Autologous 111 Indium-Oxinate-Labelled Platelet Sequestration Study in Patients with Immune Thrombocytopenia Treated By Thrombopoietic Receptor-Agonists

Abstract Introduction In immune thrombocytopenia (ITP), isotopic assessment of the site of platelet destruction using autologous111Indium-oxinate-labelled platelet sequestration study could be an helpful parameter to determine whether or not to perform splenectomy. Two independent studies have suggested that a purely splenic sequestration could be a significant predictive factor of long-term complete response after splenectomy. An increasing number of patients receives thrombopoietic receptor-agonists (TPO-RAs) but such treatments are not curative and therefore do not necessarily prevent from considering splenectomy in the course of ITP. TPO-RAs increase platelet production by inducing proliferation and differentiation of the megakaryocyte lineage. We have only very few data evaluating the impact of TPO-RAs, on mean platelet life span (MPLS), platelet production and platelet site of destruction. The aim of this study was to assess these parameters and clinical outcome of patients treated with TPO-RAs who underwent kinetic study of autologous111Indium-oxinate-labelled platelet. Patients and Methods We carried out a retrospective study in the Ile de France region, between 2008 and 2016. Patients were retrospectively selected from a prospective clinical database at the Cellular Biology Department of Saint Louis Hospital. We selected adult patients with definite ITP according to the international criteria. The isotopic method used to study platelet lifespan was previously described. Analyses were based on the radioactivity accumulation slopes in the hepatic or splenic area. We excluded patients who had received less than 3Mbeq of 111In. Data from patients' medical charts were collected using the standardized form of the Referral Center for Adult ITP. Complete response (CR) and Response (R) were defined according to standardized international criteria: platelet count > 30x 109/L with at least a doubling of the baseline value or >100 x 109/L. Results of platelet kinetic study from patients treated with TPO-RAs were compared with those from patients receiving no treatments. Results Two hundred and fifty three adults ITP patients were included. At the time of platelet kinetic study, 24 patients (10 men/14 women) with a median age of 63 years [range: 22-83] were treated with TPO-RAs (romiplostim n= 10, eltrombopag n = 14) and 229 (81 men/148 women) had no treatment. Among the TPO-RAs treated patients, some also received low dose steroids (n=6), dapsone (n=1) or intravenous immunoglobulins (n=2) at least two weeks before the kinetic study. Three were newly diagnosed, 9 had persistent ITP and 12 chronic ITP. The median platelet count was 62 x109/L [range: 22-175], and 7 patients had a platelet count > 100 x109/L. The median Mean Platelet Life Span (MPLS) was reduced in both groups (1.44 day [range: 0.4-7.5] (normal: 7-10) in patients treated with TPO-RAs), but was significantly higher in untreated patients (2.3 day [0.4-11], p = 0.004). The median turnover platelets ratio was increased in both groups (48% per day [range: 11-173] in patients treated with TPO-RAs), but was significantly lower in untreated patients (30% per day [range: 0.8-247]). Ratio of platelet production was significantly increased in patients treated with TPO-RAs (median: 2, [range: 0.1-5.0]) compared with untreated patients (median: 0.84, [range: 0.1-85.0]). Repartition of the site of platelet sequestration was similar in the two groups, 12 (50%) patients treated with TPO-RAs had a splenic uptake, versus 112 (49.1%) in untreated patients, and 2 (20%) patients treated with TPO-RAs had an hepatic uptake versus 9 (3.9%) in untreated patients. A splenectomy was performed in 9 out of the 12 patients with a purely splenic sequestration. After a median follow-up of 26 months [range 0-53], 8 (88%) had achieved CR and 1 had relapsed 5 months after splenectomy. Conclusion Our study shows that despite an increase production and turnover of platelets due to the stimulation of the megakaryopoiesis by TPO-RAs, the MPLS was clearly reduced and the repartition of platelet sequestration was not modified in patients receiving these drugs. Moreover, it would seem that a purely splenic sequestration is also predictive of CR after splenectomy in this group of patients. More importantly platelet kinetic study can be used in patients treated with TPO-RAs to position the splenectomy in the therapeutic management. Disclosures No relevant conflicts of interest to declare.

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Long Term Discontinuation of Eltrombopag after Remission in Primary Immune Thrombocytopenia: 8-Year Follow-up Data from 15 Spanish Centers

Blood ◽

10.1182/blood-2019-129274 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2352-2352

Author(s):

Tomas Jose Gonzalez-Lopez ◽

Fernando Fernandez-Fuertes ◽

Maria Cristina Pascual Izquierdo ◽

Isabel Caparros ◽

Silvia Bernat ◽

...

Keyword(s):

Platelet Count ◽

Median Time ◽

Research Funding ◽

Immune Thrombocytopenia ◽

Previous Treatment ◽

Complete Response ◽

Platelet Response ◽

Platelet Counts

Background: Successful discontinuation of eltrombopag in certain immune thrombocytopenia (ITP) patients after complete response has already been demonstrated. However, the frequency of this phenomenon and type of candidate patients are still matter of discussion. Moreover, possibility of long term discontinuation responses is not clearly established. Methods: Here we retrospectively evaluated our whole cohort of 508 adult patients (aged 18 years or more) with primary ITP treated with eltrombopag included in the Spanish Eltrombopag Registry with a focus on the patients who achieved a durable (at least six months) platelet response after stopping eltrombopag. Successful discontinuation of eltrombopag (SDOE) was defined as those patients who reached remission and maintained platelet counts ≥ 50x109/l for at least 6 months in absence of eltrombopag or any rescue therapies administered. Long term discontinuation of eltrombopag (LTDOE) was defined as those patients who reached remission and maintained platelet counts ≥ 50x109/l for at least 36 months in the absence of eltrombopag or any rescue therapies administered. The study was approved by the Hospital Universitario de Burgos Ethics Committee and fulfilled Helsinki declaration standards. Results: While 37.4% of our patients relapsed of ITP with subsequent platelet count drop sometime during first six months of discontinuation of eltrombopag, a total of 74 patients (14.6%) were able to achieve SDOE. The median age of SDOE patients was 62 [range, 47-79] years. There were 47 women and 27 men. According to the standard definition, patients were allocated to newly diagnosed (n=17), persistent (n=15) and chronic (n=42) ITP groups. The median time from diagnosis to eltrombopag initiation was 31 [range, 4-104] months. The median number of previous therapies was 2 [range, 1-2], including splenectomy (14%), rituximab (18%) and romiplostim (12%). As expected, all patients but 1 achieved a complete response (platelet count ≥100 x 109/L) prior to eltrombopag discontinuation The median duration of eltrombopag treatment was 7 [range, 2-19] months. Reasons for eltrombopag discontinuation were: persistent response despite a reduction in dose over time (n=43), platelet count >400x109/L (n=16), aspartate aminotransferase elevation (n=5), diarrhea (n=4), thrombosis (n=3), patient's request (n=2) and other reasons (n=1). Analysis of these SDOE discontinued patients show that with a median follow-up of 55 [range, 29-79] months, 38 patients (51.3%) maintained treatment-free response 36 months after stopping eltrombopag with no need of additional ITP therapies (median time of eltrombopag discontinuation was 70 [range, 50-77] months).This condition is what we define now as LTDOE. Nevertheless, 36 patients relapsed beyond 6 months but before 36 months of eltrombopag discontinuation (median time of eltrombopag discontinuation was 10 [range,7 -22] months). Characteristics of LTDOE population were a median time since ITP diagnosis of 32 [range, 5-88] months with 15/38 patients having ITP <1 year. 9 patients (24%) were male and their median age was 50 [range, 37-64] years. They had received a median of only two previous treatment lines [range: 1-2 lines]. The median platelet count before starting eltrombopag was 19 x 109/L [range, 8-40]. Meanwhile, platelet count before eltrombopag stop was 218 x 109/L [range, 123-356]. The main characteristics (age, gender, duration of ITP, prior ITP lines, platelet count before starting eltrombopag, duration of eltrombopag treatment, and platelet count before eltrombopag withdrawal) of the 38 patients with LTDOE were compared with those of the SDOE cohort who did not achieve a LTDOE. Unfortunately, no predictive factors of LTDOE could be identified. Conclusion: Durable platelet response following eltrombopag cessation may be observed in only 15% of primary ITP patients treated with this drug. On the contrary, half of patients who achieve a sustained response after eltrombopag withdrawal will get a long term discontinuation. However, we are lacking predictor factors for successful and long-term discontinuation of eltrombopag in primary ITP. Disclosures Gonzalez-Lopez: Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Pascual Izquierdo:Novartis: Consultancy; Sanofi: Consultancy. Sánchez-González:Amgen: Consultancy, Speakers Bureau; Gilead: Speakers Bureau; Navartis: Consultancy, Speakers Bureau; Shire: Speakers Bureau; Takeda: Consultancy, Speakers Bureau. Jarque:Takeda: Consultancy, Speakers Bureau; Shire: Consultancy, Speakers Bureau; Shionogi: Consultancy, Speakers Bureau; Servier: Speakers Bureau; Roche: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Grifols: Consultancy; Gilead: Consultancy, Speakers Bureau; CellTrion: Consultancy; Celgene: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Abbie: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau.

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Platelet Survival and Platelet Production in Systemic Lupus Erythematosus (SLE)

10.1055/s-0039-1689624 ◽

1975 ◽

Author(s):

A.-L. Bergström ◽

J. Kutti

Keyword(s):

Systemic Lupus Erythematosus ◽

Platelet Count ◽

Life Span ◽

Lupus Erythematosus ◽

Control Group ◽

Healthy Male ◽

Systemic Lupus ◽

Platelet Production ◽

Platelet Survival ◽

The Mean

In 16 patients (3 males and 13 females) with SLE platelet survival and platelet production were determined. At the time of study 3 patients received no therapy, 10 were treated with corticosteroids, and the remaining 3 received corticosteroids and azathioprin. The control group consists of 21 healthy male volunteers. In all experiments autologous platelets labelled with 51Cr were employed.The mean peripheral platelet count for the SLE patients was 222,000/μl, range 122,000-347,000/μl. In this group the mean for platelet mean life span (MLS) was 6.8±0,3 (S. E.), range 5.5-9.7 days, and did not differ from the mean for the controls (6.9±0.3 days). In the SLE group the mean platelet turnover was 49,000 ±8,000/μl/day. The corresponding value for the controls was 43,000 ± 3,000/μl/day. The values for platelet MLS and platelet turnover in SLE patients were not related to given therapy.Previously it has been suggested that a state of compensated thrombocytolysis is present i SLE. Our results could, however, not confirm this.

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Autoimmune Thrombocytopenic Purpura Complicating Chronic Lymphocytic Leukemia: Analysis of 60 Patients.

Blood ◽

10.1182/blood.v108.11.4932.4932 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4932-4932

Author(s):

Carlo Visco ◽

Roberto Stasi ◽

Marco Ruggeri ◽

Achille Ambrosetti ◽

Stefania Fortuna ◽

...

Keyword(s):

Platelet Count ◽

Chronic Lymphocytic Leukemia ◽

Complete Response ◽

Lymphocytic Leukemia ◽

Severe Thrombocytopenia ◽

Short Term ◽

Thrombocytopenic Purpura ◽

Autoimmune Thrombocytopenic Purpura ◽

Cytotoxic Treatment ◽

The Impact

Abstract Autoimmune thrombocytopenic purpura (AITP) represents the autoimmune condition most frequently associated with chronic lymphocytic leukemia (CLL) after autoimmune haemolytic anemia. However, the main characteristics and outcome of AITP in the course of CLL, as well as the impact of this complication in the natural history of the tumor remain unknown. We identified 60 consecutive patients with CLL who developed AITP, representing 3,5% of CLL patients diagnosed in the three participating centers between 1995 and 2004. To be included in this study patients had to experience at least one episode of AITP, which was defined as the occurrence of acute and severe thrombocytopenia in the presence of normal or augmented number of megakariocytes in the bone marrow, without extensive lymphoid marrow infiltration, splenomegaly or recent cytotoxic treatment. A complete response (CR) to AITP treatment was defined by a platelet count > or = 150×10(9)/L, and a partial response (PR) by a platelet count > 50×10(9)/L or by an increase of at least twofold the initial level. Remaining patients were considered as no responders (NR). Median age of our 60 patients was 65 years (range 48–83) and 40 were males. At CLL presentation RAI stage was 0 to 2 in 88%, time to CLL treatment was 13,8 months (range 0–120), while first line treatment for CLL consisted of Chlorambucile alone (Chl) in 73% of patients with 18% of patients that received no treatment for their malignancy. Median overall survival was 57 months. AITP occurred concomitantly to CLL diagnosis in 13 patients (22%), while median time to AITP for remaining 47 patients was 30 months (range 2–147). The median platelet count at AITP diagnosis was 23 × 10(9)/L(range, 1–81). Twenty-five patients (42%) presented with moderate bleeding signs at AITP diagnosis, while 4 patients (7%) experienced severe hemorrhagic episodes, requiring hospitalization and blood transfusions. Fifty-two of the 60 patients (87%) received at least one treatment for AITP: 32 patients received i.v.Ig alone or in combination with steroids, leading to a short-term NR in 66% (CR 19%, PR 15%); nine patients underwent splenectomy and 7 (78%) experienced a durable CR; patients who were treated with chemotherapy (Chl, COP, CVP) +/− steroids had at least a PR in 73% of cases. With a median follow-up from AITP onset of 35 months, 17 of the 52 treated patients are still NR (33%) and 13 of them are on treatment. In our series of patients with CLL and AITP we observed an unexpectedly short survival regardless of a large prevalence of low RAI stages at diagnosis. Treatment of AITP with i.v. Ig +/− steroids leaded to a low rate of short-term responses, while splenectomy and chemotherapy seemed sufficiently adequate therapeutic approaches.

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Effect of Pregnancy in Women with a History of Primary Immune Thrombocytopenia Considered As Cured

Blood ◽

10.1182/blood.v128.22.2552.2552 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2552-2552

Author(s):

Thibault Comont ◽

Guillaume Moulis ◽

Karen Delavigne ◽

Pierre Cougoul ◽

Olivier Parant ◽

...

Keyword(s):

Platelet Count ◽

Complete Remission ◽

Epidural Analgesia ◽

Pregnant Women ◽

Immune Thrombocytopenia ◽

Specific Treatment ◽

Severe Bleeding ◽

Adult Women ◽

History Of ◽

The Impact

Abstract Immune thrombocytopenia (ITP) is an autoimmune disease that occurs in young women. Pregnancy is a well-known risk factor for developing newly diagnosed ITP as well as for inducing disease flares in patients with current ITP. However, the impact of pregnancy in women with an old history of ITP, considered as cured, has not been assessed. The aim of this study was to describe the course of ITP in pregnant women with an ITP in complete remission (platelets count >100x109/L and absence of bleeding symptoms) for at least 5 years without any ITP treatment. We retrospectively selected all pregnant women with delivery at Toulouse University Hospital, South of France, between 2010 and 2015 with a hospital discharge code of ITP (international classification of diseases; version 10 code D69.3). This code has a sensitivity of 81.2% and a positive predictive value of 89.8% in this database. All medical charts were reviewed to confirm the diagnosis of ITP. We included adult women (≥18 years) with a diagnosis of primary ITP according to French guidelines (platelet count <150 x 109 /L and exclusion of other causes of thrombocytopenia, especially other causes of thrombocytopenia during pregnancy) in complete remission for at least 5 years. We identified 50 pregnancies in 39 ITP patients during the study period. Eleven pregnancies occurred in 10 patients in long-term complete remission of ITP at the time of pregnancy onset. Baseline characteristics were: median age at ITP diagnosis: 21 years (range: 4-29); median age at pregnancy onset:32 years (range: 26-34; history of ITP during a previous pregnancy: 1; history of bleeding: 4 (36.4%); previous treatment for ITP: 8 (72.7%), corticosteroids-CS (5), CS and intravenously immunoglobulin-IVIg (3), splenectomy (4), dapsone (1); last median platelet count before pregnancy: 170x109/L (range: 118-363). Platelets count decreased below 100x109/L in 3 pregnancies (27.2%) from the first trimester for one patient, from the second trimester for one other and from the third trimester for the last one, with a nadir of 3, 39 and 87 (x109/L) respectively. One of them experienced a severe bleeding (grade 3 according to the International Working Group bleeding classification). All thrombocytopenic patients required treatment during pregnancy: CS+IVIg for 2 (one for bleeding and one to allow epidural analgesia) and IVIg for the other (to allow epidural analgesia). For these 3 women, the median platelet count at delivery was 128 (range: 38-159) and consequently only 2 of them could have epidural analgesia. No bleeding during delivery was observed. Transient thrombocytopenia occurred in 2 newborns. Primary ITP considered as cured may relapse during pregnancy and may induce severe bleeding requiring specific treatment. A tight monitoring should be proposed to all pregnant women with a history of primary ITP, even after several years of complete remission. Disclosures Récher: Celgene, Sunesis, Amgen, Novartis, Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Thrombopoietin Receptor Agonist Use, Efficacy and Toxicity in Children with Immune Thrombocytopenia: Data from an Italian Multicenter Survey

Blood ◽

10.1182/blood-2018-99-110652 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4997-4997

Author(s):

Paola Giordano ◽

Giuseppe Lassandro ◽

Marco Spinelli ◽

Momcilo Jancovic ◽

Paola Saracco ◽

...

Keyword(s):

Platelet Count ◽

Immune Thrombocytopenia ◽

Conflicts Of Interest ◽

Immunosuppressive Agents ◽

Real Life ◽

Complete Response ◽

Clinical Use ◽

First Line ◽

Thrombopoietin Receptor ◽

Multicenter Survey

Abstract Background: Immune Thrombocytopenia (ITP) is one of the most common conditions encoutered by the pediatric hematologist. Current first-line therapy includes: observation without drug therapy, corticosteroids and intravenous immune globulin. A minority of patients are refractory to first-line approaches. Second-line treatment options are: immunosuppressive agents and thrombopoietin receptor agonists (TPO-RA). Eltrombopag and Romiplostin are TPO-RA licensed for clinical use. Eltrombopag is, actually, the only TPO-RA approved in Italy (since two years ago) for children, over one year old, with a chronic and/or refractory ITP. Real life data of Eltrombopag are limited. Methods: We performed an Italian multicenter retrospective survey to study the clinical on-label use of TPO-RA, focus on Eltrombopag, in pediatric ITP. Our aims were, primarily, to bring out the prevalence of the use in clinical practice and secondarily to collect data on efficacy and toxicity. Results: We enrolled 69 pediatric ITP subjects from 15 Italian treatment centers (TC). 4 patients received Romiplostin as TPO-RA and were excluded by the analysis. 36/65 patients weer female (55%). Median age at ITP diagnosis: 6 years + 6 months (min 1 y + 2 m; max 16 y + 7 m). Median age at first Eltrombopag assumption: 11 years + 5 months (min 2 y + 0 m; max 17 y + 8 m). Accounting in 344 the total number of chronic ITP subjects treated by TC in the same observation period (July 2016-June 2018), we observed an Eltrombopag clinical use prevalence of 0.19 (95% CI 0.15 to 0.26). We underlined a "no response" to Eltrombopag (platelet count persistently less than 30000 per microliter) in 16/65 (25%); a "partial response" (platelet count between 30000 and 100000 per microliter) in 14/65 (21%) and a "complete response" (platelet count persistently up than 100000 per microliter) in 35/65 (54%). The overall response (partial or complete) was described in 49/65 (75%) children. During the follow up was seen in 16/49 (33%) subjects with initial response a platelet rise that waned to no response. There was no evidence of significant adverse events (clinicians are obliged, to monthly surveillance, by Italian drug agency for hypertransaminasemia and peripheral smear cell abnormalities). Conclusions: Our results demonstrate that Eltrombopag is a therapeutic option quite considered by Italian clinicians. Moreover, according with the percentages of clinical trials, Eltrombopag is safe and effective to rise platelet count. Further studies need to emphasize how factors favor a complete response and to know the incidence of long-term adverse effects. A prospective study designed and driven by Italian Association of Pediatric Hematology Oncology (AIEOP) Coagulation Disorders Working Group is, already, in progress. Disclosures No relevant conflicts of interest to declare.

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Analysis of Interleukin-4 in Thrombocytopenia Autoimmune Patients

Biomedika ◽

10.31001/biomedika.v13i2.708 ◽

2021 ◽

Vol 13 (2) ◽

pp. 131-135

Author(s):

Sitti Nurfaizah ◽

Mansyur Arief ◽

Uleng Bahrun

Keyword(s):

Platelet Count ◽

Medical Records ◽

Immune Thrombocytopenia ◽

Interleukin 4 ◽

Subject Group ◽

Elisa Method ◽

Platelet Production ◽

Cytokine Levels ◽

Primary Immune Thrombocytopenia ◽

Loss Of Tolerance

Thrombocytopenia is a disease characterized by a decreased platelet count. Some of the causes are decreased platelet production, increased platelet use, such as due to infection, and autoimmune causes, namely the loss of tolerance of the immune system to self-antigens on the surface of the platelets and megakaryocytes marked with a platelet count <100,000 / μL and based on the pathomechanism classified as primary Immune Thrombocytopenia (ITP) and secondary, as well as several other causes. IL-4, one of the cytokines produced by Th2 which stimulates B cells to increase antibody production. The aim of this study was to compare IL-4 levels in primary ITP patients and non-primary ITP tombocytopenia. This study involved 30 primary ITP subjects and 30 non-ITP primary tombocytopenia subjects obtained based on data medical records, examination of IL-4 cytokine levels by the ELISA method. The results of this study that the IL-4 levels of the primary non ITP tombocytopenia subject group were higher than the primary ITP subject group, which means that there were differences in IL-4 levels in the primary ITP subject group and the non-ITP primary tombocytopenia subject group.

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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.

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Helicobacter pylori eradication affects platelet count recovery in immune thrombocytopenia

Scientific Reports ◽

10.1038/s41598-020-66460-5 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 1

Author(s):

Ayoung Lee ◽

Junshik Hong ◽

Hyunsoo Chung ◽

Youngil Koh ◽

Soo-Jeong Cho ◽

...

Keyword(s):

Helicobacter Pylori ◽

Platelet Count ◽

Immune Thrombocytopenia ◽

Complete Response ◽

Long Term Effects ◽

Infection Group ◽

Platelet Recovery ◽

First Line Therapy ◽

H Pylori ◽

Count Recovery

Abstract Helicobacter pylori (H. pylori) infection is on the rise as a cause of immune thrombocytopenia (ITP). It has been suggested that platelet recovery can be achieved following successful microbial eradication, although, the exact pathophysiology has yet to be fully elucidated. This study evaluated the long-term effects of H. pylori eradication monotherapy on platelet count recovery in patients with ITP. H. pylori eradication was analysed in 61 ITP patients. Patients who maintained a complete response (CR) for more than six months were classified as sustained responders (SR). The prevalence of H. pylori infection was 54.3% (75/138), and the success rate of eradication with first-line therapy was 71.4% (35/49). Patients who had achieved a CR at 2 months maintained a higher platelet count thereafter. At 1 year following eradication, platelet counts had increased 2.78 times in the eradicated group, 1.36 times in the sustained infection group, and 1.33 times in the no infection group compared with the baseline (P = 0.016).

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The Effect of Eltrombopag on Human Platelet Resistance to Apoptosis: The Role of the Bcl-Xl Pathway

Blood ◽

10.1182/blood.v116.21.2520.2520 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2520-2520

Author(s):

W. Beau Mitchell ◽

Michele N Edison ◽

Mariana P Pinheiro ◽

Nayla Boulad ◽

Bethan Psaila ◽

...

Keyword(s):

Platelet Count ◽

Life Span ◽

Signal Transduction Pathway ◽

Transduction Pathway ◽

Apoptotic Pathway ◽

Platelet Production ◽

Akt Activation ◽

Platelet Counts ◽

Ic50 Values ◽

Apoptotic Factors

Abstract Abstract 2520 Introduction: Immune thrombocytopenia (ITP) is typically characterized by increased platelet destruction and reduced platelet production. Eltrombopag is a thrombopoietin receptor (TPO-R) agonist that is known to increase platelet counts in patients with ITP by stimulating thrombopoiesis, but it is unknown whether it has any effect on platelet life span. Platelet survival is mediated by two molecular intermediates in an apoptotic pathway, Bcl-xL and Bak. Bcl-xL protein expression in megakaryocytes is thought to be regulated in part by TPO-mediated activation of Akt pathways through Jak2 and Stat5. Although controversial, in a very small number of ITP patients, Eltrombopag may increase platelet counts in 2–5 days. We hypothesized that any increase in platelet count in the first week of treatment might be due to effects of Eltrombopag on platelet survival. Therefore, this study explored whether Eltrombopag treatment has anti-apoptotic effects in patients with ITP. Methods: Following a treatment wash out period, 75 mg of Eltrombopag once daily was initiated for 2 weeks. Blood counts were measured on days 1, 3, 5, 8, 10, 12, and 15. Platelet function and survival was assessed on days 1, 8, and 15 by: immature platelet fraction (IPF); glycocalicin index; Bcl-xL inhibitor (ABT-737) IC50, a novel assay adapted for human platelets; measurement of Bcl-xL by western blot; measurement of several members of the Bcl-xL Akt mediated, apoptotic pathway by flow cytometry (FACS); bleeding score; measurement of thrombin-anti-thrombin complexes (TATs); and quantification of microparticles. Results: Seven of the 9 patients responded to treatment with Eltrombopag with a platelet count ≥ 50,000/μL, and 6 of the 7 responders at least doubled their counts during the 2 weeks of treatment. There was a significant increase in median platelet count (p<0.001), median large platelet count (p<0.01), and median absolute IPF (A-IPF, p<0.01), while there was a significant decrease in median % IPF (p<0.05). The dose of ABT-737 required to kill half of the platelets in the sample (IC50) did not differ significantly between patients or between patients and controls during the first two weeks of treatment, and remained stable over the 2 weeks of study. However, the relative IC50 values (% of day 1 IC50 value) increased after the first week of treatment but returned to baseline after the second week. While these changes were not significant, their kinetics were similar to those seen in the AKT/ Bcl-xL signal transduction pathway (Figure). There was no significant correlation between the platelet counts and the IC50 values. FACS analysis of members of the AKT signal transduction pathway revealed significant increase in each of the markers between days 1 and 8 (p<0.01), followed by a significant decrease between days 8 and 15 (p<0.05), with no difference between days 1 and 15 (Figure). The other lab tests are pending. Discussion: Because the A-IPF increased by less than the platelet increase and because the life span of the A-IPF is not known, it is unclear if the overall platelet count increase is entirely a result of increased platelet production. Platelet life span may be enhanced by Eltrombopag treatment as there was a parallel albeit transient increase in AKT activation markers and platelet apoptosis resistance. Our data suggest that platelets are more resistant to apoptosis when the levels of anti-apoptotic factors (eg. PTEN, Phospho-GSK3β) involved in the AKT/Bcl-xL pathway are greatest despite a concomitant increase in pro-apoptotic factors (eg. Bak, Bax). Since both increased AKT activation and apoptotic resistance returned to baseline at day 15, megakaryocytes and platelets already present at the start of treatment may respond differently than those generated de novo in the presence of Eltrombopag. Disclosures: No relevant conflicts of interest to declare.

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Results of the Russian Registry of Primary Immune Thrombocytopenia in Pediatric Patients

Blood ◽

10.1182/blood.v126.23.4643.4643 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4643-4643

Author(s):

Anastasia Shamardina ◽

Inna Markova ◽

Tatyana Sycheva ◽

Elena Volodicheva ◽

Alexander Rumyantsev ◽

...

Keyword(s):

Platelet Count ◽

Immune Thrombocytopenia ◽

Disease Onset ◽

Specific Treatment ◽

Complete Response ◽

Second Line ◽

Second Line Therapy ◽

Chronic Itp ◽

Line Therapy ◽

Clinically Significant

Abstract Study objectives We aim to evaluate disease characteristics and treatment practices of pediatric pts. with Immune thrombocytopenia (ITP) in Russia. Materials and methods The ITP Registry was a multicenter, prospective, observational cohort study. Inclusion criteria: diagnosis of primary ITP, informed consent of the patient/guardians. Exclusion criteria: secondary or congenital thrombocytopenia. Data from medical records were registered in the e-CRF in average every 3 months. Descriptive statistics were used. Patients were registered since June 2011 till June 2014. Results Ninety-three pediatric pts, 46 male (49.5%) and 47 female (50.5%) with a median age 8.4 yrs (range 0.5-17.8) from 5 centers in various regions of Russia were included. The mean observation period reached 17.1 ± 6.5 mo (range1.4 to 28.6 months). Seventy (75.3%) pts had acute and 24.7% pts had insidious disease onset. The presence of trigger factors for ITP development was found in more than half of the cases (in 61.3% of patients), they are listed in Table 1. Table 1. Triggers N % No triggers 36 38.7% Infection 46 49.5% Vaccination 8 8.6% Other 3 3.2% Total 93 100% Median disease duration at enrollment was 1.07 years (range 0 to 16.7 yrs). ITP duration shorter than 5 years at the enrollment was reported in 89.2% pts, up to 1 year - in 43 (46.2%), 1- 5 years - in 40 (43%), 5-10 years - in 8 (8.6%), >10 years - in 2 (2.2%) pts. Newly diagnosed ITP was reported in 35 (37.6 %) pts, persistent ITP - in 12 (12.9 %), chronic ITP - in 46 (49.5 %) pts.Median platelets count was 12,0 x 109/L (range 0.0 - 72.0 109/L). Ninety-two (98%) pts experienced hemorrhagic manifestations during the course of ITP: skin hemorrhages - in 98.9%, oral bleeding - in 15.1%, epistaxis - in 36.6%, gastrointestinal bleeding - in 1.1%, intracranial bleeding - in 1.1%, hematuria - in 1.1%, and other hemorrhages - in 9.7% of pts. Relationship between hemorrhagic syndrome and platelet count at the enrollment is provided in table 2. Table 2. Relationship between hemorrhagic syndrome and platelet count (at enrollment) Hemorrhage highest grade according to WHO Platelet count (visit 1) Total pts / % < 30,000 30,000 -50,000 >50,000 0 3 5.5% 3 5.5% 49 89.1% 55 100% 1 11 40.7% 5 18.5% 11 40.7% 27 100% 2 5 62.5% 0 0% 3 37.5% 8 100% 3 2 66.7% 1 33.3% 0 0% 3 100% Total 21 22,6% 9 9.7% 63 67.7% 93 100% Severe course of ITP after enrollment was observed in 12 (13%) pts (of whose 6 (6.5%) had clinically significant hemorrhage at the disease onset and 6 (6.5%) had new clinically significant hemorrhages during follow-up period. Refractory ITP at enrollment was reported in 9 (9.7%) pts and was associated with the resistance to the first-, second- and subsequent lines of therapy. At enrollment 42 (45.2%) pts received specific treatment for ITP. Before enrollment, splenectomy was reported in only 1 (1.1%) 14-years old patient who had a complete response. During the study, splenectomy was performed in 6 (6.6%) pts with chronic ITP; the duration of the disease at the time of splenectomy varied from 2 to 10 years, with average duration of 4.69 years (median - 4.5 years). Complete response to splenectomy was observed in 3 (50%) pts, a partial response - in 2 (33.3%), no response - in 1 (16.7%) patient. Loss of response to splenectomy was not reported. During the study, severe ITP was reported in 8 (8.7%) pts, 41 (44.6%) pt had various hemorrhagic manifestations of ITP at least at 1 visit, grade IV hemorrhagic syndrome was not reported. Thirty-eight (41%) pts received 1-st line treatment: glucocorticosteroids (GCS) - 23 (60.5%) pts, IVIG - 5 (13.2%), alfa-interferons -16 pts (42.1%). Twenty-three pts (24.7%) received second-line therapy: GCS - 1 (4.3%), IVIG -1 (4.3%), immunosupression - 1 (4.3%), rituximab - 2 (8.7%), romiplostim - 11 (47.8%), eltrombopag - 14 (60.9%). Conclusion For the first time new information on the features of the disease and patterns of management of pediatric pts with primary ITP in Russia was obtained in a prospective study. Interestingly, the preferred therapy for the 2nd or subsequent lines are TPO receptor agonists used outside the approved indications in research institutions, based on published clinical trial data. Splenectomy rate before and during the study was only 7.5% (7 pts) with chronic ITP; in 1 child (14.3%) splenectomy was ineffective. Low acceptance of splenectomy suggests TPO-mimetics as potential second-line therapy. In total, good disease control is achievable in the majority of pediatric pts with ITP. Disclosures Off Label Use: use of TPO-mimetics in children.

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