Adult Immune Thrombocytopenia Patients Research Articles

Clonal hematopoiesis in patients with autoimmune thrombocytopenia: an international multicenter study.

Diagnostic boundaries between immune thrombocytopenia (ITP) and other thrombocytopenic states such as thrombocytopenic myelodysplastic syndromes, may be difficult to establish, and the detection of somatic mutations by next generation sequencing (NGS) may be of aid. Here we aimed at characterizing the prevalence and clinical significance of clonal hematopoiesis in ITP. In this multicentric retrospective observational study we enrolled 167 adult ITP patients, followed at 13 centers in Italy, UK, and USA. Patients underwent NGS evaluation after a median of 3.6 years from ITP onset and 83% had received at least one therapy line, median 2 (0-9) lines; 51 out of 167 patients had at least one mutation (30%). After exclusion of germline variants and polymorphisms, 18.5% (31/167) were defined as having clonal hemopoiesis. Most commonly mutated genes were TET2, DNMT3A, SRSF2, and ASXL1 (median VAF 29%); 19 of 31 subjects (68%) had high-risk variants, and 8 multiple mutations. Mutated patients were more frequently elderly males and showed a shorter time from first to second line therapy, particularly with TPO-RA. Additionally, clonal hematopoiesis was associated with increased thrombotic risk (26% vs 8% in NGS-negative cases, p=0.01), independently from TPO-RA exposure, though with an age effect. These data demonstrated the prevalence of clonal hematopoiesis in 18% of adult ITP patients, being associated with older age, relapsed/refractory disease, and high risk of thrombotic complications.

Management of Adult Patients with Newly Diagnosed or Relapsed Primary Immune Thrombocytopenia in Eastern Austria.

Treatment sequence in primary immune thrombocytopenia (ITP) is based on national and international recommendations, treatment availability, and physician expertise. This article aimed to provide real-world data on treatment sequence and responses to first- and second-line treatments in newly diagnosed and relapsed adult ITP patients. We analyzed a cohort of 46 adult ITP patients from the Vienna ITP Biobank, who started first-line therapy within 1 week before their first study visit between February 2016 and March 2023. We investigated clinical patient characteristics and patient management in our specialized center and examined the impact of the international ASH guidelines on ITP treatment. Forty-six primary ITP patients, 27 (58.7%) with newly diagnosed ITP and 19 (41.3%) with relapsed ITP, were investigated. Most patients were female (65.2%) with a median platelet count of 9 × 109/L, and 31 patients (67.4%) had bleeding symptoms. All patients received first-line treatment with oral prednisolone; 15 patients received oral prednisolone combined with intravenous immunoglobulins (IVIGs), which were more commonly administered in newly diagnosed than in relapsed ITP patients. First-line therapy resulted an overall response in 82.6% of patients after a median (interquartile range [IQR]) time of 10 (5-25) days. There was no difference in treatment responses between newly diagnosed and relapsed ITP patients, but newly diagnosed patients had a shorter time to response (median [IQR]: 8 [5-14] and 14 [8-27], p = 0.02). Twenty-three (50%) of the patients (11/27 newly diagnosed [40.7%], 12/19 relapsed [63.2%]) required second-line ITP therapy. Thrombopoietin-receptor agonists (TPO-RAs) were the most commonly used second-line therapy with a response rate of 73.7%, and a median (IQR) time to treatment response of 15 (12-20) days. Overall response rates to TPO-RA treatment did not differ between newly diagnosed and relapsed ITP. Following the publication of novel guidelines in 2019, the median (IQR) duration of corticosteroid treatment shortened (100-52 days, p = 0.01), as did the time to second-line treatment (160-47 days, p = 0.01), and the median number of first-line therapies decreased from 2 (1-3) to 1 (1-2). Initial treatment with corticosteroids was effective in the majority of newly diagnosed and relapsed ITP. Response rates to initial corticosteroid treatment in ITP patients are consistent with previous data, but only 50% achieve sustained remission. TPO-RAs, which are well tolerated and effective, are the most commonly used second-line therapy in our study population. International guidelines have led to faster treatment transitions and reduced splenectomy rates. Integration of real-life experience, expert consensus, and guidelines optimizes ITP patient management.

Real-world evidence of avatrombopag for the treatment of immune thrombocytopenia intolerant or ineffective to eltrombopag/hetrombopag.

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

Fibrinolysis is impaired in patients with primary immune thrombocytopenia

BackgroundPatients with primary immune thrombocytopenia (ITP) have an increased risk of thrombosis, which may be due to altered fibrinolysis. ObjectivesTo elucidate the clinical impact of delayed fibrinolysis in ITP patients. MethodsA turbidimetric clot formation and lysis assay and a fluorometric plasmin generation (PG) assay were performed, and levels of plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA), tPA-PAI-1 complexes, α2-antiplasmin, thrombin activatable fibrinolysis inhibitor, and D-dimer were assessed in 86 adult primary ITP patients and 78 healthy controls (HCs). ResultsITP patients showed significantly delayed clot formation, increased clot density, and prolonged clot lysis time (CLT) compared with HCs, with a median (IQR) CLT of 28.0 (13.7-34.7) minutes in patients and 17.3 (12.0-28.0) minutes in HCs, while in the PG assay, only the lag time was prolonged. In ITP patients compared with controls, PAI-1 was higher (1.2 [0.8-2.6] vs 1.1 [0.6-2.1] U/mL) and tPA antigen and activity were lower (tPA antigen: 2.6 [1.1-4.4] vs 3.7 [3.2-4.7] ng/mL; tPA activity ≤ 0 U/mL: 26% vs 7%). TPA-PAI-1 complex levels were positively associated with CLT in multiple linear regression analysis (β = 0.241; P = .019), whereas PG parameters were not associated with CLT. Six patients who developed thrombosis during follow-up had higher levels of tPA-PAI-1 complexes. ConclusionProlonged CLT and delayed onset of PG may indicate a hypofibrinolytic tendency in ITP patients, as also indicated by high PAI-1 and low tPA levels. No association was found between fibrinolytic potential and the bleeding phenotype, whereas higher tPA-PAI-1 complex levels were associated with prolonged CLT and increased in patients with future thrombosis.

Can COVID-19 Increase Platelet in Adult Immune Thrombocytopenia During the TPO-RA Administration? A Real-World Observational Study.

COVID-19 infection has brought new challenges to the treatment of adult patients with immune thrombocytopenia (ITP). In adult ITP patients, there have been no relevant reports exploring the incidence, clinical characteristics, and risk factors of platelet elevation after COVID-19 infection. A total of 66 patients with previously diagnosed ITP from December 2022 to February 2023 in a single-center were collected and analyzed for this real-world clinical retrospective observational study. In the platelet count increased group (n = 19), 13 patients (68.4%) were using thrombopoietin receptor agonists (TPO-RA) treatment at the time of COVID-19 infection; the median platelet count was 52 (2-207) ×109/L at the last visit before infection and 108 (19-453) ×109/L at the first visit after infection. In the platelet count stable group (n = 19) and platelet count decreased group (n = 28), 9 (47.4%) and 8 (28.6%) patients were using TPO-RA at the time of infection, respectively. ITP patients treated with TPO-RA had a significantly higher risk of increased platelet count than those not treated with TPO-RA at the time of infection (platelet count increased group vs platelet count decreased group: OR: 5.745, p = 0.009; platelet count increased group vs the non-increased group: OR: 3.616, p = 0.031). In the platelet count increased group, the median platelet count at 6 months post-infection was 67 (14-235) × 109/L, which was significantly higher than the platelet level at the last visit before infection (p = 0.040). This study showed that some adult ITP patients had an increase in platelet count after COVID-19 infection, and this phenomenon was strongly associated with the use of TPO-RA at the time of infection. Although no thrombotic events were observed in this study, it reminds clinicians that they should be alert to the possibility of thrombotic events in the long-term management of adult ITP patients during the COVID-19 pandemic.

Evaluation of vitamin D status in adult patients with newly diagnosed immune thrombocytopenia.

It has been shown that 25-OH vitamin D not only preserves calcium and bone homeostasis but also has immunomodulatory effects. The purpose of this study was to assess the association between adult patients with recently diagnosed immune thrombocytopenia (ITP) and vitamin D levels. Retrospective technique was employed in this study. The associations between 25(OH)D value and platelet count, as well as the clinical symptoms of ITP upon diagnosis and 25(OH)D value, were our main findings. A total of 60 patients diagnosed and followed up in our clinic were included in the study. Forty-one patients (68.3%) were female and 19 (31.7%) were male. The median age of the patients was 52.5 (19-88). The median vitamin D level of all patients at diagnosis of ITP was 11.5 (3-86). There was no statistically significant difference between the patients divided into three groups according to their vitamin D levels, in terms of laboratory parameters. There was no statistically significant difference in clinical findings according to vitamin D status in ITP patients. There was no statistically significant difference in terms of relapse-free survival in all three groups (p = 0.71). In conclusion, in our study, no correlation was found between laboratory and clinical findings at diagnosis and vitamin D levels in adult ITP patients. Additional investigations, particularly randomized controlled trials, are required to examine the relationship between 25(OH)D and the incidence and severity of ITP.

Tacrolimus and Danazol Combination As a Second-Line Therapeutic Strategy for Steroid-Resistant or Relapsed Immune Thrombocytopenia: A Prospective, Randomized, Multicenter, Open-Label Study

Introduction: Immune thrombocytopenia (ITP) is an important health concern as a severe autoimmune bleeding disorder characterized by low platelet counts and an increased risk of bleeding. Traditionally, the first-line treatment for ITP involves glucocorticoids. However, a substantial number of patients develop resistance or relapse within the first year of treatment, presenting a formidable challenge for medical practitioners. The consequences of prolonged glucocorticoid therapy, such as severe adverse effects, further necessitate the exploration of alternative, more effective, and safer treatments. In recent years, tacrolimus, a potent calcineurin inhibitor, has emerged as a potential candidate for managing ITP. It has shown promising efficacy against anti-platelet antibody-mediated thrombocytopenia, thus expanding the therapeutic options for resistant or relapsed ITP patients. Our previous work ( BJH 2022) also highlighted the potential of tacrolimus in suppressing the activation of NLRP3 inflammasomes and the apoptosis of MSCs-C+ cells both in vivo and in vitro. This research formed a solid foundation for further investigation into the roles of tacrolimus in ITP. Building on this background, our current research focuses on evaluating the effectiveness and safety of combining tacrolimus and danazol as a second-line therapy for patients with steroid-resistant or relapsed ITP. This study was designed to provide a comprehensive understanding of this therapeutic combination, which could pave the way for optimized treatment regimens for ITP, ultimately improving patient outcomes and quality of life. Methods: This phase 2, randomized, open-label trial involved adult ITP patients demonstrating drug resistance or relapse from seven tertiary medical centers across China. Participants were randomly assigned to receive a 12-week treatment of either tacrolimus (initial dose 0.03 mg/kg/d, maintaining a blood concentration between 3-5 ng/mL) combined with danazol (200 mg bid) or monotherapy with danazol (200 mg bid). The primary endpoint entailed a 6-month sustained response, denoted by maintaining platelet counts > 50×10^9/L without additional ITP-modifying therapies at the 6-month follow-up. Secondary endpoints comprised an initial response, response duration, bleeding scores, and adverse events. This trial is registered with ClinicalTrials (NCT05471050). Results: The study enrolled 90 steroid-resistant or relapsed ITP patients, with 43 assigned to the tacrolimus plus danazol group and 47 to the danazol monotherapy group. The participants in the combination group had a median age of 48 years (range: 30-53), and in the monotherapy group, it was 40 years (range: 28-51). Both groups had a marginally higher proportion of female participants. The median primary ITP duration was two months for both groups. Baseline bleeding scores and bleeding or platelet transfusion instances at enrollment were similar across groups. The results showed a promising improvement in the patient response. The tacrolimus plus danazol group showed a significantly higher 6-month sustained response rate (53%, n=23) than the danazol group (30%, n=14) (odds ratio: 2.17, 95% CI: 1.16-6.13, p=0.032). While there was no significant difference in the response times across the groups, the combination group attained a significantly higher peak platelet count (90 ×10^9/L) than the monotherapy group (70 ×10^9/L) (p=0.031). This suggests that the addition of tacrolimus to the therapy can significantly boost the platelet count, potentially improving the clinical outcomes for the patients. Response durations were comparable in both groups, indicating that the addition of tacrolimus did not negatively impact the duration of response. Last, treatment was well-tolerated with no grade 3 or 4 events or treatment-related deaths reported in both groups. Conclusions: The tacrolimus and danazol combination emerges as a promising second-line treatment for steroid-resistant or relapsed ITP. This regimen demonstrated a higher 6-month sustained response rate and peak platelet count compared to danazol monotherapy, substantiating its potential role as a novel treatment strategy for adult ITP patients.

Effects of Intermittent Fasting on Patients with Immune Thrombocytopenia (ITP) Receiving TPO-RA : Multicenter Mixed-Design Study

Introduction The thrombopoietin receptor agonists (TPO-RAs), such as Avatrombopag (AVA), Eltrombopag (ELT), and Romiplostim (ROM), have, in recent years, changed ITP treatment, showing that there is both increased platelet destruction and suboptimal platelet production in ITP. ELT and AVA are oral drugs, while ROM is subcutaneous, and studies have shown that absorption of ELT can be affected by meals. Thus, for optimum absorption, patients are counseled to take it on an empty stomach at least 1 hour before or 2 hours after a meal and at least 2 hours before and 4 hours after calcium-containing meals. However, in Muslim countries where the 16/8 type of intermittent fasting is practiced by religion, the scheduling of drug consumption can be affected. Objective The aim of this study is to evaluate the effect of fasting on patients with ITP receiving different Thrombopoietin receptor agonists (TPO-RAs) brands. Methods A Multicenter, mixed design study was performed in which we interviewed Muslim patients (n = 100) who were 18 years of age or older in Qatar, Kuwait, and Saudi Arabia and fasted Ramadan while receiving TPO-RA treatment between the years of 2015 and 2023. Clinical and biological parameters are recorded using using a standardized patient form. Fasting status was confirmed by a telephone call to each patient. Patients' responses were retrospectively evaluated before, during, and after Ramadan. A statistically significant result was identified with a P-value of < 0.05. Bleeding tendency was also evaluated as either no bleeding, minor cutaneous and mucosal bleeding, or life-threatening bleeding involving major organs (i.e., central nervous system, gastrointestinal, or genitourinary). Results A hundred patients were identified who matched our inclusion criteria for this study. Platelet responses were different among the 3 products, and statistical significance was attributed to the product's compromised efficacy due to disturbed meal schedules and decreased absorption. For patients on AVA, the drug efficacy was not directly affected by meal schedule and absorption but instead was affected by patient compliance. The mean platelet count before Ramadan was estimated at 146.11 ± 111.76, while during Ramadan it dropped to 131.7 ± 107.6. Whereas when comparing platelets before and after Ramadan, there was an insignificant difference 146.11 ± 111.76 vs. 134.17 ± 60.9. For patients on ELT, the mean platelet count before Ramadan was estimated at 120.02 ± 59.7, while during Ramadan it dropped to 100.8 ± 68.16. Whereas when comparing platelets before and after Ramadan, there was an insignificant difference 120.02 ± 59.7 vs. 136.04 ± 74.86. For patients on ROM, the mean platelet count before Ramadan was estimated at 122.68 ± 80.57, while during Ramadan it was 130.94 ± 84.96. Whereas when comparing platelets before and after Ramadan, there was an insignificant difference but an increase in platelet count 122.68 ± 80.57 vs 212.0 ± 113.72. Only 3% (3 patients on ELT) of the patients fasting during Ramadan experienced bleeding episodes. 2 of which experienced minor bleeding (ecchymosis and gingival bleeding), and 1 had major bleeding episodes (Lt. hemorrhagic infarction). 47% of the patients experienced a complete response (PLT>100x10 9) among the three products, and 17% experienced a partial response (PLT 51-100x10 9) 36.6% of the patients on AVA showed a complete response, 46.15% of patients on ELT, and 63.15% of patients on ROM. Conclusion TPO-RAs achieve target platelet counts in adult ITP patients. However, the absorption of ELT is highly affected by food consumption, and thus it is critical to adhere to the instructions given on how the dose should be adjusted and consumed on an empty stomach. AVA absorption didn't show compromise with food consumption, and its efficacy may depend only on patient's compliance. ROM showed better adherence to the medication schedule compared to ELT, contributing to its subcutaneous form and a tailored home visit program given weekly by trained nurses, enhancing patient compliance. The general tolerability and efficacy of TPO-RAs may be reflected on incidence of no major bleeding and the better efficacy of AVA and ROM, which are not affected by fasting.

The Combination of Iguratimod and Danazol Versus Danazol As a Treatment of Corticosteroid-Resistant/Relapse Immune Thrombocytopenia: A Randomized, Controlled, Multicenter, Open-Label Trial

Introduction: The treatment of choice in corticosteroid-resistant or relapsed immune thrombocytopenia (ITP) is still controversial due to the unclear mechanism and unpredictable efficacy of available therapies. The small molecule compound iguratimod is widely used as a novel antirheumatic drug to treat several autoimmune diseases. According to studies involving ITP mice, iguratimod may represent a new approach for the prevention and treatment of anti-platelet antibody-mediated ITP by modulating T-cell differentiation. Since iguratimod and danazol share disparate mechanisms in treating ITP, a combination of iguratimod and danazol may work synergistically based on a “double-hit” mechanism targeting both platelet production and destruction. The aim of this study was to evaluate the efficacy and safety of iguratimod and danazol versus danazol alone in patients with corticosteroid-resistant or relapsed primary immune thrombocytopenia. Methods: Across seven tertiary medical centers in China, adult ITP patients from this randomized, controlled, multicenter, open-label trial participated. Eligible corticosteroid-resistant or relapsed ITP patients with a platelet count <30×10 9/L or bleeding symptoms at enrollment were randomlyallocated by masked statisticians in a 1:1 ratio to receive oral iguratimod at 25 mg twice daily plus oral danazol at 200 mg twice daily or oral danazol monotherapy at 200 mg twice daily for 12 weeks. The group assignment was not masked for clinicians or patients. Following the first eight weeks of treatment, patients were assessed every two weeks thereafter. The primary endpoint was a 6-month sustained response (SR), defined as a platelet count of 30×10 9/L or more and at least a doubling of the baseline platelet count (partial response) or a platelet count of 100×10 9/L or more (complete response) and the absence of bleeding without rescue medication. This trial was registered with ClinicalTrials.gov (NCT05281068). Results: From September 1, 2021, to December 31, 2022, a total of 106 patients were screened for eligibility; 35 were excluded, and 71 were randomly assigned: 37 to the iguratimod plus danazol group and 34 to the danazol group. The median age of the patients was 41 years, and 69.0% (49/71) of them were females. All patients enrolled failed to respond to the first-line treatment with corticosteroids, and 21 (29.6%) of all patients had received three or more therapies. The data cutoff for the analyses was July 1, 2023. The median follow-up was 14 months (IQR 11-15) in the iguratimod plus danazol group and 12.5 months (11-15) in the danazol group. Six-month follow-up results showed that iguratimod plus danazol was more likely to produce SR than danazol alone (20 [54.1%] of 37 vs. 9 [26.5%] of 34; odds ratio 1.82, 95% CI 1.22-2.70, p = 0.003). The combination group had 25 (67.6%) patients with at least one response (overall response), and 13 (35.1%) patients had a complete response by the end of the follow-up; whereas 15 (44.1%) of 34 patients in the monotherapy group had an overall response, and three (8.8%) had a complete response. A target platelet count of 30×10 9/L was achieved in 18 (48.6%) of 37 patients given iguratimod plus danazol after 4 weeks and five (14.7%) of 34 patients given danazol monotherapy, indicating that the combination therapy significantly increased the initial response rate ( p = 0.002). Both groups experienced similar serious adverse events (AEs), rescue treatment, and treatment side effects, and all patients tolerated the treatment well, without any grade 4 AEs or treatment-related deaths reported. Conclusions: Patients with corticosteroid-resistant or relapsed ITP responds well to iguratimod plus danazol. This regimen achieved a rapid and long-lasting response. It is necessary to conduct further studies to determine the optimal dosage and a variety of combination therapies using several immune-suppressing agents, including iguratimod, to achieve a sustained response in patients with corticosteroid-resistant or relapsed ITP.

Real-World Evidence of Avatrombopag for the Treatment of Immune Thrombocytopenia Intolerant or Ineffective to Eltrombopag/Hetrombopag

Abstract Objectives: Thrombopoietin receptor agonists (TPO-RA) have dramatically changed the treatment landscape for immune thrombocytopenia (ITP). Although avatrombopag has been confirmed to achieve platelet response for chronic ITP in clinical trials, and it has no hepatotoxicity unlike eltrombopag or hetrombopag, there is still a lack of real-world research on the application of avatrombopag in Chinese ITP patients. Here, we aimed to evaluate the effect and safety of avatrombopag in ITP treatment in a real-world clinical practice. Methods: In this retrospective analysis, we enrolled consecutive cohorts of 50 adult ITP patients who received avatrombopag in two centers from January 2021 to March 2023. The median duration of follow-up of these patients was 16.5 months (range from 3.8 to 25.4 months). Results: The median age of patients was 44 years when they received the treatment of avatrombopag, and 42% of them were males. Most patients (n=45) had a persistent (3-12 months) or chronic course (more than 12 months) of ITP. The patients in our study were heavily treated, who received a median of 4 kinds of ITP treatment prior to avatrombopag. The baseline TPO levels was 88.1 (110.2±84.5) pg/ml. Based on the reasons for choosing avatrombopag, these patients were divided into eltrombopag/hetrombopag intolerance group (IG, n=14) and eltrombopag/hetrombopag unresponsive group (UG, n=36). The reasons for choosing avatrombopag in IG included active hepatitis B (n=4), hepatic insufficiency before using TPO-RA (n= 6), autoimmune hepatitis (n=1), hepatic lesion after using eltrombopag (n=2), and myelofibrosis after using eltrombopag (n=1). Compared with UG, more patients had a history of liver disease (active Hepatitis B and autoimmune liver diseases, P=0.003). The median platelet count before avatrombopag was 9 × 10 9/L. The median duration of avatrombopag treatment was 12 weeks and the median weekly dose of avatrombopag was 140 mg. Among the total cohort, platelet response (platelet count ≥30 × 10 9 /L) was achieved in 44/50 (88%) and complete platelet response (platelet count ≥100 × 10 9 /L) was seen in 35/50 patients (70%) after using avatrombopag. The median time of platelets rising above 30 × 10 9 /L was 7 days, while it was 8 days when platelet count exceeded 50 × 10 9 /L. Nearly half patients (47%) were able to discontinue more than 1 concomitant ITP medication after avatrombopag treatment. Besides, most patients (74%) in our study tapered off or withdrew steroids. There were no significant differences in baseline platelet count, 30-day response rate, the maximum effective dose of avatrombopag and duration of avatrombopag between IG and UG. So far, 19 patients achieved platelet response were still taking avatrombopag, and 58% of them maintained platelet count above 100× 10 9 /L. Meanwhile, 31 patients discontinued avatrombopag.The reasons for withdrawal of drug included adverse events (n=2), sustained remission in ITP (n=8), no/lose response to avatrombopag (n=10), and unablity to afford the cost consistently (n=11). Avatrombopag was well tolerated in most patients, even those suffered from hepatic insufficiency and/or myelofibrosis after other TPO-RA. However, two cases had thrombosis and two patients reported mild fatigue. Conclusion: In the ITP population, avatrombopag was effective and safe, especially for those intolerant or ineffective to eltrombopag/hetrombopag. However, most patients with ITP were not able to afford the long-term usage of avatrombopag in China.

An Epidemiology Study of Adult Immune Thrombocytopenia Patients in a Teaching Hospital in Northeastern Malaysia

An Epidemiology Study of Adult Immune Thrombocytopenia Patients in a Teaching Hospital in Northeastern Malaysia

Clonal Hematopoiesis in Patients with Immune Thrombocytopenia: Preliminary Results of a Cross-Sectional Study

Immune thrombocytopenia (ITP) is an acquired disorder marked by immune-mediated attack to platelets. However, the borders between ITP and clonal cytopenias, such as low risk myelodysplastic syndromes, may be difficult to establish. Detection of somatic mutations on peripheral blood leukocytes (PBL) through next generation sequencing (NGS) is gaining diagnostic and prognostic power in myeloid disorders and may be found also in individuals without blood malignancies, namely clonal hematopoiesis with indeterminate potential (CHIP). The prevalence and significance of CHIP in immune-mediated hematological diseases, such as ITP, is not clearly known. Here we present the preliminary results of a cross-sectional study on adult ITP patients followed at our clinics from 2019 until March 2023. History of any hematological malignancy was an exclusion criterion. An NGS study on PBL was performed by Ion Torrents5, Ion Reporters software 5.2, evaluating mutations in 69 potentially oncogenic genes present in the Oncomine Myeloid Research Assay diagnostic panel. Only mutations with a variant allele frequency (VAF) of 2% were considered, while mutations with VAF > 40% were regarded as potentially germline and discarded. To correlate mutational status with clinical features, a two-tailed Fisher's exact test was used for analysis of dichotomic variables, while a two-sided student's t was used for continuous ones. We included 37 ITP patients (Table 1), 14 of which (38%) had at least one mutation. After exclusion of 4 mutations with VAF > 40%, a total of 17 mutations were considered, affecting 11/37 (30%) patients (NGS-positive). Mutated genes were TET2 (7/17, 41%), DNMT3A (4/17, 18%), SRSF2 (2/17, 12%), and SF3B1, MPL, ASXL1 and NF1 in 1/17 (6%) case each. All patients, except two, had received at least one treatment line (steroids +/- intravenous immunoglobulins), 32 (86%) and 14 (38%) subjects 2 or 3 lines, respectively. Median age of NGS-positive was significantly higher than NGS-negative patients: 73 years, interquartile range (IQR) 68 - 76 vs 62 years, IQR 52 - 70 (p = 0.02). NGS-positive had a slightly lower rate of complete response (CR; PLT > 100 x 10 9/L) after steroid treatment, compared with NGS-negative patients (40% vs 60%, respectively). Among the 9 NGS-positive patients who received thrombopoietin receptor agonists (TPO-RA), only 2 were evaluated before, and the remaining after a median of 2.6 years from TPO-RA start. Considering the 9 patients treated with TPO-RA, NGS-positive had a slightly lower rate of CR than NGS-negative patients (44% vs 79%, respectively). In this respect, we did not find substantial disparities in distribution or VAF of gene mutations between patients who fully responded to TPO-RA and those failing to achieve CR. With the caveat of a cross-sectional analysis in a limited number of cases, these data show the presence of CHIP in 1/3 of multi-treated ITP patients, a frequency similar to that of a much more elderly Italian population >80-year-old (Rossi et al, Blood. 2021), suggesting a possible role of autoimmunity/inflammation and treatment in clonal selection.

Health Related Quality of Life in Patients with Primary ITP Compared with Population Norms: A Multicenter Retrospective Analysis of Data from Norwegian ITP Registry

Introduction: Immune thrombocytopenia (ITP) is characterized by thrombocytopenia and varying grades of bleeding manifestations. Many patients develop a fear of bleeding, which can impact their health-related quality of life (HRQoL). In addition, often necessary lifestyle adjustments as well as treatment-related side effects may further reduce HRQoL. Aims: to estimate HRQoL in adult patients diagnosed with ITP and to compare their HRQoL to that of the general population using the EuroQol-5 Dimensions-3 Levels (EQ-5D-3L) questionnaire. Methods: Data from the Norwegian ITP (NOR-ITP) Registry was used. Adult ITP patients registered in NOR-ITP from Dec 2016 to May 2023 were included in this study. Patients included in NOR-ITP complete the EQ-5D-3L questionnaire, when included in the registry and then annually as part of their scheduled follow-up. In patients who had completed several EQ-5D-3L questionnaires, the most recent one was used. The age-adjusted Norwegian EQ-5D-3L populations norms were used as reference values for Index and VAS scores. Missing data were replaced using multiple imputation. Results: Median (IQR) age of 247 patients was 57 years (34); M:F ratio = 1:1.5. ITP was newly diagnosed in 18 (7%), persistent in 14 (6%), and chronic in 215 (87%) patients. Platelet count was >50*10 9/L in 166 (67%) patients, between 31 and 50*10 9/L in 15 (6%), and < 30*10 9/L in 18 (7%), unknown for 19% (48). Thirty-nine (16%) patients were never treated for ITP, 80 (32%) patients had remission induced by glucocorticoids +/- IVIGs, and 128 (52%) were treated with second-line agents. Ongoing treatment was an immunosuppressive agent (i.e. glucocorticoids +/- IVIGs, rituximab (received during the last 3 months), azathioprine, cyclosporine-A, mycophenolate mofetil) in 43 (17%) patients, a thrombopoietin receptor agonist in 42 (17%) patients, while 162 (66%) were off-ttraetment. Median time from diagnosis of ITP to most recent EQ-5D questionnaire was 4 (10) years. Figure1a displays the frequency of reported problems (levels 2 and 3) in ITP patients compared to the population norms. ITP patients reported significantly more problems in 4 out of 5 domains. EQ-5D index score was significantly lower in ITP patients compared to the general population [Mean (SD) = 0.790 (0.23) vs 0.830 ([0.041); p-value 0.007]. Likewise, we found VAS to be significantly lower in ITP patients compared to the general population [Mean (SD) = 70.82 (21.09) vs 77.32 (5.554); p-value 0.0001). Within the ITP cohort, we found significantly lower VAS scores in ITP patients receiving ongoing treatment compared to those off treatment (p-value 0.01), as shown in figure1b. However, no significant difference was found concerning Index scores when comparing patients with ongoing to off-treatment. Comparing index scores and VAS according to platelet count category (<30; 31-50; >50*109/L) and the phase of ITP did not reveal any significant differences. Conclusion: This study is the first to evaluate HR-QoL using EQ-5D in a well-characterized cohort of patients with ITP. In line with existing evidence, using other HRQoL instruments, we found significantly reduced HRQoL in ITP patients compared to the general population. ITP patients receiving ongoing treatment had worse HRQoL compared to those off-treatment. Limitations of this study are the the long time period between diagnosis and completing the questionnaire, the observational and retrospective study design, and the lack of predictors for HRQoL.

Epidemiology of immune thrombocytopenia: study of adult patients at a referral hematology service in Northeastern Brazil

Immune thrombocytopenia (ITP) is an acquired bleeding disorder observed in the clinical practice. Little is known about its epidemiology in Brazil. The present study was conducted at a hematology referral center which covers a population of over 8 million in 184 municipalities in the state of Ceará. The purpose of this study was to draw a demographic profile of adult ITP patients with regard to sex, age, geographical origin and distribution across the state, and the proportion of secondary ITP. Following ethics committee approval, information was collected with an ad hoc instrument. The sample consisted of 187 adult ITP patients attending the Walter Cantídio University Hospital in 2015. The median follow-up time was 67 months (range: 1 month to 29 years). Female sex (n = 154; 82.35 %) was strongly prevalent in all age brackets, with an overall female/male ratio of 4.7:1. The median age was 41 ± 16.1 with an interquartile range of 29–55.5 years; there was no difference between the genders. Secondary ITP (18/187; 9.6 %) displayed a bimodal distribution and a linear increase between 38 and >68 years of age. The results of this survey on the epidemiology of ITP in Brazil suggest that ethnic and geographical factors may have a great impact on age and sex distribution and on the distribution of secondary ITP.

Prevalence of Helicobacter pylori infection in adult immune thrombocytopenia patients

Background: Helicobacter pylori is a Gram-negative, microaerophilic bacteria colonizing more than half of the world’s human stomachs. It is the causal agent of active chronic gastritis and the most common cause of peptic ulceration, including gastric and duodenal ulcers. Aims and Objectives: This study aims to the prevalence of H. pylori infection in adult immune thrombocytopenia (ITP) patients. Materials and Methods: An interventional and prospective study was conducted over 6 months with over 50 ITP patients, including those admitted to the general medicine ward and those in regular follow-up in medicine outpatient department. In addition, in all primary ITP patients, a stool antigen test for H. pylori Ag and baseline complete blood count, including platelet count, were done. In addition, all patients’ platelet count was monitored twice weekly for 6 months. Results: Of the 50 patients, 40 are female and 10 are male. The bleeding manifestation was present in 34 patients (68%) and absent in 16 (32%). Among 34 patients, purpura was more frequent (35.3%), followed by gum bleeding 17.6%. Fourteen people tested positive for the H. pylori antigen. Thirty-six patients were found to be H. pylori antigen negative. H. pylori positive frequency was 28%. Patients who receive both steroids and an H. pylori regimen are 9 (18%). Patients who received the H. pylori regimen were only 5 (10%). Patients only receiving steroid doses are 27 (54%). Conclusion: We conclude that 28% of our study patients are infected with H. pylori, and eradicating this organism significantly improves the platelet count. However, a more extended follow-up period is needed to detect the true prevalence of H. pylori infection and the duration of remission.

Bleeding risk assessment in immune thrombocytopenia.

The bleeding risk in immune thrombocytopenia (ITP) is related not only to low platelet count but also to the presence of platelet dysfunction. However, diagnosing a concomitant platelet dysfunction is challenging as most of the available platelet function assays (PFAs) require a platelet count of greater than 100,000/μL. Sonoclot coagulation and platelet function analyzer works on the principle of viscoelastometry, and results remain unaffected by the platelet counts. To assess the platelet function in adult acute ITP patients with the help of sonoclot coagulation and platelet function analyzer and correlate it with the risk of bleeding. Newly diagnosed acute ITP patients with a platelet count less than 20,000/μL were divided into two groups based on WHO bleeding grade: ITP non-bleeder (ITP-NB) group (WHO bleeding grade ≤1) and ITP bleeder (ITP-B) group (WHO bleeding grade ≥2). Platelet function was assessed by sonoclot in both groups. The patients without significant bleeding (ITP-NB) were followed up monthly for six months with the assessment of platelet function during each contact. Eighty patients (30 ITP-B and 50 ITP-NB) were prospectively included in this study. The median age of patients in the two groups was 37 years and 30 years, respectively. The female-to-male ratio was 4:1 and 1:1 in ITP-B and ITP-NB groups. The median platelet count in ITP-B and ITP-NB was 12000/μL (range 1000-19000/μL) and 8000/μL (range 1000-19000/μL), respectively. Mean platelet functions by sonoclot in both groups were lower than the normal cut-off (>1.6). However, the mean platelet function in the ITP-B group (0.2 + 0.17) was significantly lower than the ITP-NB group (1.2 ± 0.52) (p = 0.01). During the follow-up period of 6 months, patients in ITP-NB with a normal platelet function (>1.6) on sonoclot had lesser episodes (one episode) of clinically significant bleeding than patients with a low platelet function (4 episodes). Patients with acute severe thrombocytopenia and bleeding phenotype have a greater abnormality on platelet function by sonoclot than patients with non-bleeding phenotype. This information may help in taking therapeutic decisions in patients with acute ITP.

Refractory immune thrombocytopenia in adults: Towards a new definition.

Immune thrombocytopenia (ITP) is an autoimmune haematological disorder characterized by immune-mediated thrombocytopenia and a variable risk of bleeding. Despite the availability of multiple treatment options, some patients are considered refractory since they do not achieve a platelet count response to multiple treatments and are at risk of bleeding. The term 'refractory' has been used to identify this patient group; however, with the advent of multiple lines of treatment, its meaning has become ambiguous. To address this issue, we reviewed previous definitions of refractory ITP, solicited the views of ITP experts and collected data from registries to inform a definition. Twenty ITP experts who attended the 7th Expert Meeting of the Intercontinental Cooperative ITP Study Group in September 2022 answered a web-based survey: 95% felt that there was a need for a new definition of refractory ITP for clinical and research purposes. The use of the term refractory, accompanied by a clear indication of the type and timing of failed treatments, was supported by 85% of respondents. Preliminary data on the frequency of refractory patients from the McMaster and Norwegian ITP Registries demonstrated that the proportion of adult ITP patients who had failed first-line therapy, rituximab, thrombopoietin receptor agonists, any immune suppressant medication and splenectomy ranged from 0.4% to 3.8%. We propose a definition of refractory ITP that could be evaluated in future studies.

Expression and prognostic value of C-reactive protein in adult immune thrombocytopenia (ITP) patients.

The aim of this study was to investigate the effect of C-reactive protein (CRP) on the prognosis of adult patients with Immune thrombocytopenia purpura (ITP). A retrospective study of 628 adult ITP patients, as well as 100 healthy and 100 infected patients, attending the Affiliated Hospital of Xuzhou Medical University from January 2017 to June 2022 was performed. The ITP patients were grouped according to their CRP levels, and the differences in clinical characteristics of each group and the influencing factors of efficacy in newly diagnosed ITP patients were analyzed. CRP levels were significantly higher in the ITP and infected groups compared with healthy controls (P < 0.001), and platelet counts were significantly lower in the ITP group (P < 0.001). Between the CRP normal and elevated group, their age, white blood cell count, neutrophil count, lymphocyte count, red blood cell count, hemoglobin, platelet count, complement C3 and C4, PAIgG, bleeding score, proportion of severe ITP, and proportion of refractory ITP were significantly different (P < 0.05). Patients of severe ITP (P < 0.001), refractory ITP (P = 0.002), and with active bleeding (P < 0.001) had significantly higher CRP levels. Patients with no response after treatment had significantly higher CRP levels than those who achieved CR or R (P < 0.001). Platelet counts (r = - 0.261, P < 0.001) in newly diagnosed ITP patients and treatment outcomes (r = - 0.221, P < 0.001) were negatively correlated with CRP levels, and bleeding score was positively correlated with CRP levels (r = 0.207, P < 0.001). Treatment outcome was positively correlated with decrease in CRP levels (r = 0.313, P = 0.027). A multifactorial regression analysis of the influencing factors of treatment outcomes on newly diagnosed patients found that CRP was an independent risk factor of the prognosis (P = 0.011). In conclusion, CRP can help assess the severity and predict the prognosis of ITP patients.

Secondary spleen in immune thrombocytopenia: Not so accessory after all….

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by an isolated thrombocytopenia. The pathophysiology is complex but involves platelet-autoantibodies and/or cytotoxic T cells, with the spleen playing an important regulatory role. Accessory spleen (AcS) may possibly contribute to ITP relapse following splenectomy; however, the microenvironment of AcS has not been directly compared to the main spleen. Pizzi et al. conducted a histological study of adult ITP patients where they compared eight matched AcS to main spleens, and they observed a similar immunological composition in both groups. This supports the possibility of AcS-mediated ITP relapse post splenectomy. Commentary on: Pizzi et al. Accessory spleens recapitulate the immune microenvironment of the main spleen in immune thrombocytopenia. Br J Haematol 2023;202:147-152.

Plasma long noncoding RNAs lncDC and THRIL as potential diagnostic markers of adult primary immune thrombocytopenia.

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. 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. 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. 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.