Research and Practice in Thrombosis and Haemostasis最新文献

{"title":"Gene therapy in hemophilia: the dawn of a new era","authors":"Roberta Gualtierotti ,&nbsp;Andrea Giachi ,&nbsp;Niccolò Bitto ,&nbsp;Vincenzo La Mura ,&nbsp;Flora Peyvandi","doi":"10.1016/j.rpth.2024.102640","DOIUrl":"10.1016/j.rpth.2024.102640","url":null,"abstract":"<div><div>Hemophilia A and B are hereditary bleeding disorders associated with the X chromosome, stemming from genetic defects in the coding of coagulation factor (F)VIII or FIX protein, leading to partial or complete deficiency. In the absence of effective prophylaxis, these deficiencies can result in irreversible joint damage, known as hemophilic arthropathy, and subsequent disability.</div><div>Despite advancements in hemophilia treatment, individuals with severe forms of the disease continue to face a high risk of bleeding, particularly in instances of trauma or major surgical procedures. In such scenarios, it remains imperative to administer replacement or bypassing drugs, especially when inhibitors are present.</div><div>Within this context, gene therapy emerges as a compelling alternative, ensuring sustained expression of the deficient factor at levels often surpassing current recommendations. Some studies report an effect lasting up to 8 years, contributing significantly to clinical improvement and enhancing the quality of life for patients. However, a comprehensive evaluation of this innovative therapy is essential, encompassing both its benefits and potential risks. It is crucial to undertake a multidisciplinary assessment, engage in thoughtful discussions with the patient, and closely monitor the therapy’s effects and any eventual side effects of therapy. This approach aims to facilitate an informed and collaborative decision-making process, ultimately maximizing the benefits for each individual patient.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 1","pages":"Article 102640"},"PeriodicalIF":3.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730942/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142984621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of bleeding in thrombotic thrombocytopenic purpura in the precaplacizumab era: a retrospective nationwide analysis","authors":"Amir A. Mahmoud ,&nbsp;Mariam Mostafa ,&nbsp;Ali Abdelhay ,&nbsp;Mouhamed Yazan Abou-Ismail ,&nbsp;Shruti Chaturvedi","doi":"10.1016/j.rpth.2024.102654","DOIUrl":"10.1016/j.rpth.2024.102654","url":null,"abstract":"<div><h3>Background</h3><div>The addition of caplacizumab to immune thrombotic thrombocytopenia (iTTP) treatment options has led to a renewed interest in characterizing the epidemiology and risk factors for bleeding in iTTP. Limited data exist on the bleeding risk in iTTP due to systemic underreporting in earlier cohorts.</div></div><div><h3>Objectives</h3><div>To describe the incidence, patterns, and predictors of bleeding in hospitalized iTTP patients independent of caplacizumab use.</div></div><div><h3>Methods</h3><div>We retrospectively analyzed the National Inpatient Sample database (2012-2019) and identified adult patients with a diagnosis of iTTP. Predictors of bleeding were determined by multivariable logistic regression analysis.</div></div><div><h3>Results</h3><div>We identified 3103 iTTP hospitalizations; bleeding occurred in 594 (19.1%), and 157 (5.1%) were characterized by major bleeding. Mucocutaneous bleeding (7.6%) was the most frequent type of bleeding and included heavy menstrual bleeding (2.6%), gingival (2.3%), epistaxis (1.4%), and skin/procedure-related bleeding (1.3%). This was followed closely by gastrointestinal bleeding (5.6%). Patients with bleeding were more likely to be Hispanic, have a weekend admission, and have a higher prevalence of comorbidities. In the multivariable analysis, Hispanic race (odds ratio [OR], 1.48; 1.14-1.91), Asian/Pacific Islander/Native American race (OR, 2.04; 1.51-2.76), coronary artery disease (OR, 1.70; 1.38-2.11), heart failure (OR, 1.39; 1.13-1.72), autoimmune disease (OR, 2.61; 2.08-3.26), Charlson Comorbidity Index ≥ 3 (OR, 2.08; 1.66-2.61), weekend admission (OR, 1.45; 1.22-1.72), and delay ≥2 days in plasma exchange initiation (OR, 1.63; 1.38-1.92), were significantly associated with major bleeding.</div></div><div><h3>Conclusions</h3><div>Bleeding is a relatively common issue in acute iTTP that has not been adequately addressed in existing literature. Further studies are needed to elucidate this risk and associated factors, especially given the incorporation of caplacizumab in the treatment of iTTP.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 1","pages":"Article 102654"},"PeriodicalIF":3.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143010674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"External validation of a novel cancer-associated venous thromboembolism risk assessment score in a safety-net hospital","authors":"Karlynn N. Dulberger ,&nbsp;Jennifer La ,&nbsp;Ang Li ,&nbsp;Saran Lotfollahzadeh ,&nbsp;Asha Jose ,&nbsp;Nhan V. Do ,&nbsp;Mary T. Brophy ,&nbsp;J. Michael Gaziano ,&nbsp;Katya Ravid ,&nbsp;Vipul C. Chitalia ,&nbsp;Nathanael R. Fillmore","doi":"10.1016/j.rpth.2024.102650","DOIUrl":"10.1016/j.rpth.2024.102650","url":null,"abstract":"<div><h3>Background</h3><div>Cancer-associated thrombosis (CAT) is a leading cause of death in patients diagnosed with cancer. However, pharmacologic thromboprophylaxis use in cancer patients must be carefully evaluated due to a 2-fold increased risk of experiencing a major bleeding event within this population. The electronic health record CAT (EHR-CAT) risk assessment model (RAM) was recently developed, and reports improved performance over the widely used Khorana score. Extensive RAM external validation is crucial to determine accuracy across diverse patient populations prior to clinical utilization.</div></div><div><h3>Objectives</h3><div>To externally validate EHR-CAT using data from 2103 patients with cancer at the Boston Medical Center (BMC), New England’s largest safety-net hospital, and to compare this RAM with the Khorana score.</div></div><div><h3>Methods</h3><div>We conducted a retrospective study of BMC cancer patients diagnosed between January 2014 and December 2022 using data from the BMC tumor registry and EHR system. We validated the RAM using measures of discrimination and calibration.</div></div><div><h3>Results</h3><div>The EHR-CAT score exhibited a strong ability to discriminate the risk of CAT (C statistic, 0.67), which was substantially higher than the classic Khorana score (C statistic, 0.58). This increased discrimination power reflects the 20% of patients that were reclassified into high or low risk by the expanded score. Model calibration was also strong in this dataset.</div></div><div><h3>Conclusion</h3><div>In our external validation, the recently published EHR-CAT score showed clear and improved separation of patients at high and low risk for CAT. The utilization of this expanded CAT score could facilitate improved targeting of at-risk cancer patients for prophylactic therapy.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 1","pages":"Article 102650"},"PeriodicalIF":3.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11745955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143010675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Venous thromboembolism still leads on maternal death","authors":"Amelia Shard ,&nbsp;Catherine Prodger ,&nbsp;Sue Pavord","doi":"10.1016/j.rpth.2024.102675","DOIUrl":"10.1016/j.rpth.2024.102675","url":null,"abstract":"","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 1","pages":"Article 102675"},"PeriodicalIF":3.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143155132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Challenges and considerations of genetic testing in von Willebrand disease","authors":"Omid Seidizadeh ,&nbsp;Luciano Baronciani ,&nbsp;Flora Peyvandi","doi":"10.1016/j.rpth.2025.102686","DOIUrl":"10.1016/j.rpth.2025.102686","url":null,"abstract":"<div><div>von Willebrand disease (VWD) is the most common inherited bleeding disorder characterized by defects in the quantity or function of the von Willebrand factor (VWF). The diagnosis of VWD is complex, requiring a battery of tests to evaluate the amount, functions, and multimeric structure of the VWF glycoprotein. The diagnosis can also be accomplished or confirmed by sequencing the VWF gene (<em>VWF</em>). Genetic testing of <em>VWF</em> has been around for 4 decades following the cloning of <em>VWF</em>, and nowadays, it has been integrated into the diagnostic panel of VWD. With the introduction of next-generation sequencing, genetic analysis of the <em>VWF</em> has become more practical than it was in the past, when Sanger sequencing was used. A number of laboratories have applied or started to use genetic testing with next-generation sequencing for VWD diagnosis. Considering the increasing application of genetic testing in VWD and the wide availability and decreasing cost of gene sequencing, we sought to discuss the challenges and considerations involved in applying genetic testing to VWD.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 1","pages":"Article 102686"},"PeriodicalIF":3.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143155137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Functional Characterization of Venous Thromboembolic Disease (FUVID) study: rationale, design, and methods of a prospective, observational, multicenter study to evaluate mechanisms of exercise intolerance and dyspnea following pediatric pulmonary embolism","authors":"Ayesha Zia ,&nbsp;Michael D. Nelson ,&nbsp;Jimin Ren ,&nbsp;Song Zhang ,&nbsp;Robert F. Mattrey ,&nbsp;Brian L. Han ,&nbsp;Tarique Hussain ,&nbsp;Joshua S. Greer ,&nbsp;Manal Al-Qahtani ,&nbsp;Kendra Malone ,&nbsp;Sonja E. Stutzman ,&nbsp;Deseray V. Sida ,&nbsp;Sharon Primeaux ,&nbsp;Marcela D. Torres ,&nbsp;Clay T. Cohen ,&nbsp;Shelley Crary ,&nbsp;Jonathan Bernstein ,&nbsp;Hilary B. Whitworth ,&nbsp;Riten Kumar ,&nbsp;Kisha A. Beg ,&nbsp;Song Zhang PhD","doi":"10.1016/j.rpth.2024.102669","DOIUrl":"10.1016/j.rpth.2024.102669","url":null,"abstract":"<div><h3>Background</h3><div>To date, the focus of investigation in pediatric pulmonary embolism (PE) has been on PE recurrence and anticoagulant-related bleeding. While highly relevant, these outcomes do not fully capture functional limitations and the psychological impact that comprises post-PE syndrome.</div></div><div><h3>Objectives</h3><div>The primary objective of the Functional Characterization of Venous Thromboembolic Disease (FUVID) study was to investigate mechanisms of post-PE syndrome in children.</div></div><div><h3>Methods</h3><div>The ongoing FUVID study will prospectively enroll and systematically follow, over 12 months and with standardized pulmonary, cardiac, and muscle testing, a multicenter prospective cohort of 80 pediatric patients with first-episode PE without comorbidities. FUVID has 2 coprimary outcomes: exercise intolerance and exertional dyspnea. Exercise intolerance will be defined objectively as a percent predicted peak oxygen uptake based on ideal body weight or milliliters per minute per kilogram of lean body mass during cardiopulmonary exercise testing. Dyspnea will be objectively quantified using Borg questionnaires and defined as a mean difference of &gt;1 at the end of the warm-up and submaximal work rates during exercise testing, simulating conditions during daily life that induce dyspnea. Pertinent secondary outcomes include anxiety, depression, and quality of life.</div></div><div><h3>Conclusion</h3><div>The FUVID study will investigate the relationship between symptoms (exercise intolerance and exertional dyspnea) and multiple mechanisms—hemodynamic, ventilatory, or peripheral/muscle—within the same patient at rest, submaximal exercise (simulating activities of daily living), and maximal exercise using objective measures. It will provide new evidence for selecting patients for long-term follow-up, including psychological sequelae, after PE, the modalities this follow-up should include, and the findings interpreted as indicating functional limitations after PE.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 1","pages":"Article 102669"},"PeriodicalIF":3.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143641706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Type of D-dimer assay determines the diagnostic yield of computed tomography in patients suspected for pulmonary embolism","authors":"Jorn L.J.C. Assmann ,&nbsp;Adriaan J. van Gammeren ,&nbsp;Reinier A. Sprenger ,&nbsp;Saskia de Wit ,&nbsp;Huib Ceelie ,&nbsp;Frank W.G. Leebeek ,&nbsp;Mark W.M. Schellings","doi":"10.1016/j.rpth.2024.102638","DOIUrl":"10.1016/j.rpth.2024.102638","url":null,"abstract":"<div><h3>Background</h3><div>Pulmonary embolism (PE) is a life-threatening condition with high morbidity and mortality. The diagnosis of PE is challenging due to nonspecific symptoms, making reliable diagnostic tools essential. This study addresses the clinical impact of interassay variability in D-dimer measurements on the utilization and diagnostic yield of computed tomography pulmonary angiography (CTPA).</div></div><div><h3>Objectives</h3><div>To investigate the effect of different D-dimer assays on the decision to perform CTPA and the subsequent diagnostic yield in patients with suspected PE.</div></div><div><h3>Methods</h3><div>This retrospective, multicenter cohort study analyzed data from 3 teaching hospitals in the southwest region of the Netherlands, covering the years 2018, 2019, 2022, and 2023. The study included data from 40,096 clinically requested D-dimer results and 11,372 CTPA records of patients with suspected PE. The D-dimer assays used were the Roche Tina-quant and Siemens INNOVANCE.</div></div><div><h3>Results</h3><div>The study found significant differences in CTPA utilization and diagnostic yield based on the D-dimer assay used. In 2018 to 2019, hospitals using the Roche Tina-quant assay ordered 21% fewer CTPA scans and had a 9% higher positivity rate compared with those using the Siemens INNOVANCE assay.</div></div><div><h3>Conclusion</h3><div>The findings highlight the necessity for assay-specific cutoff values or, ideally, the standardization of the D-dimer assay to optimize the accuracy and efficiency of PE diagnosis. This study demonstrates that the choice of D-dimer assay significantly influences the clinical management of suspected PE, affecting both the number of CTPA scans performed and the positivity rate of these scans. Implementing assay-specific cutoff values or standardization of the D-dimer assay could reduce unnecessary CTPA scans, minimize patient exposure to radiation, and lower healthcare costs. These results advocate enhanced collaboration between clinicians and laboratory specialists to accurately interpret D-dimer results within the context of the specific assay used. Future research should validate these findings in prospective studies and explore standardized protocols that account for interassay variability.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 1","pages":"Article 102638"},"PeriodicalIF":3.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11731453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142984633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Changes in platelet maturity and reactivity following acute ST-segment elevation myocardial infarction","authors":"Oliver Buchhave Pedersen ,&nbsp;Peter H. Nissen ,&nbsp;Leonardo Pasalic ,&nbsp;Anne-Mette Hvas ,&nbsp;Steen Dalby Kristensen ,&nbsp;Erik Lerkevang Grove","doi":"10.1016/j.rpth.2024.102652","DOIUrl":"10.1016/j.rpth.2024.102652","url":null,"abstract":"<div><h3>Background</h3><div>Reduced effect of antiplatelet therapy has been reported in patients with ST-segment elevation myocardial infarction (STEMI). This could partly be explained by an increase of highly reactive immature platelets.</div></div><div><h3>Objectives</h3><div>To investigate changes in platelet maturity and reactivity after acute STEMI.</div></div><div><h3>Methods</h3><div>Patients diagnosed with STEMI, admitted for primary percutaneous coronary intervention, and treated according to international guidelines, were included. Blood samples were obtained within 24 hours after admission and at 2- to 3-months follow-up. Platelet maturity and reactivity using multicolor flow cytometry with SYTO-13 to categorize platelet maturity, whole blood platelet aggregation, serum thromboxane B2 levels, and standard immature platelet markers (eg, immature platelet count and fraction, and mean platelet volume) were measured.</div></div><div><h3>Results</h3><div>A total of 44 STEMI patients were included. The reactivity of immature platelets was consistently higher at baseline and at follow-up when compared to the entire platelet population and the mature platelet population (all <em>P</em> values &lt; .05). The expression of CD63 (a dense granule marker) in immature platelets was consistently high compared to the entire platelet population and the mature platelet population and did not change from baseline to follow-up (<em>P</em> values &gt; .24). Additionally, a positive significant correlation was found between standard immature platelet markers and the expression of CD63 on platelets both at baseline and follow-up (rho ranging from 0.32 to 0.62, all <em>P</em> values &lt; .05).</div></div><div><h3>Conclusion</h3><div>Immature platelets represent a highly reactive platelet subpopulation crucial for the overall platelet reactivity, partly due to a high expression of dense granules. Despite treatment with loading and maintenance doses of antiplatelet therapy, the reactivity of immature platelets remained high in STEMI patients.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 1","pages":"Article 102652"},"PeriodicalIF":3.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11751529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143024638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adeno-associated virus-based gene therapy for hemophilia–addressing the gaps","authors":"Wolfgang Miesbach ,&nbsp;Paul Batty ,&nbsp;Pratima Chowdary ,&nbsp;Sylvia Fong ,&nbsp;Radoslaw Kaczmarek ,&nbsp;Frank W.G. Leebeek ,&nbsp;Brian Long ,&nbsp;Johnny Mahlangu ,&nbsp;Mike Makris ,&nbsp;Glenn F. Pierce ,&nbsp;Steven W. Pipe ,&nbsp;Alok Srivastava ,&nbsp;Jan Voorberg ,&nbsp;Flora Peyvandi","doi":"10.1016/j.rpth.2024.102673","DOIUrl":"10.1016/j.rpth.2024.102673","url":null,"abstract":"<div><div>Adeno-associated virus-based gene therapy for hemophilia has emerged as a revolutionary treatment option, offering potential correction of clotting factor deficiency through a single intravenous infusion of functional genes directed to hepatocytes. With 3 gene therapies recently approved, this approach shows promise in transforming the lives of individuals with hemophilia. However, the complexity of gene therapy and the lack of standardization of methods in different components of this therapy can lead to unique challenges for clinical implementation. This manuscript follows literature reviews and structured discussions by the International Society on Thrombosis and Haemostasis Scientific and Standardization Committee Working Group on Gene Therapy that identified specific areas requiring standardization of methods, including viral vector production, liver function assessment, quantification of factor (F)VIII and FIX expression levels, assessment of antiadeno-associated viral antibodies, and genomic integration detection methods. Standardization strategies aim to achieve consistent vector quality, effective patient selection, and uniform assessment methods by implementing advanced laboratory techniques and standardized protocols. Standardizing these parameters is essential for improving the understanding of short-term and long-term safety and efficacy of gene therapy in hemophilia. This effort aims to enhance the predictability of individual responses, address variability in outcomes, and ultimately provide more effective, safer, and personalized treatment options for individuals with hemophilia.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 1","pages":"Article 102673"},"PeriodicalIF":3.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11787635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recombinant factor VIIa: new insights into the mechanism of action through product innovation","authors":"Miguel A. Escobar ,&nbsp;Maureane Hoffman ,&nbsp;Giancarlo Castaman ,&nbsp;Cedric Hermans ,&nbsp;Johnny Mahlangu ,&nbsp;Johannes Oldenburg ,&nbsp;Charles L. Percy ,&nbsp;Mark T. Reding ,&nbsp;Amy D. Shapiro ,&nbsp;Steven W. Pipe","doi":"10.1016/j.rpth.2024.102670","DOIUrl":"10.1016/j.rpth.2024.102670","url":null,"abstract":"<div><div>Management of bleeding in persons with hemophilia and inhibitors involves treatment with bypassing agents, including recombinant activated factor VII (rFVIIa). Two rFVIIa products are commercially approved for use in the United States and the European Union. Eptacog alfa and eptacog beta share the same amino acid sequence but differ in posttranslational modifications. Although rFVIIa has been used to manage bleeding in persons with hemophilia and inhibitors for over 30 years, its mechanisms of action is still being studied. <em>In vitro</em> and <em>in vivo</em> studies have suggested that rFVIIa could promote hemostasis by (1) increasing tissue factor-dependent activation of factor (F)X (FX); (2) directly activating FX on the surface of activated platelets; and (3) downregulating protein C anticoagulant activity through binding to the endothelial protein C receptor (EPCR). Studies of rFVIIa and rFVIIa variants in murine models demonstrate that platelet-dependent activity is sufficient for hemostatic efficacy. Dosing levels required in clinical practice are most consistent with a platelet-dependent mechanism of action. However, <em>in vivo</em> models also suggest that pathways involving EPCR binding contribute to rFVIIa hemostatic activity. Eptacog beta displays increased platelet- and EPCR-dependent endothelial cell binding compared to eptacog alfa. Thus, the relative contribution of these mechanisms to the overall hemostatic efficacy of eptacog alfa and eptacog beta may differ. Further research is required to assess the clinical relevance of these differences. A better understanding of the mechanisms by which rFVIIa promotes hemostasis in patients will provide insights when evaluating clinical outcomes of safety and efficacy for innovative bypassing therapies.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 1","pages":"Article 102670"},"PeriodicalIF":3.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143155135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}