Agonistas de la trombopoyetina como manejo farmacológico de la trombocitopenia inmune primaria

La trombocitopenia inmune primaria (TIP) es una enfermedad hematológica autoinmune que se distingue por tener plaquetas en un número inferior a 100.000, la cual provoca en los pacientes manifestaciones clínicas como la presencia de equimosis, petequias hasta hemorragias masivas que pueden comprometer la vida del paciente. Para su diagnóstico se realizan exámenes complementarios, ya que es una patología en la que no existe una prueba estándar o específica para diagnosticarla, y su tratamiento sea de primera, segunda o línea va a depender del número de plaquetas y de la fase de la enfermedad, sobresaliendo los agonistas de la trombopoyetina. Objetivo. Describir el manejo farmacológico de la Trombocitopenia Inmune Primaria (TIP) mediante la administración de los agonistas de la trombopoyetina. Metodología. Se realizó una revisión sistemática utilizando la metodología PRISMA, la información recopilada se hizo en bases de datos científicas como Pubmed, Science Direct, incluyendo artículos publicados dentro de los últimos 5 años, en inglés y español, relacionada al uso de los agonistas de la trombopoyetina y de la trombocitopenia inmune primaria. Resultados. Fueron seleccionados inicialmente 102 en PubMed y ScienceDirect, después de los procesos de verificación quedaron 18 artículos para la extracción y análisis de datos. Conclusión. Los agonistas de la trombopoyetina son fármacos seguros, pero siempre se debe valorar el riesgo-beneficio antes de usarlos en pacientes con TIP, porque cada paciente es único y su respuesta al tratamiento puede variar. Sin embargo, deben ser usados con precaución en pacientes con antecedentes de enfermedad tromboembólica o que presenten un riesgo elevado de desarrollarla.

Primary immune thrombocytopenia (PIT) is an autoimmune hematological disease that is distinguished by having platelets in a number lower than 100,000, which causes in patients clinical manifestations such as the presence of ecchymosis, petechiae to massive hemorrhages that can compromise the patient's life. For its diagnosis, complementary tests are performed, since it is a pathology in which there is no standard or specific test to diagnose it, and its treatment, whether first, second or third line, will depend on the number of platelets and the stage of the disease, with thrombopoietin agonists standing out. Objective. To describe the pharmacological management of Primary Immune Thrombocytopenia (PIT) through the administration of thrombopoietin agonists. Methodology. A systematic review was performed using PRISMA methodology, the information collected was done in scientific databases such as Pubmed, Science Direct, including articles published within the last 5 years, in English and Spanish, related to the use of thrombopoietin agonists and primary immune thrombocytopenia. Results. Initially 102 were selected in PubMed and ScienceDirect, after the verification processes, 18 articles remained for data extraction and analysis. Conclusion. Thrombopoietin agonists are safe drugs, but the risk-benefit should always be assessed before using them in patients with PIT, because each patient is unique and their response to treatment may vary. However, they should be used with caution in patients with a history of thromboembolic disease or who are at high risk of developing it.

A trombocitopenia imune primária (TPI) é uma doença hematológica autoimune que se distingue pela contagem de plaquetas abaixo de 100.000, o que causa manifestações clínicas como equimoses, petéquias e até hemorragias maciças que podem ser fatais. São realizados exames complementares para o diagnóstico, pois não existe um exame padrão ou específico para diagnosticá-la, e seu tratamento, seja de primeira, segunda ou terceira linha, depende do número de plaquetas e do estágio da doença, destacando-se os agonistas da trombopoetina. Objetivo. Descrever o manejo farmacológico da Trombocitopenia Imune Primária (TPI) por meio da administração de agonistas da trombopoetina. Metodologia. Foi realizada uma revisão sistemática utilizando a metodologia PRISMA, as informações coletadas foram feitas em bancos de dados científicos como Pubmed, Science Direct, incluindo artigos publicados nos últimos 5 anos, em inglês e espanhol, relacionados ao uso de agonistas da trombopoetina e trombocitopenia imune primária. Resultados. Um total de 102 artigos foi inicialmente selecionado no PubMed e no ScienceDirect e, após o processo de verificação, restaram 18 artigos para extração e análise de dados. Conclusão. Os agonistas da trombopoetina são medicamentos seguros, mas o risco-benefício deve ser sempre avaliado antes de usá-los em pacientes com TPI, pois cada paciente é único e sua resposta ao tratamento pode variar. No entanto, eles devem ser usados com cautela em pacientes com histórico de doença tromboembólica ou que tenham alto risco de desenvolver doença tromboembólica.

Effect of Recombinant Human Thrombopoietin (rhTPO) on Long-term Hematopoietic Recovery in Mice with Acute Radiation Sickness and Relative Mechanism / 中国实验血液学杂志

OBJECTIVE@#To investigate the effect and relative mechanism of Recombinant Human Thrombopoietin (rhTPO) on long-term hematopoietic recovery in mice with acute radiation sickness.@*METHODS@#Mice were intramuscularly injected with rhTPO (100 μg/kg) 2 hours after total body irradiation with 60Co γ-rays (6.5 Gy). Moreover, six months after irradiation, peripheral blood, hematopoietic stem cells (HSC) ratio, competitive transplantation survival rate and chimerization rate, senescence rate of c-kit+ HSC, and p16 and p38 mRNA expression of c-kit+ HSC were detected.@*RESULTS@#Six months after 6.5 Gy γ-ray irradiation, there were no differences in peripheral blood white blood cells, red blood cells, platelets, neutrophils and bone marrow nucleated cells in normal group, irradiated group and rhTPO group (P>0.05). The proportion of hematopoietic stem cells and multipotent progenitor cells in mice of irradiated group was significantly decreased after irradiation (P<0.05), but there was no significant changes in rhTPO group (P>0.05). The counts of CFU-MK and BFU-E in irradiated group were significantly lower than that in normal group, and rhTPO group was higher than that of the irradiated group(P<0.05). The 70 day survival rate of recipient mice in normal group and rhTPO group was 100%, and all mice died in irradiation group. The senescence positive rates of c-kit+ HSC in normal group, irradiation group and rhTPO group were 6.11%, 9.54% and 6.01%, respectively (P<0.01). Compared with the normal group, the p16 and p38 mRNA expression of c-kit+ HSC in the irradiated mice were significantly increased (P<0.01), and it was markedly decreased after rhTPO administration (P<0.01).@*CONCLUSION@#The hematopoietic function of mice is still decreased 6 months after 6.5 Gy γ-ray irradiation, suggesting that there may be long-term damage. High-dose administration of rhTPO in the treatment of acute radiation sickness can reduce the senescence of HSC through p38-p16 pathway and improve the long-term damage of hematopoietic function in mice with acute radiation sickness.

Effect of Recombinant Human Thrombopoietin (rhTPO) on Hematopoietic Reconstitution in Allogeneic Hematopoietic Stem Cell Transplantation Model / 中国实验血液学杂志

OBJECTIVE@#To explore the effect of recombinant human thrombopoietin (rhTPO) on hematopoietic reconstruction in allogeneic hematopoietic stem cell transplantation (allo-HSCT) model.@*METHODS@#The C57BL/6 mice were employed as the donors, and BALB/c mice as recipients. The bone marrow mononuclear cells of the donor mice were extracted and pretreated, which then were injected with 5×106 per mouse through the tail vein of the recipient to establish an allo-HSCT model. The implantation of hematopoietic stem cells in the recipient mice was detected by flow cytometry on the 28th day after transplantation. Next, the successfully modeled recipient mice were randomly divided into experimental group and control group. The rhTPO was injected into mice in the experimental group on the first day after transplantation, while the saline was injected into mice in the control group. Both groups were injected for 14 consecutive days. The peripheral blood and bone marrow hematopoiesis of the two groups were observed on day 1, 3, 7, 14, and 21 after transplantation.@*RESULTS@#The expression rate of H-2Kb in the bone marrow of recipient mice was 43.85% (>20%) on the 28th day after transplantation, which indicated that the recipient mice were successfully chimerized. Meanwhile, counts of PLTs on the day 3, 7, 14, and 21 after transplantation in the experimental group were higher than those in the control group with statistical significances (P<0.05). In addition, hematopoietic function of bone marrow was suppressed in both groups on day 1, 3 and 7 after transplantation, but hematopoietic bone marrow hyperplasia was better in the experimental group than in the control group. On day 14 and 21 after transplantation, the hematopoietic function of bone marrow in the two groups was recovered, and the experimental group showed more obvious than the control group.@*CONCLUSION@#rhTPO can effectively stimulate the production of PLTs and facilitate the recovery of white blood cells and hemoglobin after allo-HSCT, and promote hematopoietic recovery and reconstitution of bone marrow.

Clinical observation of herombopag combined with recombinant human thrombopoietin in the treatment of primary immune thrombocytopenia / 中国药房

OBJECTIVE To investigate the clinical efficacy and safety of herombopag combined with recombinant human thrombopoietin （rhTPO） in the treatment of primary immune thrombocytopenia （ITP） in the real world. METHODS A retrospective study was conducted on the patients diagnosed with ITP in the Second Affiliated Hospital of Bengbu Medical College from January 2021 to December 2022. Among them， 98 patients who were treated with a combination of herombopag and rhTPO were included in the observation group， and 157 patients who were treated with rhTPO alone were included in the control group. The changes in platelet count， clinical efficacy， bleeding， platelet transfusion rate and adverse drug reactions before and after treatment were observed and compared between the two groups. RESULTS Since the 8th day of treatment， there was a statistically significant difference in platelet count between the two groups （[ 61.04±13.46）×109 L－1 in observation group， （52.11±12.06）× 109 L－1 in control group] （P＜0.05）， and there also was a statistically significant difference in the peak and stable values of platelet count between the two groups （P＜0.05）. The total effective rates of the observation group and the control group were 79.59% and 66.88%， with cumulative response rates of 81.32% and 68.68%， and median response durations of 8 days and 10 days， respectively； these differences were statistically significant （P＜0.05）. During the treatment period， the bleeding rates of the observation group and control group were 3.06% and 8.28% （P＜0.05）， bleeding events were categorized as grade 1 or 2， and platelet transfusion rates were 31.63% and 40.76%； the differences in bleeding rates and platelet transfusion rates between the two groups was statistically significant （P＜0.05）. The incidences of adverse drug reactions in the two groups were 11.22% and 9.55%， respectively， with no statistically significant difference （P＞0.05）， and no moderate to severe adverse drug reaction was found. CONCLUSIONS The combination of herombopag and rhTPO can significantly increase platelet levels and response rate， and reduce bleeding rate and platelet transfusion rate in ITP patients， with good safety.

Clinical efficacy of avatrombopag combined with recombinant human thrombopoietin versus avatrombopag in the treatment of severe thrombocytopenia associated with chronic liver disease / 中华消化外科杂志

Objective:To investigate the clinical efficacy of avatrombopag combined with recombinant human thrombopoietin (rhTPO) versus avatrombopag in the treatment of severe thrombocytopenia associated with chronic liver disease.Methods:The retrospective cohort study was conducted. The clinical data of 56 patients with severe thrombocytopenia associated with chronic liver disease who were admitted to the First Affiliated Hospital of University of Science and Technology of China from May 2020 to October 2021 were collected. There were 36 males and 20 females, aged from 33 to 74 years, with a median age of 54 years. Of 56 patients, 21 cases undergoing treatment of avatrombopag combined with rhTPO were allocated into the combined treatment group and 35 cases undergoing treatment of avatrombopag were allocated into the monotherapy group. Observation indicators: (1) changes of platelet after treatment; (2) adverse drug reaction. Follow-up was conducted using outpatient examination and telephone interview to detect changes of platelet and effects of treatment within 2 weeks after treatment. The follow-up was up to October 2021. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was analyzed using the t test. Measurement data with skewed distribution were represented as M(range), and comparison between groups was analyzed using the Mann-Whitney U test. Count data were described as absolute numbers or percentages, and compari-son between groups was analyzed using the chi-square test or Fisher exact probability. Repeated measurement data were analyzed using the repeated ANOVA. Results:(1) Changes of platelet after treatment. The platelet level within 1 to 5 days and 6 to 10 days after treatment in the combined treatment group were (35±19)×10 9/L and (73±41)×10 9/L, respectively. The above indicators of the monotherapy group were (40±30)×10 9/L and (70±51)×10 9/L, respectively. There was no significant difference in change trends of platelet before and after treatment between the two groups ( Fgroup=0.30, P>0.05). There was a significant difference in platelet count before and after treatment between the two groups ( Ftime=59.96, P<0.05). There was no interaction effect in change trends of platelet between the two groups ( Finteraction=0.40, P>0.05). The effective rates were 66.67%(14/21) in the combination therapy group and 54.29%(19/35) in the monotherapy group. There was no significant difference in the effective rate between the two groups ( χ2=0.83, P>0.05). (2) Adverse drug reaction. Cases with headache, dizziness, blood transfusion reaction, hematuria, proteinuria, fever, abdominal pain, diarrhea, dyspepsia, fatigue, nausea or peripheral tissue edema were 2, 4, 1, 2, 2, 7, 10, 6, 8, 14, 12, 5 in the combined treatment group, versus 5, 8, 1, 3, 5, 7, 19, 11,20, 19, 14, 5 in the monotherapy group, respectively. There was no significant difference in cases with headache, dizziness, blood transfusion reaction, hematuria, proteinuria between the two groups ( P>0.05), and there was no significant difference in cases with fever, abdominal pain, diarrhea, dyspepsia, fatigue, nausea, peripheral tissue edema between the two groups ( χ2=1.24, 0.23, 0.05, 1.91, 0.83, 2.04, 0.81, P>0.05). Conclusion:Both of avatrombopag combined with rhTPO and monotherapy of avatrom-bopag can be used to promote the platelet level in patients with severe thrombocytopenia associated with chronic liver disease, and avatrombopag combined with rhTPO does not provide better clinical benefits compared with monotherapy avatrombopag.

Effect of artificial liver with double plasma molecular absorb system model on patients' platelets and corresponding treatment strategy / 北京大学学报(医学版)

OBJECTIVE@#To compare the effects of artificial liver treatment with double plasma molecular adsorption system(DPMAS) mode and traditional plasma exchange (PE) mode on platelets in patients, and to evaluate the clinical efficacy of recombinent human thrombopoietin (rhTPO) in the treatment of thrombocytopenia.@*METHODS@#A total of fifteen patients undergoing artificial liver with DPMAS model admitted to the Fifth Affiliated Hospital of Guangzhou Medical University from January 2018 to November 2020 were selected and included in the DPMAS group, and another 15 patients receiving PE were selected and included in the PE group. The improvement of clinical symptoms, such as fatigue, jaundice, oliguria, edema, etc. before and after artificial liver treatment was compared between the two groups, and the trend of blood routine (especially platelet), coagulation function and other indexes before and after treatment were compared between the two groups. The use of rhTPO and the number of platelets were recorded during treatment.@*RESULTS@#The improvement rate of clinical symptoms in DPMAS group was 86.67%, which was higher than that in PE group, but the difference was not statistically significant (P>0.05). There was no statistical significance in the outcome of the two groups within 90 days (P>0.05). There was no significant difference in white blood cell (WBC) and hemoglobin (HB) between the two groups after treatment (P>0.05). However, the level of platelet(PLT) in DPMAS group was significantly lower than that before treatment (P < 0.05), and was significantly lower than that in PE group (P < 0.05). After treatment, the international normalized ratio (INR) level in PE group was significantly improved (P < 0.05), but there was no significant difference in the INR level in DPMAS group (P>0.05). The patients in the DPMAS group received an average of (8.2±3.1) doses of rhTPO and (1.5±0.3) IU of platelet transfusions during hospitalization. In DMPAS group, platelets increased significantly after infusion of terbium.@*CONCLUSION@#Compared with PE mode, the artificial liver with DPMAS mode can reduce platelet levels in patients, but the application of rhTPO can stimulate platelet regeneration and increase platelet levels in the patients, thereby reducing the risk of bleeding due to platelet hypoplasia.

The Treatment of Newly Diagnosed Primary Immune Thrombocytopenia by Recombinant Human Thrombopoietin Combined with Glucocorticoid / 中国实验血液学杂志

OBJECTIVE@#To evaluate the efficacy and safety of recombinant human thrombopoietin (rhTPO) combined with glucocorticoid in treatment of newly diagnosed adult primary immune thrombocytopenia (ITP).@*METHODS@#Eleven male and 23 female patients with the diagnosis of primary ITP in our hospital from November 2018 to October 2019 were enrolled and randomly divided into test group (17 cases) and control group (17 cases), the median age was 52 years old (range: 20-76 years old). The patients in test group were treated with rhTPO 300 IU/(kg·d) combined with glucocorticoid , while the patients in control group were treated with rhTPO (15 000 IU/d) combined with glucocorticoid. Platelet count, platelet increase, as well as the overall response rate were compared. At the same time, the drug tolerance and any adverse drug reactions were observed.@*RESULTS@#The platelet counts and platelet increase of the patients in the test group were significantly higher than those in control group (P<0.05). There was no significant difference in platelet counts and platelet increase between the patients in the test group and control group at day 3, 7 after treatment. There was no significant difference in overall response rates and complete response rates at day 7, 14 between the two groups either. In test group, there were 13 cases received platelet transfusion, while 12 cases in control group. The muscle aches occurred in one patient, and mild aminotransferase increased in another patient in test group which was self-recovery without treatment.@*CONCLUSION@#RhTPO 300 U/(kg·d) combined with glucocorticoid could rapidly increase the platelet count with a low incidence of tolerable adverse events compared with conventional dose rhTPO with glucocorticoid.

Effect of rhTPO and rhIL-11 on Thrombocytopenia after Chemotherapy in Leukemia / 中国实验血液学杂志

OBJECTIVE@#To analyze and compare the efficacy of recombinant human thrombopoietin (rhTPO) and recombinant human interleukin-11 (rhIL-11) in the treatment of thrombocytopenia after chemotherapy in acute leukemia patients.@*METHODS@#180 patients with acute leukemia complicated with thrombocytopenia after chemotherapy in the First Affiliated Hospital of Anhui Medical University were analyzed retrospectively. Among them, 50 patients who treated with rhTPO and did not receive platelet transfusion were set as group A, 50 patients treated with rhTPO and receive platelet transfusion were set as group B, Forty patients treated with rhIL-11 without platelet transfusion were set as group C, Forty patients who treated with rhIL-11 and received platelet transfusion were set as group D. The duration of PLT below 20×109/L, the days it takes for PLT to recover to more than 100×109/L, and the incidence of different bleeding degrees were compared among several groups.@*RESULTS@#The duration of PLT<20×109/L in group A(3.72±1.14 d) was significantly shorter than that in group C(4.93±1.33 d) (P<0.001), and there was no significant difference from group B (P>0.05). The duration of PLT<20×109/L in group B(3.06±0.91 d) was significantly shorter than that in group D(4.65±0.98 d) (P<0.001), while the difference in duration of days between group C and D was not statistically significant (P>0.05). The times for PLT to recover to 100×109/L in group A(13.46±1.67 d) were significantly shorter than that in group C(16.85±2.13 d) (P<0.05), but there was no significant difference from group B (P>0.05). The time required for PLT to recover to 100×109/L in group B(13.36±1.49 d) were significantly shorter than that in group D(16.18±1.78 d) (P<0.05), while the difference in the days required for group C and group D was not statistically significant (P>0.05). The incidence of high bleeding risk in group B was significantly lower than that in group A (22% vs 44%, P<0.05), the incidence of high bleeding risk in group D was significantly lower than that in group C (32% vs 65%, P<0.05), and the incidence of high bleeding risk in group A was significantly lower than that in group C (44% vs 65%, P<0.05). The incidence of high bleeding risk in group B(22%) was lower than that in group D(32.5%), and the difference was not statistically significant (P>0.05).@*CONCLUSION@#In the treatment of acute leukemia patients with thrombocytopenia after chemotherapy, compared with rhIL-11, rhTPO can significantly shorten the duration for patients in a status with extremely low levels of PLT and the recovery time of PLT to normal range. In addition, PLT transfusion cannot speed up the time for patients to raise platelets to a safe range, nor can it shorten the duration of low PLT levels, but it can reduce the incidence of high bleeding risk events.

Cost-utility analysis of Recombinant human thrombopoietin injection and Etrapopa ethanolamine tablets in the second-line treatment of primary immune thrombocytopenia / 中国药房

OBJECTIVE To evaluate the econo mical efficiency of Recombinant human thrombopoietin injection （called “rhTPO”for short ）versus Etrapopa ethanolamine tablets （called“Etrapopa”for short ）in the second-line treatment of primary immune thrombocytopenia （ITP）in the Chinese adult patients. METHODS Based on the decision tree-embedded Markov model with a 4-week cycle ，the cost and utility related to bleeding events and adverse events after the use of the two drugs were measured and compared from the perspective of Chinese health system. The horizon was 12 weeks，and the cost and health outcome were not discounted. RESULTS Compared with Etrapopa ，rhTPO improved the quality adjusted life year by 0.002 5 and reduced the cost by 1 824.36 yuan，which was the absolute advantage scheme. Univariate sensitivity analysis showed that the base results were greatly affected by the dosage of rhTPO and Etrapopa during maintainance period. In most cases ，rhTPO was economical. Probability sensitivity analysis showed that when willingness-to-pay threshold varied between 0 yuan and 250 000 yuan，the probability about that rhTPO was economical ranges from 99.90％ to 100％. CONCLUSIONS Based on the available evidence ，rhTPO is more economical in the short term than Etrapopa in the second-line treatment of ITP.

Progress in the treatment of chronic immune thrombocytopenia / 国际儿科学杂志

Immune thrombocytopenia is a common bleeding disease characterized by isolated thrombocytopenia.Some patients last for more than 12 months and suffer from chronic immune thrombocytopenia(CITP). The pathogenesis of CITP is complex, and the traditional first-line has little improvement.In recent years, researches on second-line treatments(thrombopoietin and its receptor agonists, rituximab and splenectomy), immunosuppressive agents, all-trans retinoic acid, atorvastatin, and hematopoietic stem cell transplantation have provided new ideas for the treatment of CITP.This review summarizes the recent progress in the treatments of CITP and will be helpful for individualized treatment.

El papel de los estimulantes de trombopoyetina (eltrombopag y romiplostim) en trombocitopenia inmune secundaria a Lupus

Introducción: la púrpura trombocitopénica inmune (PTI) es una manifestación hematológica frecuente en el lupus eritematoso sistémico (LES). Los corticoesteroides son la primera línea de manejo para la trombocitopenia moderada o grave, en conjunto con antimaláricos y otros inmunosupresores. En casos particulares, en donde la respuesta a las intervenciones iniciales no sea la adecuada, se cuenta con terapias de segunda línea. Objetivo: esta revisión narrativa se enfocará en dos medicamentos agonistas del receptor de trombopoyetina (RTPO): eltrombopag y romiplostim y en su papel en la PTI secundaria a LES. Además, se revisará su perfil farmacológico, dosis e indicaciones en el contexto de esta enfermedad. Métodos: se realizó una búsqueda de literatura en diferentes bases de datos, se analizaron artículos científicos y guías de manejo, tanto de LES como de trombocitopenia inmune, con el fin de contestar diferentes preguntas clínicas surgidas en el escenario de la práctica cotidiana. Resultados y conclusiones: el uso de los estimulantes de TPO es una alternativa terapéutica para escenarios particulares de pacientes con LES y trombocitopenia inmune. Sin embargo, son necesarios estudios enfocados en esta población específica para poder hacer recomendaciones acertadas acerca de su manejo. Los datos actuales son extrapolados de la trombocitopenia inmune primaria.

SUMMARY Introduction: Immune thrombocytopenia is a frequent hematologic manifestation in systemic lupus erythematosus (SLE). Corticosteroids are the first line of treatment for moderate to severe thrombocytopenia in this disease, in conjunction with antimalarials or other immunosuppressants. In particular cases where the response to initial interventions is not achieved, second-line therapies with different mechanisms of action are available. Objective: This narrative review will focus on two thrombopoietin receptor agonist drugs (TPO-RA): eltrombopag and romiplostim, and their role in immune thrombocytopenia secondary to SLE. In addition, its pharmacological profile, dose and indications will be reviewed in the context of this disease. Methods: A literature search was conducted in different databases; scientific articles and guidelines were analyzed, both for SLE and immune thrombocytopenia. With the purpose of answering different clinical questions that constantly arise in the scene of daily practice. Results and conclusions: The use of TPO-RA stimulants is a therapeutic alternative for particular scenarios in patients with SLE and immune thrombocytopenia, however studies focused on this particular population are necessary to be able to make strong recommendations about its utility. Current data are extrapolated from primary immune thrombocytopenia.

Correlation between P-selectin, thrombopoietin and severity of glioma / 中国医师进修杂志

Objective:To analyze the expression of P-selectin and thrombopoietin (TPO) in patients with glioma, and explore their correlation with severity of disease.Methods:One hundred and six patients with glioma who were treated in the Third People's Hospital of Dalian City from June 2017 to June 2019 were selected as the observation group, and 50 physical examination person in the same period were selected as the healthy control group. The clinic data of patients in two groups were analyzed.Results:The serum P-selectin and TPO levels in the observation group were significantly higher than those in the healthy control group: (62.35 ± 16.71) μg/L vs. (25.42 ± 9.18) μg/L, (12.64 ± 3.26) μg/L vs. (6.93 ± 1.77) μg/L ( P<0.01). In patients with different severity of glioma, serum P-selectin and TPO levels in the high-grade group were significantly higher than those in the low-level group: (65.14 ± 17.19) μg/L vs. (53.71 ± 15.26) μg/L, (14.57 ± 3.38) μg/L vs. (9.04 ± 1.97) μg/L ( P<0.01). Serum P-selectin and TPO levels in patients with glioma after treatment were significantly lower than those before treatment: (57.28 ± 16.22) μg/L vs. (62.35 ± 16.71) μg/L, (10.85 ± 2.97) μg/L vs. (12.64 ± 3.26) μg/L ( P<0.01). Spearman correlation analysis result showed that there was a significant positive correlation between serum P-selectin, TPO levels and WHO classification in patients with glioma ( r = 0.417 and 0.361, P<0.05). The results of receiver operating characteristic (ROC) curve analysis showed that the area under curve (AUC) of serum P-selectin in the diagnosis of glioma was 0.859 (95% CI 0.794 to 0.910, P<0.01), the sensitivity was 90.00%, and the specificity was 74.53%. The ROC curve analysis result showed that the AUC of serum TPO in the diagnosis of glioma was 0.720 (95% CI 0.643 to 0.789, P<0.01), the sensitivity was 69.81%, and the specificity was 72.00%. Conclusions:Serum P-selectin and TPO are abnormally expressed in glioma patients, and their level changes are related to the severity of the disease.

Thrombopoietin is associated with a prognosis of gastric adenocarcinoma

SUMMARY OBJECTIVE Thrombopoietin (THPO) is well-known as a megakaryocyte growth and development factor (MGDF) involved in megakaryocyte proliferation and maturation. To explore the biological effects of THPO in gastric adenocarcinoma, we conducted this study. Methods: By accessing the TCGA database, the expression level of THPO was determined in tumor tissues. The association between THPO expression and clinical features, or prognostic significance was described by Cox regression analysis and Kaplan-Meier. The SiRNA method was used to decline the THPO expression; then cell viability, invasion, and migration were detected to verify the effects of the knockdown of THPO. qPCR and western blotting were implemented to examine the expression level of THPO. Results: The expression of THPO was increased in tumor tissue and cells, its high-regulation was associated with a poor prognosis in patients with gastric adenocarcinoma. Cell viability, invasion, and migration were suppressed in AGS with the down-regulation of THPO. Furthermore, on the basis of si-THPO transfection, E-cadherin was promoted while N-cadherin and Vimentin were attenuated. CONCLUSION Our results revealed that THPO may be a potent marker of gastric adenocarcinoma, providing a novel potential screening method for gastric adenocarcinoma.

RESUMO OBJETIVO Trombopoetina (THPO) é um conhecido fator de desenvolvimento e crescimento megacariócito (MGDF) envolvido na proliferação e maturação de megacariócitos. Realizamos este estudo para explorar os efeitos biológicos do THPO no adenocarcinoma gástrico. Metodologia: O nível de expressão do THPO em tecidos tumorais foi determinado acessando a banco de dados TCGA. A associação entre a expressão de THPO e características clínicas ou relevância no prognóstico foi descrita através da análise de Kaplan-Meier e regressão de Cox. O método SiRNA foi utilizado para reduzir a expressão da THPO e, em seguida, a viabilidade, invasão, e migração celular foram detectadas para verificar os efeitos da redução do THPO. qPCR e western blotting foram utilizados para examinar o nível de expressão do THPO. Resultados: A expressão do THPO estava aumentada em tecido e células tumorais, esse aumento estava associado com um prognóstico negativo para pacientes com adenocarcinoma gástrico. A invasão e migração celular foram suprimidos em AGS com a redução do THPO. Além disso, com base na transfecção de si-THPO, a E-caderina foi promovida, enquanto a N-caderina e Vimentina foram atenuadas. Conclusão nossos resultados demonstram que o thpo pode ser um potente marcador de adenocarcinoma gástrico, com potencial para ser um novo tipo de triagem para adenocarcinoma gástrico.

Thrombopoietin promotes megakaryopoiesis protecting bone marrow endothelial function in patients undergoing chemotherapy for hematological malignancies / 南方医科大学学报

OBJECTIVE@#To explore whether thrombopoietin (TPO) can rescue megakaryopoiesis by protecting bone marrowderived endothelial progenitor cells (BM-EPCs) in patients receiving chemotherapy for hematological malignancies.@*METHODS@#Bone marrow samples were collected from 23 patients with hematological malignancies 30 days after chemotherapy and from 10 healthy volunteers. BM-EPCs isolated from the samples were identified by staining for CD34, CD309 and CD133, and their proliferation in response to treatment with TPO was assessed using CCK8 assay. DiL-Ac-LDL uptake and FITC-UEA-I binding assay were performed to evaluate the amount of BM-EPCs from the subjects. Tube-formation and migration experiments were used for functional assessment of the BM-EPCs. The BM-EPCs with or without TPO treatment were co-cultured with human megakaryocytes, and the proliferation of the megakaryocytes was detected with flow cytometry.@*RESULTS@#Flow cytometry indicated that the TPO-treated cells had high expressions of CD34, CD133, and CD309. CCK8 assay demonstrated that TPO treatment enhanced the proliferation of the BM-EPCs, and the optimal concentration of TPO was 100 μg/L. Double immunofluorescence assay indicated that the number of BM-EPC was significantly higher in TPO-treated group than in the control group. The TPO-treated BM-EPCs exhibited stronger tube-formation and migration abilities ( < 0.05) and more significantly enhanced the proliferation of co-cultured human megakaryocytes than the control cells ( < 0.05).@*CONCLUSIONS@#TPO can directly stimulate megakaryopoiesis and reduce hemorrhage via protecting the function of BM-EPCs in patients following chemotherapy for hematological malignancies.

Efficacy and safety of recombinant human thrombopoietin in adult patients with primary immune thrombocytopenia during the perioperative period / 中华血液学杂志

Objective@#To evaluate the efficacy and safety of recombinant human thrombopoietin (rhTPO) treatment for primary immune thrombocytopenia (ITP) patients during the perioperative period.@*Methods@#Adult ITP patients who were refractory to first-line glucocorticoid therapy and underwent selective surgery were enrolled to be treated with rhTPO at the dosage of 1.5×104U/d subcutaneously during the perioperative period. rhTPO treatment would not be terminated until one of the following conditions occurred: ①Platelet counts met the requirement of surgery; ②Platelet counts were ≥100×109/L; ③Completed the 14 days of therapy. End points of the study were surgery rate, rhTPO therapy response rate, rescue therapy rate and adverse responses.@*Results@#42 patients were enrolled from Jan. 1, 2016 to Jun. 30, 2018. 14 were male and 28 were female. The median age was 60 (25-73) years old. There were no newly diagnosed patients. 5 patients were persistent and 37 were chronic. 27 patients completed selective surgery. The surgery rate was 64.3% (27/42) . Among them, 13 patients were under local anesthesia and 14 under general anesthesia. Of 42 cases receiving rhTPO therapy. 31 patients achieved responses, The overall response rate was of 73.8%. Among them, 24 patients achieved CR. The CR ratio was 77.4% (24/31) . 7 achieved response. The response ratio was 22.6% (7/31) . 11 patients did not respond to rhTPO therapy. The non-response rate was 26.2% (11/42) . The median time to reach CR was 7 (3-16) days. The median time to reach the peak of platelet counts were 10 (3-21) days. rhTPO was used for a median of 7 (3-14) days. The median platelet counts of patients undergoing surgery before rhTPO therapy, before surgery and at day 7 after surgery were 33 (20-89) ×109/L, 125 (78-245) ×109/L and 72 (30-250) ×109/L, respectively. The median peak of platelet counts was 149 (101-466) ×109/L. No infection, bleeding, thromboembolism and therapy-related adverse responses occurred in the patients.@*Conclusion@#rhTPO for ITP patients during the perioperative period is safe and effective.

Effect of recombinant human thrombopoietin on endotoxin-induced thrombocytopenia in mice / 中华危重病急救医学

Objective@#To investigate the effect of recombinant human thrombopoietin (rhTPO) on thrombocytopenia (TCP) induced by endotoxin lipopolysaccharide (LPS) in mice.@*Methods@#Sixty male C57BL/6 mice were divided into normal saline (NS) control group (NS group), sepsis-induced TCP model group (LPS group) and rhTPO treatment group (LPS+rhTPO group) by random number table with 20 mice in each group. Sepsis-induced TCP model was reproduced by one intraperitoneal injection of LPS 30 mg/kg, and the mice in NS group were given the same amount of NS. In LPS+rhTPO group, 2.7 kU/kg rhTPO was subcutaneously injected into mice immediately after intraperitoneal injection of LPS, once every 24 hours. The mice in NS group and LPS group were injected subcutaneously with the same amount of NS. The observation period of each group lasted for 72 hours. The inner canthus blood was harvested before and every 24 hours after modeling, and the platelet count (PLT) was measured by animal blood cell counter. The eyeball blood of mice was harvested at 72 hours after modeling, and the proportion of CD61+CD62p+ cells in platelet-rich plasma was detected by flow cytometry, by which the platelet activation was reflected. Lung and spleen tissues of mice were harvested, and the positive expression of CD41 was determined by immunohistochemistry, by which the platelet sequestration in organs was reflected. Bone marrow cells from unilateral femur of mice were harvested, and the proportion of CD41+CD61+ cells was determined by flow cytometry to reflect the proliferation of bone marrow megakaryocytes.@*Results@#There was no significant difference in PLT among the groups before modeling. With the extension of the time after modeling, PLT in LPS group was decreased continuously, and increased slightly at 72 hours, but it was still significantly lower than that in NS group (×109/L: 308.60±21.70 vs. 1 152.72±50.27, P < 0.05); PLT in LPS+rhTPO group was increased continuously with the extension of modeling time, and it was significantly higher at 72 hours than that in LPS group (×109/L: 926.78±48.85 vs. 308.60±21.70, P < 0.05). At 72 hours after modeling, the proportion of CD61+CD62p+ cells in platelet-rich plasma of LPS group was significantly higher than that of NS group [(25.07±2.55)% vs. (4.17±0.38)%, P < 0.05], while the value in LPS+rhTPO group was significantly lower than that of LPS group [(15.92±1.26)% vs. (25.07±2.55)%, P < 0.05]. The proportion of CD41+CD61+ cells in bone marrow megakaryocytes of LPS group was significantly higher than that of NS group [(11.84±0.80)% vs. (3.60±0.42)%, P < 0.05], and the proportion of CD41+CD61+ cells in LPS+rhTPO group was significantly higher than that in LPS group [(30.96±2.49)% vs. (11.84±0.80)%, P < 0.05]. Immunohistochemistry showed that the positive expressions of CD41 in lung and spleen tissues of LPS group increased significantly than NS group [A value: 828.94±119.30 vs. 447.09±16.19 in lung tissue, (280.15±16.71)×103 vs. (0.65±0.26)×103 in spleen tissue, both P < 0.05], while the positive expressions of CD41 in lung and spleen tissues of LPS+rhTPO group decreased significantly than LPS group [A value: 542.78±2.95 vs. 828.94±119.30 in lung tissue, (129.40±13.49)×103 vs. (280.15±16.71)×103 in spleen tissue, both P < 0.05].@*Conclusion@#The rhTPO in endotoxin-induced TCP may stimulate the proliferation of bone marrow megakaryocytes, inhibit platelet activation and affect platelet sequestration in organs, so as to increase platelet levels.

Effect of recombinant human thrombopoietin on platelet activation and pyroptosis in mice with thrombocytopenia / 中华急诊医学杂志

Objective@#To study the effect and mechanism of recombinant human thrombopoietin (rhTPO) on platelet activation and pyroptosis in mice with lipopolysaccharide (LPS)- induced thrombocytopenia, and provide a theoretical basis for the clinical use of rhTPO.@*Methods@#One hundred C57BL/6 mice were randomly(random number) divided into 5 groups: blank control group (sham group), experimental control group (LPS group), low dose (L group, 1.35 ×103U·kg-1·d-1), medium dose (M group, 2.7 ×103U·kg-1·d-1), and high dose (H group, 5.4 ×103U·kg-1·d-1) rhTPO treatment groups. Continuous observation for 72 h. The positive expression rates of CD61/CD62p, Gasdermin D and Caspase-1 in washed platelets were detected by flow cytometry at 72 h, and the levels of IL-1β and IL-18 in plasma were detected by ELISA.@*Results@#Compared with the sham group, the survival rate of the LPS group was significantly lower (P< 0.01). Compared with the LPS group, the survival rates of the L, M and H groups were slightly increased, but the difference was not statistically significant (P>0.05). There was no significant change in platelet count of the sham group before and after the experiment. The platelet count in the LPS group decreased significantly. The platelet count at 72 h in the L group was significantly higher than those in the LPS, M and H groups (P<0.01), and there was no significant difference between the M and H groups and LPS group (P>0.05). Compared with the sham group, CD61/CD62p and Gasdermin-D protein expressions in the LPS group were significantly increased (P<0.01), significantly decreased in the L group (P<0.05), and not significantly changed in the M and H groups (P>0.05). Caspase-1 expression was significantly increased in the LPS group compared with the sham group (P<0.01), significantly decreased in the L and M groups compared with the LPS group (P<0.05), and not significantly changed in the H group compared with the LPS group (P>0.05). The levels of platelet-rich plasma IL-1 beta and IL-18 in the LPS group were significantly higher than those in the sham group (P<0.01), while those in the L group were significantly lower than those in the LPS group (P<0.01), and those in the M and H groups were not significantly changed than those in the LPS group (P>0.05).@*Conclusions@#rhTPO can inhibit platelet activation and pyroptosis in LPS-induced thrombocytopenia mice, which provides basic research basis for the treatment of sepsis thrombocytopenia.

Effect of recombinant human thrombopoietin on endotoxin-induced thrombocytopenia in mice / 中华危重病急救医学

Objective To investigate the effect of recombinant human thrombopoietin (rhTPO) on thrombocytopenia (TCP) induced by endotoxin lipopolysaccharide (LPS) in mice. Methods Sixty male C57BL/6 mice were divided into normal saline (NS) control group (NS group), sepsis-induced TCP model group (LPS group) and rhTPO treatment group (LPS+rhTPO group) by random number table with 20 mice in each group. Sepsis-induced TCP model was reproduced by one intraperitoneal injection of LPS 30 mg/kg, and the mice in NS group were given the same amount of NS. In LPS+rhTPO group, 2.7 kU/kg rhTPO was subcutaneously injected into mice immediately after intraperitoneal injection of LPS, once every 24 hours. The mice in NS group and LPS group were injected subcutaneously with the same amount of NS. The observation period of each group lasted for 72 hours. The inner canthus blood was harvested before and every 24 hours after modeling, and the platelet count (PLT) was measured by animal blood cell counter. The eyeball blood of mice was harvested at 72 hours after modeling, and the proportion of CD61+CD62p+ cells in platelet-rich plasma was detected by flow cytometry, by which the platelet activation was reflected. Lung and spleen tissues of mice were harvested, and the positive expression of CD41 was determined by immunohistochemistry, by which the platelet sequestration in organs was reflected. Bone marrow cells from unilateral femur of mice were harvested, and the proportion of CD41+CD61+ cells was determined by flow cytometry to reflect the proliferation of bone marrow megakaryocytes. Results There was no significant difference in PLT among the groups before modeling. With the extension of the time after modeling, PLT in LPS group was decreased continuously, and increased slightly at 72 hours, but it was still significantly lower than that in NS group (×109/L: 308.60±21.70 vs. 1 152.72±50.27, P < 0.05); PLT in LPS+rhTPO group was increased continuously with the extension of modeling time, and it was significantly higher at 72 hours than that in LPS group (×109/L: 926.78±48.85 vs. 308.60±21.70, P < 0.05). At 72 hours after modeling, the proportion of CD61+CD62p+ cells in platelet-rich plasma of LPS group was significantly higher than that of NS group [(25.07±2.55)% vs. (4.17±0.38)%, P < 0.05], while the value in LPS+rhTPO group was significantly lower than that of LPS group [(15.92±1.26)% vs. (25.07±2.55)%, P < 0.05]. The proportion of CD41+CD61+ cells in bone marrow megakaryocytes of LPS group was significantly higher than that of NS group [(11.84±0.80)% vs. (3.60±0.42)%, P < 0.05], and the proportion of CD41+CD61+ cells in LPS+rhTPO group was significantly higher than that in LPS group [(30.96±2.49)% vs. (11.84±0.80)%, P < 0.05]. Immunohistochemistry showed that the positive expressions of CD41 in lung and spleen tissues of LPS group increased significantly than NS group [A value: 828.94±119.30 vs. 447.09±16.19 in lung tissue, (280.15±16.71)×103 vs. (0.65±0.26)×103 in spleen tissue, both P < 0.05], while the positive expressions of CD41 in lung and spleen tissues of LPS+rhTPO group decreased significantly than LPS group [A value: 542.78±2.95 vs. 828.94±119.30 in lung tissue, (129.40±13.49)×103 vs. (280.15±16.71)×103 in spleen tissue, both P < 0.05]. Conclusion The rhTPO in endotoxin-induced TCP may stimulate the proliferation of bone marrow megakaryocytes, inhibit platelet activation and affect platelet sequestration in organs, so as to increase platelet levels.

Effect of recombinant human thrombopoietin on platelet activation and pyroptosis in mice with thrombocytopenia / 中华急诊医学杂志

Objective To study the effect and mechanism of recombinant human thrombopoietin (rhTPO) on platelet activation and pyroptosis in mice with lipopolysaccharide (LPS)-induced thrombocytopenia,and provide a theoretical basis for the clinical use of rhTPO.Methods One hundred C57BL/6 mice were randomly(random number) divided into 5 groups:blank control group (sham group),experimental control group (LPS group),low dose (L group,1.35 ×103U · kg-1 · d-1),medium dose (M group,2.7 ×103U · kg-1 · d-1),and high dose (H group,5.4 ×103U · kg-1 · d-1) rhTPO treatment groups.Continuous observation for 72 h.The positive expression rates of CD61/CD62p,Gasdermin D and Caspase-1 in washed platelets were detected by flow cytometry at 72 h,and the levels of IL-1β and IL-18 in plasma were detected by ELISA.Results Compared with the sham group,the survival rate of the LPS group was significantly lower (P＜ 0.01).Compared with the LPS group,the survival rates of the L,M and H groups were slightly increased,but the difference was not statistically significant (P＞0.05).There was no significant change in platelet count of the sham group before and after the experiment.The platelet count in the LPS group decreased significantly.The platelet count at 72 h in the L group was signiftcantly higher than those in the LPS,M and H groups (P＜0.01),and there was no significant difference between the M and H groups and LPS group (P＞0.05).Compared with the sham group,CD61/CD62p and Gasdermin-D protein expressions in the LPS group were significantly increased (P＜0.01),significantly decreased in the L group (P＜0.05),and not significantly changed in the M and H groups (P＞0.05).Caspase-1 expression was significantly increased in the LPS group compared with the sham group (P＜0.01),significantly decreased in the L and M groups compared with the LPS group (P＜0.05),and not significantly changed in the H group compared with the LPS group (P＞0.05).The levels ofplatelet-rich plasma IL-1 beta and IL-18 in the LPS group were significantly higher than those in the sham group (P＜0.01),while those in the L group were significantly lower than those in the LPS group (P＜0.01),and those in the M and H groups were not significantly changed than those in the LPS group (P＞0.05).Conclusions rhTPO can inhibit platelet activation and pyroptosis in LPS-induced thrombocytopenia mice,which provides basic research basis for the treatment of sepsis thrombocytopenia.

Treatment research progress of primary immune thrombocytopenia / 中国基层医药

Primary immune thrombocytopenia is an autoimmune disease characterized by reduced platelets, accompanied by or without skin mucous bruises,epistaxis,internal bleeding,etc. Recent years,the treatment of primary immune thrombocytopenia developed very quickly, including the appearance of platelet receptor agonist - Eltrom-bopag. Here,we reviewed the treatment and research development of primary immune thrombocytopenia.