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There are variations in individual eltrombopag concentrations that may impact efficacy and adverse drug reactions (ADRs) in paediatric immune thrombocytopaenia (ITP). To solve this problem, we tailored the eltrombopag dosage refer to concentration, then followed up to assess concentration value in paediatric ITP. This is a single-centre, prospective, observational study. The eltrombopag dosage was adjusted, and children were divided into three groups: the maintenance, discontinuation, and increase groups. Concentration and other data were compared to explore concentration value in guiding the individualized treatment of paediatric ITP. Thirty-nine patients were enrolled, including 23 in the maintenance group, 3 in the discontinued group and 13 in the increase group. 3 patients discontinued eltrombopag due to ADRs, which was significantly higher than patients in the maintenance group (t = 3.606, p = 0.001). In all, 13 patients increased their dosage due to poor response, whose concentration and platelet count were significantly lower than patients in the maintenance group (t = 2.461, p = 0.019; t = 4.633, p < 0.001). Two months after the increase, the number of patients reaching CR and R respectively increased by 2 and 3, while the median platelet count was significantly raised (Z = -2.411, p = 0.016). Concentration could be used as a reference index for the individualized treatment of eltrombopag in paediatric ITP.

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To use proteomic techniques to identify sensitive diagnostic biomarkers for paediatric immune thrombocytopenia (ITP). We selected children in ITP and control groups, using a four-dimensional data-independent acquisition approach (4D-DIA) to analyse its protein expression. The significantly differentially expressed proteins were selected for enzyme-linked immunosorbent assay (ELISA) validation in a cohort comprising 50 samples (13 healthy controls, 15 secondary thrombocytopenia controls and 22 children with ITP). Receiver operating characteristics (ROC) were generated to diagnose ITP and to assess the diagnostic effectiveness of this approach. Compared with the control group, 55 differentially expressed proteins (43 increased and 12 decreased) were determined in the ITP group. Matrix metalloproteinases-9 (MMP-9) and thrombospondin-1 (THBS1) were significantly expressed and selected for ELISA. The verification outcomes aligned with the findings from the proteomic examinations. In contrast to the control cohort, the ITP subjects exhibited markedly elevated plasma MMP-9 levels and reduced plasma THBS1 concentrations. Additionally, the ROC curves indicated the diagnostic value of these biomarkers. In conclusion, proteomics facilitates identifying the sensitive biomarkers for ITP diagnosis. We have preliminarily selected two differentially expressed proteins, MMP-9 and THBS1, whose potential role as biomarkers for diagnosing ITP requires further research.

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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-ß1, 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.

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BACKGROUND: Adenoviral vector-based COVID-19 vaccine-induced immune thrombotic thrombocytopenia (VITT) is rare but carries significant risks of mortality and long-term morbidity. The underlying pathophysiology of severe disease is still not fully understood. The objectives were to explore the pathophysiological profile and examine for clinically informative biomarkers in patients with severe VITT. METHODS: Twenty-two hospitalized patients with VITT, 9 pre- and 21 post-ChAdOx1 vaccine controls, were recruited across England, United Kingdom. Admission blood samples were analyzed for cytokine profiles, cell death markers (lactate dehydrogenase and circulating histones), neutrophil extracellular traps, and coagulation parameters. Tissue specimens from deceased patients were analyzed. RESULTS: There were strong immune responses characterized by significant elevations in proinflammatory cytokines and T helper 1 and 2 cell activation in patients with VITT. Markers of systemic endothelial activation and coagulation activation in both circulation and organ sections were also significantly elevated. About 70% (n = 15/22) of patients met the International Society for Thrombosis and Haemostasis criteria for disseminated intravascular coagulation despite negligible changes in the prothrombin time. The increased neutrophil extracellular trap formation, in conjunction with marked lymphopenia, elevated lactate dehydrogenase, and circulating histone levels, indicates systemic immune cell injury or death. Both lymphopenia and circulating histone levels independently predicted 28-day mortality in patients with VITT. CONCLUSION: The coupling of systemic cell damage and death with strong immune-inflammatory and coagulant responses are pathophysiologically dominant and clinically relevant in severe VITT.

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In children, the majority of cases are self-limiting and thus many paediatric patients can be managed conservatively with minimal complications. This varies considerably compared to adult newly diagnosed immune thrombocytopaenia (NDITP) where, in most cases, thrombocytopaenia persists with higher risk of moderate to severe bleeding complications. In the past decade, local and international guidelines have emerged to support approaches to the investigation and management of NDITP, with a focus primarily on adult immune thrombocytopaenia (ITP). International consensus guidelines on paediatric NDITP have been developed, however gaps remain, and approaches vary between North American, Asia, Europe and the UK. There are no current Australian or New Zealand paediatric ITP guidelines readily available, rather differing guidelines for each state, territory or island. These inconsistencies cause uncertainty for patients, families and physicians managing cases. Subsequently, physicians, including paediatric haematologists and general paediatricians, have come together to provide a consensus approach guideline specific to paediatric NDITP for Australian or New Zealand. Persistent or chronic paediatric ITP remains a complex and separate entity and are not discussed here.

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Antinuclear antibodies (ANA) have been detected in children with primary immune thrombocytopaenia (ITP), but the effect of ANA titres on clinical outcomes is unclear. Liu et al. retrospectively analysed a cohort of 324 children with primary ITP with a median follow-up time of 25 months and found that patients with high-ANA titres (≥1:160) had lower platelet counts at the onset with a higher subsequent platelet count recovery rate, and additionally were at an increased risk to develop autoimmune disease. These data highlight the possible predictive potential of ANA titres with respect to platelet counts and the development of autoimmunity in children with primary ITP. Commentary on: Liu, et al. The effect of antinuclear antibody titre and its variation on outcomes in children with primary immune thrombocytopaenia. Br J Haematol 2023;202:412-421.

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INTRODUCTION: Immune thrombocytopenia (ITP) is a common acquired hemorrhagic disease without "gold standard" for the diagnosis, long non-coding RNA (lncRNAs) can participate in regulating gene expression through various mechanisms and may play a role in immune intolerance in ITP. Several previous studies have confirmed that lncRNA lncDC and THRIL are involved in the development of autoimmune diseases. This study investigates the relationship between expression levels of two plasma lncRNAs (lncDC and THRIL) and clinical characteristics of adult primary ITP patients, ascertain their potential applications as diagnostic markers of ITP. METHODS: We recruited 102 subjects, including 41 ITP patients, 41 healthy controls (HCs) and 20 patients under myelosuppression phase after chemotherapy (MS). qRT-PCR was used to detect the expression of two lncRNAs in the peripheral blood plasma of the three groups. Receiver operating characteristic (ROC) curves were used to test the diagnostic efficacy of lncDC and THRIL in ITP. RESULTS: The expression level of lncDC was downregulated in ITP patients compared with HCs (p = . 012) and MS (p = .035), whereas THRIL was significantly upregulated (p = .0005, p < . 0001). We further revealed that lncDC has a high sensitivity (78. 05%), while THRIL has a high specificity (97. 56%). The area under the curve (AUC) (0.869, 95% CI: 0.795-0.943, p < .0001) of the ROC curve for this combination increased significantly. CONCLUSIONS: THRIL and lncDC expression levels were changed in adult ITP patients. The lncRNAs lncDC and THRIL can serve as potential diagnostic markers for adult primary ITP.

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INTRODUCTION: Thrombopoietin receptor agonists (TPO-RAs) increase platelet counts (PC) in the majority of patients with chronic immune thrombocytopaenia (ITP). Platelet kinetics study (PKS) might contribute to the understanding of mechanisms that lead to durable response. OBJECTIVES: To evaluate the effects of TPO-RAs on PKS parameters in chronic ITP patients. METHODS: Fifteen chronic ITP patients, aged 59 years [range: 22-84], female/male: 10/5, splenectomised 7/15, were treated with TPO-RAs (eltrombopag/romiplostim: 11/4). Durable response was defined as PC ≥30 × 109 /L at 6 months. Autologous 111 Indium-oxinate PKS was performed before and 5 months after TPO-RAs initiation. Accordingly, platelet survival (PS), platelet turnover, production ratio and sequestration site were assessed. RESULTS: Durable response was achieved in 13/15 of patients (eltrombopag/romiplostim: 10/3). Pre-treatment parameters were: PC 10 × 109 /L [range: 1-110], PS 0.5 days [range: 0.1-1.7 (normal values: 7-10)], platelet turnover 30 857 Plt/µL/day [range: 944-103 500] and platelet production ratio 0.64 [range: 0.01-3.2 (normal values: 1 ± 0.2)]. Post-treatment assessment showed significantly higher: PC 92.5 × 109 /L [range: 28-260, p = .001], PS 2.2 days [range: 0.1-3.6, p = .008], platelet turnover 70 213 Plt/µL/day [range: 2800-462 236, p = .02] and platelet production ratio 1.8 [range: 0.5-37.9, p = .011] compared to the pre-treatment values. Platelet sequestration site altered in 3/15 treated with TPO-RAs. CONCLUSIONS: TPO-RAs could increase PC by simultaneous increasing of platelet production and decreasing of platelet destruction.

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INTRODUCTION: Thrombocytopaenia, one of the most common haematological disorders worldwide, is characterised by platelet counts <150,000/mm3. Patients with coronavirus disease (COVID-19) were found to commonly exhibit haematological abnormalities, often with mild forms of thrombocytopaenia. Absolute thrombocytopaenia tends to be rare among these patients and is believed to be secondary to immune-induced thrombocytopaenia. CASE PRESENTATION: A 53-y-old man presented with fever and generalised body ache that persisted for a few days. His polymerase chain reaction test was positive for COVID-19, for which he was treated with acetaminophen, levofloxacin, and favipiravir. On the third day of treatment, he noticed bruising and bleeding, mainly in the oral cavity, with clot formation. A complete blood picture (CBP) revealed severe thrombocytopaenia with an almost-zero count. Prednisone 1 mg/kg/d and frequent doses of intravenous platelet transfusion were administered as rescue therapy to prevent fatal bleeding. The patient was able to recover. CLINICAL DISCUSSION: Immune thrombocytopaenia should be considered in patients presenting with bleeding tendencies after severe acute respiratory syndrome coronavirus 2 infection. Serial CBP is recommended for vulnerable patients, especially during the second and third weeks of hospitalisation, for the early detection and prevention of life-threatening COVID-19 complications. CONCLUSIONS: Absolute thrombocytopaenia is a rare condition. Such a condition should be considered in patients presenting with bleeding tendencies with severe Covid-19 infection. With early diagnosis and appropriate treatment, patients' lives can be saved.

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Loss of sialic acid from the carbohydrate side chains of platelet glycoproteins can affect platelet clearance, a proposed mechanism involved in the etiopathogenesis of immune thrombocytopaenia (ITP). We aimed to assess whether changes in platelet glycosylation in patients with ITP affected platelet counts, function, and apoptosis. This observational, prospective, and transversal study included 82 patients with chronic primary ITP and 115 healthy controls. We measured platelet activation markers and assayed platelet glycosylation and caspase activity, analysing samples using flow cytometry. Platelets from patients with ITP with a platelet count <30 × 103/µL presented less sialic acid. Levels of α1,6-fucose (a glycan residue that can directly regulate antibody-dependent cellular cytotoxicity) and α-mannose (which can be recognised by mannose-binding-lectin and activate the complement pathway) were increased in the platelets from these patients. Platelet surface exposure of other glycoside residues due to sialic acid loss inversely correlated with platelet count and the ability to be activated. Moreover, loss of sialic acid induced the ingestion of platelets by human hepatome HepG2 cells. Changes in glycoside composition of glycoproteins on the platelets' surface impaired their functional capacity and increased their apoptosis. These changes in platelet glycoside residues appeared to be related to ITP severity.

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Background and Objectives: The aim of this study was to determine the impact of the COVID-19 pandemic on the lives of patients with immune thrombocytopaenia (ITP) treated at our hospital. Materials and Methods: The study was conducted in the Community of Madrid, which has the highest number of COVID-19 cases in Spain. We included 143 adult patients with ITP (130 with chronic ITP, 8 with persistent ITP, and 5 with newly diagnosed ITP). We conducted a telephone survey to collect the data and created a registry. Materials and Methods: Overall, 24 patients presented symptoms suggestive of COVID-19, which was confirmed by RT-PCR in 8 cases. The cumulative incidence of confirmed SARS-CoV-2 infection was higher in the patients with ITP than in the Madrid population. There were no differences in the disease incidence or clinical course of infection in the patients treated with immunosuppressants. Almost all of the patients reported adherence to the prescribed treatment, although 49.2% of the hospital visits were either cancelled or postponed, 17.2% because of the patients' fear of coming to the centre. Nearly half of the cohort was considered vulnerable, and 17% had been granted a dependency or disability benefit. Conclusions: COVID-19 had a major impact on the psychosocial, occupational, and quality of care of patients with ITP.

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Considerable attention has been paid to interleukin (IL)-35 because of its immunosuppressive effects in a variety of autoimmune diseases. IL-35, a recently identified cytokine of the IL-12 family, is a negative regulatory factor secreted by IL-35-inducible regulatory T cells (iTr35 cells) and the recently reported regulatory B cells (Breg cells). Four biological effects of IL-35 have been discovered in vitro and in vivo: (i) suppression of T cell proliferation; (ii) conversion of naive T cells into iTr35 cells; (iii) downregulation of type 17 helper T (Th17) cells; and (iv) conversion of Breg cells into a Breg subset that produces IL-35 and IL-10. IL-35 plays an important role in a variety of autoimmune diseases, such as rheumatoid arthritis, allergic asthma and systemic lupus erythematosus. Primary immune thrombocytopaenia (ITP), which is characterized by isolated thrombocytopaenia and mild mucocutaneous to life-threatening bleeding, is an autoimmune disease with complex dysregulation of the immune system. Both antibody-mediated and/or T cell-mediated platelet destruction are key processes. In addition, impairment of T cells and cytokine imbalances have now been recognized to be important. This review summarizes the immunomodulatory effects of IL-35 and its role in the pathogenesis of ITP as mediated by T and B cells.

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Multifactorial mechanisms leading to diminished platelet counts in immune thrombocytopaenia (ITP) might condition the ability of patients with ITP to respond to treatments. Examining their platelet and immune features, we aimed to detect singular characteristics of patients with ITP who do not respond to any treatment. We studied patients with chronic primary ITP who had been without treatment, or untreated (UT-ITP), for at least six months; included were responders to agonists of thrombopoietin receptors (TPO-RA), patients who showed no response to first- and second-line treatments (NR-ITP), and healthy controls. Platelets from NR-ITP patients exposed a reduced amount of sialic acid residues. Increased loss of platelet surface sialic acid residues was associated with increased platelet apoptosis. NR-ITP patients had an increased fraction of naive lymphocyte (L) B cells and a reduced LTreg (Lymphocyte T-regulator) subset. They also presented an anomalous monocyte and NK (Natural Killer) cells distribution. TPO-RA-treated patients seemed to recover an immune homeostasis similar to healthy controls. In conclusion, our results indicate a severe deregulation of the immune system of NR-ITP. The inverse correlation between loss of sialic acid and LTreg count suggests a potential relationship between glycan composition on the platelet surface and immune response, positing terminal sugar moieties of the glycan chains as aetiopathogenic agents in ITP.

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Evans syndrome is a rare haematological disease that may cause several complications during heart surgery. Herein we documented heart valve surgery in a patient with Evans syndrome who was receiving monoclonal antibody therapy, and valve replacement was successfully performed via prophylactic measures against haemolysis.

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Immune thrombocytopaenia (also known as idiopathic thrombocytopaenic purpura) (ITP) is a chronic condition with isolated low platelet counts. Although it is largely perceived that ITP predisposes to bleeding risks, thrombotic events, such as ischaemic strokes, do happen paradoxically in patients with ITP. A 68-year-old lady presented with right upper limb weakness and was diagnosed with an ischaemic stroke and was started on clopidogrel. She had a history of ITP. Two months later, she again had another ischaemic stroke. Prednisolone was added as her platelet count was below 50 x 109/L. Based on this case and recent case studies, we suggest the administration of antiplatelet or anticoagulant agents judiciously if the platelet count is 50 x 109/L or above with monitoring of bleeding risks. As for the management of ITP, we do agree with the general opinion that treatment is rarely required for patients with a platelet count above 50 x 109/L. We recommend a haematology consult for discussion on treatment initiation if the platelet count is below 50 x 109/L.

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It is widely admitted that neonates' platelet counts (PCs) are always normal in babies born to mothers with incidental gestational thrombocytopaenia. However, results of PC determinations at delivery have led us to wonder whether incidental gestational thrombocytopaenia is actually safe for the neonate under all circumstances, and to recommend that for every baby born to a mother with a pregnancy-associated thrombocytopaenia, even in the case of confirmed IGT, platelet counts on umbilical cord blood be closely monitored.

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