Clonal hematopoiesis of indeterminate potential (CHIP) might contribute to the pathogenesis of immune thrombocytopenia (ITP) through immune dysfunction or impairment of megakaryopoiesis and platelet formation. However, little is known about subsequent risk of ITP among individuals with CHIP.

To investigate the risk of ITP among individuals with CHIP.

We investigated the association of CHIP with risk of ITP by a prospective cohort study, including 466,064 participants in the UK Biobank, during 2006 to 2022. CHIP was ascertained based on data of whole exome sequencing. Incident ITP was identified in inpatient hospital records and death register. Cox regression models were utilized to estimate risk of ITP associated with CHIP. We also performed subgroup analyses by CHIP mutations (DNMT3A, TET2, ASXL1, SRSF2, and JAK2).

The study included 14,466 and 451,598 individuals with and without CHIP, respectively. We identified 34 and 390 cases of ITP among the CHIP group and the reference group, respectively. CHIP was associated with an increased risk of ITP (hazard ratio [HR] 2.33, 95% confidence interval [CI]: 1.64-3.32). Subgroup analysis revealed that the heightened risk of ITP was greatest in CHIP with JAK2 mutation (HR 54.31, 95% CI: 17.39-169.59), followed by CHIP with SRSF2 (HR 20.11, 95% CI: 8.27-48.87), TET2 (HR 4.00, 95% CI: 2.34-6.83), or DNMT3A (HR 1.95, 95% CI: 1.16-3.27) mutation.

CHIP was associated with an increased risk of being diagnosed with ITP, particularly for CHIP with JAK2 or SRSF2 mutation. These findings call for clinical awareness of the risk of ITP among individuals with CHIP.

Sustained remissions off-treatment (SROTs) after tapering of thrombopoietin receptor agonists (TPO-RAs) have been reported in 15%-50% of patients with immune thrombocytopenia (ITP). The STIP (Stop TPO-Receptor Agonist in ITP Patients) study is a prospective trial aimed to investigate the clinical effects of romiplostim tapering. Adult patients (22/40) with ITP ≥3 months received romiplostim for 1 year, were tapered and followed for 1 year. Anti-platelet antibodies (APAs), TPO levels and indium-111 platelet scintigraphy were assessed before, during and after romiplostim. Censored survival analysis showed that the probability of SROT at 1 year after tapering was 23.6% (95% confidence interval: 11.0%-50.5%). Patients with SROT had higher platelet levels on romiplostim (median: 332.5 vs. 84.5 × 109/L) and lower romiplostim doses at the start of tapering (median: 1.0 vs. 4.5 μg/kg) compared to those with a non-sustained response (NSR). APAs were detected in 8/25 patients at baseline, of which 5 showed a substantial decrease during romiplostim. The indium-111 scan revealed an improved platelet survival at the start of tapering for 50% of patients with SROT (2/4, missing n = 1) versus none with an NSR (0/14, missing n = 3). Overall, the STIP study demonstrated a probability of SROT of 23.6% in a diverse and largely chronic group of adult patients with ITP.

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by antiplatelet autoantibodies, with many patients refractory or relapsing on conventional treatments. GPIbα, an important autoantigen in ITP, is notably linked to refractoriness, highlighting the need for novel treatments. We assessed CD19 chimeric antigen receptor (CAR)-T cell therapy's potential in a modified murine model targeting GPIbα. CD19 CAR-T cell infusion accelerated platelet count recovery compared to the control group, effectively depleted CD19+ B cells and CD138+ plasma cells, and markedly reduced anti-GPIbα autoantibodies in vivo. In vitro CD19 CAR-T cells reduced both plasma cells and B cells in the spleens of mice and ITP patients. CD19 CAR-T cell therapy significantly altered T-cell subsets, increasing regulatory T cells, T helper 1 and T helper 17 populations, suggesting a role in modulating the immune response for sustained ITP remission. Monitoring of body/spleen weights and temperature showed no significant cytokine release syndrome, indicating a favourable safety profile. These promising results support the potential of CD19 CAR-T cell therapy as a novel treatment option for refractory ITP, particularly in GPIbα-positive autoantibody patients. Further clinical studies are warranted to assess the safety and efficacy of this approach in human patients.

Advancements in the understanding of ITP pathogenesis have led to significant improvements in disease management through the use of both traditional immunosuppressive strategies and novel targeted therapies. However, a subset of patients remains refractory to treatment or achieves only transient benefits, underscoring the need for alternative therapeutic approaches. Bruton's tyrosine kinase (BTK) inhibitors have emerged as a promising strategy for autoimmune cytopenias, including ITP, due to their ability to modulate key immune pathways. Rilzabrutinib, an oral, reversible BTK inhibitor, represents a novel therapeutic approach for ITP. Rilzabrutinib, an oral, reversible BTK inhibitor, offers a novel mechanism of action by preserving platelet aggregation while reducing macrophage-mediated platelet clearance, distinguishing it from irreversible BTK inhibitors. This review provides an updated and comprehensive analysis of the Phase 1/2 LUNA 2 trial and its long-term extension, contextualizing rilzabrutinib within the broader treatment landscape. We also offer a comparative assessment of other BTK inhibitors investigated for ITP and discuss rilzabrutinib's potential positioning relative to existing therapies, including thrombopoietin receptor agonists (TPO-RAs), rituximab, fostamatinib, and immunosuppressants. Results from the phase 1/2 LUNA 2 trial and its long-term extension demonstrated that Rilzabrutinib induced a durable platelet response in 40% of patients, with a median time to response of 11.5 days. The treatment exhibited a favorable safety profile, with predominantly grade 1 or 2 adverse events and no significant safety concerns commonly associated with BTK inhibitors, such as increased bleeding risk, hepatic toxicity, or cardiac arrhythmias. Preliminary data presented at ASH 2024 from the ongoing Phase 3 LUNA 3 trial, a randomized, double-blind study, further support rilzabrutinib's efficacy and long-term safety. If confirmed, these findings suggest that rilzabrutinib could represent a valuable therapeutic option for patients with refractory ITP, addressing a critical unmet need and potentially redefining treatment paradigms.

In patients with X-linked agammaglobulinemia (XLA), serum immunoglobulins are almost completely lacking. The prevalence of autoimmune diseases is low in XLA compared with other primary immunodeficiency diseases because antibodies are absent in XLA. Immune thrombocytopenia (ITP) is considered an antibody-mediated disease characterized by increased platelet destruction, and adult-onset ITP in XLA has not been reported in detail. The case of a 29-year-old Japanese man with XLA and ITP is described. The patient was treated with prednisolone and intravenous immunoglobulins, resulting in rapid improvement of thrombocytopenia. Clinicians should consider co-existing ITP when progressive thrombocytopenia is observed in a patient with XLA.

Immune checkpoint inhibitors (ICIs) have revolutionized classical treatment approaches of various cancer entities, but are also associated with a number of side effects. One of these may be life-threatening clotting disorders with the risk of thrombotic or hemorrhagic complications, the mechanisms of which are still poorly understood. In the present study, we analyzed the direct effects of pembrolizumab, nivolumab, and ipilimumab on platelet aggregation as well as plasma coagulation followed by fibrinolysis in an ex vivo model.

Microplate spectrometry was used to analyze aggregation, coagulation, and fibrinolysis in platelet-free (PFP) and platelet-rich (PRP) healthy donor plasma samples treated with pembrolizumab, nivolumab, ipilimumab, and appropriate isotype controls. Aggregation was induced by TRAP-6. Clotting of PFP and PRP followed by lysis was initiated with a tissue factor in a mixture of phosphatidylserine:phosphatidylcholine and the addition of t-PA. Among other parameters, the area under the curve (AUC) was used to compare the effect of ICIs on aggregation, coagulation, and fibrinolysis.

Upon direct contact with platelets, pembrolizumab stimulated platelet aggregation in PRP, while nivolumab and ipilimumab promoted disaggregation with corresponding changes in the AUC. Pembrolizumab and nivolumab, both PD-1 receptor inhibitors, had no effect on the plasma coagulation cascade. Ipilimumab, a CTLA-4 receptor inhibitor, significantly increased the rate of PRP clotting. When clotting was followed by lysis, all ICIs were found to prolong the growth of the PRP-derived fibrin clot and delay its elimination. This was manifested by an increase in AUC relative to control PRP.

This study characterizes the potential impact of pembrolizumab, nivolumab, and ipilimumab on hemostasis. Nivolumab and ipilimumab are able to reduce aggregation and increase the procoagulant properties of platelets, which can cause side effects associated with hemostatic imbalance leading to thrombosis or bleeding. The observed ICI-specific effects may contribute to our understanding of the mechanisms by which ICI affects platelets and suggest how, in a clinical setting, to reduce coagulation disorders during ICI treatment in the future.

Killer Ig-like Receptors (KIRs) regulate immune responses, maintaining the balance between activation and inhibition of the immune system. KIRs are expressed on natural killer cells and some CD8 T cells and interact with HLA class I molecules, influencing various physiological and pathological processes. KIRs' polymorphism creates a variability in immune responses among individuals. KIRs are involved in autoimmune disorders, cancer, infections, neurological diseases, and other diseases. Specific combinations of KIRs and HLA are linked to several diseases' susceptibility, progression, and outcomes. In particular, the balance between inhibitory and activating KIRs can determine how the immune system responds to pathogens and tumors. An imbalance can lead to an excessive response, contributing to autoimmune diseases, or an inadequate response, allowing immune evasion by pathogens or cancer cells. The increasing number of studies on KIRs highlights their essential role as diagnostic and prognostic biomarkers and potential therapeutic targets. This review provides a comprehensive overview of the role of KIRs in all clinical conditions and diseases, listed alphabetically, where they are analyzed.

Immunotherapy is now an integral aspect of cancer therapy. Strategies employing adoptive cell therapy (ACT) have seen the establishment of chimeric antigen receptor (CAR)-T cells using peripheral blood lymphocytes as well as tumor-infiltrating lymphocytes (TILs) with significant clinical results. The bone marrow (BM) is an immunological niche housing T cells with specificity for previously encountered antigens, including tumor-associated antigens from certain solid cancers. This study sought to improve our understanding of tumor-specific BM T cells in the context of solid tumors by comparing them with TILs, and to assess whether there is a rationale for using the BM as a source of T cells for ACT against solid malignancies.

We used the murine B16 melanoma model examining both the endogenous OVA-specific T cell response using an OVA-specific tetramer or examining the OVA-specific response with OVA-specific transgenic CD8+ (OT-1) T cells. Specifically, we compared baseline intrinsic properties of TILs or BM T cells from tumor-bearing mice and their changes following adoptive transfer in the tumor and bone marrow (as well as other compartments when indicated).

In tumor-bearing mice, endogenous tumor-specific T cells could be detected in the BM early in the course of tumor progression and possessed a more stem-cell-like and memory phenotype in an unsupervised cluster analysis compared with TILs which appeared more exhausted. The BM and tumor microenvironments significantly impact the fate of T cells. Naïve OT-1 transferred T cells acquired an exhausted phenotype in the tumor but maintained a more memory-like phenotype in the BM with tumor progression. Importantly, in a competitive transfer experiment, BM T cells infiltrated the tumor more efficiently than TILs, displayed a higher polyfunctionality with interleukin-2, interferon-γ, tumor necrosis factor-α production and showed greater persistence compared with TILs.

T cells from the BM appear superior to TILs as a source of cells for cellular therapy. They possess a memory-enriched phenotype and exhibit improved effector function, greater persistence within a tumor-bearing host, and the capacity for increased tumor infiltration. These data provide a foundation for further exploring the BM as a source of tumor-specific T cells for ACT in solid malignancies.

Immune thrombocytopenia (ITP) is an autoimmune disease, characterized by increased bleeding due to a reduced platelet count. The pathogenesis of ITP is very complex and involves autoantibody production and T-cell-mediated immune abnormalities. An imbalance of effector and regulatory CD4+ T cells and the breach of tolerance primarily cause ITP, leading to the dysfunctional development of autoreactive Th cells (including Th1, Th2, and Th17 cells) and Tregs. The loss of auto-platelet antigen tolerance in ITP results in autoantibody- and cytotoxic T-cell-mediated platelet clearance. T-cell-related genetic risk factors significantly influence the development and progression of this disease. New therapies targeting T cells have emerged as potentially effective cures for this disease. This review summarizes the role of T cells in ITP.

In patients with severe refractory immune thrombocytopenia (ITP), especially those unable to receive blood transfusions due to religious beliefs, alternative non-cytotoxic therapies are important to avoid worsening cytopenias. Immunomodulatory agents such as mycophenolate mofetil and daratumumab should be used alongside traditional therapies including steroids, IVIG and rituximab.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by enhanced platelet destruction and impaired platelet production, due to a loss of immune tolerance that leads to targeting of platelets and megakaryocytes by glycoprotein-autoantibodies and/or cytotoxic T cells. There is a high degree of heterogeneity in ITP patients signified by unpredictable disease trajectories and treatment responses. Initial studies in humans have identified intestinal microbiota perturbance in ITP. Recently, gut microbial perturbance has been linked to other autoimmune diseases. Based on these findings, we hypothesize that intestinal microbiota may influence ITP pathophysiology through several mechanisms, including induction of platelet-autoantibody production, increasing complement-dependent platelet cytotoxicity, disturbing T cell homeostasis, impairing megakaryocyte function, and increasing platelet-desialylation and -clearance. The pathophysiological heterogeneity of ITP may, at least in part, be attributed to a perturbed intestinal microbiota. Therefore, a better understanding of intestinal microbiota in ITP may result in a more personalized therapeutic approach.

Thrombocytopenia will occur in 10% of pregnancies-ranging from the clinically benign to processes that can threaten both mother and fetus. Accurately identifying the specific etiology and appropriate clinical management is challenging due to the breadth of possible diagnoses and the potential of shared features among them. Further complicating diagnostic certainty is the lack of confirmatory testing for most possible pathophysiologies. Immune thrombocytopenia (ITP) is recognized in less than 0.1% of pregnancies but is the most common cause of thrombocytopenia in early trimesters. ITP is an autoimmune disease of IgG-mediated enhanced platelet clearance and reduced platelet production. While there is an increasing number of drugs approved to treat ITP and more being examined in clinical trials, few have been sufficiently studied in pregnancy, representing a major unmet need in clinical practice. As such, treatment options for ITP in pregnancy are limited to corticosteroids and immunoglobulin therapy, which will not be effective in all cases. Maternal ITP also may have fetal impact, and any proposed therapeutic intervention must account for this possibility. Optimal care requires multidisciplinary collaboration between hematology, obstetrics, and anesthesia to enhance diagnostic clarity, develop an optimized treatment regimen, and shepherd mother and neonate to delivery safely.

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by an isolated thrombocytopenia and variable phenotype as some patients suffer no bleeding whilst others have bleeding from mild to severe, which may be fatal. This variability probably reflects the disease's complex pathophysiology; a dysregulated hyperreactive immune effector cell response involving the entire adaptive immune system (e.g. B and T cell subsets) that leads to platelet and megakaryocyte (MK) destruction. It appears that these effector responses are due to a breakdown in immune tolerance, and this is characterized by defects in several immunosuppressive cell types. These include defective T regulatory cells (Tregs), B regulatory cells (Bregs) and Myeloid-derived suppressor cells (MDSC), all of which are all intimately associated with antigen presenting cells (APC) such as dendritic cells (DC). The loss of this immunosuppressive axis allows for the activation of unchecked autoreactive T cells and B cells, leading to the development of autoantibodies and cytotoxic T cells (CTL), which can directly destroy platelets in the periphery and inhibit MK platelet production in the bone marrow (BM). This review will focus on the effector cell mechanisms in ITP and highlight the defective immunosuppressive axis that appears responsible for this platelet-specific immune hyperreactivity.

Immune thrombocytopenic purpura (ITP) is an immune bleeding disorder that is reported in approximately 2 out of every 100,000 adults with a mean age of 50 years. Several factors such as various genetic backgrounds are associated with the pathogenesis of ITP. Interleukin (IL)-10 is a complicated cytokine that has a role in tumor progression, antitumor immunity, and immune system regulation. rs1800890 is an IL-10 single nucleotide polymorphism linked to lower levels of IL-10. A total of 67 patients with ITP and 70 healthy individuals (controls) were considered in this study. The IL-10 polymorphism was detected by the amplification refractory mutation system-polymerase chain reaction technique. According to our analysis, individual carriers of the AA genotype were less likely to develop ITP. The AT genotype was more common in patients with ITP in comparison to the control group. However, there was no significant association between rs1800890 genotypes ( p  = 0.775, odds ratio =1.517, 95%) in the acute and chronic groups. We observed that women had a higher mean frequency of this polymorphism ( p  = 0.0012). The rs1800890 AA genotype was associated with the highest platelet counts. However, the mean platelet volume and platelet distribution width values among alleles of the polymorphisms did not vary significantly. The IL-10 rs1800890 polymorphism may have a role in idiopathic thrombocytopenic purpura etiology. As a result, more research with a larger number of sample sizes is suggested.

Immune thrombocytopenia (ITP) is an autoimmune disease in which platelet autoantibodies play a significant role in its pathogenesis. Regulatory T cell dysfunction and T cell-mediated cytotoxicity also contribute to thrombocytopenia. Current therapies are directed towards immune suppression and modulation as well as stimulation of platelet production with thrombopoietin receptor agonists. Additional mechanisms of the pathogenesis of ITP have been suggested by recent experimental data. One of these processes, known as desialylation, involves antibody-induced removal of terminal sialic acid residues on platelet surface glycoproteins, leading to hepatic platelet uptake and thrombocytopenia. Apoptosis, or programmed platelet death, may also contribute to the pathogenesis of ITP. The extent of the impact of desialylation and apoptosis on ITP, the relative proportion of patients affected, and the role of antibody specificity are still the subject of investigation. This review will discuss both historical and new evidence of the influence of desialylation and apoptosis in the pathogenesis of ITP, with an emphasis on the clinical implications of these developments. Further understanding of both platelet desialylation and apoptosis might change current clinical practice and improve patient outcomes.

Autoantibodies that cause platelet apoptosis may play a role in the development of immune thrombocytopenia (ITP), specifically antibodies that target GPIIbIIIa and GPIbα. Our research aims to compare the impact of the antigen specificity of antiplatelet antibodies on normal platelets under conditions that do not rely on complement. Using a modified monoclonal antibody-specific immobilization of platelet antigen (MAIPA) assay, we detected the levels of autoantibodies against specific platelet membrane glycoproteins (GPIIb/IIIa, GPIb/IX) in the plasma of 36 patients diagnosed with chronic ITP. IgG was isolated and purified using a protein A agarose affinity chromatography column, and their concentrations were measured using spectrophotometry. We obtained normal platelets and treated them with the purified IgG anti-GPIIb/IIIa and/or anti-GPIb/IX antibodies, as well as an IgG-free buffer and healthy control IgG. Flow cytometry was used to analyze markers of apoptosis, including phosphatidylserine (PS) exposure, mitochondrial inner membrane potential (ΔΨm), and platelet particle formation. Our results indicate that ITP patients with GPIb/IX-specific autoantibodies can induce platelet apoptosis and platelet particle formation through complement-independent pathways, which are not associated with platelet activation, while GPIIb/IIIa-specific autoantibodies did not have this effect. This suggests that specific autoantibodies may serve as a valuable predictive tool to identify patients who could potentially benefit from complement-inhibiting therapy in the future.

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.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disease caused by immune-mediated platelet destruction and decreased platelet production. ITP is characterized by an isolated thrombocytopenia (<100 × 109/L) and increased risk of bleeding. The disease has a complex pathophysiology wherein immune tolerance breakdown leads to platelet and megakaryocyte destruction. Therapeutics such as corticosteroids, intravenous immunoglobulins (IVIg), rituximab, and thrombopoietin receptor agonists (TPO-RAs) aim to increase platelet counts to prevent hemorrhage and increase quality of life. TPO-RAs act via stimulation of TPO receptors on megakaryocytes to directly stimulate platelet production. Romiplostim is a TPO-RA that has become a mainstay in the treatment of ITP. Treatment significantly increases megakaryocyte maturation and growth leading to improved platelet production and it has recently been shown to have additional immunomodulatory effects in treated patients. This review will highlight the complex pathophysiology of ITP and discuss the usage of Romiplostim in ITP and its ability to potentially immunomodulate autoimmunity.

Immune thrombocytopenia (ITP) is a complex autoimmune disorder characterized by thrombocytopenia and an increased bleeding risk, arising from autoantibody-mediated platelet destruction and impaired megakaryocyte function. The pathogenesis of ITP involves a multifaceted interplay of genetic predispositions, immune dysregulation, and environmental triggers, though the precise mechanisms remain uncertain. Several infectious agents, mostly viruses, have been implicated in both acute and chronic ITP through mechanisms such as molecular mimicry, direct bone marrow suppression, and immune dysregulation. Vaccinations, particularly those containing adjuvants like aluminum and those capable of inducing molecular mimicry, have also been associated with ITP, either as a new onset or as a relapse in preexisting cases. The role of drugs, particularly quinine, quinidine and certain antibiotics, in inducing ITP through various immunological pathways further illustrates the diverse etiologies of this condition. The multiple triggers of the disease raise the question of whether ITP may be classified as an autoimmune/inflammatory syndrome induced by adjuvants (ASIA). This condition encompasses a range of autoimmune and inflammatory symptoms triggered by adjuvants, such as silicones, polypropylene meshes, metal implants, and mineral oils present in various medical materials and medications. Similar to that observed in some cases of ITP, adjuvants can trigger autoimmune or autoinflammatory responses via molecular mimicry, epitope spreading, and polyclonal activation. This narrative review explores the underlying environmental factors related to ITP and examines ITP triggers that could potentially support an association between ITP and ASIA syndrome.

Fostamatinib, a recently approved Syk inhibitor used in adult primary immune thrombocytopenia (ITP), has been shown to be safe and effective in this disorder. However, clinical trial results may not be similarly reproduced in clinical practice. Here, 138 patients with ITP (both primary and secondary) from 42 Spanish centers who had been treated with fostamatinib were evaluated prospectively and retrospectively. The median age of our cohort (55.8% women) was 66 years (interquartile range [IQR], 56-80). The median time since ITP diagnosis at fostamatinib initiation was 51 months (IQR, 10-166). The median number of therapies before fostamatinib initiation was 4 (IQR, 2-5), including eltrombopag (76.1%), romiplostim (57.2%), and IV immunoglobulins (44.2%). Fifty-eight patients (42.0%) had signs/symptoms of bleeding in the month before treatment initiation. Seventy-nine percent of patients responded to fostamatinib with 53.6% complete responses (platelet count > 100 × 109/L). Eighty-three patients (60.1%) received fostamatinib monotherapy, achieving a high response rate (85.4%). The proportion of time in response during the 27-month period examined was 83.3%. The median time to platelet response was 11 days (IQR, 7-21). Sixty-seven patients (48.5%) experienced adverse events, mainly grade 1 to 2; the commonest of which were diarrhea (n = 28) and hypertension (n = 21). One patient had deep venous thrombosis, and one patient developed acute myocardial infarction. Fostamatinib was shown to be effective with good safety profile in patients with primary and secondary ITP across a wide age spectrum in this real-world study.

Management of immune thrombocytopenia (ITP) in dogs and cats is evolving, but there are no evidence-based guidelines to assist clinicians with treatment decisions. Likewise, the overall goals for treatment of ITP have not been established. Immunosuppressive doses of glucocorticoids are the first line treatment, but optimal treatment regimens beyond glucocorticoids remain uncertain. Additional options include secondary immunosuppressive drugs such as azathioprine, modified cyclosporine, and mycophenolate mofetil, usually selected based on clinician preference. Vincristine, human IV immunoglobulin (hIVIg), and transfusion of platelet or red blood cell-containing products are often used in more severe cases. Splenectomy and thrombopoietin receptor agonists are usually reserved for refractory cases, but when and in which patient these modalities should be employed is under debate. To develop evidence-based guidelines for individualized treatment of ITP patients, we asked 20 Population Intervention Comparison Outcome (PICO) format questions. These were addressed by 17 evidence evaluators using a literature pool of 288 articles identified by a structured search strategy. Evidence evaluators, using panel-designed templates and data extraction tools, summarized evidence and created guideline recommendations. These were integrated by treatment domain chairs and then refined by iterative Delphi survey review to reach consensus on the final guidelines. In addition, 19 non-PICO questions covering scenarios in which evidence was lacking or of low quality were answered by expert opinion using iterative Delphi surveys with panelist integration and refinement. Commentary was solicited from multiple relevant professional organizations before finalizing the consensus. The rigorous consensus process identified few comparative treatment studies, highlighting many areas of ITP treatment requiring additional studies. This statement is a companion manuscript to the ACVIM Consensus Statement on the Diagnosis of Immune Thrombocytopenia in Dogs and Cats.

Immune thrombocytopenia (ITP) is the most common acquired primary hemostatic disorder in dogs. Immune thrombocytopenia less commonly affects cats but is an important cause of mortality and treatment-associated morbidity in both species. Immune thrombocytopenia remains a diagnosis of exclusion for which diagnostic guidelines are lacking. Primary, or non-associative, ITP refers to autoimmune platelet destruction. Secondary, or associative, ITP arises in response to an underlying disease trigger. However, evidence for which comorbidities serve as ITP triggers has not been systematically evaluated. To identify key diagnostic steps for ITP and important comorbidities associated with secondary ITP, we developed 12 Population Evaluation/Exposure Comparison Outcome (PECO) format questions. These questions were addressed by evidence evaluators utilizing a literature pool of 287 articles identified by the panelists using a structured search strategy. Evidence evaluators, using panel-designed templates and data extraction tools, summarized evidence and created guideline recommendations that then were integrated by diagnosis and comorbidity domain chairs. The revised PECO responses underwent a Delphi survey process to reach consensus on final guidelines. A combination of panel expertise and PECO responses were employed to develop algorithms for diagnosis of ITP in dogs and cats, which also underwent 4 iterations of Delphi review. Comorbidity evidence evaluators employed an integrated measure of evidence (IME) tool to determine evidence quality for each comorbidity; IME values combined with evidence summaries for each comorbidity were integrated to develop ITP screening recommendations, which also were subjected to Delphi review. Commentary was solicited from multiple relevant professional organizations before finalizing the consensus. The final consensus statement provides clinical guidelines for the diagnosis of, and underlying disease screening for, ITP in dogs and cats. The systematic consensus process identified numerous knowledge gaps that should guide future studies. This statement is a companion manuscript to the ACVIM Consensus Statement on the Treatment of Immune Thrombocytopenia.

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by autoantibody-mediated platelet destruction. Treatment with CM313, a novel anti-CD38 monoclonal antibody, can result in targeted clearance of CD38-positive cells, including plasma cells.

We conducted a phase 1-2, open-label study to evaluate the safety and efficacy of CM313 in adult patients with ITP. CM313 was administered intravenously at a dose of 16 mg per kilogram of body weight every week for 8 weeks, followed by a 16-week follow-up period. The primary outcomes were adverse events and documentation of two or more consecutive platelet counts of at least 50×109 per liter within 8 weeks after the first dose of CM313. The status of peripheral-blood immune cells in patients and changes in the mononuclear phagocytic system in passive mouse models of ITP receiving anti-CD38 therapy were monitored.

Of the 22 patients included in the study, 21 (95%) had two consecutive platelet counts of at least 50×109 per liter during the treatment period, with a median cumulative response duration of 23 weeks (interquartile range, 17 to 24). The median time to the first platelet count of at least 50×109 per liter was 1 week (range, 1 to 3). The most common adverse events that occurred during the study were infusion-related reaction (in 32% of the patients) and upper respiratory tract infection (in 32%). After CD38-targeted therapy, the percentage of CD56dimCD16+ natural killer cells, the expression of CD32b on monocytes in peripheral blood, and the number of macrophages in the spleen of the passive mouse models of ITP all decreased.

In this study, anti-CD38 targeted therapy rapidly boosted platelet levels by inhibiting antibody-dependent cell-mediated cytotoxicity on platelets, maintained long-term efficacy by clearing plasma cells, and was associated with mainly low-grade toxic effects. (Funded by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences and others; ClinicalTrials.gov number, NCT05694767).

Immune thrombocytopenia (ITP) is an autoimmune disease associated with autoantibody-mediated platelet destruction and impaired platelet production, resulting in thrombocytopenia and a predisposition to bleeding. The ongoing, global phase 1/2 study showed that rilzabrutinib, a Bruton tyrosine kinase inhibitor specifically developed to treat autoimmune disorders, could be an efficacious and well-tolerated treatment for ITP. Clinical activity, durability of response, and safety were evaluated in 16 responding patients who continued rilzabrutinib 400 mg twice daily in the long-term extension (LTE) study. At LTE entry, the median platelet count was 87 × 109/L in all patients, 68 × 109/L in those who had rilzabrutinib monotherapy (n = 5), and 156 × 109/L in patients who received concomitant ITP medication (thrombopoietin-receptor agonists and/or corticosteroids, n = 11). At a median duration of treatment of 478 days (range, 303-764), 11 of 16 patients (69%) continued to receive rilzabrutinib. A platelet count of ≥50 × 109/L was reported in 93% of patients for more than half of their monthly visits. The median percentage of LTE weeks with platelet counts ≥30 × 109/L and ≥50 × 109/L was 100% and 88%, respectively. Five patients discontinued concomitant ITP therapy and maintained median platelet counts of 106 × 109/L at 3 to 6 months after stopping concomitant ITP therapy. Adverse events related to treatment were grade 1 or 2 and transient, with no bleeding, thrombotic, or serious adverse events. With continued rilzabrutinib treatment in the LTE, platelet responses were durable and stable over time with no new safety signals. This trial is registered at www.clinicaltrials.gov as #NCT03395210 and www.clinicaltrialsregister.eu as EudraCT 2017-004012-19.

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by an isolated decrease in the 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 impaired central megakaryopoiesis and platelet production in the bone marrow. Here, we intend to contextualize the current knowledge on the pathophysiology, terminology, epidemiology, clinical manifestations, diagnosis, and prognosis of ITP from a historical perspective and the first references to the never-stopping garnering of knowledge about this entity. We highlight the necessity to better understand ITP in order to be able to provide ITP patients with personalized treatment options, improving disease prognosis and reducing the incidence or frequency of refractoriness.

The E3 ubiquitin ligase casitas B-lineage lymphoma-b (CBLB) is a newly identified component of the ubiquitin-dependent protein degradation system and is considered an important negative regulator of immune cells. CBLB is essential for establishing a threshold of T-cell activation and regulating peripheral T-cell tolerance through various mechanisms. However, the involvement of CBLB in the pathogenesis of immune thrombocytopenia (ITP) is unknown.

We aimed to investigate the expression and role of CBLB in CD4+ T cells obtained from patients with ITP through quantitative proteomics analyses.

CD4+ T cells were transfected with adenoviral vectors overexpressing CBLB to clarify the effect of CBLB on anergic induction of T cells in patients with ITP. DNA methylation levels of the CBLB promoter and 5' untranslated region (UTR) in patient-derived CD4+ T cells were detected via MassARRAY EpiTYPER assay (Agena Bioscience).

CD4+ T cells from patients with ITP showed resistance to anergic induction, highly activated phosphoinositide 3-kinase-protein kinase B (AKT) signaling, decreased CBLB expression, and 5' UTR hypermethylation of CBLB. CBLB overexpression in T cells effectively attenuated the elevated phosphorylated protein kinase B level and resistance to anergy. Low-dose decitabine treatment led to significantly elevated levels of CBLB expression in CD4+ T cells from 7 patients showing a partial or complete response.

These results indicate that the 5' UTR hypermethylation of CBLB in CD4+ T cells induces resistance to T-cell anergy in ITP. Thus, the upregulation of CBLB expression by low-dose decitabine treatment may represent a potential therapeutic approach to ITP.

Primary immune thrombocytopenia (ITP) is an acquired autoimmune disease. Cellular and systemic lipid metabolism plays a significant role in the regulation of immune cell activities. However, the role of lipoprotein lipids and apolipoproteins in ITP remains elusive. The automatic biochemistry analyser was used to measure the levels of serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-I (apoA-I), apoB, apoE and lipoprotein a [LP(a)]. Genetic variants strongly associated with circulating lipoprotein lipids and apolipoproteins (LDL-C, apoB, TG, HDL-C and apoA-I) were extracted to perform Mendelian randomization (MR) analyses. Finally, drug-target MR and passive ITP mice model was used to investigate the potential druggable targets of ITP. Levels of HDL-C, apoA-I, decreased and LP(a) increased in ITP patients compared with healthy controls. Low HDL-C was causally associated with ITP susceptibility. Through drug-target MR and animal modelling, ABCA1 was identified as a potential target to design drugs for ITP. Our study found that lipid metabolism is related to ITP. The causative association between HDL-C and the risk of ITP was also established. The study provided new evidence of the aetiology of ITP. ABCA1 might be a potential drug target for ITP.

Immune thrombocytopenia (ITP) is an autoimmune disorder that causes a significant reduction in peripheral blood platelet count. Fortunately, due to an increased understanding of ITP, there have been significant improvements in the diagnosis and treatment of these patients. Over the past decade, there have been a variety of proven therapeutic options available for ITP patients, including intravenous immunoglobulins (IVIG), Rituximab, corticosteroids, and thrombopoietin receptor agonists (TPO-RAs). Although the effectiveness of current therapies in treating more than two-thirds of patients, still some patients do not respond well to conventional therapies or fail to achieve long-term remission. Recently, a significant advancement has been made in identifying various mechanisms involved in the pathogenesis of ITP, leading to the development of novel treatments targeting these pathways. It seems that new agents that target plasma cells, Bruton tyrosine kinase, FcRn, platelet desialylation, splenic tyrosine kinase, and classical complement pathways are opening new ways to treat ITP. In this study, we reviewed the pathophysiology of ITP and summarized updates in this population's management and treatment options. We also took a closer look at the 315 ongoing trials to investigate their progress status and compare the effectiveness of interventions. May our comprehensive view of ongoing clinical trials serve as a guiding beacon, illuminating the path towards future trials of different drugs in the treatment of ITP patients.

Thrombocytopenia is a common hematologic abnormality in pregnancy, encountered in ∼10% of pregnancies. There are many possible causes, ranging from benign conditions that do not require intervention to life-threatening disorders necessitating urgent recognition and treatment. Although thrombocytopenia may be an inherited condition or predate pregnancy, most commonly it is a new diagnosis. Identifying the responsible mechanism and predicting its course is made challenging by the tremendous overlap of clinical features and laboratory data between normal pregnancy and the many potential causes of thrombocytopenia. Multidisciplinary collaboration between hematology, obstetrics, and anesthesia and shared decision-making with the involved patient is encouraged to enhance diagnostic clarity and develop an optimized treatment regimen, with careful consideration of management of labor and delivery and the potential fetal impact of maternal thrombocytopenia and any proposed therapeutic intervention. In this review, we outline a diagnostic approach to pregnant patients with thrombocytopenia, highlighting the subtle differences in presentation, physical examination, clinical course, and laboratory abnormalities that can be applied to focus the differential. Four clinical scenarios are presented to highlight the pathophysiology and treatment of the most common causes of thrombocytopenia in pregnancy: gestational thrombocytopenia, preeclampsia, and immune thrombocytopenia.

The management of immune thrombocytopenia (ITP) and the prediction of patient response to therapy still represent a significant and constant challenge in hematology. ITP is a heterogeneous disease with an unpredictable evolution. Although the pathogenesis of ITP is currently better known and its etiology has been extensively studied, up to 75% of adult patients with ITP may develop chronicity, which represents a significant burden on patients' quality of life. A major risk of ITP is bleeding, but knowledge on the exact relationship between the degree of thrombocytopenia and bleeding symptoms, especially at a lower platelet count, is lacking. The actual management of ITP is based on immune suppression (corticosteroids and intravenous immunoglobulins), or the use of thrombopoietin receptor agonists (TPO-RAs), rituximab, or spleen tyrosine kinase (Syk) inhibitors. A better understanding of the underlying pathology has facilitated the development of a number of new targeted therapies (Bruton's tyrosine kinase inhibitors, neonatal Fc receptors, strategies targeting B and plasma cells, strategies targeting T cells, complement inhibitors, and newer TPO-RAs for improving megakaryopoiesis), which seem to be highly effective and well tolerated and result in a significant improvement in patients' quality of life. The disadvantage is that there is a lack of knowledge of the predictive factors of response to treatments, which would help in the development of an optimized treatment algorithm for selected patients.

COVID-19 is a severe infectious disease caused by a SARS-CoV-2 infection. It has caused a global pandemic and can lead to acute respiratory distress syndrome (ARDS). Beyond the respiratory system, the disease manifests in multiple organs, producing a spectrum of clinical symptoms. A pivotal factor in the disease's progression is autoimmunity, which intensifies its severity and contributes to multi-organ injuries. The intricate interaction between the virus' spike protein and human proteins may engender the generation of autoreactive antibodies through molecular mimicry. This can further convolute the immune response, with the potential to escalate into overt autoimmunity. There is also emerging evidence to suggest that COVID-19 vaccinations might elicit analogous autoimmune responses. Advanced technologies have pinpointed self-reactive antibodies that target diverse organs or immune-modulatory proteins. The interplay between autoantibody levels and multi-organ manifestations underscores the importance of regular monitoring of serum antibodies and proinflammatory markers. A combination of immunosuppressive treatments and antiviral therapy is crucial for managing COVID-19-associated autoimmune diseases. The review will focus on the generation of autoantibodies in the context of COVID-19 and their impact on organ health.

A State of the Art lecture titled "Immune Attack on Megakaryocytes in ITP: The Role of Megakaryocyte Impairment" was presented at the International Society on Thrombosis and Haemostasis Congress in 2023. Immune thrombocytopenia (ITP) is an acquired autoimmune disorder caused by autoantibodies against platelet surface glycoproteins that provoke increased clearance of circulating platelets, leading to reduced platelet number. However, there is also evidence of a direct effect of antiplatelet autoantibodies on bone marrow megakaryocytes. Indeed, immunologic cells responsible for autoantibody production reside in the bone marrow; megakaryocytes progressively express during their maturation the same glycoproteins against which ITP autoantibodies are directed, and platelet autoantibodies have been detected in the bone marrow of patients with ITP. In vitro studies using ITP sera or monoclonal antibodies against platelet and megakaryocyte surface glycoproteins have shown an impairment of many steps of megakaryopoiesis and thrombopoiesis, such as megakaryocyte differentiation and maturation, migration from the osteoblastic to the vascular niche, adhesion to extracellular matrix proteins, and proplatelet formation, resulting in impaired and ectopic platelet production in the bone marrow and diminished platelet release in the bloodstream. Moreover, cytotoxic T cells may target bone marrow megakaryocytes, resulting in megakaryocyte destruction. Altogether, these findings suggest that antiplatelet autoantibodies and cellular immunity against bone marrow megakaryocytes may significantly contribute to thrombocytopenia in some patients with ITP. Finally, we summarize relevant new data on this topic presented during the 2023 International Society on Thrombosis and Haemostasis Congress. The complete unraveling of the mechanisms of immune attack-induced impairment of megakaryopoiesis and thrombopoiesis may open the way to new therapeutic approaches.

Immune checkpoint inhibitors are a class of antineoplastic therapies that unleash immune cells to kill malignant cells. These medications commonly cause immune-related adverse effects due to activated adaptive and innate immune cells, autoantibody production, and/or cytokine dysregulation. Hematologic toxicities are rare and of uncertain mechanism, and therefore management is often based on experiences with familiar conditions involving these perturbed immune responses. Management is challenging because one must attend to the hematologic toxicity while simultaneously attending to the malignancy, with the imperative that therapeutic effects be maintained or minimally interrupted when possible.

Immune thrombocytopenia (ITP) is an acquired bleeding disorder mediated by pathogenic autoantibodies secreted by plasma cells (PCs) in many patients. In refractory ITP patients, the persistence of splenic and bone marrow autoreactive long-lived PCs (LLPCs) may explain primary failure of rituximab and splenectomy respectively. The reactivation of autoreactive memory B cells generating new autoreactive PCs contributes to relapses after initial response to rituximab. Emerging strategies targeting B cells and PCs aim to prevent the settlement of splenic LLPCs with the combination of anti-BAFF and rituximab, to deplete autoreactive PCs with anti-CD38 antibodies, and to induce deeper B-cell depletion in tissues with novel anti-CD20 monoclonal antibodies and anti-CD19 therapies. Alternative strategies, focused on controlling autoantibody mediated effects, have also been developed, including SYK and BTK inhibitors, complement inhibitors, FcRn blockers and inhibitors of platelet desialylation.

Emerging evidence has demonstrated that obesity impacts multiple immune-related diseases. It remains unclear whether and how obesity alters treatment outcomes in patients with primary immune thrombocytopenia (ITP). Thus, we retrospectively investigated 214 treatment-naïve patients who received standard high-dose dexamethasone therapy in Qilu Hospital. Patients with obesity showed significantly lower overall initial response (underweight vs. normal vs. overweight vs. obese: 85.7% vs. 85.2% vs. 72.0% vs. 52.3%, p = 0.001) and initial complete response ([CR], 71.4% vs. 70.4% vs. 53.3% vs. 27.3%, p < 0.001) rates. The same trend was observed in the 6-month sustained response (63.6% vs. 52.3% vs. 35.6% vs. 22.7%, p = 0.03) and sustained CR (36.4% vs. 44.6% vs. 24.4% vs. 9.1%, p = 0.01). The Kaplan-Meier analysis revealed a shortened duration of remission in the obese group (median duration of remission, not reached vs. 16 months vs. 2 months vs. 1 month, p = 0.002). In multivariate regression analysis, obesity was independently associated with poor initial and sustained responses, and an increased risk for relapse. In conclusion, obesity is a negative predictor for outcomes of corticosteroid treatment. A stratified strategy according to body mass index status may facilitate the precision management of ITP.