109/L. We provide a stepwise approach according to platelet count and response to initial therapy, starting with corticosteroids, with or without intravenous immunoglobulin (IVIG) with a dose limit of 35 g, followed by thrombopoietin receptor agonists (TPO-RAs) to a target platelet count of 200 × 109/L and then rituximab.

Our review may serve as a practical guide for clinicians in the management of ITP co-existing with ACS.

Eltrombopag has demonstrated efficacy in treating low platelet (PLT) levels, but it remains unclear whether eltrombopag can promote PLT engraftment after hematopoietic stem cell transplantation (HSCT).

Forty-one HSCT patients received eltrombopag 50 mg/d from +1 day until PLT >50 × 109/L or 1 month after HSCT. Fifty-one patients in the same period received thrombopoietin (TPO) to promote PLT graft after HSCT and served as a control group.

A total of 51 patients who applied TPO during the same period were treated as a control. In the eltrombopag group, the median time to white blood cells (WBC) graft was 12 days (range, 10-17 days) and the PLT graft was 15 days (range, 10-30 days), whereas for the patients in the TPO group, the median time to WBC and PLT graft was 12 days (range, 9-23 days) and 15.5 days (range, 9-41 days), respectively. In the first month after HSCT, the median WBC count in the eltrombopag group was 4.41 × 109/L (range, 0.87-40.01 × 109/L) and the median PLT was 89x109/L (range, 30-401 × 109/L); the median WBC and PLT \counts in the TPO group were 4.65 × 109/L (range, 0.99-23.63 × 109/L) and 86 × 109/L (range, 5-512 × 109/L), respectively. Patients in the TPO or eltrombopag group did not experience serious side effects after drug administration, and the difference in side effects on liver and kidney function between the two groups was not statistically significant.

Eltrombopag is safe and similarly promotes platelet engraftment to thrombopoietin after allogeneic HSCT.

The Kids' ITP Tools (KIT) is a questionnaire to assess quality of life of children with immune thrombocytopenia (ITP). The aim of this study was to update this previously validated tool to align with changes in clinical practice, specifically, treatment with thrombopoietin receptor agonists (TPO-RAs). Children aged 1-18 with ITP and/or their families were recruited to participate in interviews to review the KIT. Twenty-six interviews were conducted. Based on interview data from children and families, current guidelines, and expert opinion, five changes were made to the KIT in order to improve its face validity.

Mechanisms governing the maintenance of blood-producing hematopoietic stem and multipotent progenitor cells (HSPCs) are incompletely understood, particularly those regulating fate, ensuring long-term maintenance, and preventing aging-associated stem cell dysfunction. We uncovered a role for transitory free cytoplasmic iron as a rheostat for adult stem cell fate control. We found that HSPCs harbor comparatively small amounts of free iron and show the activation of a conserved molecular response to limited iron-particularly during mitosis. To study the functional and molecular consequences of iron restriction, we developed models allowing for transient iron bioavailability limitation and combined single-molecule RNA quantification, metabolomics, and single-cell transcriptomic analyses with functional studies. Our data reveal that the activation of the limited iron response triggers coordinated metabolic and epigenetic events, establishing stemness-conferring gene regulation. Notably, we find that aging-associated cytoplasmic iron loading reversibly attenuates iron-dependent cell fate control, explicating intervention strategies for dysfunctional aged stem cells.

We aimed to investigate the safety and effectiveness of eltrombopag for adult patients with refractory immune thrombocytopenia (ITP) secondary to connective tissue disease (CTD).

This is a single-centre, retrospective cohort and propensity score-matched study. Data from CTD-ITP patients treated with eltrombopag between January 2019 and January 2023 were retrospectively analysed. Baseline characteristics and follow-up information were recorded. CTD patients without ITP were matched to identify the risk factors associated with CTD-ITP performed by Logistic regression analysis.

Twenty patients were enrolled, including 5 systemic lupus erythematosus (SLE), 9 Sjögren's syndrome (SS) and 6 undifferentiated connective tissue disease (UCTD). Nineteen (95%) patients were female, and the median age was 59 years. Logistic regression analysis showed that anaemia (OR = 8.832, P = 0.007) was associated with increased risk of ITP, while non-erosive arthritis (OR = 0.045, P = 0.001) and interstitial lung disease (OR = 0.075, P = 0.031) were associated with reduced risk. Fourteen patients (70%) achieved a complete response (CR) and one (5%) achieved a partial response (PR). The median response time was 14 days. The median platelet count was 8.5 × 109/l at baseline of eltrombopag and increased to 122 × 109/l after 4 weeks. No adverse events were observed.

Eltrombopag appears to be effective, safe and well-tolerated in refractory ITP patients with CTD; larger studies are needed to confirm the generalizability of these findings.

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.

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by low platelet counts and increased risk of bleeding. After corticosteroids with or without intravenous immune globulin (first-line treatment), second-line treatment options include rituximab, splenectomy, thrombopoietin receptor agonists (TPO-RAs), and fostamatinib. In Canada, the choice of second-line therapy is influenced by access to medications. The goals of this narrative review are to 1) summarize the evidence for the use of TPO-RAs and other second-line therapies in ITP and 2) highlight differences in public funding criteria for TPO-RAs across provinces and territories in Canada.

We conducted a literature review of second-line therapies for ITP. We solicited information on public funding programs for TPO-RAs in Canada from health care providers, pharmacists, and provincial ministries of health.

Head-to-head trials involving TPO-RAs, rituximab, splenectomy, and fostamatinib are lacking. There is substantial evidence of effect for TPO-RAs in improving platelet count levels, health-related quality of life, bleeding, and fatigue from placebo-controlled trials and observational studies; however, access to TPO-RAs through provincial funding programs in Canada is variable. Splenectomy failure is a prerequisite for the funding of TPO-RAs in Ontario, Manitoba, and Saskatchewan, but not in Alberta or Quebec. Other provinces either do not have access to public funding or funding is provided on a case-by-case basis.

TPO-RAs are effective second-line therapies for the treatment of ITP; however, access is variable across Canada, which results in health disparities and poor uptake of international treatment guidelines.

Immune thrombocytopenia (ITP) is a rare autoimmune condition, due to peripheral platelet destruction through antibody-dependent cellular phagocytosis, complement-dependent cytotoxicity, cytotoxic T lymphocyte-mediated cytotoxicity, and megakaryopoiesis alteration. This condition may be idiopathic or triggered by drugs, vaccines, infections, cancers, autoimmune disorders and systemic diseases. Recent advances in our understanding of ITP immunobiology support the idea that other forms of thrombocytopenia, for instance, occurring after immunotherapy or cellular therapies, may share a common pathophysiology with possible therapeutic implications. If a decent pipeline of old and new agents is currently deployed for classical ITP, in other more complex immune-mediated thrombocytopenic disorders, clinical management is less harmonized and would deserve further prospective investigations. Here, we seek to provide a fresh overview of pathophysiology and current therapeutical algorithms for adult patients affected by this disorder with specific insights into poorly codified scenarios, including refractory ITP and post-immunotherapy/cellular therapy immune-mediated thrombocytopenia.

Immune thrombocytopenia (ITP), a disease that commonly presents with an increased risk of bleeding, can also paradoxically produce an increased risk of thromboembolic events. The risk of thromboembolism can be associated with patient-related factors (e.g. co-morbidities, age and history of thrombosis), disease-related factors (e.g. a greater proportion of younger, more reactive platelets, and the presence of microparticles and pro-inflammatory cytokines) and treatment-related factors (e.g. splenectomy, thrombopoietin receptor agonists, and IVIg).

Aspects of the pathophysiology of ITP and the effects of treatment are discussed with emphasis on individualizing treatment based on the patient's thromboembolic risk, treatment options and preferences.

An increased understanding of the pathophysiology of ITP has led to the development of new agents such as fostamatinib, a spleen tyrosine kinase inhibitor. Further research into the factors contributing to the risks for bleeding and thromboembolic events can contribute to the development of more specific therapies for ITP and allow greater individualization of therapy based on each patient's medical history and clinical status.