BACKGROUND Patients with acute-on-chronic liver failure(ACLF)have a high mortality rate,poor prognosis,and often experience concurrent thrombocytopenia and bleeding events.AIM To evaluate the efficacy and safety of re...BACKGROUND Patients with acute-on-chronic liver failure(ACLF)have a high mortality rate,poor prognosis,and often experience concurrent thrombocytopenia and bleeding events.AIM To evaluate the efficacy and safety of recombinant human thrombopoietin(rhTPO)in patients with ACLF with concomitant severe thrombocytopenia.METHODS This was a prospective,open-label study.We assigned 70 ACLF patients with severe thrombocytopenia into the rhTPO group and control group,with 35 patients in each group.Patients in the rhTPO group received subcutaneous injections of rhTPO at a dose of 15000 IU/day for 7 consecutive days,while patients in the control group did not receive rhTPO treatment.The primary endpoint was the proportion of patients with platelet count>50×10^(9)/L on day 14.RESULTS The proportion of patients with platelet count>50×10^(9)/L on day 14 was 60.7%in the rhTPO group,which was significantly higher than that(12.0%)in the control group(P<0.001).The platelet count in the rhTPO group on day 14 was 64×10^(9)/L,exceeding the baseline of 28×10^(9)/L.Compared to the control group,the rhTPO group exhibited a significant increase in platelet count from baseline(P<0.05).Model for end-stage liver disease score,albumin level and international normalized ratio improved significantly from baseline on day 14 after rhTPO injection.The concentrations of serum thrombopoietin and hepatocyte growth factor in the rhTPO group after 7 days were 143.7 and 195.4 pg/mL,respectively,showing a significant increase from baseline(P<0.05).Eight(22.9%)patients had bleeding events in the control group compared with four(11.4%)in the rhTPO group.The incidence of 90-day mortality was also higher in the control group(6,17.1%)than that in the rhTPO group(3,8.6%).CONCLUSION rhTPO significantly increased the platelet count in ACLF patients with thrombocytopenia and reduce the occurrence of bleeding events,with a good safety profile.展开更多
BACKGROUND The safety and efficacy of recombinant human thrombopoietin(rhTPO)administered after allogeneic hematopoietic stem cell transplantation(allo-HSCT)in children(0-9 years old)and adolescents(10-17 years old)wi...BACKGROUND The safety and efficacy of recombinant human thrombopoietin(rhTPO)administered after allogeneic hematopoietic stem cell transplantation(allo-HSCT)in children(0-9 years old)and adolescents(10-17 years old)with hematological disorders remain unclear.AIM To evaluate the safety and efficacy of rhTPO administered before platelet(PLT)engraftment in pediatric patients with hematological disorders undergoing HSCT,and to investigate its effects on the incidence of graft-vs-host disease(GVHD)and other transplant-related outcomes.METHODS This study enrolled 79 pediatric patients with hematological disorders who received rhTPO after allo-HSCT.The safety and tolerability of rhTPO were evaluated and compared in children(n=36)and adolescents(n=43)with hematological disorders.We also investigated the effects of rhTPO administration on the incidence of GVHD and other transplant-related outcomes.Additionally,we examined the efficacy of rhTPO after allo-HSCT in children and adolescents.RESULTS All of the children and adolescents underwent hematopoietic reconstruction.The median time to PLT engraftment was 16 days for all patients,with 14(range,11-24)days in the 0-to 9-year-old group and 16(range,11-41)days in the 10-to 17-year-old group;the difference was statistically significant(P<0.05).The median time to neutrophil engraftment was 12 days in both groups.The median recovery times for PLT counts of≥20×10^(9)/L and≥50×10^(9)/L in the 0-to 9-year-old group were 10(range,2-20)and 11(range,2-20)days,respectively,and those for the 10-to 17-year-old group were 9(range,4-23)and 12(range,5-34)days,respectively.Children exhibited significantly shorter time to PLT engraftment(14 days vs 16 days)and shorter recovery time to PLT count≥100×10^(9)/L(16 days vs 18 days)(P<0.05)than adolescents.The incidence of acute GVHD in all patients was 53.2%,with a higher incidence in children(61.1%)than in adolescents(46.5%).The incidence of chronic GVHD showed little difference between the two age groups,with an overall incidence of 10.1%.No adverse events,other than bleeding,were observed in either age group.The incidence of bleeding was 20.3%.The median follow-up time for all survivors was 573 days(range:42-1803 days)after transplantation.At the final follow-up,3 patients in the 0-to 9-year-old group died;however,none of these deaths were attributed to allo-HSCT or the use of rhTPO.All patients survived in the 10-to 17-year-old group.CONCLUSION rhTPO was not associated with any significant safety issues and was well tolerated by pediatric and adolescent patients with hematologic diseases who underwent allo-HSCT.Our results suggested that rhTPO may benefit allo-HSCT in children and adolescents by improving PLT recovery.展开更多
The cohort study by Li et al provides timely and clinically relevant evidence on the use of recombinant human thrombopoietin(rhTPO)in pediatric allogeneic hematopoietic stem cell transplantation.The authors report enh...The cohort study by Li et al provides timely and clinically relevant evidence on the use of recombinant human thrombopoietin(rhTPO)in pediatric allogeneic hematopoietic stem cell transplantation.The authors report enhanced platelet engraftment and a favorable safety profile,particularly in younger children aged 0-9 years.This age-dependent difference not only highlights the physiological responsiveness of early hematopoietic environments to rhTPO but also raises important questions about tailoring supportive therapies across pediatric age groups.While the findings are promising,the lack of a control group and single-center limitations warrant further multicenter,long-term investigations.Ne-vertheless,the study lays a compelling foundation for integrating rhTPO more broadly into pediatric transplant protocols and for advancing individualized post-transplant care.展开更多
Objective:To study the regulation of trombinol on thrombopoietin,an essential regulator of thrombocyte production.Methods:Effect of trombinol on thrombopoietin regulation was evaluated at the m RNA and protein levels ...Objective:To study the regulation of trombinol on thrombopoietin,an essential regulator of thrombocyte production.Methods:Effect of trombinol on thrombopoietin regulation was evaluated at the m RNA and protein levels in human hepatoma Hep G2 cells.The m RNA expressions were revealed by PCR and real-time PCR,while the protein expressions were analyzed using western blotting and human ELISA kit.Statistical differences between the test were determined by student's t-test with P < 0.05 was considered statistically significant.Results:Trombinol significantly increased the expression of thrombopoietin at the level of m RNA and protein secretion in Hep G2 cell lines.Trombinol with the concentration of15 mg/m L,positively induces 2.5-fold of thrombopoietin expression.Up-regulation of GABP,a transcription factor of thrombopoietin,is suggested to be involved in cellular regulatory mechanisms of trombinol.Here,our result shows convincing evidence that trombinol affects the thrombopoietin productions in vitro.This molecular explanation of thrombopoietin's stimulating function is in line with the traditional use of Psidium guajava for treatment of diseases involving thrombocytopenia.Conclusions:Thrombopoietin stimulating function of trombinol could be potentially considered as one of alternative treatment for thrombocytopenia-related cases,including post chemotherapy shock,dengue fever and liver failure.展开更多
BACKGROUND Chronic liver disease(CLD)related thrombocytopenia increases the risk of bleeding and poor prognosis.Many liver disease patients require invasive procedures or surgeries,such as liver biopsy or endoscopic v...BACKGROUND Chronic liver disease(CLD)related thrombocytopenia increases the risk of bleeding and poor prognosis.Many liver disease patients require invasive procedures or surgeries,such as liver biopsy or endoscopic variceal ligation,and most of them have lower platelet counts,which could aggravate the risk of bleeding due to liver dysfunction and coagulation disorders.Unfortunately,there is no defined treatment modality for CLD-induced thrombocytopenia.Recombinant human thrombopoietin(rhTPO)is commonly used to treat primary immune thrombocytopenic purpura and thrombocytopenia caused by solid tumor chemotherapy;however,there are few reports on the use of rhTPO in the treatment of CLD-related thrombocytopenia.AIM To evaluate the efficacy of rhTPO in the treatment of patients with CLDassociated thrombocytopenia undergoing invasive procedures.METHODS All analyses were based on the retrospective collection of clinical data of patients with CLD who were treated in the Department of Infectious Diseases at The First Affiliated Hospital of Soochow University between June 2020 and December 2021.Fifty-nine male and 41 female patients with liver disease were enrolled in this study to assess the changes in platelet counts and parameters before and after the use of rhTPO for thrombocytopenia.Adverse events related to treatment,such as bleeding,thrombosis,and disseminated intravascular coagulation,were also investigated.RESULTS Among the enrolled patients,78(78%)showed a platelet count increase after rhTPO use,while 22(22%)showed no significant change in platelet count.The mean platelet count after rhTPO treatment in all patients was 101.53±81.81×10^(9)/L,which was significantly improved compared to that at baseline(42.88±16.72×10^(9)/L),and this difference was statistically significant(P<0.001).In addition,patients were further divided into three subgroups according to their baseline platelet counts(<30×10^(9)/L,30-50×10^(9)/L,>50×10^(9)/L).Subgroup analyses showed that the median platelet counts after treatment were significantly higher(P<0.001,all).Ninety(90%)patients did not require platelet transfusion partially due to an increase in platelet count after treatment with rhTPO.No serious adverse events related to rhTPO treatment were observed.Overall,rhTPO demonstrated good clinical efficacy for treating CLD-associated thrombocytopenia.CONCLUSION rhTPO can improve platelet count,reduce the risk of bleeding,and decrease the platelet transfusion rate,which may promote the safety of invasive procedures and improve overall survival of patients with CLD.展开更多
BACKGROUND Thrombopoietin(TPO)is a primary regulator of thrombopoiesis in physiological conditions.TPO,in combination with its specific cytokine receptor c-Mpl,drives platelet production by inducing the proliferation ...BACKGROUND Thrombopoietin(TPO)is a primary regulator of thrombopoiesis in physiological conditions.TPO,in combination with its specific cytokine receptor c-Mpl,drives platelet production by inducing the proliferation and differentiation of megakaryocytes.However,the role of TPO in sepsis is not well determined.The elevated levels of TPO are often accompanied by a decrease of platelet count(PLT)in systemic infected conditions,which is contrary to the view that TPO promotes platelet production under physiological conditions.In addition,whether TPO mediates organ damage in sepsis remains controversial.AIM To explore the relationships between TPO and inflammatory factors,platelet indices,and thrombotic indicators in sepsis.METHODS A total of 90 patients with sepsis diagnosed and treated at the emergency medicine department of The First People’s Hospital of Foshan between January 2020 and March 2021 were enrolled in this study.In addition,110 patients without sepsis who came to the emergency medicine department were included as controls.Clinical and laboratory parameters including age,gender,TPO,blood cell count in peripheral blood,platelet indices,inflammatory factors such as high-sensitivity Creactive protein(hs-CRP),interleukin(IL)-21,and IL-6,organ damage indicators,and thrombotic indicators were collected and analyzed by using various statistical approaches.RESULTS The results showed that the TPO levels were higher in the sepsis group than in controls[86.45(30.55,193.1)vs 12.45(0.64,46.09)pg/mL,P<0.001],but PLT was lower(P<0.001).Multivariable analysis showed that white blood cell count(WBC)[odds ratio(OR)=1.32;95%confidence interval(CI):1.01-1.722;P=0.044],TPO(OR=1.02;95%CI:1.01-1.04;P=0.009),IL-21(OR=1.02;95%CI:1.00-1.03;P=0.019),troponin I(OR=55.20;95%CI:5.69-535.90;P=0.001),and prothrombin time(PT)(OR=2.24;95%CI:1.10-4.55;P=0.027)were independent risk factors associated with sepsis.TPO levels were positively correlated with IL-21,IL-6,hs-CRP,creatinine,D-dimer,PT,activated prothrombin time,international normalized ratio,fibrinogen,WBC count,and neutrophil count,and negatively correlated with PLT,thrombin time,red blood cell count,and hemoglobin concentration(P<0.05).Receiver operating characteristic analysis showed that TPO had fair predictive value in distinguishing septic patients and non-septic patients(the area under the curve:0.788;95%CI:0.723-0.852;P<0.001).With an optimized cutoff value(28.51 pg/mL),TPO had the highest sensitivity(79%)and specificity(65%).CONCLUSION TPO levels are independently associated with sepsis.High TPO levels and low PLT suggest that TPO might be an acute-phase response protein in patients with infection.展开更多
BACKGROUND： Previous studies have reported a neurotrophin-like motif in the N-terminal receptor binding region of the thrombopoietin （TPO） molecule, and have described localization of TPO and TPO receptor in the br...BACKGROUND： Previous studies have reported a neurotrophin-like motif in the N-terminal receptor binding region of the thrombopoietin （TPO） molecule, and have described localization of TPO and TPO receptor in the brain. Therefore, it is believed that TPO may be involved in regulation of neurogenesis. OBJECTIVE： To validate the effect of TPO on trans-differentiation, or differentiation from hematopoietic stem cells （HSCs） to neural stem cells （NSCs）. DESIGN, TIME AND SETTING： Comparative studies were performed from March 2004 to April 2007 at the Department of Experimental Medicine, Northern Hospital, and the Department of Immunology, Fourth Military Medical University of Chinese PLA. MATERIALS： Human fetal liver （FL） was obtained from fetuses after water-balloon abortion. Gestational age ranged from 16 to 20 weeks. The study was approved by the Institutional Review Board and Ethics Committee of the Northern Hospital. TPO was kindly provided by Genentech Inc （USA）. Iscove＇s Modified Dulbecco＇s Medium （IMDM） and neurobasalTM medium were purchased from Invitrogen （USA）. MACS CD34 multisort kit was purchased from Miltenyi Biotec （Germany）. METHODS： CD34^＋ cells were isolated from human FL mononuclear cells using MACS CD34 multisort kit and cultured at 1 × 10^5/mL in IMDM, containing TPO for 60 days with weekly changes of half of the medium. After culturing for 30 and 60 days, the TPO-induced cells were resuspended in neurobasalTM medium containing 10% fetal brain extracts and plated in an 8-well BIOCOAT poly-D-Lysine Culture Slide and cultured for another 7 days. MAIN OUTCOME MEASURES： Cell number, viability, phenotype and expression of hemopoiesis-related and neurogenesis-related proteins were examined by trypan blue exclusion with hemocytometer, immunoblot, immunocytochemistry and flow cytometry. RESULTS： After 60 days of induction with TPO, the cell number increased by 4.6-fold compared to the initial culture. Although the proportion of the cells expressing the hemopoietic stem cell associated antigen （CD34） decreased steadily, both proportions of the cultured FL-derived CD34^＋cells expressing CD41a and CD61 remained unchanged, which still accounted for 10%. Noticeably, the proportions of the cells expressing nestin and epidermal growth factor receptor increased significantly （both 〉 50%）, whereas the expression of more mature neural or glial proteins [microtubule-associated protein-2 （MAP2）, glial fibrillary acidic protein （GFAP）, oligodendrocyte marker 04 （04）] markers on the cultured fetal liver derived-CD34^＋ cells were at lower levels. After another 7 days incubation in neurobasalTM medium, these TPO-induced cells formed neurospheres, which were labeled with nestin, and differentiated into cells with morphological characteristics of neurons, astrocytes and oligodendrocytes, which were labeled with MAP-2, GFAE and 04, respectively. CONCLUSION： TPO can induce FL-derived HSCs to differentiate or trans-differentiate into NSCs and its progenitors.展开更多
BACKGROUND During cirrhosis,the liver is impaired and unable to synthesize and clear thrombopoietin properly.At the same time,the spleen assumes the function of hemofiltration and storage due to liver dysfunction,resu...BACKGROUND During cirrhosis,the liver is impaired and unable to synthesize and clear thrombopoietin properly.At the same time,the spleen assumes the function of hemofiltration and storage due to liver dysfunction,resulting in hypersplenism and excessive removal of platelets in the spleen,further reducing platelet count.When liver function is decompensated in cirrhotic patients,the decrease of thrombopoietin(TPO)synthesis is the main reason for the decrease of new platelet production.This change of TPO leads to thrombocytopenia and bleeding tendency in cirrhotic patients with hypersplenism.AIM To investigate the clinical efficacy of recombinant human TPO(rhTPO)in the treatment of perioperative thrombocytopenia during liver transplantation in cirrhotic mice with hypersplenism.METHODS C57BL/6J mice and TPO receptor-deficient mice were used to establish models of cirrhosis with hypersplenism.Subsequently,these mice underwent orthotopic liver transplantation(OLT).The mice in the experimental group were given rhTPO treatment for 3 consecutive days before surgery and 5 consecutive days after surgery,while the mice in the control group received the same dose of saline at the same frequency.Differences in liver function and platelet counts were determined between the experimental and control groups.Enzyme-linked immunosorbent assay was used to assess the expression of TPO and TPO receptor(c-Mpl)in the blood.RESULTS Preoperative administration of rhTPO significantly improved peri-OLT thrombocytopenia in mice with cirrhosis and hypersplenism.Blocking the expression of TPO receptors exacerbated peri-OLT thrombocytopenia.The concentration of TPO decreased while the concentration of c-Mpl increased in compensation in the mouse model of cirrhosis with hypersplenism.TPO pre-treatment significantly increased the postoperative TPO concentration in mice,which in turn led to a decrease in the c-Mpl concentration.TPO pre-treatment also significantly enhanced the Janus kinase(Jak)/signal transducers and activators of transcription pathway protein expressions in bone marrow stem cells of the C57BL/6J mice.Moreover,the administration of TPO,both before and after surgery,regulated the levels of biochemical indicators,such as alanine aminotransferase,alkaline phosphatase,and aspartate aminotransferase in the C57BL/6J mice.CONCLUSION Pre-treatment with TPO not only exhibited therapeutic effects on perioperative thrombocytopenia in the mice with cirrhosis and hypersplenism,who underwent liver transplantation but also significantly enhanced the perioperative liver function.展开更多
Objective To demonstrate whether heparin could act synergically with thrombopoietin (TPO) instimulating megakaryocytopoiesis and thrombopoiesis. Methods Megakaryocytic leukemia cell line M- 07e,human cord blood CD34+ ...Objective To demonstrate whether heparin could act synergically with thrombopoietin (TPO) instimulating megakaryocytopoiesis and thrombopoiesis. Methods Megakaryocytic leukemia cell line M- 07e,human cord blood CD34+ cells and Balb/c mice were used for studies. The effectS of hoparin and/or TPO onmegakaryocytopoiesis and thrombopoiesis were studied by [ 3H ] - TdR incoroperation assay, CFU- MK plasmicsemi- solid culture and experiment in Balb/c mice in vivo. In addition, M- 07e cells were used as targets tofurther investigate the possible molecular mechanism by which heparin might act synergically with TPO throughNorthern and Western blot analyses. Results Heparin can act synergically with TPO in stimulating theproliferation of leukemia cell line M- 07e, growth of CFU- MK from human cord blood CD34+ cells andmegakaryocytopoiesis and thrombopoiesis in vivo in mice, possibly by antagonizing downregulation of c- mplexpression by TPO at the level of mRNA transcription, and increasing the phosphotyrosine content Of Jak2,triggered by TPO. Conclusion Heparin participated in positive regulation of megakaryocytopoiesis andthrombopoiesis by enhancing the megakaryocytopoietic activities of TPO, and the mechanism of which might beinvolved in the modification of the molecules c- mpl and Jak2 on the way of signal transduction triggered by TPO.展开更多
Objective:To explore whether thrombopoietin can exert a protective effect against doxorubicin-induced cardiotoxicity by modulating the sirtuin 1(SIRT1)signaling pathway.Methods:H9c2 cell viability was determined by CC...Objective:To explore whether thrombopoietin can exert a protective effect against doxorubicin-induced cardiotoxicity by modulating the sirtuin 1(SIRT1)signaling pathway.Methods:H9c2 cell viability was determined by CCK-8 and cardiomyocyte apoptosis was detected by TUNEL assay.The protein expressions of SIRT1 and p38 MAPK were measured by Western blot.RT-qPCR was also used to determine SIRT1 mRNA expression.In addition,intracellular reactive oxygen species levels and antioxidant enzyme activities were evaluated.Results:Thrombopoietin treatment reversed doxorubicin-induced decline in H9c2 cell viability.It also increased SIRT1 and decreased p-p38 MAPK protein expressions.In addition,thrombopoietin significantly attenuated doxorubicin-induced apoptosis and oxidative stress,and enhanced antioxidant enzyme activities.However,silencing SIRT1 abrogated the protective effects of thrombopoietin,as evidenced by reduced cell viability and increased oxidative stress and reactive oxygen species levels.Conclusions:Thrombopoietin alleviates doxorubicin-induced cardiomyocyte injury by reducing oxidative stress and apoptosis via the SIRT1/p38 MAPK pathway.However,its protective effects need to be further verified in animal tests.展开更多
Thrombocytopenia is a multifactorial disorder that is common in patients with chronic liver disease(CLD),leading to challenging perioperative planning.As thrombocytopenia in CLD is associated with thrombopoietin(TPO)d...Thrombocytopenia is a multifactorial disorder that is common in patients with chronic liver disease(CLD),leading to challenging perioperative planning.As thrombocytopenia in CLD is associated with thrombopoietin(TPO)deficiency,the use of TPO-receptor agonists(TPO-RAs)to increase platelet counts is a promising approach.This has led to the development of various TPO-RAs,including romiplostim,eltrombopag,avatrombopag,and lusutrombopag.Of these,only avatrombopag and lusutrombopag are approved by the United States Food and Drug Administration for the perioperative treatment of thrombocytopenia in patients with CLD.Platelet transfusion is commonly used for the clinical management of thrombocytopenia in patients with CLD undergoing invasive procedures.However,the limitations and possible risks of transfusion,including short duration of efficacy,development of antiplatelet antibodies,risk of infections and such complications as transfusion-related acute lung injury or circulatory overload,and possibility of refractoriness,limit its use.Moreover,there is no consensus among guidelines as to the platelet count at which transfusions are indicated.Results from studies using TPO-RAs perioperatively in patients with thrombocytopenia and CLD are promising and provide an alternative to platelet transfusions in the pre-and post-operative setting.These TPO-RAs are the subject of this review,with focus on their use in the perioperative setting in patients with thrombocytopenia,associated supporting clinical trials,efficacy and safety data,and their use with respect to platelet transfusions.展开更多
Objectives To investigate the protective effect of thrombopoietin (TPO) on myocardial cells in vitro. Methods H9C2 cell line was maintained in Iscove’s modified Dulbecco’s medium (IMDM) supplemented with 10% calf se...Objectives To investigate the protective effect of thrombopoietin (TPO) on myocardial cells in vitro. Methods H9C2 cell line was maintained in Iscove’s modified Dulbecco’s medium (IMDM) supplemented with 10% calf serum. Beating cells from heart ventricles of neonatal heart were cultured at an in vitro system. Apoptosis of the cell line above was induced by treatment of doxorubicin (DOX) and was blocked by TPO. Cell survival rate of H9C2 cell was measured by the MTT assay. Changes of beating rate of neonatal myocardial cells were captured by digital camera and beating rate was calculated. Flow cytometry was employed to study anti-apoptotic effect of TPO by staining JC-1 protein to H9C2 cell. Results MTT assay demonstrated that doxorubicin reduced cell survival rate by 73.8%±1.1%, 50 ng·mL-1 and 100 ng·mL-1 TPO increased cell survival rate by 84.6%±3.6% (P<0.05), 86%±4% (P<0.01) at a dose-dependent manner. Beating rate of primary neonatal myocardial cells also decreased to 15%±8% at 48 h, 100 ng·mL-1 TPO improved beating rate to 48%±11% (P<0.01). TPO decreased apoptotic rate from 19%±9% to 11%±6% (P<0.05). Conclusions TPO has protective effect on myocardial cells in vitro. Anti-apoptosis is one of the mechanisms by which TPO protects injured heart.展开更多
Immune thrombocytopenia(ITP)is a rare autoimmune disorder characterized by a platelet count below 100×10^(9)/L.This review aims to comprehensively summarize the current evidence on the use of thrombopoietin recep...Immune thrombocytopenia(ITP)is a rare autoimmune disorder characterized by a platelet count below 100×10^(9)/L.This review aims to comprehensively summarize the current evidence on the use of thrombopoietin receptor agonists(TPO-RAs),with a focus on Hetrombopag,for the treatment of both primary and secondary ITP.Conventional first-line therapies,including glucocorticoids and immunoglobulins,are effective for most ITP patients.Hetrombopag,a novel oral TPO-RA developed in China,has demonstrated superior platelet-raising effects compared to Eltrombopag and shows a more favorable safety profile.Recent clinical trials indicate sustained platelet count improvements in both primary and secondary ITP patients,even after discontinuing concurrent corticosteroid therapy.While initial clinical outcomes of Hetrombopag are promising,additional large-scale,multicenter,randomized controlled trials are required to determine the optimal dosing regimen and confirm long-term efficacy and safety in treating primary and secondary ITP.展开更多
OBJECTIVE: To evaluate the role of thrombopoietin (TPO) in the pathology of chronic thrombocytopenic disease. METHODS: We measured the endogenous plasma concentration of TPO in 40 patients with acquired aplastic anaem...OBJECTIVE: To evaluate the role of thrombopoietin (TPO) in the pathology of chronic thrombocytopenic disease. METHODS: We measured the endogenous plasma concentration of TPO in 40 patients with acquired aplastic anaemia (AA) and in 32 patients with idiopathic thrombocytopenic purpura (ITP) by a sensitive Sandwich enzyme-linked immunosorbent assay (ELISA) and compared the results. RESULTS: Plasma TPO concentrations were significantly higher in AA patients (774 +/- 393 pg/ ml) in comparison with healthy control subjects (55 +/- 34 pg/ml, P 0.05). There was also no relationship between their plasma TPO levels and platelet counts. CONCLUSIONS: TPO levels may be regulated not only by platelets but also by megakaryocytes in AA and ITP, and measurement of TPO levels is useful for diagnosing thrombocytopenia and understanding the pathophysiology of thrombocytopenia.展开更多
Background The management of patients with refractory immune thrombocytopenia （ITP） is challenging, as there is no standard treatment option. The aim of this study was to investigate the efficacy of recombinant huma...Background The management of patients with refractory immune thrombocytopenia （ITP） is challenging, as there is no standard treatment option. The aim of this study was to investigate the efficacy of recombinant human thrombopoietin （rhTPO） in combination with cyclosporin A （CsA） for the management of patients with corticosteroid-resistant primary ITP.展开更多
Background To evaluate the effect of recombinant human thrombopoietin(rhTPO)on clinical prognosis by exploring changes in endothelial cell injury markers and inflammatory factors in patients with sepsis after treatmen...Background To evaluate the effect of recombinant human thrombopoietin(rhTPO)on clinical prognosis by exploring changes in endothelial cell injury markers and inflammatory factors in patients with sepsis after treatment with rhTPO.Methods This retrospective observational study involved patients with sepsis(diagnosed according to Sepsis 3.0)admitted to Shanghai General Hospital intensive care unit from January 1,2019 to December 31,2022.Patients were divided into two groups(control and rhTPO)according to whether they received rhTPO.Baseline information,clinical data,prognosis,and survival status of the patients,as well as inflammatory factors and immune function indicators were collected.The main monitoring indicators were endothelial cell-specific molecule(ESM-1),human heparin-binding protein(HBP),and CD31;secondary monitoring indicators were interleukin(IL)-6,tumor necrosis factor(TNF)-α,extravascular lung water index,platelet,antithrombin III,fibrinogen,and international normalized ratio.We used intraperitoneal injection of lipopolysaccharide(LPS)to establish a mouse model of sepsis.Mice were randomly divided into four groups:normal saline,LPS,LPS+rhTPO,and LPS+rhTPO+LY294002.Plasma indicators in mice were measured by enzyme-linked immunosorbent assay.Results A total of 84 patients were included in the study.After 7 days of treatment,ESM-1 decreased more significantly in the rhTPO group than in the control group compared with day 1(median=38.6[interquartile range,IQR:7.2 to 67.8]pg/mL vs.median=23.0[IQR:−15.7 to 51.5]pg/mL,P=0.008).HBP and CD31 also decreased significantly in the rhTPO group compared with the control group(median=59.6[IQR:−1.9 to 91.9]pg/mL vs.median=2.4[IQR:−23.2 to 43.2]pg/mL;median=2.4[IQR:0.4 to 3.5]pg/mL vs.median=−0.6[IQR:−2.2 to 0.8]pg/mL,P<0.001).Inflammatory markers IL-6 and TNF-αdecreased more significantly in the rhTPO group than in the control group compared with day 1(median=46.0[IQR:15.8 to 99.1]pg/mL vs.median=31.2[IQR:19.7 to 171.0]pg/mL,P<0.001;median=17.2[IQR:6.4 to 23.2]pg/mL vs.median=0.0[IQR:0.0 to 13.8]pg/mL,P=0.010).LPS+rhTPO-treated mice showed significantly lower vascular von Willebrand factor(P=0.003),vascular endothelial growth factor(P=0.002),IL-6(P<0.001),and TNF-α(P<0.001)than mice in the LPS group.Endothelial cell damage factors vascular von Willebrand factor(P=0.012),vascular endothelial growth factor(P=0.001),IL-6(P<0.001),and TNF-α(P=0.001)were significantly elevated by inhibiting the PI3K/Akt pathway.Conclusion rhTPO alleviates endothelial injury and inflammatory indices in sepsis,and may regulate septic endothelial cell injury through the PI3K/Akt pathway.展开更多
Background:Recombinant human thrombopoietin(rh-TPO)and eltrombopag are two distinct TPO receptor agonists(TPO-RAs)with different mechanisms.During the pandemic,when immunosuppressive medications are controversial,swit...Background:Recombinant human thrombopoietin(rh-TPO)and eltrombopag are two distinct TPO receptor agonists(TPO-RAs)with different mechanisms.During the pandemic,when immunosuppressive medications are controversial,switching to another TPO-RA may be worth exploring in patients who do not benefit from their first TPO-RA.We investigated the outcomes of switching from rh-TPO to eltrombopag or vice versa in immune thrombocytopenia(ITP)patients.Methods:This prospective,open-label,observational investigation included 96 adult ITP patients who needed to switch between rh-TPO and eltrombopag between January 2020 and January 2021 at Peking University People’s Hospital in China.The study evaluated response rates and platelet counts at different time points after the switch,bleeding events,time to response,duration of response,and adverse events.Results:At 6 weeks after switching,response was observed in 21/49 patients(43%)who switched for inefficacy and 34/47 patients(72%)who switched for non-efficacy-related issues.In the inefficacy group,9/27 patients(33%)responded to eltrombopag,and 12/22 patients(55%)responded to rh-TPO.In the non-efficacy-related group,21/26(81%)and 13/21(62%)patients in the eltrombopag and rh-TPO groups maintained their response rates at 6 weeks after switching,respectively.Response at 6 months was achieved in 24/49 patients(49%)switching for inefficacy and 37/47 patients(79%)switching for non-efficacy issues.In the inefficacy group,13/27 patients(48%)responded to eltrombopag,and 11/22 patients(50%)responded to rh-TPO.In the non-efficacy-related group,22/26 patients(85%)and 15/21 patients(71%)in the eltrombopag and rh-TPO groups maintained their response rates at 6 months after switching,respectively.Both eltrombopag and rh-TPO were well tolerated.Conclusions:Our study confirmed the safety and effectiveness of switching between rh-TPO and eltrombopag for ITP patients who had no response to or experienced adverse events with their first TPO-RA.When the switch was motivated by other reasons,including patient preference and platelet count fluctuations,the probability of response was high.Registration:ClinicalTrials.gov,NCT04214951.展开更多
Thrombopoietin (TPO) functions as a regulator of megakaryocytes in their differentiation and maturation, and is a candidate pharmaceutical for the curing of thrombocytopenia. Erythropoietin (EPO) is a hematopoietic cy...Thrombopoietin (TPO) functions as a regulator of megakaryocytes in their differentiation and maturation, and is a candidate pharmaceutical for the curing of thrombocytopenia. Erythropoietin (EPO) is a hematopoietic cytokine that regulates the level of red blood cell. It is widely used in renal anemia and tumor associated anemia, and is proved to be safe and effective. In order to study the possibility of using TPO EPO fusion protein for the curing of anemia and thrombocytopenia induced by high dose chemotherapy, a fusion gene is constructed by linking TPO N terminal 153 peptide and EPO mature peptide coding region. The fusion gene is expressed in mammalian cells, revealing that the expression product can support the growth of TPO responsive Ba/F3 mpl cells and EPO dependent Bet 2 cells in the absence of any other stimulating cytokine. It also stimulates the formation of erythroid colonies and megakaryocytic colonies in semi solid bone marrow cultures. These results indicate that the fusion protein has both the in vitro activities of TPO and EPO. The preliminary in vivo experiment reveals that the TPO EPO fusion protein containing cell supernatant raises the platelet level by 37% in mice, while its function on erythroid hematopoiesis remains to be determined. These results indicate that the construction of TPO EPO fusion protein and the further study of its use in high dose chemotherapy are possible展开更多
基金Supported by Tianjin Key Medical Discipline(Specialty)Construction Project,No.TJYXZDXK-034A.
文摘BACKGROUND Patients with acute-on-chronic liver failure(ACLF)have a high mortality rate,poor prognosis,and often experience concurrent thrombocytopenia and bleeding events.AIM To evaluate the efficacy and safety of recombinant human thrombopoietin(rhTPO)in patients with ACLF with concomitant severe thrombocytopenia.METHODS This was a prospective,open-label study.We assigned 70 ACLF patients with severe thrombocytopenia into the rhTPO group and control group,with 35 patients in each group.Patients in the rhTPO group received subcutaneous injections of rhTPO at a dose of 15000 IU/day for 7 consecutive days,while patients in the control group did not receive rhTPO treatment.The primary endpoint was the proportion of patients with platelet count>50×10^(9)/L on day 14.RESULTS The proportion of patients with platelet count>50×10^(9)/L on day 14 was 60.7%in the rhTPO group,which was significantly higher than that(12.0%)in the control group(P<0.001).The platelet count in the rhTPO group on day 14 was 64×10^(9)/L,exceeding the baseline of 28×10^(9)/L.Compared to the control group,the rhTPO group exhibited a significant increase in platelet count from baseline(P<0.05).Model for end-stage liver disease score,albumin level and international normalized ratio improved significantly from baseline on day 14 after rhTPO injection.The concentrations of serum thrombopoietin and hepatocyte growth factor in the rhTPO group after 7 days were 143.7 and 195.4 pg/mL,respectively,showing a significant increase from baseline(P<0.05).Eight(22.9%)patients had bleeding events in the control group compared with four(11.4%)in the rhTPO group.The incidence of 90-day mortality was also higher in the control group(6,17.1%)than that in the rhTPO group(3,8.6%).CONCLUSION rhTPO significantly increased the platelet count in ACLF patients with thrombocytopenia and reduce the occurrence of bleeding events,with a good safety profile.
文摘BACKGROUND The safety and efficacy of recombinant human thrombopoietin(rhTPO)administered after allogeneic hematopoietic stem cell transplantation(allo-HSCT)in children(0-9 years old)and adolescents(10-17 years old)with hematological disorders remain unclear.AIM To evaluate the safety and efficacy of rhTPO administered before platelet(PLT)engraftment in pediatric patients with hematological disorders undergoing HSCT,and to investigate its effects on the incidence of graft-vs-host disease(GVHD)and other transplant-related outcomes.METHODS This study enrolled 79 pediatric patients with hematological disorders who received rhTPO after allo-HSCT.The safety and tolerability of rhTPO were evaluated and compared in children(n=36)and adolescents(n=43)with hematological disorders.We also investigated the effects of rhTPO administration on the incidence of GVHD and other transplant-related outcomes.Additionally,we examined the efficacy of rhTPO after allo-HSCT in children and adolescents.RESULTS All of the children and adolescents underwent hematopoietic reconstruction.The median time to PLT engraftment was 16 days for all patients,with 14(range,11-24)days in the 0-to 9-year-old group and 16(range,11-41)days in the 10-to 17-year-old group;the difference was statistically significant(P<0.05).The median time to neutrophil engraftment was 12 days in both groups.The median recovery times for PLT counts of≥20×10^(9)/L and≥50×10^(9)/L in the 0-to 9-year-old group were 10(range,2-20)and 11(range,2-20)days,respectively,and those for the 10-to 17-year-old group were 9(range,4-23)and 12(range,5-34)days,respectively.Children exhibited significantly shorter time to PLT engraftment(14 days vs 16 days)and shorter recovery time to PLT count≥100×10^(9)/L(16 days vs 18 days)(P<0.05)than adolescents.The incidence of acute GVHD in all patients was 53.2%,with a higher incidence in children(61.1%)than in adolescents(46.5%).The incidence of chronic GVHD showed little difference between the two age groups,with an overall incidence of 10.1%.No adverse events,other than bleeding,were observed in either age group.The incidence of bleeding was 20.3%.The median follow-up time for all survivors was 573 days(range:42-1803 days)after transplantation.At the final follow-up,3 patients in the 0-to 9-year-old group died;however,none of these deaths were attributed to allo-HSCT or the use of rhTPO.All patients survived in the 10-to 17-year-old group.CONCLUSION rhTPO was not associated with any significant safety issues and was well tolerated by pediatric and adolescent patients with hematologic diseases who underwent allo-HSCT.Our results suggested that rhTPO may benefit allo-HSCT in children and adolescents by improving PLT recovery.
文摘The cohort study by Li et al provides timely and clinically relevant evidence on the use of recombinant human thrombopoietin(rhTPO)in pediatric allogeneic hematopoietic stem cell transplantation.The authors report enhanced platelet engraftment and a favorable safety profile,particularly in younger children aged 0-9 years.This age-dependent difference not only highlights the physiological responsiveness of early hematopoietic environments to rhTPO but also raises important questions about tailoring supportive therapies across pediatric age groups.While the findings are promising,the lack of a control group and single-center limitations warrant further multicenter,long-term investigations.Ne-vertheless,the study lays a compelling foundation for integrating rhTPO more broadly into pediatric transplant protocols and for advancing individualized post-transplant care.
文摘Objective:To study the regulation of trombinol on thrombopoietin,an essential regulator of thrombocyte production.Methods:Effect of trombinol on thrombopoietin regulation was evaluated at the m RNA and protein levels in human hepatoma Hep G2 cells.The m RNA expressions were revealed by PCR and real-time PCR,while the protein expressions were analyzed using western blotting and human ELISA kit.Statistical differences between the test were determined by student's t-test with P < 0.05 was considered statistically significant.Results:Trombinol significantly increased the expression of thrombopoietin at the level of m RNA and protein secretion in Hep G2 cell lines.Trombinol with the concentration of15 mg/m L,positively induces 2.5-fold of thrombopoietin expression.Up-regulation of GABP,a transcription factor of thrombopoietin,is suggested to be involved in cellular regulatory mechanisms of trombinol.Here,our result shows convincing evidence that trombinol affects the thrombopoietin productions in vitro.This molecular explanation of thrombopoietin's stimulating function is in line with the traditional use of Psidium guajava for treatment of diseases involving thrombocytopenia.Conclusions:Thrombopoietin stimulating function of trombinol could be potentially considered as one of alternative treatment for thrombocytopenia-related cases,including post chemotherapy shock,dengue fever and liver failure.
基金Supported by the Science and Technology Development Plan of Suzhou,Jiangsu Province,China,No.SYS2020009.
文摘BACKGROUND Chronic liver disease(CLD)related thrombocytopenia increases the risk of bleeding and poor prognosis.Many liver disease patients require invasive procedures or surgeries,such as liver biopsy or endoscopic variceal ligation,and most of them have lower platelet counts,which could aggravate the risk of bleeding due to liver dysfunction and coagulation disorders.Unfortunately,there is no defined treatment modality for CLD-induced thrombocytopenia.Recombinant human thrombopoietin(rhTPO)is commonly used to treat primary immune thrombocytopenic purpura and thrombocytopenia caused by solid tumor chemotherapy;however,there are few reports on the use of rhTPO in the treatment of CLD-related thrombocytopenia.AIM To evaluate the efficacy of rhTPO in the treatment of patients with CLDassociated thrombocytopenia undergoing invasive procedures.METHODS All analyses were based on the retrospective collection of clinical data of patients with CLD who were treated in the Department of Infectious Diseases at The First Affiliated Hospital of Soochow University between June 2020 and December 2021.Fifty-nine male and 41 female patients with liver disease were enrolled in this study to assess the changes in platelet counts and parameters before and after the use of rhTPO for thrombocytopenia.Adverse events related to treatment,such as bleeding,thrombosis,and disseminated intravascular coagulation,were also investigated.RESULTS Among the enrolled patients,78(78%)showed a platelet count increase after rhTPO use,while 22(22%)showed no significant change in platelet count.The mean platelet count after rhTPO treatment in all patients was 101.53±81.81×10^(9)/L,which was significantly improved compared to that at baseline(42.88±16.72×10^(9)/L),and this difference was statistically significant(P<0.001).In addition,patients were further divided into three subgroups according to their baseline platelet counts(<30×10^(9)/L,30-50×10^(9)/L,>50×10^(9)/L).Subgroup analyses showed that the median platelet counts after treatment were significantly higher(P<0.001,all).Ninety(90%)patients did not require platelet transfusion partially due to an increase in platelet count after treatment with rhTPO.No serious adverse events related to rhTPO treatment were observed.Overall,rhTPO demonstrated good clinical efficacy for treating CLD-associated thrombocytopenia.CONCLUSION rhTPO can improve platelet count,reduce the risk of bleeding,and decrease the platelet transfusion rate,which may promote the safety of invasive procedures and improve overall survival of patients with CLD.
基金Supported by the Guangdong Province Medical Science and Technology Research Foundation,No.B2014377the Medical Scientific Research Project of Foshan,No.20190036.
文摘BACKGROUND Thrombopoietin(TPO)is a primary regulator of thrombopoiesis in physiological conditions.TPO,in combination with its specific cytokine receptor c-Mpl,drives platelet production by inducing the proliferation and differentiation of megakaryocytes.However,the role of TPO in sepsis is not well determined.The elevated levels of TPO are often accompanied by a decrease of platelet count(PLT)in systemic infected conditions,which is contrary to the view that TPO promotes platelet production under physiological conditions.In addition,whether TPO mediates organ damage in sepsis remains controversial.AIM To explore the relationships between TPO and inflammatory factors,platelet indices,and thrombotic indicators in sepsis.METHODS A total of 90 patients with sepsis diagnosed and treated at the emergency medicine department of The First People’s Hospital of Foshan between January 2020 and March 2021 were enrolled in this study.In addition,110 patients without sepsis who came to the emergency medicine department were included as controls.Clinical and laboratory parameters including age,gender,TPO,blood cell count in peripheral blood,platelet indices,inflammatory factors such as high-sensitivity Creactive protein(hs-CRP),interleukin(IL)-21,and IL-6,organ damage indicators,and thrombotic indicators were collected and analyzed by using various statistical approaches.RESULTS The results showed that the TPO levels were higher in the sepsis group than in controls[86.45(30.55,193.1)vs 12.45(0.64,46.09)pg/mL,P<0.001],but PLT was lower(P<0.001).Multivariable analysis showed that white blood cell count(WBC)[odds ratio(OR)=1.32;95%confidence interval(CI):1.01-1.722;P=0.044],TPO(OR=1.02;95%CI:1.01-1.04;P=0.009),IL-21(OR=1.02;95%CI:1.00-1.03;P=0.019),troponin I(OR=55.20;95%CI:5.69-535.90;P=0.001),and prothrombin time(PT)(OR=2.24;95%CI:1.10-4.55;P=0.027)were independent risk factors associated with sepsis.TPO levels were positively correlated with IL-21,IL-6,hs-CRP,creatinine,D-dimer,PT,activated prothrombin time,international normalized ratio,fibrinogen,WBC count,and neutrophil count,and negatively correlated with PLT,thrombin time,red blood cell count,and hemoglobin concentration(P<0.05).Receiver operating characteristic analysis showed that TPO had fair predictive value in distinguishing septic patients and non-septic patients(the area under the curve:0.788;95%CI:0.723-0.852;P<0.001).With an optimized cutoff value(28.51 pg/mL),TPO had the highest sensitivity(79%)and specificity(65%).CONCLUSION TPO levels are independently associated with sepsis.High TPO levels and low PLT suggest that TPO might be an acute-phase response protein in patients with infection.
基金National Key Basic Research Program of China, No. 2001CB510004the National Natural Science Foundation of China,No.30030130
文摘BACKGROUND： Previous studies have reported a neurotrophin-like motif in the N-terminal receptor binding region of the thrombopoietin （TPO） molecule, and have described localization of TPO and TPO receptor in the brain. Therefore, it is believed that TPO may be involved in regulation of neurogenesis. OBJECTIVE： To validate the effect of TPO on trans-differentiation, or differentiation from hematopoietic stem cells （HSCs） to neural stem cells （NSCs）. DESIGN, TIME AND SETTING： Comparative studies were performed from March 2004 to April 2007 at the Department of Experimental Medicine, Northern Hospital, and the Department of Immunology, Fourth Military Medical University of Chinese PLA. MATERIALS： Human fetal liver （FL） was obtained from fetuses after water-balloon abortion. Gestational age ranged from 16 to 20 weeks. The study was approved by the Institutional Review Board and Ethics Committee of the Northern Hospital. TPO was kindly provided by Genentech Inc （USA）. Iscove＇s Modified Dulbecco＇s Medium （IMDM） and neurobasalTM medium were purchased from Invitrogen （USA）. MACS CD34 multisort kit was purchased from Miltenyi Biotec （Germany）. METHODS： CD34^＋ cells were isolated from human FL mononuclear cells using MACS CD34 multisort kit and cultured at 1 × 10^5/mL in IMDM, containing TPO for 60 days with weekly changes of half of the medium. After culturing for 30 and 60 days, the TPO-induced cells were resuspended in neurobasalTM medium containing 10% fetal brain extracts and plated in an 8-well BIOCOAT poly-D-Lysine Culture Slide and cultured for another 7 days. MAIN OUTCOME MEASURES： Cell number, viability, phenotype and expression of hemopoiesis-related and neurogenesis-related proteins were examined by trypan blue exclusion with hemocytometer, immunoblot, immunocytochemistry and flow cytometry. RESULTS： After 60 days of induction with TPO, the cell number increased by 4.6-fold compared to the initial culture. Although the proportion of the cells expressing the hemopoietic stem cell associated antigen （CD34） decreased steadily, both proportions of the cultured FL-derived CD34^＋cells expressing CD41a and CD61 remained unchanged, which still accounted for 10%. Noticeably, the proportions of the cells expressing nestin and epidermal growth factor receptor increased significantly （both 〉 50%）, whereas the expression of more mature neural or glial proteins [microtubule-associated protein-2 （MAP2）, glial fibrillary acidic protein （GFAP）, oligodendrocyte marker 04 （04）] markers on the cultured fetal liver derived-CD34^＋ cells were at lower levels. After another 7 days incubation in neurobasalTM medium, these TPO-induced cells formed neurospheres, which were labeled with nestin, and differentiated into cells with morphological characteristics of neurons, astrocytes and oligodendrocytes, which were labeled with MAP-2, GFAE and 04, respectively. CONCLUSION： TPO can induce FL-derived HSCs to differentiate or trans-differentiate into NSCs and its progenitors.
基金All procedures involving animals were reviewed and approved by the Tianjin Tiancheng New Drug Evaluation Co.,Ltd(Approval No.2023041701).
文摘BACKGROUND During cirrhosis,the liver is impaired and unable to synthesize and clear thrombopoietin properly.At the same time,the spleen assumes the function of hemofiltration and storage due to liver dysfunction,resulting in hypersplenism and excessive removal of platelets in the spleen,further reducing platelet count.When liver function is decompensated in cirrhotic patients,the decrease of thrombopoietin(TPO)synthesis is the main reason for the decrease of new platelet production.This change of TPO leads to thrombocytopenia and bleeding tendency in cirrhotic patients with hypersplenism.AIM To investigate the clinical efficacy of recombinant human TPO(rhTPO)in the treatment of perioperative thrombocytopenia during liver transplantation in cirrhotic mice with hypersplenism.METHODS C57BL/6J mice and TPO receptor-deficient mice were used to establish models of cirrhosis with hypersplenism.Subsequently,these mice underwent orthotopic liver transplantation(OLT).The mice in the experimental group were given rhTPO treatment for 3 consecutive days before surgery and 5 consecutive days after surgery,while the mice in the control group received the same dose of saline at the same frequency.Differences in liver function and platelet counts were determined between the experimental and control groups.Enzyme-linked immunosorbent assay was used to assess the expression of TPO and TPO receptor(c-Mpl)in the blood.RESULTS Preoperative administration of rhTPO significantly improved peri-OLT thrombocytopenia in mice with cirrhosis and hypersplenism.Blocking the expression of TPO receptors exacerbated peri-OLT thrombocytopenia.The concentration of TPO decreased while the concentration of c-Mpl increased in compensation in the mouse model of cirrhosis with hypersplenism.TPO pre-treatment significantly increased the postoperative TPO concentration in mice,which in turn led to a decrease in the c-Mpl concentration.TPO pre-treatment also significantly enhanced the Janus kinase(Jak)/signal transducers and activators of transcription pathway protein expressions in bone marrow stem cells of the C57BL/6J mice.Moreover,the administration of TPO,both before and after surgery,regulated the levels of biochemical indicators,such as alanine aminotransferase,alkaline phosphatase,and aspartate aminotransferase in the C57BL/6J mice.CONCLUSION Pre-treatment with TPO not only exhibited therapeutic effects on perioperative thrombocytopenia in the mice with cirrhosis and hypersplenism,who underwent liver transplantation but also significantly enhanced the perioperative liver function.
文摘Objective To demonstrate whether heparin could act synergically with thrombopoietin (TPO) instimulating megakaryocytopoiesis and thrombopoiesis. Methods Megakaryocytic leukemia cell line M- 07e,human cord blood CD34+ cells and Balb/c mice were used for studies. The effectS of hoparin and/or TPO onmegakaryocytopoiesis and thrombopoiesis were studied by [ 3H ] - TdR incoroperation assay, CFU- MK plasmicsemi- solid culture and experiment in Balb/c mice in vivo. In addition, M- 07e cells were used as targets tofurther investigate the possible molecular mechanism by which heparin might act synergically with TPO throughNorthern and Western blot analyses. Results Heparin can act synergically with TPO in stimulating theproliferation of leukemia cell line M- 07e, growth of CFU- MK from human cord blood CD34+ cells andmegakaryocytopoiesis and thrombopoiesis in vivo in mice, possibly by antagonizing downregulation of c- mplexpression by TPO at the level of mRNA transcription, and increasing the phosphotyrosine content Of Jak2,triggered by TPO. Conclusion Heparin participated in positive regulation of megakaryocytopoiesis andthrombopoiesis by enhancing the megakaryocytopoietic activities of TPO, and the mechanism of which might beinvolved in the modification of the molecules c- mpl and Jak2 on the way of signal transduction triggered by TPO.
基金supported by the Natural Science Foundation of Hainan Province High-level Talent Project(grant number 820RC644)Innovative Research Projects for Postgraduate Students at Hainan Medical University(grant number HYYS2022B08).
文摘Objective:To explore whether thrombopoietin can exert a protective effect against doxorubicin-induced cardiotoxicity by modulating the sirtuin 1(SIRT1)signaling pathway.Methods:H9c2 cell viability was determined by CCK-8 and cardiomyocyte apoptosis was detected by TUNEL assay.The protein expressions of SIRT1 and p38 MAPK were measured by Western blot.RT-qPCR was also used to determine SIRT1 mRNA expression.In addition,intracellular reactive oxygen species levels and antioxidant enzyme activities were evaluated.Results:Thrombopoietin treatment reversed doxorubicin-induced decline in H9c2 cell viability.It also increased SIRT1 and decreased p-p38 MAPK protein expressions.In addition,thrombopoietin significantly attenuated doxorubicin-induced apoptosis and oxidative stress,and enhanced antioxidant enzyme activities.However,silencing SIRT1 abrogated the protective effects of thrombopoietin,as evidenced by reduced cell viability and increased oxidative stress and reactive oxygen species levels.Conclusions:Thrombopoietin alleviates doxorubicin-induced cardiomyocyte injury by reducing oxidative stress and apoptosis via the SIRT1/p38 MAPK pathway.However,its protective effects need to be further verified in animal tests.
文摘Thrombocytopenia is a multifactorial disorder that is common in patients with chronic liver disease(CLD),leading to challenging perioperative planning.As thrombocytopenia in CLD is associated with thrombopoietin(TPO)deficiency,the use of TPO-receptor agonists(TPO-RAs)to increase platelet counts is a promising approach.This has led to the development of various TPO-RAs,including romiplostim,eltrombopag,avatrombopag,and lusutrombopag.Of these,only avatrombopag and lusutrombopag are approved by the United States Food and Drug Administration for the perioperative treatment of thrombocytopenia in patients with CLD.Platelet transfusion is commonly used for the clinical management of thrombocytopenia in patients with CLD undergoing invasive procedures.However,the limitations and possible risks of transfusion,including short duration of efficacy,development of antiplatelet antibodies,risk of infections and such complications as transfusion-related acute lung injury or circulatory overload,and possibility of refractoriness,limit its use.Moreover,there is no consensus among guidelines as to the platelet count at which transfusions are indicated.Results from studies using TPO-RAs perioperatively in patients with thrombocytopenia and CLD are promising and provide an alternative to platelet transfusions in the pre-and post-operative setting.These TPO-RAs are the subject of this review,with focus on their use in the perioperative setting in patients with thrombocytopenia,associated supporting clinical trials,efficacy and safety data,and their use with respect to platelet transfusions.
文摘Objectives To investigate the protective effect of thrombopoietin (TPO) on myocardial cells in vitro. Methods H9C2 cell line was maintained in Iscove’s modified Dulbecco’s medium (IMDM) supplemented with 10% calf serum. Beating cells from heart ventricles of neonatal heart were cultured at an in vitro system. Apoptosis of the cell line above was induced by treatment of doxorubicin (DOX) and was blocked by TPO. Cell survival rate of H9C2 cell was measured by the MTT assay. Changes of beating rate of neonatal myocardial cells were captured by digital camera and beating rate was calculated. Flow cytometry was employed to study anti-apoptotic effect of TPO by staining JC-1 protein to H9C2 cell. Results MTT assay demonstrated that doxorubicin reduced cell survival rate by 73.8%±1.1%, 50 ng·mL-1 and 100 ng·mL-1 TPO increased cell survival rate by 84.6%±3.6% (P<0.05), 86%±4% (P<0.01) at a dose-dependent manner. Beating rate of primary neonatal myocardial cells also decreased to 15%±8% at 48 h, 100 ng·mL-1 TPO improved beating rate to 48%±11% (P<0.01). TPO decreased apoptotic rate from 19%±9% to 11%±6% (P<0.05). Conclusions TPO has protective effect on myocardial cells in vitro. Anti-apoptosis is one of the mechanisms by which TPO protects injured heart.
基金supported by grants from the National Natural Science Foundation of China(NSFC Project,Nos.82171754 and 81971484)the Natural Science Foundation of the Shanghai Higher Education Institutions of China(No.21ZR1478900)+1 种基金the Scientific Research Project of Shanghai Municipal Health Commission(No.202340061)the Basic Medical Research Special Surface Cultivation Project of the First Affiliated Hospital of Naval Medical University(No.2023PY40).
文摘Immune thrombocytopenia(ITP)is a rare autoimmune disorder characterized by a platelet count below 100×10^(9)/L.This review aims to comprehensively summarize the current evidence on the use of thrombopoietin receptor agonists(TPO-RAs),with a focus on Hetrombopag,for the treatment of both primary and secondary ITP.Conventional first-line therapies,including glucocorticoids and immunoglobulins,are effective for most ITP patients.Hetrombopag,a novel oral TPO-RA developed in China,has demonstrated superior platelet-raising effects compared to Eltrombopag and shows a more favorable safety profile.Recent clinical trials indicate sustained platelet count improvements in both primary and secondary ITP patients,even after discontinuing concurrent corticosteroid therapy.While initial clinical outcomes of Hetrombopag are promising,additional large-scale,multicenter,randomized controlled trials are required to determine the optimal dosing regimen and confirm long-term efficacy and safety in treating primary and secondary ITP.
文摘OBJECTIVE: To evaluate the role of thrombopoietin (TPO) in the pathology of chronic thrombocytopenic disease. METHODS: We measured the endogenous plasma concentration of TPO in 40 patients with acquired aplastic anaemia (AA) and in 32 patients with idiopathic thrombocytopenic purpura (ITP) by a sensitive Sandwich enzyme-linked immunosorbent assay (ELISA) and compared the results. RESULTS: Plasma TPO concentrations were significantly higher in AA patients (774 +/- 393 pg/ ml) in comparison with healthy control subjects (55 +/- 34 pg/ml, P 0.05). There was also no relationship between their plasma TPO levels and platelet counts. CONCLUSIONS: TPO levels may be regulated not only by platelets but also by megakaryocytes in AA and ITP, and measurement of TPO levels is useful for diagnosing thrombocytopenia and understanding the pathophysiology of thrombocytopenia.
文摘Background The management of patients with refractory immune thrombocytopenia （ITP） is challenging, as there is no standard treatment option. The aim of this study was to investigate the efficacy of recombinant human thrombopoietin （rhTPO） in combination with cyclosporin A （CsA） for the management of patients with corticosteroid-resistant primary ITP.
基金supported by grants from the Shenkang Municipal Hospital emerging Frontier technology joint project(grant no.SHDC12019131)the National Natural Science Foundation of China(grant no.82202423)+4 种基金the Clinical Research Innovation Plan of Shanghai General Hospital(grant no.CCTR-2022B04)the 3rd Sansheng TCP Young and Middleaged Scientific Research FundingShanghai Jiao Tong University“Medicine-Engineering Interdisciplinary Research Fund”(grant no.YG2021QN79)National Key Clinical Specialist Construction Project(grant no.Z155080000004)Shanghai Committee(grant no.23Y31900100).
文摘Background To evaluate the effect of recombinant human thrombopoietin(rhTPO)on clinical prognosis by exploring changes in endothelial cell injury markers and inflammatory factors in patients with sepsis after treatment with rhTPO.Methods This retrospective observational study involved patients with sepsis(diagnosed according to Sepsis 3.0)admitted to Shanghai General Hospital intensive care unit from January 1,2019 to December 31,2022.Patients were divided into two groups(control and rhTPO)according to whether they received rhTPO.Baseline information,clinical data,prognosis,and survival status of the patients,as well as inflammatory factors and immune function indicators were collected.The main monitoring indicators were endothelial cell-specific molecule(ESM-1),human heparin-binding protein(HBP),and CD31;secondary monitoring indicators were interleukin(IL)-6,tumor necrosis factor(TNF)-α,extravascular lung water index,platelet,antithrombin III,fibrinogen,and international normalized ratio.We used intraperitoneal injection of lipopolysaccharide(LPS)to establish a mouse model of sepsis.Mice were randomly divided into four groups:normal saline,LPS,LPS+rhTPO,and LPS+rhTPO+LY294002.Plasma indicators in mice were measured by enzyme-linked immunosorbent assay.Results A total of 84 patients were included in the study.After 7 days of treatment,ESM-1 decreased more significantly in the rhTPO group than in the control group compared with day 1(median=38.6[interquartile range,IQR:7.2 to 67.8]pg/mL vs.median=23.0[IQR:−15.7 to 51.5]pg/mL,P=0.008).HBP and CD31 also decreased significantly in the rhTPO group compared with the control group(median=59.6[IQR:−1.9 to 91.9]pg/mL vs.median=2.4[IQR:−23.2 to 43.2]pg/mL;median=2.4[IQR:0.4 to 3.5]pg/mL vs.median=−0.6[IQR:−2.2 to 0.8]pg/mL,P<0.001).Inflammatory markers IL-6 and TNF-αdecreased more significantly in the rhTPO group than in the control group compared with day 1(median=46.0[IQR:15.8 to 99.1]pg/mL vs.median=31.2[IQR:19.7 to 171.0]pg/mL,P<0.001;median=17.2[IQR:6.4 to 23.2]pg/mL vs.median=0.0[IQR:0.0 to 13.8]pg/mL,P=0.010).LPS+rhTPO-treated mice showed significantly lower vascular von Willebrand factor(P=0.003),vascular endothelial growth factor(P=0.002),IL-6(P<0.001),and TNF-α(P<0.001)than mice in the LPS group.Endothelial cell damage factors vascular von Willebrand factor(P=0.012),vascular endothelial growth factor(P=0.001),IL-6(P<0.001),and TNF-α(P=0.001)were significantly elevated by inhibiting the PI3K/Akt pathway.Conclusion rhTPO alleviates endothelial injury and inflammatory indices in sepsis,and may regulate septic endothelial cell injury through the PI3K/Akt pathway.
基金Beijing Natural Science Foundation(No.H2018206423)National Natural Science Foundation of China(No.81970113)+1 种基金Key Program of National Natural Science Foundation of China(No.81730004)National Key Research and Development Program of China(No.2017YFA0105503)。
文摘Background:Recombinant human thrombopoietin(rh-TPO)and eltrombopag are two distinct TPO receptor agonists(TPO-RAs)with different mechanisms.During the pandemic,when immunosuppressive medications are controversial,switching to another TPO-RA may be worth exploring in patients who do not benefit from their first TPO-RA.We investigated the outcomes of switching from rh-TPO to eltrombopag or vice versa in immune thrombocytopenia(ITP)patients.Methods:This prospective,open-label,observational investigation included 96 adult ITP patients who needed to switch between rh-TPO and eltrombopag between January 2020 and January 2021 at Peking University People’s Hospital in China.The study evaluated response rates and platelet counts at different time points after the switch,bleeding events,time to response,duration of response,and adverse events.Results:At 6 weeks after switching,response was observed in 21/49 patients(43%)who switched for inefficacy and 34/47 patients(72%)who switched for non-efficacy-related issues.In the inefficacy group,9/27 patients(33%)responded to eltrombopag,and 12/22 patients(55%)responded to rh-TPO.In the non-efficacy-related group,21/26(81%)and 13/21(62%)patients in the eltrombopag and rh-TPO groups maintained their response rates at 6 weeks after switching,respectively.Response at 6 months was achieved in 24/49 patients(49%)switching for inefficacy and 37/47 patients(79%)switching for non-efficacy issues.In the inefficacy group,13/27 patients(48%)responded to eltrombopag,and 11/22 patients(50%)responded to rh-TPO.In the non-efficacy-related group,22/26 patients(85%)and 15/21 patients(71%)in the eltrombopag and rh-TPO groups maintained their response rates at 6 months after switching,respectively.Both eltrombopag and rh-TPO were well tolerated.Conclusions:Our study confirmed the safety and effectiveness of switching between rh-TPO and eltrombopag for ITP patients who had no response to or experienced adverse events with their first TPO-RA.When the switch was motivated by other reasons,including patient preference and platelet count fluctuations,the probability of response was high.Registration:ClinicalTrials.gov,NCT04214951.
文摘Thrombopoietin (TPO) functions as a regulator of megakaryocytes in their differentiation and maturation, and is a candidate pharmaceutical for the curing of thrombocytopenia. Erythropoietin (EPO) is a hematopoietic cytokine that regulates the level of red blood cell. It is widely used in renal anemia and tumor associated anemia, and is proved to be safe and effective. In order to study the possibility of using TPO EPO fusion protein for the curing of anemia and thrombocytopenia induced by high dose chemotherapy, a fusion gene is constructed by linking TPO N terminal 153 peptide and EPO mature peptide coding region. The fusion gene is expressed in mammalian cells, revealing that the expression product can support the growth of TPO responsive Ba/F3 mpl cells and EPO dependent Bet 2 cells in the absence of any other stimulating cytokine. It also stimulates the formation of erythroid colonies and megakaryocytic colonies in semi solid bone marrow cultures. These results indicate that the fusion protein has both the in vitro activities of TPO and EPO. The preliminary in vivo experiment reveals that the TPO EPO fusion protein containing cell supernatant raises the platelet level by 37% in mice, while its function on erythroid hematopoiesis remains to be determined. These results indicate that the construction of TPO EPO fusion protein and the further study of its use in high dose chemotherapy are possible
