Journal of Thrombosis and Haemostasis最新文献

{"title":"Love for lysis in the time of catheters: is it time to resurrect an old standby?","authors":"Stanislav Henkin , Gregory Piazza","doi":"10.1016/j.jtha.2024.11.004","DOIUrl":"10.1016/j.jtha.2024.11.004","url":null,"abstract":"","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 2","pages":"Pages 401-403"},"PeriodicalIF":5.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rivaroxaban, in combination with low-dose aspirin, is associated with a reduction in proinflammatory and prothrombotic circulating vesicle signatures in patients with cardiovascular disease","authors":"Luisa Weiss ,&nbsp;Aideen O’Doherty ,&nbsp;Wido Uhrig ,&nbsp;Paulina B. Szklanna ,&nbsp;Molly Hong-Minh ,&nbsp;Kieran Wynne ,&nbsp;Alfonso Blanco ,&nbsp;Jan Zivny ,&nbsp;Valeria Lima Passos ,&nbsp;Barry Kevane ,&nbsp;Seán Murphy ,&nbsp;Fionnuala Ní Áinle ,&nbsp;Martin O’Donnell ,&nbsp;Patricia B. Maguire","doi":"10.1016/j.jtha.2024.09.030","DOIUrl":"10.1016/j.jtha.2024.09.030","url":null,"abstract":"<div><h3>Background</h3><div>Despite secondary prevention with aspirin, patients with stable cardiovascular disease (CVD) remain at elevated long-term risk of major adverse cardiovascular events. The Cardiovascular Outcomes in People Using Anticoagulant Strategies (COMPASS) double-blind, randomized clinical trial demonstrated that aspirin plus low-dose rivaroxaban (COMPASS regime) significantly decreased the incidence of major adverse cardiovascular events by 24% compared with aspirin alone. However, the mechanisms underlying these potential synergistic/nonantithrombotic effects remain elusive. Extracellular vesicles (EVs) are crucial messengers regulating a myriad of biological/pathological processes and are highly implicated in CVD.</div></div><div><h3>Objectives</h3><div>We hypothesized that circulating EV profiles reflect the cardioprotective properties of the COMPASS regime.</div></div><div><h3>Methods</h3><div>A cohort of stable CVD patients (<em>N</em> = 40) who participated in the COMPASS trial and were previously randomized to receive aspirin were prospectively recruited and assigned a revised regimen of open-label aspirin plus rivaroxaban. Blood samples were obtained at baseline (aspirin only) and 6-month follow-up. Plasma EV concentration, size, and origin were analyzed by nanoparticle tracking analysis and flow cytometry. EVs were enriched by ultracentrifugation for proteomic analysis.</div></div><div><h3>Results</h3><div>The COMPASS regime fundamentally altered small (&lt;200 nm) and large (200-1000 nm) EV concentration and size compared with aspirin alone. Crucially, levels of platelet-derived and myeloperoxidase-positive EVs became significantly decreased at follow-up. Comparative proteomic characterization further revealed a significant decrease in highly proinflammatory protein expression at follow-up.</div></div><div><h3>Conclusion</h3><div>The observed changes in EV subpopulations, together with the differential protein expression profiles, suggest amelioration of an underlying proinflammatory and prothrombotic state upon dual therapy, which may be of clinical relevance toward understanding the fundamental mechanism underlying the reported superior cardiovascular outcomes associated with this antithrombotic regimen.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 2","pages":"Pages 531-545"},"PeriodicalIF":5.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142468678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic basis of activation and inhibition of protein disulfide isomerase by allosteric antithrombotic compounds","authors":"Nathan Ponzar ,&nbsp;Mathivanan Chinnaraj ,&nbsp;Anna Pagotto ,&nbsp;Vincenzo De Filippis ,&nbsp;Robert Flaumenhaft ,&nbsp;Nicola Pozzi","doi":"10.1016/j.jtha.2024.09.036","DOIUrl":"10.1016/j.jtha.2024.09.036","url":null,"abstract":"<div><h3>Background</h3><div>Protein disulfide isomerase (PDI) is a promising target for combating thrombosis. Extensive research over the past decade has identified numerous PDI-targeting compounds. However, limited information exists regarding how these compounds control PDI activity, which complicates further development.</div></div><div><h3>Objectives</h3><div>To define the mechanism of action of 2 allosteric antithrombotic compounds of therapeutic interest, quercetin-3-O-rutinoside and bepristat-2a.</div></div><div><h3>Methods</h3><div>A multipronged approach that integrates single-molecule spectroscopy, steady-state kinetics, single-turnover kinetics, and site-specific mutagenesis.</div></div><div><h3>Results</h3><div>PDI is a thiol isomerase consisting of 2 catalytic <strong>a</strong> domains and 2 inactive <strong>b</strong> domains arranged in the order <strong>a-b-b'-a'</strong>. The active sites CGHC are located in the <strong>a</strong> and <strong>a'</strong> domains. The binding site of quercetin-3-O-rutinoside and bepristat-2a is in the <strong>b'</strong> domain. Using a library of 9 Förster resonance energy transfer sensors, we showed that quercetin-3-O-rutinoside and bepristat-2a globally alter PDI structure and dynamics, leading to ligand-specific modifications of its shape and reorientation of the active sites. Combined with enzyme kinetics and mutagenesis of the active sites, Förster resonance energy transfer data reveal that binding of quercetin-3-O-rutinoside results in a twisted enzyme with reduced affinity for the substrate. In contrast, bepristat-2a promotes a more compact conformation of PDI, in which a greater enzymatic activity is achieved by accelerating the nucleophilic step of the <strong>a</strong> domain, leading to faster formation of the covalent enzyme–substrate complex.</div></div><div><h3>Conclusion</h3><div>This work reveals the mechanistic basis underlying PDI regulation by antithrombotic compounds quercetin-3-O-rutinoside and bepristat-2a and points to novel strategies for furthering the development of PDI-targeting compounds into drugs.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 2","pages":"Pages 577-587"},"PeriodicalIF":5.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application of platelet transcriptomics for assessing treatment effectiveness and predicting long-term platelet counts recovery in aplastic anemia","authors":"Jin Mao ,&nbsp;Jingyu Zhao ,&nbsp;Hong Pan ,&nbsp;Zhen Gao ,&nbsp;Lele Zhang ,&nbsp;Weiwang Li ,&nbsp;Liwei Fang ,&nbsp;Cuicui Liu ,&nbsp;Pei Su ,&nbsp;Hongtao Wang ,&nbsp;Jiaxi Zhou ,&nbsp;Jun Shi","doi":"10.1016/j.jtha.2024.10.032","DOIUrl":"10.1016/j.jtha.2024.10.032","url":null,"abstract":"<div><h3>Background</h3><div>Aplastic anemia (AA) is a bone marrow failure disease for which the means of assessing and predicting the therapeutic effectiveness are still relatively limited. Thrombocytopenia is often the earliest and most severe symptom in patients newly diagnosed with AA. While clinical consideration is usually given to the quantitative changes in platelets during treatment, there is little focus on the resolution of the molecular characteristics of platelets in AA.</div></div><div><h3>Objectives</h3><div>To investigate the changes in platelet molecular characteristics throughout the treatment process of AA, and to explore the use of transcriptomics for monitoring and predicting treatment outcomes.</div></div><div><h3>Methods</h3><div>We comprehensively analyzed platelet transcriptomic changes in patients with AA at initial diagnosis and different stages of treatment effectiveness using bulk transcriptome sequencing.</div></div><div><h3>Results</h3><div>Genes associated with cell proliferation, erythroid function, and amino acid transport were elevated in newly diagnosed AA. Conversely, genes linked to histones, thrombopoiesis, mitochondrial energy metabolism, and signaling pathways were significantly downregulated. Additionally, 60.6% of the differentially expressed genes were substantially restored following complete remission. Furthermore, through the examination of longitudinal samples, we identified recovery ascending genes that could serve as viable biomarkers for assessing treatment effectiveness in AA. Besides, we observed that higher expression levels of recovery ascending genes may predict superior long-term platelet counts recovery 6 months in advance in patients with partial response.</div></div><div><h3>Conclusion</h3><div>The platelet transcriptome undergoes profound changes and can serve as a potential indicator for assessing treatment effectiveness and predicting long-term platelet counts recovery in AA.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 2","pages":"Pages 692-703"},"PeriodicalIF":5.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bortezomib for rituximab-refractory immune-mediated thrombotic thrombocytopenic purpura in the caplacizumab era: an Italian multicenter study","authors":"Juri Alessandro Giannotta ,&nbsp;Andrea Artoni ,&nbsp;Ilaria Mancini ,&nbsp;Pasquale Agosti ,&nbsp;Monica Carpenedo ,&nbsp;Addolorata Truma ,&nbsp;Syna Miri ,&nbsp;Barbara Ferrari ,&nbsp;Pasqualina De Leo ,&nbsp;Prassede Salutari ,&nbsp;Giorgia Mancini ,&nbsp;Alfredo Molteni ,&nbsp;Ermina Rinaldi ,&nbsp;Monica Bocchia ,&nbsp;Mariasanta Napolitano ,&nbsp;Lucia Prezioso ,&nbsp;Annarosa Cuccaro ,&nbsp;Elisabetta Scarpa ,&nbsp;Annalisa Condorelli ,&nbsp;Daniele Grimaldi ,&nbsp;Flora Peyvandi","doi":"10.1016/j.jtha.2024.10.034","DOIUrl":"10.1016/j.jtha.2024.10.034","url":null,"abstract":"<div><h3>Background</h3><div>Immune-mediated thrombotic thrombocytopenic purpura (iTTP) patients are not responsive to standard rituximab in approximately 10% to 15% of cases, and oral immunosuppressants showed controversial results with significant toxicity. Targeting plasma cells with bortezomib appears promising, but the available evidence is scarce and stems only from isolated reports in the precaplacizumab era.</div></div><div><h3>Objectives</h3><div>To evaluate the safety and efficacy of bortezomib in rituximab-refractory iTTP patients.</div></div><div><h3>Methods</h3><div>We conducted a retrospective observational multicenter study among 13 Italian iTTP treating centers, collecting data from May 2017 to May 2023 (caplacizumab was licensed in Italy in January 2020).</div></div><div><h3>Results</h3><div>Bortezomib was effective in 10/17 patients (59%). Eleven were treated in the acute phase (9/11 responders, 82%, allowing discontinuation of caplacizumab in 5/6 treated patients), and 7 during clinical remission (2/7 responders, 28%). Responses occurred at a median time of 30 days, but 3 patients responded after 4 months. The median duration of response was 22 months (IQR, 10-38), still ongoing in 6 patients at the time of data cutoff. Responders had fewer previous acute iTTP episodes than nonresponders (median [IQR], 1 [<span><span>1</span></span>,<span><span>2</span></span>] vs 5.5 [<span><span>[2]</span></span>, <span><span>[3]</span></span>, <span><span>[4]</span></span>, <span><span>[5]</span></span>, <span><span>[6]</span></span>, <span><span>[7]</span></span>]; <em>P</em> = .03). Eight subjects (47%) reported toxicities, mostly in those treated with ≥2 cycles.</div></div><div><h3>Conclusion</h3><div>Durable responses to bortezomib were registered in about 60% of multirefractory iTTP patients with mild to moderate toxicities. The occurrence of late responses (ie, after 30 days) suggests a “watchful waiting” approach after bortezomib treatment.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 2","pages":"Pages 704-716"},"PeriodicalIF":5.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Guidelines and guidance: what is the path forward for the ISTH?","authors":"Fionnuala Ní Áinle ,&nbsp;Saskia Middeldorp ,&nbsp;Andrea Hickman ,&nbsp;Cary Clark ,&nbsp;Walter Ageno ,&nbsp;Patricia Casais ,&nbsp;Jean M. Connors ,&nbsp;Sabine Eichinger ,&nbsp;Damon Houghton ,&nbsp;Tadashi Matsushita ,&nbsp;Joost C.M. Meijers ,&nbsp;Angela C. Weyand ,&nbsp;James Douketis ,&nbsp;International Society on Thrombosis and Haemostasis (ISTH) Guidelines and Guidance Committee","doi":"10.1016/j.jtha.2024.11.006","DOIUrl":"10.1016/j.jtha.2024.11.006","url":null,"abstract":"","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 2","pages":"Pages 361-367"},"PeriodicalIF":5.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative phosphoproteomic analyses reveal hemostatic-endothelial signaling interplay","authors":"Stijn A. Groten ,&nbsp;Bart L. van den Eshof ,&nbsp;Floris P.J. van Alphen ,&nbsp;Alexander B. Meijer ,&nbsp;Maartje van den Biggelaar ,&nbsp;Arie J. Hoogendijk","doi":"10.1016/j.jtha.2024.10.011","DOIUrl":"10.1016/j.jtha.2024.10.011","url":null,"abstract":"<div><h3>Background</h3><div>The vascular endothelial cell (EC) monolayer plays a crucial part in maintaining hemostasis. An extensive array of G protein-coupled receptors allows ECs to dynamically act on key hemostatic stimuli such as thrombin and histamine. The impact of these individual stimuli on EC signal transduction has been the subject of various studies, but insight into discordant and concordant EC signaling between different G protein-coupled receptors remains limited.</div></div><div><h3>Objectives</h3><div>To elucidate histamine and protease-activated receptor (PAR1-4) signaling cascades in ECs, discern overlapping and diverging regulation between these stimuli and their effect on the EC monolayer.</div></div><div><h3>Methods</h3><div>We employed stable isotope labeling by amino acids in cell culture mass spectrometry-based phosphoproteomics on <em>in vitro</em> cultured blood outgrowth ECs stimulated with histamine and different PAR1 to 4 peptides. We investigated key phosphosites through immuno(fluorescence) staining and determined effects on barrier function through transendothelial resistance assays.</div></div><div><h3>Results</h3><div>EC histamine activation initiated an extensive (kinase) signaling network (including MAPK3, STAT3, and CTNND1). PAR1 and PAR2 receptors induced highly similar signaling cascades, whereas PAR3 and PAR4 induced minimal phospho-regulation. Integration of all applied stimuli indicated uniquely activated proteins between both stimuli, as well as a general overlapping activation of cell junction and actin cytoskeletal proteins.</div></div><div><h3>Conclusion</h3><div>We provide an integrative phosphoproteomic analysis of histamine and PAR agonists in the endothelium that highlights the endothelial response programs that are at the basis of regulating hemostasis.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 2","pages":"Pages 717-730"},"PeriodicalIF":5.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intensive FVIII replacement in hemophilia patients with hypertrophic synovium: a randomized study","authors":"Matteo Nicola Dario Di Minno ,&nbsp;Ilenia Lorenza Calcaterra ,&nbsp;Erminia Baldacci ,&nbsp;Renato Marino ,&nbsp;Federica Valeri ,&nbsp;Rita Carlotta Santoro ,&nbsp;Gianluigi Pasta ,&nbsp;Carlo Martinoli ,&nbsp;Italian Association of Haemophilia Centers Musculoskeletal Working Group","doi":"10.1016/j.jtha.2024.10.018","DOIUrl":"10.1016/j.jtha.2024.10.018","url":null,"abstract":"<div><h3>Background</h3><div>Hypertrophic synovium (HS) is a marker of disease activity in persons with hemophilia (PwH). Although some recommendations suggest intensifying prophylaxis in PwH with HS, no validated schedules are available.</div></div><div><h3>Objectives</h3><div>We explored the efficacy of intensive factor VIII (FVIII) replacement treatment in PwH with HS.</div></div><div><h3>Methods</h3><div>In a randomized, open-label study, PwH with HS were randomized to receive pharmacokinetics-driven prophylaxis targeting a FVIII trough level of 8% to 12% (intensive treatment arm [ITA]) or 3% to 5% (standard treatment arm [STA]). The primary outcome was HS reduction/resolution in the 2 treatment arms.</div></div><div><h3>Results</h3><div>A total of 39 PwH were randomized to ITA and 36 to STA. During the study, we found a lower annual bleeding rate and a higher rate of annual bleeding rate zero in the ITA than in the STA. HS reduction/resolution was reported in 35.9% of cases in the ITA and 8.4% in the STA. In detail, in the ITA ,10.3% achieved HS reduction and 25.6% complete HS resolution, as compared to 5.6% and 2.8% in the STA. Cox regression showed that ITA was associated with HS reduction/resolution (hazard ratio: 4.75; 95% CI: 1.36-16.57; <em>P</em> = .014) and HS complete resolution (hazard ratio: 10.79; 95% CI: 1.38-84.45; <em>P</em> = .023). The analysis of the 127 joints with HS (54 elbows, 41 knees, and 32 ankles) consistently confirmed similar results.</div></div><div><h3>Conclusion</h3><div>In this randomized study, we found a ∼5-fold higher rate of HS reduction/resolution and a ∼10-fold higher rate of HS resolution in the ITA than in the STA.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 2","pages":"Pages 458-465"},"PeriodicalIF":5.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biophysical characterization of blood coagulation factor VIII binding to lipid nanodiscs that mimic activated platelet surfaces","authors":"Nathan G. Avery,&nbsp;Isabelle R. Young,&nbsp;Selena Lu,&nbsp;Jordan D. Vaughan,&nbsp;Patrick S. Korus,&nbsp;Tera N. Richardson,&nbsp;Kenneth C. Childers,&nbsp;Serge L. Smirnov,&nbsp;P. Clint Spiegel Jr.","doi":"10.1016/j.jtha.2024.11.003","DOIUrl":"10.1016/j.jtha.2024.11.003","url":null,"abstract":"<div><h3>Background</h3><div>Following proteolytic activation, activated blood coagulation factor (F)VIII (FVIIIa) binds to activated platelet membranes, forming the intrinsic tenase complex with activated FIX (FIXa). Previous studies have identified the C1 and C2 domains as the membrane binding domains of FVIII through conserved arginine residues. A membrane binding model for the FVIII C domains proposes that surface-exposed hydrophobic and positively charged residues at each C domain interact with the membrane, yet a comprehensive thermodynamic and structural description of this interaction is lacking.</div></div><div><h3>Objectives</h3><div>To determine residues of interaction, thermodynamics, and membrane binding preference for FVIII membrane association.</div></div><div><h3>Methods</h3><div>The binding of FVIII constructs to lipid nanodiscs was characterized by nuclear magnetic resonance, isothermal titration calorimetry, bio-layer interferometry, and X-ray crystallography.</div></div><div><h3>Results</h3><div>The thermodynamics of FVIII membrane binding indicated that the C1 domain associates through an enthalpically driven process while the C2 domain is entropically driven. Alanine mutations to surface-exposed hydrophobic residues in the C2 domain revealed differential effects on membrane binding, highlighting important determinants at the residue level. The structure of a C2 double mutant, L2251A/L2252A, demonstrated that its decreased affinity is likely due to decreasing the surface area hydrophobicity. Nuclear magnetic resonance studies with the C2 domain identified residues of interaction with soluble O-phospho-L-serine as well as lipid nanodiscs. Lastly, increasing phosphatidylethanolamine and decreasing phosphatidylserine content decreased overall FVIII affinity for membrane surfaces.</div></div><div><h3>Conclusion</h3><div>This study provides further insight into the molecular basis for how FVIII interacts with platelets to form the intrinsic tenase complex.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 2","pages":"Pages 513-524"},"PeriodicalIF":5.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular basis of platelet granule defects","authors":"Helen H.Y. Yao ,&nbsp;Walter H.A. Kahr","doi":"10.1016/j.jtha.2024.11.016","DOIUrl":"10.1016/j.jtha.2024.11.016","url":null,"abstract":"<div><div>Platelets are small, discoid, anucleate blood cells that play key roles in clotting and other functions involved in health and disease. Platelets are derived from bone marrow-resident megakaryocytes, which undergo a complex developmental process where they increase dramatically in size and produce an abundance of organelles destined for platelets. These organelles include mitochondria, lysosomes, peroxisomes, and 2 unique types of secretory organelles: α- and dense (δ-) granules. δ-Granules contain small molecules, including adenosine triphosphate, adenosine diphosphate, serotonin, and ions, such as calcium and zinc (Ca²⁺ and Zn²⁺). α-Granules contain a variety of cargo proteins, which, when secreted by activated platelets, are involved in processes such as hemostasis (eg, fibrinogen and von Willebrand factor), angiogenesis, inflammation, and wound healing. Investigations of patients with inherited conditions resulting in decreased/abnormal platelet secretory granules have led to the identification of proteins, protein complexes, and cellular processes involved in their production by megakaryocytes. Notably, studies of ARPC1B deficiency, Hermansky–Pudlak, and Chediak–Higashi syndromes have linked several genes/proteins to δ-granule biogenesis. Studies of multisystemic arthrogryposis, renal dysfunction, and cholestasis syndrome revealed the requirement of 2 proteins, VPS33B and VPS16B, in α-granule formation. Identification of the genetic cause of gray platelet syndrome established that NBEAL2 is an additional protein needed for α-granule cargo retention. These discoveries enabled studies using animal models, cell culture, and molecular analysis to gain insights into the roles of proteins and cellular processes involved in platelet secretory granule production, which are discussed in this review.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 2","pages":"Pages 381-393"},"PeriodicalIF":5.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}