Pub Date : 2026-02-01DOI: 10.1016/j.jtha.2025.07.007
Neil A. Zakai , Katherine Wilkinson , Andrew D. Sparks , Ryan T. Packer , Nicholas S. Roetker , Allen B. Repp , Mansour Gergi , Chris Holmes , Mary Cushman , Timothy B. Plante , Hanny Al-Samkari , Allyson M. Pishko , William A. Wood , Camila Masias , Radhika Gangaraju , Ang Li , David Garcia , Kerri L. Wiggins , Jordan K. Schaefer , Nicholas L. Smith , Leslie A. McClure
Background
Hospital-acquired (HA) bleeding in medical inpatients is a serious complication with limited tools to predict risk.
Objectives
This study aimed to develop and validate risk assessment models (RAMs) for anatomic location-specific HA bleeding in medical inpatients using objective and routinely available risk factors.
Methods
Patients aged ≥18 years admitted to medical hospital services from 6 health systems and 15 hospitals in the United States between 2016 and 2020 for at least 1 midnight and without bleeding at admission were eligible for inclusion. Two health systems (10 hospitals) formed the development cohort, and 4 systems (5 hospitals) constituted the validation cohort. Bayesian Least absolute shrinkage and selection operator was used to develop anatomic site-specific RAMs.
Results
Among the development (153 707 admissions) and validation (137 460 admissions) cohorts, 5999 (3.9%) and 3282 (2.4%) HA bleeds occurred. RAMs had varied risk factors by anatomic bleeding location; for instance, older age was associated with genitourinary bleeding in men but not in women. Different cancer types were associated with different anatomic bleeding locations such as genitourinary cancers associated with genitourinary bleeding and gynecologic bleeding. The RAMs demonstrated good predictive performance for most anatomical bleeding locations; the C-statistic was ≥0.67 for all anatomic location bleeding in the development and validation cohorts and generally higher in the anatomic location specific RAMs.
Conclusion
These RAMs provide anatomic location-specific and sex-specific HA-bleeding risk stratification, addressing a critical gap in individualized risk assessment. Integration into clinical workflows could enhance patient safety and outcomes. Implementation studies are essential to maximize their clinical utility.
{"title":"Development and validation of risk models for hospital-acquired bleeding in medical inpatients: the Medical Inpatients Thrombosis and Hemostasis (MITH) study","authors":"Neil A. Zakai , Katherine Wilkinson , Andrew D. Sparks , Ryan T. Packer , Nicholas S. Roetker , Allen B. Repp , Mansour Gergi , Chris Holmes , Mary Cushman , Timothy B. Plante , Hanny Al-Samkari , Allyson M. Pishko , William A. Wood , Camila Masias , Radhika Gangaraju , Ang Li , David Garcia , Kerri L. Wiggins , Jordan K. Schaefer , Nicholas L. Smith , Leslie A. McClure","doi":"10.1016/j.jtha.2025.07.007","DOIUrl":"10.1016/j.jtha.2025.07.007","url":null,"abstract":"<div><h3>Background</h3><div>Hospital-acquired (HA) bleeding in medical inpatients is a serious complication with limited tools to predict risk.</div></div><div><h3>Objectives</h3><div>This study aimed to develop and validate risk assessment models (RAMs) for anatomic location-specific HA bleeding in medical inpatients using objective and routinely available risk factors.</div></div><div><h3>Methods</h3><div>Patients aged ≥18 years admitted to medical hospital services from 6 health systems and 15 hospitals in the United States between 2016 and 2020 for at least 1 midnight and without bleeding at admission were eligible for inclusion. Two health systems (10 hospitals) formed the development cohort, and 4 systems (5 hospitals) constituted the validation cohort. Bayesian Least absolute shrinkage and selection operator was used to develop anatomic site-specific RAMs.</div></div><div><h3>Results</h3><div>Among the development (153 707 admissions) and validation (137 460 admissions) cohorts, 5999 (3.9%) and 3282 (2.4%) HA bleeds occurred. RAMs had varied risk factors by anatomic bleeding location; for instance, older age was associated with genitourinary bleeding in men but not in women. Different cancer types were associated with different anatomic bleeding locations such as genitourinary cancers associated with genitourinary bleeding and gynecologic bleeding. The RAMs demonstrated good predictive performance for most anatomical bleeding locations; the C-statistic was ≥0.67 for all anatomic location bleeding in the development and validation cohorts and generally higher in the anatomic location specific RAMs.</div></div><div><h3>Conclusion</h3><div>These RAMs provide anatomic location-specific and sex-specific HA-bleeding risk stratification, addressing a critical gap in individualized risk assessment. Integration into clinical workflows could enhance patient safety and outcomes. Implementation studies are essential to maximize their clinical utility.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 418-430"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667838","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}
Pub Date : 2026-02-01DOI: 10.1016/j.jtha.2025.05.005
Timothy Hoberstorfer , Stephan Nopp , Daniel Steiner , Julia Deinsberger , Oliver Schlager , Ingrid Pabinger , Benedikt Weber , Cihan Ay
Background
Patients with venous thromboembolism (VTE) are at risk of bleeding during anticoagulation.
Objectives
This study aimed to assess bleeding risk and the performance of risk assessment models (RAMs) VTE-PREDICT, HAS-BLED, RIETE, and VTE-BLEED in patients with acute VTE initiating anticoagulation.
Methods
We used data from a prospective observational cohort study (BACH-VTE) including patients with acute VTE who initiated anticoagulation with a follow-up period of up to 2 years. Exclusion criteria were active cancer, pregnancy, and postpartum period. Major bleeding, clinically relevant nonmajor bleeding (CRNMB), and minor bleeding were recorded and their frequencies calculated. RAM performance was evaluated by discrimination and calibration. Predictors associated with clinically relevant bleeding (CRB; composite of major and CRNMB) were assessed.
Results
In total, 308 patients (median age, 55 years; 42% women, 47% pulmonary embolism, 62% unprovoked VTE) were included. During a median follow-up time of 12.6 months, we observed 2 major bleedings, 41 CRNMBs, and 66 minor bleedings, corresponding to 2-year cumulative incidences (95% CI) of 0.9% (0%-2.1%), 16.2% (10.7%-21.3%), and 20.6% (15.1%-25.8%), respectively, and of 33.4% (26.7-39.5) for any bleeding. RAM discrimination was poor to moderate with C-statistics (95% CI) for CRB of 0.71 (0.61-0.80) for VTE-PREDICT, 0.59 (0.49-0.68) for HAS-BLED, 0.52 (0.41-0.62) for RIETE, and 0.56 (0.45-0.68) for VTE-BLEED. Calibration analysis revealed underestimation of bleeding risk. Female sex, lower hemoglobin, and bleeding history were associated with CRB in a univariable but not in a multivariable model.
Conclusion
In patients treated with anticoagulants for VTE, we found high rates of CRB. Only the VTE-PREDICT model showed acceptable discrimination, but poor calibration.
{"title":"Bleeding risk and performance of bleeding risk assessment models in patients with venous thromboembolism on anticoagulation: results from the prospective observational bleeding and assess long-term outcomes on health in patients with venous thromboembolism (BACH-VTE) study","authors":"Timothy Hoberstorfer , Stephan Nopp , Daniel Steiner , Julia Deinsberger , Oliver Schlager , Ingrid Pabinger , Benedikt Weber , Cihan Ay","doi":"10.1016/j.jtha.2025.05.005","DOIUrl":"10.1016/j.jtha.2025.05.005","url":null,"abstract":"<div><h3>Background</h3><div>Patients with venous thromboembolism (VTE) are at risk of bleeding during anticoagulation.</div></div><div><h3>Objectives</h3><div>This study aimed to assess bleeding risk and the performance of risk assessment models (RAMs) VTE-PREDICT, HAS-BLED, RIETE, and VTE-BLEED in patients with acute VTE initiating anticoagulation.</div></div><div><h3>Methods</h3><div>We used data from a prospective observational cohort study (BACH-VTE) including patients with acute VTE who initiated anticoagulation with a follow-up period of up to 2 years. Exclusion criteria were active cancer, pregnancy, and postpartum period. Major bleeding, clinically relevant nonmajor bleeding (CRNMB), and minor bleeding were recorded and their frequencies calculated. RAM performance was evaluated by discrimination and calibration. Predictors associated with clinically relevant bleeding (CRB; composite of major and CRNMB) were assessed.</div></div><div><h3>Results</h3><div>In total, 308 patients (median age, 55 years; 42% women, 47% pulmonary embolism, 62% unprovoked VTE) were included. During a median follow-up time of 12.6 months, we observed 2 major bleedings, 41 CRNMBs, and 66 minor bleedings, corresponding to 2-year cumulative incidences (95% CI) of 0.9% (0%-2.1%), 16.2% (10.7%-21.3%), and 20.6% (15.1%-25.8%), respectively, and of 33.4% (26.7-39.5) for any bleeding. RAM discrimination was poor to moderate with C-statistics (95% CI) for CRB of 0.71 (0.61-0.80) for VTE-PREDICT, 0.59 (0.49-0.68) for HAS-BLED, 0.52 (0.41-0.62) for RIETE, and 0.56 (0.45-0.68) for VTE-BLEED. Calibration analysis revealed underestimation of bleeding risk. Female sex, lower hemoglobin, and bleeding history were associated with CRB in a univariable but not in a multivariable model.</div></div><div><h3>Conclusion</h3><div>In patients treated with anticoagulants for VTE, we found high rates of CRB. Only the VTE-PREDICT model showed acceptable discrimination, but poor calibration.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 498-507"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086312","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}
Pub Date : 2026-02-01DOI: 10.1016/j.jtha.2025.10.005
Jihee Han , Vincent ten Cate , Ruifang Li-Gao , Alejandro Pallares Robles , Harsini Raaja Sulochana , Miguel A. Andrade-Navarro , Linjun Ao , Raymond Noordam , Angel Martinez-Perez , Maria Sabater-Lleal , José Manuel Soria , Juan Carlos Souto , Frits R. Rosendaal , Philipp S. Wild , Astrid van Hylckama Vlieg
Background
Elevated coagulation factor (F) IX activity is associated with an increased risk of cardiovascular diseases, including venous thromboembolism. However, a genome-wide association study for FIX activity remains to be performed.
Objectives
We aimed to identify genetic loci associated with FIX activity.
Methods
We conducted a meta-analysis of genome-wide association studies across 2 population-based cohorts (N = 9628), followed by conditional and joint analyses and replication analyses (N = 1894). Using the identified variants, we explored genetic associations between FIX activity and both hemostatic and metabolic phenotypes and conducted Mendelian randomization analysis to investigate potential causal effects on cardiovascular diseases.
Results
We identified 10 genomic loci associated with FIX activity: AHCTF1, GCKR, KNG, HRG, HRG-AS1, F12, ABO, and F9, of which F12 and ABO were replicated at a Bonferroni-corrected significance, and GCKR and F9 reached nominal significance. Structural modeling of the F9 missense variant revealed its proximity to a critical cleavage site, providing mechanistic insight into FIX regulation. A polygenic score based on 10 genomic loci was associated with hemostatic phenotypes (activated partial thromboplastin time and FVIII, FXI, and FXII activity) and metabolic phenotypes (triglycerides, γ-glutamyl transferase, and low-density lipoprotein cholesterol levels). Mendelian randomization analyses suggested potential detrimental effects of FIX activity on venous thromboembolism.
Conclusion
Our findings enhance understanding of biological mechanisms regulating FIX activity and provide evidence for a causal role of FIX activity in the etiology of these cardiovascular conditions.
{"title":"Genome-wide identification of loci associated with plasma coagulation factor IX activity","authors":"Jihee Han , Vincent ten Cate , Ruifang Li-Gao , Alejandro Pallares Robles , Harsini Raaja Sulochana , Miguel A. Andrade-Navarro , Linjun Ao , Raymond Noordam , Angel Martinez-Perez , Maria Sabater-Lleal , José Manuel Soria , Juan Carlos Souto , Frits R. Rosendaal , Philipp S. Wild , Astrid van Hylckama Vlieg","doi":"10.1016/j.jtha.2025.10.005","DOIUrl":"10.1016/j.jtha.2025.10.005","url":null,"abstract":"<div><h3>Background</h3><div>Elevated coagulation factor (F) IX activity is associated with an increased risk of cardiovascular diseases, including venous thromboembolism. However, a genome-wide association study for FIX activity remains to be performed.</div></div><div><h3>Objectives</h3><div>We aimed to identify genetic loci associated with FIX activity.</div></div><div><h3>Methods</h3><div>We conducted a meta-analysis of genome-wide association studies across 2 population-based cohorts (<em>N</em> = 9628), followed by conditional and joint analyses and replication analyses (<em>N</em> = 1894). Using the identified variants, we explored genetic associations between FIX activity and both hemostatic and metabolic phenotypes and conducted Mendelian randomization analysis to investigate potential causal effects on cardiovascular diseases.</div></div><div><h3>Results</h3><div>We identified 10 genomic loci associated with FIX activity: <em>AHCTF1</em><em>, GCKR, KNG, HRG, HRG-AS1, F12, ABO,</em> and <em>F9</em>, of which <em>F12</em> and <em>ABO</em> were replicated at a Bonferroni-corrected significance, and <em>GCKR</em> and <em>F9</em> reached nominal significance. Structural modeling of the <em>F9</em> missense variant revealed its proximity to a critical cleavage site, providing mechanistic insight into FIX regulation. A polygenic score based on 10 genomic loci was associated with hemostatic phenotypes (activated partial thromboplastin time and FVIII, FXI, and FXII activity) and metabolic phenotypes (triglycerides, γ-glutamyl transferase, and low-density lipoprotein cholesterol levels). Mendelian randomization analyses suggested potential detrimental effects of FIX activity on venous thromboembolism.</div></div><div><h3>Conclusion</h3><div>Our findings enhance understanding of biological mechanisms regulating FIX activity and provide evidence for a causal role of FIX activity in the etiology of these cardiovascular conditions.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 545-557"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145401235","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}
Pub Date : 2026-02-01DOI: 10.1016/j.jtha.2025.10.008
Xin Lu , Linlin Chen , Ye Tu , Xinzhu Liu , Guimei Guo , Zixin Li , Yan Wang , Xin Wei , Zhibin Wang
Background
Sepsis-induced coagulopathy (SIC) is often a sign of high mortality and poor prognosis in patients with sepsis. Thrombomodulin (TM) plays an important anticoagulant role by activating protein (AP)C.
Objectives
Our previous study has shown that the overexpression of Nur77 upregulates TM expression in human umbilical vein endothelial cells (HUVECs). This study aimed to investigate whether upregulation of Nur77 using cytosporone (Csn)-B could ameliorate SIC.
Methods
A mouse model of SIC was prepared by cecum ligation and puncture (CLP) operation. Five hours after CLP, coagulation-related indicators and histopathologic injury of the liver, lungs, and kidneys were investigated. The effect of Csn-B on the clotting time of HUVECs transfected with Nur77 or TM small-interfering RNA in response to tumor necrosis factor α stimulation was observed. The effects of Csn-B on survival, organ damage, microthrombosis, coagulation factors, TM activated protein C anticoagulant system, fibrinolytic system, and complement system were observed in vascular endothelial conditional knockout Nur77 mice after CLP.
Results
Sepsis-induced upregulation of Nur77 in vascular endothelial cells. Knockout of Nur77 in vascular endothelium exacerbated organ damage and early coagulation dysfunction in sepsis. Csn-B attenuated the procoagulant response of HUVEC to tumor necrosis factor α stimulation, which is dependent on the activation of Nur77-TM pathway. Furthermore, Csn-B relied on activation of vascular endothelial Nur77 to inhibit the increase of coagulation factors, enhance activation of TM activated protein C, restore fibrinolysis homeostasis, and inhibit C3 and C5 activation to ameliorate hypercoagulability in SIC.
Conclusion
Csn-B improves early coagulopathy in sepsis by increasing endogenous TM through upregulating Nur77 in the vascular endothelium.
{"title":"Cytosporone B ameliorates hypercoagulability in sepsis by agonizing the Nur77-thrombomodulin pathway","authors":"Xin Lu , Linlin Chen , Ye Tu , Xinzhu Liu , Guimei Guo , Zixin Li , Yan Wang , Xin Wei , Zhibin Wang","doi":"10.1016/j.jtha.2025.10.008","DOIUrl":"10.1016/j.jtha.2025.10.008","url":null,"abstract":"<div><h3>Background</h3><div>Sepsis-induced coagulopathy (SIC) is often a sign of high mortality and poor prognosis in patients with sepsis. Thrombomodulin (TM) plays an important anticoagulant role by activating protein (AP)C.</div></div><div><h3>Objectives</h3><div>Our previous study has shown that the overexpression of Nur77 upregulates TM expression in human umbilical vein endothelial cells (HUVECs). This study aimed to investigate whether upregulation of Nur77 using cytosporone (Csn)-B could ameliorate SIC.</div></div><div><h3>Methods</h3><div>A mouse model of SIC was prepared by cecum ligation and puncture (CLP) operation. Five hours after CLP, coagulation-related indicators and histopathologic injury of the liver, lungs, and kidneys were investigated. The effect of Csn-B on the clotting time of HUVECs transfected with <em>Nur77</em> or <em>TM</em> small-interfering RNA in response to tumor necrosis factor α stimulation was observed. The effects of Csn-B on survival, organ damage, microthrombosis, coagulation factors, TM activated protein C anticoagulant system, fibrinolytic system, and complement system were observed in vascular endothelial conditional knockout Nur77 mice after CLP.</div></div><div><h3>Results</h3><div>Sepsis-induced upregulation of Nur77 in vascular endothelial cells. Knockout of <em>Nur77</em> in vascular endothelium exacerbated organ damage and early coagulation dysfunction in sepsis. Csn-B attenuated the procoagulant response of HUVEC to tumor necrosis factor α stimulation, which is dependent on the activation of Nur77-TM pathway. Furthermore, Csn-B relied on activation of vascular endothelial Nur77 to inhibit the increase of coagulation factors, enhance activation of TM activated protein C, restore fibrinolysis homeostasis, and inhibit C3 and C5 activation to ameliorate hypercoagulability in SIC.</div></div><div><h3>Conclusion</h3><div>Csn-B improves early coagulopathy in sepsis by increasing endogenous TM through upregulating Nur77 in the vascular endothelium.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 618-632"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145431322","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}
Pub Date : 2026-02-01DOI: 10.1016/j.jtha.2025.10.014
Ayesha Zia , Hilary Whitworth , Laura Avila , Frederikus A. Klok , Manal Alqahtani , Deepa Gopalan , Megan Griffiths , Rachel P. Rosovsky , Suzan Williams , Tony G. Babb , Madhvi Rajpurkar
{"title":"Clinically relevant outcomes for research in pediatric pulmonary embolism: communication from the ISTH SSC Subcommittee on Pediatric/Neonatal Thrombosis and Hemostasis","authors":"Ayesha Zia , Hilary Whitworth , Laura Avila , Frederikus A. Klok , Manal Alqahtani , Deepa Gopalan , Megan Griffiths , Rachel P. Rosovsky , Suzan Williams , Tony G. Babb , Madhvi Rajpurkar","doi":"10.1016/j.jtha.2025.10.014","DOIUrl":"10.1016/j.jtha.2025.10.014","url":null,"abstract":"","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 766-780"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145452061","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}
We report the first case of immune-mediated thrombotic thrombocytopenic purpura (iTTP) successfully treated with recombinant ADAMTS13 (rhADAMTS13) during pregnancy. A 36-year-old woman with a history of severe iTTP and persistently undetectable ADAMTS13 activity despite multiple immunosuppressive therapies, remained relapse free for 10 years. In the 33rd week of pregnancy, she showed the first signs of relapse, whereupon rhADAMTS13 40 IU/kg was administered twice daily. ADAMTS13 activity and platelet count recovered rapidly, allowing a healthy newborn to be delivered safely by cesarean section. No adverse event was observed. rhADAMTS13 could represent an effective, well-tolerated therapeutic alternative for patients with iTTP and clinical or ADAMTS13 relapse. During pregnancy, where plasma exchange or caplacizumab are undesirable and recommendations are uncertain, this strategy could represent a promising therapeutic alternative in selected cases.
{"title":"Successful use of recombinant ADAMTS13 in a pregnant patient with immune-mediated thrombotic thrombocytopenic purpura","authors":"Raphael Cauchois , Pascale Poullin , Alexandre Hertig , Bérangère Joly , Gilles Kaplanski , Paul Coppo","doi":"10.1016/j.jtha.2025.10.012","DOIUrl":"10.1016/j.jtha.2025.10.012","url":null,"abstract":"<div><div>We report the first case of immune-mediated thrombotic thrombocytopenic purpura (iTTP) successfully treated with recombinant ADAMTS13 (rhADAMTS13) during pregnancy. A 36-year-old woman with a history of severe iTTP and persistently undetectable ADAMTS13 activity despite multiple immunosuppressive therapies, remained relapse free for 10 years. In the 33rd week of pregnancy, she showed the first signs of relapse, whereupon rhADAMTS13 40 IU/kg was administered twice daily. ADAMTS13 activity and platelet count recovered rapidly, allowing a healthy newborn to be delivered safely by cesarean section. No adverse event was observed. rhADAMTS13 could represent an effective, well-tolerated therapeutic alternative for patients with iTTP and clinical or ADAMTS13 relapse. During pregnancy, where plasma exchange or caplacizumab are undesirable and recommendations are uncertain, this strategy could represent a promising therapeutic alternative in selected cases.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 682-684"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145452073","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}
Pub Date : 2026-02-01DOI: 10.1016/j.jtha.2025.10.011
Ravi S. Keshari , Robert Silasi , Stephanie D. Byrum , Narcis I. Popescu , Girija Regmi , Tomohiro Abe , Cristina Lupu , Constantin Georgescu , Vivian E. Taylor , Dennis Province , Rick D. Edmondson , Samuel G. Mackintosh , Nathan L. Avaritt , Susan Kovats , A. Darise Farris , Joe H. Simmons , Owen J.T. McCarty , Alan J. Tackett , Florea Lupu
Background
Anthrax, caused by Bacillus anthracis, leads to severe sepsis due to multiple virulence factors, including toxins and bacterial cell wall components, which disrupt immune responses and induce cytotoxic effects. However, the relative contributions of toxins vs bacterial overload during systemic disease remain unclear.
Objectives
We aimed to investigate the differential effects of toxigenic B anthracis Sterne strains and nontoxigenic ΔSterne strains on coagulation, complement activation, immune response, endothelial function, and organ damage in a baboon model of anthrax.
Methods
Healthy baboons were intravenously infused with a sublethal dose (1 × 108 colony-forming units/kg) of either B anthracis Sterne or ΔSterne strains. Animals were monitored for 7 days and assessed for vital signs, hematologic parameters, coagulation markers, endothelial dysfunction, complement activation, and proteomic profiles.
Results
The toxigenic Sterne strain induced more severe systemic effects than the ΔSterne strain, including prolonged bacterial persistence, enhanced coagulopathy, increased complement activation, endothelial dysfunction, neutrophil activation, and neutrophil extracellular trap formation. Coagulopathy was evidenced by elevated protease-antithrombin complexes, prolonged clotting times, fibrinogen consumption, and thrombocytopenia. Proteomic analysis of plasma revealed stronger upregulation of proteins involved in innate immunity, metabolism, coagulation, and cell death pathways in Sterne animals compared with ΔSterne-challenged animals.
Conclusion
Our findings suggest that anthrax toxins contribute to the exacerbation of pathological host responses during anthrax sepsis, including coagulopathy, complement activation, endothelial dysfunction, and organ injury. These observations provide insight into the role of toxins in intensifying disease severity beyond bacterial burden alone. Therapeutic strategies targeting coagulation and complement pathways, while preserving endothelial function, may help mitigate anthrax-induced sepsis.
{"title":"Anthrax toxins exacerbate sepsis-induced coagulopathy and endothelial dysfunction in a baboon model of anthrax","authors":"Ravi S. Keshari , Robert Silasi , Stephanie D. Byrum , Narcis I. Popescu , Girija Regmi , Tomohiro Abe , Cristina Lupu , Constantin Georgescu , Vivian E. Taylor , Dennis Province , Rick D. Edmondson , Samuel G. Mackintosh , Nathan L. Avaritt , Susan Kovats , A. Darise Farris , Joe H. Simmons , Owen J.T. McCarty , Alan J. Tackett , Florea Lupu","doi":"10.1016/j.jtha.2025.10.011","DOIUrl":"10.1016/j.jtha.2025.10.011","url":null,"abstract":"<div><h3>Background</h3><div>Anthrax, caused by <em>Bacillus anthracis</em>, leads to severe sepsis due to multiple virulence factors, including toxins and bacterial cell wall components, which disrupt immune responses and induce cytotoxic effects. However, the relative contributions of toxins vs bacterial overload during systemic disease remain unclear.</div></div><div><h3>Objectives</h3><div>We aimed to investigate the differential effects of toxigenic <em>B anthracis</em> Sterne strains and nontoxigenic ΔSterne strains on coagulation, complement activation, immune response, endothelial function, and organ damage in a baboon model of anthrax.</div></div><div><h3>Methods</h3><div>Healthy baboons were intravenously infused with a sublethal dose (1 × 10<sup>8</sup> colony-forming units/kg) of either <em>B anthracis</em> Sterne or ΔSterne strains. Animals were monitored for 7 days and assessed for vital signs, hematologic parameters, coagulation markers, endothelial dysfunction, complement activation, and proteomic profiles.</div></div><div><h3>Results</h3><div>The toxigenic Sterne strain induced more severe systemic effects than the ΔSterne strain, including prolonged bacterial persistence, enhanced coagulopathy, increased complement activation, endothelial dysfunction, neutrophil activation, and neutrophil extracellular trap formation. Coagulopathy was evidenced by elevated protease-antithrombin complexes, prolonged clotting times, fibrinogen consumption, and thrombocytopenia. Proteomic analysis of plasma revealed stronger upregulation of proteins involved in innate immunity, metabolism, coagulation, and cell death pathways in Sterne animals compared with ΔSterne-challenged animals.</div></div><div><h3>Conclusion</h3><div>Our findings suggest that anthrax toxins contribute to the exacerbation of pathological host responses during anthrax sepsis, including coagulopathy, complement activation, endothelial dysfunction, and organ injury. These observations provide insight into the role of toxins in intensifying disease severity beyond bacterial burden alone. Therapeutic strategies targeting coagulation and complement pathways, while preserving endothelial function, may help mitigate anthrax-induced sepsis.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 732-746"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145452056","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}
Pub Date : 2026-02-01DOI: 10.1016/j.jtha.2025.09.028
Amanda P. Waller , Katelyn J. Wolfgang , Zachary S. Stevenson , Lori A. Holle , Alisa S. Wolberg , Bryce A. Kerlin
Background
Hypoalbuminemia is a thrombotic disease risk biomarker. Albumin is a negative acute-phase reactant and may thus be an indirect biomarker of thromboinflammation. However, nephrotic syndrome (resulting from noninflammatory proteinuric glomerular disease) causes both hypoalbuminemia and an elevated thrombotic risk. Hypofibrinolysis has been observed in nephrotic syndrome, and published data suggest that albumin may directly enhance fibrinolysis. These observations suggest that albumin may directly influence thrombotic risk.
Objectives
To test the hypothesis that hypoalbuminemia impairs fibrinolysis.
Methods
Hypoalbuminemic blood and plasma from nephrotic syndrome rat models and nephrotic patients were analyzed by thromboelastometry, clot lysis assays, fibrin clot turbidity, confocal microscopy, and immunoblotting. Some studies were conducted without vs with albumin repletion. Plasma from an analbuminemic mutant rat model was used to confirm albumin-dependent observations.
Results
Hypoalbuminemia was associated with hypofibrinolysis in nephrotic whole blood. Albumin levels were positively associated with fibrinolysis in both nephrotic rats and patient plasma. Albumin altered both fibrin clot formation and fiber diameter. Dense fibrin clots are known to be resistant to fibrinolysis, and fibrin clot network density was increased in hypoalbuminemic plasma clots from both nephrotic rats and patients. Clots formed from hypoalbuminemic plasma contained less albumin than controls, and repletion with recombinant albumin to healthy control levels corrected both fibrin network density and fibrinolysis in nephrotic and analbuminemic rat plasma.
Conclusion
These data show that albumin directly increases fibrin network porosity and enhances fibrinolysis. Hypoalbuminemia may mechanistically contribute to nephrotic syndrome thrombotic complications, and may similarly increase thrombotic risk in other hypoalbuminemic conditions.
{"title":"Hypoalbuminemia increases fibrin clot density and impairs fibrinolysis","authors":"Amanda P. Waller , Katelyn J. Wolfgang , Zachary S. Stevenson , Lori A. Holle , Alisa S. Wolberg , Bryce A. Kerlin","doi":"10.1016/j.jtha.2025.09.028","DOIUrl":"10.1016/j.jtha.2025.09.028","url":null,"abstract":"<div><h3>Background</h3><div>Hypoalbuminemia is a thrombotic disease risk biomarker. Albumin is a negative acute-phase reactant and may thus be an indirect biomarker of thromboinflammation. However, nephrotic syndrome (resulting from noninflammatory proteinuric glomerular disease) causes both hypoalbuminemia and an elevated thrombotic risk. Hypofibrinolysis has been observed in nephrotic syndrome, and published data suggest that albumin may directly enhance fibrinolysis. These observations suggest that albumin may directly influence thrombotic risk.</div></div><div><h3>Objectives</h3><div>To test the hypothesis that hypoalbuminemia impairs fibrinolysis.</div></div><div><h3>Methods</h3><div>Hypoalbuminemic blood and plasma from nephrotic syndrome rat models and nephrotic patients were analyzed by thromboelastometry, clot lysis assays, fibrin clot turbidity, confocal microscopy, and immunoblotting. Some studies were conducted without vs with albumin repletion. Plasma from an analbuminemic mutant rat model was used to confirm albumin-dependent observations.</div></div><div><h3>Results</h3><div>Hypoalbuminemia was associated with hypofibrinolysis in nephrotic whole blood. Albumin levels were positively associated with fibrinolysis in both nephrotic rats and patient plasma. Albumin altered both fibrin clot formation and fiber diameter. Dense fibrin clots are known to be resistant to fibrinolysis, and fibrin clot network density was increased in hypoalbuminemic plasma clots from both nephrotic rats and patients. Clots formed from hypoalbuminemic plasma contained less albumin than controls, and repletion with recombinant albumin to healthy control levels corrected both fibrin network density and fibrinolysis in nephrotic and analbuminemic rat plasma.</div></div><div><h3>Conclusion</h3><div>These data show that albumin directly increases fibrin network porosity and enhances fibrinolysis. Hypoalbuminemia may mechanistically contribute to nephrotic syndrome thrombotic complications, and may similarly increase thrombotic risk in other hypoalbuminemic conditions.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 685-700"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145329487","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}
Pub Date : 2026-02-01DOI: 10.1016/j.jtha.2025.10.023
Michael Mazzeffi , Jerrold H. Levy , Kenichi Tanaka
{"title":"Prophylactic von Willebrand factor replacement in durable left ventricular assist device patients: a sticky subject","authors":"Michael Mazzeffi , Jerrold H. Levy , Kenichi Tanaka","doi":"10.1016/j.jtha.2025.10.023","DOIUrl":"10.1016/j.jtha.2025.10.023","url":null,"abstract":"","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 378-380"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146102416","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}
Pub Date : 2026-02-01DOI: 10.1016/j.jtha.2025.09.042
Adam Hansen , Georgios Kementzidis , Bernard Essuman , Ziyuan Niu , Jawaad Sheriff , Volodymyr Chernyshenko , Yuefan Deng , Miriam Rafailovich , Dennis K. Galanakis
Background
Thrombosis caused by contact of blood with surfaces is a serious complication in the incorporation of biomedical devices. Adsorption of fibrinogen to these commonly hydrophobic surfaces can lead to conformational changes in the molecule, which eventually leads to thrombogenesis. The origin of these thrombi and the underlying mechanism through which the surfaces contribute to the outcome remains undefined.
Objectives
This study aimed to investigate and understand the interactions of fibrinogen with surfaces at the molecular level.
Methods
Visualization of fibrinogen interactions following adsorption to polystyrene surfaces was performed using atomic force microscopy, transmission electron microscopy, and fluorescence microscopy and further evaluated using various antibodies and platelet flow assays.
Results
Surface adsorption led to a misfolding of fibrinogen molecules, namely untethering of αC-domains. Conformational changes resulted in the onset of intermolecular interactions and random linkages of neighboring molecules, mediated by the N-terminal subdomain of the αC-domain (Aα406-483). When concentration of fibrinogen solutions was increased to 20 to 500 μg/mL, structured monolayers that grew continuously into multilayers were observed but were self-limited due to the decrease in untethered αC-domains in subsequent fibrinogen bilayers. Soluble fibrin structure was determined to be a clustered complex of fibrinogen and fibrin with a protofibril core. These complexes adsorbed and aggregated onto multilayers through exposed αC-domains on both surfaces, leading to large fiber formations. Surface fibers promoted platelet adhesion and activation, implying exposure of binding domain γ400-411.
Conclusion
This comprehensive study models the precise molecular mechanism of surface-initiated thrombogenesis and may provide the foundation necessary to design effective inhibition techniques.
{"title":"Unraveling the molecular mechanism of in situ surface-initiated thrombogenesis","authors":"Adam Hansen , Georgios Kementzidis , Bernard Essuman , Ziyuan Niu , Jawaad Sheriff , Volodymyr Chernyshenko , Yuefan Deng , Miriam Rafailovich , Dennis K. Galanakis","doi":"10.1016/j.jtha.2025.09.042","DOIUrl":"10.1016/j.jtha.2025.09.042","url":null,"abstract":"<div><h3>Background</h3><div>Thrombosis caused by contact of blood with surfaces is a serious complication in the incorporation of biomedical devices. Adsorption of fibrinogen to these commonly hydrophobic surfaces can lead to conformational changes in the molecule, which eventually leads to thrombogenesis. The origin of these thrombi and the underlying mechanism through which the surfaces contribute to the outcome remains undefined.</div></div><div><h3>Objectives</h3><div>This study aimed to investigate and understand the interactions of fibrinogen with surfaces at the molecular level.</div></div><div><h3>Methods</h3><div>Visualization of fibrinogen interactions following adsorption to polystyrene surfaces was performed using atomic force microscopy, transmission electron microscopy, and fluorescence microscopy and further evaluated using various antibodies and platelet flow assays.</div></div><div><h3>Results</h3><div>Surface adsorption led to a misfolding of fibrinogen molecules, namely untethering of αC-domains. Conformational changes resulted in the onset of intermolecular interactions and random linkages of neighboring molecules, mediated by the N-terminal subdomain of the αC-domain (Aα406-483). When concentration of fibrinogen solutions was increased to 20 to 500 μg/mL, structured monolayers that grew continuously into multilayers were observed but were self-limited due to the decrease in untethered αC-domains in subsequent fibrinogen bilayers. Soluble fibrin structure was determined to be a clustered complex of fibrinogen and fibrin with a protofibril core. These complexes adsorbed and aggregated onto multilayers through exposed αC-domains on both surfaces, leading to large fiber formations. Surface fibers promoted platelet adhesion and activation, implying exposure of binding domain γ400-411.</div></div><div><h3>Conclusion</h3><div>This comprehensive study models the precise molecular mechanism of surface-initiated thrombogenesis and may provide the foundation necessary to design effective inhibition techniques.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 2","pages":"Pages 530-544"},"PeriodicalIF":5.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145431525","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}
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