Journal of Thrombosis and Haemostasis最新文献

{"title":"Causal insights into the role of metabolites in venous thromboembolism pathogenesis: A metabolome-wide mendelian randomization study.","authors":"Wei Hu, Yun Bei, Guoquan Chen, Junjun Xu, Mingdong Yang, Lingyan Yu, Wei He, Yani Hu, Fengqian Mao, Shunan Chen, Donghang Xu, Haibin Dai","doi":"10.1016/j.jtha.2025.03.022","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.03.022","url":null,"abstract":"<p><strong>Background: </strong>Venous thromboembolism (VTE) is a significant global health burden, and metabolic alterations play a key role in its pathogenesis. However, previous studies have been constrained by several limitations, hindering clarification of the causal role of metabolites.</p><p><strong>Methods: </strong>Genetic associations involving 690 plasma and 211 urinary metabolites were analyzed as exposures, while the outcomes for VTE were derived from a large-scale meta-analysis of genome-wide association studies. Metabolome-wide Mendelian randomization (MR) and colocalization analyses were performed to assess the causal role of metabolites in VTE. Metabolic pathway analysis was performed using MetOrigin, and druggability assessments were conducted to prioritize potential therapeutic targets. Additionally, a two-step MR framework was employed to elucidate the mediating effects of metabolites on the relationships between modifiable risk factors and VTE.</p><p><strong>Results: </strong>After Bonferroni correction, 51 plasma metabolites and 18 urinary metabolites were significantly associated with VTE risk. Colocalization evidence supported causal relationships for 37 metabolites with VTE. Eleven metabolic pathways were identified for VTE-related metabolites, and six metabolites were prioritized as potential therapeutic targets. Twenty-four modifiable risk factors were associated with 28 VTE-related metabolites, seven of which were linked to VTE risk. Mediation analyses further revealed significant mediating effect of 8 metabolites on how 6 modifiable factors influenced VTE.</p><p><strong>Conclusion: </strong>This study identifies potential metabolite biomarkers associated with VTE risk and uncovered the metabolic mediators between modifiable risk factors and VTE, offering new insights for future prevention and treatment strategies.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743245","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":"Maternal platelet-derived factors induce trophoblastic LAIR2 expression to promote trophoblast invasion and inhibit platelet activation at the fetal-maternal interface.","authors":"Freya Lyssy, Désirée Forstner, Jacqueline Guettler, Nadja Kupper, Kaja Ujčič, Lena Neuper, Christine Daxboeck, Amin El-Heliebi, Daniel Kummer, Julian C Krappinger, Djenana Vejzovic, Beate Rinner, Gerhard Cvirn, Stefan Wernitznig, Gerit Moser, Daniela S Valdes, Florian Herse, Anna-Lena Höbler, Juergen Pollheimer, Joanna L James, Julia Feichtinger, Martin Gauster","doi":"10.1016/j.jtha.2025.03.020","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.03.020","url":null,"abstract":"<p><strong>Background: </strong>During human placentation extravillous trophoblasts (EVTs), arising from cell column trophoblasts (CCT) invade the highly differentiated uterine mucosa, called decidua, where they erode blood vessels and replace vascular endothelial cells. Maternal platelets have been detected in intercellular gaps of CCTs but their physiological role remained unclear so far.</p><p><strong>Objective: </strong>This study aimed to elucidate the impact of platelet-derived factors on trophoblasts that are exposed to maternal platelets through erosion of decidual blood vessels.</p><p><strong>Methods: </strong>Trophoblast cell line ACH-3P spheroids were incubated either with platelet-derived factors or isolated platelets obtained from pregnant women, and afterwards subjected to RNA sequencing, and validation by qPCR, ELISA and in situ padlock hybridization. Amongst deregulated genes, LAIR2 expression was confirmed in first trimester placenta and primary trophoblast organoids. The functional role of LAIR2 in trophoblast invasion and platelet activation was studied.</p><p><strong>Results: </strong>Platelet-derived factors altered the transcription profile of ACH-3P spheroids, including deregulation of genes linked to embryonic development. Amongst them, LAIR2 was exclusively detected in CCTs and invaded EVTs of first trimester decidua. Histology showed extravasated maternal erythrocytes within interstitial gaps of highly invaded decidua samples, coinciding with LAIR2 positive EVTs. LAIR2 inhibited type 1 collagen -induced platelet activation and enhanced invasiveness of trophoblasts.</p><p><strong>Conclusion: </strong>This study suggests that maternal platelet-derived factors affect the transcription profile of trophoblasts, including upregulation of LAIR2, which may be involved in fine-tuning the coagulation of maternal blood leaking from eroded decidual blood vessels and could increase the invasiveness of EVTs into the decidua through an autocrine mechanism.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743247","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":"The Incidence and Risk Of Venous thromboembolism in patients with Active Malignancy and Isolated Superficial Venous Thrombosis: A systematic review and meta-analysis. (The IROVAM-iSVT review).","authors":"Adrian Joseph Michel Bailey, Owen Dan Luo, Shi Qi Zhou, Phillip S Wells","doi":"10.1016/j.jtha.2025.03.019","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.03.019","url":null,"abstract":"<p><strong>Background: </strong>The management of cancer-associated isolated superficial venous thrombosis (iSVT) remains controversial as cancer patients are at higher risk of bleeding and venous thromboembolism (VTE).</p><p><strong>Objectives: </strong>We performed a systematic review and meta-analysis to determine the incidence and risk of VTE in patients with iSVT and active malignancy.</p><p><strong>Methods: </strong>Medline, Embase, Web of Science and the Cochrane Library were searched from inception to December 2nd, 2024 to identify studies investigating VTE rates in adult patients with iSVT and active malignancy. The incidence of VTE in patients with active malignancy and iSVT was pooled by meta-analysis and compared to patients with iSVT without active malignancy. Secondary outcomes included the incidence of major bleeding, clinically relevant non major bleeding (CRNMB), hospitalization, and all-cause death.</p><p><strong>Results: </strong>8 full-text studies were included comprising 5998 iSVT patients and 448 with active malignancy. Patients with cancer-associated iSVT had an overall incidence of VTE of 18.2 events per 100 patient years (95%CI [5.2-31.2], I²=76%), and a higher rate of VTE compared to patients with iSVT without active malignancy (RR 2.57, 95%CI [1.78-3.71], I²=0%, P<0.001). There were 2 major bleeding events per 100 patient years (95%CI [0 to 6.7], I²=59%) and 22.8 deaths per 100 patient years (95%CI [0 to 58.7], I² = 73%) for cancer-associated iSVT. Only one study reported on CRNMD and hospitalization rates, respectively.</p><p><strong>Conclusions: </strong>Patients with iSVT and active malignancy have high rates of VTE despite treatment. Future studies should investigate the role of extended duration anticoagulation on VTE rates in this population.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743249","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":"Enhancing hemostasis potency in hemophilia with a small interfering RNA targeting protein S.","authors":"Raja Prince Eladnani, Ute Schaeper, Rim Diab, Julia Aretz, Kristina Vrotniakaite-Bajerciene, Sara Çaku, Rafika Yasmin, Bojun Li, Maria Desiré Reina Caro, Sibylle Dames, Mona Eisermann, Kathrin Löffler, Alberto Martinez, Bas de Laat, Justine Brodard, Alessandro Casini, Johanna A Kremer Hovinga, Ramanjaneyulu Allam, José A Fernández, John H Griffin, Mike A Laffan, Rinku Majumder, Josefin Ahnström, Anne Angelillo-Scherrer","doi":"10.1016/j.jtha.2025.03.021","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.03.021","url":null,"abstract":"<p><strong>Background: </strong>One hemophilia treatment concept focuses on rebalancing coagulation and anticoagulation to restore normal blood clotting. Targeting the coagulation regulator, protein S (PS), in hemophilia shows promise to increase the generation of thrombin-a critical enzyme in the clotting process.</p><p><strong>Objectives: </strong>This study aimed to: (1) assess whether inhibiting PS increases thrombin generation (TG) in plasma from individuals with hemophilia A (HA) and B (HB); and (2) develop a hepatocyte-targeted PS-silencing RNA (siRNA) therapy using N-acetylgalactosamine (GalNAc) conjugation to restore hemostasis in hemophilia without increasing thromboembolic risks.</p><p><strong>Methods: </strong>We assessed TG in plasma from patients with HA and HB. To target the liver specifically, we developed a PS-siRNA conjugated with GalNAc. This approach ensures that PS levels remain adequate in other cells, thereby minimizing the risk of thrombosis. Additionally, we evaluated the therapeutic potential of PS-siRNA in preclinical models.</p><p><strong>Results: </strong>Inhibiting PS with a polyclonal antibody in plasma resulted in a 3-5 fold increase in TG in HA and a 4-9 fold increase in HB plasma, with a 70% reduction in plasma PS. In preclinical models, subcutaneous PS-siRNA therapy in HA mice and non-human primates successfully lowered PS levels and improved clot formation. It also prevented bleeding in both saphenous vein puncture and knee-injury models in HA mice. Notably, it enhanced clotting without triggering widespread clot formation.</p><p><strong>Conclusions: </strong>Reducing PS levels enhances TG in hemophilia models, and PS-siRNA therapy shows promise in improving hemostasis. This approach warrants further clinical investigation as a potential treatment for hemophilia.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743246","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":"Plasminogen and plasmin induce specialized pro-resolving mediators and promote efferocytosis via 5-lipoxygenase.","authors":"Luiza O Perucci, Fernanda S Carneiro, Josiane C Souza, Laís C Grossi, Jessica A M Souza, Isabella Zaidan, Camila Cardoso, Edvaldo S Lara, Franciel B Felix, Nagyung Baik, Luciana P Tavares, Frederico M Soriani, Mauro M Teixeira, Robert J Parmer, Lindsey A Miles, Lirlândia P Sousa","doi":"10.1016/j.jtha.2025.03.018","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.03.018","url":null,"abstract":"<p><strong>Background: </strong>The plasminogen (Plg)/plasmin (Pla) system has been recognized for its pro-resolving actions, such as promoting efferocytosis. However, the role of specialized pro-resolving mediators (SPMs) in these Plg/Pla effects remains unexplored.</p><p><strong>Objectives: </strong>To investigate whether Plg/Pla promotes SPMs production in macrophages and to elucidate the role of the 5-lipoxygenase (5-LO) pathway in Pla-induced efferocytosis.</p><p><strong>Methods: </strong>Bone marrow-derived macrophages (BMDMs) from wild-type (WT) and Plg-knockout (KO) mice were treated or not with Plg/Pla, with or without leupeptin (protease inhibitor) and tranexamic acid (lysine analog), for 24 hours. SPMs and leukotriene B4 (LTB₄) production, and the mRNA expression of 5-, 12-, and 15-LO (SPMs biosynthetic enzymes) were assessed in WT-BMDMs. Additionally, 12/15-LO expression was analyzed in pleural macrophages from Pla-injected mice. Efferocytosis of apoptotic neutrophils was examined in Pla-injected WT and 5-LO KO mice and using the 5-LO inhibitor MK886 in Pla-stimulated BMDMs.</p><p><strong>Results: </strong>Plg/Pla enhanced the production of LXA₄, MaR1, and RvD1, as well as the mRNA expression of 5-, 12-, and 15-LO in macrophages, a process dependent on proteolytic activity and lysine binding sites. Macrophages from Plg KO mice produced lower LXA4 levels, while LTB₄ levels remained comparable to WT cells. Pla injection promoted macrophage recruitment to the pleural cavity alongside 12/15-LO protein upregulation. Furthermore, Pla increased the efferocytosis of apoptotic neutrophils in WT mice, but not in 5-LO KO mice, and pharmacological inhibition of 5-LO reduced Pla-induced efferocytosis in vitro.</p><p><strong>Conclusion: </strong>In summary, Plg/Pla pro-resolving actions are associated with SPMs production in macrophages and a 5-LO-dependent pro-efferocytosis mechanism.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730683","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":"Consensus protocol for platelet desialylation (β-galactose exposure) quantification using lectins by flow cytometry: Communication from the ISTH SSC Subcommittee on Platelet Physiology.","authors":"Alexandre Kauskot, Sofia Ramstrom, Thomas Nipoti, Dianne E van der Wal","doi":"10.1016/j.jtha.2025.03.017","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.03.017","url":null,"abstract":"<p><strong>Introduction: </strong>Platelets contain many heterogeneous carbohydrates (glycans): often capped by sialic acid. The removal of sialic acid (desialylation) is important for platelet function and clearance, leading to novel diagnostic markers. Platelet desialylation can be easily measured using inexpensive, user-friendly lectins, and flow cytometry.</p><p><strong>Aims: </strong>Here, the Platelet Physiology Scientific and Standardization Committee (SSC) of the International Society for Thrombosis and Haemostasis (ISTH) carried out a survey to assess current methods used for platelet desialylation. Based on the survey results, a consensus protocol was drafted and tested.</p><p><strong>Methods: </strong>A survey/questionnaire was posted on the ISTH Platelet Physiology SSC pages. Washed platelets and diluted apheresis platelets were diluted to 50 and 200x10⁶/mL, ± CaCl₂. Platelets were stained with a concentration range of either β-galactose binding fluoresceine-conjugated lectins Ricinus communis agglutinin 1(RCA-1) or Erythrina cristagalli lectin (ECL) respectively. As positive controls, different recombinant sialidases were tested.</p><p><strong>Results: </strong>Results of the survey (n=20) showed that flow cytometry and RCA-1 are mostly used to assess platelet desialylation. Calcium did not significantly influence lectin binding and optimal binding was achieved with ECL and RCA-1 at 2 and 5 μg/mL, respectively. The specificity of lectins varied, particularly after sialidase treatment, compared to cold-stored platelets. These findings contribute to standardization of desialylation measurements, particularly in patient samples.</p><p><strong>Conclusions: </strong>Our findings demonstrate that flow cytometry using RCA-1 and ECL is a robust method for quantifying platelet desialylation. The proposed standardised protocol addresses key pre-analytical variables, enabling reproducible and accurate analysis of platelet glycosylation.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730682","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":"Factor Activity Levels and Bleeding Scores in Hemophilia Carriers: Apparent Paradoxes.","authors":"John Puetz","doi":"10.1016/j.jtha.2025.03.013","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.03.013","url":null,"abstract":"<p><p>Multiple studies report abnormal bleeding in hemophilia carriers with normal factor activity levels. Other studies report the lack of abnormal bleeding in carriers with hemophilia. In addition, limited data suggests that the bleeding risk in carriers increases with age while at the same time, factor activity levels are rising. Potential explanations for these paradoxical findings include inadequate data, inadequate measures of bleeding, inadequate measures of factor activity, or uncharacterized biological modifiers.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692665","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":"Effect of direct oral anticoagulants in cirrhosis: an in vitro study.","authors":"Cindy Pereira Portela, Debora Bertaggia Calderara, Elise Mdawar-Bailly, Alessandro Aliotta, Lucas Veuthey, Lucas A Gautier, Darius Moradpour, Montserrat Fraga, Maxime G Zermatten, Lorenzo Alberio","doi":"10.1016/j.jtha.2025.03.011","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.03.011","url":null,"abstract":"<p><strong>Background and aims: </strong>Cirrhosis is associated with a procoagulant state that may worsen disease evolution. Anticoagulation could be of particular interest in these patients. However, evidence on the use of DOAC in patients with cirrhosis is limited. Our aim was to explore the in vitro effect of DOAC on thrombin generation (TG) in plasma from patients with cirrhosis compared to healthy controls.</p><p><strong>Methods and results: </strong>Platelet-poor-plasma was obtained from patients with cirrhosis (n=87; Child-Turcotte-Pugh score: A n=68; B n=14; C n=5) and controls (n=17). TG was assessed with ST-Genesia. Plasma from patients with cirrhosis and TM-mediated inhibition of endogenous thrombin potential <20% (ThromboScreen) were defined as \"highly procoagulant\" (n=36), ≥20-50% as \"procoagulant\" (n=31) and >50% as \"non-procoagulant\" (n=20). Plasma samples were spiked with apixaban, edoxaban, rivaroxaban or dabigatran at final concentrations of 50 and 150 ng/ml. TG was measured (DrugScreen) in plasma samples without and with DOAC. Apixaban, edoxaban, and rivaroxaban demonstrated a significantly reduced inhibition of in vitro TG parameters in highly procoagulant plasma from patients with cirrhosis compared to controls, whereas possibly artefactual results were observed with dabigatran.</p><p><strong>Conclusion: </strong>The anticoagulant potency of DOAC differs according to the individual procoagulant potential. Highly procoagulant plasmas from patients with cirrhosis are less sensitive to the anticoagulant action of apixaban, edoxaban, and rivaroxaban compared to control plasmas. These results, if confirmed in vivo, would support the concept of personalizing anticoagulant treatment in patients with a highly procoagulant state.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692664","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":"Anticoagulation and Other Risk Factors for Clinically Relevant Bleeding after Medical Hospitalization: The Medical Inpatient Thrombosis and Hemostasis Study.","authors":"Mansour Gergi, Katherine Wilkinson, Andrew Sparks, Nicholas S Roetker, Hanny Al-Samkari, Nicholas L Smith, Timothy B Plante, Mary Cushman, Allen B Repp, Chris E Holmes, Karlyn Martin, Neil A Zakai","doi":"10.1016/j.jtha.2025.02.044","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.02.044","url":null,"abstract":"<p><strong>Introduction: </strong>Clinically relevant Bleeding after discharge from a medical hospitalization is associated with increased morbidity and mortality. There is limited knowledge of the risk factors for this bleeding.</p><p><strong>Objective: </strong>To determine the risk factors for bleeding leading to rehospitalization after hospital discharge.</p><p><strong>Methods: </strong>The study population consisted of primary care patients followed longitudinally from October 2010 to September 2019 for medical hospitalization and clinically relevant bleeding. People discharged alive from a medical hospitalization were followed for up to 90 days for post discharge bleeding requiring rehospitalization. Age and sex and length of stay-adjusted hazard ratios (HR) for candidate bleeding risk factors were estimated using Cox proportional hazards models.</p><p><strong>Results: </strong>Over 9 years, there were 15,630 medical hospitalization discharges and 414 (2.6%) post-discharge clinically relevant bleeding events requiring re-admission. Clinical and patient factors related to post-discharge bleeding risk were increasing age, active cancer, liver disease, creatinine >2 g/dl, heart disease, and history of previous gastrointestinal or central nervous system bleeding. Hemoglobin <12 g/dl for women and <13.6 g/dl for men as well as a platelet count <50x10³ mm³ as well as anticoagulation at discharge were also associated with an increased risk for post-discharge clinically relevant bleeding.</p><p><strong>Conclusion: </strong>Bleeding requiring re-hospitalization occurs after 2.6% of medical hospitalizations and has objective and readily identifiable risk factors. Findings suggest post-discharge clinically relevant bleeding may be predictable and quantifiable which could help increase the safety of anticoagulation decisions at discharge.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692634","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":"The critical role of platelet adenylyl cyclase 6 in haemostasis and thrombosis.","authors":"Beth A Webb, Lih T Cheah, Jawad S Khalil, Matthew S Hindle, Mary McKay, Neil A Turner, Mark T Kearney, Robert A S Ariens, Cedric Duval, Khalid M Naseem","doi":"10.1016/j.jtha.2025.02.045","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.02.045","url":null,"abstract":"<p><strong>Background: </strong>Platelet activation is constrained by endothelial-derived prostacyclin (PGI₂) through cyclic adenosine-5'-monophosphate (cAMP) signalling involving multiple isoforms of adenylyl cyclase (AC). The roles of specific AC isoforms in controlling haemostasis remain unclear and require clarification.</p><p><strong>Objectives: </strong>To understand the specific contribution of AC6 in platelet haemostatic and thrombotic function.</p><p><strong>Methods: </strong>A platelet-specific AC6 knockout (AC6-KO) mouse was generated. Biochemical approaches were used to determine intracellular signalling, with flow cytometry, tail bleeding time assays and in vivo thrombosis by ferric chloride were used to measure the haemostatic and thrombotic importance of platelet AC6.</p><p><strong>Results: </strong>Loss of AC6 resulted in diminished accumulation of platelet cAMP in response to PGI_2, while basal cAMP was unaffected. We found no differences in phosphodiesterase 3A (PDE3A) activity, suggesting the defect was in generation rather than hydrolysis of cAMP. Consistent with this, phosphorylation of PKA substrates, vasodilator-stimulated phosphoprotein and glycogen synthase kinase were diminished but not ablated. Functional studies demonstrated that the inhibition of thrombin-induced fibrinogen binding and P-selectin expression by PGI₂ was severely compromised, while inhibition of GPVI-mediated platelet activation was largely unaffected. Under conditions of flow formed stable thrombi, but in the absence of AC6, thrombi were insensitive to PGI₂. In vivo diminished sensitivity to PGI₂ manifested as significantly reduced tail bleeding and accelerated occlusive arterial thrombus formation in response to vascular injury that were highly unstable and prone to embolisation in AC6-KO mice.</p><p><strong>Conclusions: </strong>These data demonstrate that AC6 is linked directly to PGI₂-mediated platelet inhibition and regulation of haemostasis and thrombosis in vivo.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692666","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}