Immune Thrombocytopenia Research Articles

Emerging Thrombotic Disorders Associated with Virus-Based Innovative Therapies: From VITT to AAV Gene Therapy-Related Thrombotic Microangiopathy.

Gene therapy is a promising therapeutic approach for treating life-threatening disorders. Despite the clinical improvements observed with gene therapy, immune responses either innate or adaptive against the vector used for gene delivery, can affect treatment efficacy and lead to adverse reactions. Thrombotic microangiopathy (TMA) is a thrombosis with thrombocytopenia syndrome (TTS) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and small vessel occlusion known to be elicited by several drugs, that has been recently reported as an adverse event of adeno-associated virus (AAV)-based gene therapy. TMA encompasses a heterogenous group of disorders, its classification and underlining mechanisms are still uncertain, and still lacks validated biomarkers. The identification of predictors of TMA, such as vector dose and patient characteristics, is a pressing need to recognize patients at risk before and after AAV-based gene therapy administration. This review aims to explore the literature on TMA associated with AAV-based gene therapy in the larger context of TMA (i.e., hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura, and other drug-related TMAs). Considering the wide attention recently gained by another TTS associated with a non-gene therapy viral platform (adenovirus, AV COVID-19 vaccine), namely vaccine-induced immune thrombocytopenia and thrombosis (VITT), AAV gene therapy-related TMA mechanisms will be discussed and differentiated from those of VITT to avoid recency bias and favor a correct positioning of these two recently emerged syndromes within the heterogenous group of drug-related TTS. Finally, the review will discuss strategies for enhancing the safety and optimize the management of AAV-based gene therapy that is emerging as an efficacious therapeutic option for disparate, severe, and often orphan conditions.

Familial autoimmunity and risk of developing immune thrombocytopenia and Evans syndrome.

Immune thrombocytopenia (ITP) and Evans syndrome (ES) are manifestations of immune dysregulation. Genetic variants in immune-related genes have been identified in patients with ITP and especially ES. We aimed to explore familial autoimmunity in patients with ITP and ES to understand possible contributions to chronicity. We assessed family history in two ways: via patient report for ITP and ES and by population-based analysis using the Utah Population Database (UPDB) for ITP. A total of 266 patients with ITP and 21 patients with ES were identified via chart review, and 252 of the 266 patients with ITP were also identified in the UPDB. Chart review showed familial autoimmunity in 29/182 (15.9%) and 25/84 (29.8%) of patients with newly diagnosed+persistent (nd+p) ITP and chronic ITP (cITP), respectively, (p=.009). The UPDB analysis revealed that autoimmunity in relatives of patients with nd+pITP was higher than in relatives of controls (odds ratio [OR]: 1.69 [1.19-2.41], p=.004), but was not significantly increased in relatives of patients with cITP (OR 1.10 [0.63-1.92], p=.734). Incomplete family history in medical records likely contributed to the observed discrepancy. The findings suggest that familial autoimmunity may have a stronger association with the development of ITP rather than its duration. Twelve (57.1%) patients with ES reported autoimmunity in their relatives. UPDB analysis was omitted due to the small number of patients with ES. The use of population databases offers a unique opportunity to assess familial health and may provide clues about contributors to immune dysregulation features within families.

Tapering and Sustained Remission of Thrombopoietin Receptor Agonists (TPO-RAs): Is it Time for Paediatric ITP?

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

Research Advances in the Treatment of Eltrombopag for Adult Patients with Primary Immune Thrombocytopenia--Review

Primary immune thrombocytopenia (ITP) is an autoimmune disease characterized by thrombocytopenia, and T cell immune dysfunction plays an important role in the formation of ITP. As a thrombopoietin receptor agonist (TPO- RA), eltrombopag can not only directly stimulate megakaryocytes to produce platelets, but also play an immunomodulatory role by inducing regulatory T cell generation and reducing proinflammatory factors. As a second-line treatment drug for adult ITP, eltrombopag is increasingly widely used in clinical practice. This review summarized the latest research progress on the mechanism of action, efficacy, safety, and how to reduce the dosage of eltrombopag in ITP.

Analysis of Frequencies and Subsets of Peripheral Helper T Cells in Patients with Immune Thrombocytopenia

To investigate the frequencies and subset distribution of peripheral helper (Tph) T cells in patients with immune thrombocytopenia (ITP), and explore the pathogenesis of ITP. A total of 25 newly diagnosed ITP patients treated in The Second Affiliated Hospital of Dalian Medical University from January to December 2022 were selected, and 25 healthy volunteers (age- and sex-matched) were recruited as the control group. Flow cytometry was used to detect the subsets of CD4+ T cells and Tph cells. The frequency of effector memory (CCR7- CD45RO+CD4+) T cells in ITP patients was significantly higher than that in healthy controls(P < 0.05). The frequency of Tph cells in ITP patients was also significantly higher than that in healthy controls (P < 0.001), and most of the Tph cells in ITP patients were effector memory T cells. Furthermore, the expressions of T-cell costimulatory molecules in Tph cells, including ICOS and CD84, were similar to those in follicular helper T(Tfh) cells. CXCR3 - CCR6 -Tph (Tph2) subgroup was dominant in Tph cells, but the frequency of CXCR3+CCR6- Tph (Tph1) cells in ITP patients was much higher than that in healthy controls (P < 0.05). Tph cells, especially Tph1 cells, were abnormally expanded in ITP patients, which may be a potential etiology of ITP.

Quality of life in childhood immune thrombocytopenia: Revision of the Kids' ITP Tools (KIT).

The Kids ITP Tools (KIT) is a health-related quality of life (HRQoL) questionnaire that evaluates quality of life in children with immune thrombocytopenia (ITP). There are three formats: Child Self-Report, Parent Proxy-Report and Parent Impact-Report. This study aimed to develop a domain structure by grouping-related questions from the questionnaire into domains that independently reflect various aspects of HRQoL. The study was conducted in two phases. Phase 1 involved an online survey distributed to experts to identify conceptual domains for the KIT. Phase 2 utilized a statistical approach to analyse responses from patients with ITP and their families. A revised KIT 2.0 was ultimately developed to aid in treatment decision-making and monitoring of ITP.

Activation of the HMGB1-TLR4 pathway impacts the functionality of bone marrow mesenchymal stem cells and disrupts macrophage polarization in immune thrombocytopenia.

Recent evidence suggests that immune thrombocytopenia (ITP), a common bleeding disorder, is linked to an imbalance in macrophage polarization and impaired bone marrow mesenchymal stem cells (BMSCs). However, the relationship between macrophage polarization imbalance and functional defects in BMSCs, as well as the involvement of associated molecules in BMSCs' defects, is not well understood. This study aimed to investigate the regulatory effects of high mobility group protein 1 (HMGB1) on the physiological functions of BMSCs, specifically in relation to macrophage polarization imbalance. Patients with ITP showed dysregulation in monocyte/macrophage polarization and impaired BMSCs function. HMGB1 was found to have a negative impact on the ability of BMSCs to regulate the imbalance in macrophage polarization, especially when inflammatory factors are present. The MyD88-dependent pathway downstream of BMSCs was found to be significantly enhanced with HMGB1 treatment. Furthermore, treatment with toll-like receptor 4 (TLR4) inhibitors successfully restored the regulatory capacity of BMSCs in ameliorating macrophage polarization imbalance and effectively inhibited the activation of the MyD88-dependent pathway. Meanwhile, infusion of si-TLR4-BMSCs reversed HMGB1-induced platelet dysfunction and reduced over-polarization to M1-like macrophages in the ITP mouse model. Consequently, targeting the HMGB1-TLR4 pathway could be a potential approach to restore the immunoregulatory function of BMSCs.

What is the best second-line treatment for immune thrombocytopenia?

The choice between thrombopoietin receptor agonists (TPO-RAs) and anti-CD20 as the preferred second-line therapies for immune thrombocytopenia remains in the eye of the beholders. Each has major advantages and certain weaknesses. Stolz etal. describe a single-centre experience that whets our appetite for a large randomized controlled trial comparing a TPO agonist and an anti-CD20 agent. Commentary on: Stolz etal. Efficacy of thrombopoietin receptor agonists versus rituximab in non-responsive immune thrombocytopenia - A single center retrospective analysis. Br J Haematol 2024; 205:1121-1125.

Mechanistic insight into multiple antibody binding to ADAMTS-13 in immune thrombotic thrombocytopenic purpura

BackgroundAntibody-mediated inhibition of von Willebrand factor (VWF) cleavage by ADAMTS-13 results in immune thrombotic thrombocytopenic purpura (iTTP). However, the effects of multiple antibody binding to ADAMTS-13 are not fully understood. MethodsSingle-chain fragments of the variable region isolated via phage display from patients with iTTP, FRETS-VWF73, native ADAMTS-13 in normal human plasma, and hydrogen-deuterium exchange plus mass spectrometry were used. ResultsWe found that 2 stimulatory antibodies affect ADAMTS-13 turnover rate more than its substrate recognition. Hydrogen-deuterium exchange plus mass spectrometry revealed that 1 of these 2 stimulatory antibodies bound to the CUB2 domain that presumably interacts with the spacer domain of ADAMTS-13. Spacer domain is targeted by most inhibitory antibodies in iTTP. Both inhibitory and stimulating antibodies could bind ADAMTS-13 simultaneously but when both were present the inhibitory activity predominates. The antibody-mediated stimulation was lost, but the inhibition persisted when a modified substrate with the amino acid residue leucine at position 1603 of VWF was replaced by an alanine (VWF73-L1603A), interfering with active site binding. ConclusionThese results support the hypothesis that the mechanism of action of both stimulatory and inhibitory anti-ADAMTS-13 antibodies in iTTP is through allosteric modification of the catalytic domain and that inhibition of ADAMTS-13 dominates when both are present. Our findings may provide a new avenue of exploration to develop targeted diagnostic and therapeutic approaches in the management of iTTP.

Thrombotic Microangiopathy Treated with Eculizumab in a Patient with Known Immune Thrombocytopenic Purpura

Thrombotic Microangiopathy Treated with Eculizumab in a Patient with Known Immune Thrombocytopenic Purpura

A Unique Case of IgA Nephropathy Associated with Both Immune Thrombocytopenia and Erythrocytosis

A Unique Case of IgA Nephropathy Associated with Both Immune Thrombocytopenia and Erythrocytosis

CXCL13/CXCR5 axis facilitates TFH expansion and correlates with disease severity in adults with immune thrombocytopenia

BackgroundImmune thrombocytopenia (ITP) is an autoimmune bleeding disorder defined by a diminished platelet count. ITP pathogenesis involves intricate changes to both cellular and humoral immunity. The pivotal roles of follicular helper T (TFH) cells in the maturations of B cells and the production of antibodies are well-established. However, the specific role of TFH to the immunopathogenesis of ITP remain incompletely understood. This study aimed to clarify the association of CXCL13/CXCR5 axis with TFH in adults with ITP. MethodsA total of 97 ITP patients and 41 healthy controls were enrolled. CD4+CXCR5+ TFH, CD4+CXCR5+PD-1+ TFH, CD4+CXCR5+Foxp3+ follicular regulatory T cells (TFR), and desialylated platelets in peripheral blood were measured by flow cytometry. Plasma cytokines were assessed by enzyme-linked immunosorbent assay. CD4+ T cells cocultured with chemokine CXCL13 in vitro was performed for the measurement of TFH proliferation. Intracellular production of reactive oxygen species (ROS) was examined by dichlorodihydrofluorescein diacetate (DCFH-DA) probe staining. ResultsWe observed a significant increase in circulating TFH and a marked decrease in circulating TFR in the entire ITP cohort. The ratio of TFH/TFR was elevated, accompanied by heightened levels of platelet desialylation, cytokines BAFF, HMGB1, and IL-21, while levels of IL-10 were downregulated in adults with ITP. Notably, patients with ITP exhibiting platelet count below 50 × 109/L had dramatically elevated levels in both chemokine CXCL13 and its receptor CXCR5+ TFH compared to those with platelet count above 100 × 109/L. High frequencies of TFH correlated with poor therapeutic response. Furthermore, in vitro CD4+ T cell proliferation assay demonstrated a CXCL13 dose-dependent increase in the frequencies in both CD4+CXCR5+ TFH and CD4+CXCR5+PD-1+ TFH from ITP patients. Intriguingly, DCFH-DA assay illustrated a significant enhancement in intracellular ROS generation in CXCR5+ T cell subsets, especially in CD4+CXCR5+PD-1+ TFH from 4 patients with ITP. ConclusionsThese results underscore the pivotal role of CXCL13/CXCR5 axis-drived TFH expansion in the pathogenesis of ITP, providing a potential disease severity biomarker.

Association of paediatric autoimmune cytopenia and inflammatory bowel disease suggests a common genetic origin.

The association of autoimmune cytopenia (AIC) and inflammatory bowel disease (IBD) has been reported in small series, but the incidence of and risk factors for IBD in children with AIC are not known. One thousand six hundred nine children with chronic immune thrombocytopenic purpura, autoimmune haemolytic anaemia or Evans syndrome from the prospective OBS'CEREVANCE cohort are included in this study. Overall, 15 children were diagnosed with IBD, including 14 who developed IBD after AIC diagnosis (median delay: 21 months). The only risk factor for IBD development is age at AIC over 10 years. Out of 10 children genetically tested, germline variants associated with autoimmune disorders were identified in three (CTLA4: two, DOCK11: one). In children and adolescents monitored for AIC or past history of AIC, especially children over 10 years, gastro-intestinal (GI) symptoms (recurrent abdominal pains, GI bleeding, chronic diarrhoea, weight loss) should suggest IBD and deserve specific work-up and genetic studies. Identification of a causal germline variant will allow targeted therapy.

Mucocutaneous Manifestations in a Case of Immune Thrombocytopenia: Reporting a Rare Presentation with Dermoscopic Findings

Mucocutaneous Manifestations in a Case of Immune Thrombocytopenia: Reporting a Rare Presentation with Dermoscopic Findings

Anti-platelet factor 4 immunothrombotic syndromes.

Anti-platelet factor 4 immunothrombotic syndromes comprise a group of disorders that include heparin-induced thrombocytopenia and vaccine-induced immune thrombocytopenia and thrombosis. These are highly prothrombotic, immunological disorders characterised by specific clinical and pathological criteria which include thrombocytopenia and thrombosis. While they are predominantly triggered by heparin and the adenoviral vector vaccines, respectively, other provoking factors have been described, as well as spontaneous forms. The unexplained co-occurrence of thrombocytopenia with thrombosis should raise suspicion and prompt testing. This nutshell review discusses the pathophysiology, presenting features and diagnostic criteria for these conditions.

Prevalence of Immune Thrombocytopenia Purpura in Wasit Province

A lower than normal platelet count is a hallmark of the acquired autoimmune disease immune thrombocytopenic purpura (ITP). This autoimmune disease is characterized by low platelet counts, purpura, and hemorrhagic episodes caused by antiplatelet autoantibodies. Additionally, it inhibits the production of platelets, which can be affected by drugs, infections, cancer, or other autoimmune disorders. Immune thrombocytopenia purpura can be classified into two types: acute and chronic. The acute type, which affects both sexes and typically manifests in childhood, may be brought on by a viral infection, Conversely, the chronic form, more common in women than in males, can affect adults of any gender and is not always associated with a virus infection . Immune thrombocytopenic purpura is a heterogeneous disease with varying biological behavior in terms of clinical outcome and response to treatment ,Better results are shown in children with the condition, but worse results are seen in adults.

Frequency of CD40-1C>T polymorphism (rs1883832) and association with response to treatment in children with primary immune thrombocytopenia.

To investigate whether (cluster of differentiation) CD40-1C>T (rs1883832) contributes to predisposition and treatment response of primary immune thrombocytopenia (pITP) in children. A case-control study that included 100 children with newly diagnosed pITP and 50 age- and sex-matched healthy controls. CD40 rs1883832 was genotyped using TaqMan allele discrimination real-time polymerase chain reaction (PCR). Patients were categorized into responders and non-responders according to their response to corticosteroids and thrombopoietin-receptor agonists (TPO-RA) at 3-month intervals. The genotypic distribution of the CD40 rs1883832 was significantly different among cases and controls (CC 48% vs. 30%; CT 44% vs. 42%; TT 8% vs. 28%; p=.003). Compared with controls, children with newly diagnosed pITP had significantly higher C allele frequency (70% vs. 51%; odds ratio [OR] 2.2, 95% confidence interval [CI]: 1.3-3.8; p=.001). The association between C allele frequency and pITP risk was evident in females (OR 4.3, 95% CI: 2.1-8.8; p<.001), but not in males (OR 0.9, 95% CI: 0.4-2.1; p=.822). Compared with responders, the C allele frequency was significantly higher among non-responders to corticosteroids (87% vs. 66%; OR 3.4, 95% CI: 1.2-11.7; p=.012), but not to TPO-RA (92% vs. 85%; OR 2, 95% CI: 0.2-107; p=.550). CD40 rs1883832 polymorphism may contribute to predisposition and response to upfront corticosteroids therapy of pediatric pITP. These findings improve our understanding of the compound pathophysiology of ITP, suggest important clinical potentials, and open the door for further research on the mechanistic role of CD40 rs1883832 in ITP development and progression.

Long-term safety and effectiveness of romiplostim for chronic idiopathic thrombocytopenic purpura in real-world settings.

Idiopathic thrombocytopenic purpura (ITP), an autoimmune hematologic disorder characterized by severe platelet count reduction, can be treated with romiplostim. However, post-marketing safety and effectiveness data for romiplostim in Japan are scarce. This prospective, observational, post-marketing Specified Use-Results Survey evaluated the real-world safety and effectiveness of romiplostim for 2years. All patients treated with romiplostim during the survey period were eligible. Of the 1622 patients in the safety analysis set, 94.08% (1526/1622) had chronic ITP. The mean single dose of romiplostim was stable after 12weeks and remained < 6μg/kg in approximately 70% of patients until 104weeks. Within 2years, 14.92% of patients discontinued romiplostim because of adverse events, while 6.47% discontinued because of suspected adverse drug reactions. In contrast, 14.00% of patients discontinued romiplostim because of symptom improvement. Before romiplostim initiation, platelet count was < 2.0 × 104/µL in 60.54% of patients, and the mean platelet count was 2.84 ± 5.76 × 104/µL. Platelet count was 9.19 ± 13.01 × 104/µL after 4weeks, and remained between 10.34 ± 10.72 and 12.38 ± 12.63 × 104/µL from 8 to 104weeks of treatment. No specific concerns were revealed regarding the safety and effectiveness of romiplostim in chronic ITP; the findings demonstrated a favorable risk-benefit balance for romiplostim in this population. Trial registration: UMIN000047864 ( www.umin.ac.jp/ctr ).

Immune Thrombocytopenia: Immune Dysregulation and Genetic Perturbations Deciphering the Fate of Platelets.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder. It involves impaired production and excessive destruction of platelets. It is a complex and heterogeneous disorder with unknown pathophysiology. Both genetic and immunologic perturbations have been implicated in the disease pathogenesis. Immune dysregulations involve both the humoral and cellular immunity. Attack of anti-platelet autoantibodies has been found to be the fundamental cause of platelet destruction. Other mechanisms including T cell mediated platelet destruction, complement activation, apoptosis, and desialylation have also been found in the development of ITP. Genetic testing has revealed various predispositions including single nucleotide polymorphisms (SNPs), copy number variations (CNVs), and epigenetic changes in the immunoregulatory genes of ITP subjects. Varying methylation patterns have also been found in the immune-related genes. This review summarizes the dysregulated immune cells, immunologic cascades, altered signaling pathways, genetic mutations and epigenetic changes in ITP pathogenesis. These alterations induce autoimmune responses against the platelets resulting in complex bleeding manifestations and onset of ITP.

Current state and potential applications of neonatal Fc receptor (FcRn) inhibitors in hematologic conditions.

The neonatal fragment crystallizable (Fc) receptor (FcRn) transports IgG across mucosal surfaces and the placenta and protects IgG from degradation. Numerous clinical trials are investigating therapeutic FcRn inhibition for various immune-mediated neuromuscular and rheumatologic conditions; however, FcRn inhibition also represents a potential therapy for IgG-mediated hematologic conditions (e.g., immune thrombocytopenia, autoimmune hemolytic anemia, immune thrombotic thrombocytopenic purpura, acquired hemophilia, red blood cell/platelet alloimmunization). Current evidence derived from both in vitro and in vivo studies suggests that FcRn inhibitors effectively reduce total IgG levels without impacting its production or altering the levels of other immunoglobulin isotypes. Moreover, the risk of serious adverse events, including serious infections, appears to be lower than that seen with other commonly used immunomodulatory/immunosuppressive therapies, albeit in the setting of limited clinical trial data. Ultimately, additional clinical trials that include varied patient populations are required prior to incorporating these agents into standard treatment algorithms for most hematologic conditions. However, based on the pathophysiology of IgG-mediated hematologic disorders and the mechanism of action of FcRn inhibitors, these agents may represent a future novel therapeutic strategy for patients with hematologic conditions caused by IgG antibodies.