Immune Thrombocytopenia Onset 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.

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

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

Clinical characteristics, treatment, and outcomes of nivolumab induced immune thrombocytopenia.

Immune thrombocytopenia (ITP) represents an uncommon hematological side effect associated with nivolumab, and its distinct clinical attributes remain poorly defined. This research aimed to explore the clinical manifestations and outcomes of ITP induced by nivolumab. Reports on nivolumab induced ITP up to April 30, 2024, were collected for retrospective analysis. The study involved 34 patients with a median age of 67 years (range 32, 82). The onset of ITP varied from 10 to 100 days post initial dosage, with a median onset at 70 days. The majority of patients exhibited no symptoms, with only 23.5% experiencing clinically significant bleeding and 11.8% facing non-clinically significant bleeding. The median platelet count was 12 × 109/L (range 0, 115), with 67.6% of patients having platelet levels below 25 × 109/L. Bone marrow biopsy revealed mainly elevated megakaryocytes. Platelet-associated IgG levels were elevated with a median of 210 ng/107 cells (range 73, 1130). Subsequent interventions, which included cessation of nivolumab, administration of systemic corticosteroids, intravenous immunoglobulin therapy, a thrombopoietin receptor agonist, platelet transfusion, and rituximab treatment, resulted in 82.4% of subjects achieving normalized platelet counts, whereas 5.9% passed away due to ITP. ITP is a rare life-threatening immune-related adverse event and necessitates close monitoring. Systemic steroids are the primary treatment for ITP, while intravenous immunoglobulin, thrombopoietin receptor agonist and rituximab are other options.

Gut microbiota alterations in children and their relationship with primary immune thrombocytopenia.

Gut microbiota reportedly play a critical role in some autoimmune diseases by maintaining immune homeostasis. Only a few studies have examined the correlation between gut microbiota and the onset of primary immune thrombocytopenia (ITP), especially in children. The purpose of this study was to investigate changes in the composition and diversity of the fecal microbiota of children with ITP, as well as the correlation between such microbiota and the onset of ITP. Twenty-five children newly diagnosed with ITP and 16 healthy volunteers (controls) were selected for the study. Fresh stool samples were collected to identify changes in the composition and diversity of gut microbiota as well as for potential correlation analysis. In ITP patients, the phyla that were most frequently encountered were Firmicutes (54.3%), followed by Actinobacteria (19.79%), Bacteriodetes (16.06%), and Proteobacteria (8.75%). The phyla that were predominantly found in the controls were, Firmicutes (45.84%), Actinobacteria (40.15%), Bacteriodetes (3.42%), and Proteobacteria (10.23%). Compared with those of the controls, the proportions of Firmicutes and Bacteriodetes in the gut microbiota of ITP patients were increased while the proportions of Actinobacteria and Proteobacteria were decreased. Furthermore, gut microbiota in ITP patients varied by age group, showed specific changes in diversity, and were correlated with antiplatelet antibodies. IgG levels were significantly positively correlated with Bacteroides (P<0.01). The gut microbiota of children with ITP are imbalanced, as shown by the increase in Bacteroidetes, which was positively correlated with IgG. Thus gut microbiota may contribute to ITP pathogenesis via IgG. The clinical trial were registered and approved by the Institutional Review Committee of The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University. Ethics number KY-2023-106-01.

Risk of Immune Thrombocytopenia Relapse and Onset Related to Sars-Cov-2 Infection and Vaccination

New diagnoses and relapses of primary immune thrombocytopenia (ITP) have been reported following SARS-CoV-2 infection and vaccination. In a large monocenter cohort, we assessed: 1) incidence, risk factors and outcome of newly diagnosed ITP and ITP relapses after SARS-CoV-2 infection/vaccination; 2) incidence and risk factors for SARS-CoV-2 infection in the ITP cohort. After IRB approval, 1142 ITP patients (pts) followed at our Hematology Center from 1982 to Feb 2022 were registered in an electronic database. Between Feb 2020 (pandemic start) and Feb 2022, 60 pts were newly diagnosed with ITP. Among the 1082 pts with ITP diagnosis prior to Feb 2020, 297 (27.4%) were deceased before the pandemic start and 403 (37.2%) were untraceable. Taken together, 442 ITP (60 newly and 382 previously diagnosed) pts were included in this study. Information on SARS-CoV-2 infection/vaccination, platelet (PLT) count, and ITP therapy, was collected via phone call/e-mail or during routine medical visits. Laboratory data were verified through health electronic records. Risk factors for ITP relapse included sex, age, vaccine type, previous splenectomy, comorbidities (CCI), active disease (ongoing ITP therapy and/or PLT <100 x109/L), other immune diseases and ITP relapse to previous vaccine doses. Newly diagnosed ITP was considered infection-related (inf-ITP) or vaccine-related (vax-ITP) if the onset occurred <30 days from infection or vaccination, respectively. ITP relapse (rel-ITP) was defined as a drop in PLT count (<30 days from vaccination/infection) that required a rescue therapy OR a dose increase of an ongoing therapy OR a PLT count <30 x109/L with ≥20% decrease from baseline. Eighteen (30%) out of 60 newly diagnosed pts had SARS-CoV-2-related ITP. Inf-ITP was diagnosed in 5 pts (8.3%). Compared to the 55 pts whose ITP was not related to Sars-CoV-2 infection, Inf-ITP pts were younger (median, 41.9 vs 70.2 yrs, p=0.02). ITP outcome was comparable in inf-ITP and other newly diagnosed pts, in terms of response to fist-line steroids (p=0.09), no. of therapeutic lines (p=0.9), and no. of pts still on therapy (p=0.9) at 6 months from diagnosis. Vax-ITP was diagnosed in 13 (21.7%) pts after the first (no.4, 30.8%), second (no.4, 30.8%) or third vaccine dose (no.5, 38.4%). Vaccines were: Comirnaty (53.8%), Vaxzervria (23.1%) or Spikevax (23.1%). Compared to the 47 pts whose ITP was not related to Sars-CoV-2 vaccine, Vax-ITP pts were older (median, 74 vs 55 yrs, p=0.04). ITP treatment duration was longer in Vax-ITP pts (median, 150 days vs 54 days in no Vax-ITP pts, p=0.04); 53.8% of vax-ITP pts were still on therapy 6 months after diagnosis (vs 23.4%, p=0.03). Between Feb 2020 and Feb 2022, 69/382 (18.1%) had a relapse of ITP. In 36/69 pts (52.2%), relapse was related to SARS-CoV-2 infection (1 case) or vaccination (35 cases out of 360 pts who received ≥1 vaccine dose, 9.7%). Ten pts experienced multiple relapses (46 total cases). Post-vaccine relapse occurred in 3.3%, 4.7%, and 5.4% of these 35 pts after the 1st, 2nd, and booster dose, respectively (p=0.65). In multivariate analysis (MVA), active disease at the time of the 1st and the 2nd vaccine dose was associated with Rel-ITP (Odds ratio, OR 10.81, p=0.002; OR 6.88, p=0.001, respectively). After booster, active disease (OR 9.90, p<0.001) and previous Rel-ITP (OR 5.33, p=0.007) was associated with relapse (Fig.1). No major bleeding occurred in newly diagnosed and relapsed pts. Overall, 89/442 (20.1%) ITP pts had a SARS-CoV-2 infection (g≥3 in 10.1%). In MVA with death as competing risk, ≥2 vaccine doses (SHR 0.18; p<0.001) was associated with a lower risk of SARS-CoV-2 infection. SARS-CoV-2 is a risk factor for ITP onset, with 30% of new diagnoses being related to infection/vaccination. In older pts, the risk of vax-ITP is higher, and ITP requires more prolonged therapy, suggesting closer hematological monitoring. Also, >50% of total ITP relapses were related to SARS-CoV-2, mainly occurring after vaccination and regardless of vaccine dose. Thus, strict hematological monitoring may be recommended after all doses. In pts with active disease at vaccination and/or previous ITP relapse after vaccine, the completion of the vaccine program and subsequent laboratory follow-up should be personalized. Notably, vaccination confirmed to be the most protective factor against SARS-CoV-2 infection also in ITP pts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The short-term predictive value of CD4+ cells for combination therapy with high-dose dexamethasone and immunoglobulin in newly diagnosed primary immune thrombocytopenia patients

IntroductionDexamethasone (DXM) or immunoglobulin (IVIg) are first-line therapies for primary immune thrombocytopenia (ITP), with an effective rate of 80 %. Some patients with both severe bleeding symptoms and platelet counts of <30 × 109/L received a combination of DXM and IVIg. Autoimmune disorders, especially involving CD4+ T-cells, play a key role in the pathogenesis of ITP. We assumed that variations in the immune status of CD4+ T-cells will lead to different treatment responses. Until now, there have been few relevant clinical studies on CD4+ T-cells and the outcome of first-line therapies. MethodsA prospective study enrolling 42 newly diagnosed ITP patients and 30 normal control volunteers was performed. The profiles of major CD4+ T-cells, including T helper (Th)1, Th2, Th17, and regulatory T (Treg) cells, and the related levels of interleukin (IL)-2, IL-17, and IL-23 were examined. The platelet number was recorded at the time point of day 0, day 14, and day 30. ResultsGreater concentrations of Th1 and Th17 cells and lower relative numbers of Treg cells were found in the ITP group. As for the treatment outcome on day 14, the profiles of Th2 and IL-2 were significantly greater in the NR group, while the expression of IL-17 was elevated in the CR group. As for the treatment outcome on day 30, higher levels of Th2 cells were observed in those patients who needed 2× pulses of HD DXM compared to those who needed only 1× pulse of HD DXM and IVIg, and receiver operating characteristic curve analysis showed that lower Treg cell may predict favorable values. Meanwhile, the higher IL-23 value may predict a poor early response. ConclusionsOur results indicate that Th1, Th17, and Treg cells and IL-2 and IL-23 participate in the onset of ITP. Higher profiles of Th2, IL-2 and IL-23 may predict poor treatment outcomes. Higher levels of IL-17 and lower profile of Treg may predict sensitivity to HD DXM and IVIg combination therapy.

Clinical Epidemiology, Treatment Outcome and Mortality Rate of Newly Diagnosed Immune Thrombocytopenia in Adult Multicentre Study in Malaysia.

BackgroundImmune thrombocytopenia (ITP) is well characterized in Western, European and other Asia-Pacific countries. Nevertheless, the clinical epidemiology, treatment pattern and disease outcome of ITP in Malaysia are still limited and not well known.ObjectiveThis study aimed to describe the clinical epidemiology, treatment outcome and mortality of ITP patients in haematology tertiary multicentre in Malaysia.MethodsClinical and laboratory data of newly diagnosed adults with ITP by a platelet count <100 × 109/L from January 2010 to December 2020 were identified and analyzed.ResultsOut of 500 incident ITP, 71.8% were females with a striking age preponderance of both genders among those aged 18–29 years. The median age was 36 years. The median platelet count was 17.5 × 109/L, 23.0% had a secondary ITP, 34.6% had a Charlson’s score ≥1, 53.0% had bleeding symptoms including 2.2% intracranial bleedings (ICB). Helicobacter pylori screening was performed in <5% of cases. Persistency and chronicity rates were 13.6% and 41.8%, respectively. Most (80.6%) were treated at diagnosis onset and 31.2% needed second-line treatment. Throughout the course of ITP, 11.0% of patients died; 3.0% and 8.0% with bleeding and non-bleeding related ITP.ConclusionThis study confirms the epidemiology of ITP is comparable with worldwide studies. Our incidence is high in the female, Malay ethnicity, primary ITP and events of cutaneous bleeding at ITP onset with 18–29 years predominance age group for both genders. The frequency of persistent and chronic ITP is inconsistent with published literature. Corticosteroids and immunotherapies are the most prescribed first-line and second-line pharmacological treatments. Thrombopoietin receptor agonist medications (TPO-RAs) usage is restricted and splenectomy is uncommon. Our mortality rate is similar but ITP related bleeding death is fourth-fold lower than previous studies. Mortality risks of our ITP patients include age ≥60 years, male, severe bleeding at presentation, CCI≥1 and secondary ITP.

A polygenic stacking classifier revealed the complicated platelet transcriptomic landscape of adult immune thrombocytopenia

Immune thrombocytopenia (ITP) is an autoimmune disease with the typical symptom of a low platelet count in blood. ITP demonstrated age and sex biases in both occurrences and prognosis, and adult ITP was mainly induced by the living environments. The current diagnosis guideline lacks the integration of molecular heterogenicity. This study recruited the largest cohort of platelet transcriptome samples. A comprehensive procedure of feature selection, feature engineering, and stacking classification was carried out to detect the ITP biomarkers using RNA sequencing (RNA-seq) transcriptomes. The 40 detected biomarkers were loaded to train the final ITP detection model, with an overall accuracy 0.974. The biomarkers suggested that ITP onset may be associated with various transcribed components, including protein-coding genes, long intergenic non-coding RNA (lincRNA) genes, and pseudogenes with apparent transcriptions. The delivered ITP detection model may also be utilized as a complementary ITP diagnosis tool. The code and the example dataset is freely available on http://www.healthinformaticslab.org/supp/resources.php

Chronic Pediatric Immune Thrombocytopenia Is Not Associated With Herpes Virus Infection Status.

Background: Immune thrombocytopenia (ITP) is characterized by non-chronic (transient, <12 months) and chronic (≥12 months) decline in the number of platelets. Herpes virus infections have been shown, in many studies, to be associated with the development of ITP. However, it remains unclear whether the herpes virus infection status is associated with the chronic ITP.Methods: We reviewed 480 primary pediatric patients with ITP in the period from January 2017 to December 2019. The prevalence of herpes virus antibodies including the Cytomegalovirus (CMV), Herpes simplex virus 1 (HSV-1), Herpes simplex virus 2 (HSV-2), and Epstein Barr virus were recorded. The levels of serum complement C3 and C4, T (CD3+, CD4+, CD8+), B (CD19+) lymphocytes, and natural killer (CD16+ 56+) cells were also analyzed. Multivariate analysis was used to evaluate the associations between chronic ITP and herpes virus infection status.Results: Compared with non-chronic, patients with chronic ITP had older age (≥3 years), lower levels of hemoglobin and complement C3, and lower probability of CMV and HSV-2 infections (IgM positive; p < 0.05). Patients with herpes virus infection had lower serum platelet counts (p < 0.001), lower complement C3 levels and lower CD4+/CD8+ cells ratio (p < 0.05). Furthermore, platelet counts were positively correlated with CD4+/CD8+ cells ratios (r = 0.519; p = 0.0078), and negatively correlated with T cells (CD3+: r = −0.458, p = 0.0213; CD8+: r = −0.489, p = 0.0131). Multivariate analysis showed that age (OR, 1.644; 95%CI, 1.007–2.684; p = 0.047) was an adverse risk factor for chronic ITP and CMV IgM positive (OR, 0.241; 95%CI, 0.072–0.814; p = 0.022) had lower risk of chronic ITP development, while other herpes virus infection statuses and clinical features were not.Conclusion: Although herpes virus infections were associated with the onset of ITP, our findings indicated that herpes virus infection status might not be a risk factor for chronic ITP.

Essential Thrombocythemia Following Immune thrombocytopenia With JAK2 V617F Mutation: A Case Report

Immune Thrombocytopenia (ITP) is an autoimmune bleeding disorder. Tyrosine Kinase JAK2 (JAK2 V617F) mutation occurs in nearly 60% of Essential Thrombocythemia (ET) patients. Both diseases produce impaired platelet. We describe a case with ET following ITP. So far, only 3 reports described ET following ITP. We report the fourth patient with JAK2 V617F mutation at the onset of ITP presented 20 years ago that needed splenectomy. The association of these two diseases may recommend similar pathogenic mechanisms between Myeloproliferative Neoplasms (MPNs) and ITP that should be further explored.

Primary immune thrombocytopenia in very elderly patients: particularities in presentation and management: results from the prospective CARMEN-France Registry.

Data about the presentation and the management of primary immune thrombocytopenia (ITP) in very elderly patients (VEPs; aged ≥80 years) are lacking. The aim of the present study was to describe ITP in this subgroup. The data source was the prospective CARMEN-France registry. Patients included between 2013 and 2018 were selected. ITP presentation and management in VEPs was compared to elderly patients (EPs; aged 65-79 years). We assessed factors associated with bleeding at ITP onset in VEPs. Of 541 patients, 184 were included: 87 in the VEP group and 97 in the EP group. The mean age was 85·7 years in the VEP group. Comorbidities were more frequent in the VEP group (67·4% vs. 47·9%). The median platelet count at ITP onset was similar but severe bleeding tended to be more frequent in VEPs (10·3% vs. 4·1%, P = 0·1) as well as mortality. Exposure to ITP drugs, response to first-line treatment, need of second-line treatment, evolution towards persistency, occurrence of bleeding, infection and thrombosis did not differ between groups. In VEPs, factors associated to bleeding were female sex [odds ratio (OR) 4·75, 95% confidence interval (CI) 1·31-17·32] and platelet count of <20 × 109 /l (OR 10·05, 95% CI 4·83-67·39). Exposure to anticoagulants was strongly associated with severe bleeding (OR 7·61, 95% CI 1·77-32·83).

Splenectomy for Primary Immune Thrombocytopenia Revisited at the Era of Thrombopoietin Receptor Agonists: New Insights for an Old Treatment

▪IntroductionAlthough splenectomy is still considered as the most effective curative treatment for primary immune thrombocytopenia (ITP), its use has significantly declined in the last decade, especially since the emergence of thrombopoietin receptor agonist (TPO-RAs) and anti-CD20 monoclonal antibodies 1-3. The main objective of our study was to evaluate if splenectomy was still as effective in the modern era, particularly for patients who failed to respond to TPO-RAs and rituximab. One of the secondary objectives was to assess, among patients who did not respond to or relapse after splenectomy, the pattern of response to subsequent intervention with treatments used before splenectomy and particularly TPO-RAs.MethodsThis multicentre retrospective observational study involved adults who underwent surgical splenectomy for primary ITP in France from 2011 (authorization of TPO-RAs in France) to 2020. To be included in the study, patients had to fulfil the following criteria : age ³18 years, primary ITP diagnosis defined according to the usual international criteria 2. Patients with abnormal spleen histology (other than reactional lymphoid hyperplasia, white-pulp hypoplasia or red pulp hyperplasia) or yet definite secondary ITP were excluded. Response was defined according to international criteria 4. Sustained response was defined as the absence of ITP relapse at last visit. We performed univariable and multivariable logistic regression procedures to calculates the odds ratio associated with a sustained response.ResultsIn total,185 patients, 98 (53 %) women, with median age at splenectomy of 43.3 [interquartile range 27.6-64.3] years, were included in 18 French university and general hospitals from the French reference center network. Most of the patients were splenectomised at the chronic phase of ITP (n=150, 81.1%) and only two patients had undergone surgery within 3 months after ITP onset. Of note, 100 (54.1%) and 135 (73.0%) patients received TPO-RAs and/or rituximab prior to the splenectomy, respectively. The median time of follow-up after splenectomy was 39.2 months [16.5-63.0]. Overall, 144 (77.8%) of patients had an initial response and 23 patients (12.4%) relapsed during follow-up leading to an overall rate of sustained response of 65.4%, similar to the one observed in the pre-TPO-RA's era 1. Characteristics of patients according to the period during which occurred the splenectomy is available in Table 1.Among the 14 patients who failed to respond to both eltrombopag and romiplostim prior to splenectomy a sustained response after splenectomy was observed in 7 (50%). Among the 13 patients who had failed after both TPO-RAs and rituximab, we observed a sustained response in 6 (46%).In the multivariate analysis, an older age (60-75 years: OR 0,39 [0,17-0,86], p=0.02; >75 years: OR 0,28 [0,10-0,75], p=0.013) and a history of more than 4 treatment lines for ITP before splenectomy (OR 0.25 [0.08-0.66], p=0.010) were significantly associated with a lack of sustained response after splenectomy.TPO-RAs were used for 57/64 (89.1%) patients who failed to respond to splenectomy. Among them, 21 were treated with one TPO-RA (i.e. eltrombopag or romiplostim) which was previously used before splenectomy without any efficacy and a response was observed in 13 (62%) of them.ConclusionsIn conclusion, splenectomy seems to be still a relevant option for treating adult primary ITP not responding to TPO-RAs and rituximab. Patients who fail to respond or relapse after splenectomy should be re-challenged with TPO-RAs.1. Kojouri, K., Vesely, S. K., Terrell, D. R. & George, J. N. Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term2. Provan, D. et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv.3.Neunert, C. et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 3, 3829-3866 (2019).4. Rodeghiero, F. et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood 113, 2386-2393 (2009). [Display omitted] DisclosuresTerriou: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ebbo: Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Other: Attendance Grant; Sobi: Other: Attendance Grant. Viallard: Novartis: Consultancy; Amgen: Consultancy; Grifols: Consultancy; LFB: Consultancy. Jeandel: Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Support for congress; Sobi: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Support for congress; GSK: Other: Support for congress; Pharming: Other: support for congress. Michel: Amgen: Consultancy; Novartis: Consultancy; Rigel: Honoraria; UCB: Honoraria; Alexion: Honoraria; Argenx: Honoraria. Godeau: Grifols: Consultancy; Sobi: Consultancy; Amgen: Consultancy; Novartis: Consultancy. Comont: Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding.

Favorable prognosis of vaccine-associated immune thrombocytopenia in children is correlated with young age at vaccination: Retrospective survey of a nationwide disease registry.

Childhood vaccine-associated immune thrombocytopenia (ITP) has a mostly favorable prognosis. To identify factors associated with prognosis, a retrospective survey was conducted with children with ITP who were registered in the Japanese Society of Pediatric Hematology/Oncology registry from 2008 to 2011. A total of 477 patients were categorized into four groups by event preceding ITP onset: vaccine-precedence (VP; n = 43), vaccine/infection-precedence (VIP; n = 34), infection-precedence (IP; n = 162), and no vaccine/infection-precedence (NVI; n = 238). Compared to IP and NVI, VP and VIP were significantly younger at diagnosis, with the age distribution peaking at infancy, and more frequently had favorable prognosis. Time to platelet recovery to 100 × 103/µL was significantly faster for VP and VIP than NVI. Multivariate Cox regression analysis with sex, age at diagnosis, infection-precedence, and vaccine-precedence as variables revealed age < 36months (HR 0.992, 95% CI 0.989-0.995; p < 0.001) and male sex (HR 0.770, 95% CI 0.623-0.952; p = 0.015) as associated factors, but not infection-precedence (p = 0.149) or vaccine-precedence (p = 0.650). In subgroup analysis in patients < 36months, age at diagnosis (p < 0.001) was the only associated factor. Favorable prognosis of childhood vaccine-associated ITP is correlated with young age at vaccination, but not with vaccination itself.

Evans syndrome in adults: an observational multicenter study

AbstractEvans syndrome (ES) is a rare condition, defined as the presence of 2 autoimmune cytopenias, most frequently autoimmune hemolytic anemia and immune thrombocytopenia (ITP) and rarely autoimmune neutropenia. ES can be classified as primary or secondary to various conditions, including lymphoproliferative disorders, other systemic autoimmune diseases, and primary immunodeficiencies, particularly in children. In adult ES, little is known about clinical features, disease associations, and outcomes. In this retrospective international study, we analyzed 116 adult patients followed at 13 European tertiary centers, focusing on treatment requirements, occurrence of complications, and death. ES was secondary to or associated with underlying conditions in 24 cases (21%), mainly other autoimmune diseases and hematologic neoplasms. Bleeding occurred in 42% of patients, mainly low grade and at ITP onset. Almost all patients received first-line treatment (steroids with or without intravenous immunoglobulin), and 23% needed early additional therapy for primary refractoriness. Additional therapy lines included rituximab, splenectomy, immunosuppressants, thrombopoietin receptor agonists, and others, with response rates >80%. However, a remarkable number of relapses occurred, requiring ≥3 therapy lines in 54% of cases. Infections and thrombotic complications occurred in 33% and 21% of patients, respectively, mainly grade ≥3, and correlated with the number of therapy lines. In addition to age, other factors negatively affecting survival were severe anemia at onset and occurrence of relapse, infection, and thrombosis. These data show that adult ES is often severe and marked by a relapsing clinical course and potentially fatal complications, pinpointing the need for high clinical awareness, prompt therapy, and anti-infectious/anti-thrombotic prophylaxis.

Effect of Pregnancy on the Clinical Course of ITP Pregnant Women and Their Newborns. Resuts of a Spanish Case Series of 297 Primary ITP Pregnancies

Introduction:Given that there is no large case-series, effect of pregnancy on the course of pre-existing primary immune thrombocytopenia (ITP) patients is unclear1,2. Furthermore, outcome predictors evidence of neonates born to mothers with ITP is very scarce1. Due to obvious ethical reasons, no clinical trial regarding ITP and pregnancy has been reported until recent days3. Nevertheless, the relationship between ITP and pregnancy is considered a “trending topic” nowadays. As it is the, until now, unknown safety and efficacy of new drugs as TPO mimetics in this setting3-6.Aims:To evaluate outcome and global management of pregnancy and delivery on ITP women an on their offspring.Methods:Primary ITP was defined as a platelet count < 100 x 109/L in the absence of other causes or disorders that may be associated with thrombocytopenia.All women diagnosed of primary ITP from 2011 to 2016 in 24 Spanish Hematology Departments who had at least one pregnancy after ITP onset were included in this registry.Results:We included 297 primary ITP pregnancies from 204 women. At pregnancy diagnosis, we observed a majority of chronic ITP cases (71.9 %). At ITP diagnosis, median age of our case-series was 23 years (IQR, 18-31) and median platelet count was 18 x 109/l (IQR, 6-36). Median time from ITP diagnosis to pregnancy was 162 months (IQR, 0-364). Median number of pregnancies prior to ITP diagnosis was 1 (IQR, 0-2) with 1 pregnancy (IQR, 1-2) after ITP diagnosis as a median.51.6% of women received corticosteroids, immunoglobulins (IVIG) (16.6%), rituximab (7.1%) and/or splenectomy (8.7%) as ITP treatments between or before new pregnancies. On the other hand, 26.5% of women needed treatment for ITP during pregnancy, mainly steroids (13.9%) and IVIG (10.2%).The median platelet-count nadir during pregnancy was 73 x 109/l (IQR, 31-174). 135 (45.4%) pregnancies had less than 50 x 109 platelets/l with 77 (25.9%) with less than 30 x 109 platelets/l. 57 women (19.2%) exhibited hemorrhagic symptoms, being 30 (10.1%) of them severe bleedings.Regarding type of delivery, this was vaginal in 187 (62.9%) of pregnancies. Median platelet count at delivery was 111 x 109/l (IQR, 70-187). 47 patients (15.8 %) experienced 60 bleeding episodes. We only observed 52 cases (19.5%) of neonatal thrombocytopenia among 266 living newborns.Conclusions:Our results are comparable to previously reported1,2. No severe bleeding complications during pregnancy and/or delivery were observed in our study. Rate of neonatal thrombocytopenia, and therefore, newborn bleeding is low. DisclosuresNo relevant conflicts of interest to declare.

Risk Factors for Bleeding, Including Platelet Count Threshold, in Newly Diagnosed ITP Patients

Introduction: Bleeding is a main cause of morbidity and mortality in adult immune thrombocytopenia (ITP). Treatment is indicated in case of bleeding or of low platelet count. However, the threshold of platelet count associated with bleeding and therefore to initiation of treatment is debated. Most of guidelines recommend the threshold of <30 x 109/L. However, some authors recommend other thresholds, as low as 10 x 109/L. Moreover, the risk factors for bleeding are not well known in ITP. The aim of this study is to assess the risk of bleeding by platelet count and to identify these risk factors.Methods: We studied all the patients included between June 2013 and December 2016 in the CARMEN (Cytopénies Auto-immunes : Registre Midi-PyréneEN) registry. This multicenter registry is aimed at the prospective follow-up of all incident ITP adults in the French Midi-Pyrénées region (South-West of France, 3 million inhabitants). Each investigator follows every patient newly diagnosed for ITP in routine visit or hospital stay and detailed information on patients' characteristics and management of ITP are recorded prospectively. We also included all adult patients newly diagnosed for ITP at the French National Referral Center for autoimmune cytopenias (Créteil) from November 2015 to December 2016 where data are prospectively recorded in the same database. ITP was defined by platelet count <100 x 109/L and exclusion of other causes of thrombocytopenia. We described the frequency of any bleeding, of mucosal bleeding and of severe bleeding (defined by macroscopic hematuria, gastrointestinal or central nervous system bleedings) at ITP onset by platelet count and by subgroups of interest: age groups (according to quartiles: ≤45, 45-64, 65-79 and ≥80 years), sex, arterial hypertension, history or current symptoms of gastroduodenal ulcer, Charlson's comorbidity score, exposure to non-steroidal anti-inflammatory drugs (NSAIDs), antiplatelet drugs, anticoagulant drugs and serotonin reuptake inhibitors (SRIs). Lastly, we assessed in the whole cohort the factors associated with any bleeding, mucosal bleeding and severe bleeding using multivariate logistic regression analysis.Results: 302 newly diagnosed ITP adults were prospectively included in the study. Median age was 66 years, 49.7% were females, 46.8% had a Charlson's score ≥1, 3.7% had a history or current symptoms of gastroduodenal ulcer, 16.0% had secondary ITP, 19.5% were exposed to antiplatelet drugs, 7.6% to anticoagulant drugs, 7.6% to NSAIDs and 6.6 to SRIs at the time of diagnosis. Median platelet count was 18 x109/L. At diagnosis, 57.9% experienced any bleeding symptom, 30.1% mucosal bleeding, and 6.6% severe bleeding (including 4 central nervous system bleedings).The rates of bleeding, mucosal bleeding and severe bleeding by platelet count is shown in Figure 1. The rate of any bleeding was >50% if platelet count was <20 x109/L. The rate of mucosal bleeding was >40% if platelet count was <10 x109/L. In contrast, a similar risk of severe bleeding was observed with all platelet count categories. Only slight differences were observed in other subgroups, except an increased frequency of any bleeding in case of exposure to NSAIDs, as well as an increased rate of severe bleeding in elderly and patients exposed to anticoagulant drugs and SRIs.In multivariate analysis, the factors associated with any bleeding at ITP diagnosis were a low platelet count (<10 x109/L vs. >20 x109/L: OR, 46.3, 95% CI: 19.4-110.6; between 10 and 19 x109/L vs. >20 x109/L: OR, 5.1, 95% CI: 2.3-11.2), female sex (OR for males, 0.4, 95%CI: 0.2-0.8) and exposure to NSAIDs (OR, 4.4, 95 %CI: 1.1-18.7). Only a low platelet count was associated with mucosal bleeding (<10 x109/L vs. >20 x109/L: OR, 6.2, 95% CI: 3.4-11.6; between 10 and 19 x109/L vs. >20 x109/L: OR, 2.6, 95% CI: 1.1-6.1). Lastly, only exposure to anticoagulant drugs was associated with severe bleeding (OR, 4.5, 95% CI: 1.4-14.4). Analyses restricted to primary ITPs led to similar results.Conclusion: Platelet counts <20 x109/L and <10 x109/L were thresholds with major increased risk for both any and mucosal bleedings. Platelet count, female sex and exposure to NSAIDs should be considered to assess the risk of any bleeding. In contrast, severe bleeding seemed not linked to platelet count but to individual factors, particularly exposure to anticoagulant. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Secondary immune thrombocytopenia in children: Characteristics and outcome of a large cohort from two Spanish centres.

To evaluate the incidence and outcome of secondary immune thrombocytopenia (ITP) in a large cohort of paediatric Spanish patients. A retrospective observational study was conducted in two paediatric University hospitals in Spain between 2009 and 2019, which included children from 4months to 18years old diagnosed with ITP. Data were recorded from clinical charts: gender, age at diagnosis, coexisting condition and associated characteristics, outcome and treatment. Secondary ITP was diagnosed in 87 out of 442 patients (19.6%). Post-immunisation ITP was seen in younger children. The onset of secondary ITP to autoimmune diseases (AD) and immunodeficiencies (ID) was at an older age and had more tendency to be insidious, and platelet level was higher than primary ITP. Mean time from ITP onset to AD diseases or ID diagnosis was 1.2 and 2.6years, respectively. Whereas the cumulative incidence of remission was significantly higher in post-immunisation and post-viral infection (compared with primary ITP patients), it was worse in AD and ID patients. Identification of secondary ITP is important as it predicts outcome. Most of them are diagnosed at ITP onset, but AD diseases and ID should be ruled out periodically as they are usually identified later.

Maternal and Fetal Outcomes of Pregnancy in Patients with Immune Thrombocytopenia.

Immune thrombocytopenia (ITP) complicates 1-2 cases/10,000 pregnancies in India. Management of these patients is a challenge as it is associated with potential risks of maternal bleeding episodes and neonatal alloimmune thrombocytopenia (NAITP). To study the maternal and fetal/neonatal outcome of pregnancy in Indian patients with ITP and identify the risk factors for NAITP. In this retrospective study, all ITP patients with pregnancy who were diagnosed and treated at our center over 8years (August2010-August2018) were evaluated for their hematological, obstetrical, and fetal outcomes. Twenty-nine pregnancies in 27 ITP patients were studied. The mean interval between the diagnosis of ITP and each pregnancy was 29 ± 14.9months. The mean baseline platelet count was 0.18 ± 0.05 X 109/L. Twenty-seven (93.1%) cases were treated with oral prednisolone. Twenty deliveries (69.0%) were vaginal and 9 (31.0%) deliveries were by cesarean section. There were no major bleeding episodes during pregnancy or delivery.The mean neonatal platelet count was 1.23 ± 0.58 × 109/L at birth. NAITP was seen in 3 (3.5%) neonates. No bleeds or intracranial hemorrhages were observed. Only maternal platelet count < 50 X 109/L at delivery showed a statistical correlation with NAITP (p = 0.022). There was no positive correlation between NAITP and the duration of maternal ITP, the timing of ITP onset, or type of treatment. Successful outcome of pregnancies in ITP patients is possible, and the risk of maternal bleeding and NAITP is low.

Eltrombopag for Immune Thrombocytopenia in Adult Patients in the Real-World in France. Final Results of the Elextra Study

Introduction:Eltrombopag has been available in Europe for the treatment of chronic primary immune thrombocytopenia (ITP) since 2010. Since 2019, it has been indicated in patients with primary ITP, lasting 6 months or longer from diagnosis and who are refractory to other treatments, aged 1 year and above. However, data are lacking regarding the use, the efficacy and the safety of eltrombopag in clinical practice in Europe. The ELEXTRA study aimed to assess these questions in France. The intermediate results were presented at the 2019 ASH Annual Meeting. We present here the final results of the ELEXTRA study. Methods:Population source was the CARMEN-France registry. The CARMEN (Cytopénies Auto-immunes : Registre Midi-PyréneEN) registry is aimed at the prospective follow-up of all incident ITP adults in the French Midi-Pyrénées region (South-West of France, 3 million inhabitants) since June 2013. Each investigator follows all adult patients (aged ≥18 years) newly diagnosed with ITP in routine visits or hospital stays, and detailed information on patients' characteristics and management of ITP are prospectively recorded. This registry has been implemented in other French centers since 2016, taking the name of CARMEN-France. ITP was defined by platelet count &amp;lt;100 x 109/L and exclusion of other causes of thrombocytopenia. The study population consisted of all incident ITP adults included in the CARMEN-France registry from June 2013 to December 2019 who were exposed to eltrombopag during the disease course. We described the time from ITP diagnosis to first exposure to eltrombopag, and patients' characteristics. Efficacy was assessed in patients who had a platelet count &amp;lt;30 x 109/L at eltrombopag initiation. Overall response was defined by platelet count ≥30 x 109/L and complete response by platelet count ≥100 x 109/L. Adverse drug reactions (ADRs) that occurred during eltrombopag exposure were collected and assessed according to the World Health Organization causality assessment scale. All ADRs with causality score assessed at least as "possible"were described. Results:Out of 795 patients included in the registry, 156 (19.6%) had been exposed to eltrombopag for a median duration of 100 days (range: 1-1427). Mean age was 60.2 years (standard deviation: 20.9) and 79 (50.6%) were males; 60 (38.5%) had at least one comorbidity of the Charlson Comorbidity Index score; 89 (57.1%) had at least one cardiovascular risk factor (not including age and sex) and 9 (5.8%) a history of venous thrombosis. At ITP diagnosis, the median platelet count was 8 x 109/L (range: 1-88 x 109/L) and 118 (75.6%) patients had bleeding. Median time from ITP onset to first exposure to eltrombopag was 3.3 months (range: 0.1-82.2): 74 (47.4%) patients were exposed before 3 months of ITP duration, 21 (13.5%) between 3 and 6 months and 61 (39.1%) after 6 months. Exposures to ITP treatments before eltrombopag initiation were: corticosteroids in 150 (96.2%) patients, intravenous immunoglobulin (IVIg) in 106 (67.9%), dapsone in 28 (17.9%), rituximab in 26 (16.7%), romiplostim in 12 (7.7%), hydroxychloroquine in 14 (9.0%), danazol in 8 (5.1%), vinblastine in 5 (3.2%), azathioprine in 2 (1.3%), ciclosporin in 1 (0.6%) and splenectomy in none. Eltrombopag was used as second-line agent in 52 (33.3%) patients and third-line in 56 (35.9%). Among the 156 patients, 75 (48.1%) had a platelet count &amp;lt;30 x 109/L at eltrombopag initiation; among them, 65 (86.7%) achieved overall response and 53 (70.7%) complete response at any time during exposure to eltrombopag. Among the 65 patients who achieved overall response, 58 (89.2%) had a concomitant exposure to another ITP treatment at eltrombopag initiation (including steroids, n=42; IVIg during the past month, n=44; rituximab in the past 6 months, n=11). Overall, 47 ADRs were reported: the most frequent were: thrombocytosis (n=10), thrombosis (n=8: 6 pulmonary embolism, 1 deep and 1 superficial vein thrombosis), rash (n=4), hepatitis (n=3),and headache (n=3). Conclusion:In French real-world practice, eltrombopag is used early in the ITP course. Efficacy is similar to that observed in clinical trials. The safety profile identified in clinical trials is also confirmed. Disclosures Moulis: Grifols: Research Funding; Amgen: Other: meeting attendance grant; Novartis SAS: Membership on an entity's Board of Directors or advisory committees, Other: meeting attendance grant, Research Funding. OffLabel Disclosure: Real-World use of eltrombopag in immune thrombocytopenia

Primary immunodeficiencies, autoimmune hyperthyroidism, coeliac disease and systemic lupus erythematosus in childhood immune thrombocytopenia.

To evaluate the cumulative prevalence of coeliac disease, systemic lupus erythematosus, autoimmune hyperthyroidism and primary immunodeficiencies in children with either newly diagnosed/persistent or chronic immune thrombocytopenia (ITP). Monocentric retrospective analysis of the clinical and biochemical features of 330 consecutive patients with ITP referred to our Pediatric Hematology Unit between January 2009 and December 2018. The prevalence of systemic lupus erythematosus (0.3%), coeliac disease (0.3%) and autoimmune hyperthyroidism (0.6%) was not increased compared to general paediatric population. Of note, the prevalence of underlying primary immunodeficiencies was 2.4%, remarkably higher than the general paediatric population (P=.005). All the patients diagnosed with immunodeficiency developed either bi-/trilinear cytopenia or splenomegaly. Whilst autoimmune and immunological screening is already recommended at the onset of immune thrombocytopenia, we recommend that primary immunodeficiencies be regularly screened during follow-up, especially in case of additional cytopenia or lymphoproliferation.