Thrombosis and haemostasis最新文献

{"title":"Inhibition of IP3 (Inositol 1,4,5-Trisphosphate) Receptors Retards SARS-CoV-2-Induced Endothelial von Willebrand Factor Secretion and Thrombosis.","authors":"Xin-Yi Yu, Xin-Yu Jia, Ting-Yu Wang, Yan-Hong Zhang, Hao Song, Kan Li, Zhuo-Zheng Chen, Yi Zhu, Liu Yao","doi":"10.1055/a-2471-8767","DOIUrl":"https://doi.org/10.1055/a-2471-8767","url":null,"abstract":"<p><p>Patients with coronavirus disease 2019 (COVID-19) are at high risk of developing a hypercoagulable state and thrombosis. The von Willebrand factor (vWF) produced by endothelial cells (ECs) is a critical thrombosis regulator. We previously found that cytoskeleton-associated protein 4 (CKAP4) is a novel receptor for the spike protein of severe acute respiratory syndrome coronavirus-2 and is involved in COVID-19-associated coagulopathy. However, the underlying mechanism involved remains unclear. This study aimed to explore the signaling pathways involved in spike protein-CKAP4-induced vWF secretion and thrombosis. Treatment of ECs with the spike protein significantly induced vWF secretion, coagulation factor VIII (FVIII)-vWF binding, and platelet adhesion to ECs, which were blocked by the selective intracellular calcium chelator, BAPTA-AM. Furthermore, using several calcium channel-blocking drugs and small-molecule inhibitors, we found that calcium released from the endoplasmic reticulum (ER) is involved in this process. IP3 (inositol 1,4,5-trisphosphate) receptors (IP3Rs) inhibition ameliorated spike protein-induced vWF secretion, FVIII-vWF binding affinity, and platelet adhesion to ECs. Specifically, the knockdown of IP3R1, a crucial type of IP3Rs, reversed spike protein-induced endothelial vWF secretion, and the procoagulant state. Moreover, KT-362, an investigational and clinically relevant antihypertensive drug targeting IP3Rs-mediated calcium release, repressed spike protein-induced endothelial vWF secretion. Conversely, the IP3Rs agonist promoted endothelial vWF secretion, which was not affected by CKAP4 knockdown. In vivo treatment of endothelial-specific human CKAP4 overexpression mice with KT-362 retarded spike protein-induced vWF secretion and thrombosis. Thus, IP3Rs mediated calcium release from the ER and contributed to spike protein-induced vWF secretion and thrombosis, making them potential therapeutic targets for COVID-19-associated coagulopathy.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143574117","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":"Differences in the Outcome of Cancer-Associated Thrombosis Depending on Cancer Type.","authors":"Ramón Lecumberri, María Marcos-Jubilar, José Hermida, Pedro Ruiz-Artacho","doi":"10.1055/a-2535-7400","DOIUrl":"10.1055/a-2535-7400","url":null,"abstract":"<p><p>The outcome of venous thromboembolism in patients with cancer is worse than in patients without cancer, with a higher risk of recurrences, bleeding and death. However, these risks appear to vary depending on the cancer type. While in some tumours the risk of recurrences outweighs the risk of bleeding, in others the risk of major bleeding (MB) during the anticoagulation markedly exceeds the risk of a recurrent event. Balancing these risks could be helpful to tailor the management of cancer-associated thrombosis (CAT) and improve outcomes. In this article, published data from recent randomized clinical trials as well as from some large registries that have reported separated outcomes of CAT depending on cancer type were reviewed. A careful balance of the risk of recurrences and MB events could provide useful insights for clinicians for individualizing treatment strategies in order to improve the outcomes of CAT, as well as for the design of future clinical trials.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391845","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":"Relationship between Surgery and Trauma and Risk of Recurrence in Patients with an Associated First Venous Thrombotic Event: A Nested Case-Control Study.","authors":"T Gregorio, K J Creeper, L Pagliani, R Providencia, A Buzea, C Wallenhorst, J I Weitz, A T Cohen","doi":"10.1055/a-2535-7321","DOIUrl":"https://doi.org/10.1055/a-2535-7321","url":null,"abstract":"<p><p>The duration of anticoagulation treatment for venous thromboembolism (VTE) depends on whether the event was provoked or unprovoked. Major surgery or trauma are well-established major provoking factors associated with a low risk of recurrence, but the magnitude of risk with VTE after minor surgery or trauma is uncertain.To compare the rate of recurrence in patients with VTE provoked by minor surgery or trauma with that in patients with VTE provoked by major surgery or trauma.Nested, case-control study of patients with a first VTE diagnosed within 90 days after major or minor surgery or trauma. Patients with unprovoked VTE or VTE provoked by cancer or nonsurgical risk factors were excluded. Crude and adjusted odds ratios with 95% confidence intervals (CI) were calculated and results were adjusted for potential confounders.A total of 319 patients with recurrent VTE (cases) were matched to 974 patients without recurrence (controls). The incidence of recurrence after VTE provoked by minor surgery (6.5%; 95% CI: 5.6-7.6) was more than double that after VTE provoked by major surgery (3.0%; 95% CI: 2.4-3.6), a difference that remained even after adjustment for known VTE risk factors. There were no differences in recurrence rates between VTE provoked by minor and major trauma.The risk of recurrence is higher in patients with VTE provoked by minor surgery than major surgery. These findings support the concept that the risk of recurrence is higher with minimally provoked VTE than with VTE provoked by major transient risk factors.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143568215","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":"Binding Promiscuity of Therapeutic Factor VIII.","authors":"Alejandra Reyes Ruiz, Aishwarya S Bhale, Krishnan Venkataraman, Jordan D Dimitrov, Sébastien Lacroix-Desmazes","doi":"10.1055/a-2358-0853","DOIUrl":"10.1055/a-2358-0853","url":null,"abstract":"<p><p>The binding promiscuity of proteins defines their ability to indiscriminately bind multiple unrelated molecules. Binding promiscuity is implicated, at least in part, in the off-target reactivity, nonspecific biodistribution, immunogenicity, and/or short half-life of potentially efficacious protein drugs, thus affecting their clinical use. In this review, we discuss the current evidence for the binding promiscuity of factor VIII (FVIII), a protein used for the treatment of hemophilia A, which displays poor pharmacokinetics, and elevated immunogenicity. We summarize the different canonical and noncanonical interactions that FVIII may establish in the circulation and that could be responsible for its therapeutic liabilities. We also provide information suggesting that the FVIII light chain, and especially its C1 and C2 domains, could play an important role in the binding promiscuity. We believe that the knowledge accumulated over years of FVIII usage could be exploited for the development of strategies to predict protein binding promiscuity and therefore anticipate drug efficacy and toxicity. This would open a mutational space to reduce the binding promiscuity of emerging protein drugs while conserving their therapeutic potency.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":"194-206"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141477498","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":"A European-Multicenter Network for the Implementation of Artificial Intelligence to Manage Complexity and Comorbidities of Atrial Fibrillation Patients: The ARISTOTELES Consortium.","authors":"Giuseppe Boriani, Davide Antonio Mei, Gregory Y H Lip","doi":"10.1055/a-2508-5708","DOIUrl":"10.1055/a-2508-5708","url":null,"abstract":"","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":"189-193"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143042049","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":"Off-Label Dosing of Direct Oral Anticoagulants: Prescribing Error or Opportunity in Treating Patients with Atrial Fibrillation?","authors":"Daniela Poli","doi":"10.1055/a-2441-8902","DOIUrl":"10.1055/a-2441-8902","url":null,"abstract":"","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":"286-289"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142627486","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":"Comparison of Clinical Outcomes in Patients with Active Cancer Receiving Rivaroxaban or Low-Molecular-Weight Heparin: The OSCAR-UK Study.","authors":"Alexander T Cohen, Christopher Wallenhorst, Marcella Rivera, Cihan Ay, Bernhard Schaefer, Khaled Abdelgawwad, George Psaroudakis, Gunnar Brobert, Anders Ekbom, Agnes Y Y Lee, Alok A Khorana, Cecilia Becattini, Marc Carrier, Craig I Coleman, Carlos Martinez","doi":"10.1055/a-2259-0662","DOIUrl":"10.1055/a-2259-0662","url":null,"abstract":"<p><strong>Background: </strong> In most patients with cancer-associated venous thromboembolism (CT), essentially those not at high risk of bleeding, guidelines recommend treatment with direct oral anticoagulants as an alternative to low-molecular-weight heparins (LMWHs). Population-based studies comparing these therapies are scarce.</p><p><strong>Objectives: </strong> To compare the risk of venous thromboembolism (VTE) recurrences, significant bleeding, and all-cause mortality in patients with CT receiving rivaroxaban or LMWHs.</p><p><strong>Patients/methods: </strong> Using UK Clinical Practice Research Datalink data from 2013 to 2020, we generated a cohort of patients with first CT treated initially with either rivaroxaban or LMWH. Patients were observed 12 months for VTE recurrences, significant bleeds (major bleeds or clinically relevant nonmajor bleeding requiring hospitalization), and all-cause mortality. Overlap weighted sub-distribution hazard ratios (SHRs) compared rivaroxaban with LMWH in an intention-to-treat analysis.</p><p><strong>Results: </strong> The cohort consisted of 2,259 patients with first CT, 314 receiving rivaroxaban, and 1,945 LMWH, mean age 72.4 and 66.9 years, respectively. In the 12-month observational period, 184 person-years following rivaroxaban and 1,057 following LMWH, 10 and 66 incident recurrent VTE events, 20 and 102 significant bleeds, and 10 and 133 deaths were observed in rivaroxaban and LMWH users, respectively. The weighted SHR at 12 months for VTE recurrences in rivaroxaban compared with LMWH were 0.80 (0.37-1.73); for significant bleeds 1.01 (0.57-1.81); and for all-cause mortality 0.49 (0.23-1.06).</p><p><strong>Conclusion: </strong> Patients with CT, not at high risk of bleeding, treated with either rivaroxaban or LMWH have comparable effectiveness and safety outcomes. This supports the recommendation that rivaroxaban is a reasonable alternative to LMWH for the treatment of CT.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":"265-277"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11858610/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139672755","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":"Pneumococcal Neuraminidases Increase Platelet Killing by Pneumolysin.","authors":"Kristin J Fritsch, Laura Krüger, Stefan Handtke, Thomas P Kohler, Arina Ozhiganova, Kristin Jahn, Jan Wesche, Andreas Greinacher, Sven Hammerschmidt","doi":"10.1055/a-2369-8680","DOIUrl":"10.1055/a-2369-8680","url":null,"abstract":"<p><strong>Background: </strong> Platelets prevent extravasation of capillary fluids into the pulmonary interstitial tissue by sealing gaps in inflamed endothelium. This reduces respiratory distress associated with pneumonia. <i>Streptococcus pneumoniae</i> is the leading cause of severe community-acquired pneumonia. Pneumococci produce pneumolysin (PLY), which forms pores in membranes of eukaryotic cells including platelets. Additionally, pneumococci express neuraminidases, which cleave sialic acid residues from eukaryotic glycoproteins. In this study, we investigated the effect of desialylation on PLY binding and pore formation on platelets.</p><p><strong>Materials and methods: </strong> We incubated human platelets with purified neuraminidases and PLY, or nonencapsulated <i>S. pneumoniae</i> D39/TIGR4 and isogenic mutants deficient in PLY and/or NanA. We assessed platelet desialylation, PLY binding, and pore formation by flow cytometry. We also analyzed the inhibitory potential of therapeutic immunoglobulin G preparations (IVIG [intravenous immunoglobulin]).</p><p><strong>Results: </strong> Wild-type pneumococci cause desialylation of platelet glycoproteins by neuraminidases, which is reduced by 90 to 100% in NanA-deficient mutants. NanC, cleaving only α2,3-linked sialic acid, induced platelet desialylation. PLY binding to platelets then x2doubled (<i>p</i> = 0.0166) and pore formation tripled (<i>p</i> = 0.0373). A neuraminidase cleaving α2,3-, α2,6-, and α2,8-linked sialic acid like NanA was even more efficient. Addition of polyvalent IVIG (5 mg/mL) decreased platelet desialylation induced by NanC up to 90% (<i>p</i> = 0.263) and reduced pore formation >95% (<i>p</i> < 0.0001) when incubated with pneumococci.</p><p><strong>Conclusion: </strong> Neuraminidases are key virulence factors of pneumococci and desialylate platelet glycoproteins, thereby unmasking PLY-binding sites. This enhances binding of PLY and pore formation showing that pneumococcal neuraminidases and PLY act in concert to kill platelets. However, human polyvalent immunoglobulin G preparations are promising agents for therapeutic intervention during severe pneumococcal pneumonia.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":"243-254"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141727816","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":"Percutaneous Coronary Intervention in Acute Coronary Syndrome with Mild-to-Moderate Thrombocytopenia.","authors":"Yicong Ye, Yongchen Hao, Xiliang Zhao, Jun Liu, Na Yang, Sidney C Smith, Yong Huo, Gregg C Fonarow, Junbo Ge, Louise Morgan, Zhaoqing Sun, Danqing Hu, Yiqian Yang, Chang-Sheng Ma, Dong Zhao, Yaling Han, Jing Liu, Yong Zeng","doi":"10.1055/a-2225-5263","DOIUrl":"10.1055/a-2225-5263","url":null,"abstract":"<p><strong>Background: </strong> Baseline thrombocytopenia is commonly observed in patients with acute coronary syndrome (ACS) requiring percutaneous coronary intervention (PCI).</p><p><strong>Aim: </strong> The purpose of this analysis was to investigate safety and effectiveness of PCI in ACS patients with baseline mild-to-moderate thrombocytopenia.</p><p><strong>Methods: </strong> The data were collected from the Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome project. A total of 50,009 ACS patients were recruited between July 2017 and December 2019. Among them, there were 6,413 patients with mild-to-moderate thrombocytopenia, defined as a platelet count of ≥50 × 10⁹/L and <150 × 10⁹/L on admission. The primary outcome was in-hospital net adverse clinical events (NACE), consisting of major adverse cardiac events (MACE) and major bleeding events. The associations between PCI and in-hospital outcomes were analyzed by inverse probability treatment weighting (IPTW) method.</p><p><strong>Results: </strong> PCI was performed in 4,023 of 6,413 patients (62.7%). The IPTW analysis showed that PCI was significantly associated with a reduced risk of in-hospital MACE (odd ratio [OR]: 0.45; 95% confidence interval [CI]: 0.31-0.67; <i>p</i> < 0.01) and NACE (OR: 0.59; 95% CI: 0.42-0.83; <i>p</i> < 0.01). PCI was also associated with an increased risk of any bleeding (OR: 1.56; 95% CI: 1.09-2.22; <i>p</i> = 0.01) and minor bleeding (OR: 1.52; 95% CI: 1.00-2.30; <i>p</i> = 0.05), but not major bleeding (OR: 1.51; 95% CI: 0.76-2.98; <i>p</i> = 0.24).</p><p><strong>Conclusion: </strong> Compared with medical therapy alone, PCI is associated with better in-hospital outcomes in ACS patients with mild-to-moderate thrombocytopenia. Further studies with long-term prognosis are needed.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":"218-229"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138800536","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":"An Inhibitory Single-Domain Antibody against Protein Z-Dependent Protease Inhibitor Promotes Thrombin Generation in Severe Hemophilia A and FXI Deficiency.","authors":"Claire Auditeau, Tung-Son Nguyen, Floriane Devaux, François Saller, Ivan Peyron, Adeline Blandinières, Christelle Repérant, Sadyo Daramé, Cécile V Denis, Peter Lenting, Delphine Borgel, Elsa P Bianchini","doi":"10.1055/a-2373-2829","DOIUrl":"10.1055/a-2373-2829","url":null,"abstract":"<p><strong>Background: </strong> Protein Z-dependent protease inhibitor (ZPI) is an anticoagulant serpin that targets factor Xa (FXa) in the presence of protein Z (PZ), and factor XIa (FXIa). In factor-VIII-deficient mice, PZ or ZPI gene knock-out mitigates the bleeding phenotype, and pharmacological inhibition of PZ enhances thrombin generation in plasma from patients with hemophilia.</p><p><strong>Aims: </strong> To develop a single-domain antibody (sdAb) directed against ZPI to inhibit its anticoagulant activity.</p><p><strong>Methods: </strong> We screened for anti-ZPI sdAbs in a llama-derived phage display immune library of sdAbs. The sdAbs that bound ZPI were produced and purified for characterization. The binding of sdAbs to ZPI or other serpins was evaluated using ELISAs, and ZPI inhibition was measured in an anti-FXa or anti-FXIa chromogenic assay. The sdAbs's procoagulant activity was assessed in a thrombin generation assay in normal plasma, factor VIII- and FXI-deficient plasma.</p><p><strong>Results: </strong> Of the four sdAbs found to bind to ZPI, one (referred to as ZPI-sdAb2) dose-dependently inhibited ZPI's anti-FXa and anti-FXIa activities with a mean half-maximal inhibitory concentration of 1.8 and 1.3 µM, respectively. ZPI-sdAb2 did not cross-react with other plasma serpins, such as antithrombin and α1-antitrypsin. ZPI-sdAb2 induced a significant increase in thrombin generation in plasma samples from healthy donors, patients with severe hemophilia A, and patients with FXI deficiency.</p><p><strong>Conclusion: </strong> ZPI-sdAb2 is the first specific, direct ZPI inhibitor found to exhibit procoagulant activity in plasma. This sdAb might have potential as a treatment for hemophilia or other bleeding disorders.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":"207-217"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141760998","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}