Secondary Immune Thrombocytopenia Research Articles

Pathophysiology and Diagnostics of Immune Thrombocytopenia

Immune thrombocytopenia (ITP) is due to autoantibodies against platelet surface antigens. ITP is considered as either primary, with no clear etiology, or as secondary ITP (drug-induced; underlying diseases). Autoantibodies lead both to loss of platelets in the spleen and/or liver but simultaneously reduce their production. Contrary to other disorders with thrombocytopenia, ITP has reduced levels of thrombopoetin. ITP remains a diagnosis of exclusion. A single defining laboratory test does not exist. Glycoprotein-specific antibodies can be detected in only about 50% of cases. Ruling out EDTA-induced pseudo thrombocytopenia is of particular relevance. Secondary causes of thrombocytopenia should be excluded through medical history (especially medication history), physical examination and possibly bone-marrow puncture.

Fostamatinib effectiveness and safety for immune thrombocytopenia in clinical practice

AbstractFostamatinib, 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.

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.

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

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

SECONDARY IMMUNE THROMBOCYTOPENIA ASSOCIATED WITH RHEUMATOID ARTHRITIS AND SJÖGREN’S SYNDROME: CASE REPORT

SECONDARY IMMUNE THROMBOCYTOPENIA ASSOCIATED WITH RHEUMATOID ARTHRITIS AND SJÖGREN’S SYNDROME: CASE REPORT

Helicobacter pylori-Associated Immune Thrombocytopenia: Diagnostic and Therapeutic Approach.

The relationship between immune thrombocytopenia (ITP) and Helicobacterpylori infection has largely been an unexplored entity. This review article aims at focusing on the role of H. pylori in secondary ITP. We also elucidated the importance of diagnostic workup and treatment of H. pylori in this article. The mechanisms of H. pylori-associated ITP have been covered in this article. The factors determining platelet response to H. pylori eradication therapy have been mentioned. It is extremely crucial to be aware that H. pylori is a major causative pathogen for new-onset ITP as well as chronic ITP. Upper gastrointestinal endoscopic biopsy is the best invasive method for the diagnosis of the same. Further studies need to be conducted across larger, more diverse groups to validate our observation that eradication of H. pylori could aid platelet recovery in ITP.

Real-world use of thrombopoietin receptor agonists for the management of immune thrombocytopenia in adult patients in the United Kingdom: Results from the TRAIT study.

Few studies have reported the real-world use of both romiplostim and eltrombopag in immune thrombocytopenia (ITP). TRAIT was a retrospective observational study aimed to evaluate the platelet responses and adverse effects associated with the use of these thrombopoietin receptor agonists (TPO-RAs) in adult patients with ITP in the United Kingdom. Of 267 patients (median age at diagnosis, 48 years) with ITP (primary ITP [n = 218], secondary ITP [n = 49]) included in the study, 112 (42%) received eltrombopag and 155 (58%) received romiplostim as the first prescribed TPO-RA. A platelet count ≥30 × 109/L was achieved in 89% of patients with the first TPO-RA treatments, while 68% achieved a platelet count ≥100 × 109/L. Treatment-free response (TFR; platelet count ≥30 × 109/L, 3 months after discontinuing treatment) was achieved by 18% of the total patients. Overall, 61 patients (23%) switched TPO-RAs, most of whom achieved platelet counts ≥30 × 109/L with the second TPO-RA (23/25 who switched from eltrombopag to romiplostim [92%]; 28/36 who switched from romiplostim to eltrombopag [78%]). TFR was associated with secondary ITP, early TPO-RA initiation after diagnosis, the presence of comorbidity and no prior splenectomy or treatment with steroids or mycophenolate mofetil. Both TPO-RAs had similar efficacy and safety profiles to those reported in clinical studies.

Risk of fractures and use of bisphosphonates in adult patients with immune thrombocytopenia-A nationwide population-based study.

Corticosteroids remain the first-line treatment of immune thrombocytopenia (ITP), but increase the risk of osteoporosis and fractures. Bisphosphonates are used for the treatment of osteoporosis, but their usage among patients with ITP has not been systemically described. We investigated the risk of fractures and the use of bisphosphonates in adult patients with primary (pITP) and secondary ITP (sITP) compared with matched comparators in a nationwide registry-based cohort study. We identified 4030 patients with pITP (median age 60 years [IQR, 40-74]), 550 with sITP (median age 59 years [IQR, 43-74]) and 182 939 age-sex-matched general population comparators. All individuals were followed for incident fractures. Bisphosphonate use was estimated for calendar-years and in temporal relation to the ITP diagnosis. Adjusted cause-specific hazard ratio (csHR) for any fracture was 1.37 (95% confidence interval [CI] 1.23; 1.54) for pITP and 1.54 (1.17; 2.03) for sITP. The first-year csHR was 1.82 (1.39; 2.40) for pITP and 2.78 (1.58; 4.91) for sITP. Bisphosphonate use over calendar-years and in the early years following ITP diagnosis was higher among patients with ITP diagnosis compared with the general population. In conclusion, the risk of fractures and the use of bisphosphonates are higher in patients with ITP compared with the general population.

A case of secondary immune thrombocytopenia induced by atezolizumab plus bevacizumab therapy for hepatocellular carcinoma resulting in death from intracranial hemorrhage

An 84-year-old woman underwent laparoscopic partial hepatectomy for a single 3.0-cm-diameter nodule of hepatocellular carcinoma at segment 5. Although the postoperative condition was uneventful, multiple recurrences were observed six months after hepatic resection. Transcatheter arterial chemoembolization (TACE) was the second-line therapy. However, she was later diagnosed as TACE refractory due to residual tumor and presence of portal vein tumor thrombus. Third-line therapy was the combination of atezolizumab and bevacizumab, which was discontinued after 22 courses due to disease progression. Two months after the conclusion of chemotherapy, sudden onset of purpura was observed around her eyes and on her lower legs. Laboratory tests revealed severe thrombocytopenia, and she was diagnosed with secondary immune thrombocytopenic purpura. Steroids and immunoglobulin therapy were then administered. Although the immature platelet fraction increased after treatment, the platelet count did not. The patient died of intracranial hemorrhage 10 days after initiation of steroid and immunoglobulin therapy.

Good Prognosis of Adult Immune Thrombocytopenia in a Provincial Hospital

Background: Immune thrombocytopenia (ITP) is an autoimmune disease resulting from platelet destruction and impaired platelet production. Some patients experience relapses or refractoriness after corticosteroid treatment, necessitating second-line treatments. The majority of adult ITP cases become chronic or relapsing. The aim of this study was to assess the clinical course and identify factors related to sustained responses to treatment in patients with ITP. Methods: This observational retrospective cohort study was conducted from January 2013 to December 2022 at Trang Hospital, Trang Province, Thailand. Results: A total of 125 newly diagnosed ITP patients were enrolled, with an average follow-up duration of 48.49 ± 41.49 (mean ± SD) months. The average age was 42.34 ± 18.44 years, the average platelet count was 11.66 ± 14.39 x 10 9 /L, and the average platelet recovery time after treatment was 43.14 ± 101.32 days. The mean response duration after the first-line treatment was 25.99 ± 29.39 months. The characteristics of the patients were as follows: age below 60 years (78.4%), female sex (75.2%), pregnancy (1.6%), primary ITP (67.2%), secondary ITP (32.8%), bleeding symptoms (54.4%), platelet count <10 x 10 9 /L (64%), platelet count 10-30 x 10 9 /L (28.8%), platelet count 30-50 x 10 9 /L (5.6%), platelet count >50 x 10 9 /L (1.6%), splenectomy (4%), observation only (2.4%), loss to follow-up (10.4%), and death (4%). The most common cause of secondary ITP was systemic lupus erythematosus (63%). The first-line treatment consisted of dexamethasone (70.4%), prednisolone (23.2%), and/or intravenous immunoglobulin (4%). The clinical courses were as follows: recovery within 3 months in 68.8%, persistence in 13.6%, and chronic ITP in 17.6%. The sustained responses to corticosteroid treatment at 6 months included complete response (CR) (58.4%) and response (R) (9.6%), as shown in Table 1. Second-line treatments were required in 22.4% of cases, including colchicine (60.7%), azathioprine (35.7%), cyclophosphamide (25%), dapsone (17.8%), vincristine (10.7%), mycophenolate mofetil (7.1%), cyclosporine (3.5%), and/or eltrombopag (3.5%). The sustained responses to second-line treatments at 6 months were CR in 12% and R in 8.8%. Female sex ( P-value 0.007) and primary ITP ( P-value 0.046) were significantly associated with the sustained response (CR+R) to corticosteroids at 6 months. Secondary ITP ( P-value 0.036) was also associated with the sustained response (CR+R) to second-line treatments at 6 months (Table 2). Conclusions: This study reveals a favorable prognosis for ITP, with a majority of patients showing sustained response (CR+R), which differs from findings in studies conducted at referral centers. Female patients and those with primary ITP are more likely to respond. Further confirmation is needed through a large prospective cohort study in community hospitals.

First-Time Users of Advanced Therapies Among Adult Patients with Persistent or Chronic Primary Immune Thrombocytopenia: Patient Characteristics, Treatment Switching Patterns, and Clinical Outcomes

Background Primary immune thrombocytopenia (ITP) is a rare acquired autoimmune disorder characterized by low platelet count, with an overall age/sex-standardized annual incidence of 6.1 per 100,000 persons in the US in 2016. Patients who fail to respond or maintain a response to initial therapy (e.g., corticosteroids, intravenous immunoglobulins), move to advanced therapies with robust evidence such as thrombopoietin receptor agonists (TPO-RAs [eltrombopag/ romiplostim/ avatrombopag]), rituximab, and fostamatinib, as per the international consensus guidelines. Among patients with primary ITP lasting ≥3 months who are first-time users of advanced therapies, there is limited real-world evidence on patient characteristics, treatment patterns, and clinical outcomes. Objectives The key objectives were to assess patient characteristics, treatment patterns, and clinical outcomes of first-time users of advanced therapy in patients with primary ITP lasting ≥3 months. Methods This retrospective, cohort study included patients identified from Optum de-identified Clinformatics ® Data Mart database, aged ≥18 years with primary ITP lasting 3 months or more, who initiated advanced therapy for the first time between October 1, 2015, and August 31, 2020. Patients were required to have ≥365 days of available data prior to index date, without evidence of conditions associated with secondary ITP. Patients were indexed on the date of initiation of advanced therapies. Baseline characteristics, including demographics, comorbidities, use of medication, and bleeding events requiring medical attention (e.g., intracranial bleeding, gastrointestinal bleeding, hematuria) were assessed 365 days prior to index and reported using descriptive statistics. Treatment patterns and rates of bleeding events, thromboembolic events (TEs), bacterial infections, and hospitalizations were assessed during follow-up, which began one-day after index date and until discontinuation of the index therapy. Patients were censored on death, end of data accrual, disenrollment, or switch to another advanced therapy. Outcomes were reported as the number of events per 1000 person-years and time to first event. Results Total 375 patients with primary ITP lasting ≥3 months, who were first-time users of advanced therapies were included, with 51% (n=192) initiating TPO-RAs, 49% (n=182) initiating rituximab, and <1% (n=2) initiating fostamatinib. Mean (SD) age of overall population was 62 (19) years, and 55.7% were female. About 9% of patients were Black, 4% Asian, and 11% Hispanic ( Table 1). In year prior to index date, previous bleeding events were most common clinical symptoms in patients with ITP initiating advanced therapies (any bleeding, 39.7%). Other frequently reported comorbidities were diabetes (28.5%), coronary artery disease (18.9%), and asthma (17.3%); 13.1% of patients had a TE. About 5% patients reported bacterial infections ( Table 1). Patients initiating TPO-RA and those starting rituximab were observed for a median (interquartile range, IQR) duration of 22.2 (14.5-34.9) months and 27.1 (13.5-43.2) months, respectively. Almost 9% of TPO-RAs initiators switched to rituximab (median [IQR] time to switch: 3.2 [1.7-6.9] months), while 23.6% of rituximab initiators switched to TPO-RAs (median [IQR] time to switch: 3.1 [1.7-7.6] months) during follow-up. After initiating advanced therapies, the rates of any bleeding event and TEs were 288 per 1000 person-years (95% CI: 240-336) and 129 per 1000 person-years (95% CI: 99-158), respectively. Mean (SD) time to first bleeding event was 299 (351) days and that of TE was 257 (325) days. Infection rate was 70 per 1000 person-years ( Table 2). In follow-up, 31% of patients had ≥1 ITP-related hospitalization and 38% had an all-cause hospitalization, resulting in rates of 215 [95% CI: 176-255] and 299 [95% CI: 250-349] per 1000 person-years, respectively. Approximately 5% of patients underwent splenectomy (incidence rate: 27 per 1000 person-years [95% CI: 15-40]) with mean (SD) time of 245 (186) days post initiation of advanced ITP therapy ( Table 2). Conclusion This study demonstrated high clinical burden and need for subsequent additional therapies among patients with primary ITP lasting ≥3 months, which is evident from high rates of switching between advanced therapies, bleeding events requiring medical attention, TEs, and ITP-related hospitalizations.

Current Management of Pregnant Persons with ITP: Systematic Literature Review

Introduction: Immune thrombocytopenia (ITP) often occurs during pregnancy and thrombocytopenia can worsen as the pregnancy progresses. Thrombocytopenia during pregnancy is significant because of concerns regarding risk of postpartum hemorrhage and neonatal thrombocytopenia. Ideally, patients are managed jointly by hematologists and high-risk obstetricians with a treatment goal to minimize the risk of bleeding complications. The 2019 American Society of Hematology ITP guidelines do not address pregnancy. The 2019 International ITP Consensus Report recommends initial therapy with steroids or intravenous immunoglobulin (IVIG), and patients refractory to initial therapy may need anti-D (Rh(D) positive nonsplenectomized persons), combination therapy, thrombopoietin receptor agonists (TPO-RAs), or rituximab in severe cases. Although the 2019 American College of Obstetricians and Gynecologists (ACOG) guidelines agree with initial management, they disagree with 2nd and 3rd line recommendations stating there is not enough evidence to recommend either anti-D or rituximab during pregnancy and do not mention TPO-RAs at all. Therefore, the purpose of this study was to perform a systematic literature review to describe current management of pregnant persons with ITP. Methods: In March 2023, we conducted a systematic search in the MEDLINE, Embase and Web of Science databases to identify articles on treatment of ITP in pregnancy from 2001-present. Keywords included terms for primary ITP and terms for pregnancy. Inclusion criteria included: 1) English language, 2) humans, and 3) at least 10 pregnant persons in the cohort. Exclusion criteria were: 1) did not contain original data, 2) conference abstracts, 3) unable to separate primary vs secondary ITP, and 4) unable to separate data for only the patients managed after 2001. Three persons independently reviewed articles and performed data abstraction. The online Covidence systematic review management system was utilized to standardize data abstraction and determine consensus. Adverse outcomes were abstracted as reported in the original article. Results: After removal of duplicates, a total of 1396 articles were screened for eligibility, 420 full articles were reviewed and 30 met eligibility criteria (Figure 1). Of the included articles, the majority were retrospective cohort studies (18/30), 6 prospective cohort, 2 case-control, 2 cross-sectional, and 2 clinical trials. These 30 articles represented 3282 pregnant persons aged 16-45 years, with 3868 total pregnancies managed across 14 different countries. Fifty-seven percent of pregnancies (2207/3868) required treatment during the pregnancy and of those treated, 36% (805/2207) only required steroids. Other common treatments included: 17% (372/2207) IVIG + steroids, 14% (307/2207) IVIG only, 11% (232/2207) TPO-RAs, and 10% (225/2207) received platelet transfusions. Only 8 pregnancies were treated with rituximab and 0 with anti-D. Nine articles described management during delivery. The majority (58%; 695/1203) reported no treatment was administered during delivery. When treatment was administered during delivery, it was a platelet transfusion (59%; 302/508) or steroids (40%; 204/508). Only 2 maternal deaths were reported. There were 2 neonatal deaths and 68 intrauterine deaths. Also 7% of the total pregnancies were reported to have a post-partum hemorrhage complication. Conclusion: As expected, pregnant persons with ITP were initially managed with steroids and IVIG. However, results from this study suggest hematologists are comfortable treating pregnant persons with off-label TPO-RAs. Patients were rarely treated with rituximab and 0 were treated with anti-D. Pregnancy in ITP was not without maternal risk as 7% of the pregnancies were complicated by hemorrhage. In comparison, the rate of postpartum hemorrhage in 2019 in the United States was reported to be 4.3% (Corbetta-Rastelli, Obstetrics & Gynecology 2023; 141:152-161). Although despite the hemorrhage rate, there were only 2 maternal deaths. Strengths of this study include the number of countries and pregnancies represented; however, limitations include the country-level differences in access to therapies and differences related to risk of pregnancy complications. The treatment landscape for ITP continues to expand; therefore, guidelines reflecting current management options are critical.

Avatrombopag for Adults with Early Versus Chronic Immune Thrombocytopenia

Background Avatrombopag (AVA) is a newer thrombopoietin receptor agonist (TPO-RA) with certain advantages over other TPO-RAs. AVA is currently approved to treat adults with immune thrombocytopenia (ITP) in the chronic disease phase (duration >12 months). However, no studies have evaluated the safety and effectiveness of AVA in newly diagnosed ITP (duration <3 months) or persistent ITP (duration 9-12 months), leaving open questions regarding its safety (including thromboembolic risk) and effectiveness in these patients, and also drastically limiting availability of the drug to patients with early ITP, for whom it is off label. We hypothesize that AVA has similar safety and effectiveness in all phases of ITP. Methods We performed a multicenter, observational cohort study of all adult patients with primary or secondary ITP at 4 hospitals treated with AVA to compare outcomes of patients with newly diagnosed or persistent ITP versus patients with chronic ITP. We collected patient and disease characteristics and characteristics and outcomes of AVA treatment, including dosing, platelet counts prior to and during treatment, adverse events, concurrent and rescue therapies for ITP, and platelet transfusions. Platelet outcomes included rates of response (R, the primary outcome, defined as platelet count of ≥50 × 10 9/L) and complete response (CR, platelet count ≥100 × 10 9/L), both on at least one measurement without requirement for rescue therapy. The response fraction (RF) and complete response fraction (CRF), fractions between 0 (representing no instance of response at any timepoint for a patient) and 1 (representing a response at all timepoints for a patient) were calculated for each patient from monthly measurements during the first six months of treatment with avatrombopag. Other outcomes included major bleeding, rescue therapy requirements, thrombocytosis, and adverse events. Results Patient Population. 75 patients were included, 23 patients with newly diagnosed or persistent ITP (17.7 patient-years of AVA exposure) and 52 patients with chronic ITP (65.3 patient-years of AVA exposure). The median (range) age was 55 (18-80) years in the newly diagnosed/persistent ITP group versus 66 (22-90) years in the chronic ITP group; approximately 65% of patients in each group were female. Platelet Outcomes. With regards to the primary outcome, R was achieved in a similar proportion of newly diagnosed/persistent ITP patients (91%) as in chronic ITP patients (96%), P=0.58. Similar proportions also achieved a CR: 86% newly diagnosed/persistent ITP patients versus 81% of chronic ITP patients, P=0.78. Mean RF and CRF were also similar between the two groups ( TABLE). The median platelet count at baseline and over the first six months of treatment by disease phase is illustrated in the FIGURE. Other Outcomes. Incidence of major bleeding and requirement for rescue therapy and platelet transfusion were low in the newly diagnosed/persistent group ( TABLE) and statistically similar to incidences in the chronic group. Safety. The incidence of thrombocytosis (platelet count ≥400 × 10 9/L on ≥1 measurement) was similar (44% in the newly diagnosed/persistent ITP group and 40% in the chronic ITP group). No patient developed an arterial thromboembolic event. No patient in the newly diagnosed/persistent group developed a venous thromboembolism (VTE) and only one patient in the chronic group developed a VTE. No patient in the newly diagnosed/persistent group discontinued AVA due to an adverse event or safety concern. The rate of thromboembolic complications in the entire cohort including 83.0 patient-years of AVA exposure was 1.2 thromboembolic events per 100 patient-years, considerably lower than prior phase 2 and 3 clinical trials of AVA in ITP (which together documented 11 thromboembolic events occurring over 72.4 patient-years of AVA exposure, or 15.2 thromboembolic events per 100 patient-years). Conclusions AVA was safe and effective in patients with newly diagnosed and persistent ITP, with outcomes numerically, statistically, and clinically similar to patients receiving AVA for chronic ITP. Given its lack of dietary restrictions and hepatotoxicity, access to AVA in early ITP could improve disease outcomes and patient health-related quality of life. Further studies are needed to confirm our findings and evaluate the ability of AVA to induce sustained responses off treatment in patients with early ITP.

Immunoglobulins As a Predictor of Chronicity in Pediatric Immune Thrombocytopenia

Introduction: Immune thrombocytopenia (ITP) is the most common acquired bleeding disorder in children, but predictors of chronicity at the time of diagnosis remain largely unknown. Small studies have previously indicated predictive value of baseline immunoglobulin levels, but without definitive clinically applicable conclusions. We aim to further investigate the utility of immunoglobulin levels obtained at the time of diagnosis in predicting the development of chronic ITP (cITP) in children. Methods: We completed a retrospective review of patients aged 6 months - 21 years diagnosed with ITP at tertiary referral centers from 2015 - 2022 in accordance with IRB-approved protocols. Patients with immunoglobulin levels obtained within 3 months of ITP diagnosis and prior to any treatment were included in the study. cITP was defined as ITP duration >12 months. ITP resolution was defined as achieving a platelet count > 150 x 10 9/L on 2 occasions, or on 1 occasion in the presence of normalized MPV, absent of therapy. Patients who were lost to follow-up or had ongoing disease <1 year duration were excluded. Immunoglobulins were recorded by continuous variable as well as by age-related reference values. The two groups (“spontaneously resolved” and “cITP”) were compared using Pearson's Chi-squared test for nonparametric categorical variables, Fisher's exact test for parametric categorical variables, and Wilcoxon rank sum test for nonparametric categorical variables. A multivariable logistic regression model was built to determine independent associations between immunoglobulin levels and the development of cITP after adjusting for age. R (version 4.2.1) was used for analysis. A p-value <0.05 was considered to be statistically significant. Results: We identified 497 patients for inclusion in the study. Among these, 336 patients (67.6%) had ITP resolution prior to 12 months, while 161 patients (32.4%) developed cITP. Within the full cohort, 257 (51.7%) were male and 218 (43.9%) were Hispanic. Median age of diagnosis was 4.1 years among those with resolution, and 9.4 years among those with cITP. Patients were more likely to have secondary ITP in the cITP group vs the resolved group (37 patients [23.0%] vs 10 patients [6.2%]). Low and high IgG levels were more prevalent in cITP (5% vs 3% and 16% vs 5.7%, respectively). The median IgG level was higher in the cITP group (991 vs 838 mg/dL). Low IgA levels were more prevalent in cITP (7% vs 2.4%) and high IgA levels more prevalent in spontaneously resolving ITP (7.8% vs. 5.7%), although the median IgA level was higher in cITP (116 vs 88 mg/dL), likely attributable to older age in the cITP group. Both low and high IgM levels were more prevalent in cITP (8.9% vs 6.6% and 20% vs 16%, respectively), with the median IgM level being similar in both groups (89 vs 85 mg/dL). The age-adjusted multivariable logistic regression analysis demonstrated independent predictive value of IgG, IgA, and IgM for development of cITP (See Table, Figure). Each 100 mg/dL increase in IgG level was associated with a 17% increase in the odds of developing cITP (p=0.001); while each 100 mg/dL increase in IgA or IgM level was associated with decreased odds of developing cITP (37% [p=0.025] and 56% [p<0.001] decrease, respectively). Additionally, every 1-year increase in age was associated with a 16% increase in the odds of developing cITP (p<0.001). We also found that patients with a known secondary cause of ITP at the time of diagnosis had increased likelihood of developing cITP (p<0.001). Performance scores for the predictive model include a C-index of 0.72 and Nagelkerke R 2 of 0.21. Conclusions: We utilized pre-treatment immunoglobulin values obtained within 3 months of diagnosis from 497 children with ITP to investigate the predictive value of immunoglobulin measurements for the development of cITP. We found that IgG, IgA, and IgM values are predictive of cITP development after accounting for age. Increasing age was also associated with increased risk of cITP. In future work, we plan to evaluate the value of additional variables for predicting the development of cITP and then validate the predictions in an external cohort. Better defining the predictive value of clinical data available at the time of ITP diagnosis will allow hematologists to provide improved prognostication and individualized management much earlier in a patient's disease course, ultimately improving the quality of care for children with ITP.

Genetic Variants in Canonical Wnt Signaling Pathway Associated with Pediatric ITP

Introduction : Pediatric immune thrombocytopenia (ITP) is thought to develop when a triggering event inappropriately activates an autoimmune anti-platelet response in the context of predisposing genetic factors. Inborn errors of immunity are increasingly being identified in cases of chronic, refractory autoimmune cytopenias. We sought to identify genetic variants associated with predisposition to 1) primary or secondary pediatric ITP of any disease duration versus healthy controls and 2) chronic ITP (cITP) versus disease that spontaneously resolves in < 1 year (sr-ITP). Methods : DNA and clinical data were derived from 8 sites from the Pediatric ITP Consortium of North America's (ICON) biorepository. Samples were genotyped using the Illumina Global Screening Array BeadChip. Genotypes were imputed using the Michigan Imputation Server HRC reference panel. Genetic variants that passed standard quality metrics and had a MAF ≥1% were retained. Control samples (n=8,372) were obtained from the National Longitudinal Study of Adolescent to Adult Health (Add Health) cohort. Logistic regression models were used to estimate adjusted odds ratios (aORs) comparing (1) ITP and control cohorts and (2) cITP and sr-ITP cohorts. Models assumed additive allelic effects and accounted for the top 3 principal components. Genome-wide significance was defined as P <5 × 10 -8 and suggestive of genome-wide significance, P <1 x 10 -5. Results : Six-hundred ten unique patient samples were genotyped. Nineteen (3.1%) did not pass quality control, leaving 591 for analysis. This cohort included 307 (52.0%) cITP patients, 209 (35.4%) sr-ITP patients, and 75 (12.7%) individuals without complete follow-up data to allow for classification of cITP or sr-ITP. The ITP cohort was 50.1% male, 50.1% non-Hispanic (NH) white, 29.4% Hispanic, 6.1% NH Black, 3.1% NH Asian, and 11.3% Other/Unknown. Compared with healthy controls, we identified 6 loci associated with ITP at genome-wide significance (Figure 1). Located within the intronic region of SLC24A4 rs75650997 was associated with an increased risk of ITP compared with controls (aOR: 2.38, P=3.9x10 -8). An intronic variant, rs2165798, in NAV2 was inversely associated with ITP (aOR: 0.52, P=3.2x10 -11). A variant in NKD1 rs4785216, was inversely associated with ITP (aOR: 0.43, P=8.86x10 -15).Another intergenic variant, rs4785426, in close proximity to NKD1 was also inversely associated with ITP (aOR: 0.48, P=1.84x10 -16) . An additional 20 variants met suggestive of genome-wide significance. When comparing sr-ITP and cITP patients, no SNVs (single nucleotide variant) reached genome-wide significance, but one variant, rs117609649, in ABCC4 met suggestive of genome-wide significance (aOR: 0.26, P=4.49x10 -7). Discussion : This is the largest, unbiased genetic study of pediatric ITP patients. The analysis comparing ITP versus healthy controls identified 20 suggestive SNVs and 6 which met genome-wide significance. Several of the top SNVs identified in this study affect Wnt/β-catenin signaling. Wnt-signaling impacts the development and regulation of immune cell populations including dendritic cells, macrophages, NK cells, B cells, and T cells. NAV2 activates Wnt/β-catenin signaling. NAV2 variants have been implicated in autoimmune conditions including Celiac disease and rheumatoid arthritis. NKD1 inhibits the canonical Wnt/β-catenin signaling pathway. The cumulative impact of these variants on Wnt activity in ITP should be evaluated in the future. No genetic variants met genome-wide significance in a comparison of sr-ITP and cITP patients. Collectively, these findings suggest there may be genetic variants implicated in ITP risk, but those genetic features are not specific to sr-ITP or cITP. A focused analysis of 632 genes that cause inborn errors of immunity (IEI) is ongoing. This includes gene burden testing and analysis of pathogenic variants within this gene subset. Variants in IEI genes will also be evaluated in a sub-population of patients with Evans syndrome. Conclusion : ITP is highly heterogenous in its presentation, disease course, and response to therapy. Mirroring its clinical behavior, the genetic contribution to ITP development is complex. This study identified potential SNVs associated with ITP, but not specific to sr-ITP or cITP. Variants in genes that affect the canonical Wnt-signaling pathway may play a role in ITP risk.

Proposal of New Diagnostic Criteria for Primary Immune Thrombocytopenia

Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by isolated thrombocytopenia due to accelerated platelet destruction and impaired platelet production. Diagnosis of ITP is still challenging because ITP has been diagnosed by exclusion. Exclusion of thrombocytopenia due to bone marrow failure is especially important in Japan because of high prevalence of aplastic anemia compared to Western countries. Hence, we propose new diagnostic criteria involving the measurement of plasma thrombopoietin (TPO) levels and percentage of immature platelet fraction (RP% or IPF%) as shown in Fig. 1. These biomarkers reflect the pathology of ITP, in which shortened platelet lifespan associated with increased platelet destruction and relatively maintained platelet production. Diagnostic criteria is as follows: 1. ALL of the following *1 ・Thrombocytopenia (＜100,000/μL) ・Absence of anemia (excluding anemia due to bleeding and/or iron deficiency) ・Normal leukocyte count (but may present with mild abnormal leukocyte count) ・No morphological evidence of dysplasia in any blood cell type in a blood smear 2. Normal or slightly increased plasma TPO level (<cutoff) 3. Elevated percentage of immature platelet fraction (RP% or IPF%; > upper limit of normal) 4. Absence of other conditions that potentially cause thrombocytopenia including secondary ITP ⋆2 ● A diagnosis of ITP is made if conditions 1 - 4 above are all met (ITP) ● Cases in which criterion 2 or 3 is not met or unavailable are defined as “possible ITP, pITP”. A diagnosis of ITP can be made if the patient is a glycoprotein (GP)-specific platelet-antibody positive, increased GP-specific platelet antibody-producing B cells, or typical clinical course. (Footnotes) *1 Bone marrow examination is strongly recommended to rule out other diseases if peripheral blood demonstrates any of the following findings: leukocyte count <3,000 or ≥10,000/μL, MCV ≥110, neutrophils <30% or lymphocytes ≥50%, presence of immature leukocytes *2 Includes drug-related thrombocytopenia, radiation injury, aplastic anemia, myelodysplastic syndrome (MDS), paroxysmal nocturnal hemoglobinuria (PNH), systemic lupus erythematosus (SLE), leukemia, malignant lymphoma, bone marrow metastasis of cancer cells, disseminated intravascular coagulation (DIC) , thrombotic thrombocytopenic purpura (TTP), hypersplenism, megaloblastic anemia, sepsis, infections (tuberculosis, etc.), sarcoidosis, and huge hemangioma such as Kasabach-Merritt syndrome. Congenital diseases involving thrombocytopenia include Bernard-Soulier syndrome, Wiskott-Aldrich syndrome, MYH9-related disease and Upshaw-Schulman syndrome. Sensitivity and specificity analysis of this criteria was performed by using data of previously performed prospective study (Kuwana et al. J Thromb Haemost 2006). In this study plasma TPO level were measured by R&D Systems ELISA Kit and RP% were measured by flow cytometry. 112 thrombocytopenic patients who were initially suspected ITP (final diagnosis: ITP 88, aplastic anemia 11, MDS 10, others 3) were included in the study. The sensitivity and specificity of “ITP” who met all 4 conditions of the new criteria were 53.4% (47/88) and 95.8% (23/24), respectively. If cases of diagnosed as “ITP” or “pITP” by the new criteria were considered as ITP, sensitivity and specificity were 94.3% (83/88) and 75.0% (18/24), respectively. More importantly, these criteria exclude aplastic anemia completely from true ITP. For clinical diagnostic use, new CLEIA-based TPO measurement kit (MBL, Japan) has recently been developed in Japan. However, it is still crucial to carefully differentiate ITP from other thrombocytopenic diseases before applying these biomarkers. These new criteria enable us to clearly differentiate ITP from aplastic anemia and other forms of hypoplastic thrombocytopenia, and can be highly useful in clinical practice for avoiding unnecessary bone marrow examination as well as for appropriate selection of treatments.

The Risk of Infections in Adults with Primary Immune Thrombocytopenia (ITP)

Background Immunosuppressive treatment has remained a cornerstone in the management of primary ITP (pITP) for decades. Infections are known complications to immunosuppressive therapy, but the actual risk is not well studied in ITP. We have previously shown that the overall mortality risk is increased in pITP patients and specifically that death due to infections is 1.5-2.4-fold elevated compared to the general population. In this study,we aimed at quantifying the risk of infection, including infection subtypes, in adults with pITP and matched comparators from the general population. Study design We constructed a nationwide cohort of patients ≥18 years with pITP using the Danish Civil Registration System (CRS) and the Danish National Patient Registry (DNPR). We identified ITP patients using the specific ICD-10 diagnosis registration and age-sex matched these with up to 40 comparators without ITP from the general population. We excluded prevalent ITP, non-ITP thrombocytopenic disorders, and secondary ITP defined as one or more associated diagnosis registered any time before or up to 30 days after diagnosis of ITP. The latter included ITP in combination with hematological malignancies, autoimmune disorders etc. Hospital registered infections were identified through the DNPR, prior to 1995 using ICD-8 and ICD-10 diagnoses codes thereafter. Diagnosis codes were grouped, defining the following seven types or sites of infection: respiratory, urogenital, bloodstream, gastrointestinal, tissue and musculoskeletal, central nervous system (CNS), candidiasis and other fungal infections. Date of first registration of pITP marked start of follow-up and comparators were assigned the same start date. Patients and comparators were followed to the first of following events in each of the seven subgroups: infection, emigration, death, or end of study period (31 st of December 2016). Infections occurring before start date were categorized as prevalent. We computed 1-year, 5-year, and 10-year as well as overall cumulative incidences. In addition, relative increases in risk were estimated using Cox-specific hazard (csHR) and Fine-Gray subhazard ratios (subHR) with and without equivalent time-splits, and death as competing event. Results We identified 4,030 pITP patients and 161,020 matched comparators. In the combined group of all types of infections total follow-up time was 22,075 person-years (average 5.5 years) for pITP patients and 1,118,304 person-years (average 6.9 years) for comparators. Median age was 60 years [IQR 40-74]. Previous hospital registered infections had occurred in 37% of patients and 27% of comparators. Comorbidity was more frequent among pITP patients than among comparators. The 1-year cumulative incidences in all subgroups of infections were higher in patients compared with the general population (Figure 1). For blood stream infections the 1-year cumulative incidence reached 3.36% [95% CI 2.83-3.96] in patients and 0.47% [95% CI 0.44-0.51] in comparators. The cumulative incidences for all subtypes of infections remained higher for patients than comparators throughout the study period, but differences decreased over time. During the first year adjusted csHR for infections overall was 2.82 [95%CI 2.61-3.05] and the adjusted subHR was 2.20 [95% CI 2.01-2.41]. Blood stream infections had the relative highest risk with an adjusted csHR of 6.58 [95% CI 5.46-7.92] and adjusted subHR of 2.08 [95% CI 1.71-2.54] (Figure 2). Risks of the other types of infections were also increased during first year but diminished over time in general (Figure 2). For the entire study period the overall adjusted csHR of all infections was 1.51 [95% CI 1.35-1.67] with a subHR of 1.34 [95% CI 1.20-1.49]. Blood stream infections continued having the highest risk in the period between 6 th-10 th year with a csHR of 1.40 [95% CI 1.03-1.91]. Conclusion The risk of incident infection in patients with pITP is increased compared with the general population. This risk is especially elevated within the first year after diagnosis but remains higher than the general population also in subsequent years. The risk of blood stream infection is especially high within the first year after diagnosis, but remains higher even 20 years after diagnosis. These data may help clinicians to improve management of ITP and support shared decision making with patients.

High Titer ANA at Pediatric ITP Presentation Associated with Progression to Systemic Lupus Erythematosus

Introduction: Immune thrombocytopenia (ITP) is a feature of systemic lupus erythematosus (SLE) in 5-20% of cases. ITP may present at the time of SLE presentation or may precede SLE diagnosis by up to nearly a decade. Even in the absence of an SLE diagnosis, ITP patients may have a positive ANA in ~20% of cases. Some studies suggest that a positive ANA in ITP may herald chronic and more refractory disease, while other studies have not demonstrated a link between ANA+ ITP and progression to SLE. The natural history of ANA+ pediatric ITP patients remains unclear. With the concept that hydroxychloroquine may modulate progression to systemic autoimmunity, European hematologists report using hydroxychloroquine in ANA+ pediatric ITP patients with titers as low as 1:160. However, whether ANA+ ITP patients represent a distinct cohort clinically and should receive different therapies is not well established. The goals of this study were to evaluate the significance and degree of a positive ANA titer at presentation in a cohort of pediatric ITP patients. Methods: Data from a retrospective cohort of 711 ITP patients treated at Texas Children's Hospital from 2012-2022 were reviewed. Patients were defined as SLE if diagnosed as such by rheumatology. To focus on the prognostic value of an ANA upfront, the cohort was refined to include only ITP patients with ANA testing within the newly diagnosed period (0-3 months). Individuals who received IVIG prior to ANA testing were coded as having a missing ANA result given the possibility of false positive results. Being diagnosed concurrently with SLE and ITP was defined as diagnoses within 1 month of each other. Fisher's exact tests were used to compare nonparametric data with a P <0.05 defined as statistically significant. P values were corrected for multiple testing. Results: One hundred sixty-one ITP patients were included for analysis. The cohort was an average of 11.9 years-of-age with a slight female predominance (58.4%). Most of the population self-identified as White and non-Hispanic (84.7%, 45.5%). Nearly 80% had primary ITP and 66.7% were ultimately diagnosed with chronic ITP (cITP). The mean follow-up time for the cohort was 2.2 years (with a range from 0 to 12 years). Forty-seven of 161 (29.2%) individuals had a high titer ANA ³1:1280 at ITP presentation. (Figure 1) There was a statistically significant difference in ANA titer and presence of secondary ITP (P<0.001). Sixty-eight percent (n=23) of secondary ITP patients had a high titer (≥1:1280) ANA versus 20% (n=24) of the primary ITP patients. There was no difference between ANA titer and development of cITP vs. non-cITP. Of this cohort, 20 patients had an ANA tested at ITP presentation and were diagnosed with SLE by rheumatology. Most of these patients had an ANA titer ≥1:1280 (84.2%). The remaining 3 patients had titers of 1:320. Of this cohort, 9 patients had SLE and ITP diagnosed concurrently and 2 had SLE preceding ITP diagnosis by an average of 3.8 years. All 11 patients had an ANA ≥1:1280. Of the 9 who were not diagnosed with SLE at ITP presentation, 6 (66.6%) had an ANA ≥1:1280 and 3 had a titer of 1:320. The lead time to being diagnosed with SLE after presenting with ITP was 1.76 years. Discussion and Conclusions: In this cohort, high titer ANAs in newly diagnosed ITP patients were linked to development of secondary ITP and SLE. Lower titer ANAs were less common, even in those who went on to develop SLE. These findings suggest that specifically high titer ANA results may herald SLE development in pediatric ITP patients. To allow the onset of SLE to be identified earlier, individuals with a high titer ANA at ITP presentation may warrant closer follow-up to monitor for progression to systemic autoimmune disease. This subset of ITP patients could benefit from earlier institution of SLE-directed therapy, such as hydroxychloroquine. Further analysis is underway, including expansion of this analysis to multiple sites within the Pediatric ITP Consortium of North America, as well as surveying pediatric ITP treaters on their practice regarding ANA testing and management in ITP patients.

Reference guide for the diagnosis of adult primary immune thrombocytopenia, 2023 edition

Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by isolated thrombocytopenia due to accelerated platelet destruction and impaired platelet production. Diagnosis of ITP is still challenging because ITP has been diagnosed by exclusion. Exclusion of thrombocytopenia due to bone marrow failure is especially important in Japan because of high prevalence of aplastic anemia compared to Western countries. Hence, we propose a new diagnostic criteria involving the measurement of plasma thrombopoietin (TPO) levels and percentage of immature platelet fraction (RP% or IPF%); 1) isolated thrombocytopenia with no morphological evidence of dysplasia in any blood cell type in a blood smear, 2) normal or slightly increased plasma TPO level (< cutoff), 3) elevated RP% or IPF% (> upper limit of normal), and 4) absence of other conditions that potentially cause thrombocytopenia including secondary ITP. A diagnosis of ITP is made if conditions 1-4 are all met. Cases in which criterion 2 or 3 is not met or unavailable are defined as “possible ITP,” and diagnosis of ITP can be made mainly by typical clinical course. These new criteria enable us to clearly differentiate ITP from aplastic anemia and other forms of hypoplastic thrombocytopenia and can be highly useful in clinical practice for avoiding unnecessary bone marrow examination as well as for appropriate selection of treatments.

Efficacy and Safety of Fostamatinib for Immune Thrombocytopenia in Clinical Practice in Spain: Interim Results of Fostames, Our National Fostamatinib Registry

Background: Fostamatinib is a splenic tyrosine kinase (SYK) inhibitor that prevents antibody-mediated platelet destruction. This drug has demonstrated to be effective and safe in immune thrombocytopenia (ITP). However, clinical trials may not accurately reflect what happens in clinical practice. Here we evaluated the efficacy and safety of eltrombopag in ITP in a real-world setting. Aims: To assess the management of adult patients with immune thrombocytopenia (ITP) with fostamatinib (Tavlesse®) in routine clinical practice outside controlled clinical trials. Methods: Multicentre, retrospective and prospective observational study at national level to evaluate the management of fostamatinib (Tavlesse®) in adult patients with ITP. An interim analysis of the medical records of all patients treated with fostamatinib (Tavlesse®) and suffering from ITP at each center was performed. Data were obtained in a retrospective and prospective observational, non-interventional manner to fulfil the exclusively scientific objective of this study, by conducting a review of the patient's clinical history. Thus, a total of 46 adult patients with ITP from 19 Spanish centers, who had been treated with fostamatinib, were evaluated. Results: The median age of our cohort was 74 yr (interquartile range, IQR, 60-81 yr). 25/46 (54%) were women. 43 of them were Primary ITP, 2 Secondary ITP and only one Evans Syndrome. 20 (47.6%) had ≥ 1 comorbidity of the Charlson Comorbidity Index. At the time of ITP diagnosis, the median platelet count was 8 x 10 9/L (IQR, 4-21 x 10 9/L) while 31 (69%) patients had hemorrhages. The median time with a diagnosis of ITP at initiation of fostamatinib was 61 months (IQR, 9-160 months). The median number of therapies prior to fostamatinib was 4 (IQR, 3-6). Of the entire cohort of 46 patients, 35 had been exposed to eltrombopag, 33 to romiplostim, 23 to intravenous immunoglobulins (IVIG), and 21 to rituximab. Only eight and two patients had received avatrombopag and splenectomy prior to fostamatinib treatment, respectively. 26/46 patients (56.5%) were treated with fostamatinib monotherapy throughout ITP. Twenty-three patients (50%) had signs/symptoms of bleeding in the month prior to treatment initiation. The median platelet count at baseline on fostamatinib was 12 × 10 9/L (IQR, 6-28 × 10 9/L), while the median platelet count to best response achieved after fostamatinib treatment was 84 × 10 9/L (IQR, 28-187 × 10 9/L). The median time from initiation of fostamatinib to maximum response to treatment was 2 months (IQR, 0-3.25). Similarly, the median duration of treatment with fostamatinib was 2 months (IQR, 1-4.25). The median time from initiation of fostamatinib to dose increase to 150 mg twice a day was 16 days (IQR, 8-38). A total of 32/46 patients (69.5%) responded to fostamatinib. Thus, 21 patients (45.7%) achieved a complete response (platelet count &amp;gt; 100 x 10 9/L) and 11 achieved a response. Twenty-one patients (45.6%) experienced adverse events, mainly grade 1-2, with diarrhea (n=13) and hypertension (n=8) being the most frequent. Twenty-five patients (54.3%) discontinued fostamatinib treatment: 18 did so due to inefficacy with three exitus due to severe bleeding in the context of refractory ITP. On the contrary, only three patients discontinued the drug due to toxicity/severe adverse events. Summary/Conclusion: Fostamatinib was used in heavily treated patients. However, fostamatinib proved to be effective and well tolerated in unselected patients with primary and secondary ITP. The association of fostamatinib with other drugs or its use in earlier lines of therapy may be associated with higher platelet response rates.