2,074 results on '"Receptors, Thrombopoietin"'
Search Results
2. The role of thrombopoietin receptor agonists in the management of adult primary immune thrombocytopenia: A single centre experience
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Virijević Marijana, Mitrović Mirjana, Pantić Nikola, Pravdić Zlatko, Sabljić Nikica, and Suvajdžić-Vuković Nada
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eltrombopag ,purpura, thrombocytopenic, idiopathic ,receptors, thrombopoietin ,romiplostim ,treatment outcome ,Medicine (General) ,R5-920 - Abstract
Background/Aim. The availability of thrombopoietin receptor agonists (TPO-RA) for treating primary immune thrombocytopenia (ITP) has transformed its management over the last decade. The aim of this study was to assess the efficacy of TPO-RA in adults with chronic ITP treated at the University Clinical Center of Serbia. Methods. A total of 28 adult ITP patients ( 10 m ales and 18 females), who were given eltrombopag and/or romiplostim, were enrolled in the study. Data on demographic characteristics, ITP duration, previous therapeutic modalities, comorbidities, concomitant therapy both for comorbidities and ITP, indications for TPO-RA, bleeding episodes before and during TPO-RA, TPO-RA doses, adverse events, and response rates were collected from the patients’ medical records. TPO-RAs were administered in patients with chronic refractory ITP when splenectomy was contraindicated/unfeasible and as preparation for splenectomy. Favorable treatment response was defined as a stable platelet count ≥ 50 × 109/L. Results. A total of 22 (78.57%) and 14 (50.0%) patients were treated with eltrombopag and romiplostim, respectively. A good treatment response (GTR) was achieved in 81.8% of the patients receiving eltrombopag and 71.4% of those treated with romiplostim. The non-responders to eltrombopag (4 patients) and those who had lost their response to eltrombopag (4 patients) were switched to romiplostim. Six of 8 patients achieved a GTR. At the time of TPO-RA initiation, 46.4% of the patients used concomitant ITP therapy, which was ceased in all those with a GTR. The following adverse effects of TPO-RA were registered: transaminitis and transient ischemic attack for eltrombopag – one patient each, and pulmonary embolism in one romiplostim-treated patient. Conclusion. Our study showed that TPO-RAs are an effective and safe treatment option since the majority of patients achieved stable remission without bleeding episodes.
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- 2022
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3. Management of refractory immune thrombocytopaenia in pregnancy
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Jessica M Heenan
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Adult ,Pediatrics ,medicine.medical_specialty ,medicine.medical_treatment ,Recombinant Fusion Proteins ,Receptors, Fc ,Refractory ,Pregnancy ,hemic and lymphatic diseases ,parasitic diseases ,medicine ,Humans ,Caesarean section ,Thrombopoietin ,Purpura, Thrombocytopenic, Idiopathic ,Romiplostim ,business.industry ,Cesarean Section ,Platelet Count ,Infant, Newborn ,General Medicine ,medicine.disease ,Thrombocytopenia, Neonatal Alloimmune ,Platelet transfusion ,Gestation ,Rituximab ,Female ,business ,Receptors, Thrombopoietin ,medicine.drug - Abstract
A 25-year-old woman with a history of immune thrombocytopaenia (ITP) in childhood was referred to haematology clinic for review with a platelet count of 50 μ/L at 9 weeks gestation, gravida 2, para 0. She developed progressive severe thrombocytopaenia as the pregnancy progressed, with associated bleeding complications. The thrombocytopaenia was refractory to standard therapies. This led to a need for a planned delivery, which was performed via caesarean section under general anaesthetic with platelet transfusion support, Intravenous Immune Globulin (IVIG), high-dose corticosteroid and the thrombopoietin (TPO) mimetic romiplostim. Both the mother and the neonate survived; however, the neonate required treatment for severe prolonged neonatal thrombocytopaenia. The patient subsequently re-presented 15 months later with recurrent ITP complicating another pregnancy, refractory to rituximab but responsive to romiplostim. She had a successful elective caesarean section under epidural anaesthesia, but the neonate once again suffered severe thrombocytopaenia, which was responsive to IVIG.
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- 2023
4. Antithrombotic and hemostatic stewardship: Evaluation of romiplostim for treatment of thrombocytopenia at a large academic medical center.
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Wong A, Ahuja T, Cirrone F, and Xiang E
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- Adult, Humans, Fibrinolytic Agents, Receptors, Thrombopoietin, Receptors, Fc therapeutic use, Thrombopoietin therapeutic use, Recombinant Fusion Proteins adverse effects, Academic Medical Centers, Treatment Outcome, Hemostatics therapeutic use, Purpura, Thrombocytopenic, Idiopathic drug therapy, Thrombocytopenia drug therapy, Thrombocytopenia chemically induced
- Abstract
Romiplostim is indicated for immune thrombocytopenia (ITP), though is often used off-label for other indications such as chemotherapy-induced thrombocytopenia (CIT) and thrombocytopenia post hematopoietic stem cell transplantation (HSCT). Although romiplostim is FDA approved at a starting dose of 1 mcg/kg, it is often initiated at 2-4 mcg/kg depending on the severity of thrombocytopenia in clinical practice. Given the limited data, but interest in higher doses of romiplostim for indications other than ITP, we aimed to assess our inpatient romiplostim utilization at NYU Langone Health.This was a single-center, retrospective review of 84 adult patients from January 2019 to July 2021. The top three indications were ITP (51, 60.7%), CIT (13, 15.5%), and HSCT (10, 11.9%). The median initial romiplostim dose was 3.8 mcg/kg (range, 0.9-10.8). 51% of patients achieved a platelet count of ≥50 × 10
9 /L by the end of week 1 of therapy. For patients achieving goal platelets by the end of week 1, the median dose of romiplostim was 2.4 mcg/kg (range, 0.9-10.8). There was 1 episode of thrombosis and 1 episode of stroke.We found that higher than FDA-recommended initial doses should be considered to achieve a platelet response. It appears to be safe to initiate romiplostim as higher doses, and to increase doses by greater increments than 1 mcg/kg in order to achieve a platelet response. Future prospective studies are needed to confirm the safety and efficacy of romiplostim in off-label indications and should evaluate clinical outcomes such as bleeding and need for transfusions., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.- Published
- 2024
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5. Long-term eltrombopag in children with chronic immune thrombocytopenia: A single-centre extended real-life observational study in China.
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Wang Z, Wang N, Juntao O, Ma J, Dong S, Meng J, Liu J, Chen Z, Cheng X, and Wu R
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- Male, Humans, Child, Retrospective Studies, Treatment Outcome, Receptors, Thrombopoietin, Hydrazines therapeutic use, Benzoates therapeutic use, China, Purpura, Thrombocytopenic, Idiopathic drug therapy, Pyrazoles
- Abstract
We have previously confirmed the efficacy and safety of eltrombopag (ELT) in children with chronic immune thrombocytopenia (cITP). However, data on both long-term exposure and early use of TPO-RAs are lacking, so further 'field-practice' evidence on treatment is required. Here, we report the long-term follow-up results (between September 2018 and June 2023) of our previous study. The main objective of this study was to retrospectively review our large institutional experience with ITP patients previously enrolled in our paediatric cITP study. We had more than 3 years of follow-up by June 2023 for treatment patterns and outcomes. A total of 65 patients (28 males) were enrolled, with a median age at ELT initiation of 6.34 (range 1.65, 14.13) years and a follow-up of 47.07 (36.00, 57.00) months, with 40.36 (10.53, 56.83) months of ELT therapy at the time of analysis. In total, 29.23% (19/65) of patients discontinued ELT due to stable response, and 18.46% (12/65) of patients switched to other ITP therapies due to loss of response (LOR) after 19.13 (14.53, 26.37) months. Of the 19 patients who discontinued ELT due to a stable response, 24.62% (16/65) achieved a 12 m sustained response off-treatment (SRoT); the last recorded platelet count ranged from 56 to 166 × 10
9 /L (median 107 × 109/L); and 4.62% (3/65) patients relapsed at 5, 6 and 9 months after discontinuation. Of the 12 patients who LOR to ELT after 19.13 (14.53, 26.37) months of therapy, four switched to avatrombopag, three switched to hetrombopag, two switched to traditional Chinese medicine (TCM), one underwent splenectomy and two received additional prednisolone under ELT treatment. Thirty-four patients who tapered and maintained a durable response. The patients with LOR and the patients with tapering were compared; the platelet count at the start of ELT is lower, and the time to response is longer in the patients with LOR. The platelet count at the start of ELT and the time to response may be the predictive factors for LOR during ELT treatment. We report more than 3 years of long-term clinical data on children with cITP using ELT. These data do not raise any new safety concerns regarding the long-term use of ELT in children with cITP., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)- Published
- 2024
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6. Detection of Rehabilitation Training Effect of Upper Limb Movement Disorder Based on MPL-CNN.
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Shi L, Wang R, Zhao J, Zhang J, and Kuang Z
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- Humans, Upper Extremity physiology, Hand, Movement physiology, Treatment Outcome, Recovery of Function physiology, Receptors, Thrombopoietin, Stroke Rehabilitation, Stroke, Movement Disorders
- Abstract
Stroke represents a medical emergency and can lead to the development of movement disorders such as abnormal muscle tone, limited range of motion, or abnormalities in coordination and balance. In order to help stroke patients recover as soon as possible, rehabilitation training methods employ various movement modes such as ordinary movements and joint reactions to induce active reactions in the limbs and gradually restore normal functions. Rehabilitation effect evaluation can help physicians understand the rehabilitation needs of different patients, determine effective treatment methods and strategies, and improve treatment efficiency. In order to achieve real-time and accuracy of action detection, this article uses Mediapipe's action detection algorithm and proposes a model based on MPL-CNN. Mediapipe can be used to identify key point features of the patient's upper limbs and simultaneously identify key point features of the hand. In order to detect the effect of rehabilitation training for upper limb movement disorders, LSTM and CNN are combined to form a new LSTM-CNN model, which is used to identify the action features of upper limb rehabilitation training extracted by Medipipe. The MPL-CNN model can effectively identify the accuracy of rehabilitation movements during upper limb rehabilitation training for stroke patients. In order to ensure the scientific validity and unified standards of rehabilitation training movements, this article employs the postures in the Fugl-Meyer Upper Limb Rehabilitation Training Functional Assessment Form (FMA) and establishes an FMA upper limb rehabilitation data set for experimental verification. Experimental results show that in each stage of the Fugl-Meyer upper limb rehabilitation training evaluation effect detection, the MPL-CNN-based method's recognition accuracy of upper limb rehabilitation training actions reached 95%. At the same time, the average accuracy rate of various upper limb rehabilitation training actions reaches 97.54%. This shows that the model is highly robust across different action categories and proves that the MPL-CNN model is an effective and feasible solution. This method based on MPL-CNN can provide a high-precision detection method for the evaluation of rehabilitation effects of upper limb movement disorders after stroke, helping clinicians in evaluating the patient's rehabilitation progress and adjusting the rehabilitation plan based on the evaluation results. This will help improve the personalization and precision of rehabilitation treatment and promote patient recovery.
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- 2024
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7. Treatment patterns and outcomes of second-line rituximab and thrombopoietin receptor agonists in adult immune thrombocytopenia: A Canadian retrospective cohort study
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John Podstawka, Erika Wall, Lauren Bolster, Jeffery M. Patterson, M. Dawn Goodyear, Natalia Rydz, and Haowei L. Sun
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Adult ,Purpura, Thrombocytopenic, Idiopathic ,Canada ,Recombinant Fusion Proteins ,Hemorrhage ,Receptors, Fc ,Hematology ,Thrombocytopenia ,Hydrazines ,Thrombopoietin ,Chronic Disease ,Humans ,Rituximab ,Receptors, Thrombopoietin ,Intracranial Hemorrhages ,Retrospective Studies - Abstract
The optimal choice of second-line treatment for immune thrombocytopenia (ITP) is unclear. Guidelines recommend either rituximab, splenectomy, or thrombopoietin receptor agonists (TPO-RA). There is, however, scarce data comparing treatment patterns, outcomes and resource utilization across second-line treatments. Despite Canada's universal healthcare system, publicly funded access to second-line ITP therapies is highly variable across provinces/territories.To describe treatment patterns and compare health service utilization and outcomes among recipients of second-line rituximab and TPO-RA for ITP.In this multicentre retrospective cohort study, we included adults who received second-line ITP therapies rituximab, eltrombopag and romiplostim (2012-2020) in Alberta, Canada. Patients were identified through a provincially-funded special drug access (STEDT) program. We examined treatment patterns, predictors of second-line treatment, hospitalizations, blood product utilization, and outcomes. Kaplan-Meier survival curves were used to estimate the cumulative incidence of ITP-related hospitalizations (bleeding or infections), overall survival (OS) and relapse-free survival (RFS). Cox proportional hazards regression was used to examine the impact of second-line therapy on OS.223 patients received rituximab (67 %), eltrombopag (29 %), and romiplostim (4 %). TPO-RA recipients experienced significantly longer time from ITP diagnosis to second-line therapy compared with rituximab recipients (15.9 vs 6.7 months, P 0.0001), accompanied by significantly higher platelet and IVIG utilization prior to second-line therapy. Age (adjusted odds ratio [aOR] 1.04, 95 % CI 1.02-1.07, P 0.0001) and prior intracranial hemorrhage (aOR 12.7, 95 % CI 1.6-272.8, P = 0.03) were significant predictors of second-line TPO-RA. TPO-RA is associated with a trend towards longer median RFS (6.3 vs 3.8 years, P = 0.06) compared with rituximab, and similar rates of ITP-related hospitalizations, major bleeding, and thromboembolism. Age, time period, and Charlson comorbidity index, but not second-line ITP therapy, were significant predictors of OS.Our study identified older age and intracranial hemorrhage as predictors of second-line TPO-RA prescription in a real-world practice. There were no significant differences in hospitalizations and outcomes between second-line rituximab and TPO-RA, although delayed initiation of TPO-RA was associated with higher blood product utilization.
- Published
- 2022
8. Whole-genome CRISPR screening identifies N-glycosylation as a genetic and therapeutic vulnerability in CALR-mutant MPNs
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Jonas S. Jutzi, Anna E. Marneth, Michele Ciboddo, Angel Guerra-Moreno, María José Jiménez-Santos, Anastasia Kosmidou, James W. Dressman, Hongyan Liang, Rebecca Hamel, Patricia Lozano, Elisa Rumi, John G. Doench, Jason Gotlib, Anandi Krishnan, Shannon Elf, Fátima Al-Shahrour, and Ann Mullally
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Glycosylation ,Myeloproliferative Disorders ,Immunology ,Cell Biology ,Hematology ,Janus Kinase 2 ,Biochemistry ,Mice ,Glucose ,Mutation ,Animals ,Humans ,Clustered Regularly Interspaced Short Palindromic Repeats ,Blood Commentary ,Calreticulin ,Receptors, Thrombopoietin - Abstract
Calreticulin (CALR) mutations are frequent, disease-initiating events in myeloproliferative neoplasms (MPNs). Although the biological mechanism by which CALR mutations cause MPNs has been elucidated, there currently are no clonally selective therapies for CALR-mutant MPNs. To identify unique genetic dependencies in CALR-mutant MPNs, we performed a whole-genome clustered regularly interspaced short palindromic repeats (CRISPR) knockout depletion screen in mutant CALR-transformed hematopoietic cells. We found that genes in the N-glycosylation pathway (among others) were differentially depleted in mutant CALR-transformed cells as compared with control cells. Using a focused pharmacological in vitro screen targeting unique vulnerabilities uncovered in the CRISPR screen, we found that chemical inhibition of N-glycosylation impaired the growth of mutant CALR-transformed cells, through a reduction in MPL cell surface expression. We treated Calr-mutant knockin mice with the N-glycosylation inhibitor 2-deoxy-glucose (2-DG) and found a preferential sensitivity of Calr-mutant cells to 2-DG as compared with wild-type cells and normalization of key MPNs disease features. To validate our findings in primary human cells, we performed megakaryocyte colony-forming unit (CFU-MK) assays. We found that N-glycosylation inhibition significantly reduced CFU-MK formation in patient-derived CALR-mutant bone marrow as compared with bone marrow derived from healthy donors. In aggregate, our findings advance the development of clonally selective treatments for CALR-mutant MPNs.
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- 2022
9. Generation of a thrombopoietin‐deficient thrombocytopenia model in zebrafish
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Lian Yang, Liangliang Wu, Panpan Meng, Xuebing Zhang, Dejian Zhao, Qing Lin, and Yiyue Zhang
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Disease Models, Animal ,Thrombopoietin ,Animals ,Humans ,Hematology ,Receptors, Thrombopoietin ,Thrombocytopenia ,Zebrafish ,Thrombopoiesis - Abstract
The production of platelets is tightly regulated by thrombopoietin (THPO). Mutations in the THPO gene cause thrombocytopenia. Although mice lacking Thpo present with thrombocytopenia, predicting phenotypes and pathogenicity of novel THPO mutations in mice is limited. Zebrafish can be a powerful tool for fast validation and study of candidate genes of human hematological diseases and have already been used as a model of human thrombocytopenia.We aim to investigate the role of Thpo in zebrafish thrombopoiesis and to establish a Thpo-deficient zebrafish model. The model could be applied for illustrating the clinically discovered human THPO variants of which the clinical significance is not known and to evaluate the effect of THPO receptor agonists (THPO-Ras), as well as a screening platform for new drugs.We generated a thpo loss-of-function zebrafish model using CRISPR/Cas9. After disruption of zebrafish thpo, thpoZebrafish with the mutation thpo
- Published
- 2022
10. Pharmacokinetic Assessment and Treatment Effect of Lusutrombopag in Child–Pugh Class C Patients: Review of Patient Data from Two Clinical Studies and Post-Marketing Surveillance
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Steven L, Flamm, Markus, Peck-Radosavljevic, Takahiro, Fukuhara, Roy, Bentley, Takayuki, Katsube, Toshimitsu, Ochiai, Takeshi, Kano, Eri, Tsukimura, Ritsue, Sasaki, and Yukio, Osaki
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Thiazoles ,Pharmaceutical Preparations ,Cinnamates ,Liver Diseases ,Product Surveillance, Postmarketing ,Humans ,Pharmacology (medical) ,General Medicine ,Receptors, Thrombopoietin ,Thrombocytopenia - Abstract
Patients with thrombocytopenia and chronic liver disease are at increased risk of bleeding during invasive procedures due to low platelet counts. Lusutrombopag, an orally active thrombopoietin receptor agonist, increases platelet count and reduces the need for platelet transfusion in chronic liver disease patients with thrombocytopenia undergoing a planned invasive procedure. The safety of lusutrombopag in patients with Child-Pugh class C chronic liver disease is not known. The present analysis was performed to determine the pharmacokinetics, efficacy, and safety of lusutrombopag in patients with Child-Pugh class C chronic liver disease.Data for patients with Child-Pugh class C chronic liver disease were collected from three data sets: a phase 1/2 Child-Pugh class C study (n = 5) (JapicCTI-163289 [Japan Pharmaceutical Information Center]), a phase 3 pivotal study (L-PLUS 2, n = 3) (NCT02389621 [Clinicaltrials.gov]), and ongoing post-marketing surveillance (n = 27) (JapicCTI-163432 [Japan Pharmaceutical Information Center]). Patients received lusutrombopag at 3 mg for up to 7 days. Safety and efficacy assessments were collected from two clinical studies and the post-marketing surveillance; pharmacokinetic data were collected from the phase 1/2 study.Mean CThe analysis presented in this study suggests that lusutrombopag increases platelet counts in Child-Pugh class C patients and is safe and well tolerated in this patient population.L-PLUS 2: NCT02389621 (Clinicaltrials.gov). Phase 1/2: JapicCTI-163289 (Japan Pharmaceutical Information Center [JAPIC]). Post-marketing surveillance: JapicCTI-163432 (JAPIC).
- Published
- 2022
11. Oncogenic CALR mutant C-terminus mediates dual binding to the thrombopoietin receptor triggering complex dimerization and activation
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Nicolas Papadopoulos, Audrey Nédélec, Allison Derenne, Teodor Asvadur Şulea, Christian Pecquet, Ilyas Chachoua, Gaëlle Vertenoeil, Thomas Tilmant, Andrei-Jose Petrescu, Gabriel Mazzucchelli, Bogdan I. Iorga, Didier Vertommen, Stefan N. Constantinescu, and UCL - SSS/DDUV/SIGN - Cell signalling
- Subjects
Myeloproliferative Disorders ,Multidisciplinary ,Mutation ,Humans ,General Physics and Astronomy ,General Chemistry ,Janus Kinase 2 ,Calreticulin ,Frameshift Mutation ,Dimerization ,Receptors, Thrombopoietin ,General Biochemistry, Genetics and Molecular Biology - Abstract
Calreticulin (CALR) frameshift mutations represent the second cause of myeloproliferative neoplasms (MPN). In healthy cells, CALR transiently and non-specifically interacts with immature N-glycosylated proteins through its N-terminal domain. Conversely, CALR frameshift mutants turn into rogue cytokines by stably and specifically interacting with the Thrombopoietin Receptor (TpoR), inducing its constitutive activation. Here, we identify the basis of the acquired specificity of CALR mutants for TpoR and define the mechanisms by which complex formation triggers TpoR dimerization and activation. Our work reveals that CALR mutant C-terminus unmasks CALR N-terminal domain, rendering it more accessible to bind immature N-glycans on TpoR. We further find that the basic mutant C-terminus is partially α-helical and define how its α-helical segment concomitantly binds acidic patches of TpoR extracellular domain and induces dimerization of both CALR mutant and TpoR. Finally, we propose a model of the tetrameric TpoR-CALR mutant complex and identify potentially targetable sites.
- Published
- 2023
12. Thrombopoietin receptor agonist for treating bone marrow aplasia following anti-CD19 CAR-T cells—single-center experience
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Ofrat Beyar-Katz, Chava Perry, Yael Bar On, Odelia Amit, Odit Gutwein, Ofir Wolach, Rotem Kedar, Oleg Pikovsky, Irit Avivi, Ronit Gold, Jonathan Ben-Ezra, David Shasha, Ronen Ben Ami, and Ron Ram
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Adult ,Receptors, Chimeric Antigen ,T-Lymphocytes ,Antigens, CD19 ,Anemia, Aplastic ,Hematology ,General Medicine ,Thrombocytopenia ,Thrombopoietin ,Bone Marrow ,Hematologic Agents ,Humans ,Lymphoma, Large B-Cell, Diffuse ,Receptors, Thrombopoietin ,Aged - Abstract
Anti CD-19 chimeric antigen receptor T (CAR-T) cells demonstrate effective early anti-tumor response; however, impaired hematopoietic recovery is observed in about 30% of patients with prolonged cytopenia appearing as an unmet need for optimal treatment. All adult patients given commercially available anti CD-19 CAR-T for diffuse large B cell lymphoma (DLBCL) were screened at 21-28 days after CAR-T infusion for cytopenia. In case of severe persistent cytopenia, patients were given TPO receptor agonists. Initial dose of eltrombopag was 50 mg/day and gradually increased to a maximal dose of 150 mg/day. Romiplostim was given as subcutaneous injection once a week for 2 doses (125 mcg). Response was defined as transfusion independency along with resolution of severe neutropenia (ANC 500 /microL) and/or platelets 20,000/microL for three consecutive values on different days. TPO receptor agonists were tapered down when response was met. From May 2019 to December 2021, 93 patients were eligible (74%, tisagenlecleucel and 26%, axicabtagene ciloleucel). The median age was 69 (range, 19-85) years. Six patients (6.5%) (tisagenlecleucel, n = 4 or axicabtagene ciloleucel, n = 2) demonstrated prolonged severe cytopenia and were treated with TPO receptor agonists (eltrombopag, n = 4; romiplastim, n = 1, both drugs, n = 1). Median time from CAR-T infusion to initiation of TPO receptor agonist was 43 (range, 21-55) days. All patients were transfusion-dependent and were given daily GCSF prior to TPO receptor agonist administration. Response to TPO receptor agonists was seen in all 6 patients. Median time from TPO receptor agonist initiation to resolution of cytopenia was 22 (range, 8-124) days for Hb, 27 (range, 6-38) days for platelets, and 29 (range, 7-61) days for neutrophils. A complete resolution of all blood counts (ANC 500 /microL and platelets 20,000/microL and hemoglobin 8 gr/dL) was seen in 5/6 patients. No toxicity was observed during the therapy course. This paper supports further investigation of TPO receptor agonists in the treatment of persistent cytopenia following CAR-T cell therapy.
- Published
- 2022
13. Tapering of the thrombopoietin receptor agonist in paediatric patients with chronic immune thrombocytopenia: Is it possible?
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María Solsona, Rubén Berrueco, Elena Sebastián, Áurea Cervera, Ana Sastre, Itziar Astigarraga, Bienvenida Argilés, María Ángeles Dasí, José Luís Dapena, and Emilio Monteagudo
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Blood Platelets ,Pharmacology ,Purpura, Thrombocytopenic, Idiopathic ,Platelet Count ,Recombinant Fusion Proteins ,Receptors, Fc ,Benzoates ,Hydrazines ,Thrombopoietin ,Hematologic Agents ,Humans ,Pyrazoles ,Pharmacology (medical) ,Child ,Receptors, Thrombopoietin - Abstract
It is not clear if platelet responses are sustained after thrombopoietin receptor agonist (ar-TPO) withdrawal in paediatric patients. A multicentre retrospective observational study was performed in children with chronic immune thrombopenia (cITP) to describe ar-TPO tapering and withdrawal in patients who had achieved a sustained complete response to ar-TPOs. Ten patients (eltrombopag n = 6, romiplostim n = 4) were included. Treatment withdrawal was performed after a mean tapering time of 7.6 months. Two patients relapsed (median follow-up time of 24 months). Slow tapering and withdrawal of ar-TPOs can be safely performed in cITP paediatric patients after achieving a sustained complete response.
- Published
- 2022
14. Investigational drugs for immune thrombocytopenia
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Drew, Provan and Adrian C, Newland
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Pharmacology ,Purpura, Thrombocytopenic, Idiopathic ,Complement Inactivating Agents ,Thrombopoietin ,Recombinant Fusion Proteins ,Receptors, IgG ,Humans ,Pharmacology (medical) ,Drugs, Investigational ,General Medicine ,Receptors, Thrombopoietin - Abstract
Primary immune thrombocytopenia (ITP) is an acquired autoimmune disease of unknown cause. Autoantibodies, self-reactive T cells and other immune abnormalities, with impairment of platelet production, lead to a reduced platelet count. Until recently, therapy was largely empirical using immune suppressants (none of which have undergone randomized clinical trials). These therapies have variable efficacy and are associated with predictable unwanted effects which impact patient quality-of-life. With greater understanding of the underlying pathophysiology, better, more targeted therapies have been developed; however, there is still an urgent need for additional classes of treatment.This article covers new TPO receptor agonists, Syk inhibitors, Fcγ receptor antagonists, BTK and complement inhibitors, and other therapies. Insights into the most promising therapies are offered. Novel ITP treatments currently in clinical trials and those recently approved come under the spotlight.Thrombopoietin receptor agonists remain the most effective treatment for ITP and have changed the ITP therapeutic landscape remarkably. Other new molecules such as Fcγ receptor blockers, Bruton tyrosine kinase, complement inhibitors, and others are unlikely to enjoy the same success rate as the TPO-RAs, but nonetheless they will find a place in the management of patients with ITP.
- Published
- 2022
15. Clinical and molecular characteristics of acute myeloid leukemia with MPL mutation
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Yu Chen, Jundan Xie, Zhen Shen, Jie Shi, Suning Chen, and Gang Wang
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Leukemia, Myeloid, Acute ,Myeloproliferative Disorders ,Myelodysplastic Syndromes ,hemic and lymphatic diseases ,Mutation ,Humans ,Hematology ,Prognosis ,Myelodysplastic-Myeloproliferative Diseases ,Receptors, Thrombopoietin ,Retrospective Studies - Abstract
The current study aimed to explore the incidence of MPL mutations and the clinical and molecular characteristics of AML with MPL mutation. In total, 1509 patients with newly diagnosed AML were retrospectively analyzed between January 2017 and December 2020. MPL mutations were detected via next-generation sequencing. During the same period, we also enrolled 30 patients with other myeloid neoplasms (MNs) with MPL mutation, which included myelodysplastic syndrome (n = 15), myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) (n = 6), and MPN (n = 9). The clinical characteristics of MPL-mutated AML and other types of MNs or MPL-wide type (MPL-wt) AML were compared, and the spectrum of co-mutations and MPL mutation profiles in MPL-mutated AML were analyzed. MPL mutations were identified in 19 (1.26%) of 1509 patients with AML. The waterfall diagram showed that the co-mutations were mainly epigenetic modifications (TET2, IDH1, and EZH2), spliceosomes (SRSF2), and transcription factors (RUNX1). The platelet count of the AML group was significantly lower than that of the MPN group (p = 0.001). MPL mutations were commonly observed in the intracellular region in AML but the transmembrane region in MPN (p = 0.013). The MPL-mutated AML group had a lower white blood cell count and a lower rate of complete remission than the MPL wild-type AML group (p = 0.037). MPL mutations are clinically relevant in patients with AML, and they may be a novel subtype characterized by lower white blood cell counts and poor complete remission rates. However, further studies must be conducted to identify its correlated mechanism.
- Published
- 2022
16. Rituximab, methotrexate, procarbazine and lomustine (R-MPL) for the treatment of primary Central nervous system lymphoma
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Eyal Lebel, Neta Goldschmidt, Tali Siegal, Alexander Lossos, Shai Rosenberg, Chen Makranz, Eduard Linetski, Moshe E. Gatt, Alexander Gural, Revital Saban, David Lavie, Vladimir Vainstein, Eran Zimran, Batia Avni, Sigal Grisaro, Adir Shaulov, and Boaz Nachmias
- Subjects
Central Nervous System ,Cancer Research ,Lymphoma ,Cytarabine ,Hematology ,Middle Aged ,Central Nervous System Neoplasms ,Methotrexate ,Oncology ,Lomustine ,Procarbazine ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Rituximab ,Receptors, Thrombopoietin - Abstract
The optimal high-dose methotrexate (HDMTX)-based combination therapy for primary central nervous system lymphoma is unknown. We report our experience with rituximab, HDMTX, procarbazine and lomustine (R-MPL) given as first-line treatment in our center. Fifty-two patients between 2006 and 2019 were included. Eighteen patients proceeded to autologous transplant or two cycles of intermediate-dose cytarabine. The median age was 62 y (range 28-94) and the Eastern Cooperative Oncology Group performance status (ECOG-PS) was ≥2 in 62% (32/52). The overall/complete response rates were 79% (41/52) and 52% (27/52), respectively. The median progression-free/overall survival was 19 m/84m, respectively. Grade 3-4 adverse events included infections (17%) and kidney injury (13%). Ten patients (19%) discontinued therapy for toxicity. There were no treatment-related deaths. In summary, in a cohort enriched in frail patients, R-MPL achieved good responses and OS and was safe for all ages. The PFS was sub-optimal, possibly explained by a low proportion of consolidation. This regimen should be evaluated prospectively.
- Published
- 2022
17. Study of CALR, MPL, and c-kit Gene Mutations in Thai Patients with JAK2 V617F Negative Myeloproliferative Neoplasms
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Kriangpol, Wiriyaukaradecha, Supanee, Nimsanor, Nithiphut, Tantirukdham, Jin, Tongsom, Chakrit, Bunyoo, Kamonwan, Soonklang, Narongrit, Sritana, and Chirayu, Auewarakul
- Subjects
Proto-Oncogene Proteins c-kit ,Myeloproliferative Disorders ,Neoplasms ,Mutation ,Humans ,General Medicine ,Janus Kinase 2 ,Calreticulin ,Thailand ,Receptors, Thrombopoietin ,Retrospective Studies ,Thrombocythemia, Essential - Abstract
The aim of this study to determine the prevalence of CALR, MPL and c-kit gene mutations in JAK2 V617F negative-MPN patients.The retrospective study of CALR, MPL and c-kit mutations were analyzed in 113 samples collected from March 2010 to May 2017 and identified as JAK2 V617F-negative MPN Thai patients. The samples were analysis by gel electrophoresis and direct sequencing.28.3% of JAK2 V617F-negative MPN patients showed CALR gene mutations. Within the MPN patients with CALR mutation, 46.9% were classified as essential thrombocythemia (ET) and 20.9% were classified as primary myelofibrosis (PMF). Previous studies classified CALR mutations into three types using negatively charged amino acid stretches at the C-terminal domain. Type 1-like mutations were observed in 12 of 49 (24.5%) ET patients and type 2-like mutations were observed in 10 of 49 (20.4%) patients. In addition, 8 of 43 (18.6%) PMF patients showed type 1-like mutations and 1 of 43 (2.3%) showed type 2-like CALR mutation. Interestingly, platelet counts were higher in patients with CALR gene mutation than in patients without CALR gene mutation. MPL mutations (W515K and W515L) were identified in 2 of 109 (1.8%) MPN patients; the MPL mutations were only found in ET patients, which was consistent with previous studies. We did not detect exon 17 c-kit mutation in JAK2-negative MPN patients but detected intronic single nucleotide polymorphisms at c.74,978 and c.75,255 in these samples. Approximately 66% of patients did not have mutations in CALR and MPL genes, in addition to lacking JAK2 gene mutation, and these cases are classified as triple-mutations.Our results showed that 66% of cases were triple-negative mutation MPN because they lacked mutations in JAK2, CALR and MPL genes. The frequencies of CALR and MPL mutation in this study are similar to other CALR and MPL patient data.
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- 2022
18. Treatment patterns of thrombopoietin receptor agonists among adults with primary immune thrombocytopenia: A Korean nationwide population-based study
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Ji Yun, Lee, Ju-Hyun, Lee, Sang-A, Kim, Koung Jin, Suh, Ji-Won, Kim, Se Hyun, Kim, Jeong-Ok, Lee, Jin Won, Kim, Yu Jung, Kim, Keun-Wook, Lee, Jee Hyun, Kim, Jong Seok, Lee, and Soo-Mee, Bang
- Subjects
Adult ,Male ,Purpura, Thrombocytopenic, Idiopathic ,Recombinant Fusion Proteins ,Infant, Newborn ,Infant ,Receptors, Fc ,Hematology ,Benzoates ,Thrombocytopenia ,Hydrazines ,Thrombopoietin ,Child, Preschool ,Splenectomy ,Humans ,Female ,Receptors, Thrombopoietin ,Retrospective Studies - Abstract
Thrombopoietin receptor agonists (TPO-RAs) are a reliable second-line immune thrombocytopenia (ITP) treatment. Despite an increase in use of TPO-RAs, the treatment pattern among adults with ITP is not well understood.From January 2015 to December 2018, ITP patients were identified using the Korean Health Insurance Review and Assessment Service database.Of the total 3885 adult patients with ITP, 1745 (44.9%) required treatment, with a median follow-up duration of 31.4 months (range, 0.1-59.8 months). Of these, 46.5% and 36.6% continued treatment for more than 6 months and more than 12 months, respectively. Corticosteroids were the most common first-line therapy. Of the treated patients, 83 (4.8%) received TPO-RAs (eltrombopag, 86.7%; romiplostim, 13.3%). The median age of the group treated with TPO-RAs was 62 years, 62.6% were female, and the median time from first diagnosis to initial TPO-RA treatment was 12.5 months (range, 0.4-48.0 months). A total of 52 (62.7%) patients received TPO-RAs as a second-line treatment for ITP. Splenectomy was performed in 19 patients (22.9%) before initiation of TPO-RAs. When clinical efficacy was analyzed before and during TPO-RA use, there was a significant decrease in platelet transfusion and a tendency toward reduced bleeding events.This population-based study is the first to describe the treatment pattern of TPO-RAs for ITP among patients in Korea.
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- 2022
19. Avatrombopag, a promising novel thrombopoietin receptor agonist for refractory/relapsed/intolerant non-severe aplastic anemia: a phase 2 single-arm clinical trial.
- Author
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Wan Z, Chen M, and Han B
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- Humans, Receptors, Thrombopoietin, Pyrazoles adverse effects, Anemia, Aplastic drug therapy
- Abstract
Introduction: The therapeutic options for thrombocytopenia in non-severe aplastic anaemia (NSAA) are limited. Avatrombopag (AVA) is prescribed for thrombocytopenic diseases but not for NSAA., Methods: Herein, we conducted a phase 2, non-randomized, single-arm trial to explore the efficacy and safety of AVA in refractory/relapsed/intolerant NSAA. AVA dose was initiated at 20 mg/d and titrated to a maximum of 60 mg/d. The primary endpoint was the haematological response at 3 months., Results: Twenty-five patients were analyzed. The overall response rate (ORR) at 3 months was 56% (14/25), with 12% (3/25) achieving a complete response (CR). At a median follow-up of 7 (3-10) months, the OR and CR rates were 52% and 20%, respectively. Responders had a shorter duration of diagnosis of AVA administration than non-responders (10 (6-80) vs 37 (6-480) months, p = 0.027) and belonged to the relapsed/intolerant NSAA type (71% vs 27%, p = 0.047); 44% (8/18) patients previously treated with eltrombopag before enrollment responded at 3 months, with an average prior eltrombopag dose of median 72.5 (50-100) mg/d and an average AVA dose for a response of median 43.5 (20-60) mg/d. 3-month ORR had no significant correlation with eltrombopag exposure ( p = 0.09), prior eltrombopag length ( R
2 =0.11), or cumulative eltrombopag dose ( R2 =0.30). Only one patient relapsed after stopping AVA for 1 month. No serious AVA-related side effects or clone evolution were detected., Conclusion: AVA is effective and well-tolerated in NSAA patients who are refractory, relapsed, or intolerant to CsA/tacrolimus ± eltrombopag. Earlier treatment and relapsed/intolerant AA may show a better short-term response rate. More studies are needed to define the optimal dose and the long-term efficacy (NCT04728789).- Published
- 2023
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20. Assessment of intestinal status in MPL W515L mutant myeloproliferative neoplasms mice model.
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Zhu S, Xu K, Li S, Yu X, Liu Y, Zhang Q, Zeng L, Xu K, and Fu C
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- Humans, Animals, Mice, Mutation, Signal Transduction, Disease Models, Animal, Janus Kinase 2 metabolism, Inflammation, Calreticulin genetics, Calreticulin metabolism, Receptors, Thrombopoietin, Neoplasms, Myeloproliferative Disorders
- Abstract
The MPL
W515L mutation is a prevalent genetic mutation in patients with myeloproliferative neoplasms (MPN), and utilizing this mutation in mice model can provide important insights into the disease. However, the relationship between intestinal homeostasis and MPN mice model remains elusive. In this study, we utilized a retroviral vector to transfect hematopoietic stem cells with the MPLW515L mutation, creating mutated MPN mice model to investigate their intestinal status. Our results revealed that the MPLW515L in MPN mice model aggravated inflammation in the intestines, decreased the levels of tight junction proteins and receptors for bacteria metabolites. Additionally, there was increased activation of the caspase1/IL-1β signaling pathway and a significant reduction in phos-p38 levels in the intestinal tissue in MPN mice. The MPLW515L mutation also led to up-expression of anti-microbial genes in the intestinal tract. Though the mutation had no impact on the alpha diversity and dominant bacterial taxa, it did influence the rare bacterial taxa/sub-communities and consequently impacted intestinal homeostasis. Our findings demonstrate the significance of MPLW515L mice model for studying MPN disease and highlight the mutation's influence on intestinal homeostasis, including inflammation, activation of the IL-1β signaling pathway, and the composition of gut microbial communities., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)- Published
- 2023
- Full Text
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21. Hidden conformational codes.
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Lv K and Tong W
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- Humans, Receptors, Thrombopoietin, Janus Kinase 2
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- 2023
- Full Text
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22. Real-world experience of treatment with thrombopoietin receptor agonists in anti-thymocyte globulin-naïve patients with aplastic anemia: an observational retrospective analysis in a single institution
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Masaki Iino, Atsushi Jinguji, Ayato Nakadate, and Tomoya Sato
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Thrombopoietin Receptor Agonists ,business.industry ,Anemia, Aplastic ,Hematology ,medicine.disease ,Anti-thymocyte globulin ,Therapy naive ,Treatment Outcome ,Immunology ,Retrospective analysis ,Medicine ,Humans ,Observational study ,Single institution ,Aplastic anemia ,business ,Receptors, Thrombopoietin ,Aged ,Antilymphocyte Serum ,Retrospective Studies - Abstract
Thrombopoietin receptor agonists (TPO-RAs) are used to treat bone marrow failure in aplastic anemia (AA). Treatment with TPO-RAs, cyclosporine A (CsA) and anti-thymocyte globulin (ATG) induces remission and a sustained response. However, the efficacy of TPO-RAs without ATG remains unclear. We retrospectively assessed 45 patients with AA refractory to CsA and naïve for ATG treatment who received eltrombopag without ATG at our hospital during 2017-2021. Of these, 28 (62%) achieved a hematologic response in at least one lineage after six months of treatment, and 38 (84%) achieved best response at any point during the follow-up period. Four patients (25%) achieved trilineage responses during the follow-up period. Five patients switched from eltrombopag to romiplostim because of adverse events or lack of efficacy. Two developed hematologic malignancies. Eltrombopag was effective even in elderly ATG-ineligible patients with severe AA. The two-year overall survival rate was 84.3%, with a median follow-up of 26.3 months. Time from diagnosis to eltrombopag treatment initiation tended to affect the response (p = 0.0727), but no factors that significantly predicted hematologic response were identified. In conclusion, patients who are ineligible for ATG treatment because of age, complications, or even severe AA should nevertheless be considered for TPO-RA treatment.
- Published
- 2022
23. CAMK2G is identified as a novel therapeutic target for myelofibrosis
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Kazuki Taoka, Ken Sasaki, Yosuke Masamoto, Mineo Kurokawa, Masashi Miyauchi, Shunya Arai, Sho Yamazaki, Hideaki Mizuno, and Yuki Kagoya
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Effector ,Chemistry ,Therapeutic effect ,Bone Marrow Cells ,Hematology ,Berbamine ,medicine.disease ,Mice ,chemistry.chemical_compound ,Phenotype ,Primary Myelofibrosis ,Mutation ,medicine ,Cancer research ,Animals ,Humans ,Leukocytosis ,medicine.symptom ,Signal transduction ,Calcium-Calmodulin-Dependent Protein Kinase Type 2 ,Myelofibrosis ,Protein kinase A ,Induced pluripotent stem cell ,Receptors, Thrombopoietin - Abstract
Although JAK1/2 inhibition is effective in alleviating symptoms of myelofibrosis (MF), it does not result in the eradication of MF clones, which can lead to inhibitor-resistant clones emerging during the treatment. Here, we established induced pluripotent stem cells (iPSCs) derived from MF patient samples (MF-iPSCs) harboring JAK2 V617F, CALR type 1, or CALR type 2 mutations. We demonstrated that these cells faithfully recapitulate the drug sensitivity of the disease. These cells were used for chemical screening, and calcium/calmodulin-dependent protein kinase 2 (CAMK2) was identified as a promising therapeutic target. MF model cells and mice induced by MPL W515L, another type of mutation recurrently detected in MF patients, were used to elucidate the therapeutic potential of CAMK2 inhibition. CAMK2 inhibition was effective against JAK2 inhibitor-sensitive and JAK2 inhibitor-resistant cells. Further research revealed CAMK2 γ subtype was important in MF model cells induced by MPL W515L. We showed that CAMK2G hetero knockout in the primary bone marrow cells expressing MPL W515L decreased colony-forming capacity. CAMK2G inhibition with berbamine, a CAMK2G inhibitor, significantly prolonged survival and reduced disease phenotypes, such as splenomegaly and leukocytosis in a MF mouse model induced by MPL W515L. We investigated the molecular mechanisms underlying the therapeutic effect of CAMK2G inhibition and found that CAMK2G is activated by MPL signaling in MF model cells and is an effector in the MPL-JAK2 signaling pathway in these cells. These results indicate CAMK2G plays an important role in MF, and CAMK2G inhibition may be a novel therapeutic strategy that overcomes resistance to JAK1/2 inhibition.
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- 2022
24. Adults with immune thrombocytopenia who switched to avatrombopag following prior treatment with eltrombopag or romiplostim: A multicentre US study
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Hanny Al‐Samkari, Debbie Jiang, Terry Gernsheimer, Howard Liebman, Susie Lee, Matthew Wojdyla, Michael Vredenburg, and Adam Cuker
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Adult ,Purpura, Thrombocytopenic, Idiopathic ,Recombinant Fusion Proteins ,Receptors, Fc ,Thiophenes ,Hematology ,Benzoates ,Thrombocytopenia ,Thiazoles ,Hydrazines ,Thrombopoietin ,Humans ,Pyrazoles ,Receptors, Thrombopoietin - Abstract
Patients with immune thrombocytopenia (ITP) may respond to one thrombopoietin receptor agonist (TPO-RA) but not another. Limited data are available describing outcomes in patients who switched from romiplostim or eltrombopag to avatrombopag, a newer oral TPO-RA. We performed a retrospective observational study of adults with ITP who switched from eltrombopag or romiplostim to avatrombopag at four US tertiary ITP referral centres. Forty-four patients were included, with a mean ITP duration of 8.3 years and a median (range) of four prior ITP treatments. On avatrombopag, 41/44 patients (93%) achieved a platelet response (≥50 × 10
- Published
- 2022
25. Lusutrombopag has slightly stronger effects on patients with mild thrombocytopenia compared with those with severe thrombocytopenia: A multicenter propensity score matching study
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Yoshihiro Furuichi, Hirohito Takeuchi, Haruki Uojima, Masanori Atsukawa, Taeang Arai, Yoshitaka Arase, Makoto Kako, Hisashi Hidaka, and Takao Itoi
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Thiazoles ,Hepatology ,Cinnamates ,Humans ,Surgery ,Propensity Score ,Receptors, Thrombopoietin ,Thrombocytopenia - Abstract
Lusutrombopag effectively increases platelet count in patients with severe thrombocytopenia. However, no multicenter studies analyzing the effects of Lusutrombopag on patients with mild thrombocytopenia (platelet count 50 000/µL) have been performed. In this study, we aimed to clarify the efficacy of Lusutrombopag on these patients by unifying background factors by propensity score matching.A total of 139 patients with thrombocytopenia were enrolled, and matched for age, sex, etiology, disease, treatment, liver function, renal function, peripheral blood count, and spleen index. The primary endpoint was to compare the increase in platelet count from baseline between the high-platelet group (50 000/µL) and the low-platelet group (50 000/µL) after Lusutrombopag treatment, using propensity score matching. The secondary endpoint was to clarify platelet transfusion avoidance rate and adverse events, moreover, to identify independent predictors associated with the increase in platelet count.The mean increase in platelet count was 67 000/μL vs 48 000/μL in all patients (high- vs low-platelet group, P = .024), and 64 000/μL vs 48 000/μL (P = .12) after propensity score matching. The increase in platelet count and the platelet transfusion avoidance rate tended to be higher in the high-platelet group. There was no significant difference between adverse events. Predictors associated with an increase in platelet count were sex, estimated glomerular filtration rate, and spleen index by multivariate analysis.Lusutrombopag has a little stronger effect in patients with mild thrombocytopenia than those with severe thrombocytopenia and showed a more substantial effect in patients with impaired renal function and small spleen.
- Published
- 2022
26. Thrombopoietin receptor‐based protein–protein interaction screening (THROPPIS)
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Makiko Horikawa, Daiki Kashima, Kenichiro Ogawa, Yosuke Kakiuchi, and Masahiro Kawahara
- Subjects
Thrombopoietin receptor ,biology ,Chemistry ,Recombinant Fusion Proteins ,Bioengineering ,Type I cytokine receptor ,Applied Microbiology and Biotechnology ,Receptor tyrosine kinase ,Cell Line ,Cell biology ,Mice ,Insulin receptor ,Protein Interaction Mapping ,biology.protein ,Animals ,Protein–protein interaction screening ,Protein Interaction Domains and Motifs ,Epidermal growth factor receptor ,Signal transduction ,Receptor ,Receptors, Thrombopoietin ,Cell Proliferation ,Signal Transduction ,Biotechnology - Abstract
As protein-protein interactions (PPIs) are involved in many cellular events, development of mammalian cytosolic PPI detection systems is important for drug discovery as well as understanding biological phenomena. We have previously reported a c-kit-based PPI screening (KIPPIS) system, in which proteins of interest were fused with a receptor tyrosine kinase c-kit, leading to intracellular PPI-dependent cell growth. However, it has not been investigated whether PPI can be detected using other receptors. In this study, we employed a thrombopoietin receptor, which belongs to the Type I cytokine receptor family, to develop a thrombopoietin receptor-based PPI screening (THROPPIS) system. To improve the sensitivity of THROPPIS, we examined two strategies of (i) localization of the chimeric receptors on the cell membrane, and (ii) addition of a helper module to the chimeric receptors. Intriguingly, the nonlocalized chimeric receptor showed the best performance of THROPPIS. Furthermore, the addition of the helper module dramatically improved the detection sensitivity. In total, 5 peptide-domain interactions were detected successfully, demonstrating the versatility of THROPPIS. In addition, a peptide-domain interaction was detected even when insulin receptor or epidermal growth factor receptor was used as a signaling domain, demonstrating that this PPI detection system can be extended to other receptors.
- Published
- 2021
27. Efficacy and safety of thrombopoietin receptor agonists in the treatment of thrombocytopenia after hematopoietic stem cell transplantation: a meta-analysis and systematic review
- Author
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Yaqiong Tang, Xiaoyan Xu, Rui Zhang, Yue Han, Xueqian Li, Tingting Pan, Jiaqian Qi, and Yifang Yao
- Subjects
Blood Platelets ,Oncology ,medicine.medical_specialty ,Recombinant Fusion Proteins ,medicine.medical_treatment ,Eltrombopag ,Receptors, Fc ,Hematopoietic stem cell transplantation ,Benzoates ,chemistry.chemical_compound ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Adverse effect ,Survival rate ,Cause of death ,Romiplostim ,business.industry ,Recombinant Human Thrombopoietin ,Hematopoietic Stem Cell Transplantation ,Hematology ,Thrombocytopenia ,Recombinant Proteins ,chemistry ,Meta-analysis ,business ,Receptors, Thrombopoietin ,medicine.drug - Abstract
Thrombocytopenia is a tough complication after hematopoietic stem cell transplantation (HSCT) with elusive pathogenesis and lack of well-established therapies. Thrombopoietin receptor agonists (TPO-RAs) have been used for thrombocytopenia post HSCT in recent years, but the outcomes remain debatable. We conducted this meta-analysis and systematic-review to evaluate the efficacy and safety of TPO-RAs for platelet recovery after HSCT. We searched PubMed, EMBASE, and Cochrane databases for studies on the application of TPO-RAs (eltrombopag and romiplostim) in the settings of primary or secondary thrombocytopenia after HSCT by 17 March 2021. Efficacy outcomes included response rate and survival rate, and adverse events were also evaluated. A total of 19 studies involving 378 patients were included. The pooled response rate was 73% (95%CI: 68-78%), which was significantly higher than recombinant human thrombopoietin (rhTPO) (27.8%). The pooled survival rate was 66% (95%CI: 54-77%), and infection was found to be the main cause of death. In addition, the pooled rate of adverse events was 3% (95%CI: 1-7%), with no severe adverse events reported. TPO-RAs could effectively and safely promote the recovery of platelets in patients after HSCT.
- Published
- 2021
28. Effects of Lusutrombopag on Post-invasive Procedural Bleeding in Thrombocytopenic Patients with Chronic Liver Disease
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Masakazu Fujiwara, Yoshitake Kitanishi, Kosuke Iwasaki, Shinzo Hiroi, Tomomi Takeshima, Ataru Igarashi, Yoshie Hongo, Ryosuke Tateishi, and Manami Yoshida
- Subjects
medicine.medical_specialty ,Rescue for bleeding ,Real world data ,Adolescent ,Radiofrequency ablation ,Hemorrhage ,Chronic liver disease ,law.invention ,law ,Internal medicine ,Thrombopoietin receptor agonist ,medicine ,Humans ,Pharmacology (medical) ,Medical prescription ,Platelet transfusion ,Invasive Procedure ,Original Research ,business.industry ,Incidence (epidemiology) ,Liver Diseases ,General Medicine ,medicine.disease ,Thrombocytopenia ,Rheumatology ,Surgery ,Medical costs ,Thiazoles ,Cinnamates ,Liver cirrhosis ,Chronic Disease ,Length of stay ,business ,Receptors, Thrombopoietin ,Lusutrombopag - Abstract
Introduction Thrombocytopenia can increase the bleeding risk in patients with chronic liver disease (CLD) undergoing invasive procedures. Prophylactic platelet transfusion (PT) is often performed to increase platelet counts in patients with CLD undergoing invasive procedures to prevent bleeding. Lusutrombopag, a small-molecule thrombopoietin receptor agonist, is expected to be an alternative therapy to prophylactic PT. This study aimed to compare the effects between lusutrombopag and PT. Methods Data were obtained from a Japanese administrative database (April 2008–May 2019). Patients aged ≥ 18 years who underwent planned invasive procedures after the first CLD diagnosis and were observed for ≥ 30 days prior to invasive procedures were considered eligible. Patients who underwent planned invasive procedures with lusutrombopag prescription at 5–30 days before the procedure were categorized as the lusutrombopag group, whereas those who received PT at 1 day before and/or on the same day as the procedure, without lusutrombopag prescription, were classified as the PT group. Outcomes, including bleeding frequency during hospitalization and average medical costs (costs for prophylactic treatment and total costs between the day of the invasive procedure and 30 days after the invasive procedure), were compared between the groups after matching. Results Among 738,878 patients with CLD, 379 cases for each group were identified after matching. The incidence of bleeding events was lower in the lusutrombopag group than in the PT group (3.7% vs. 8.2%, p
- Published
- 2021
29. Avatrombopag: A Review in Thrombocytopenia
- Author
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Anthony Markham
- Subjects
Adult ,Excessive Bleeding ,medicine.medical_specialty ,Thiophenes ,Chronic liver disease ,Placebo ,Gastroenterology ,Adis Drug Evaluation ,Pharmacotherapy ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Animals ,Humans ,Pharmacology (medical) ,Platelet ,Thrombopoietin ,Purpura, Thrombocytopenic, Idiopathic ,business.industry ,Liver Diseases ,Correction ,medicine.disease ,Thrombocytopenia ,Clinical trial ,Thiazoles ,Platelet transfusion ,Chronic Disease ,business ,Receptors, Thrombopoietin - Abstract
Avatrombopag (Doptelet®) is an orally administered second generation thrombopoietin receptor agonist (TPO-RA) approved for the treatment of primary chronic immune thrombocytopenia (ITP) in adult patients who are refractory or have an unsatisfactory response to other treatments, as well as for the treatment of thrombocytopenia in adult patients with chronic liver disease (CLD) scheduled to undergo an invasive procedure. In phase III studies, avatrombopag was associated with a significantly greater platelet response than placebo in patients with chronic ITP, and was superior to placebo in reducing the requirement for platelet transfusion or rescue procedures for bleeding caused by surgery in patients with CLD with a platelet count, Plain Language Summary Avatrombopag (Doptelet®) is an orally administered drug that mimics the natural compound (thrombopoietin) responsible for stimulating the production of platelets, an essential component of the clotting process that prevents excessive bleeding. Several conditions can cause reduced platelet levels (thrombocytopenia) to the point that intervention is needed to prevent excessive blood loss. Avatrombopag is approved for the treatment of primary chronic immune thrombocytopenia (ITP) and to prevent bleeding caused by surgery in patients with low platelet levels caused by chronic liver disease (CLD). Clinical trials in patients with ITP show that avatrombopag quickly increases platelet levels and that this increase is maintained in the longer term in many patients. Similarly, clinical trials in patients with low platelet levels because of CLD showed that giving avatrombopag prior to surgery reduced the need for platelet transfusions or rescue procedures for bleeding. Avatrombopag is thus a convenient and effective treatment for patients with chronic ITP and can prevent bleeding events in patients with CLD scheduled to undergo a procedure. In both indications avatrombopag offers a useful alternative to other available treatments. Supplementary Information The online version contains supplementary material available at 10.1007/s40265-021-01613-y.
- Published
- 2021
30. Splenectomy for primary immune thrombocytopenia revisited in the era of thrombopoietin receptor agonists: New insights for an old treatment
- Author
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Thibault Comont, Amandine Dernoncourt, Antoinette Perlat, Stéphane Cheze, Bernard Bonnotte, O. Souchaud-Debouverie, Pierre-Yves Jeandel, Bertrand Godeau, Jean-François Viallard, Jean-Christophe Lega, Delphine Gobert, Marc Michel, Mikael Ebbo, Corentin Orvain, Julie Graveleau, Antoine Dossier, Nathalie Costedoat-Chalumeau, Marc Ruivard, Louis Terriou, Arthur Mageau, CHU Henri Mondor, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de référence des cytopénies auto-immunes [CHU Mondor] (CeReCAI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université de Lille, CHU Lille, Hôpital de la Timone [CHU - APHM] (TIMONE), Aix Marseille Université (AMU), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Fédérations hospitalo-universitaires Grand Ouest Acute Leukemia [Angers] (FHU GOAL), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre hospitalier de Saint-Nazaire, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Institut d'Hématologie de Basse-Normandie (IHBN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université de Bourgogne (UB), Hôpital Sud [CHU Rennes], CHU Pontchaillou [Rennes], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Cochin [AP-HP], Hôpital l'Archet, Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nice (CHU Nice), CHU Amiens-Picardie, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Bernardo, Elizabeth, CHU Henri Mondor [Créteil], Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), and CHU Toulouse [Toulouse]
- Subjects
Adult ,Male ,Thrombopoietin Receptor Agonists ,medicine.medical_specialty ,medicine.medical_treatment ,Splenectomy ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Gastroenterology ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Internal medicine ,Humans ,Medicine ,Retrospective Studies ,Purpura, Thrombocytopenic, Idiopathic ,business.industry ,Retrospective cohort study ,Hematology ,Middle Aged ,Immune thrombocytopenia ,Treatment Outcome ,Curative treatment ,Sustained response ,Female ,Rituximab ,business ,Receptors, Thrombopoietin ,medicine.drug - Abstract
Although splenectomy is still considered the most effective curative treatment for immune thrombocytopenia (ITP), its use has significantly declined in the last decade, especially since the approval of thrombopoietin receptor agonists (TPO-RAs). The main objective of the study was to determine whether splenectomy was still as effective nowadays, particularly for patients with failure to respond to TPO-RAs. Our secondary objective was to assess, among patients who relapsed after splenectomy, the pattern of response to treatments used before splenectomy. This multicentre retrospective study involved adults who underwent splenectomy for ITP in France from 2011 to 2020. Response status was defined according to international criteria. We included 185 patients, 100 (54.1%) and 135 (73.0%) patients had received TPO-RAs and/or rituximab before the splenectomy. The median follow-up after splenectomy was 39.2 months [16.5-63.0]. Overall, 144 (77.8%) patients had an initial response and 23 (12.4%) experienced relapse during follow-up, for an overall sustained response of 65.4%, similar to that observed in the pre-TPO-RA era. Among patients who received at least one TPO-RA or rituximab before splenectomy, 92/151 (60.9%) had a sustained response. Six of 13 (46%) patients with previous lack of response to both TPO-RAs and rituximab had a sustained response to splenectomy. Among patients with relapse after splenectomy, 13/21 (61.2%) patients responded to one TPO-Ras that failed before splenectomy. In conclusion, splenectomy is still a relevant option for treating adult primary ITP not responding to TPO-RAs and rituximab. Patients with lack of response or with relapse after splenectomy should be re-challenged with TPO-RAs. This article is protected by copyright. All rights reserved.
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- 2021
31. Eltrombopag modulates the phenotypic evolution and potential immunomodulatory roles of monocytes/macrophages in immune thrombocytopenia
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Feifei, Yang, Hui, Zong, Feng, Li, Shulin, Luo, Xiuqun, Zhang, Yanli, Xu, and Xuezhong, Zhang
- Subjects
Purpura, Thrombocytopenic, Idiopathic ,Macrophages ,Recombinant Fusion Proteins ,Hematology ,General Medicine ,Benzoates ,Thrombocytopenia ,Monocytes ,Hydrazines ,Phenotype ,Thrombopoietin ,Humans ,Interleukin-4 ,Receptors, Thrombopoietin - Abstract
Primary immune thrombocytopenia (ITP) is an acquired autoimmune hemorrhagic disease. Loss of immune tolerance plays a crucial role in the pathogenesis of ITP. Monocytes and macrophages play an indispensable role in the pathophysiology of hematopoietic malignancies and have been implicated as key players in platelet destruction. Approximately 80% of adult patients with ITP exhibit corticosteroid treatment failure or become dependent, requiring novel therapy. Thrombopoietin (TPO) receptor agonists (TPO-RAs) have been used clinically to manage ITP effectively, however, little is known about the effect of TPO-RAs on monocyte and macrophage modulation in adult ITP. In this study, we investigated the phenotypic evolution and potential immunomodulatory roles of monocytes/macrophages in ITP patients receiving eltrombopag therapy. Results showed that the peripheral monocyte count positively correlated with IFN-γ/IL-4 ratio in ITP patients. Moreover, numerous phenotype-associated genes in ITP macrophages exhibited diverse responses, and ITP macrophages exhibited more M1-related characteristics. After eltrombopag therapy, the peripheral monocyte count and IFN-γ/IL-4 ratio significantly decreased in ITP patients. M1-related characteristics of ITP macrophages were partially reversed by eltrombopag. Therefore, this study revealed eltrombopag restored the monocyte dynamics and the associated Th1/Th2 imbalance, and partially reversed the M1-related characteristics of the ITP macrophages, which suggest the potential vital roles of TPO-RAs in regulating the monocyte/macrophage plasticity in ITP.
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- 2022
32. c-Mpl-del, a c-Mpl alternative splicing isoform, promotes AMKL progression and chemoresistance
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Fei Li, Yuanyan Xiong, Mo Yang, Peiling Chen, Jingkai Zhang, Qiong Wang, Miao Xu, Yiming Wang, Zuyong He, Xin Zhao, Junyu Huang, Xiaoqiong Gu, Li Zhang, Rui Sun, Xunsha Sun, Jingyao Li, Jinxin Ou, Ting Xu, Xueying Huang, Yange Cao, Xiaohong Ruby Xu, Danielle Karakas, June Li, Heyu Ni, and Qing Zhang
- Subjects
Cancer Research ,Immunology ,Cell Biology ,Alternative Splicing ,Mice ,Phosphatidylinositol 3-Kinases ,Cellular and Molecular Neuroscience ,Thrombopoietin ,Drug Resistance, Neoplasm ,Leukemia, Megakaryoblastic, Acute ,Animals ,Protein Isoforms ,Proto-Oncogene Proteins c-akt ,Receptors, Thrombopoietin - Abstract
Acute megakaryocytic leukemia (AMKL) is a clinically heterogeneous subtype of acute myeloid leukemia characterized by unrestricted megakaryoblast proliferation and poor prognosis. Thrombopoietin receptor c-Mpl is a primary regulator of megakaryopoeisis and a potent mitogenic receptor. Aberrant c-Mpl signaling has been implicated in a myriad of myeloid proliferative disorders, some of which can lead to AMKL, however, the role of c-Mpl in AMKL progression remains largely unexplored. Here, we identified increased expression of a c-Mpl alternative splicing isoform, c-Mpl-del, in AMKL patients. We found that c-Mpl-del expression was associated with enhanced AMKL cell proliferation and chemoresistance, and decreased survival in xenografted mice, while c-Mpl-del knockdown attenuated proliferation and restored apoptosis. Interestingly, we observed that c-Mpl-del exhibits preferential utilization of phosphorylated c-Mpl-del C-terminus Y607 and biased activation of PI3K/AKT pathway, which culminated in upregulation of GATA1 and downregulation of DDIT3-related apoptotic responses conducive to AMKL chemoresistance and proliferation. Thus, this study elucidates the critical roles of c-Mpl alternative splicing in AMKL progression and drug resistance, which may have important diagnostic and therapeutic implications for leukemia accelerated by c-Mpl-del overexpression.
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- 2022
33. Clinical and molecular predictors of fibrotic progression in essential thrombocythemia: A multicenter study involving 1607 patients
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Ayalew Tefferi, Elena Rossi, Naseema Gangat, Silvia Betti, Alessandro M. Vannucchi, Carmela Mannarelli, Chiara Paoli, Francesco Ramundo, Chiara Maccari, Giuseppe Gaetano Loscocco, Animesh Pardanani, Yamna Jadoon, Sara Ceglie, Paola Guglielmelli, Francesca Gesullo, and Valerio De Stefano
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,Risk category ,Young Adult ,Internal medicine ,medicine ,Humans ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Essential thrombocythemia ,Retrospective cohort study ,Hematology ,Variant allele ,Janus Kinase 2 ,Middle Aged ,Prognosis ,medicine.disease ,Fibrosis ,Multicenter study ,Mutation ,Cohort ,Disease Progression ,Female ,business ,Receptors, Thrombopoietin ,Thrombocythemia, Essential - Abstract
The current retrospective study involving a total of 1607 patients was designed to identify clinical and molecular variables that were predictive of inferior myelofibrosis-free survival (MFS) in WHO-defined essential thrombocythemia (ET), utilizing three independent patient cohorts: University of Florence, Italy (n = 718); Mayo Clinic, USA (n = 479) and Policlinico Gemelli, Catholic University, Rome, Italy (n = 410). The Florence patient cohort was first examined to identify independent risk factors for MFS, which included age > 60 years (HR 2.5, 95% CI 1.3-4.9), male sex (2.1, 1.2-3.9), palpable splenomegaly (2.1, 1.2-3.9), CALR 1/1-like or MPL mutation (3.4, 1.9-6.1) and JAK2V617F variant allele frequency > 35% (4.2, 1.6-10.8). Subsequently, an operational molecular risk category was developed and validated in the other two cohorts from Mayo Clinic and Rome: "high molecular risk" category included patients with JAK2V617F VAF >35%, CALR type 1/1-like or MPL mutations; all other driver mutation profiles were assigned to "low molecular risk" category. The former, compared to the latter molecular risk category, displayed significantly higher risk of fibrotic transformation: Florence cohort with respective fibrotic transformation risk rates of 8% vs. 1.2% at 10 years and 33% vs. 8% at 20 years (p
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- 2021
34. Eltrombopag treatment of patients with secondary immune thrombocytopenia: retrospective EHR analysis
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Adam Cuker, Lincy Geevarghese, Savita Nandal, Lincy S. Lal, Lisa Le, Pallavi Patwardhan, and Adrienne Landsteiner
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Adult ,Male ,medicine.medical_specialty ,Eltrombopag ,Hemorrhage ,Benzoates ,chemistry.chemical_compound ,Internal medicine ,medicine ,Electronic health records ,Humans ,Platelet ,Complete response ,Aged ,Retrospective Studies ,Purpura, Thrombocytopenic, Idiopathic ,Hematology ,Secondary immune thrombocytopenia ,business.industry ,Platelet Count ,Retrospective cohort study ,Platelet response ,Thrombosis ,General Medicine ,Hepatitis C ,Middle Aged ,medicine.disease ,Immune thrombocytopenia ,Discontinuation ,Retrospective study ,Hydrazines ,Treatment Outcome ,chemistry ,Pyrazoles ,Original Article ,Female ,business ,Receptors, Thrombopoietin - Abstract
Immune thrombocytopenia (ITP) may occur in isolation (primary) or in association with a predisposing condition (secondary ITP [sITP]). Eltrombopag is a well-studied treatment for primary ITP, but evidence is scarce for sITP. We evaluated real-world use of eltrombopag for sITP using electronic health records. Eligible patients had diagnoses of ITP and a qualifying predisposing condition, and eltrombopag treatment. We described patient characteristics, treatment patterns, platelet counts, and thrombotic and bleeding events. We identified 242 eligible patients; the most common predisposing conditions were hepatitis C and systemic lupus erythematosus. Average duration of eltrombopag treatment was 6.1 months. Most (81.4%) patients achieved a platelet count ≥ 30,000/µL at a mean of 0.70 months, 70.2% reached ≥ 50,000/µL at a mean of 0.95 months, and 47.1% achieved a complete response of > 100,000/µL at a mean of 1.43 months after eltrombopag initiation. At eltrombopag discontinuation, 105 patients (43%) experienced a treatment-free period for a mean 3.3 months. Bleeding events occurred with similar frequency before and during eltrombopag treatment whereas thrombotic events were less frequent during eltrombopag treatment. Our results suggest similar rates of platelet response with eltrombopag in patients with sITP as compared with primary ITP. In addition, a treatment-free period is possible for a substantial minority of patients. Supplementary Information The online version contains supplementary material available at 10.1007/s00277-021-04637-2.
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- 2021
35. In and out: Traffic and dynamics of thrombopoietin receptor
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Anita Roy, Saurabh Shrivastva, and Saadia Naseer
- Subjects
Golgi Apparatus ,Reviews ,Review ,myeloproliferation ,Biology ,Structure-Activity Relationship ,Megakaryocyte ,Drug Discovery ,medicine ,Animals ,Humans ,Thrombopoiesis ,Thrombopoietin ,TYK2 Kinase ,traffic ,Thrombopoietin receptor ,thrombopoietin receptor ,Hematopoietic stem cell ,Cell Biology ,Janus Kinase 2 ,Hematopoietic Stem Cells ,receptor dimerization ,Protein Transport ,Haematopoiesis ,medicine.anatomical_structure ,Gene Expression Regulation ,JAK2 ,Mutation ,Cancer research ,Molecular Medicine ,Disease Susceptibility ,Bone marrow ,Protein Multimerization ,Stem cell ,Calreticulin ,Receptors, Thrombopoietin ,Protein Binding ,Signal Transduction - Abstract
Thrombopoiesis had long been a challenging area of study due to the rarity of megakaryocyte precursors in the bone marrow and the incomplete understanding of its regulatory cytokines. A breakthrough was achieved in the early 1990s with the discovery of the thrombopoietin receptor (TpoR) and its ligand thrombopoietin (TPO). This accelerated research in thrombopoiesis, including the uncovering of the molecular basis of myeloproliferative neoplasms (MPN) and the advent of drugs to treat thrombocytopenic purpura. TpoR mutations affecting its membrane dynamics or transport were increasingly associated with pathologies such as MPN and thrombocytosis. It also became apparent that TpoR affected hematopoietic stem cell (HSC) quiescence while priming hematopoietic stem cells (HSCs) towards the megakaryocyte lineage. Thorough knowledge of TpoR surface localization, dimerization, dynamics and stability is therefore crucial to understanding thrombopoiesis and related pathologies. In this review, we will discuss the mechanisms of TpoR traffic. We will focus on the recent progress in TpoR membrane dynamics and highlight the areas that remain unexplored.
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- 2021
36. The use of genetic tests to diagnose and manage patients with myeloproliferative and myeloproliferative/myelodysplastic neoplasms, and related disorders
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Catherine Cargo, Mamta Garg, Adam J. Mead, Anna L. Godfrey, Nicholas C.P. Cross, and Paper, A British Society for Haematology Good Practice
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medicine.medical_specialty ,Receptor, Platelet-Derived Growth Factor alpha ,Oncogene Proteins, Fusion ,Mutation, Missense ,Severity of Illness Index ,Receptors, Colony-Stimulating Factor ,Humans ,Point Mutation ,Medicine ,Eosinophilia ,Genetic Testing ,mRNA Cleavage and Polyadenylation Factors ,Biological Products ,Myeloproliferative Disorders ,business.industry ,Disease Management ,Bone Marrow Examination ,Exons ,Hematology ,Janus Kinase 2 ,Prognosis ,Dermatology ,Clone Cells ,Proto-Oncogene Proteins c-kit ,Molecular Diagnostic Techniques ,Myelodysplastic Syndromes ,medicine.symptom ,Calreticulin ,business ,Receptors, Thrombopoietin ,Forecasting - Published
- 2021
37. Comparison of the effects between MPL and JAK2V617F on thrombosis and peripheral blood cell counts in patients with essential thrombocythemia: a meta-analysis
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Jing Ming, Richeng Quan, Yujin Li, Mingjing Wang, Ziqing Wang, Xueying Wang, Haiyan Xiao, Erpeng Yang, Xiao-Mei Hu, and Weiyi Liu
- Subjects
Blood cells ,medicine.medical_specialty ,MPL ,Mutation, Missense ,Essential thrombocythemia ,Cochrane Library ,Gastroenterology ,Risk Factors ,White blood cell ,Internal medicine ,medicine ,Humans ,Peripheral blood cell ,Platelet ,Prospective Studies ,JAK2V617F ,Retrospective Studies ,Hematology ,business.industry ,Thrombosis ,General Medicine ,Janus Kinase 2 ,medicine.disease ,Blood Cell Count ,Meta-analysis ,medicine.anatomical_structure ,Mutation ,Original Article ,business ,Receptors, Thrombopoietin ,Thrombocythemia, Essential - Abstract
To assess the effects between MPL and JAK2V617F on the thrombosis risk and peripheral blood cell counts in patients with essential thrombocythemia (ET), we identified eligible studies from PubMed, Embase, and the Cochrane Library. Seven studies were ultimately included in this meta-analysis. All studies reported the peripheral blood cell counts of ET patients, and three of them reported the eligible thrombotic events. In comparing the effect of MPL versus JAK2V617F on thrombosis, 1257 ET patients (73 MPL + and 1184 JAK2V617F +) were included. MPL-positive (MPL +) ET patients had a higher risk of thrombosis than JAK2V617F-positive (JAK2V617F +) ET patients [RR = 1.80 (1.08–3.01), P = 0.025]. And 3453 ET patients (138 MPL + and 3315 JAK2V617F +) were included in the comparison of peripheral blood cell counts. Platelet counts of MPL + ET patients were higher than that of JAK2V617F + ET patients [WMD = 81.18 (31.77–130.60), P = 0.001]. MPL + ET patients had lower hemoglobin [WMD = − 11.66 (− 14.32 to − 9.00), P = 0.000] and white blood cell counts [WMD = − 1.01 (− 1.47 to − 0.56), P = 0.000] than JAK2V617F + ET patients. These findings indicate that the MPL mutation is a high-risk factor for thrombosis in ET patients, and it may be rational to include MPL mutation in the revised IPSET as a criterion for thrombosis prediction scores. And given the differences in peripheral blood, it is necessary to further study whether MPL + ET patients differ from JAK2V617F + ET patients in bleeding and survival.
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- 2021
38. Risk factors of hospitalisation for thrombosis in adults with primary immune thrombocytopenia, including disease‐specific treatments: a French nationwide cohort study
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Agnès Sommet, Margaux Lafaurie, Mette Nørgaard, Charlotta Ekstrand, Bérangère Baricault, Shahram Bahmanyar, Julien Maquet, Christian Fynbo Christiansen, Maryse Lapeyre-Mestre, Marie Linder, Laurent Sailler, and Guillaume Moulis
- Subjects
Male ,pharmacoepidemiology ,medicine.medical_treatment ,Comorbidity ,corticosteroids ,Adrenal Cortex Hormones ,Risk Factors ,intravenous immunoglobulin ,hemic and lymphatic diseases ,education.field_of_study ,Hazard ratio ,Age Factors ,Immunoglobulins, Intravenous ,Hematology ,Middle Aged ,Combined Modality Therapy ,Hospitalization ,Venous thrombosis ,immune thrombocytopenia ,Cardiovascular Diseases ,Cohort ,Splenectomy ,Female ,France ,Receptors, Thrombopoietin ,Cohort study ,Adult ,medicine.medical_specialty ,Adolescent ,Population ,splenectomy ,Young Adult ,Sex Factors ,Internal medicine ,medicine ,Humans ,education ,thrombosis ,Aged ,Proportional Hazards Models ,Purpura, Thrombocytopenic, Idiopathic ,Proportional hazards model ,business.industry ,Thrombosis ,medicine.disease ,Thrombocytopenia ,Confidence interval ,thrombopoietin-receptor agonists ,Anemia, Hemolytic, Autoimmune ,business - Abstract
We aimed to assess the risk factors of venous thrombosis (VT) and arterial thrombosis (AT) in adults with primary immune thrombocytopenia (ITP), particularly in relation to treatments. The population comprised all incident primary ITP adults in France between 2009 and 2017 (FAITH cohort; NCT03429660) built in the national health database. Outcomes were the first hospitalisation for VT and AT. Multivariable Cox regression models included baseline risk factors, time-varying exposure to ITP drugs, splenectomy and to cardiovascular drugs. The cohort included 10 039 patients. A higher risk of hospitalisation for VT was observed with older age, history of VT, history of cancer, splenectomy [hazard ratio (HR) 3·23, 95% confidence interval (CI) 2·26-4·61], exposure to corticosteroids (HR 3·55, 95% CI 2·74-4·58), thrombopoietin-receptor agonists (TPO-RAs; HR 2·28, 95% CI 1·59-3·26) and intravenous immunoglobulin (IVIg; HR 2·10, 95% CI 1·43-3·06). A higher risk of hospitalisation for AT was observed with older age, male sex, a history of cardiovascular disease, splenectomy (HR 1·50, 95% CI 1·12-2·03), exposure to IVIg (HR 1·85, 95% CI 1·36-2·52) and TPO-RAs (HR 1·64, 95% CI 1·26-2·13). Rituximab was not associated with an increased risk. These findings help to estimate the risk of thrombosis in adult patients with ITP and to select treatment.
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- 2021
39. Hereditary thrombocytosis: the genetic landscape
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Mary Frances McMullin, Eun Young Han, and Mark Catherwood
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Thrombocytosis ,Janus kinase 2 ,biology ,Hematology ,Janus Kinase 2 ,medicine.disease ,Thrombopoietin ,Mutation ,biology.protein ,medicine ,Cancer research ,Humans ,Genetic Predisposition to Disease ,Receptors, Thrombopoietin ,Gelsolin - Published
- 2021
40. Romiplostim in children with newly diagnosed or persistent primary immune thrombocytopenia
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Thomas Kühne, Jane Hippenmeyer, Nichola Cooper, and John D. Grainger
- Subjects
medicine.medical_specialty ,Pediatrics ,Recombinant Fusion Proteins ,Eltrombopag ,Hemorrhage ,Review Article ,Receptors, Fc ,Disease ,Newly diagnosed ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Romiplostim ,Thrombopoietin receptor agonist ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Corticosteroids ,Humans ,Child ,Clinical Trials as Topic ,Purpura, Thrombocytopenic, Idiopathic ,Hematology ,business.industry ,Bleeding ,Disease Management ,General Medicine ,Immune thrombocytopenia ,Clinical trial ,Thrombopoietin ,chemistry ,030220 oncology & carcinogenesis ,Rituximab ,business ,Receptors, Thrombopoietin ,030215 immunology ,medicine.drug - Abstract
Immune thrombocytopenia (ITP) is a disease of heterogenous origin characterized by low platelet counts and an increased bleeding tendency. Three disease phases have been described: newly diagnosed (≤ 3 months after diagnosis), persistent (> 3–12 months after diagnosis), and chronic (> 12 months after diagnosis). The majority of children with ITP have short-lived disease and will not need treatment. For children with newly diagnosed ITP, who have increased bleeding symptoms, short courses of steroids are recommended. In children who do not respond to first-line treatment or who become steroid dependent, thrombopoietin receptor agonists (TPO-RAs) are recommended because of their efficacy and safety profiles. In this narrative review, we evaluate the available evidence on the use of the TPO-RA romiplostim to treat children with newly diagnosed or persistent ITP and identify data from five clinical trials, five real-world studies, and a case report. While the data are more limited for children with newly diagnosed ITP than for persistent ITP, the collective body of evidence suggests that romiplostim is efficacious in increasing platelet counts in children with newly diagnosed or persistent ITP and may result in long-lasting treatment-free responses in some patients. Furthermore, romiplostim was found to be well tolerated in the identified studies. Collectively, the data suggest that earlier treatment with romiplostim may help children to avoid the side effects associated with corticosteroid use and reduce the need for subsequent treatment.
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- 2021
41. Primary and secondary immune thrombocytopenia (ITP): Time for a rethink.
- Author
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González-López TJ, Provan D, Bárez A, Bernardo-Gutiérrez A, Bernat S, Martínez-Carballeira D, Jarque-Ramos I, Soto I, Jiménez-Bárcenas R, and Fernández-Fuertes F
- Subjects
- Adult, Humans, Platelet Count, Receptors, Thrombopoietin, Thrombopoietin therapeutic use, Purpura, Thrombocytopenic, Idiopathic diagnosis, Purpura, Thrombocytopenic, Idiopathic etiology, Purpura, Thrombocytopenic, Idiopathic therapy, Thrombocytopenia
- Abstract
There are not many publications that provide a holistic view of the management of primary and secondary ITP as a whole, reflecting the similarities and differences between the two. Given the lack of major clinical trials, we believe that comprehensive reviews are much needed to guide the diagnosis and treatment of ITP today. Therefore, our review addresses the contemporary diagnosis and treatment of ITP in adult patients. With respect to primary ITP we especially focus on establishing the management of ITP based on the different and successive lines of treatment. Life-threatening situations, "bridge therapy" to surgery or invasive procedures and refractory ITP are also comprehensively reviewed here. Secondary ITP is studied according to its pathogenesis by establishing three major differential groups: Immune Thrombocytopenia due to Central Defects, Immune Thrombocytopenia due to Blocked Differentiation and Immune Thrombocytopenia due to Defective Peripheral Immune Response. Here we provide an up-to-date snapshot of the current diagnosis and treatment of ITP, including a special interest in addressing rare causes of this disease in our daily clinical practice. The target population of this review is adult patients only and the target audience is medical professionals., Competing Interests: Declaration of Competing Interest Tomás José González-López has received research grants from Amgen and Novartis and speaker honoraria from Amgen, Novartis, Sobi, Grifols and Argenx. Drew Provan has received research support and honoraria from Amgen and Novartis and has acted as a consultant for UCB, MedImmune, Ono and Takeda. Dr. Jarque-Ramos reports consulting honorarium from Amgen, Novartis and Shionogi. Rest of authors declare no competing financial interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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- 2023
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42. Sustained response off treatment in eltrombopag for children with persistent/chronic primary immune thrombocytopenia: A multicentre observational retrospective study in China.
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Wang Z, Wang L, Liu Y, Meng J, Dong S, Ma J, Hu Y, Chen Z, Cheng X, and Wu R
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- Adult, Humans, Child, Retrospective Studies, Treatment Outcome, Receptors, Thrombopoietin, Benzoates, Hydrazines, China, Purpura, Thrombocytopenic, Idiopathic drug therapy, Purpura, Thrombocytopenic, Idiopathic chemically induced
- Abstract
Eltrombopag (ELT) is effective and safe in adult persistent/chronic immune thrombocytopenia (p/cITP); a proportion could achieve a sustained response off treatment (SRoT); however, data on children are lacking. We attempted to analyse SRoT of ELT in children with p/cITP in this study. A multicentre retrospective observational study was performed in November 2022 for children with p/cITP who used ELT alone for >2 months between January 2017 and November 2021. Clinical data of pre-, during and post-ELT were collected. SRoT was defined as maintaining a platelet count of ≥30 × 10
9 /L without rescue therapy for at least 6 months off ELT. There were 143 patients enrolled; 69.2% (99/143) achieved an overall response of 43.3% and 25.9% achieved complete response (CR) and response (R). Among the 35 patients analysed from whom ELT was withdrawn, 71.4% (25/35) showed SRoT after discontinuing ELT without additional ITP therapy, with a median follow-up of 0.94 (range, 0.53-3.8) years, equal to 17.5% (25/143) in all patients treated with ELT. Compared with the patients with relapse (n = 10), the SRoT patients (n = 25) had a higher rate of CR (80% [20/25] vs. 40% [4/10]), shorter interval time from initiation to taper (6.4 months vs. 9.4 months), longer time from taper to withdrawal (1.1 years vs. 0.3 years) and a longer duration of ELT treatment (1.6 years vs. 0.5 years) with p < 0.05. Patients who achieved CR could attain SRoT more easily (p = 0.02). ELT had a response in 69.2% of children with p/cITP and 17.5% of them attained SRoT with good tolerance. The patients who achieved CR and began ELT treatment as early as possible, with a longer treatment duration and slower tapering, had a higher probability of SRoT., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)- Published
- 2023
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43. Thrombopoietin-Dependent Myelo-Megakaryopoiesis Fuels Thromboinflammation and Worsens Antibody-Mediated Chronic Renal Microvascular Injury.
- Author
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Douté M, Sannier A, Even G, Tran TT, Gaston AT, Delbosc S, Loyau S, Bruneval P, Witko-Sarsat V, Mouthon L, Nicoletti A, Caligiuri G, and Clement M
- Subjects
- Humans, Mice, Animals, Thrombopoietin metabolism, Thrombopoietin pharmacology, Receptors, Thrombopoietin, Inflammation, Thromboinflammation, Hematopoiesis physiology, Antibodies pharmacology, Kidney metabolism, Transforming Growth Factor beta pharmacology, Thrombosis, Renal Insufficiency, Chronic etiology, Glomerulonephritis
- Abstract
Significance Statement: Kidney-derived thrombopoietin (TPO) increases myeloid cell and platelet production during antibody-mediated chronic kidney disease (AMCKD) in a mouse model, exacerbating chronic thromobinflammation in microvessels. The effect is mirrored in patients with extracapillary glomerulonephritis associated with thromboinflammation, TGF β -dependent glomerulosclerosis, and increased bioavailability of TPO. Neutralization of TPO in mice normalized hematopoiesis, reduced chronic thromboinflammation, and ameliorated renal disease. The findings suggest that TPO is a relevant biomarker and a promising therapeutic target for patients with CKD and other chronic thromboinflammatory diseases.Neutralization of TPO in mice normalized hematopoiesis, reduced chronic thromboinflammation, and ameliorated renal disease. The findings suggest that TPO is a relevant biomarker and a promising therapeutic target for patients with CKD and other chronic thromboinflammatory diseases., Background: Chronic thromboinflammation provokes microvascular alterations and rarefaction, promoting organ dysfunction in individuals with various life-threatening diseases. Hematopoietic growth factors (HGFs) released by the affected organ may sustain emergency hematopoiesis and fuel the thromboinflammatory process., Methods: Using a murine model of antibody-mediated chronic kidney disease (AMCKD) and pharmacological interventions, we comprehensively monitored the response to injury in the circulating blood, urine, bone marrow, and kidney., Results: Experimental AMCKD was associated with chronic thromboinflammation and the production of HGFs, especially thrombopoietin (TPO), by the injured kidney, which stimulated and skewed hematopoiesis toward myelo-megakaryopoiesis. AMCKD was characterized by vascular and kidney dysfunction, TGF β -dependent glomerulosclerosis, and microvascular rarefaction. In humans, extracapillary glomerulonephritis is associated with thromboinflammation, TGF β -dependent glomerulosclerosis, and increased bioavailability of TPO. Analysis of albumin, HGF, and inflammatory cytokine levels in sera from patients with extracapillary glomerulonephritis allowed us to identify treatment responders. Strikingly, TPO neutralization in the experimental AMCKD model normalized hematopoiesis, reduced chronic thromboinflammation, and ameliorated renal disease., Conclusion: TPO-skewed hematopoiesis exacerbates chronic thromboinflammation in microvessels and worsens AMCKD. TPO is both a relevant biomarker and a promising therapeutic target in humans with CKD and other chronic thromboinflammatory diseases., (Copyright © 2023 by the American Society of Nephrology.)
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- 2023
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44. Clonal evolution in hereditary thrombocytosis with MPL T487A mutation
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Loic Vasseur, Remi Favier, Rathana Kim, Florence Rabian, Aurelie Cabannes‐Hamy, Bruno Cassinat, Nabih Maslah, Nadia Vasquez, Emmanuelle Clappier, Jean‐Jacques Kiladjian, and Nicolas Boissel
- Subjects
Thrombocytosis ,Clonal Evolution ,Thrombopoietin ,Oncology ,Mutation ,Pediatrics, Perinatology and Child Health ,Humans ,Hematology ,Janus Kinase 2 ,Receptors, Thrombopoietin - Published
- 2022
45. An updated evaluation of avatrombopag for the treatment of chronic immune thrombocytopenia
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Hanny Al-Samkari and Andrew Song
- Subjects
Purpura, Thrombocytopenic, Idiopathic ,Thiazoles ,Recombinant Fusion Proteins ,Immunology ,Immunology and Allergy ,Humans ,Thiophenes ,Receptors, Thrombopoietin - Abstract
Multiple agents are available for the management of chronic immune thrombocytopenia (ITP), including thrombopoietin-receptor agonists (TPO-RAs), rituximab, and fostamatinib. Although TPO-RAs are often selected as treatments for chronic ITP, when choosing between the TPO-RAs, clinicians must balance safety profile, dosing restrictions, and method of administration incorporating patient preference.We provide an overview of the thrombopoietin receptor agonists with a particular focus on avatrombopag, the newest agent in this class. In phase II and III clinical trials, avatrombopag was shown to offer durable improvement in platelet counts. We also include recent real-world evidence describing avatrombopag effectiveness in patients with poor response to prior treatments (including other TPO-RAs).Compared with other TPO-RAs used to treat ITP, avatrombopag offers practical oral dosing with a single pill strength, does not require long-term dietary restrictions, and has no warning for hepatotoxicity. It is frequently effective after use of other TPO-RAs in ITP. The primary downside with avatrombopag use at present is the lack of longer-term safety data in ITP that presently exists for romiplostim and eltrombopag.
- Published
- 2022
46. Pro106Leu MPL mutation is associated with thrombocytosis and a low risk of thrombosis, splenomegaly and marrow fibrosis
- Author
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Musa Alzahrani, Saeed Al Turki, Waleed Al Rajban, Fatimah Alshalati, Fahad Almodaihsh, Khadega A. Abuelgasim, Bader Alahmari, Thamer Al Bogami, Osama Ali, Talal Al Harbi, Mohammed A. AlBalwi, Maram Alotaibi, Aamer Aleem, Ahmed Al Asker, and Areej Al Mugairi
- Subjects
Adult ,Male ,Thrombocytosis ,Thrombosis ,Hematology ,General Medicine ,Bone Marrow ,Primary Myelofibrosis ,Mutation ,Splenomegaly ,Humans ,Female ,Child ,Receptors, Thrombopoietin ,Retrospective Studies - Abstract
The P106L mutation in the human myeloproliferative leukemia virus oncogene (MPL) was shown to be associated with hereditary thrombocythemia in Arabs. The clinical and bone marrow (BM) features of P106L mutation are unknown. Genetic databases at two tertiary hospitals in Saudi Arabia were searched to identify patients with the MPL P106L mutation. Clinical data were collected retrospectively and the BM aspirates and biopsies were independently reviewed by two hematopathologists. In total, 115 patients were included. Median age was 33 years of which 31 patients were pediatric and 65 were female. The mutation was homozygous in 87 patients. Thrombocytosis was documented in 107 patients, with a median platelet count of 667 × 10
- Published
- 2022
47. Thrombopoietin Receptor Agonists (TPO-RAs): Drug Class Considerations for Pharmacists
- Author
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Joseph Bubalo, Mimi Lo, and Jeffrey A. Gilreath
- Subjects
Health Knowledge, Attitudes, Practice ,medicine.medical_specialty ,Recombinant Fusion Proteins ,Eltrombopag ,Review Article ,Receptors, Fc ,Thiophenes ,Pharmacists ,Chronic liver disease ,Benzoates ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Pharmacotherapy ,medicine ,Humans ,Pharmacology (medical) ,Adverse effect ,Intensive care medicine ,Romiplostim ,Dose-Response Relationship, Drug ,Platelet Count ,business.industry ,Hepatitis C ,medicine.disease ,Thrombocytopenia ,Thiazoles ,Hydrazines ,Drug class ,Thrombopoietin ,chemistry ,Cinnamates ,030220 oncology & carcinogenesis ,Pyrazoles ,Drug Monitoring ,Stem cell ,business ,Receptors, Thrombopoietin ,030217 neurology & neurosurgery ,medicine.drug - Abstract
The thrombopoietin receptor agonists (TPO-RAs) romiplostim, eltrombopag, avatrombopag, and lusutrombopag carry unique US Food and Drug Administration (US FDA)- and European Medicines Agency (EMA)-approved indications and may be used to increase platelet counts in a variety of conditions. Current indications for available TPO-RAs include treatment of chronic immune thrombocytopenia (ITP) in cases of insufficient response to prior treatment (avatrombopag, eltrombopag, romiplostim), management of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure (avatrombopag, lusutrombopag), management of severe aplastic anemia (eltrombopag), and management of thrombocytopenia associated with interferon-based therapy for hepatitis C (eltrombopag). Across current indications, pharmacists can assist in stabilizing platelet counts and help to reduce large undulations commonly seen when starting, stopping, or transitioning between these agents. If therapy modifications may benefit the patient, pharmacists should discuss possible changes with the patient's treatment team or treating physician. When used for ITP, romiplostim, eltrombopag, and avatrombopag stimulate TPO receptors on hematopoietic stem cells (also known as c-Mpl, or CD110) to promote platelet production; however, romiplostim is the only TPO-RA that binds at the same site as endogenous TPO. These subtle mechanistic differences may explain why switching TPO-RA may be clinically advantageous in some situations. As pharmacists are called to counsel patients on TPO-RA use, a deep understanding of potential adverse events and management strategies, as well as appropriate monitoring, will increase the likelihood that patients meet their goals of therapy in the shortest timeframe. Other uses of TPO-RAs are also discussed in this review, including use following hematopoietic stem cell transplant, use in myelodysplastic syndrome, and use in chemotherapy-induced thrombocytopenia.
- Published
- 2021
48. Eltrombopag for myelodysplastic syndromes or chronic myelomonocytic leukaemia with no excess blasts and thrombocytopenia: a French multicentre retrospective real‐life study
- Author
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Emmanuel Gyan, Pierre Fenaux, Pascale Cony-Makhoul, Odile Beyne-Rauzy, Kamel Laribi, Clémence Santana, Bohrane Slama, Jean-Thomas Giraud, Clément Gaudin, Laurence Sanhes, Ana Berceanu, Sophie Dimicoli, Amina Cherait, Berangere Gruson, Groupe Francophone des Myélodysplasies, Jose Miguel Torregrosa, Thibault Comont, Vincent Jachiet, Marie-Agnès Azerad, Mathieu Meunier, Thomas Cluzeau, Claire Guerveno, Pr Lionel Ades, Thierry Guillaume, Ahmad Al Jijakli, Lenaïg Le Clech, and Jonathan Broner
- Subjects
Blood Platelets ,Male ,medicine.medical_specialty ,Eltrombopag ,Benzoates ,Gastroenterology ,Myelomonocytic leukaemia ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,Humans ,Medicine ,Medical history ,Platelet ,Aged ,Retrospective Studies ,Aged, 80 and over ,Thrombopoietin receptor ,business.industry ,Myelodysplastic syndromes ,Leukemia, Myelomonocytic, Chronic ,Hematology ,medicine.disease ,Thrombocytopenia ,Discontinuation ,Venous thrombosis ,Hydrazines ,chemistry ,Myelodysplastic Syndromes ,030220 oncology & carcinogenesis ,Pyrazoles ,Female ,France ,business ,Receptors, Thrombopoietin ,030215 immunology - Abstract
Despite a moderate prevalence in low-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML), thrombocytopenia remains a risk of severe bleeding and therapeutic options are still limited. There are only a few studies with eltrombopag (ELT), a thrombopoietin receptor agonist, in those patients. In this retrospective multicentre study, ELT was used in 50 patients with MDS and 11 with CMML, with no excess of marrow blasts and platelet counts of
- Published
- 2021
49. Current Concepts of Pathogenesis and Treatment of Philadelphia Chromosome-Negative Myeloproliferative Neoplasms
- Author
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Sara C. Meyer and Franziska Zeeh
- Subjects
Male ,0301 basic medicine ,Ruxolitinib ,Myeloid ,medicine.medical_treatment ,DNA Mutational Analysis ,Hematopoietic stem cell transplantation ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Nitriles ,medicine ,Humans ,Janus Kinase Inhibitors ,Philadelphia Chromosome ,Myelofibrosis ,Polycythemia Vera ,Myeloproliferative neoplasm ,Aged ,Myeloproliferative Disorders ,business.industry ,Essential thrombocythemia ,Hematopoietic Stem Cell Transplantation ,food and beverages ,Hematopoietic stem cell ,Myeloid leukemia ,Hematology ,Janus Kinase 2 ,Middle Aged ,Allografts ,Hematopoietic Stem Cells ,medicine.disease ,Combined Modality Therapy ,Pyrimidines ,030104 developmental biology ,medicine.anatomical_structure ,Primary Myelofibrosis ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,Pyrazoles ,Female ,Calreticulin ,business ,Receptors, Thrombopoietin ,Thrombocythemia, Essential ,medicine.drug - Abstract
Philadelphia chromosome-negative myeloproliferative neoplasms are hematopoietic stem cell disorders characterized by dysregulated proliferation of mature myeloid blood cells. They can present as polycythemia vera, essential thrombocythemia, or myelofibrosis and are characterized by constitutive activation of JAK2 signaling. They share a propensity for thrombo-hemorrhagic complications and the risk of progression to acute myeloid leukemia. Attention has also been drawn to JAK2 mutant clonal hematopoiesis of indeterminate potential as a possible precursor state of MPN. Insight into the pathogenesis as well as options for the treatment of MPN has increased in the last years thanks to modern sequencing technologies and functional studies. Mutational analysis provides information on the oncogenic driver mutations in JAK2, CALR, or MPL in the majority of MPN patients. In addition, molecular markers enable more detailed prognostication and provide guidance for therapeutic decisions. While JAK2 inhibitors represent a standard of care for MF and resistant/refractory PV, allogeneic hematopoietic stem cell transplantation remains the only therapy with a curative potential in MPN so far but is reserved to a subset of patients. Thus, novel concepts for therapy are an important need, particularly in MF. Novel JAK2 inhibitors, combination therapy approaches with ruxolitinib, as well as therapeutic approaches addressing new molecular targets are in development. Current standards and recent advantages are discussed in this review.
- Published
- 2021
50. Prolonged maintenance of hematopoietic stem cells that escape from thrombopoietin deprivation
- Author
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Makiko Mochizuki-Kashio, Deng Jianwen, Toshio Suda, Takayoshi Matsumura, Desmond Wai Loon Chin, Darren Qiancheng Tan, and Ayako Nakamura-Ishizu
- Subjects
0301 basic medicine ,Agonist ,Hematopoiesis and Stem Cells ,medicine.drug_class ,Recombinant Fusion Proteins ,medicine.medical_treatment ,Immunology ,Apoptosis ,Mice, Transgenic ,Receptors, Fc ,Biochemistry ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Cell Self Renewal ,Receptor ,Thrombopoietin ,Mice, Knockout ,Romiplostim ,Chemistry ,Cell Cycle ,hemic and immune systems ,Cell Biology ,Hematology ,Hematopoietic Stem Cells ,Mitochondria ,Cell biology ,Oxidative Stress ,Haematopoiesis ,030104 developmental biology ,Cytokine ,Stem cell ,Energy Metabolism ,Transcriptome ,Receptors, Thrombopoietin ,030217 neurology & neurosurgery ,Signal Transduction ,medicine.drug - Abstract
Hematopoietic stem cells (HSC) rarely divide, rest in quiescence, and proliferate only upon stress hematopoiesis. The cytokine thrombopoietin (Thpo) has been perplexingly described to induce quiescence and promote self-renewal divisions in HSCs. To clarify the contradictory effect of Thpo, we conducted a detailed analysis on conventional (Thpo−/−) and liver-specific (Thpofl/fl;AlbCre+/−) Thpo-deletion models. Thpo−/− HSCs exhibited profound loss of quiescence, impaired cell cycle progression, and increased apoptosis. Thpo−/− HSCs also exhibited diminished mitochondrial mass and impaired mitochondrial bioenergetics. Abnormal HSC phenotypes in Thpo−/− mice were reversible after HSC transplantation into wild-type recipients. Moreover, Thpo−/− HSCs acquired quiescence with extended administration of a Thpo receptor agonist, romiplostim, and were prone to subsequent stem cell exhaustion during competitive bone marrow transplantation. Thpofl/fl;AlbCre+/− HSCs exhibited similar stem cell phenotypes but to a lesser degree compared with Thpo−/− HSCs. HSCs that survive Thpo deficiency acquire quiescence in a dose-dependent manner through the modification of their metabolic state.
- Published
- 2021
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