Cutaneous Hemorrhage Types As Supportive Factors for Predicting Chronic Immune Thrombocytopenia in Children

Our objective was to assess risk factors for developing chronic immune thrombocytopenia (ITP) in children. The charts of all consecutive children diagnosed with ITP between 2000 and 2015 at a single center were retrospectively reviewed, and clinical characteristics at initial presentation were analyzed. Sixty-two children were included in the study (mean age, 6.15 y); 44 (71%) were found to have acute ITP, and 18 (29%) developed chronic ITP (permanent or relapsing thrombocytopenia >12 mo). In a univariate analysis, cutaneous hemorrhages were observed significantly more in acute patients (90.9%) than in chronic patients (61.1%). Patients who had acute ITP were more likely to present with a combination of petechiae, purpura, and/or ecchymosis (75%) than patients with chronic disease (44.4%, P=0.010). In multivariate analysis, older age increased the risk (odds ratio=1.1; P<0.05) for chronic disease, and manifestations of combination skin hemorrhages (petechiae/purpura/ecchymosis) reduced the risk (odds ratio=0.167; P<0.05). In conclusion, the most important risk factor for chronic disease is older age. Skin hemorrhage types were found to be a supportive factor for the prediction process: the combination of petechia/purpura/ecchymosis was associated with a lower risk for developing chronic disease compared with petechiae alone. Future studies should assess the prognostic value of skin hemorrhage types that are a simple way to predict the course of ITP in children. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Immediate Pre-Splenectomy Platelet Count Predicts Splenectomy Response in Adult Immune Thrombocytopenia Patients

Blood ◽

10.1182/blood-2020-135905 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 11-11

Author(s):

O. A. Soboleva ◽

K. I. Ntanisian ◽

E. K. Egorova ◽

A. L. Melikyan ◽

E. G. Gemdzhian ◽

...

Keyword(s):

Risk Factors ◽

Platelet Count ◽

Immune Thrombocytopenia ◽

Conflicts Of Interest ◽

Univariate Analysis ◽

Multivariate Logistic Regression Analysis ◽

Complete Response ◽

Preoperative Treatment ◽

Female Ratio ◽

Factors Associated

Background: Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by isolated thrombocytopenia. Splenectomy remains an effective and safe treatment for ITP. Objective: Identify and estimate risk factors associated with no response (platelet count < 30 x 109/L) to splenectomy for adult ITP patients. Patients and Methods: The study conducted at National Research Center for Hematology (Moscow) from 03/2015 to 11/2019 included all patients (in total, 111) with ITP, who underwent laparoscopic splenectomy. Median (Med) platelet count at admission was 12 x 109/L (range from 1 to 239 x 109/L). The time from diagnosis of ITP to splenectomy varied from 3 months to 51 years. All patients had received from 1 to 3 lines of treatment prior to splenectomy. Pre-splenectomy treatment was carried out at platelet count < 20 x 109/L and/or in the presence of bleeding. Results: Of the 111 patients 31 were male (Med age 43 years [IQR 27-55]) and 80 were female (Med age 37 [IQR 29-49]). The male/female ratio was 1:2.6. Complete response to splenectomy (platelet count > 100 x 109/L) was achieved in 79/111 (71.2%) cases, 11/111 (9.9%) patients had partial response (platelet count: 30-100 x 109/L) and 21/111 (18.9%) failed to respond (platelet count < 30 x 109/L). Patients who achieved complete response to splenectomy had a significantly higher immediate pre-splenectomy platelet count than non-responders: Med platelet count (95% CI): 47 (35-58) vs 16 (9-20) (x 109/L), Mann-Whitney U test, P < 0.001 (CI, confidence interval) (Figure 1). Multivariate logistic regression analysis was carried out to identify factors associated with splenectomy outcome (response/no response). Multivariate analysis included patient's gender and age, duration of ITP, grade of bleeding at admission, platelet count at admission, preoperative platelet count and number of prior lines of therapy. Continuous variables were dichotomized using ROC analysis, in particular, cut-off point for preoperative platelet count was 23 x 109/L. As a result, following statistically significant (Wald test) factors were selected: • an unfavorable predictor: immediate pre-splenectomy platelet count < 23 x 109/L, RR (95% CI): 2.5 (1.1-8.6), P = 0.001 (RR, relative risk) (Figure 1) and • combined unfavorable risk factor: male gender in the age over 60 (compared to men in the age ≤60 and women in general), RR (95% CI): 2.0 (0.9-7.1), P = 0.05 (Figure 2). Response rate was negatively correlated (in univariate analysis) with the number of treatment lines prior to splenectomy (negative Spearman's rank correlation coefficient, −0.30; P = 0.01). When preoperative platelet count ≥ 23 x 109/L was achieved, probability of complete response to splenectomy was 80% (Figure 3). The rate of postoperative complications was 12.6%. According to our follow-up data (up to 5 years) 66/79 (83.5%) patients maintained complete response. Conclusions: High-risk groups were identified: patients with immediate pre-splenectomy platelet count < 23 x 109/L (i.e. with no effect of preoperative treatment) and men over the age of 60. Identified risk factors could be taken into account in decision-making process. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Impact of Therapeutics On Fatigue in Chronic Immune Thrombocytopenia (ITP).

Blood ◽

10.1182/blood.v114.22.4455.4455 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4455-4455

Author(s):

James B. Bussel

Keyword(s):

Immune Thrombocytopenia ◽

Conflicts Of Interest ◽

Short Form ◽

Medical Center ◽

Laboratory Finding ◽

Age Group ◽

Therapeutic Modalities ◽

Role Physical ◽

The Mean ◽

Chronic Immune Thrombocytopenia

Abstract Abstract 4455 Complaints of tiredness, lethargy or lack of energy are common in patients with chronic Immune ThrombocytoPenia (ITP), however they are not well understood. This study assessed whether different clinical and laboratory aspects are related to fatigue and how different therapeutic modalities might impact these symptoms. Methods Patients with chronic ITP older than 15 years old were enrolled from 2007-2008 at the Platelet Disorders Center at the Weill-Cornell Medical Center, NY. They completed the Short-Form 36 questionnaire (SF-36) and Fatigue severity scale (FSS) (2 standardized Health-related quality of life [HRQoL] questionnaires) and the Beck Depression Inventory (BDI). Laboratory testing included CBC, TSH, ferritin, iron + TIBC, and blood serotonin levels. Results 83 patients with a mean age of 40.2 years (67.5% women) were enrolled. The mean platelet counts were 109,000/ul (range of 12,000-500,000/ul). Forty-one % of patients had duration of ITP of 10 years or more and 25% had had previous splenectomy. Sixty-one% were on treatment: 11% steroids, 23% Tpo-R agents and 28% “Other” (7.2 % Rigel, 13.3 % IVIG, 3.6 % anti-D, 2.4 % rituximab and 1.2% Danazol/Azathioprine). Surprisingly, analysis of the SF36 showed that the study (ITP) population is similar to the general US population and that they do not report increased fatigue or depression. These results contrast with a previous report by McMillan, AJH, 2007 (fig 1). However when the current patients were divided according to age, abnormal low scores on SF36 were observed on vitality domain (mean 50) for the age group of 45-55 years and on role physical domain (mean 48) for the age group of 55-65 years. Furthermore, differences were observed in patients stratified according to treatment (figure 2) where the mean scores for patients on the steroid group on the respective domains were lower: vitality 49 and role physical 42. The Tpo-R agonists group had better results in all SF36 domains; similar findings were seen with the FSS and BDI. The only laboratory finding is that patients with low ferritin levels had worse results on FSS. Conclusion Although fatigue and related symptoms have been previously reported by others including an improvement with successful treatment eg in studies of the TPO-R agonists, to our surprise we did not find the same results. Whether this study population is intrinsically different or receiving different treatments, eg avoidance of steroids, might impact these results here are 2 possible hypotheses. Use of different fatigue assessments as ITP-PAQ or CDC symptom inventory and further studies addressing the role of the pro-inflammatory cytokines in these patients would be useful. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Immunoglobulin Levels As Predictors of the Development of Chronic Disease in Pediatric Immune Thrombocytopenia

Blood ◽

10.1182/blood-2019-132285 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 388-388

Author(s):

Amanda Bell Grimes ◽

Taylor Olmsted Kim ◽

Jenny M. Despotovic ◽

Susan Kirk

Keyword(s):

Chronic Disease ◽

Autoimmune Disease ◽

Immune Thrombocytopenia ◽

Spontaneous Resolution ◽

Systemic Autoimmune Disease ◽

Chronic Itp ◽

Age Of Diagnosis ◽

Acute Itp ◽

Immunoglobulin Levels

Background: Immune thrombocytopenia (ITP) is the most common acquired bleeding disorder in children. Although ~75% of these patients will go on to have spontaneous resolution of disease, up to 25% will develop chronic ITP, with significant and prolonged bleeding symptomatology and impaired quality of life. At this time, there is no definitive method to predict the development of chronic disease at the time of ITP diagnosis. Aims: We aim to identify clinical biomarkers predictive of the development of chronic ITP at the time of diagnosis among pediatric ITP patients. Methods: The clinical records of 280 pediatric ITP patients enrolled in a biological banking study at a large pediatric tertiary care referral center from July 1, 2015 to July 1, 2019 were reviewed in accordance with IRB-approved protocols. ITP diagnosis and chronicity of disease (vs. spontaneous resolution within 1 year of diagnosis) was confirmed by a pediatric hematologist, as defined by current international expert committee standards (Neunert et al, Blood, 2011;117(16):4190-207; Provan et al, Blood, 2010;115(2):168-186). Patients with non-classical ITP were excluded (1 child with drug-induced ITP in the setting of acyclovir therapy, and 1 neonate with passive ITP in the setting of maternal lupus); and patients who were lost to follow-up or had ongoing disease of <1 year duration were subsequently excluded. Patient characteristics including age, gender, ethnicity, presence of concurrent autoimmune disease, and time to resolution were collected. Pertinent biomarkers including immunoglobulin levels (IgG, IgA, and IgM), anti-nuclear antibody (ANA), C-reactive protein (CRP), and immature platelet fraction (IPF) which were obtained at the time of diagnosis were documented, if if obtained prior to the administration of any ITP-directed therapy, and within 2 weeks of diagnosis. Chi-squared test or Fisher's exact test was utilized to compare nonparametric categorical data. Mann-Whitney U test was used to compare nonparametric continuous data. A multivariate backwards logistic regression model was conducted to determine independent associations with the development of chronic ITP. Statistical analyses were performed using SPSS Statistics 26 (IBM, Armonk, New York). A Bonferroni correction was applied to correct for multiple comparisons. A p value < 0.05 was defined as statistically significant. Results: We identified 251 pediatric ITP patients with sufficient length of follow-up to define acute (<1 year) vs. chronic (>1 year) disease within our 4-year study period. This included 132 patients with acute ITP (53%) and 119 patients who went on to develop chronic ITP (47%). Mean age of diagnosis among those with acute ITP was 5.5 years, while mean age of diagnosis among those with chronic ITP was 7.7 years. Within the entire cohort, 126 (50%) were male, and 124 (49%) were of Hispanic ethnicity. Fifty-eight had ITP attributable to systemic autoimmune disease - 17% within the Acute ITP group, and 30% within the Chronic ITP group. Among all patients (n=251), 188 with evaluable biomarkers (immunoglobulin levels, ANA, CRP, or IPF) at the time of diagnosis were identified. These included 174 patients with Ig levels at diagnosis, 43 patients with ANA titers at diagnosis, 25 patients with CRP levels at diagnosis, and 78 patients with IPF at diagnosis. By univariate analysis, we found that abnormalities in immunoglobulin levels at diagnosis were significantly associated with the development of chronic ITP. Low IgG levels (p = 0.015) were more prevalent in chronic (10.3%) vs. acute ITP (1.9%). High IgG levels (p = 0.015) were more prevalent in chronic (6.7%) vs. acute ITP (1.9%). High IgM levels (p = 0.03) were more prevalent in chronic (26.5%) vs. acute ITP (13.3%). Of note, the presence of Evans syndrome (p = 0.0005) and other systemic autoimmune disease (p = 0.011) were also significantly associated with the development of chronic ITP. Subsequent multivariate analysis identified low IgG level at diagnosis to be independently predictive of chronic ITP (p = 0.043, with an odds ratio of 5.7). Conclusion: Although further study is needed within a larger international pediatric ITP cohort, the findings from this institutional study indicate that biomarkers obtained in routine clinical care at the time of ITP diagnosis, specifically immunoglobulin levels, can be utilized to help predict development of chronic disease among pediatric ITP patients. Disclosures Despotovic: Amgen: Research Funding; Dova: Honoraria; Novartis: Research Funding.

Download Full-text

Increased FVIII and Anti-Phospholipid Antibodies Do Not Modify the Clinical Course of Chronic Immune Thrombocytopenia

Blood ◽

10.1182/blood.v124.21.5013.5013 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5013-5013

Author(s):

Meet Kumar ◽

Maitryee Bhattyacharyya ◽

Shyamali Datta

Keyword(s):

Platelet Count ◽

Lupus Anticoagulant ◽

Immune Thrombocytopenia ◽

Clinical Course ◽

Conflicts Of Interest ◽

Age Groups ◽

Platelet Counts ◽

Bleeding Score ◽

Chronic Immune Thrombocytopenia

Abstract INTRODUCTION: Immune thrombocytopenia is a heterogenous disease with majority patients having a mild bleeding phenotype and one-fourth being asymptomatic. Bleeding episodes are usually seen in patients with platelet counts typically <30,000/cumm. There is no study till date to identify patients with platelet count <30,000/cumm and at high risk for bleeding. Although patients who harbor anti phospholipid antibodies have a higher risk of arterial and venous thrombosis, it is not known whether presence of acquired thrombophilia modifies the clinical course of bleeding in low platelet count ITP patients. We evaluated the role of FVIII and lupus anticoagulant in modifying the clinical course of such patients. MATERIALS AND METHODS: Patients of all age groups with persistent and chronic immune thrombocytopenia were eligible for study enrolment. Patients with acute ITP and secondary ITP were excluded. Eligible patients were evaluated with baseline parameters, ITP bleeding score (ITP-BAT, version 1.0 by IWG on ITP) at baseline and then at every visit and FVIII and lupus anticoagulant at baseline and repeat at six months.Patients were called for monthly scheduled visits if platelet counts were >30,000/cummand more frequently at lower platelet counts. Patients with any evidence of underlying infection or raised c-reactive protein and procalcitonin were deferred evaluation.All patients were treated as per institutional protocol to avoid treatment bias. Patients were followed up for one year. We finally calculated the average bleeding scores of all patients at different platelet counts (for eg. average of skin, mucosal and organ bleeding scores of all patients that had platelet counts <10,000/cumm, 10-30,000/cumm etc) and analysed it with FVIII and anti-phospholipid antibody levels. RESULTS: A total of 45 patients were enrolled with M:F=1:3.2. Median age of patients is 28years (3-72 years). Two patients were excluded (both progressed to SLE) and another two were lost to follow-up. Median duration from ITP diagnosis to study enrolment was 62.4months (8-590 months). Median follow-up of all patients was 14.2 months (13.2-16.4 months). Nine patients had persistent and 32 patients had chronic ITP. ITP-BAT could differentiate intensity of bleeding at different platelet counts by means of bleeding scores (Table 1). Correlation of bleeding scores with prothrombotic markers could not establish a disease course modifying relationship between the two (Table 2). CONCLUSION: Presence of high FVIII and anti phosphoilipid antibodies donot modify the bleeding risks in patients with ITP and low platelet counts. Table 1Platelet count (x109/cumm)Total episodesAverage bleeding scoreP value<1014S2.4 M1.4 O0 0.00210-3015S1.4 M0.9 O030-6018S0.3 M0.1 O0>600S0 M0 O0 Table 2 Platelet count <10,000/cumm Platelet count 10-30,000/cumm N Av BS P= N Av BS P= FVIII>150 5 S2.5M1.1O0 0.02 6 S1.1M0.8O0 0.1 FVIII<150 9 S2M0.7O0 11 S1.4M0.6O0 LA1:LA2>2 1 S2.2M1.5O0 0.03 S1.1M0.8O0 0.2 LA1:LA2<1 12 S2.6M1.2O0 S1.2M0.6O0 Table 3 Platelet count 30-60,000/cumm Av BS P= FVIII>150 4 S0.9M0.1O0 0.2 FVIII<150 11 S0.3M0.1O0 LA1:LA2>2 Nil LA1:LA2<1 9 S1.1M0.4O0 Disclosures No relevant conflicts of interest to declare.

Download Full-text

Outcomes and Prognostic Factors Following Double-Induction Chemotherapy in AML – A Large, Single Institutional Experience,

Blood ◽

10.1182/blood.v118.21.3605.3605 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3605-3605

Author(s):

Jeffrey E. Lancet ◽

Alan F. List ◽

Celeste M. Bello ◽

Najla H Al Ali ◽

Rami S. Komrokji

Keyword(s):

Bone Marrow ◽

Logistic Regression ◽

Induction Chemotherapy ◽

Odds Ratio ◽

Conflicts Of Interest ◽

Univariate Analysis ◽

Multivariable Analysis ◽

Categorical Variables ◽

High Dose ◽

Cox Regression Analysis

Abstract Abstract 3605 Background: Although a majority of patients with AML achieve complete response (CR) following 1 or 2 cycles of induction chemotherapy, rates of relapse-free and overall survival remain poor. In the US, typically the decision to administer re-induction chemotherapy depends upon the degree of leukemic cell clearance from the bone marrow at 10–14 days after initial induction. In this single-institution study, we assessed patients who underwent double induction chemotherapy for AML in an attempt to delineate specific clinical variables that might influence outcomes and decisions to utilize re-induction chemotherapy. Methods: Between 2004 and 2010, patients who received 2 courses of induction chemotherapy for AML at the H. Lee Moffitt Cancer Center were analyzed. Individual charts were reviewed. Chi square test was used to compare categorical variables in univariate analysis. Kaplan Meier estimates were used to calculate OS. Log rank test was used for comparison between the 2 groups and Cox regression analysis was used for multivariable analysis of survival. Binomial logistic regression was used for multivariate assessment of response rates. All analyses were conducted using SPSS version 19.0 software. Results: We identified 164 patients with previously untreated AML who underwent double-induction chemotherapy at our center, 127 of whom had residual blasts ≥ 10% following initial induction. Baseline characteristics (%): male:female (68%:32%), age less than:greater than 60 (57%:43%), adverse:non adverse karyotype (39%:58%), de-novo:secondary AML (66%:32%). The majority (97%) initially received anthracycline + cytarabine (“7+3”) based induction chemotherapy. Second induction utilized a high-dose cytarabine based regimen in 65% of patients. Overall response rate (CR + CRi) was 62%. Median survival for the entire cohort was 13.3 months (95% CI 11.4–15.3). Univariate analysis of prognostic variables associated with response and survival are shown in Table 1. On multivariate analysis, only adverse karyotype (p=0.02, HR 1.67) and non-hypocellular (≥ 20%) bone marrow at day 14 after 1st induction (p=0.002, HR 1.934) were statistically significant predictors of inferior survival (figure 1), but there was a trend toward inferior OS for re-induction beginning after day 21. The only statistically significant predictors for response (CR+CRi) in the logistic regression model were age < 60 (p=0.034, odds ratio 2.850) and hypocellular day 14 bone marrow after 1st induction (p <0.005, odds ratio 7.87). Conclusions: In patients who received double induction therapy for AML, response was achieved in the majority, and the bone marrow cellularity at day 14 after induction cycle 1 was the strongest predictor of response and survival, strongly suggesting its consideration as a prognostic/stratification factor in future outcomes studies as well as studies testing new agents in refractory disease. Future analyses will include direct comparisons of outcomes and analysis of risk factors between patients receiving 1 versus 2 cycles of induction. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Response to Steroids Predicts Response to Rituximab In Pediatric Chronic Immune Thrombocytopenia.

Blood ◽

10.1182/blood.v116.21.3681.3681 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3681-3681

Author(s):

Rachael F. Grace ◽

Carolyn M. Bennett ◽

A. Kim Ritchey ◽

Michael R. Jeng ◽

Courtney Thornburg ◽

...

Keyword(s):

Platelet Count ◽

Research Funding ◽

Immune Thrombocytopenia ◽

Univariate Analysis ◽

Multivariable Analysis ◽

Evans Syndrome ◽

Chronic Itp ◽

Predictors Of Response ◽

Count Response ◽

Acute Itp

Abstract Abstract 3681 Background: Pediatric Immune Thrombocytopenia (ITP) has an incidence of 4–6/100,000 with 1/3 of cases becoming chronic. Treatment choice is arbitrary, because few studies are powered to identify predictors of therapy response. Increasingly, rituximab is becoming a treatment of choice in those refractory to other therapies (Neunert CE, et al. Pediatr Blood Cancer 2008; 51(4):513). Previous studies in ITP have not examined predictors of response to rituximab or whether response to prior treatments predicts response. Objective: To evaluate univariate and multivariable predictors of platelet count response to rituximab. Methods: After local IRB approval, 550 patients with chronic ITP enrolled in the longitudinal, North American Chronic ITP Registry (NACIR) between January 2004 and June 2010. Eligibility included: ages 6 months-18 years at ITP diagnosis, clinical diagnosis of ITP, and ITP duration >6 months. Primary ITP was defined as isolated thrombocytopenia without associated conditions. Secondary ITP included those patients with immune thrombocytopenia associated with other immune-mediated medical conditions, including Evans Syndrome. Treatment response was defined as a post-treatment platelet count ≥50,000/uL within 16 weeks of rituximab and within 14 days of steroids. Steroids were prescribed as 1–4 mg/kg prednisone or adult equivalent over 4–14 days with or without taper. The NACIR captured treatment responses both retrospectively prior to enrollment and then prospectively, and both periods were included in this analysis. The multivariable logistic regression modeling process utilized SAS 9.1 using binary variables which were either significant in the univariate analysis or clinically important. A backwards elimination procedure was used to select the final model. Results: Seventy-six (13.8%) patients were treated with rituximab. Demographics of the patients treated with rituximab include: 42% male; 81% Caucasian, 17% Black, and 2% Asian. The mean age at diagnosis of ITP was 8.4 ± SD 5.1 years. The median platelet count at diagnosis of acute ITP was 10,000/uL (IQR 5,000-20,000/uL). 19 (25%) patients had secondary ITP or Evans syndrome. Treatment with rituximab had an overall response rate of 63.2% (48/76). Univariate predictors of response to rituximab are shown in Table I. The strongest univariate predictor of response to rituximab was response to steroids. Gender, ethnicity, and race were not predictive of response to rituximab. Furthermore, other variables which did not predict rituximab response include: history of a bleeding score ≥3 (Buchanan and Adix, J Pediatr 2002; 141: 683), symptoms ≥1 month prior to ITP diagnosis, older age (age >5 years), platelets ≥20,000/uL at acute ITP diagnosis, and a positive ANA. In multivariable analysis, response to steroids remained a strong predictor of response to rituximab with an OR 6.2 (95% CI 1.8–21.3, p=0.004). Secondary ITP also remained a strong a predictor of a positive response to rituximab with an OR 5.9 (95% CI 1.2–33.3, p=0.03). Conclusion: In the NACIR, response to steroids and secondary ITP were strong predictors of response to rituximab, a finding not previously reported in children or adults. Although this finding requires further validation, this result may provide evidence that rituximab should be most considered in patients previously responsive to steroids. Disclosures: Off Label Use: Rituximab for chronic ITP. Lambert:Cangene: Membership on an entity's Board of Directors or advisory committees. Klaassen:Novartis: Research Funding; Cangene: Research Funding. Neufeld:Novartis, Inc: Research Funding.

Download Full-text

Expression Differences Distinguish Pediatric Acute and Chronic ITP Using RNA Sequencing

Blood ◽

10.1182/blood-2018-99-118581 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 127-127

Author(s):

Taylor Kim ◽

Hyunjae Kim ◽

Pavel Sumazin ◽

Amanda Bell Grimes ◽

Katherine Jenson ◽

...

Keyword(s):

Board Of Directors ◽

Rna Sequencing ◽

Research Funding ◽

Healthy Controls ◽

Rna Seq ◽

Chronic Patients ◽

Advisory Committees ◽

Chronic Itp ◽

Acute Itp ◽

Acute Patients

Abstract Background: Clinical features have been previously associated with the development of chronic immune thrombocytopenia (ITP) in children, but biomarkers to distinguish acute, self-resolving ITP from chronic disease remain elusive. Identifying biomarkers specific for chronic ITP would guide treatment decisions and also inform disease pathogenesis, which remains poorly understood. Prior studies have shown that inflammatory cytokines are elevated in chronic ITP patients as compared to acute patients, and DNA and RNA microarray data stratified chronic and acute ITP patients. This study leverages RNA sequencing data to characterize acute and chronic ITP cohorts. RNA sequencing has the advantage of examining RNA expression differences in a systematic and unbiased manner, as opposed to prior studies which were limited by candidate approach or by array technology. Methods: We collected biologic materials for sequencing and clinical data from 274 pediatric ITP Texas Children's Hospital patients from July 2015 to July 2018 under an approved IRB protocol. Patients were followed prospectively and classified as (1) chronic with disease persisting >12 months or (2) acute with spontaneous resolution in <12 months. Whole blood samples were collected at two time points over disease course. For acute patients, the initial sample was collected within 1 month of initial diagnosis and the second sample was drawn at the time of disease resolution. Two samples, 3-6 months apart, were taken from known chronic ITP patients with active disease at both time points. Acute patients were excluded if they had received any ITP directed therapy. Chronic patients were excluded if they had any therapy within the six months prior to the first sample or had ever received rituximab. Peripheral blood mononuclear cells were isolated using a ficoll separation from whole blood, and total RNA was extracted and purified using an RNeasy Mini Kit (QIAGEN). Those sample pairs which met standards for amount and purity of RNA for both samples were sequenced. RNA-Seq libraries were generated using Ovation® Universal RNA-Seq System (NuGen), sequenced on an Illumina NextSeq 500 instrument, and generated 40 million paired end reads. In total, 9 acute pairs, 12 chronic pairs and 9 healthy controls were sequenced. All protein coding transcripts were collapsed by gene, then rank statistics were applied and scaled by z-score. Cohorts were refined such that samples met uniform quality standards. Cluster analysis was performed using t-distributed stochastic neighbor embedding (t-SNE), a nonlinear method to reduce dimensionality and identify similar structures between samples. Results: Over 20,000 RNA transcripts were identified in approximately 2,000 genes. This preliminary analysis focused on initial samples only, when all ITP patients had active disease. T-SNE analysis showed that healthy controls, acute, and chronic ITP patients stratify into three separate clusters (Figure 1). A hierarchical clustering heatmap demonstrated a stratification between samples from acute patients at presentation, samples from chronic patients, and samples from healthy pediatric controls. Transcripts which stratified patients via hierarchical clustering were analyzed using Gene Set Enrichment Analysis (GSEA) to provide functional annotations. Applying transcripts with high expression in active acute ITP, mid-range expression in chronic ITP, and low expression in healthy controls identified pathways which are also important in other autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel disease. Individual transcript expression profiles were not specifically compared in this analysis, but transcripts with immune function including Fc-Gamma Receptor IIIb, CXCL8, BMP7, DEFA1, DEFA1B, HLA-DRB4, and HLA-DRB5 were differentially expressed between ITP patient samples and controls. Conclusions: This study is the first to use RNA sequencing to show that active, acute ITP is distinct from chronic ITP. This study confirmed that ITP patient RNA expression patterns differ from that of healthy controls. Both transcripts with differential expression between cohorts and functional annotation pathways identified patterns with relevance to autoimmunity. Disclosures Grace: Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Research Funding; Agios Pharmaceuticals: Consultancy. Lambert:Summus: Consultancy; Shionogi: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Educational Concepts in Medicine: Consultancy; Rigel: Consultancy; Sysmex: Consultancy; CSL: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Despotovic:Sanofi: Consultancy; Novartis: Research Funding; AmGen: Research Funding.

Download Full-text

GPIIB ALLELIC POLYMORPHISM AS A FACTOR ASSOCIATED WITH THE PROBABILITY OF IMMUNE THROMBOCYTOPENIA AND THE SEVERITY OF HEMORRHAGIC SYNDROME

Oncohematology ◽

10.17650/1818-8346-2018-13-2-93-99 ◽

2018 ◽

Vol 13 (2) ◽

pp. 93-99

Author(s):

I. I. Zotova ◽

S. I. Kapustin ◽

S. V. Gritsaev ◽

N. V. Mineeva ◽

I. I. Krobinets ◽

...

Keyword(s):

Odds Ratio ◽

Immune Thrombocytopenia ◽

Scientific Research Institute ◽

Control Group ◽

Allelic Polymorphism ◽

Saint Petersburg ◽

Russian Scientific ◽

Russian Scientific Research Institute ◽

Prognostic Criterion ◽

Chronic Immune Thrombocytopenia

Russian Scientific Research Institute of Hematology and Transfusiology under the Federal Medico-Biological Agency; 16 Vtoraya Sovetskaya St., 191024 Saint Petersburg, RussiaPolymorphism of platelet glycoproteins GPIIIa (T1565C), GPIba (T434C), GPIIb (T2622G) and GPIa (A1648G) genes, responsible for the formation of alloantigenic platelet systems HPA-1, -2, -3 and -5, in patients with chronic immune thrombocytopenia (ITP) and in control group (CG) was investigated. Among ITP patients, the proportion of homozygotes of the GPIIb 2622 GG (HPA-3b/3b) gene was more than 2 times higher than in CG: 23.9 % versus 11.4 % (odds ratio (OR) = 2.4, 95 % confidence interval (CI): 1.0–5.8, p = 0.05). The frequency of HPA-3a/3a (GPIIb 2622TT,843Ile/Ile) genotype was higher in ITP patients with 2–3rd degrees of hemorrhagic syndrome (HS): 55.6% versus 25.0% in the group with 0–1st degree of HS (OR = 3.8, 95 % CI: 1.3–10.7, p = 0.02). The obtained data suggest the effect of T2622G polymorphism GPIIb gene both on development of disease (2622 GG genotype), and on serious manifestations of HS (2622 TT genotype), which allows considering this polymorphism as unfavorable prognostic criterion in ITP patients.

Download Full-text

Autoimmune Markers in Children with Chronic Immune Thrombocytopenia

Blood ◽

10.1182/blood-2018-99-109839 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2447-2447

Author(s):

Tuba Nur Tahtakesen Güçer ◽

Ali Aycicek ◽

Gonul Aydogan ◽

Zafer Salcioglu ◽

Ebru Yilmaz ◽

...

Keyword(s):

Autoimmune Diseases ◽

Immune Thrombocytopenia ◽

Conflicts Of Interest ◽

Tissue Transglutaminase ◽

Hormone Replacement ◽

Autoimmune Disorder ◽

Hashimoto Thyroiditis ◽

Chronic Itp ◽

Number Of Patients ◽

Chronic Immune Thrombocytopenia

Abstract Introduction: Chronic immune thrombocytopenia (ITP) is defined as isolated thrombocytopenia lasting longer than 12 months. Rheumatologic diseases, immunodeficiencies and thyroid diseases may coexist with chronic ITP due to possible immune dysregulation. Aim: To evaluate the accompanying autoimmune diseases in children with chronic ITP. Materials-Methods: A total of 154 children with chronic ITP (F /M: 1) diagnosed between 1995 and 2018 were included. Patients were evaluated with immunoglobulin levels, ANA, anti dsDNA, C3, C4, anti TPO, anti TG, T4, TSH, tissue transglutaminase IgA and Ig G. Results: Of the 154 patients, 79 were female (51.3%) and 75 were male (48.7%). Mean age of the patients was 13.6 ± 5.8 years, mean age of diagnosis was 7 years ± 4. None of the patients had severe infections requiring hospitalisation. None of the patients had symptoms or findings of an autoimmune disorder. Of 154, two had low IgA levels (<7 mg / dL) and they were diagnosed as IgA deficiency. IgM and IgG levels were normal in all. C3 level was low in four patients (3%) and C4 level was low in one patient (0.7%). ANA was positive in 16 (12%) of the patients and anti-dsDNA was positive in four patients (0,3%). In three patients, Anti-dsDNA positivity was accompanied with ANA positivity and in one patient, C3 was low. These patients were followed up by pediatric rheumatology clinic. Twenty two patients had elevated anti TPO (15.5%) and 18 patients had elevated anti TG (12.7%) levels. Majority of patients with high thyroid autoantibodies were female (67.5%). Out of 129 patients evaluated by thyroid tests including fT4, TSH, AntiTPO and AntiTG, 29 (% 22,4) were diagnosed as Hashimoto thyroiditis. Thyroid hormone replacement was started in one patient . Of 93 patients evaluated with anti-tissue transglutaminases, 7 were found to have at least one positive TTG IgA or IgG. Two of these patients underwent endoscopy, but no evidence of celiac disease was found. In total, the number of patients with at least onepositive autoimmune marker was 54 (35%). Discussion and Conclusion: Chronic ITP is known to accompany autoimmune diseases. Autoimmune diseases in patients with ITP may occur at any time in 10 years of diagnosis. Further studies for the detection of subclinical autoimmune conditions should be performed with a profit- loss account. Antibodies may be positive even when there is no clinical findings of the diseases. Further follow-up is needed to understand the clinical significance of autoimmune markers in chronic ITP. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Long term evaluation of etiological treatment of Chagas disease with benznidazole

Revista do Instituto de Medicina Tropical de São Paulo ◽

10.1590/s0036-46652002000100006 ◽

2002 ◽

Vol 44 (1) ◽

pp. 29-37 ◽

Cited By ~ 208

Author(s):

J. Romeu CANÇADO

Keyword(s):

Chronic Disease ◽

Chagas Disease ◽

Chronic Patients ◽

Serological Tests ◽

Term Evaluation ◽

Acute Form ◽

Acute Patients

The aim of this article is to present an investigation of cure rate, after long follow up, of specific chemotherapy with benznidazole in patients with both acute and chronic Chagas disease, applying quantitative conventional serological tests as the base of the criterion of cure. Twenty one patients with the acute form and 113 with one or other of the various chronic clinical forms of the disease were evaluated, after a follow up period of 13 to 21 years, for the acute, and 6 to 18 years, for the chronic patients. The duration of the acute as well as the chronic disease, a condition which influences the results of the treatment, was determined. The therapeutic schedule was presented, with emphasis on the correlation between adverse reactions and the total dose of 18 grams, approximately, as well as taking into consideration precautions to assure the safety of the treatment. Quantitative serological reactions consisting of complement fixation, indirect immunofluorescence, indirect hemagglutination, and, occasionally, ELISA, were used. Cure was found in 76 per cent of the acute patients but only in 8 per cent of those with chronic forms of the disease. In the light of such contrasting results, fundamentals of the etiological therapy of Chagas disease were discussed, like the criterion of cure, the pathogenesis and the role of immunosuppression showing tissue parasitism in long standing chronic disease, in support of the concept that post-therapeutic consistently positive serological reactions mean the presence of the parasite in the patient's tissues. In relation to the life-cycle of T. cruzi in vertebrate host, there are still some obscure and controversial points, though there is no proof of the existence of resistant or latent forms. However, the finding over the last 15 years, that immunosuppression brings about the reappearance of acute disease in long stand chronic patients justifies a revision of the matter. Facts were quoted in favor of the treatment of chronic patients.

Download Full-text