Journal of Thrombosis and Haemostasis最新文献

{"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, Shoko Furukawa, Keito Inaba, Kana Sasai, Yuto Nakajima, Naruto Shimonishi, Takehisa Kitazawa, Keiji Nogami","doi":"10.1016/j.jtha.2025.03.034","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.03.034","url":null,"abstract":"<p><strong>Introduction: </strong>Concomitant administration of activated prothrombin complex concentrate (aPCC) at doses >100 U/kg/day is associated with thrombotic risk under emicizumab prophylaxis. In vitro 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.</p><p><strong>Aim: </strong>To investigate the in vitro effects of rFVIII, rFVIIa, and aPCC during NXT007 treatment and estimate tolerable doses with reference to emicizumab.</p><p><strong>Methods: </strong>Thrombin generation assays, clot waveform analysis, and rotational thromboelastometry (ROTEM) were performed using hemophilia A plasma and blood samples spiked with NXT007 and others.</p><p><strong>Results: </strong>A single dose of NXT007 at ≥10 μg/mL (plasma) achieved a non-hemophiliac coagulation potential. The concomitant addition of rFVIII, rFVIIa, and aPCC each boosted various parameters following NXT007 levels at 0.1-50 μg/mL. In the co-presence of NXT007 at 15 μg/mL (blood) and aPCC at 0.13 U/mL, with the blood level immediately following the administration of 10 U/kg, the ROTEM parameters were comparable to those observed with clinical emicizumab level and aPCC at 0.63 U/mL, corresponding to the blood level immediately after administrating 50 U/kg (recommended initial dose).</p><p><strong>Conclusions: </strong>Concomitant addition of coagulation agents increased coagulation potentials in vitro in the presence of NXT007. A dose of 10 U/kg may serve as a rough indicator for the initial dose when exploring the concomitant use of aPCC at plasma NXT007 levels of approximately 30 μg/mL. Importantly, plasma NXT007 at ≥10 μg/mL demonstrated non-hemophiliac coagulation potentials in vitro.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"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, Michael Joyce, Joaquin Lopez-Orozco, Holly A Saffran, Max Saito, Amir Asgari, Subha Kalyaanamoorthy, Khaled Barakat, Tom C Hobman, D Lorne Tyrrell, Paul Jurasz","doi":"10.1016/j.jtha.2025.03.030","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.03.030","url":null,"abstract":"<p><strong>Background: </strong>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 pathological feature of COVID-19, can create microenvironments of both high angiostatin concentration and hypoxia/acidosis, conditions known to favour angiostatin's pro-apoptotic actions on endothelial and epithelial cells, angiostatin may be a biomarker contributing to COVID-19 pathophysiology.</p><p><strong>Objective: </strong>To assess the role of angiostatin in COVID-19.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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 7-8 h 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.</p><p><strong>Conclusions: </strong>Angiostatin has dual roles during COVID-19, both preventing infection and promoting cell death. Selective angiostatin neutralizing peptides may be novel therapeutics for further pre-clinical evaluation in models of severe COVID-19.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"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 Anti-Prothrombin Antibodies: Embracing the Future.","authors":"Vittorio Pengo, Nicola Pozzi","doi":"10.1016/j.jtha.2025.03.029","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.03.029","url":null,"abstract":"<p><p>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 anti-prothrombin antibodies, their connection to LAC, and novel detection methods. Our premise is that a deeper understanding of how anti-prothrombin 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.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"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, Fanny Vardon-Bounes, Baptiste Compagnon, Céline Guilbeau-Frugier, Sophie Voisin, Jean-Baptiste Rieu, Véronique De Mas, Bernard Payrastre, Agnès Ribes","doi":"10.1016/j.jtha.2025.03.036","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.03.036","url":null,"abstract":"<p><strong>Background: </strong>Thrombocytopenia and altered platelet activation correlate with COVID-19 severity and mortality. COVID-19 patients have modifications of the platelet and blood circulating megakaryocytes (MK) transcriptome. Our objective was to explore the features of bone marrow MK, which remain poorly characterized in SARS-CoV-2 infected patients, particularly those with thrombocytopenia.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>A reduction in bone marrow cellularity and a decrease in the megakaryocytic lineage, were observed suggesting a central component of the thrombocytopenia. Bone marrow MK exhibited significantly increased emperipolesis and vacuolization. Moreover, transmission electron microscopy pointed to the presence of viral particles inside bone marrow MK. Immunolabeling confirmed the presence of two SARS-CoV-2 proteins, spike and Orf3a, as well as double-stranded RNA suggesting a potential viral replication cycle.</p><p><strong>Conclusion: </strong>In this series of COVID-19 patients with thrombocytopenia we report the presence of SARS-CoV-2 in bone marrow MK as well as a decrease in MK lineage and an increase in emperipolesis.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"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 PAD4 deficiency in a fecal-induced peritonitis model of sepsis.","authors":"Erblin Cani, Dhruva Dwivedi, Sean Carlin, Neha Sharma, Alex Chen, Patricia C Liaw","doi":"10.1016/j.jtha.2025.03.025","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.03.025","url":null,"abstract":"<p><strong>Background: </strong>Peptidylarginine deiminase 4 (PAD4) citrullinates histones, enabling the release of neutrophil extracellular traps (NETs). While NETs 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.</p><p><strong>Objectives: </strong>To evaluate the impact of PAD4 deficiency in a fecal-induced peritonitis (FIP) sepsis model, with and without antibiotic treatment, and incorporating fluid resuscitation and both sexes.</p><p><strong>Methods: </strong>Wild-type and PAD4^-/- C57Bl/6 mice received intraperitoneal injections of fecal slurry (0.6 mg/g). Mice received buprenorphine every 8h and antibiotics/fluids every 12h. Survival studies were also conducted without antibiotics at a reduced fecal dose (0.4 mg/g). Mice were culled at 8h or 48h post-infection. Organs, blood, and peritoneal cavity fluid (PCF) 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 PCF. Organ histology/immunohistochemistry was performed.</p><p><strong>Results: </strong>Female PAD4-/- mice had worsened survival compared to 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.</p><p><strong>Conclusion: </strong>PAD4 deficiency in female mice worsened survival in the FIP sepsis model. In both strains, male mice exhibited worse survival compared to 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.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"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, Robert Turner, Erik Lerkevang Grove, Sam Schulman, Jecko Thachil","doi":"10.1016/j.jtha.2025.03.026","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.03.026","url":null,"abstract":"<p><p>Management of recurrent thrombotic events in patients taking a direct oral anticoagulant can be challenging. In this review, we consider causes of so-called DOAC 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 VTE recurrence in these situations and provide practical guidance to assist clinicians faced with these challenging cases.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"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 α_E, fibrinogen γ´, and sialylated fibrinogen with development of ischemic stroke in patients with recently diagnosed type 2 diabetes.","authors":"Nicoline Daugaard, Else-Marie Bladbjerg, Helene Matilde Lundsgaard Svane, Reimar Wernich Thomsen, Jens Steen Nielsen, Yaseelan Palarasah, Moniek P M de Maat, Anna-Marie Bloch Münster","doi":"10.1016/j.jtha.2025.03.023","DOIUrl":"https://doi.org/10.1016/j.jtha.2025.03.023","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Objectives: </strong>To investigate the association of total fibrinogen and fibrinogen variants with risk of ischemic stroke in T2D patients.</p><p><strong>Methods: </strong>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 three 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.</p><p><strong>Results: </strong>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, both 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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"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}

{"title":"Applying artificial intelligence to uncover the genetic landscape of coagulation factors","authors":"Giulia Soldà ,&nbsp;Rosanna Asselta","doi":"10.1016/j.jtha.2024.12.030","DOIUrl":"10.1016/j.jtha.2024.12.030","url":null,"abstract":"<div><div>Artificial intelligence (AI) is rapidly advancing our ability to identify and interpret genetic variants associated with coagulation factor deficiencies. This review introduces AI, with a specific focus on machine learning (ML) methods, and examines its applications in the field of coagulation genetics over the past decade. We observed a significant increase in AI-related publications, with a focus on hemophilia A and B. ML approaches have shown promise in predicting the functional impact of genetic variants and establishing genotype–phenotype correlations, exemplified by tools like “Hema-Class” for factor VIII variants. However, some challenges remain, including the need to expand variant selection beyond missense mutations (which is now the standard of most studies). For the future, the integration of AI in calling, detecting, and interpreting genetic variants can significantly improve our ability to process large-scale genomic data. In this frame, we discuss various AI/ML-based tools for genetic variant detection and interpretation, highlighting their strengths and limitations. As the field evolves, the synergistic application of multiple AI models, coupled with rigorous validation strategies, will be crucial in advancing our understanding of coagulation disorders and for personalizing treatment approaches.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 4","pages":"Pages 1133-1145"},"PeriodicalIF":5.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971419","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":"The individual fibrinolytic capacity predicts the efficacy of ultrasound-assisted catheter-directed thrombolysis in patients with acute pulmonary embolism","authors":"Dominik F. Draxler ,&nbsp;Justine Brodard ,&nbsp;Heidi Ho ,&nbsp;Konstantina Chalkou ,&nbsp;Elisabeth Turovskij ,&nbsp;Charithani B. Keragala ,&nbsp;Thomas Lillicrap ,&nbsp;Dierik Heg ,&nbsp;Johanna A. Kremer Hovinga ,&nbsp;Stephan Windecker ,&nbsp;Robert L. Medcalf ,&nbsp;Anne Angelillo-Scherrer ,&nbsp;Stefan Stortecky","doi":"10.1016/j.jtha.2024.12.043","DOIUrl":"10.1016/j.jtha.2024.12.043","url":null,"abstract":"<div><h3>Background</h3><div>Ultrasound-assisted catheter-directed thrombolysis (USAT) is nowadays available as an alternative reperfusion approach for acute pulmonary embolism (PE). The lytic agent recombinant tissue-type plasminogen activator (rt-PA) activates the effector protease plasmin to induce fibrinolysis.</div></div><div><h3>Objectives</h3><div>The aim of this study was to identify predictive markers for the efficacy of USAT in patients with acute PE.</div></div><div><h3>Methods</h3><div>In a single-center cohort study of USAT for intermediate-high or high-risk PE, pulmonary-arterial hemodynamic measurements were performed, and plasma samples were obtained from 35 patients before treatment start, at 6 hours (during infusion of rt-PA), and at 24 hours after treatment start (postlysis). The hemostatic properties were evaluated with thromboelastometry, and fibrinolytic markers and the <em>ex vivo</em> capacity of rt-PA–spiked plasma to generate the plasmin-antiplasmin complex were assessed.</div></div><div><h3>Results</h3><div>Patients presented with an elevated mean pulmonary artery pressure (32.9 ± 7.6 mm Hg), with an average postlysis reduction of 9.4 ± 8.3 mm Hg, yet the treatment response varied markedly across individuals. The endogenous fibrinolytic capacity, as represented by the plasmin-antiplasmin complex and D-dimer, as well as consumption of the endogenous fibrinolysis inhibitor α2-antiplasmin at 6 hours, predicted the individual treatment efficacy, indicated by the reduction in mean pulmonary artery pressure (all <em>P</em> &lt; .05). Furthermore, <em>ex vivo</em> assessment of the fibrinolytic potential before the start of USAT also predicted efficacy. Both maximum clot lysis INTEM and the novel parameter fibrin-sensitivity ratio were identified as predictors of USAT responsiveness (both <em>P</em> &lt; .05).</div></div><div><h3>Conclusion</h3><div>Markers of fibrinolysis may be harnessed to predict treatment responsiveness to USAT in patients with acute PE.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"23 4","pages":"Pages 1416-1427"},"PeriodicalIF":5.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066719","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}