Rituximab as a treatment for refractory immune thrombocytopenia during pregnancy.

Immune thrombocytopenia (ITP) is most common in women during their reproductive years. When a low platelet count occurs for the first time during pregnancy, the differential diagnosis includes pregnancy-specific conditions. Although ITP is the most common cause of thrombocytopenia early in pregnancy, pregnancy-related thrombocytopenia develops mainly in late gestation. As maternal and neonatal outcomes are usually favourable, ITP per se is not a contraindication for pregnancy. We report the case with a literature review of patient with ITP, whose diagnosis was established in early pregnancy. This condition was refractory to first-line treatments, such as high-dose steroids and intravenous immunoglobulin and other splenectomy-sparing approaches, as rituximab, having the control been reached on the third trimester after splenectomy. Although not effective in this case, we still believe that rituximab should be considered before surgery during pregnancy.

The role of platelet desialylation as a biomarker in primary immune thrombocytopenia: mechanisms and therapeutic perspectives.

Primary immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by the destruction of platelets. Although it was long believed that the critical role of autoantibodies in platelet destruction, primarily through the Fc-dependent platelet clearance pathway, recent findings indicate that the significance of the Fc-independent platelet clearance pathway mediated by hepatocytes, thus shedding light on a previously obscure aspect of ITP pathogenesis. Within this context, the desialylation of platelets has emerged as a pivotal biochemical marker. Consequently, targeting platelet desialylation emerges as a novel therapeutic strategy in the pathogenesis of ITP. Notably, prevailing research has largely focused on antiplatelet antibodies and the glycosylation-associated mechanisms of platelet clearance, while comprehensive analysis of platelet desialylation remains scant. In response, we retrospectively discuss the historical progression, inducing factors, generation process, and molecular regulatory mechanisms underlying platelet desialylation in ITP pathogenesis. By systematically evaluating the most recent research findings, we contribute to a comprehensive understanding of the intricate processes involved. Moreover, our manuscript delves into the potential application of desialylation regulatory strategies in ITP therapy, heralding novel therapeutic avenues. In conclusion, this manuscript not only fills a critical void in existing literature but also paves the way for future research by establishing a systematic theoretical framework. By inspiring new research ideas and offering insights into the development of new therapeutic strategies and targeted drugs, our study is poised to significantly advance the clinical management of ITP.

A Case of Intravenous IVIg Interfering with Serological Test Results of HBV.

BACKGROUND: Since Imbach [1] first reported the use of high-dose intravenous immunoglobulin (IVIg) in the treatment of idiopathic thrombocytopenic purpura (ITP) in children, indications for IVIg therapy have been increaseing. At present, IVIg infusion has become an important means of clinical treatment. The phenomenon of anti-HBs and anti-HBc elevation caused by IVIg infusion in patients has been reported in journals, but similar reports in journals related to laboratory diagnosis are rare. METHODS: We reported a case of a patient with immune thrombocytopenia (ITP) which interfered with hepatitis B virus (HBV) serological detection after receiving intravenous IVIg. We used chemiluminescence immunoassay to detect serological markers of HBV. IU/mL was used to represent the detection data of HBsAg and HBsAb and cutoff value was used to represent the detection HBeAg, HBeAb, and HbcAb. RESULTS: The serological markers of HBV were all negative before IVIg infusion. One week after IVIG infusion, the item was tested again, and the results of HBsAb, HBeAb, and HBcAb were positive. As the time increased after infusion, HBsAb, HBeAb, and HBcAb in the patient gradually decreased. CONCLUSIONS: After IVIg infusion, the sudden positive change of HBsAb, HBeAb, and HbcAb in the patient's body was not caused by HBV infection, but caused by the infusion of foreign antibody. This case study shows that physicians should be particularly careful when interpreting results in patients treated with intravenous IVIg involving viral hepatitis B.

Differential alterations of CXCR3, CXCR5 and CX3CR1 in patients with immune thrombocytopenia.

As a versatile element for maintaining homeostasis, the chemokine system has been reported to be implicated in the pathogenesis of immune thrombocytopenia (ITP). However, research pertaining to chemokine receptors and related ligands in adult ITP is still limited. The states of several typical chemokine receptors and cognate ligands in the circulation were comparatively assessed through various methodologies. Multiple variable analyses of correlation matrixes were conducted to characterize the correlation signatures of various chemokine receptors or candidate ligands with platelet counts. Our data illustrated a significant decrease in relative CXCR3 expression and elevated plasma levels of CXCL4, 9-11, 13, and CCL3 chemokines in ITP patients with varied platelet counts. Flow cytometry assays revealed eminently diminished CXCR3 levels on T and B lymphocytes and increased CXCR5 on cytotoxic T cell (Tc) subsets in ITP patients with certain platelet counts. Meanwhile, circulating CX3CR1 levels were markedly higher on T cells with a concomitant increase in plasma CX3CL1 level in ITP patients, highlighting the importance of aberrant alterations of the CX3CR1-CX3CL1 axis in ITP pathogenesis. Spearman's correlation analyses revealed a strong positive association of peripheral CXCL4 mRNA level, and negative correlations of plasma CXCL4 concentration and certain chemokine receptors with platelet counts, which might serve as a potential biomarker of platelet destruction in ITP development. Overall, these results indicate that the differential expression patterns and distinct activation states of peripheral chemokine network, and the subsequent expansion of circulating CXCR5+ Tc cells and CX3CR1+ T cells, may be a hallmark during ITP progression, which ultimately contributes to thrombocytopenia in ITP patients.

The Differences of Serum Thrombopoietin Levels Between Acquired Aplastic Anemia and Immune Thrombocytopenia in Pediatric Patients.

Thrombopoietin (TPO) is the critical regulator of platelet production. However, the role of TPO in pediatric patients with thrombocytopenic disorders has not been fully elucidated. In the present study, we attempted to investigate serum TPO levels in patients with acquired aplastic anemia (aAA) and immune thrombocytopenia (ITP). We analyzed the endogenous plasma concentration of TPO and platelet count at the time of TPO measurement in 166 patients with aAA and 280 patients with ITP retrospectively. We further observed a correlation between platelet counts and TPO. Serum TPO levels were significantly higher in aAA compared with ITP (1142 vs. 77.99 pg/mL, P <0.001). In patients with aAA, an elevation for TPO levels in very severe AA (VSAA) was seen when compared with non-severe AA (NSAA) (1360 vs. 984.4 pg/mL, P <0.05). In contrast, the circulating TPO levels with chronic ITP (CITP) showed a decrease than newly diagnosed ITP (NITP) and persistent ITP (PITP) (62.28 vs. 81.56 pg/mL, P <0.01, 62.28 vs. 87.82 pg/mL, P <0.05, respectively). There was a negative correlation between platelet counts and TPO levels in aAA (r s =-0.3325, P <0.001) as well as ITP (r s =-0.2570, P <0.001). Especially, TPO levels were inversely correlated with platelet counts in NSAA (r s =-0.3672, P <0.001) and NITP (r s =-0.3316, P <0.001). After grouping by age or sex, there were no statistical differences in aAA or ITP. Serum TPO levels were markedly elevated in pediatric patients with aAA compared with ITP. It was higher in VSAA and lower in CITP, suggesting that serum TPO level could play a role in classifying disease severity or clinical course in aAA and ITP.

The early and rapid response to daratumumab in children with chronic refractory immune thrombocytopenia from a referral single centre of China.

Chronic refractory primary immune thrombocytopenia (CRITP) is currently defined as refractory to multiple therapeutic of second-line agents with or without splenectomy, faced with the threat of severe bleeding and challenging to obtain effective treatment. Although stable and effective drug therapy is needed, it is tough to find one. Daratumumab (Dara), an anti-CD38 monoclonal antibody presented the target cloned plasma cells in multiple myeloma, has also been reported to be effective in refractory autoimmune cytopenia in some case or series reports and ongoing clinical trials for adult patients with CRITP. Here, we report the early and durable response of Dara combination with avatrombopag in three CRITP patients (2 male and 1 female aged 12, 5 and 7 years, respectively) in our centre, with a follow-up period of more than 25 weeks. Before Dara, the duration of immune thrombocytopenia was 9, 1.4 and 4 years, respectively, a baseline platelet count of 4, 6, 9 × 109/L, the bleeding score was all above level 2 and the number of previous drugs was >3. The time to response (R: Plt ≥30 × 109/L with at least a twofold increase in the baseline count) of Dara was on Day 45, 6 and 4 and achieved complete response (CR: Plt ≥100 × 109/L) on Day 51, 6 and 8, the sustained response (SR: Plt >30 × 109/L following Dara at ≥75% of the platelet count assessment at follow-up end-point since the patient achieved response) was 48, 175 and 204 days with the follow-up time of 39.1, 25.9 and 29.7 weeks. The bleeding score decreased from grade 3 to grade 0 during follow-up. No significant treatment-related adverse events were found during follow-up. Dara combination with avatrombopag may be a safe and efficacious therapy for children with CRITP, but it needs to be further explored.

The long-term efficacy of eltrombopag in children with immune thrombocytopenia.

Immune thrombocytopenia (ITP) is the most common autoimmune disorder characterized by decreased platelet counts and impaired platelet production. Eltrombopag has been demonstrated to be safe and effective for children with ITP. It is reported eltrombopag can achieve a sustained response off treatment. However, data on its overall efficacy and safety profile are scarce in children. This study aimed to investigate the long-term efficacy of eltrombopag in children with ITP. Treatment overall response (OR), complete response (CR), response (R), durable response (DR), no response (NR), treatment free remission (TFR), and relapse rate, were assessed in 103 children with ITP during eltrombopag therapy. The OR rate, CR rate, R rate, DR rate, NR rate, TFR rate, and relapse rate were 67.0%, 55.3%, 11.7%, 56.3%, 33.0%, 60%, 36.2%, respectively. Importantly, we discovered that newly diagnosed ITP patients showed a higher DR rate, TFR rate and lower relapse rate compared to persistent and chronic ITP patients. Furthermore, the CR rate, DR rate, and TFR rate of 5 patients under six months were 100%. None of them suffered relapse. The most common adverse event (AEs) was hepatotoxicity (7.77%). Our study highlighted the critical role of eltrombopag as the second-line treatment in children with ITP who were intolerant to first-line therapy.

Switching from eltrombopag to hetrombopag in patients with primary immune thrombocytopenia: a post-hoc analysis of a multicenter, randomized phase III trial.

While studies have explored the feasibility of switching between various thrombopoietin receptor agonists in treating immune thrombocytopenia (ITP), data on the switching from eltrombopag to hetrombopag remains scarce. This post-hoc analysis of a phase III hetrombopag trial aimed to assess the outcomes of ITP patients who switched from eltrombopag to hetrombopag. In the original phase III trial, patients initially randomized to the placebo group were switched to eltrombopag. Those who completed this 14-week eltrombopag were eligible to switch to a 24-week hetrombopag. Treatment response, defined as a platelet count of ≥ 50 × 109/L, and safety were evaluated before and after the switch. Sixty-three patients who completed the 14-week eltrombopag and switched to hetrombopag were included in this post-hoc analysis. Response rates before and after the switch were 66.7% and 88.9%, respectively. Among those with pre-switching platelet counts below 30 × 109/L, eight out of 12 patients (66.7%) responded, while eight out of nine patients (88.9%) with pre-switching platelet counts between 30 × 109/L and 50 × 109/L responded post-switching. Treatment-related adverse events were observed in 50.8% of patients during eltrombopag treatment and 38.1% during hetrombopag treatment. No severe adverse events were noted during hetrombopag treatment. Switching from eltrombopag to hetrombopag in ITP management appears to be effective and well-tolerated. Notably, hetrombopag yielded high response rates, even among patients who had previously shown limited response to eltrombopag. However, these observations need to be confirmed in future trials.

Comprehensive analysis of the clinical manifestations and hematological parameters associated with secondary immune thrombocytopenia in patients with primary Sjögren syndrome: An observational study.

Primary Sjögren Syndrome (pSS) is a chronic autoimmune disease that primarily affects exocrine glands and can lead to various extraglandular manifestations, including secondary immune thrombocytopenia (ITP). Understanding the clinical and hematological differences in pSS patients with and without secondary ITP is crucial for improved patient management and treatment strategies. This retrospective study, conducted from January 2020 to December 2023, involved a cohort of pSS patients, dividing them into 2 groups: those with secondary ITP and those without. Patients were evaluated using the European League Against Rheumatism Sjögren Syndrome Disease Activity Index (ESSDAI), EULAR Sjögren Syndrome Patient-Reported Index (ESSPRI), Health Assessment Questionnaire, and other hematological parameters. Inclusion criteria were based on the American-European Consensus Group or ACR/EULAR classification criteria for pSS. Exclusion criteria included other autoimmune or hematological disorders, prior splenectomy, recent blood transfusions, and lack of informed consent. Statistical analysis was performed using SPSS software, with various tests applied to analyze the data, including logistic regression to identify risk factors for secondary ITP. Significant differences were noted in fatigue, lymphadenopathy, arthritis, mean age, and ESSDAI scores between the secondary ITP and non-secondary ITP groups. Patients with secondary ITP exhibited higher platelet counts, more prevalent lymphopenia, higher immunoglobulin G (IgG) levels, lower complement 3 levels, and reduced white blood cell and hemoglobin levels. Logistic regression analysis identified lymphadenopathy as a risk factor and arthritis as a protective factor for the development of secondary ITP. The study reveals distinct clinical and hematological characteristics in pSS patients with secondary ITP, suggesting a higher disease activity in this subset. These findings underscore the need for further exploration of these associations to develop more precise treatment approaches for pSS, focusing on preventing secondary ITP and improving patient outcomes.

Effect of ADSCs on Th17/Treg and T-bet/GATA-3 in model mice with primary immune thrombocytopenia.

We aimed to observe the effects of adipose-derived mesenchymal stem cells (ADSCs) on T helper 17 (Th17)/regulatory T cells (Treg) and T-box transcription factor (T-bet)/GATA-binding protein 3 (GATA-3) in model mice with primary immune thrombocytopenia (ITP). 32 BALB/C mice were selected. ADSCs were isolated from 2 mice and cultured. The other 30 mice were randomly divided into the normal control group, the ITP model control group, and the ITP experimental group. Platelet count (PLT), Th17/Treg cells, related serum cytokines [interleukin-6 (IL-6), IL-17A, IL-10, and transforming growth factor ß1 (TGF-ß1)], T-bet and GATA-3 mRNA levels in peripheral blood mononuclear cells (PBMCs) in the 3 groups were detected. PLT and Treg in the ITP experimental group were significantly lower than those in the normal control group (P<0.05), but significantly higher than those in the ITP model control group (P<0.05). Th17 and Th17/Treg in the ITP experimental group were significantly higher than those in the normal control group (P<0.05), but significantly lower than those in the ITP model control group (P<0.05). Serum IL-6 and IL-17A levels, and T-bet mRNA levels in the ITP experimental group were significantly higher than those in the normal control group (P<0.05), but significantly lower than those in the ITP model control group (P<0.05). Serum IL-10 and TGF-ß levels, and GATA-3 mRNA levels in the ITP experimental group were significantly lower than those in the normal control group (P<0.05), but significantly higher than those in the ITP model control group (P<0.05). ADSCs can effectively regulate Th17/Treg balance and improve T-bet/GATA-3 mRNA expression levels in ITP model mice.

Broadening the horizon of immune thrombocytopenia through Omics approaches.

Immune thrombocytopenia (ITP) is a highly heterogeneous autoimmune bleeding disorder characterized by low platelet counts due to an immune-mediated platelet destruction and impaired platelet production. The pathophysiology is multifactorial and remains to be fully unravelled. Consequently, disease trajectories and responses to therapeutics, despite the availability of multiple agents, can be unpredictable and differing between patients. There is an urgent need for the identification of diagnostic and therapeutic biomarkers, but this has proven to be challenging to achieve. To shed light on this, two studies in this issue of the British Journal of Haematology have recognized the opportunity of using high-throughput Omics technologies in ITP. Sun et al. performed proteomics, and Li et al. metabolomics, on bone marrow biopsy samples of patients with ITP. This was conducted using mass spectrometry and, due to the generation of large datasets, in combination with machine learning. These studies set the stage for further investigations exploring the high potential of multi-omics technologies in order to shed light on the heterogeneity in ITP, accelerating the path towards a much needed personalized medicine approach. Commentary on: Li et al. Metabolomics profile and machine learning prediction of treatment responses in immune thrombocytopenia: A prospective cohort study. Br J Haematol 2024;204:2405-2417. Commentary on: Sun et al. Proteomics landscape and machine learning prediction of long-term response to splenectomy in primary immune thrombocytopenia. Br J Haematol 2024;204:2418-2428.

Hemostatic mechanism of Jianpi Yiqi Shexue decoction in treatment of immune thrombocytopenia.

OBJECTIVE: To explore the early hemostatic mechanism of Jianpi Yiqi Shexue decoction (, JYSD) in treating immune thrombocytopathy (ITP), based on the functional homeostasis of brain-intestine axis and blood neurotransmitter METHODS: Non-drug treatment cases: Healthy volunteers were selected as normal control group and compared with patients with dysfunctional uterine bleeding, gastrointestinal tumors with bleeding and ITP, to detect the changes of blood 5-hydroxytryptamine (5-HT), ß-endorphin (ß-EP), vasoactive intestinal peptide (VIP) and compare the changes of blood neuro-transmitters in patients with different disease symptoms. Drug treatment cases: According to the randomized controlled multicenter clinical trial, 272 ITP patients were randomly divided into three groups: treatment group (JYSD) combined group (JYSD + Prednisone) control group (Prednisone). The changes of blood neuro-transmitter (5-HT, ß-EP, VIP) before and after treatment were detected on the basis of peripheral blood platelet (PLT) and grade score. RESULTS: Non-drug treatment cases: compared with the normal control group, the 5-HT level was higher, and the VIP and ß-EP levels were both lower in the ITP group (P < 0.001), and the 5-HT, VIP and ß-EP levels in the Gastrointestinal tumors with bleeding group were also lower compared with the normal control group (P < 0.05, 0.001). Drug treatment cases: The PLT grading scores of the combination group and the control group after treatment were lower than that before treatment (P < 0.05, 0.001). The PLT grading score of the 3 groups were compared in pairs after treatment: the combination group was the lowest among the 3 groups, which was better than the treatment group, but no better than the control group (vs the treatment group, P = 0.005, vs the control group, P = 0.709). The statistical results of full analysis set (FAS) and per protocol set (PPS) were consistent. The bleeding symptom scores of the treatment and combination groups began to drop 7 d after treatment, and kept dropping 14 d after treatment until the end of the study (P < 0.05). On the other hand, the control group started to show favorable results 14 d after treatment (P < 0.05). The FAS and PPS analysis results were consistent. In the control group, the 5-HT level was higher and VIP level was lower after treatment, compared with those before treatment (P < 0.05, 0.001). The ß-EP levels were both increased in the treatment and combination group after treatment, compared with those before treatment (P < 0.05). After treatment, the ß-EP levels in the treatment and control groups were significantly lower compared with the combination groups (P < 0.05). After treatment, compared with the control group, the VIP levels in the treatment and combination groups were up-regulated, and the differences were statistically significant by rank sum test (P < 0.01), and by t-test (P = 0.0002, 0.0001). CONCLUSIONS: The prednisone tablet is better than the JYSD in increasing the level of PLT, while prednisone tablet combined with JYSD has more advantages in improving patients' peripheral blood PLT levels. However, in improving the bleeding time of ITP patients, the combination of the two drugs was significantly delayed compared with the single usage, showing the characteristics and advantages of traditional Chinese medicine. JYSD can regulate the neurotransmitter level of ITP patients through the function of the brain-gut axis, mobilize 5-HT in the blood of ITP patients to promote the contraction of blood vessels and smooth muscles, and activate the coagulation mechanism are the early hemostatic mechanisms of JYSD. Up-regulate the levels of ß-EP and balancing VIP levels may be an important part of the immune mechanism of JYSD for regulating ITP patients.

Clinical study reveals the efficacy of sirolimus in treating primary immune thrombocytopenia: findings from a single-center study.

Immune thrombocytopenia (ITP) is an autoimmune disease that arises because of self-destruction of circulating platelets. The mechanism remains complicated and lacks a standard clinical treatment. Current first-line and second-line medications for ITP have shown limited effectiveness, necessitating the exploration of new therapeutic options. Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor that has been demonstrated to inhibit lymphocyte activity, indicating potential for SRL in the treatment of ITP. This study aimed to evaluate the clinical efficacy of sirolimus as a second-line drug in patients with ITP. The starting dose of sirolimus for adults ranged from 2 to 4 mg/day, with a maintenance dose of 1 to 2 mg/day. For children, the starting dose was 1-2 mg/day, with a maintenance dose of 0.5-1 mg/day. The dosage could be adjusted if needed to maintain a specific blood concentration of sirolimus, typically between 5 and 15 ng/ml, throughout the treatment period. After 3 months, the overall response rate was 60% (12/20), with 30% of patients (6/20) achieving a complete response (CR) and 30% (6/20) achieving a partial response (PR). The CR rate at 6 months remained consistent with the 3-month assessment. No major adverse events were reported, indicating that sirolimus was well tolerated and safe. Analysis of peripheral blood Treg cell percentages in both the control and ITP showed no significant difference before treatment. The percentage of Treg cells increased after treatment with sirolimus, suggesting that sirolimus increases Treg cells. These findings suggest that sirolimus serves as an effective second-line treatment option for ITP, demonstrating favorable clinical efficacy.

Incidence and risk factors of systemic lupus erythematosus in patients with primary immune thrombocytopenia: a systematic review and meta-analysis.

Background: Immune disorders and autoantibodies has been noted in both primary immune thrombocytopenia (ITP) and systemic lupus erythematosus (SLE). Whether the two disorders are correlated is unclear. The lack of evidence on the incidence of and risk factors for SLE in primary ITP patients poses a challenge for prediction in clinical practice. Therefore, we conducted this study. Methods: The protocol was registered with PROSPERO (CRD42023403665). Web of Science, Cochrane, PubMed, and EMBASE were searched for articles published from inception to 30 September 2023 on patients who were first diagnosed with primary ITP and subsequently developed into SLE. Furthermore, the risk factors were analyzed. Study quality was estimated using the Newcastle-Ottawa Scale. The statistical process was implemented using the R language. Results: This systematic review included eight articles. The incidence of SLE during the follow-up after ITP diagnosis was 2.7% (95% CI [1.3-4.4%]), with an incidence of 4.6% (95% CI [1.6-8.6%]) in females and 0 (95% CI [0.00-0.4%]) in males. Older age (OR = 6.31; 95% CI [1.11-34.91]), positive antinuclear antibody (ANA) (OR = 6.64; 95% CI [1.40-31.50]), hypocomplementemia (OR = 8.33; 95% CI [1.62-42.91]), chronic ITP (OR = 24.67; 95% CI [3.14-100.00]), organ bleeding (OR = 13.67; 95% CI [2.44-76.69]), and female (OR = 20.50; 95% CI [4.94-84.90]) were risk factors for subsequent SLE in ITP patients. Conclusion: Patients with primary ITP are at higher risk of SLE. Specific follow-up and prevention strategies should be tailored especially for older females with positive ANA, hypocomplementemia, or chronic ITP. In subsequent studies, we need to further investigate the risk factors and try to construct corresponding risk prediction models to develop specific prediction strategies for SLE.

High dimensional proteomic mapping of bone marrow immune characteristics in immune thrombocytopenia.

To investigate the role of co-stimulatory and co-inhibitory molecules on immune tolerance in immune thrombocytopenia (ITP), this study mapped the immune cell heterogeneity in the bone marrow of ITP at the single-cell level using Cytometry by Time of Flight (CyTOF). Thirty-six patients with ITP and nine healthy volunteers were enrolled in the study. As soluble immunomodulatory molecules, more sCD25 and sGalectin-9 were detected in ITP patients. On the cell surface, co-stimulatory molecules like ICOS and HVEM were observed to be upregulated in mainly central memory and effector T cells. In contrast, co-inhibitory molecules such as CTLA-4 were significantly reduced in Th1 and Th17 cell subsets. Taking a platelet count of 30×109 L-1 as the cutoff value, ITP patients with high and low platelet counts showed different T cell immune profiles. Antigen-presenting cells such as monocytes and B cells may regulate the activation of T cells through CTLA-4/CD86 and HVEM/BTLA interactions, respectively, and participate in the pathogenesis of ITP. In conclusion, the proteomic and soluble molecular profiles brought insight into the interaction and modulation of immune cells in the bone marrow of ITP. They may offer novel targets to develop personalized immunotherapies.

Metabolomics profile and machine learning prediction of treatment responses in immune thrombocytopenia: A prospective cohort study.

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by antibody-mediated platelet destruction and impaired platelet production. The mechanisms underlying ITP and biomarkers predicting the response of drug treatments are elusive. We performed a metabolomic profiling of bone marrow biopsy samples collected from ITP patients admission in a prospective study of the National Longitudinal Cohort of Hematological Diseases. Machine learning algorithms were conducted to discover novel biomarkers to predict ITP patient treatment responses. From the bone marrow biopsies of 91 ITP patients, we quantified a total of 4494 metabolites, including 1456 metabolites in the positive mode and 3038 metabolites in the negative mode. Metabolic patterns varied significantly between groups of newly diagnosed and chronic ITP, with a total of 876 differential metabolites involved in 181 unique metabolic pathways. Enrichment factors and p-values revealed the top metabolically enriched pathways to be sphingolipid metabolism, the sphingolipid signalling pathway, ubiquinone and other terpenoid-quinone biosynthesis, thiamine metabolism, tryptophan metabolism and cofactors biosynthesis, the phospholipase D signalling pathway and the phosphatidylinositol signalling system. Based on patient responses to five treatment options, we screened several metabolites using the Boruta algorithm and ranked their importance using the random forest algorithm. Lipids and their metabolism, including long-chain fatty acids, oxidized lipids, glycerophospholipids, phosphatidylcholine and phosphatidylethanolamine biosynthesis, helped differentiate drug treatment responses. In conclusion, this study revealed metabolic alterations associated with ITP in bone marrow supernatants and a potential biomarker predicting the response to ITP.

Proteomics landscape and machine learning prediction of long-term response to splenectomy in primary immune thrombocytopenia.

This study aimed to identify key proteomic analytes correlated with response to splenectomy in primary immune thrombocytopenia (ITP). Thirty-four patients were retrospectively collected in the training cohort and 26 were prospectively enrolled as validation cohort. Bone marrow biopsy samples of all participants were collected prior to the splenectomy. A total of 12 modules of proteins were identified by weighted gene co-expression network analysis (WGCNA) method in the developed cohort. The tan module positively correlated with megakaryocyte counts before splenectomy (r = 0.38, p = 0.027), and time to peak platelet level after splenectomy (r = 0.47, p = 0.005). The blue module significantly correlated with response to splenectomy (r = 0.37, p = 0.0031). KEGG pathways analysis found that the PI3K-Akt signalling pathway was predominantly enriched in the tan module, while ribosomal and spliceosome pathways were enriched in the blue module. Machine learning algorithm identified the optimal combination of biomarkers from the blue module in the training cohort, and importantly, cofilin-1 (CFL1) was independently confirmed in the validation cohort. The C-index of CFL1 was >0.7 in both cohorts. Our results highlight the use of bone marrow proteomics analysis for deriving key analytes that predict the response to splenectomy, warranting further exploration of plasma proteomics in this patient population.

Efficacy and safety of avatrombopag in Chinese children with persistent and chronic primary immune thrombocytopenia: A multicentre observational retrospective study in China.

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.