Journal of Thrombosis and Haemostasis最新文献

{"title":"Updated definition and scoring of disseminated intravascular coagulation in 2025: communication from the ISTH SSC Subcommittee on Disseminated Intravascular Coagulation","authors":"Toshiaki Iba ,&nbsp;Jerrold H. Levy ,&nbsp;Cheryl L. Maier ,&nbsp;Julie Helms ,&nbsp;Yutaka Umemura ,&nbsp;Hunter Moore ,&nbsp;Maha Othman ,&nbsp;Jecko Thachil ,&nbsp;Jean M. Connors ,&nbsp;Marcel Levi ,&nbsp;Ecaterina Scarlatescu","doi":"10.1016/j.jtha.2025.03.038","DOIUrl":"10.1016/j.jtha.2025.03.038","url":null,"abstract":"<div><div>Compelling evidence supports the need to update the 2001 definition and diagnosis of disseminated intravascular coagulation (DIC) to reflect our current understanding of disease pathophysiology. DIC has been long considered a critical and untreatable sequela of various underlying causes, with resolution only after treatment of the eliciting etiology. Recent views have evolved to appreciate that DIC-associated mortality may be reduced by detection and treatment at an early stage. The International Society on Thrombosis and Haemostasis Scientific and Standardization Committee on DIC proposes an updated definition of DIC: “an acquired, life-threatening intravascular disorder characterized by systemic coagulation activation, dysregulated fibrinolysis, and endothelial injury, resulting in microthrombosis. DIC arises from various underlying etiologies and progresses from a potentially asymptomatic early phase to an advanced phase with hemorrhage and/or organ dysfunction.” In accordance with this more comprehensive definition, we propose to establish more tailored diagnostic criteria that detect early-phase DIC based on the underlying disease. We also propose a modification to overt DIC diagnostic criteria and scoring for late-phase DIC. These consensus-driven modifications reflect knowledge obtained since the original 2001 definition, which advanced clinical practice and research on DIC. This revised framework is anticipated to foster more precise and earlier diagnoses, improve patient stratification in clinical studies, and facilitate the development of targeted therapies dependent on pathophysiological context.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 7","pages":"Pages 2356-2362"},"PeriodicalIF":5.5,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143971046","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":"Sialylated glycoproteins bind to Siglec-9 in a cis manner on platelets to suppress platelet activation","authors":"Yuanting She ,&nbsp;Jin Li ,&nbsp;Yiyu Qin ,&nbsp;Yan Qi ,&nbsp;Hongmei Liu ,&nbsp;Niting Wu ,&nbsp;Jie Liu ,&nbsp;Juanjuan Liu ,&nbsp;Wenying Fu ,&nbsp;Jin Wang ,&nbsp;Changhao Han ,&nbsp;Huan Xie ,&nbsp;Xiao Wang ,&nbsp;Yi Jia ,&nbsp;Dongfeng Zeng","doi":"10.1016/j.jtha.2025.03.027","DOIUrl":"10.1016/j.jtha.2025.03.027","url":null,"abstract":"<div><h3>Background</h3><div>The endogenous negative regulation of platelets is important in preventing spontaneous thrombosis, while the mechanism of homeostasis is incompletely understood.</div></div><div><h3>Objectives</h3><div>In this study, we aimed to explore whether Siglec-9 plays a negative regulative role and identify the ligand of Siglec-9 on platelets.</div></div><div><h3>Methods</h3><div>To determine the role of Siglec-9 on platelets, platelet factor 4-cre:<em>Siglec-E</em>^{<em>flox/flox</em>} knockout mouse model and human platelet <em>in vitro</em> culture system were used. Furthermore, recombinant glycoprotein (GP) of Siglec-9 ligand on platelets was expressed and used.</div></div><div><h3>Results</h3><div>We found that Siglec-E conditional knockout can lead to significant increase in platelet coagulation activities both <em>in vivo</em> and <em>in vitro</em>, which strongly suggests that Siglec-9/E plays an inhibitory physiological role in platelet activation. Siglec-9 ligand is an O-link GP with an α2,3-linked sialic acid terminal structure, and the protein carrier of the ligand is mucin-like region of GPIbα. Our data further showed that the ligands on platelets could not engage Siglec-9 on other cells via trans-binding, which indicates that the ligands on platelets play a self-modulation role. Furthermore, we provided evidence that the activation of Siglec-9 pathway with exogenous specific ligands could inhibit the activity of platelets. These data demonstrate a previously unanticipated role for GPIbα in inhibiting platelet activation and provide a novel mechanism for the homeostasis of platelets.</div></div><div><h3>Conclusions</h3><div>We conclude that the cis-binding between mucin-like region of GPIbα and Siglec-9 acts as a “parking brake” on platelet activation. This finding provides a potential druggable target for novel antiplatelet medicine.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 7","pages":"Pages 2270-2283"},"PeriodicalIF":5.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143989461","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":"Insights from in vitro global assays on possible doses of concomitant hemostatic agents in the presence of NXT007 in hemophilia A","authors":"Kenichi Ogiwara ,&nbsp;Shoko Furukawa ,&nbsp;Keito Inaba ,&nbsp;Kana Sasai ,&nbsp;Yuto Nakajima ,&nbsp;Naruto Shimonishi ,&nbsp;Takehisa Kitazawa ,&nbsp;Keiji Nogami","doi":"10.1016/j.jtha.2025.03.034","DOIUrl":"10.1016/j.jtha.2025.03.034","url":null,"abstract":"<div><h3>Background</h3><div>Concomitant administration of activated prothrombin complex concentrate (APCC) at doses &gt;100 U/kg/d is associated with thrombotic risk under emicizumab prophylaxis. <em>In vitro</em> global assay data on the effects of concomitant coagulation factor agents in the presence of NXT007, an emicizumab-based engineered bispecific antibody under clinical development, may serve as a basis for addressing this potential risk.</div></div><div><h3>Objectives</h3><div>This study aimed to investigate the <em>in vitro</em> effects of recombinant factor (rF)VIII, rFVIIa, and APCC during NXT007 treatment and estimate tolerable doses with reference to emicizumab.</div></div><div><h3>Methods</h3><div>Thrombin generation assays, clot waveform analysis, and rotational thromboelastometry were performed using hemophilia A plasma and blood samples spiked with NXT007 and others.</div></div><div><h3>Results</h3><div>A single dose of NXT007 at ≥10.0 μg/mL (plasma) achieved a nonhemophiliac coagulation potential. The concomitant addition of rFVIII, rFVIIa, and APCC each boosted various parameters following NXT007 levels at 0.1 to 50.0 μg/mL. In the copresence of NXT007 at 15.0 μg/mL (blood) and APCC at 0.13 U/mL, with the blood level immediately following the administration of 10.0 U/kg, the rotational thromboelastometry parameters were comparable with those observed with clinical emicizumab level and APCC at 0.63 U/mL, corresponding to the blood level immediately after administrating 50.0 U/kg (recommended initial dose).</div></div><div><h3>Conclusion</h3><div>Concomitant addition of coagulation agents increased coagulation potentials <em>in vitro</em> in the presence of NXT007. A dose of 10.0 U/kg may serve as a rough indicator for the initial dose when exploring the concomitant use of APCC at plasma NXT007 levels of ∼30.0 μg/mL. Importantly, plasma NXT007 at ≥10.0 μg/mL demonstrated non-hemophiliac coagulation potentials <em>in vitro</em>.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 7","pages":"Pages 2164-2177"},"PeriodicalIF":5.5,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811676","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":"Angiostatin—a novel SARS-CoV-2 inhibitor and biomarker underlying COVID-19 pathophysiology","authors":"Aleksandra Franczak ,&nbsp;Michael Joyce ,&nbsp;Joaquin Lopez–Orozco ,&nbsp;Holly A. Saffran ,&nbsp;Max Saito ,&nbsp;Amir Asgari ,&nbsp;Subha Kalyaanamoorthy ,&nbsp;Khaled Barakat ,&nbsp;Tom C. Hobman ,&nbsp;D. Lorne Tyrrell ,&nbsp;Paul Jurasz","doi":"10.1016/j.jtha.2025.03.030","DOIUrl":"10.1016/j.jtha.2025.03.030","url":null,"abstract":"<div><h3>Background</h3><div>Despite efficacious vaccines, many individuals remain at risk of severe illness and death from COVID-19 due to immune-escape variants. Hence, a better understanding of biomarkers underlying COVID-19 pathophysiology is needed to improve disease progression prediction and identify new drug targets. Angiostatin is a plasmin(ogen)-derived protein generated by platelets. As microvascular thrombosis, a key pathologic feature of COVID-19, can create microenvironments of both high angiostatin concentration and hypoxia/acidosis, conditions known to favor angiostatin’s proapoptotic actions on endothelial and epithelial cells, angiostatin may be a biomarker contributing to COVID-19 pathophysiology.</div></div><div><h3>Objectives</h3><div>To assess the role of angiostatin in COVID-19.</div></div><div><h3>Methods</h3><div>Plasma angiostatin concentrations were compared between COVID-19 patients and COVID-19-negative controls, as were temporal changes in plasma angiostatin in COVID-19 patients. Subsequent mechanistic cellular studies investigated the effects of angiostatin and its neutralization on both SARS-CoV-2 infection and subsequent cell death.</div></div><div><h3>Results</h3><div>Plasma angiostatin concentrations increased following SARS-CoV-2 infection and remained elevated in COVID-19 patients for 21 to 28 days. Angiostatin at concentration that would be generated within a clot over 7 to 8 hours promoted cell death in acidic microenvironments characteristic of severe COVID-19. Irrespective of pH, angiostatin reduced SARS-CoV-2 cellular entry of multiple variants by interfering with spike protein proteolysis. Selective angiostatin-neutralizing peptides inhibited angiostatin-induced cell death, but not angiostatin’s ability to reduce infection.</div></div><div><h3>Conclusion</h3><div>Angiostatin has dual roles during COVID-19, both preventing infection and promoting cell death. Selective angiostatin-neutralizing peptides may be novel therapeutics for further preclinical evaluation in models of severe COVID-19.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 7","pages":"Pages 2151-2163"},"PeriodicalIF":5.5,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811670","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":"Lupus anticoagulant and antiprothrombin antibodies: embracing the future","authors":"Vittorio Pengo ,&nbsp;Nicola Pozzi","doi":"10.1016/j.jtha.2025.03.029","DOIUrl":"10.1016/j.jtha.2025.03.029","url":null,"abstract":"<div><div>Lupus anticoagulant (LAC) is a well-known laboratory test used to explore potential reasons for the prolongation of phospholipid-dependent coagulation tests. An extended clotting time in a coagulation test typically suggests a bleeding tendency, as the plasma takes longer to clot. However, a positive LAC result, defined as normalization of prolonged clotting time by adding anionic phospholipids in the system, does not necessarily imply this. In fact, quite the opposite is true: a positive LAC often strongly correlates with an increased risk of thromboembolic events. Therefore, despite being conceptually counterintuitive, LAC remains extremely valuable in routine clinical practice for identifying individuals at risk for thromboembolic events. Over the years, various factors have been recognized as potential inducers of LAC, with antiphospholipid antibodies associated with antiphospholipid syndrome (APS) playing a significant role. Today, research indicates that, among antiphospholipid antibodies, those targeting plasma proteins β₂-glycoprotein I and prothrombin are central to LAC. This article offers a historical perspective on LAC, emphasizing recent developments in antiprothrombin antibodies, their connection to LAC, and novel detection methods. Our premise is that a deeper understanding of how antiprothrombin antibodies contribute to LAC and the identification of subpopulations of these antibodies potentially responsible for it in thrombotic APS patients could lead to transformative advancements, offering new strategies for risk stratification and personalized treatments for patients with APS and beyond.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 7","pages":"Pages 2262-2269"},"PeriodicalIF":5.5,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811677","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":"Detection of SARS-CoV-2 in bone marrow megakaryocytes and elevated emperipolesis in COVID-19 patients with thrombocytopenia","authors":"Cédric Garcia ,&nbsp;Fanny Vardon-Bounes ,&nbsp;Baptiste Compagnon ,&nbsp;Céline Guilbeau-Frugier ,&nbsp;Sophie Voisin ,&nbsp;Jean-Baptiste Rieu ,&nbsp;Véronique De Mas ,&nbsp;Bernard Payrastre ,&nbsp;Agnès Ribes","doi":"10.1016/j.jtha.2025.03.036","DOIUrl":"10.1016/j.jtha.2025.03.036","url":null,"abstract":"<div><h3>Background</h3><div>Thrombocytopenia and altered platelet activation are correlated with COVID-19 severity and mortality. COVID-19 patients have modifications of the platelet and blood-circulating megakaryocyte (MK) transcriptome.</div></div><div><h3>Objectives</h3><div>To explore the features of bone marrow MKs, which remain poorly characterized in SARS-CoV-2–infected patients, particularly those with thrombocytopenia.</div></div><div><h3>Methods</h3><div>In this case series study, we analyzed bone marrow samples from a series of 11 COVID-19 patients with thrombocytopenia admitted to the intensive care unit for acute respiratory distress syndrome. Bone marrow sampling, aimed to explore thrombocytopenia’s etiology by cytology, allowed us to document bone marrow MK behavior.</div></div><div><h3>Results</h3><div>A reduction in bone marrow cellularity and a decrease in the megakaryocytic lineage were observed, suggesting a central component of the thrombocytopenia. Bone marrow MKs exhibited significantly increased emperipolesis and vacuolization. Moreover, transmission electron microscopy pointed to the presence of viral particles inside bone marrow MKs. Immunolabeling confirmed the presence of 2 SARS-CoV-2 proteins, spike and Orf3a, and double-stranded RNA, suggesting a potential viral replication cycle.</div></div><div><h3>Conclusion</h3><div>In this series of COVID-19 patients with thrombocytopenia, we report the presence of SARS-CoV-2 in bone marrow MKs as well as a decrease in MK lineage and an increase in emperipolesis.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 7","pages":"Pages 2327-2334"},"PeriodicalIF":5.5,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811671","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":"Impact of peptidylarginine deiminase 4 (PAD4) deficiency in a fecal-induced peritonitis model of sepsis","authors":"Erblin Cani ,&nbsp;Dhruva J. Dwivedi ,&nbsp;Sean Carlin ,&nbsp;Neha Sharma ,&nbsp;Alex Chen ,&nbsp;Patricia C. Liaw ,&nbsp;Canadian Critical Care Translational Biology Group (CCCTBG)","doi":"10.1016/j.jtha.2025.03.025","DOIUrl":"10.1016/j.jtha.2025.03.025","url":null,"abstract":"<div><h3>Background</h3><div>Peptidylarginine deiminase 4 (PAD4) citrullinates histones, enabling the release of neutrophil extracellular traps. While neutrophil extracellular traps capture and kill pathogens, they also drive immunothrombosis, potentially worsening sepsis outcomes. However, it remains unclear whether PAD4 deficiency is beneficial or harmful in sepsis.</div></div><div><h3>Objectives</h3><div>To evaluate the impact of PAD4 deficiency in a fecal-induced peritonitis sepsis model, with and without antibiotic treatment, and incorporating fluid resuscitation in both sexes.</div></div><div><h3>Methods</h3><div>Wild-type and PAD4 knockout (PAD4^-/-) C57Bl/6 mice received intraperitoneal injections of fecal slurry (0.6 mg/g). Mice received buprenorphine every 8 hours and antibiotics/fluids every 12 hours. Survival studies were also conducted without antibiotics at a reduced fecal dose (0.4 mg/g). Mice were culled at 8 hours or 48 hours after infection. Organs, blood, and peritoneal cavity fluid were collected. Plasma levels of interleukin (IL)-6, IL-10, cell-free DNA, and thrombin-antithrombin were quantified, as well as bacterial loads in blood and peritoneal cavity fluid. Organ histology/immunohistochemistry was performed.</div></div><div><h3>Results</h3><div>Female PAD4^-/- mice had worsened survival compared with female wild-type mice. Male mice exhibited worse survival than females in both strains. Antibiotics eliminated survival differences between strains and sexes. Septic PAD4^-/- mice had reduced IL-10 in the early phase of sepsis, increased lung myeloperoxidase, and exacerbated lung injury compared with septic wild-type mice.</div></div><div><h3>Conclusion</h3><div>PAD4 deficiency in female mice worsened survival in the fecal-induced peritonitis sepsis model. In both strains, male mice exhibited worse survival compared with their female counterparts. PAD4 deficiency is associated with reduced IL-10, increased neutrophil infiltration, and exacerbated lung injury. Antibiotics eliminated survival differences between strains and sexes.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 7","pages":"Pages 2342-2355"},"PeriodicalIF":5.5,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811673","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":"Direct oral anticoagulant failure in patients with venous thromboembolism—why and what next?","authors":"Dawn Swan ,&nbsp;Robert Turner ,&nbsp;Erik Lerkevang Grove ,&nbsp;Sam Schulman ,&nbsp;Jecko Thachil","doi":"10.1016/j.jtha.2025.03.026","DOIUrl":"10.1016/j.jtha.2025.03.026","url":null,"abstract":"<div><div>Management of recurrent thrombotic events in patients taking a direct oral anticoagulant can be challenging. In this review, we consider causes of so-called direct oral anticoagulant failure, from poor adherence, malabsorption, and drug interactions to the presence of undiagnosed antiphospholipid syndrome, cancer-associated thrombosis, severe thrombophilia, vasculitis, and other rare causes. We discuss the known or potential pathogenesis of venous thromboembolism recurrence in these situations and provide practical guidance to assist clinicians faced with these challenging cases.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 6","pages":"Pages 1774-1786"},"PeriodicalIF":5.5,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811672","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":"Association of fibrinogen αE, fibrinogen γ', and sialylated fibrinogen with development of ischemic stroke in patients with recently diagnosed type 2 diabetes","authors":"Nicoline Daugaard ,&nbsp;Else–Marie Bladbjerg ,&nbsp;Helene Mathilde Lundsgaard Svane ,&nbsp;Reimar Wernich Thomsen ,&nbsp;Jens Steen Nielsen ,&nbsp;Yaseelan Palarasah ,&nbsp;Moniek P.M. de Maat ,&nbsp;Anna–Marie Bloch Münster","doi":"10.1016/j.jtha.2025.03.023","DOIUrl":"10.1016/j.jtha.2025.03.023","url":null,"abstract":"<div><h3>Background</h3><div>Stroke is a major cause of death globally, especially in type 2 diabetes (T2D) patients. Fibrinogen is known to predict stroke risk, but fibrinogen is a highly variable protein and we hypothesized that fibrinogen variants can improve stroke prediction.</div></div><div><h3>Objectives</h3><div>We aimed to investigate the association of total fibrinogen and fibrinogen variants with risk of ischemic stroke in T2D patients.</div></div><div><h3>Methods</h3><div>In a nested case-control study with a median follow-up of 4.1 years, we included 144 T2D patients with ischemic stroke (cases) and 144 matched T2D patients without ischemic stroke (controls). We measured total fibrinogen, absolute, and relative levels of 3 fibrinogen variants (fibrinogen α_E, fibrinogen γ′, and sialylated fibrinogen) and compared levels between cases and controls. We used logistic regression to determine the association with stroke risk.</div></div><div><h3>Results</h3><div>Total fibrinogen and absolute levels of fibrinogen α_E, fibrinogen γ′, and sialylated fibrinogen were higher in stroke cases than controls. Absolute levels of fibrinogen positively associated with risk of stroke for total fibrinogen (highest vs lowest tertile; adjusted odds ratio (OR), 1.9 [95% CI, 0.9-4.2]), fibrinogen γ′ (OR, 1.8 [0.8-3.8]), and sialylated fibrinogen (OR, 2.5 [1.1-5.8]). Relative levels of fibrinogen variants did not convincingly associate with stroke risk.</div></div><div><h3>Conclusion</h3><div>Patients with T2D who developed stroke had increased levels of total fibrinogen, fibrinogen α_E, fibrinogen γ′, and sialylated fibrinogen compared with T2D controls. Total fibrinogen and absolute, but not relative, levels of fibrinogen γ′ and sialylated fibrinogen prospectively associated with a 2-fold increased risk of ischemic stroke.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 7","pages":"Pages 2213-2225"},"PeriodicalIF":5.5,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788588","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":"Replacement of a single residue changes the primary specificity of thrombin","authors":"Alessia Dei Rossi,&nbsp;Samantha Deavila,&nbsp;Bassem M. Mohammed,&nbsp;Sergey Korolev,&nbsp;Enrico Di Cera","doi":"10.1016/j.jtha.2024.12.024","DOIUrl":"10.1016/j.jtha.2024.12.024","url":null,"abstract":"<div><h3>Background</h3><div>Thrombin prefers substrates carrying Arg at the site of cleavage (P1) because of the presence of D189 in the primary specificity (S1) pocket but can also cleave substrates carrying Phe at P1. The structural basis of this property is unknown.</div></div><div><h3>Objectives</h3><div>Solve the X-ray structure of thrombin bound to a ligand carrying Phe at P1 and investigate the effects of replacing D189.</div></div><div><h3>Methods</h3><div>X-ray crystallography is used to solve the structure of thrombin bound to the irreversible inhibitor H-D-Phe-Pro-Phe-CH₂Cl (PPPCK). Residue D189 is mutated to Ala, Lys, Phe, and Ser.</div></div><div><h3>Results</h3><div>The X-ray structure of the thrombin-PPPCK complex is solved at 2.5 Å resolution and compared to the structure of thrombin bound to H-D-Phe-Pro-Arg-CH₂Cl (PPACK). PPPCK binds to thrombin in a conformation similar to that of PPACK, but Phe at P1 makes no contacts with D189. Replacement of D189 with Ala, Lys, Phe, or Ser reverses both substrate preference and stability enhancement from Arg to Phe.</div></div><div><h3>Conclusion</h3><div>D189 in the S1 pocket confers thrombin “trypsin-like” specificity for Arg at P1. However, the S1 pocket is wide enough to also enable “chymotrypsin-like” specificity for Phe at P1. Consistent with these structural features, a single amino acid replacement (D189A) switches thrombin specificity from trypsin-like to chymotrypsin-like, converting the substrate preference from H-D-Phe-Pro-Arg-p-nitroanilide to H-D-Phe-Pro-Phe-p-nitroanilide and preferential stability enhancement from PPACK to PPPCK. The observation that thrombin specificity is controlled mainly by a single residue establishes a new paradigm in the field of trypsin-like proteases.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 4","pages":"Pages 1241-1246"},"PeriodicalIF":5.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932191","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}