Platelets最新文献_第7页

Humanized mouse models for inherited thrombocytopenia studies. 遗传性血小板减少症研究的人源化小鼠模型。

IF 3.3 3区医学

Platelets Pub Date : 2023-12-01 Epub Date: 2023-10-17 DOI: 10.1080/09537104.2023.2267676

Xiaojie Wang, Maoshan Chen, Lanyue Hu, Chengning Tan, Xiaoliang Li, Peipei Xue, Yangzhou Jiang, Peipei Bao, Teng Yu, Fengjie Li, Yanni Xiao, Qian Ran, Zhongjun Li, Li Chen

引用次数: 0

Atorvastatin-mediated inhibition of prenylation of Rab27b and Rap1a in platelets attenuates their prothrombotic capacity and modulates clot structure. 阿托伐他汀介导的抑制血小板中Rab27b和Rap1a的戊酰化可减弱其血栓形成能力并调节凝块结构。

IF 2.5 3区医学

Platelets Pub Date : 2023-12-01 DOI: 10.1080/09537104.2023.2206921

Mohammed M Jalal, Claire S Whyte, Fraser P Coxon, Nicola J Mutch

{"title":"Atorvastatin-mediated inhibition of prenylation of Rab27b and Rap1a in platelets attenuates their prothrombotic capacity and modulates clot structure.","authors":"Mohammed M Jalal, Claire S Whyte, Fraser P Coxon, Nicola J Mutch","doi":"10.1080/09537104.2023.2206921","DOIUrl":"10.1080/09537104.2023.2206921","url":null,"abstract":"Statins inhibit the mevalonate pathway by impairing protein prenylation via depletion of lipid geranylgeranyl diphosphate (GGPP). Rab27b and Rap1a are small GTPase proteins involved in dense granule secretion, platelet activation, and regulation. We analyzed the impact of statins on prenylation of Rab27b and Rap1a in platelets and the downstream effects on fibrin clot properties. Whole blood thromboelastography revealed that atorvastatin (ATV) delayed clot formation time (P < .005) and attenuated clot firmness (P < .005). ATV pre-treatment inhibited platelet aggregation and clot retraction. Binding of fibrinogen and P-selectin exposure on stimulated platelets was significantly lower following pre-treatment with ATV (P < .05). Confocal microscopy revealed that ATV significantly altered the structure of platelet-rich plasma clots, consistent with the reduced fibrinogen binding. ATV enhanced lysis of Chandler model thrombi 1.4-fold versus control (P < .05). Western blotting revealed that ATV induced a dose-dependent accumulation of unprenylated Rab27b and Rap1a in the platelet membrane. ATV dose-dependently inhibited ADP release from activated platelets. Exogenous GGPP rescued the prenylation of Rab27b and Rap1a, and partially restored the ADP release defect, suggesting these changes arise from reduced prenylation of Rab27b. These data demonstrate that statins attenuate platelet aggregation, degranulation, and binding of fibrinogen thereby having a significant impact on clot contraction and structure.","PeriodicalId":20268,"journal":{"name":"Platelets","volume":"34 1","pages":"2206921"},"PeriodicalIF":2.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9491279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hemostasis-on-a-chip / incorporating the endothelium in microfluidic models of bleeding. 芯片止血/内皮细胞植入出血微流控模型。

IF 2.5 3区医学

Platelets Pub Date : 2023-12-01 DOI: 10.1080/09537104.2023.2185453

Yumiko Sakurai, Elaissa T Hardy, Wilbur A Lam

引用次数: 0

Biochemical characterization of spleen tyrosine kinase (SYK) isoforms in platelets. 血小板中脾脏酪氨酸激酶（SYK）亚型的生化特征。

IF 2.5 3区医学

Platelets Pub Date : 2023-12-01 DOI: 10.1080/09537104.2023.2249549

Pankaj Kumar Singh, Carol A Dangelmaier, Hymavathi Reddy Vari, Alexander Y Tsygankov, Satya P Kunapuli

{"title":"Biochemical characterization of spleen tyrosine kinase (SYK) isoforms in platelets.","authors":"Pankaj Kumar Singh, Carol A Dangelmaier, Hymavathi Reddy Vari, Alexander Y Tsygankov, Satya P Kunapuli","doi":"10.1080/09537104.2023.2249549","DOIUrl":"10.1080/09537104.2023.2249549","url":null,"abstract":"Alternate splicing is among the regulatory mechanisms imparting functional diversity in proteins. Studying protein isoforms generated through alternative splicing is therefore critical for understanding protein functions in many biological systems. Spleen tyrosine kinase (Syk) plays an essential role in ITAM/hemITAM signaling in many cell types, including platelets. However, the spectrum of Syk isoforms expressed in platelets has not been characterized. Syk has been shown to have a full-length long isoform SykL and a shorter SykS lacking 23 amino acid residues within its interdomain B. Furthermore, putative isoforms lacking another 23 amino acid-long sequence or a combination of the two deletions have been postulated to exist. In this report, we demonstrate that mouse platelets express full-length SykL and the previously described shorter isoform SykS, but lack other shorter isoforms, whereas human platelets express predominantly SykL. These results both indicate a possible role of alternative Syk splicing in the regulation of receptor signaling in mouse platelets and a difference between signaling regulation in mouse and human platelets.","PeriodicalId":20268,"journal":{"name":"Platelets","volume":"34 1","pages":"2249549"},"PeriodicalIF":2.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10502920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10607793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

First-in-human study to assess the safety, pharmacokinetics, and pharmacodynamics of BMS-986141, a novel, reversible, small-molecule, PAR4 agonist in non-Japanese and Japanese healthy participants. BMS-986141(一种新型、可逆的小分子PAR4激动剂)在非日本人和日本健康参与者中的安全性、药代动力学和药效学的首次人体研究

IF 3.3 3区医学

Platelets Pub Date : 2023-12-01 DOI: 10.1080/09537104.2023.2222846

Samira Merali, Zhaoqing Wang, Charles Frost, Stephanie Meadows-Shropshire, Dara Hawthorne, Jing Yang, Dietmar Seiffert

{"title":"First-in-human study to assess the safety, pharmacokinetics, and pharmacodynamics of BMS-986141, a novel, reversible, small-molecule, PAR4 agonist in non-Japanese and Japanese healthy participants.","authors":"Samira Merali, Zhaoqing Wang, Charles Frost, Stephanie Meadows-Shropshire, Dara Hawthorne, Jing Yang, Dietmar Seiffert","doi":"10.1080/09537104.2023.2222846","DOIUrl":"10.1080/09537104.2023.2222846","url":null,"abstract":"BMS-986141 is a novel, oral, protease-activated, receptor 4 (PAR4)-antagonist that exhibited robust antithrombotic activity and low bleeding risk in preclinical studies. The pharmacokinetic, pharmacodynamic, and tolerability profiles of BMS-986141 in healthy participants were assessed in a randomized, double-blind, placebo-controlled, single-ascending-dose (SAD; N = 60) study; a multiple-ascending-dose (MAD; N = 32) study; and a Japanese MAD (JMAD; N = 32) study. Exposure was dose-proportional for BMS-986141 2.5 mg and 150 mg; maximum concentrations were 17.6 ng/mL and 958 ng/mL; and areas under the curve (AUC) to infinity were 183 h* × ng/mL and 9207 h* × ng/mL, respectively. Mean half-life ranged from 33.7 to 44.7 hours across dose panels. The accumulation index following once-daily administration for 7 days suggested a 1.3- to 2-fold AUC increase at steady state. In the SAD study, BMS-986141 75 and 150 mg produced ≥80% inhibition of 25-100 µM PAR4 agonist peptide (AP)-induced platelet aggregation, without affecting PAR1-AP-induced platelet aggregation, through ≥24 hours postdose. In the MAD and JMAD studies, BMS-986141 doses ≥10 mg completely inhibited 12.5 μM and 25 μM PAR4-AP-induced platelet aggregation through 24 hours. This study found BMS-986141 was safe and well tolerated, with dose-proportional pharmacokinetics and concentration-dependent pharmacodynamics in healthy participants over a wide dose range. ClinicalTrials.gov ID: NCT02341638.","PeriodicalId":20268,"journal":{"name":"Platelets","volume":"34 1","pages":"2222846"},"PeriodicalIF":3.3,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9745065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Efficacy and safety of high dose recombinant human thrombopoietin in the treatment of immune thrombocytopenia. 大剂量重组人血小板生成素治疗免疫性血小板减少症的疗效和安全性。

IF 3.3 3区医学

Platelets Pub Date : 2023-12-01 Epub Date: 2023-11-08 DOI: 10.1080/09537104.2023.2271568

Xiuli Wang, Hui Bi, Lin Liu, Yuebo Liu, Liefen Yin, Jin Yao, Jingxing Yu, Wei Tao, Yueping Wei, Yu Li, Lingmei Yin, Hongli Mu, Yadong Du, Zeping Zhou

{"title":"Efficacy and safety of high dose recombinant human thrombopoietin in the treatment of immune thrombocytopenia.","authors":"Xiuli Wang, Hui Bi, Lin Liu, Yuebo Liu, Liefen Yin, Jin Yao, Jingxing Yu, Wei Tao, Yueping Wei, Yu Li, Lingmei Yin, Hongli Mu, Yadong Du, Zeping Zhou","doi":"10.1080/09537104.2023.2271568","DOIUrl":"10.1080/09537104.2023.2271568","url":null,"abstract":"The conventional dose of recombinant human thrombopoietin (rhTPO) in the treatment of immune thrombocytopenia (ITP) is 300 U/kg per day, but the clinical reaction rate is not satisfactory. Accordingly, we explored the efficacy and safety of increasing rhTPO dose in the treatment of ITP. A retrospective study was conducted to collect the clinical data of 105 ITP patients who were divided into two groups, a low-dose group (15 000 U/day) and a high-dose group (30 000 U/day) according to the dose of rhTPO. The total effective rate of the low-dose group and the high-dose group was 31/44 (70.45%) vs. 56/61 (91.80%) (P = .049), and the average time of using rhTPO in the high-dose group was shorter than that in the low-dose group (7 days vs. 10 days, P = .001). On the 7th and 14th day of treatment, the efficacy of the high-dose group was better than that of the low-dose group [45/61 (73.77%) vs. 17/44 (38.64%), P < .001; 55/60 (91.67%) vs. 30/44 (68.18%), P < .05)]. The incidence of treatment related adverse events in the low-dose group and the high-dose group was 6/44 (13.64%) vs. 6/61 (9.84%) (P > .05), which were mild and transient in nature. In our study, high-dose rhTPO had good efficacy and high safety in the treatment of ITP with the efficacy better than low-dose rhTPO especially at day 7.","PeriodicalId":20268,"journal":{"name":"Platelets","volume":"34 1","pages":"2271568"},"PeriodicalIF":3.3,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71522412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

C-type lectin-like receptor-2 (CLEC-2) is a key regulator of kappa-carrageenan-induced tail thrombosis model in mice. c型凝集素样受体-2 (clc -2)是kappa- carragean诱导小鼠尾部血栓形成模型的关键调控因子。

IF 3.3 3区医学

Platelets Pub Date : 2023-12-01 Epub Date: 2023-11-27 DOI: 10.1080/09537104.2023.2281941

Ryohei Yokomori, Toshiaki Shirai, Nagaharu Tsukiji, Saori Oishi, Tomoyuki Sasaki, Katsuhiro Takano, Katsue Suzuki-Inoue

{"title":"C-type lectin-like receptor-2 (CLEC-2) is a key regulator of kappa-carrageenan-induced tail thrombosis model in mice.","authors":"Ryohei Yokomori, Toshiaki Shirai, Nagaharu Tsukiji, Saori Oishi, Tomoyuki Sasaki, Katsuhiro Takano, Katsue Suzuki-Inoue","doi":"10.1080/09537104.2023.2281941","DOIUrl":"10.1080/09537104.2023.2281941","url":null,"abstract":"Kappa-carrageenan (KCG), which is used to induce thrombosis in laboratory animals for antithrombotic drug screening, can trigger platelet aggregation. However, the cell-surface receptor and related signaling pathways remain unclear. In this study, we investigated the molecular basis of KCG-induced platelet activation using light-transmittance aggregometry, flow cytometry, western blotting, and surface plasmon resonance assays using platelets from platelet receptor-deficient mice and recombinant proteins. KCG-induced tail thrombosis was also evaluated in mice lacking the platelet receptor. We found that KCG induces platelet aggregation with α-granule secretion, activated integrin αIIbβ3, and phosphatidylserine exposure. As this aggregation was significantly inhibited by the Src family kinase inhibitor and spleen tyrosine kinase (Syk) inhibitor, a tyrosine kinase-dependent pathway is required. Platelets exposed to KCG exhibited intracellular tyrosine phosphorylation of Syk, linker activated T cells, and phospholipase C gamma 2. KCG-induced platelet aggregation was abolished in platelets from C-type lectin-like receptor-2 (CLEC-2)-deficient mice, but not in platelets pre-treated with glycoprotein VI-blocking antibody, JAQ1. Surface plasmon resonance assays showed a direct association between murine/human recombinant CLEC-2 and KCG. KCG-induced thrombosis and thrombocytopenia were significantly inhibited in CLEC-2-deficient mice. Our findings show that KCG induces platelet activation via CLEC-2.","PeriodicalId":20268,"journal":{"name":"Platelets","volume":"34 1","pages":"2281941"},"PeriodicalIF":3.3,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138445980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Analysis of clinical characteristics and treatment efficacy in two pediatric cases of ANKRD26-related thrombocytopenia. 两例儿童ANKRD26相关血小板减少症的临床特征和治疗效果分析。

IF 3.3 3区医学

Platelets Pub Date : 2023-12-01 Epub Date: 2023-10-18 DOI: 10.1080/09537104.2023.2262607

Congfei Pang, Xiaomei Wu, Lauriane Nikuze, Hongying Wei

{"title":"Analysis of clinical characteristics and treatment efficacy in two pediatric cases of ANKRD26-related thrombocytopenia.","authors":"Congfei Pang, Xiaomei Wu, Lauriane Nikuze, Hongying Wei","doi":"10.1080/09537104.2023.2262607","DOIUrl":"10.1080/09537104.2023.2262607","url":null,"abstract":"ANKRD26-related thrombocytopenia (ANKRD26-RT or THC2, MIM 188 000), an autosomal dominant thrombocytopenia, is unresponsive to immunosuppressive therapy and susceptible to hematological malignancies. A large number of pediatric patients are diagnosed with immune thrombocytopenia (ITP) every year; however, thrombocytopenia of genetic origin is often missed. Extensive characterization of ANKRD26-RT will help prevent missed diagnosis and misdiagnosis. Furthermore, identification of ANKRD26-RT will help in the formulation of an accurate diagnosis and a treatment plan. In our study, we report cases of two Chinese pediatric patients with ANKRD26-RT and analyze their clinical characteristics, gene mutations, and treatment modalities. Both patients were 1-year-old and presented with mild bleeding (World Health Organization(WHO) score grade 1), different degrees of platelet reduction, normal mean platelet volume, and megakaryocyte maturation impairment not obvious. Genetic tests revealed that both patients had ANKRD26 gene mutations.Patient 1 had a mutation c.-140C>G of the 5' untranslated region (UTR), and patient 2 had a mutation of c.-127A>T of 5'UTR. Both patients were treated with eltrombopag, and the treatment was no response, with no adverse reactions.","PeriodicalId":20268,"journal":{"name":"Platelets","volume":"34 1","pages":"2262607"},"PeriodicalIF":3.3,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49681386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Tissue inhibitors of metalloproteinases (TIMPs) modulate platelet ADAM10 activity. 金属蛋白酶组织抑制剂(TIMPs)调节血小板ADAM10活性。

IF 3.3 3区医学

Platelets Pub Date : 2023-12-01 Epub Date: 2023-11-30 DOI: 10.1080/09537104.2023.2288213

Christine Shu Mei Lee, Amandeep Kaur, Samantha J Montague, Sarah M Hicks, Robert K Andrews, Elizabeth E Gardiner

{"title":"Tissue inhibitors of metalloproteinases (TIMPs) modulate platelet ADAM10 activity.","authors":"Christine Shu Mei Lee, Amandeep Kaur, Samantha J Montague, Sarah M Hicks, Robert K Andrews, Elizabeth E Gardiner","doi":"10.1080/09537104.2023.2288213","DOIUrl":"https://doi.org/10.1080/09537104.2023.2288213","url":null,"abstract":"Platelet-specific collagen receptor glycoprotein (GP)VI is stable on the surface of circulating platelets but undergoes ectodomain cleavage on activated platelets. Activation-dependent GPVI metalloproteolysis is primarily mediated by A Disintegrin And Metalloproteinase (ADAM) 10. Regulation of platelet ADAMs activity is not well-defined however Tissue Inhibitors of Metalloproteinases (TIMPs) may play a role. As levels of TIMPs on platelets and the control of ADAMs-mediated shedding by TIMPs has not been evaluated, we quantified the levels of TIMPs on the surface of resting and activated platelets from healthy donors by flow cytometry and multiplex ELISA. Variable levels of all TIMPs could be detected on platelets. Plasma contained significant quantities of TIMP1 and TIMP2, but only trace amounts of TIMP3 and TIMP4. Recombinant TIMP3 strongly ablated resting and activated platelet ADAM10 activity, when monitored using a quenched fluorogenic peptide substrate with ADAM10 specificity. Whilst ADAM10-specific inhibitor GI254023X or ethylenediamine tetraacetic acid (EDTA) could modulate ligand-initiated shedding of GPVI, only recombinant TIMP2 achieved a modest (~20%) inhibition. We conclude that some platelet TIMPs are able to modulate platelet ADAM10 activity but none strongly regulate ligand-dependent shedding of GPVI. Our findings provide new insights into the regulation of platelet receptor sheddase activity.","PeriodicalId":20268,"journal":{"name":"Platelets","volume":"34 1","pages":"2288213"},"PeriodicalIF":3.3,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138462153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

An oligogenic case of severe neonatal thrombocytopenia and a purportedly benign variant in GFI1B requiring reinterpretation. 严重新生儿血小板减少的少原性病例和GFI1B的良性变异需要重新解释。

IF 2.5 3区医学

Platelets Pub Date : 2023-12-01 DOI: 10.1080/09537104.2023.2237592

Max Frenkel, April Hall, M Stephen Meyn, Carol A Diamond

{"title":"An oligogenic case of severe neonatal thrombocytopenia and a purportedly benign variant in GFI1B requiring reinterpretation.","authors":"Max Frenkel, April Hall, M Stephen Meyn, Carol A Diamond","doi":"10.1080/09537104.2023.2237592","DOIUrl":"10.1080/09537104.2023.2237592","url":null,"abstract":"Although thrombocytopenia in neonatal intensive care patients is rarely due to inherited disorders, the number of genetic variants implicated in platelet defects has grown dramatically with increasing genome-wide sequencing. Here we describe a case of severe, oligogenic neonatal thrombocytopenia and reinterpret a reportedly benign mutation that is likely pathogenic. Despite this patient's synonymous mutation (GFI1B 576 C>T, Phe192=) being annotated as benign, GFI1B is a well-known regulator of megakaryopoiesis, this variant alters splicing and megakaryocyte maturation, and our analysis of existing genome-wide associated studies demonstrates that it likely causes gray platelet syndrome. This variant has not been reported in a case of life-threatening thrombocytopenia. We propose that the severity of this patient's phenotype is due to synergistic epistasis between the intrinsic platelet defect caused by this mutation and her concomitant inherited PMM2 congenital glycosylation disorder neither of which have been associated with such a severe phenotype. This case highlights the importance of whole-exome/genome sequencing for critically ill patients, reexamining variant interpretation when clinically indicated, and the need to study diverse genetic variation in hematopoiesis.","PeriodicalId":20268,"journal":{"name":"Platelets","volume":"34 1","pages":"2237592"},"PeriodicalIF":2.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10653983/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9996743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0