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

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.

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The Transition from Childhood to Adulthood in Chronic Immune Thrombocytopenia Patients: Clinical Management and the Role of Splenectomy and Thrombopoietin Receptor Agonists in a Single Center Experience

Blood ◽

10.1182/blood-2018-99-114050 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4987-4987

Author(s):

Monica Carpenedo ◽

Marco Spinelli ◽

Sara Pezzatti ◽

Momcilo Jancovic ◽

Rossella Renso ◽

...

Keyword(s):

Chronic Disease ◽

Pharmacological Treatment ◽

Immune Thrombocytopenia ◽

Single Center ◽

Thrombopoietin Receptor Agonists ◽

Chronic Itp ◽

Thrombopoietin Receptor ◽

Limited Compliance ◽

Grade 3

Abstract Introduction. Children diagnosed with Immune thrombocytopenia (ITP) will develop a chronic disease (plt < 100 x 109/L lasting >12 months since the onset) in 20-30% of cases. The transition from ITP started in childhood to adulthood has been scarcely studied and no specific studies have been published Aims.To present the results of a single center retrospective survey on ITP pts diagnosed in childhood who were sent in an adult setting to continue the management Methods. Charts of ITP pts diagnosed in childhood (1-17 yrs) in our Pediatric Dept who developed a chronic disease, need at least one line of therapy and were sent to our adult ITP office from Jan 2013 to Feb 2018, were retrospectively reviewed. Demographic and clinical data were collected and outcome was assessed based on established guidelines Results. Our Pediatric Dept accounts for a mean of 37 newly ITP diagnosis/year in children aged 1-17 yrs, with 32.8% of pts developing a chronic disease. During the selected observation time, 60 pts was expected to become > 18 yrs old with a chronic ITP. Overall 28 pts (14 female) pts were sent to our Adult ITP office at pediatrician's discretion (46.6% of expected). Table 1 summarizes demographic and clinical characteristics of pts. Median age at ITP diagnosis was 9.5 yrs (12 moths to 17 yrs). Median age of pts coming to the adult ITP office was 21 yrs (18 to 37 yrs) and the reason they were sent for was the need to continue a pharmacological treatment in 8 cases (eltrombopag-Elt-), bleeding in 3 cases, pregnancy in 4 cases, plt count < 50 x 109/L in 13 cases. The median n of lines of treatment already received in childhood was 1 (1 to 4). 16 pts have received only steroid since diagnosis (on demand treatment for bleedings), 8 pts were treated with thrombopoietin receptor agonists (TPO-RA) and 1 also with rituximab. One patient, 8 yrs old, was splenectomized because of grade 3 multiple bleedings, with complete response (CR). He was sent to adult ITP office at 37 yrs when ITP relapsed, with grade 3 bleeding. Overall the median follow up from diagnosis, after the transition to adult ITP office is 18 yrs (4-39 yrs), the median n of lines at data cut-off was 2.5 (1-5) and the overall outcome is summarized in Fig 1. 11 patients were treated with TPO-RA (8 pts received Elt since childhood, 2 pts started Elt and 1 Rom in adulthood), ORR was 81.8% (CR=7). Since the transition 4 patients switched the TPO-RA because response to the first TPO-RA was suboptimal or minor side effect (headache) was reported or limited compliance was suspected. Splenectomy was offered to all patients treated with TPO-RA to avoid chronic pharmacological treatment, and to other selected patients with a low plt count and a history of bleeding. 8/11 patients accepted splenectomy. Median time since diagnosis to splenectomy was 8 yrs (1 to 18 yrs) and in all pts a stable CR (plt > 100 x 109/L) was achieved, with a median follow up after surgery of 36.5 months (10-48 months). Surgery was performed also in the previous splenectomized pt (29 yrs later) because an accessory spleen was detected, and a CR was achieved (follow up 40 months). 2 patients stopped TPO-RA on a personal decision, refused splenectomy or other treatments: their plt count is < 30 x 109/L without bleeding. 15 pts were on active follow up without therapy (median plt count 58 x 109/L) and without any bleeding. One patient is waiting for splenectomy, taking prednison. The 4 pregnant patients were treated with steroids and IVIG, had natural labour without adverse events and their babies had a normal plt count. After pregnancy one pt was treated with Elt for 1 year, then she refused treatment and splenectomy. All 4 women returned to a number of plts similar to pre-gestational count. In 1 pt a MYH9 related-disorder was confirm at 21 yrs. Overall a CR was achieved during TPO-RA treatment in 9/11 pts and 9/28 (32%) achieved a stable CR after splenectomy Conclusions. The transition from childhood to adulthood in chronic ITP pts leads clinicians to challenges related to growing age, especially in female pts approaching the fertility and pregnancy specific needs. However only a minority of children with ITP developed a chronic disease which required a prolonged treatment. TPO-RA seems to be effective and well tolerated but chronic administration has limited compliance. Splenectomy, even if performed in adulthood after many yrs since diagnosis, allows to achieve a stable CR sparing young adults from chronic pharmacological treatment. Disclosures Gambacorti-Passerini: Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy.

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Differential Expression of Markers of Apoptosis in Platelets From Children with Acute Versus Chronic Immune Thrombocytopenia

Blood ◽

10.1182/blood.v120.21.1092.1092 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1092-1092

Author(s):

Markus Schmugge ◽

Jeanine Winkler ◽

Sabine Kroiss ◽

Margaret L. Rand ◽

Oliver Speer

Keyword(s):

Platelet Count ◽

Immune Thrombocytopenia ◽

Caspase 3 ◽

Pediatric Patients ◽

Caspase 8 ◽

Caspase 9 ◽

Platelet Apoptosis ◽

Chronic Itp ◽

Acute Itp

Abstract Abstract 1092 Immune thrombocytopenia (ITP) is a common hematologic disorder in children that can lead to severe bleeding symptoms. In most children with ITP, platelet counts return to normal after weeks to months (acute ITP), however, in about 10–20% of patients, the low platelet counts persist for 12 months or longer (chronic ITP). No biological markers have been identified to predict the duration and/or severity of ITP. We have previously reported enhanced platelet apoptosis at the time of diagnosis of ITP in pediatric patients that was ameliorated after intravenous immunoglobulin (IVIg) (Winkler et al, Br J Haematol 2012;156:508–15). We have now investigated differences in the expression of markers of apoptosis in platelets from children with acute vs. chronic ITP. 23 pediatric patients with acute ITP were investigated and compared to 10 children with chronic ITP. In addition, from the initial group of acute ITP, 6 children developed chronic ITP and initial- and follow up results were compared. Markers of apoptosis, including activated caspase-3, caspase-8 and caspase-9, phosphatidylserine (PS) exposure, dissipation of the mitochondrial inner membrane potential (ΔYm), as well as microparticle formation, were analyzed by flow cytometry. At ITP diagnosis, the mean platelet count was 4×109/L (range: 1–14×109/L) and the proportions of platelets with activated caspase-3 (median, range) (20.4%, 1.4–64%, n=23), caspase-8 (16.7%, 1.0 – 42.7%, n=12) and caspase-9 (13.1%, 5 – 59.6%, n=12) were increased. While a higher mean platelet count was found in 10 children with chronic ITP (25×109/L, 4–60G/l), the proportions of platelets with activated caspase-3 (2.6%, 0.3–11.6%), caspase-8 (5.6%, 0.3–12.6%) and caspase-9 (4.3%, 0.3–15.6%) were significantly lower compared to children at diagnosis of acute ITP, but still higher compared to healthy controls (0.95%, 0 – 5.9%; 0.7%, 0.04 – 2.3% and 0.4%, 0.03 – 2.16%, respectively; n = 11) and children with thrombocytopenia due to chemotherapy (1.3%, 0.1 – 4.6%; 1.8%, 0.9 – 3.8%; and 1.8%, 0.6 – 2.9%, respectively; n = 11). Among the 6 children (26%) who developed chronic ITP from the initial cohort of 23 children, a mean platelet count of 29 (3–67×109/L) at >12 months after initial presentation was found. Except for one, none of the children with chronic ITP presented with bleeding symptoms; the median bleeding score was 2.5 (range: 1–3) at diagnosis and 1 (range: 0–2.5) at follow up during chronic ITP. In 5 of the children who developed chronic ITP, caspase activation was studied at diagnosis and at follow up >12 months after. In all of them, the proportions of platelets with activated caspase-3 (1.6%, 0.3–3.3%), caspase-8 (4.8%, 0.3–6.3%) and caspase-9 (4.1%, 0.3–7%) were found to be significantly lower at follow up compared to the time at diagnosis. In conclusion, although platelet apoptosis is enhanced at the time of diagnosis of pediatric ITP, this is not observed in platelets from patients with chronic ITP to the same degree. Further studies are needed to investigate other markers of apoptosis in platelets in the course of acute and chronic ITP. Disclosures: No relevant conflicts of interest to declare.

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The North American Chronic Immune Thrombocytopenia Registry (NACIR): Demographics and Treatment Responses

Blood ◽

10.1182/blood.v116.21.2509.2509 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2509-2509

Author(s):

Rachael F. Grace ◽

Ellis J. Neufeld ◽

A. Kim Ritchey ◽

Manjusha Kumar ◽

Michael R. Jeng ◽

...

Keyword(s):

Platelet Count ◽

North American ◽

Research Funding ◽

Immune Thrombocytopenia ◽

Evans Syndrome ◽

Chronic Itp ◽

The North ◽

Acute Itp ◽

Positive Direct

Abstract Abstract 2509 Background: Chronic pediatric immune thrombocytopenia (ITP) has an incidence of 1–2/100,000. Due to its low incidence, large studies in pediatric chronic ITP are difficult. This registry includes patients from 16 sites in the US and Canada and represents one of the largest longitudinal datasets of children/adolescents with chronic ITP. Objective: To describe the North American Chronic ITP Registry (NACIR) study population and evaluate univariate predictors of platelet count response to therapies, including IVIG, anti-D globulin (anti-D), steroids (5–14 day course), and splenectomy. Registry methods and patient characteristics: After local IRB approval, 550 patients with chronic ITP enrolled in the 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 7 days of IVIG, 10 days of anti-D, 14 days of steroids, and 30 days of splenectomy. 365 subjects had at least one 6 month follow-up report after enrollment; median duration of follow-up was 2.1 yrs. Demographics of participants include: 46% male; 84% Caucasian, 7% Black, and 7% Asian; and 20% Hispanic. Mean age at diagnosis of acute ITP was 8.7 ± SD 5.2 years. At the time of enrollment in NACIR, subjects had received a median of 2 prior treatments (range 0–7). Results: The median platelet count at diagnosis of acute ITP was 11,000/uL (IQR 6,000–31,000/uL) and at chronic ITP was 35,000/uL (IQR 18,000–66,000/uL). 69 (12.5%) patients had secondary ITP or Evans syndrome. Of those tested, 25.6% (98/359) of patients had a positive ANA (titer > 1:40), and 75/337 (22.3%) had a positive direct anti-globulin test (DAT). 27.5% of patients had an antecedent viral illness. Of the 550 subjects, 2 (0.4%) experienced life-threatening bleeding. Patients were treated as follows: 259 (47.1%) with steroids, 253 (46%) with IVIG, 189 (34.4%) with anti-D, and 64 (11.6%) with splenectomy. Overall responses to therapy included: 69.1% response to steroids, 74.3% response to IVIG, 66.7% response to anti-D, and 85.9% response to splenectomy. Univariate predictors of response to treatments are shown in Table I. Higher platelet count at chronic ITP diagnosis and DAT positive predicted a platelet response to a short course of steroids in univariate analysis. This was confirmed in multivariable analysis of potential confounders, using logistic regression with a backwards elimination procedure. Response to one type of therapy was often strongly associated with a response to a second therapy. Gender, ethnicity, race, older age, and platelets ≥20,000/uL at acute ITP diagnosis were not associated with response to any single therapy. Conclusion: The demographics and laboratory findings of the large, well characterized NACIR population are consistent with other reports of young people with chronic ITP. The novel finding that DAT positivity predicts steroid response, even with multivariable adjustment for confounders, provides evidence that the NACIR is a robust and useful tool for trying to predict response to ITP treatment strategies. Disclosures: Klaassen: Novartis: Research Funding; Cangene: Research Funding. Lambert: Cangene: Membership on an entity's Board of Directors or advisory committees.

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Results of high-altitude climate treatment of immune thrombocytopenia in children in the Kyrgyz Republic (five-year analysis)

Тромбоз, гемостаз и реология ◽

10.25555/thr.2020.3.0935 ◽

2020 ◽

Author(s):

А.К. Эсенгелди

Keyword(s):

High Altitude ◽

Immune Thrombocytopenia ◽

Disease Duration ◽

Objective Response ◽

Kyrgyz Republic ◽

Chronic Itp ◽

Effi Ciency ◽

The Subject ◽

Further Development

Введение: Вопрос о дальнейшем совершенствовании базисной терапии иммунной тромбоцитопении (ИТП) по-прежнему широко обсуждается специалистами и является предметом оживленных дискуссий. Цель исследования: оценить эффективность высокогорной климатотерапии при хронической ИТП у детей за 5-летний период наблюдения после ежегодного лечения на высокогорной базе. Материалы и методы: В исследование включено 22 ребенка с хронической ИТП в возрасте от 3 до 14 лет, средний возраст — 6,30 ± 1,02 года, длительность заболевания 2-8 лет. Для лечения детей поднимали на высокогорную базу. Продолжительность лечения в высокогорье составляла 40 дней. Результаты: Из 22 детей, получивших 5 курсов высокогорной климатотерапии, у двоих наблюдали полную ремиссию в виде увеличения тромбоцитов более 100×109/л без кровоточивости. Объективный ответ в виде двукратного увеличения числа тромбоцитов, но менее 100×109/л без кровоточивости установлен у 18 детей, отсутствие эффекта было зарегистрировано у 2 детей. Заключение: Повторные курсы высокогорной климатотерапии способствуют улучшению клинической картины, существенному повышению числа тромбоцитов в периферической крови и достижению ремиссии при ИТП у детей. Background: Further development of basic treatment of immune thrombocytopenia (ITP) is still widely discussed by specialists and is the subject of lively discussions. Objectives: to assess the effi ciency of high-altitude climatotherapy in children with chronic ITP for a 5-year follow-up period after annual treatment at high-altitude base. Patients/Methods: The study included 22 children with chronic ITP from 3 to 14 years, the average age was 6.30 ± 1.02 years, and disease duration was 3-8 years. Children were raised to high-altitude base. Treatment duration was 40 days. Results: 22 children received 5 courses of high-altitude climatotherapy. Complete remission was observed in 2 patients with increasing of platelets more than 100×109/L without bleeding. In 18 children an objective response was found in the form of twofold increasing of platelets number, but less than 100×109/L without bleeding; no effect was recorded in 2 children. Conclusions: Repeated courses of high-altitude climatotherapy improve clinical characteristics, significantly increase the number of platelets in the peripheral blood and contribute to remission in children with ITP.

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PS4:83 Follow-up of newborn babies from mother affected by systemic autoimmune disease

10.1136/lupus-2018-abstract.128 ◽

2018 ◽

Author(s):

Tiziana Bertero ◽

Jessica Munarin ◽

Mario Frigerio ◽

Emilia Parodi

Keyword(s):

Autoimmune Disease ◽

Systemic Autoimmune Disease

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Retrospective Analysis of 1230 Patients of Immune Thrombocytopenic Purpura Reporting to a Tertiary Care Hospital in India from 1992–2004.

Blood ◽

10.1182/blood.v104.11.5294.5294 ◽

2004 ◽

Vol 104 (11) ◽

pp. 5294-5294

Author(s):

Dharma R. Choudhary ◽

Rajat Kumar ◽

R. Saxena ◽

Manoranjan Mahapatra ◽

Atul Kotwal ◽

...

Keyword(s):

Developing Countries ◽

Response Rate ◽

Tertiary Care Hospital ◽

Tertiary Care ◽

Cost Effective ◽

Repeated Measure ◽

Care Hospital ◽

Chronic Itp ◽

Acute Itp

Abstract Background: There is very little published epidemiological data from developing countries regarding ITP and no large series from India. The aim of the study was to analyze the presenting features, response to different therapeutic options and suggest cost effective therapy. Method: The records of hematology department of All India Institute Of Medical Science were analyzed from January 1992 to June 2004. This is a premium tertiary care hospital in India. Diagnosis of ITP was made according to the standard criteria. Response criteria: complete response was defined as a platelet count increase to 100x109 /l or more, for at least 2 months: partial response was defined as doubling of platelet counts from initial levels and > 50x 109/l for at least 2 months; no response included none of the above. Statistical methods: Database was created in MS Access and SPSS ver 11 was used for statistical analysis. Descriptive statistics were calculated and appropriate tests of significance like Chi Square, repeated measure linear model were carried out. Results: During the study period, 1230 patients of ITP were seen in hematology department, with a median age of 19.6 years (range 0.9–80). Females were 51.1% and males 48.9%. Median follow-up was of 9 months (range 0–178). Presenting features were: skin bleed − 91.1%; mucosal bleed − 57.5%; hematuria − 7.2%; gastrointestinal bleed − 12.5% and intracraniall bleed − 2.8%. Per-vaginal bleeding − 31.2 % of females. History of preceding viral fever was seen in 13.1% and palpable spleen in 2.5%. The mean platelet counts at presentation were 34+ 18.3x109/l. There were 595 (48.4%) patients of acute ITP and 635 (51.6%) patients of chronic ITP. Childhood ITP (age ≤ 12 yr) was seen in 46.5% and adult ITP in 53.5%. Response to therapy: Prednisolone was given to 99.6% patients with response of 57.3 %; Intravenous gamma globulin was given to 8.9% with response in 63.6%. Splenectomy was performed in 5% of acute ITP and 15.1% of chronic ITP (p = 0.00). The overall number of splenectomies was 126, with a response rate of 83.3%. Of these 126, acute ITP constituted 23.8% while chronic ITP formed 76.2% of cases. There was no statistically significant difference in response rate in these two groups (p =0.575). Danazole was given to 66 patients with response in 44%. Various other modalities of treatment were given to 24 patients (Anti D-14; Dapsone-2; Cyclosporin-2; Azathioprine-5; and Vincristine with Cyclophosphamide -1 patient), with a response in 25% of patients. The overall response rate with all treatment modalities was 68%: in childhood ITP − 65% and in adult ITP − 70.5%. Childhood ITP did not respond as expected, possibly due to referral bias of more refractory cases being referred to the center. The values of platelets showed a continuous increase during follow up and this increase was statistically significant (P=0.000 for all, Repeated measure model). Conclusion: Pattern of ITP in India is similar to that seen in other centers. In this study Prednisolone was given as first line agent to almost all patients with response in 57.3%; Splenectomy were done in 10.2% of prednisolone refractory or dependent patients with a response in 83.3%. These should form the primary modalities of therapy in developing countries. Significant numbers of patients were refractory to above-mentioned modalities and thus there is a requirement for other cost-effective therapies.

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The Role of Oxidative Stress in Pediatric Immune Thrombocytopenia

Blood ◽

10.1182/blood.v120.21.3319.3319 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3319-3319

Author(s):

Clara Lo ◽

Bing Zhang ◽

Kristina Cusmano-Ozog ◽

Wendy Wong ◽

Michael Jeng ◽

...

Keyword(s):

Oxidative Stress ◽

Immune Thrombocytopenia ◽

Pediatric Patients ◽

Protein Carbonyl ◽

Carbonyl Content ◽

Protein Carbonyl Content ◽

Chronic Itp ◽

Redox Capacity ◽

Acute Itp

Abstract Abstract 3319 Background: An unpredictable subset of patients (∼20–30%) with pediatric immune thrombocytopenia (ITP) progress to chronic ITP; this increases the risk of morbidity and mortality from bleeding, long-term immunomodulation, and/or splenectomy. Furthermore, treatments such as chronic steroid therapy often result in intolerable side effects, raising the need for targeted therapies. We previously tested a novel list of genes that might predict progression to chronic ITP (Zhang et al Blood 2011). Oxidative stress (OS)-related pathways were among those most significantly perturbed in chronic ITP. For further evaluation of the role of OS in ITP, we measured glutathione as a marker of redox capacity and protein carbonyl content as a marker of oxidative cell damage. Methods: Pediatric patients with primary ITP were included, with exclusion of subjects with secondary thrombocytopenia, other autoimmune disorders (ie, lupus), or other chronic illnesses. Healthy pediatric volunteers were recruited as controls. Patients had blood draws within 1 month from ITP diagnosis. Reduced (GSH) to oxidized (GSSG) glutathione ratios were measured from whole blood by tandem mass-spectrometry. Protein carbonyl content (PCC) levels were measured from platelet-rich plasma by enzyme-linked immunosorbent assay (ELISA). Subjects were followed up to 15 months from diagnosis and monitored for disease resolution or progression. Chronic ITP was defined as thrombocytopenia (platelets <100,000/μL) lasting at least 12 months from diagnosis (Rodegheiro et al Blood 2009). Acute ITP was defined as thrombocytopenia resolving within 12 months from diagnosis. Statistical significance was defined as p<0.05. Results: Between July 2009 and December 2011, 67 pediatric patients with ITP were recruited. Thirty-four patients had acute ITP, and 33 patients progressed to chronic ITP. The median age of patients was 7 years (range 18 months – 17 years). Sixty-three percent were female, 37% were male. Twenty-four pediatric controls were also recruited (46% female, 54% male). The median age of controls was 8 years (range 5 years – 17 years). Patients with ITP had significantly lower GSH:GSSG ratios compared to controls, and patients with chronic ITP had lower GSH:GSSG ratios compared to those with acute ITP (Figure 1). Furthermore, patients with ITP had significantly higher PCC levels compared to controls (Figure 2). Conclusions: This data provides further evidence for a role of oxidative stress (OS) in the pathophysiology of ITP. Furthermore, decreased redox capacity, as evidenced by the decreased glutathione ratios, may be associated with progression to chronic ITP. Reactive oxidative species (ROS) may be important in the pathogenesis of autoimmunity in ITP; oxidatively altered cellular by-products induce pathogenic antibodies and become immunogenic. This also raises a potential anti-oxidant mechanism of therapy, which may play a greater role in chronic ITP treatment. Increased understanding of OS in pediatric ITP may reveal markers of disease progression, highlighting those at greatest risk for chronic ITP and creating a role for targeted therapy. Disclosures: No relevant conflicts of interest to declare.

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Geographic Remoteness Is Associated with Increased Blood Product Utilization and Higher Rates of Hospitalization and Deaths in Adults with Immune Thrombocytopenia

Blood ◽

10.1182/blood-2021-154379 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4061-4061

Author(s):

Erika Wall ◽

John Podstawka ◽

Haowei Linda Sun

Keyword(s):

Bone Marrow ◽

Blood Cells ◽

Immune Thrombocytopenia ◽

Abdominal Imaging ◽

Blood Products ◽

Coagulation Parameters ◽

Packed Red Blood Cells ◽

Chronic Itp ◽

Geographic Remoteness

Abstract INTRODUCTION Immune thrombocytopenia (ITP) is a hematological disease characterized by immune-mediated destruction of platelets. Prior to starting therapy for ITP it is critical to determine whether it is idiopathic or related to a secondary underlying condition as this informs treatment. There is significant use of blood products and components in patients with chronic ITP for management of thrombocytopenia and bleeding, including intravenous immune globulin (IVIg). Platelet transfusions are generally reserved for life-threatening bleeding or may be used in the preoperative setting in patients unresponsive to other therapies. The aims of this study are to identify gaps in process of care and to examine the impact of geographical remoteness on health service utilization and outcomes in adults with chronic ITP in Alberta. METHODS Adults who received rituximab, splenectomy, or thrombopoietin receptor agonists (TPO-RA) as second-line therapy for ITP during 2012-2019 in the province of Alberta, Canada were identified via the provincial special drug access database. Diagnostic workup including bone marrow biopsy results, abdominal imaging (ultrasound or CT scan), coagulation parameters, viral serologies for hepatitis, human immunodeficiency virus (HIV), serum protein electrophoresis (SPEP), and quantitative immunoglobulins were recorded and rates of completed tests were calculated. Utilization of IVIg, platelets, and packed red blood cells was assessed. Rates of hospitalization, mortality, and ITP-related deaths were calculated and compared according to geographic region. RESULTS Of the 204 patients identified for analysis 106 were female (52%). Most patients (123; 60%) lived within a major centre, whereas 21 (10%) lived over 250 km from a major centre. Review of diagnostic laboratory parameters revealed incomplete coagulation parameters in 117 patients (58%), and no coagulation parameters checked in 16%. Eighty-nine patients (44%) did not have quantitative immunoglobulins tested, and 57 (28%) did not have an SPEP performed. Fifty-three (26%) did not have any abdominal imaging performed to assess for splenomegaly or liver disease. Thirty-five (17%) did not have any viral serologies for hepatitis B, C, or HIV completed. Bone marrow aspirate and biopsy was performed in 110 patients (54%). Eighty-six (77%) of these biopsies yielded a normal result. Eight biopsies (7%) displayed a lymphoproliferative disorder or plasma cell disorder which was suspected or known prior to completing the test. There was significant geographic discrepancy in utilization of blood products and hospitalizations. During 527 patient years of follow up, 83 patients received a total of 343 doses of platelets. Eleven patients (13%) received platelet transfusions for inappropriate indications, and eight (9%) for unclear indications. One hundred twenty-seven patients received IVIg (mean 1290 g) with comparable usage across geographic regions. Compared to patients within 250 km from a major centre, those with geographic remoteness (>250 km from a major centre) utilized more platelets (mean 5.2 vs 1.2 doses; Figure 1) and packed red blood cells (mean 4.3 vs 1.2 units; Figure 2). Those with geographic remoteness also experienced a higher rate of ITP-related hospitalizations (mean 1.5 vs 1.1) and deaths (24% versus 9%). At a median follow-up of 3.42 years from ITP diagnosis, 27 patients (13%) were deceased. Fourteen of these deaths were ITP-related due to bleeding or infection (52%). There appears to be a gradient of rates of both all-cause and ITP-related deaths by distance from a major centre (Figures 3 and 4). DISCUSSION This study highlights gaps in quality of care in patients with chronic ITP in Alberta, Canada. A significant number of patients have an incomplete workup for ITP at the time of diagnosis with the most forgotten tests being coagulation studies, SPEP, quantitative immunoglobulins, viral serologies, and abdominal imaging. Additionally, we identified an unexpectedly high rate of bone marrow biopsies performed in our population. Most of these bone marrow examinations did not result in any change in management. Finally, this study identified that geographic remoteness is associated with increased health services utilization and ITP-related deaths. These data can be used to inform further quality improvement initiatives in chronic ITP and help address geographic inequities in healthcare outcomes. Figure 1 Figure 1. Disclosures Sun: Bayer: Consultancy; Novo Nordisk: Consultancy; Pfizer: Consultancy; Shire: Consultancy; Octapharma: Consultancy, Research Funding.

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Can Anti-Thyroid Antibodies Influence the Outcome of Primary Chronic Immune Thrombocytopenia in Children?

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530319666190905161347 ◽

2020 ◽

Vol 20 (3) ◽

pp. 351-355 ◽

Cited By ~ 1

Author(s):

Paola Giordano ◽

Maurizio Delvecchio ◽

Giuseppe Lassandro ◽

Federica Valente ◽

Valentina Palladino ◽

...

Keyword(s):

Autoimmune Thyroiditis ◽

Immune Thrombocytopenia ◽

Pediatric Patients ◽

Pediatric Population ◽

Clinical Signs ◽

Thyroid Antibodies ◽

Chronic Itp ◽

Immune Mediated

Background: Immune thrombocytopenia (ITP) is an acquired immune mediated disorder characterized by isolated thrombocytopenia. Pediatric ITP patients can develop autoantibodies such as anti-thyroglobulin (TG) and anti-thyroperoxidase (TPO), even in the absence of clinical signs of autoimmune disease. Objective: The purpose of this article is to provide a review about: 1) the prevalence of positivity of anti-thyroid antibodies (TPO and TG) in pediatric patients with chronic ITP; 2) the role of autoimmune thyroiditis on the outcome of chronic ITP. Method: The authors individually completed a review of the literature for this article. Retrospective and prospective clinical studies with pediatric cohorts were considered. Results: From the analysis of data, we found 4 papers which included studies only on pediatric population, and which corresponded to selected criteria. Pediatric ITP patients have been shown to have a statistically significant prevalence of anti-thyroid antibodies over healthy controls (11.6-36% versus 1.2-1.3%). No correlation has been found between the platelet count and the prevalence of positive anti-thyroid antibodies at any time of the follow up. Conclusion: The results of our bibliographic research demonstrated that: a) pediatric patients with chronic ITP tend to have a statistically significant prevalence of anti-thyroid antibodies positivity respect to general pediatric population; b) there are no clear data about the role of autoimmune thyroiditis as prognostic factor for chronic course of ITP in pediatric age.

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AB1051 KIKUCHI FUJIMOTO DISEASE, IS IT SLE?

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.5460 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1815.3-1816

Author(s):

J. Camins-Fàbregas ◽

V. Ortiz-Santamaria ◽

N. Busquets-Pérez ◽

A. Cuervo ◽

I. Cañas Alcántara ◽

...

Keyword(s):

Autoimmune Disease ◽

Autoimmune Diseases ◽

Lupus Erythematosus ◽

Clinical Manifestations ◽

Response To Treatment ◽

Systemic Autoimmune Disease ◽

Histiocytic Necrotizing Lymphadenitis ◽

Systemic Autoimmune Diseases ◽

Necrotizing Lymphadenitis

Background:Kikuchi-Fujimoto disease (KFD) is a rare entity characterized by adenopathies and fever. It raises a broad differential diagnosis that includes lymphoproliferative disorders, infections and systemic autoimmune diseases, and diagnostic confirmation is always by histology, which shows histiocytic necrotizing lymphadenitis. Although its course is generally benign and self-limited, it can be associated both at the time of diagnosis and during follow-up with systemic autoimmune diseases, the most frequent of which is systemic lupus erythematosus (SLE).Objectives:To describre the clinical and analytical characteristics of patients diagnosed with KFD and the development of systemic autoimmune disease.Methods:Patients diagnosed with KFD during the 1990s and 2020s are collected in a regional hospital (Granollers General Hospital). The clinic is documented at the diagnosis of EKF, the appearance of systemic autoimmune disease during follow-up and its clinical and analytical characteristics.Results:A total of 7 patients with EKF were diagnosed. All of them women with a mean age at diagnosis of 30 years. Diagnosis was made in all cases with compatible clinical symptoms, fever and lymphadenopathy, and lymph node biopsy confirming histiocytic necrotizing lymphadenitis. At the time of diagnosis, a patient was also diagnosed with SLE. During the follow-up, 4 of the 6 remaining patients developed clinical manifestations compatible with SLE (3 of them with systemic manifestations and a case of subacute cutaneous lupus. The mean time of onset of SLE was 34 months (between 6 months and 5 years). All of them received treatment with hydroxychloroquine, with good response to treatment.The clinical and analytical characteristics are presented in Table 1 below.Conclusion:In our center, 5 of the 7 patients (71%) diagnosed with EKF developed manifestations compatible with SLE. The importance of the diagnosis of EKF lies precisely in the possible association with systemic autoimmune disease, the most common being SLE, so it is recommended that patients be monitored to identify those who develop associated autoimmune disease.Disclosure of Interests:None declared

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