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1.
Biomolecules ; 14(4)2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38672505

RESUMO

Thrombopoietin, the primary regulator of blood platelet production, was postulated to exist in 1958, but was only proven to exist when the cDNA for the hormone was cloned in 1994. Since its initial cloning and characterization, the hormone has revealed many surprises. For example, instead of acting as the postulated differentiation factor for platelet precursors, megakaryocytes, it is the most potent stimulator of megakaryocyte progenitor expansion known. Moreover, it also stimulates the survival, and in combination with stem cell factor leads to the expansion of hematopoietic stem cells. All of these growth-promoting activities have resulted in its clinical use in patients with thrombocytopenia and aplastic anemia, although the clinical development of the native molecule illustrated that "it's not wise to mess with mother nature", as a highly engineered version of the native hormone led to autoantibody formation and severe thrombocytopenia. Finally, another unexpected finding was the role of the thrombopoietin receptor in stem cell biology, including the development of myeloproliferative neoplasms, an important disorder of hematopoietic stem cells. Overall, the past 30 years of clinical and basic research has yielded many important insights, which are reviewed in this paper.


Assuntos
Plaquetas , Trombopoetina , Trombopoetina/metabolismo , Humanos , Plaquetas/metabolismo , Animais , Receptores de Trombopoetina/metabolismo , Receptores de Trombopoetina/genética , Trombopoese , Trombocitopenia/metabolismo , Megacariócitos/metabolismo , Megacariócitos/citologia
2.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 32(2): 505-511, 2024 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-38660859

RESUMO

OBJECTIVE: To analyze the effect of recombinant human thrombopoietin (rhTPO) on platelet (PLT) reconstitution after autologous peripheral blood stem cell transplantation (APBSCT) in patients with multiple myeloma (MM). METHODS: The clinical data of 147 MM patients who were diagnosed in the First Affiliated Hospital of Soochow University and received APBSCT as the first-line therapy were retrospectively analyzed. According to whether rhTPO was used during APBSCT, the patients were divided into rhTPO group (80 cases) and control group (67 cases). The time of PLT engraftment, blood product infusion requirements, the proportion of patients with PLT recovery to≥50×109/L and≥100×109/L at +14 days and +100 days after transplantation, and adverse reactions including the incidence of bleeding were compared between the two groups. RESULTS: There were no significant differences between the two groups in sex, age, M protein type, PLT count at the initial diagnosis, median duration of induction therapy before APBSCT, and number of CD34+ cells reinfused (all P >0.05). The median time of PLT engraftment in the rhTPO group was 10 (6-14) days, which was shorter than 11 (8-23) days in the control group (P < 0.001). The median PLT transfusion requirement in the rhTPO group during APBSCT was 15(0-50)U, which was less than 20 (0-80)U in the control group (P =0.001). At +14 days after transplantation, the proportions of patients with PLT≥50×109/L in the rhTPO group and the control group were 66.3% and 52.2%, while the proportions of patients with PLT≥100×109/L were 23.8% and 11.9%, respectively, with no significant differences (all P >0.05). At +100 days after transplantation, the proportion of patients with PLT≥50×109/L in rhTPO group and control group was 96.3% and 89.6%, respectively (P >0.05), but the proportion of patients with PLT≥100×109/L in rhTPO group was higher than that in control group (75.0% vs 55.2%, P =0.012). There was no difference in the overall incidence of bleeding events in different locations during period of low PLT level of patients between the two groups. In rhTPO group, the rhTPO administration was well tolerated, and the incidences of abnormal liver and kidney function and infection were similar to those in the control group. CONCLUSION: When MM patients undergo first-line APBSCT, subcutaneous injection of rhTPO can shorten the time of platelet engraftment, reduce the transfusion volume of blood products, and be well tolerated, moreover, more patients have achieve a high level of PLT recovery after transplantation, which is very important for ensuring the safety of APBSCT and maintenance therapy.


Assuntos
Mieloma Múltiplo , Transplante de Células-Tronco de Sangue Periférico , Proteínas Recombinantes , Trombopoetina , Transplante Autólogo , Humanos , Mieloma Múltiplo/terapia , Proteínas Recombinantes/administração & dosagem , Plaquetas , Contagem de Plaquetas , Masculino , Feminino
3.
Stem Cell Res Ther ; 15(1): 123, 2024 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-38679747

RESUMO

BACKGROUND: Acute radiation syndrome (ARS) manifests after exposure to high doses of radiation in the instances of radiologic accidents or incidents. Facilitating regeneration of the bone marrow (BM), namely the hematopoietic stem and progenitor cells (HSPCs), is key in mitigating ARS and multi-organ failure. JNJ-26366821, a PEGylated thrombopoietin mimetic (TPOm) peptide, has been shown as an effective medical countermeasure (MCM) to treat hematopoietic-ARS (H-ARS) in mice. However, the activity of TPOm on regulating BM vascular and stromal niches to support HSPC regeneration has yet to be elucidated. METHODS: C57BL/6J mice (9-14 weeks old) received sublethal or lethal total body irradiation (TBI), a model for H-ARS, by 137Cs or X-rays. At 24 h post-irradiation, mice were subcutaneously injected with a single dose of TPOm (0.3 mg/kg or 1.0 mg/kg) or PBS (vehicle). At homeostasis and on days 4, 7, 10, 14, 18, and 21 post-TBI with and without TPOm treatment, BM was harvested for histology, BM flow cytometry of HSPCs, endothelial (EC) and mesenchymal stromal cells (MSC), and whole-mount confocal microscopy. For survival, irradiated mice were monitored and weighed for 30 days. Lastly, BM triple negative cells (TNC; CD45-, TER-119-, CD31-) were sorted for single-cell RNA-sequencing to examine transcriptomics after TBI with or without TPOm treatment. RESULTS: At homeostasis, TPOm expanded the number of circulating platelets and HSPCs, ECs, and MSCs in the BM. Following sublethal TBI, TPOm improved BM architecture and promoted recovery of HSPCs, ECs, and MSCs. Furthermore, TPOm elevated VEGF-C levels in normal and irradiated mice. Following lethal irradiation, mice improved body weight recovery and 30-day survival when treated with TPOm after 137Cs and X-ray exposure. Additionally, TPOm reduced vascular dilation and permeability. Finally, single-cell RNA-seq analysis indicated that TPOm increased the expression of collagens in MSCs to enhance their interaction with other progenitors in BM and upregulated the regeneration pathway in MSCs. CONCLUSIONS: TPOm interacts with BM vascular and stromal niches to locally support hematopoietic reconstitution and systemically improve survival in mice after TBI. Therefore, this work warrants the development of TPOm as a potent radiation MCM for the treatment of ARS.


Assuntos
Síndrome Aguda da Radiação , Medula Óssea , Camundongos Endogâmicos C57BL , Trombopoetina , Animais , Masculino , Camundongos , Síndrome Aguda da Radiação/tratamento farmacológico , Síndrome Aguda da Radiação/patologia , Medula Óssea/efeitos dos fármacos , Medula Óssea/efeitos da radiação , Medula Óssea/metabolismo , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/efeitos da radiação , Nicho de Células-Tronco/efeitos dos fármacos , Nicho de Células-Tronco/efeitos da radiação , Trombopoetina/farmacologia , Irradiação Corporal Total , Materiais Biomiméticos/farmacologia , Materiais Biomiméticos/uso terapêutico
5.
Exp Neurol ; 377: 114781, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38636773

RESUMO

Chronic hypoxia in utero causes intrauterine growth restriction (IUGR) of the fetus. IUGR infants are known to be at higher risk for neurodevelopmental disorders, but the mechanism is unclear. In this study, we analyzed the structure of the cerebral cortex using IUGR model rats generated through a reduced uterine perfusion pressure operation. IUGR rats exhibited thinner cerebral white matter and enlarged lateral ventricles compared with control rats. Expression of neuron cell markers, Satb2, microtubule-associated protein (MAP)-2, α-tubulin, and nestin was reduced in IUGR rats, indicating that neurons were diminished at various developmental stages in IUGR rats, from neural stem cells to mature neurons. However, there was no increase in apoptosis in IUGR rats. Cells positive for Ki67, a marker of cell proliferation, were reduced in neurons and all glial cells of IUGR rats. In primary neuron cultures, axonal elongation was impaired under hypoxic culture conditions mimicking the intrauterine environment of IUGR infants. Thus, in IUGR rats, chronic hypoxia in utero suppresses the proliferation of neurons and glial cells as well as axonal elongation, resulting in cortical thinning and enlarged lateral ventricles. Thrombopoietin (TPO), a platelet growth factor, inhibited the decrease in neuron number and promoted axon elongation in primary neurons under hypoxic conditions. Intraperitoneal administration of TPO to IUGR rats resulted in increases in the number of NeuN-positive cells and the area coverage of Satb2. In conclusion, suppression of neuronal proliferation and axonal outgrowth in IUGR rats resulted in cortical thinning and enlargement of lateral ventricles. TPO administration might be a novel therapeutic strategy for treating brain dysmaturation in IUGR infants.


Assuntos
Proliferação de Células , Retardo do Crescimento Fetal , Crescimento Neuronal , Neurônios , Fármacos Neuroprotetores , Ratos Sprague-Dawley , Trombopoetina , Animais , Retardo do Crescimento Fetal/patologia , Ratos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/metabolismo , Feminino , Proliferação de Células/efeitos dos fármacos , Gravidez , Crescimento Neuronal/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Células Cultivadas , Animais Recém-Nascidos , Córtex Cerebral/patologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo
6.
Front Immunol ; 15: 1340908, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38650933

RESUMO

Background: Eltrombopag has demonstrated efficacy in treating low platelet (PLT) levels, but it remains unclear whether eltrombopag can promote PLT engraftment after hematopoietic stem cell transplantation (HSCT). Methods: Forty-one HSCT patients received eltrombopag 50 mg/d from +1 day until PLT >50 × 109/L or 1 month after HSCT. Fifty-one patients in the same period received thrombopoietin (TPO) to promote PLT graft after HSCT and served as a control group. Results: A total of 51 patients who applied TPO during the same period were treated as a control. In the eltrombopag group, the median time to white blood cells (WBC) graft was 12 days (range, 10-17 days) and the PLT graft was 15 days (range, 10-30 days), whereas for the patients in the TPO group, the median time to WBC and PLT graft was 12 days (range, 9-23 days) and 15.5 days (range, 9-41 days), respectively. In the first month after HSCT, the median WBC count in the eltrombopag group was 4.41 × 109/L (range, 0.87-40.01 × 109/L) and the median PLT was 89x109/L (range, 30-401 × 109/L); the median WBC and PLT \counts in the TPO group were 4.65 × 109/L (range, 0.99-23.63 × 109/L) and 86 × 109/L (range, 5-512 × 109/L), respectively. Patients in the TPO or eltrombopag group did not experience serious side effects after drug administration, and the difference in side effects on liver and kidney function between the two groups was not statistically significant. Conclusion: Eltrombopag is safe and similarly promotes platelet engraftment to thrombopoietin after allogeneic HSCT.


Assuntos
Benzoatos , Transplante de Células-Tronco Hematopoéticas , Hidrazinas , Pirazóis , Trombopoetina , Feminino , Humanos , Masculino , Benzoatos/uso terapêutico , Plaquetas/metabolismo , Plaquetas/efeitos dos fármacos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Hidrazinas/uso terapêutico , Contagem de Plaquetas , Pirazóis/uso terapêutico , Pirazóis/farmacologia , Trombopoetina/uso terapêutico , Transplante Homólogo
8.
Cancer ; 130(S8): 1524-1538, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38515388

RESUMO

BACKGROUND: Studies on various thrombopoietic agents for cancer treatment-induced thrombocytopenia (CTIT) in China are lacking. This study aimed to provide detailed clinical profiles to understand the outcomes and safety of different CTIT treatment regimens. METHODS: In this retrospective, cross-sectional study, 1664 questionnaires were collected from 33 hospitals between March 1 and July 1, 2021. Patients aged >18 years were enrolled who were diagnosed with CTIT and treated with recombinant interleukin 11 (rhIL-11), recombinant thrombopoietin (rhTPO), or a thrombopoietin receptor agonist (TPO-RA). The outcomes, compliance, and safety of different treatments were analyzed. RESULTS: Among the 1437 analyzable cases, most patients were treated with either rhTPO alone (49.3%) or rhIL-11 alone (27.0%). The most common combination regimen used was rhTPO and rhIL-11 (10.9%). Platelet transfusions were received by 117 cases (8.1%). In multivariate analysis, rhTPO was associated with a significantly lower proportion of platelet recovery, platelet transfusion, and hospitalization due to chemotherapy-induced thrombocytopenia (CIT) than rhIL-11 alone. No significant difference was observed in the time taken to achieve a platelet count of >100 × 109/L and chemotherapy dose reduction due to CIT among the different thrombopoietic agents. The outcomes of thrombocytopenia in 170 patients who received targeted therapy and/or immunotherapy are also summarized. The results show that the proportion of platelet recovery was similar among the different thrombopoietic agents. No new safety signals related to thrombopoietic agents were observed in this study. A higher proportion of physicians preferred to continue treatment with TPO-RA alone than with rhTPO and rhIL-11. CONCLUSIONS: This survey provides an overview of CTIT and the application of various thrombopoietic agents throughout China. Comparison of monotherapy with rhIL-11, rhTPO, and TPO-RA requires further randomized clinical trials. The appropriate application for thrombopoietic agents should depend on the pretreatment of platelets, treatment variables, and risk of bleeding. PLAIN LANGUAGE SUMMARY: To provide an overview of the outcome of cancer treatment-induced thrombocytopenia in China, our cross-sectional study analyzed 1437 cases treated with different thrombopoietic agents. Most of the patients were treated with recombinant interleukin 11 (rhIL-11) and recombinant thrombopoietin (rhTPO). rhTPO was associated with a significantly lower proportion of platelet recovery and platelet transfusion compared with rhIL-11.


Assuntos
Neoplasias , Trombocitopenia , Humanos , China , Estudos Transversais , Interleucina-11/uso terapêutico , Neoplasias/tratamento farmacológico , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Trombocitopenia/induzido quimicamente , Trombocitopenia/tratamento farmacológico , Trombopoetina/uso terapêutico , Adulto Jovem , Adulto
10.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 36(2): 189-194, 2024 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-38442937

RESUMO

OBJECTIVE: To evaluate the effects of recombinant human thrombopoietin (rhTPO) on platelet count (PLT) and liver function in acute liver failure (ALF) rats by observing the dynamic changes of PLT, thrombopoietin (TPO) and liver function during ALF. METHODS: Twenty-four male Sprague-Dawley (SD) rats were divided into model group, TPO group and interleukin-11 (IL-11) group using a random number table method, with eight rats in each group. All rats were intraperitoneally injected with D-galactosamine (D-GalN, 1 500 mg/kg, dosed within 72 hours) to induce the ALF model. After modeling, rats in TPO group was received subcutaneous injection of 15 µg/kg of rhTPO for 5 days, and rats in IL-11 group was received subcutaneous injection of 0.45 mg/kg of IL-11 for 5 days. Venous blood samples were collected before and at 1, 3, 5, 7 and 12 days after molding for whole blood cell detection. The level of TPO in serum was detected by enzyme-linked immunosorbent assay (ELISA). Liver function indexes including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil) and albumin (ALB) were measured before and at 1, 3 and 5 days after modeling. The rats were sacrificed 12 days after the modeling, and the pathological changes of liver tissue were observed by hematoxylin-eosin (HE) staining. RESULTS: Two rats in each group died within 24-48 hours after modeling. HE staining showed that all three groups of ALF rats showed large flake necrosis of hepatocytes, disorder of hepatic lobular structure, mesh scaffold collapse, hepatic sinus congestion and hemorrhage, and flake infiltration of inflammatory cells on day 12 after modeling. The levels of serum ALT, AST and TBil of rats in each group were significantly increased 1 day after modeling and then decreased. The level of ALB decreased significantly on the first day after modeling and then increased, but there was no significant difference in the trend of liver function indexes among the three groups. PLT in the three groups decreased rapidly on day 1 after modeling, and then recovered gradually with the improvement of liver function. The PLT of the TPO group rose to the peak value 7 days after molding and was significantly higher than that of the model group [PLT (×109/L): 1 673.3±347.5 vs. 855.3±447.0, P < 0.05], while there was no significant difference between the IL-11 group and the model group [PLT (×109/L): 1 350.3±386.6 vs. 855.3±447.0, P > 0.05]. The level of serum TPO of the three groups increased significantly on day 1 after modeling, then decreased, and dropped to the lowest value on day 5, but there was no significant difference in the trend of serum TPO level among the three groups. CONCLUSIONS: PLT in ALF rats decreased rapidly in the early stage and recovered gradually with the improvement of liver function, and the serum TPO level increased first and then decreased. Injection of rhTPO can significantly increase PLT in ALF rats, but has no significant effect on liver function and survival rate.


Assuntos
Falência Hepática Aguda , Trombopoetina , Humanos , Masculino , Ratos , Animais , Trombopoetina/farmacologia , Interleucina-11/farmacologia , Ratos Sprague-Dawley , Plaquetas , Falência Hepática Aguda/tratamento farmacológico , Amarelo de Eosina-(YS) , Albuminas
11.
Curr Med Res Opin ; 40(5): 781-788, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38465414

RESUMO

OBJECTIVES: To describe and compare real-world treatment patterns and clinical outcomes among individuals with immune thrombocytopenia (ITP) receiving second-line therapies (rituximab, romiplostim, or eltrombopag). METHODS: A retrospective cohort study was conducted using a large administrative claims database (January 2013-May 2020) among continuously enrolled patients ≥18 years prescribed second-line ITP therapies. The index date was the date of the first claim of the study medications. Treatment patterns and outcomes were measured during the 12-month follow-up period. Inverse probability of treatment weighting (IPTW) was used to balance covariates across treatment groups. Multivariable logistic regression was used to compare treatment patterns and bleeding risk outcomes. RESULTS: A total of 695 patients were included (rituximab, N = 285; romiplostim, N = 212; eltrombopag, N = 198). After IPTW, all baseline covariates were balanced. Compared to eltrombopag, patients in the rituximab cohort were 57% more likely to receive other ITP therapies (systematic corticosteroids or third-line therapies) during the follow-up period (odds ratio [OR] = 1.571, p = .030). There was no significant difference in the odds of receiving a different second-line therapy or experiencing a bleeding-related episode among three groups (p > .050). Patients in the romiplostim cohort were 69% more likely to receive rescue therapy compared to those in the rituximab cohort (OR = 1.688, p = .025). CONCLUSION: Patients with ITP receiving rituximab were more likely to need other ITP therapies but did not experience higher risk of bleeding compared to those receiving eltrombopag or romiplostim. Benefits, risks, cost-effectiveness, and patient preference should all be considered in optimizing second-line therapy for ITP.


Assuntos
Benzoatos , Hidrazinas , Púrpura Trombocitopênica Idiopática , Pirazóis , Receptores Fc , Proteínas Recombinantes de Fusão , Rituximab , Trombopoetina , Humanos , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/epidemiologia , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Rituximab/uso terapêutico , Rituximab/efeitos adversos , Hidrazinas/uso terapêutico , Hidrazinas/efeitos adversos , Proteínas Recombinantes de Fusão/uso terapêutico , Trombopoetina/uso terapêutico , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Receptores Fc/uso terapêutico , Benzoatos/uso terapêutico , Adulto , Idoso , Resultado do Tratamento , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Bases de Dados Factuais
12.
Leukemia ; 38(6): 1342-1352, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38491305

RESUMO

Thrombopoietin (Tpo), which binds to its specific receptor, the Mpl protein, is the major cytokine regulator of megakaryopoiesis and circulating platelet number. Tpo binding to Mpl triggers activation of Janus kinase 2 (Jak2) and phosphorylation of the receptor, as well as activation of several intracellular signalling cascades that mediate cellular responses. Three tyrosine (Y) residues in the C-terminal region of the Mpl intracellular domain have been implicated as sites of phosphorylation required for regulation of major Tpo-stimulated signalling pathways: Mpl-Y565, Mpl-Y599 and Mpl-Y604. Here, we have introduced mutations in the mouse germline and report a consistent physiological requirement for Mpl-Y599, mutation of which resulted in thrombocytopenia, deficient megakaryopoiesis, low hematopoietic stem cell (HSC) number and function, and attenuated responses to myelosuppression. We further show that in models of myeloproliferative neoplasms (MPN), where Mpl is required for pathogenesis, thrombocytosis was dependent on intact Mpl-Y599. In contrast, Mpl-Y565 was required for negative regulation of Tpo responses; mutation of this residue resulted in excess megakaryopoiesis at steady-state and in response to myelosuppression, and exacerbated thrombocytosis associated with MPN.


Assuntos
Hematopoese , Transtornos Mieloproliferativos , Receptores de Trombopoetina , Trombopoetina , Tirosina , Animais , Receptores de Trombopoetina/metabolismo , Receptores de Trombopoetina/genética , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Transtornos Mieloproliferativos/patologia , Camundongos , Trombopoetina/metabolismo , Tirosina/metabolismo , Tirosina/genética , Fosforilação , Camundongos Endogâmicos C57BL , Células-Tronco Hematopoéticas/metabolismo , Transdução de Sinais , Mutação , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Trombopoese/genética
13.
Exp Hematol ; 134: 104208, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38548144

RESUMO

Germline mutations of THPO were reported as causes of hereditary thrombocythemia. Six previously reported distinct sites of the mutation were clustered at the 5`-untranslated region or the exon 3 splicing donor site of the THPO gene. Each mutation was identified in an independent pedigree, and the differences between the mutations were not compared. We cloned six distinct THPO mutations (THPO c.-47delG, THPO c.-31G>T, THPO c.13G>A, THPO c.13+1G>A, THPO c.13+2T>C, and THPO c.13+5G>A) and compared the molecular mechanisms that underlie the increased production of THPO protein. At the transcript level, all of the mutations except THPO c.-47delG showed an exon 3 skipping transcript, including two mutations (THPO c.-31G>T and THPO c.13+5G>A) that were distant from the splicing donor site. THPO c.-47delG showed the same full-length transcript as that of the wild-type transcript. At the protein level, all mutations resulted in a higher level of production of thrombopoietin (THPO) protein compared with wild-type THPO. There are only two distinct patterns of mechanisms for increased production of THPO: exon 3 skipping that deleted upstream suppressive open reading frame (ORF)7 and one base deletion that shifted ORF7 to connect to the initial codon of THPO in-frame. The common mechanisms of hereditary thrombocytosis due to THPO mutations are unleashed THPO translations, which are usually suppressed by upstream out-of-frame ORF7.


Assuntos
Trombopoetina , Humanos , Feminino , Trombopoetina/genética , Masculino , Éxons , Linhagem , Trombocitose/genética , Mutação em Linhagem Germinativa , Mutação
14.
Arch Toxicol ; 98(6): 1843-1858, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38551724

RESUMO

Acetaminophen (APAP)-induced hepatotoxicity is comprised of an injury and recovery phase. While pharmacological interventions, such as N-acetylcysteine (NAC) and 4-methylpyrazole (4-MP), prevent injury there are no therapeutics that promote recovery. JNJ-26366821 (TPOm) is a novel thrombopoietin mimetic peptide with no sequence homology to endogenous thrombopoietin (TPO). Endogenous thrombopoietin is produced by hepatocytes and the TPO receptor is present on liver sinusoidal endothelial cells in addition to megakaryocytes and platelets, and we hypothesize that TPOm activity at the TPO receptor in the liver provides a beneficial effect following liver injury. Therefore, we evaluated the extent to which TPOm, NAC or 4-MP can provide a protective and regenerative effect in the liver when administered 2 h after an APAP overdose of 300 mg/kg in fasted male C57BL/6J mice. TPOm did not affect protein adducts, oxidant stress, DNA fragmentation and hepatic necrosis up to 12 h after APAP. In contrast, TPOm treatment was beneficial at 24 h, i.e., all injury parameters were reduced by 42-48%. Importantly, TPOm enhanced proliferation by 100% as indicated by PCNA-positive hepatocytes around the area of necrosis. When TPOm treatment was delayed by 6 h, there was no effect on the injury, but a proliferative effect was still evident. In contrast, 4MP and NAC treated at 2 h after APAP significantly attenuated all injury parameters at 24 h but failed to enhance hepatocyte proliferation. Thus, TPOm arrests the progression of liver injury by 24 h after APAP and accelerates the onset of the proliferative response which is essential for liver recovery.


Assuntos
Acetaminofen , Doença Hepática Induzida por Substâncias e Drogas , Regeneração Hepática , Fígado , Camundongos Endogâmicos C57BL , Trombopoetina , Animais , Acetaminofen/toxicidade , Masculino , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Trombopoetina/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Regeneração Hepática/efeitos dos fármacos , Camundongos , Acetilcisteína/farmacologia , Pirazóis/farmacologia , Hepatócitos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Receptores de Trombopoetina/metabolismo , Proliferação de Células/efeitos dos fármacos
15.
Transplant Cell Ther ; 30(5): 500-509, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38447750

RESUMO

BACKGROUND: Recombinant human TPO (rhTPO) promotes platelet engraftment in patients after allogeneic HSCT (allo-HSCT). However, the effects of rhTPO on platelet recovery after Haplo-HSCT in patients with severe aplastic anemia (SAA) have not been intensively studied. OBJECTIVE: We aimed to evaluate the efficacy of rhTPO on platelet engraftment in patients with SAA who were treated with Haplo-HSCT using post-transplantation cyclophosphamide (PTCy). STUDY DESIGN: SAA patients who received Haplo-HSCT plus PTCy regimen were divided into the rhTPO group (with subcutaneous injection of rhTPO, n = 28) and Control group (no rhTPO administration, n = 27). The engraftment of platelet/neutrophil, platelet infusion amount, and transplant-related complications between the 2 groups were compared. RESULTS: All 55 patients showed successful hematopoietic reconstitution. The median time of platelet engraftment was 11 (9 to 29) days in the rhTPO group and 14 (9 to 28) days in the Control group (P = .003). The rhTPO group had a significantly reduced amount of infused platelets compared to the Control group (2 (1 to 11.5) versus 3 (1 to 14) therapeutic doses; P = .004). There was no significant difference between the 2 groups regarding median time of neutrophil engraftment, incidence of acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD), incidence of cytomegalovirus or Epstein-Barr virus reactivation, 3-yr overall survival rate, and failure-free-survival rate. No obvious adverse reactions were observed in the rhTPO group. CONCLUSION: rhTPO promoted platelet engraftment, reduced the amount of transfused platelets, and demonstrated good safety profiles without evidence of adverse reactions in patients with SAA who received Haplo-HSCT using PTCy regimen.


Assuntos
Anemia Aplástica , Plaquetas , Ciclofosfamida , Transplante de Células-Tronco Hematopoéticas , Proteínas Recombinantes , Trombopoetina , Humanos , Anemia Aplástica/terapia , Masculino , Ciclofosfamida/uso terapêutico , Feminino , Adulto , Transplante de Células-Tronco Hematopoéticas/métodos , Trombopoetina/uso terapêutico , Trombopoetina/administração & dosagem , Adolescente , Proteínas Recombinantes/uso terapêutico , Proteínas Recombinantes/administração & dosagem , Plaquetas/efeitos dos fármacos , Pessoa de Meia-Idade , Adulto Jovem , Criança , Doença Enxerto-Hospedeiro , Transfusão de Plaquetas , Transplante Haploidêntico
16.
Br J Haematol ; 204(6): 2442-2452, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38429869

RESUMO

Few studies have reported the real-world use of both romiplostim and eltrombopag in immune thrombocytopenia (ITP). TRAIT was a retrospective observational study aimed to evaluate the platelet responses and adverse effects associated with the use of these thrombopoietin receptor agonists (TPO-RAs) in adult patients with ITP in the United Kingdom. Of 267 patients (median age at diagnosis, 48 years) with ITP (primary ITP [n = 218], secondary ITP [n = 49]) included in the study, 112 (42%) received eltrombopag and 155 (58%) received romiplostim as the first prescribed TPO-RA. A platelet count ≥30 × 109/L was achieved in 89% of patients with the first TPO-RA treatments, while 68% achieved a platelet count ≥100 × 109/L. Treatment-free response (TFR; platelet count ≥30 × 109/L, 3 months after discontinuing treatment) was achieved by 18% of the total patients. Overall, 61 patients (23%) switched TPO-RAs, most of whom achieved platelet counts ≥30 × 109/L with the second TPO-RA (23/25 who switched from eltrombopag to romiplostim [92%]; 28/36 who switched from romiplostim to eltrombopag [78%]). TFR was associated with secondary ITP, early TPO-RA initiation after diagnosis, the presence of comorbidity and no prior splenectomy or treatment with steroids or mycophenolate mofetil. Both TPO-RAs had similar efficacy and safety profiles to those reported in clinical studies.


Assuntos
Benzoatos , Hidrazinas , Púrpura Trombocitopênica Idiopática , Pirazóis , Receptores Fc , Receptores de Trombopoetina , Proteínas Recombinantes de Fusão , Trombopoetina , Humanos , Receptores de Trombopoetina/agonistas , Proteínas Recombinantes de Fusão/uso terapêutico , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/administração & dosagem , Pessoa de Meia-Idade , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Benzoatos/uso terapêutico , Benzoatos/efeitos adversos , Masculino , Feminino , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Trombopoetina/uso terapêutico , Trombopoetina/efeitos adversos , Hidrazinas/uso terapêutico , Hidrazinas/efeitos adversos , Receptores Fc/uso terapêutico , Adulto , Reino Unido , Estudos Retrospectivos , Idoso , Contagem de Plaquetas , Resultado do Tratamento , Idoso de 80 Anos ou mais , Adulto Jovem , Adolescente
17.
Int J Mol Sci ; 25(4)2024 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-38396839

RESUMO

The management of immune thrombocytopenia (ITP) and the prediction of patient response to therapy still represent a significant and constant challenge in hematology. ITP is a heterogeneous disease with an unpredictable evolution. Although the pathogenesis of ITP is currently better known and its etiology has been extensively studied, up to 75% of adult patients with ITP may develop chronicity, which represents a significant burden on patients' quality of life. A major risk of ITP is bleeding, but knowledge on the exact relationship between the degree of thrombocytopenia and bleeding symptoms, especially at a lower platelet count, is lacking. The actual management of ITP is based on immune suppression (corticosteroids and intravenous immunoglobulins), or the use of thrombopoietin receptor agonists (TPO-RAs), rituximab, or spleen tyrosine kinase (Syk) inhibitors. A better understanding of the underlying pathology has facilitated the development of a number of new targeted therapies (Bruton's tyrosine kinase inhibitors, neonatal Fc receptors, strategies targeting B and plasma cells, strategies targeting T cells, complement inhibitors, and newer TPO-RAs for improving megakaryopoiesis), which seem to be highly effective and well tolerated and result in a significant improvement in patients' quality of life. The disadvantage is that there is a lack of knowledge of the predictive factors of response to treatments, which would help in the development of an optimized treatment algorithm for selected patients.


Assuntos
Púrpura Trombocitopênica Idiopática , Trombocitopenia , Adulto , Recém-Nascido , Humanos , Púrpura Trombocitopênica Idiopática/etiologia , Púrpura Trombocitopênica Idiopática/terapia , Qualidade de Vida , Trombocitopenia/tratamento farmacológico , Contagem de Plaquetas , Imunoglobulinas Intravenosas/uso terapêutico , Trombopoetina , Proteínas Recombinantes de Fusão/uso terapêutico
18.
Nat Commun ; 15(1): 1135, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38326297

RESUMO

Thrombopoietin (Tpo) is the primary regulator of megakaryocyte and platelet numbers and is required for haematopoetic stem cell maintenance. Tpo functions by binding its receptor (TpoR, a homodimeric Class I cytokine receptor) and initiating cell proliferation or differentiation. Here we characterise the murine Tpo:TpoR signalling complex biochemically and structurally, using cryo-electron microscopy. Tpo uses opposing surfaces to recruit two copies of receptor, forming a 1:2 complex. Although it binds to the same, membrane-distal site on both receptor chains, it does so with significantly different affinities and its highly glycosylated C-terminal domain is not required. In one receptor chain, a large insertion, unique to TpoR, forms a partially structured loop that contacts cytokine. Tpo binding induces the juxtaposition of the two receptor chains adjacent to the cell membrane. The therapeutic agent romiplostim also targets the cytokine-binding site and the characterisation presented here supports the future development of improved TpoR agonists.


Assuntos
Receptores de Trombopoetina , Trombopoetina , Animais , Camundongos , Microscopia Crioeletrônica , Receptores de Citocinas/metabolismo , Receptores de Trombopoetina/metabolismo , Transdução de Sinais
19.
Br J Haematol ; 204(4): 1143-1145, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38319005

RESUMO

Immune thrombocytopenia refractory to multiple thrombopoietin receptor agonists remains a challenging clinical problem. This commentary discusses and contextualizes the recent report on this entity from Moulis and colleagues, and how to move forward with these patients. Commentary on: Moulis et al. Difficult-to-treat primary immune thrombocytopenia in adults: Prevalence and burden. Results from the CARMEN-France Registry. Br J Haematol 2024;204:1476-1482.


Assuntos
Púrpura Trombocitopênica Idiopática , Pirazóis , Trombocitopenia , Adulto , Humanos , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Receptores de Trombopoetina/agonistas , Trombocitopenia/tratamento farmacológico , Trombopoetina/uso terapêutico , Benzoatos/uso terapêutico , Hidrazinas/uso terapêutico , Receptores Fc/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico
20.
Blood Adv ; 8(7): 1715-1724, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38386978

RESUMO

ABSTRACT: Immune thrombocytopenia (ITP) is an autoimmune disease associated with autoantibody-mediated platelet destruction and impaired platelet production, resulting in thrombocytopenia and a predisposition to bleeding. The ongoing, global phase 1/2 study showed that rilzabrutinib, a Bruton tyrosine kinase inhibitor specifically developed to treat autoimmune disorders, could be an efficacious and well-tolerated treatment for ITP. Clinical activity, durability of response, and safety were evaluated in 16 responding patients who continued rilzabrutinib 400 mg twice daily in the long-term extension (LTE) study. At LTE entry, the median platelet count was 87 × 109/L in all patients, 68 × 109/L in those who had rilzabrutinib monotherapy (n = 5), and 156 × 109/L in patients who received concomitant ITP medication (thrombopoietin-receptor agonists and/or corticosteroids, n = 11). At a median duration of treatment of 478 days (range, 303-764), 11 of 16 patients (69%) continued to receive rilzabrutinib. A platelet count of ≥50 × 109/L was reported in 93% of patients for more than half of their monthly visits. The median percentage of LTE weeks with platelet counts ≥30 × 109/L and ≥50 × 109/L was 100% and 88%, respectively. Five patients discontinued concomitant ITP therapy and maintained median platelet counts of 106 × 109/L at 3 to 6 months after stopping concomitant ITP therapy. Adverse events related to treatment were grade 1 or 2 and transient, with no bleeding, thrombotic, or serious adverse events. With continued rilzabrutinib treatment in the LTE, platelet responses were durable and stable over time with no new safety signals. This trial is registered at www.clinicaltrials.gov as #NCT03395210 and www.clinicaltrialsregister.eu as EudraCT 2017-004012-19.


Assuntos
Púrpura Trombocitopênica Idiopática , Trombocitopenia , Humanos , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/induzido quimicamente , Resultado do Tratamento , Receptores Fc , Trombopoetina/uso terapêutico , Trombocitopenia/induzido quimicamente , Hemorragia/induzido quimicamente
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