Journal of Thrombosis and Haemostasis最新文献

{"title":"Importance of individual residues in hydrophobic patch PLVIVGL (1481-1487) in FV-Short for synergistic TFPIα cofactor activity with protein S, an alanine-scanning study: AlphaFold-mediated prediction of FV-Short/TFPIα/protein S trimolecular complex structure.","authors":"Björn Dahlbäck, Sinh Tran, Piotr Draczkowski","doi":"10.1016/j.jtha.2024.11.013","DOIUrl":"10.1016/j.jtha.2024.11.013","url":null,"abstract":"<p><strong>Background: </strong>In the splice variant factor (F)V-Short, 702 residues are deleted from the B domain, resulting in exposure of an acid region (AR2; 1493-1537) that binds TFPIα. FV-Short and protein S serve as synergistic TFPIα cofactors in inhibition of FXa. In the preAR2 region, a hydrophobic patch PLVIVGL (1481-1487) is crucial for synergistic TFPIα-cofactor activity and assembly of FV-Short, TFPIα, and protein S.</p><p><strong>Objectives: </strong>To elucidate the importance of individual residues in the PLVIVGL patch for synergism between FV-Short and protein S as TFPIα cofactors.</p><p><strong>Methods: </strong>An alanine scanning of the hydrophobic patch was performed in which 7 FV-Short variants were created. The synergistic TFPIα-cofactor activity was analyzed by FXa inhibition and a microtiter-based assay tested binding between the proteins. AlphaFold 3 was used to predict protein-protein interactions between FV-Short, protein S, and TFPIα.</p><p><strong>Results: </strong>Five of the 7 variants (V1483A, I1484A, V1485A, G1486A, and L1487A) demonstrated decreased synergistic TFPIα cofactor activity; in particular, G1486A and L1487A were severely affected. Neither wild-type FV-Short nor any of the mutants bound protein S in the absence of TFPIα. In the presence of TFPIα, wild-type FV-Short, P1481A, L1482A, and V1485A bound protein S, whereas V1483A, I1484A, G1486A, and L1487A did not. AlphaFold predicted an interaction between the hydrophobic patch in FV-Short and a hydrophobic patch in protein S involving residues 268-276 and 422-426.</p><p><strong>Conclusion: </strong>Individual residues (V1483, I1484, G1486, and L1487) in the hydrophobic patch are demonstrated to be important for the synergistic TFPIα-cofactor activity and for the assembly of a trimolecular FXa-inhibitory complex.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770201","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":"Exploring red blood cells as an antigen delivery system to modulate the immune response towards FVIII in hemophilia A.","authors":"Mariarosaria Miranda, Eelke Brandsma, Lotte Robben, Helena Van Dender, Floris P J van Alphen, Karin Fijnvandraat, Maartje van den Biggelaar, Sebastien Lacroix-Desmazes, Robin van Bruggen, Jan Voorberg","doi":"10.1016/j.jtha.2024.11.012","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.11.012","url":null,"abstract":"<p><strong>Background: </strong>The main complication in hemophilia A treatment is the development of inhibitory antibodies against factor VIII (FVIII). Immune tolerance induction, the gold standard for eradicating anti-FVIII antibodies, is efficient in only 60-80% of cases. This underscores the need for more efficient induction of tolerance in hemophilia A patients with FVIII inhibitors.</p><p><strong>Objectives: </strong>In this study we explored whether red blood cells (RBCs) can be utilized as antigen delivery system to modulate the immune response against FVIII.</p><p><strong>Methods: </strong>Two promiscuously HLA-DR presented peptides derived from the A2 and C1 domains of FVIII were fused to the TAT-cell penetrating peptide and incubated with RBCs.</p><p><strong>Results: </strong>Biotinylated TAT-A2 and TAT-C1 peptides were found to interact with RBCs as shown by flow cytometry and imaging flow cytometry. Moreover, macrophages efficiently phagocytosed TAT-FVIII peptide-treated RBCs. Using mass spectrometry based immunopeptidomics we established that TAT-FVIII peptides were presented on MHC class II of macrophages that phagocytosed TAT-peptide pulsed RBCs. Specifically, the TAT-A2 peptide exhibited efficient processing and presentation on HLA-DR molecules. Importantly, incubation of TAT-C1 peptide treated RBCs loaded macrophages with a FVIII-specific T cell hybridoma led to a significant increase in IL-2 production, suggesting functional presentation of TAT-C1 derived peptides by macrophages.</p><p><strong>Conclusions: </strong>Our findings indicate that RBCs can serve as effective vehicle for the delivery of FVIII derived peptides to antigen presenting cells. The successful display of T cell epitopes on APC using ex vivo loaded RBC may be potentially utilized to modulate pathogenic immune responses such as observed in a subset of patients with hemophilia A.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770200","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 (T) thrombosis (I) in patients with (L) lower (L) limb (I) injuries (R) requiring (I) immobilisation (TILLIRI) Study.","authors":"Thomas P O Halloran, Bibi Ayesha Bassa, Banne Nemeth, Suzanne Cannegieter, Tomas Breslin, Abel Wakai, Julie O'Driscoll, Sean O'Rourke, Niamh O'Connell, Fionnuala Ní Áinle, Michael Watts, Denis O Keeffe","doi":"10.1016/j.jtha.2024.11.010","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.11.010","url":null,"abstract":"<p><strong>Background: </strong>Patients requiring lower limb immobilisation after injury have an increased venous thromboembolism (VTE) risk. The extent of this risk in published studies varies. The TRiP(cast) model quantifies VTE risk using clinical parameters. Delineating low from high-risk patients remains challenging.</p><p><strong>Aims: </strong>Determine the 90-day incidence of symptomatic VTE following temporary lower limb immobilisation after injury in an unselected cohort. Prospectively collect data on risk factors, including those incorporated in TRiP(cast) model, to calculate TRiP(cast) scores.</p><p><strong>Methods: </strong>TILLIRI is a multi-centre, pragmatic observational cohort study including 10 sites within the Irish Network for VTE Research. Patients≥18 years with an immobilised injured lower limb were included. Twenty-one clinical variables were collected at presentation. Thromboprophylaxis was prescribed according to clinical gestalt. Patients were followed up at 90-days to determine if VTE occurred.</p><p><strong>Results: </strong>Between November 2018 and February 2023, 1242 patients were recruited. Follow-up was complete for 1199 patients(96.5%).43 patients(3.5%) were lost to follow-up.44(3.6%) patients and 125(10%) patients were prescribed anticoagulation and aspirin respectively. 21 patients receiving regular anticoagulation removed from final analysis. VTE incidence at 90-day follow-up was 6/1179(0.51%; CI 0.1%-0.92%). TRiP(cast) scores were calculated for 1176/1221 patients. 846 patients(71.9%) had TRiP(cast) Score< 7, received no prophylaxis and had no VTE.</p><p><strong>Conclusion: </strong>TILLIRI indicates a low VTE incidence in an unselected cohort following lower limb immobilization with low rates of prophylaxis use. The proportion of patients with low TRiP(cast) scores and no symptomatic VTE suggests that thromboprophylaxis may be avoided in patients with TRiP(cast)scores< 7, with a low 90-day VTE risk.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770241","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":"JTH in the Clinic: Deconstructing the ISTH Hemophilia Guidelines for the Clinician.","authors":"Guy Young, Riitta Lassila, Jane Mason, Saskia Prasca","doi":"10.1016/j.jtha.2024.11.015","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.11.015","url":null,"abstract":"<p><p>Recently, the ISTH Hemophilia Guidelines were published in this journal. The authors of these guidelines should be commended for a Herculean task that took years to complete, and while this is no doubt a welcome addition to the literature, it does leave many questions for the clinician. Primarily this is due to as 11 of the 13 recommendations being conditional essentially meaning \"that clinicians and patients need to consider individual preferences as well as the specific circumstances in which the decision is being made for implementation of the recommendation.\" So, in essence, most of the recommendations leave it up to the clinician to decide whether to use them or not. In our view, most clinicians are seeking more concrete recommendations when they seek out a guidelines paper. Unfortunately, hemophilia being a rare disease and the ISTH Guidelines relying upon the GRADE methodology resulted in so many conditional recommendations. We endeavored to \"deconstruct\" the ISTH recommendations and offer clinicians a more concrete path forward based in part on the guidelines but supplemented with more recent literature and our own extensive experience and perspective managing hemophilia patients of all ages from 4 continents.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770202","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":"Etiology and Diagnosis of Heavy Menstrual Bleeding among Adolescent and Adult Patients: A Systematic Review and Meta-Analysis of the Literature.","authors":"Kyle J Comishen, Meha Bhatt, Katie Yeung, Jehan Irfan, Ayesha Zia, Robert F Sidonio, Paula James","doi":"10.1016/j.jtha.2024.11.014","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.11.014","url":null,"abstract":"<p><strong>Background: </strong>Heavy menstrual bleeding (HMB) is excessive menstrual blood loss that interferes with an individual's quality of life. Many individuals with HMB are inadequately managed by healthcare providers. This systematic review aims to provide a comprehensive summary of the etiologies and diagnosis of HMB while calculating the prevalence of underlying causes among premenopausal patients and quantifying the test accuracy of diagnostic strategies.</p><p><strong>Methods: </strong>MEDLINE, EMBASE, the Cochrane Library, and Web of Science were searched since inception to include studies investigating the prevalence of underlying etiology and diagnostic accuracy of investigations for HMB. The primary outcome was the prevalence of the causes of HMB, secondary outcome included the prevalence of etiology by age. Meta-analyses were conducted via random effects model.</p><p><strong>Results: </strong>53 studies were included. Forty-five studies included data on the prevalence of underlying HMB etiology, totaling 41541patients. The overall prevalence of bleeding disorders was 30% [95% CI 14-46], von Willebrand disease (VWD) of 8% [95% CI 7-10], platelet function defect (PFD) of 9% [95% CI 7-12], abnormal thyroid of 3% [95% CI 0-6], and polycystic ovarian syndrome (PCOS) of 8% [95% CI 4-12]. Subgroup analysis showed bleeding disorders were prevalent in 16% [95% CI -8-41] of adults with HMB, but 39% [95% CI 18-60] of adolescents with HMB.</p><p><strong>Conclusions: </strong>Many diagnoses were associated with bleeding disorders and, therefore, warrant investigation when assessing a patient with HMB of unknown etiology. The causes are likely age-dependent and should be considered when diagnosing HMB.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770199","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":"Citrullination of tissue factor pathway inhibitor alpha by peptidylarginine deiminase 4 impairs its natural anticoagulant activity toward factors Xa and VIIa/tissue factor and reduces binding to its cofactor protein S.","authors":"Bryan R C Bouwens, Elke Magdeleyns, M Christella L G D Thomassen, Freek G Bouwman, Dennis P Suylen, Tilman M Hackeng, Rory R Koenen","doi":"10.1016/j.jtha.2024.11.009","DOIUrl":"10.1016/j.jtha.2024.11.009","url":null,"abstract":"<p><strong>Background: </strong>Neutrophils are known to externalize their DNA and intracellular contents to neutralize invading pathogens. This process may enhance blood coagulation during inflammation. Tissue factor (TF) pathway inhibitor (TFPI) binds to extracellular DNA and may be citrullinated by peptidylarginine deiminase 4. Citrullination of TFPI reduces its anticoagulant activity toward factor (F)Xa but appears to retain its inhibition of TF-triggered thrombin generation, indicating differential regulation of TFPI functions by peptidylarginine deiminase 4.</p><p><strong>Objectives: </strong>This work aimed to study the effects of citrullination of TFPI-alpha on the inhibition of FXa, FVIIa/TF, and the cofactor activity of protein S.</p><p><strong>Methods: </strong>The effect of TFPI citrullination on the inhibition of FXa and FVIIa/TF was measured by chromogenic assays using purified components and by calibrated automated thrombography. Interaction with protein S was assessed by surface plasmon resonance and solid-phase binding assays using immobilized protein S, recombinant TFPI, and synthetic TFPI domains.</p><p><strong>Results: </strong>Citrullination of TFPI abolished its ability to inhibit FXa- and FXIa-triggered thrombin generation. However, its impaired inhibition of TF-triggered thrombin generation was still enhanced by protein S. Chromogenic assays revealed that citrullinated TFPI was essentially inactive as an inhibitor of the FVIIa-TF complex in the absence of protein S but partially restored by protein S. Interaction studies revealed that binding of citrullinated TFPI to protein S was reduced approximately 4-fold.</p><p><strong>Conclusion: </strong>Citrullinated TFPI shows impaired natural anticoagulant activity. While anti-FXa activity is essentially absent, its anti-TF/FVIIa activity can still be enhanced by protein S. This enhancement is incomplete; however, protein S binding to citrullinated TFPI is impaired.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755336","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":"Guidelines and guidance: what is the path forward for the ISTH?","authors":"Fionnuala Ní Áinle, Saskia Middeldorp, Andrea Hickman, Cary Clark, Walter Ageno, Patricia Casais, Jean M Connors, Sabine Eichinger, Damon Houghton, Tadashi Matsushita, Joost C M Meijers, Angela C Weyand, James Douketis","doi":"10.1016/j.jtha.2024.11.006","DOIUrl":"10.1016/j.jtha.2024.11.006","url":null,"abstract":"","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739860","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":"Real-world safety and efficacy of rADAMTS13 in the treatment of congenital thrombotic thrombocytopenic purpura in pediatric patients in Poland.","authors":"Pawel Laguna, Maria Szczepanska, Magdalena Wojdalska, Halina Bobrowska, Joanna Kulik, Danuta Pietrys, Walentyna Balwierz, Elzbieta Trembecka-Dubel, Wojciech Mlynarski, Aleksandra Laguna","doi":"10.1016/j.jtha.2024.11.008","DOIUrl":"10.1016/j.jtha.2024.11.008","url":null,"abstract":"<p><strong>Background: </strong>Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultrarare microvascular disease caused by the deficiency of the metalloprotease ADAMTS13 (a disintegrin and metalloprotease with thrombospondin motifs 13). Approximately half of all cases remain undiagnosed until a triggering event in adulthood; therefore, the prevalence rates may be underestimated. The current standard of care is based on regular transfusions of fresh frozen plasma, which often lead to allergic reactions in patients. Recombinant ADAMTS13 (rADAMTS13) is a novel treatment for cTTP, which has been approved for use in the USA, Europe, and Japan.</p><p><strong>Objectives: </strong>The primary objective of this real-world data collection was to comprehensively analyze the clinical data of pediatric patients with cTTP and to provide real-world evidence of the effectiveness of rADAMTS13 treatment in the pediatric population.</p><p><strong>Methods: </strong>Nine pediatric patients with cTTP were treated with an intravenous infusion of rADAMTS13 every 2 weeks.</p><p><strong>Results: </strong>The results showed an increase in platelet count and a decrease in lactate dehydrogenase levels compared with baseline. None of the patients experienced any adverse events or complications as a result of treatment. Patients reported an improved quality of life due to fewer hospital visits and a reduced number of recurrent episodes of cTTP.</p><p><strong>Conclusion: </strong>Treatment with rADAMTS13 resulted in the normalization of laboratory parameters in all pediatric patients with cTTP.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739803","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":"Choosing the optimal oral anticoagulant for stroke prevention in atrial fibrillation: direct oral anticoagulants vs vitamin K antagonists.","authors":"Stephanie Carlin, Noel Chan, Alejandro Godoy, Vinai Bhagirath, Jack Hirsh, John Eikelboom","doi":"10.1016/j.jtha.2024.11.005","DOIUrl":"10.1016/j.jtha.2024.11.005","url":null,"abstract":"<p><p>Direct oral anticoagulants (DOACs) have replaced vitamin K antagonists (VKAs) for stroke prevention in many patients with atrial fibrillation, but VKAs may still be preferred in some situations. We use a case-based approach to present the evidence for the possible use of a VKA in preference to a DOAC in patients with atrial fibrillation and rheumatic mitral stenosis, high body mass index, frailty, and breakthrough stroke despite being prescribed a DOAC.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142710571","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":"Use of antithrombotic therapy in patients with hemophilia: a selected synopsis of the European Hematology Association - International Society on Thrombosis and Haemostasis - European Association for Hemophilia and Allied Disorders - European Stroke Organization Clinical Practice Guidance document.","authors":"Miguel Escobar, Riitta Lassila, Carine Bekdache, Tarek Owaidah, Michelle Sholzberg","doi":"10.1016/j.jtha.2024.10.033","DOIUrl":"10.1016/j.jtha.2024.10.033","url":null,"abstract":"<p><p>Here, we summarize the European Hematology Association - International Society on Thrombosis and Haemostasis - European Association for Hemophilia and Allied Disorders - European Stroke Organization Clinical Practice Guidance document recommendations on antithrombotic therapy for cardiovascular indications among patients with hemophilia. This summary includes a discussion on primary and secondary prevention of venous and arterial thrombosis. The guidance document considers distinct and controversial challenges presented by various clinical scenarios in this aging patient population and provides thoughtful recommendations to assist the hemophilia care provider in clinical decision-making.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142687456","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}