Pub Date : 2025-01-01DOI: 10.1016/j.rpth.2024.102628
Richard J. Buka
Andexanet Alfa in Acute Intracranial Hemorrhage in Patients Receiving an Oral Factor Xa Inhibitor (ANNEXA-I), the first ever randomized controlled trial of a reversal agent for direct oral anticoagulants, was published in 2024. The trial, which randomized patients with intracranial hemorrhage to andexanet alfa or usual care, was mandated by the United States Food and Drug Administration as part of its conditional approval in 2018. This approval was originally based on the single-arm trial, The Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors (ANNEXA-4). ANNEXA-I was stopped early for benefit and showed a reduction in the number of patients with significant hematoma expansion. However, the study was not powered for clinical endpoints such as disability or death and showed no difference in these outcomes. It did, however, show an increased risk of thrombosis, predominantly stroke with andexanet alfa. In this perspective, I reflect on some of the key criticisms of the trial and the implications for its interpretation.
{"title":"Andexanet alfa: trials just leave us with more questions","authors":"Richard J. Buka","doi":"10.1016/j.rpth.2024.102628","DOIUrl":"10.1016/j.rpth.2024.102628","url":null,"abstract":"<div><div>Andexanet Alfa in Acute Intracranial Hemorrhage in Patients Receiving an Oral Factor Xa Inhibitor (ANNEXA-I), the first ever randomized controlled trial of a reversal agent for direct oral anticoagulants, was published in 2024. The trial, which randomized patients with intracranial hemorrhage to andexanet alfa or usual care, was mandated by the United States Food and Drug Administration as part of its conditional approval in 2018. This approval was originally based on the single-arm trial, The Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors (ANNEXA-4). ANNEXA-I was stopped early for benefit and showed a reduction in the number of patients with significant hematoma expansion. However, the study was not powered for clinical endpoints such as disability or death and showed no difference in these outcomes. It did, however, show an increased risk of thrombosis, predominantly stroke with andexanet alfa. In this perspective, I reflect on some of the key criticisms of the trial and the implications for its interpretation.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 1","pages":"Article 102628"},"PeriodicalIF":3.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11760292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047731","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}
Pub Date : 2025-01-01DOI: 10.1016/j.rpth.2024.102663
Liam Barrett , Nicola Curry
A state of the art lecture titled “Transfusion therapy in trauma—what to give? Empiric vs guided” was presented at the International Society on Thrombosis and Haemostasis Congress in 2024. Uncontrolled bleeding is the commonest preventable cause of death after traumatic injury. Hemostatic resuscitation is the foundation of contemporary transfusion practice for traumatic bleeding and has 2 main aims: to immediately support the circulating blood volume and to treat/prevent the associated trauma-induced coagulopathy. There are 2 broad types of hemostatic resuscitation strategy: empiric ratio-based therapy, often using red blood cells and fresh frozen plasma in a 1:1 ratio, and targeted therapy where the use of platelets, plasma, or fibrinogen is guided by laboratory or viscoelastic hemostatic tests. There are benefits, and limitations, to each strategy and neither approach has yet been shown to improve outcomes across all patient groups. Questions remain, and future directions for improving transfusion therapy are likely to require novel approaches that have greater flexibility to evaluate and treat heterogeneous trauma cohorts. Such approaches may include the integration of machine learning technologies in clinical systems, with real-time linkage of clinical and laboratory data, to aid early recognition of patients at the greatest risk of bleeding and to direct and individualize transfusion therapies. Greater mechanistic understanding of the underlying pathobiology of trauma-induced coagulopathy and the direct effects of common treatments on this process will be of equal importance to the development of new treatments. Finally, we summarize relevant new data on this topic presented at the 2024 ISTH Congress.
{"title":"Transfusion in trauma: empiric or guided therapy?","authors":"Liam Barrett , Nicola Curry","doi":"10.1016/j.rpth.2024.102663","DOIUrl":"10.1016/j.rpth.2024.102663","url":null,"abstract":"<div><div>A state of the art lecture titled “Transfusion therapy in trauma—what to give? Empiric vs guided” was presented at the International Society on Thrombosis and Haemostasis Congress in 2024. Uncontrolled bleeding is the commonest preventable cause of death after traumatic injury. Hemostatic resuscitation is the foundation of contemporary transfusion practice for traumatic bleeding and has 2 main aims: to immediately support the circulating blood volume and to treat/prevent the associated trauma-induced coagulopathy. There are 2 broad types of hemostatic resuscitation strategy: empiric ratio-based therapy, often using red blood cells and fresh frozen plasma in a 1:1 ratio, and targeted therapy where the use of platelets, plasma, or fibrinogen is guided by laboratory or viscoelastic hemostatic tests. There are benefits, and limitations, to each strategy and neither approach has yet been shown to improve outcomes across all patient groups. Questions remain, and future directions for improving transfusion therapy are likely to require novel approaches that have greater flexibility to evaluate and treat heterogeneous trauma cohorts. Such approaches may include the integration of machine learning technologies in clinical systems, with real-time linkage of clinical and laboratory data, to aid early recognition of patients at the greatest risk of bleeding and to direct and individualize transfusion therapies. Greater mechanistic understanding of the underlying pathobiology of trauma-induced coagulopathy and the direct effects of common treatments on this process will be of equal importance to the development of new treatments. Finally, we summarize relevant new data on this topic presented at the 2024 ISTH Congress.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 1","pages":"Article 102663"},"PeriodicalIF":3.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11774821/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143067431","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}
Pub Date : 2025-01-01DOI: 10.1016/j.rpth.2024.102676
Chih Jen Yang , Lyndsey E. Shorey-Kendrick , Cristina Puy , Ashley E. Benson , Phillip A. Wilmarth , Ashok P. Reddy , Keith D. Zientek , Kilsun Kim , Adam Crosland , Chaevien S. Clendinen , Lisa M. Bramer , Olivia L. Hagen , Helen H. Vu , Joseph E. Aslan , Owen J.T. McCarty , Joseph J. Shatzel , Brian P. Scottoline , Jamie O. Lo
Background
Amniotic fluid (AF) plays a key role in fetal development, yet the evolving composition of AF and its effects on hemostasis and thrombosis are poorly understood.
Objectives
To characterize the procoagulant properties of AF as a function of gestation in humans and nonhuman primates.
Methods
We analyzed the proteomes, lipidomes, and procoagulant properties of AF obtained by amniocentesis from rhesus macaque and human pregnancies at gestational age-matched time points.
Results
When added to human plasma, both rhesus and human AF accelerated clotting time and fibrin generation. We identified proteomic modules associated with clotting time and enriched for coagulation-related pathways. Proteins known to be involved in hemostasis were highly correlated with each other, and their intensity of expression varied across gestation in both rhesus and humans. Inhibition of the contact pathway did not affect the procoagulant effect of AF. Blocking tissue factor pathway inhibitor reversed the ability of AF to block the generation of activated factor X. The prothrombinase activity of AF was inhibited by phospholipid inhibitors. The levels of phosphatidylserine in AF were inversely correlated with clotting time. AF promoted platelet activation and secretion in plasma.
Conclusion
Overall, our findings reveal that the addition of AF to plasma enhances coagulation in a manner dependent on phospholipids as well as the presence of proteases and other proteins that directly regulate coagulation. We describe a correlation between clotting time and expression of coagulation proteins and phosphatidylserine in both rhesus and human AF, supporting the use of rhesus models for future studies of AF biology.
{"title":"Characterization of the procoagulant phenotype of amniotic fluid across gestation in rhesus macaques and humans","authors":"Chih Jen Yang , Lyndsey E. Shorey-Kendrick , Cristina Puy , Ashley E. Benson , Phillip A. Wilmarth , Ashok P. Reddy , Keith D. Zientek , Kilsun Kim , Adam Crosland , Chaevien S. Clendinen , Lisa M. Bramer , Olivia L. Hagen , Helen H. Vu , Joseph E. Aslan , Owen J.T. McCarty , Joseph J. Shatzel , Brian P. Scottoline , Jamie O. Lo","doi":"10.1016/j.rpth.2024.102676","DOIUrl":"10.1016/j.rpth.2024.102676","url":null,"abstract":"<div><h3>Background</h3><div>Amniotic fluid (AF) plays a key role in fetal development, yet the evolving composition of AF and its effects on hemostasis and thrombosis are poorly understood.</div></div><div><h3>Objectives</h3><div>To characterize the procoagulant properties of AF as a function of gestation in humans and nonhuman primates.</div></div><div><h3>Methods</h3><div>We analyzed the proteomes, lipidomes, and procoagulant properties of AF obtained by amniocentesis from rhesus macaque and human pregnancies at gestational age-matched time points.</div></div><div><h3>Results</h3><div>When added to human plasma, both rhesus and human AF accelerated clotting time and fibrin generation. We identified proteomic modules associated with clotting time and enriched for coagulation-related pathways. Proteins known to be involved in hemostasis were highly correlated with each other, and their intensity of expression varied across gestation in both rhesus and humans. Inhibition of the contact pathway did not affect the procoagulant effect of AF. Blocking tissue factor pathway inhibitor reversed the ability of AF to block the generation of activated factor X. The prothrombinase activity of AF was inhibited by phospholipid inhibitors. The levels of phosphatidylserine in AF were inversely correlated with clotting time. AF promoted platelet activation and secretion in plasma.</div></div><div><h3>Conclusion</h3><div>Overall, our findings reveal that the addition of AF to plasma enhances coagulation in a manner dependent on phospholipids as well as the presence of proteases and other proteins that directly regulate coagulation. We describe a correlation between clotting time and expression of coagulation proteins and phosphatidylserine in both rhesus and human AF, supporting the use of rhesus models for future studies of AF biology.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 1","pages":"Article 102676"},"PeriodicalIF":3.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143156252","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}
The bleeding disorder described here is due to a heterozygous autosomal dominant C1611>A variant in the thrombomodulin (TM) gene that significantly elevates plasma TM levels, which enhances the activation of protein C. This activation inhibits factors VIIIa and Va, reducing thrombin generation and potentially leading to severe hemorrhagic manifestations.
Key Clinical Question
What is the bleeding profile of patients with this rare condition? What are the most frequent clinical signs, and how can they be treated?
Clinical Approach
We present a case study of an index patient with the TM C1611>A variant and his 20 family members. We detail the hemostatic strategies employed during various bleeding episodes and surgical procedures.
Conclusion
Sharing clinical experiences is crucial for hematologists managing similar cases, as it provides valuable insights into effective treatment strategies.
{"title":"Clinical management of bleeding manifestations in a family with the thrombomodulin C1611>A (p.Cys537Stop) mutation","authors":"Serge Pierre-Louis , Johalene Rabout , Octavio Labrada , Fatima Radouani , Emeline Chonville , Beatrice Ferrey , Olivier Pierre-Louis , Yesim Dargaud","doi":"10.1016/j.rpth.2025.102678","DOIUrl":"10.1016/j.rpth.2025.102678","url":null,"abstract":"<div><h3>Background</h3><div>The bleeding disorder described here is due to a heterozygous autosomal dominant C1611>A variant in the thrombomodulin (TM) gene that significantly elevates plasma TM levels, which enhances the activation of protein C. This activation inhibits factors VIIIa and Va, reducing thrombin generation and potentially leading to severe hemorrhagic manifestations.</div></div><div><h3>Key Clinical Question</h3><div>What is the bleeding profile of patients with this rare condition? What are the most frequent clinical signs, and how can they be treated?</div></div><div><h3>Clinical Approach</h3><div>We present a case study of an index patient with the <em>TM</em> C1611>A variant and his 20 family members. We detail the hemostatic strategies employed during various bleeding episodes and surgical procedures.</div></div><div><h3>Conclusion</h3><div>Sharing clinical experiences is crucial for hematologists managing similar cases, as it provides valuable insights into effective treatment strategies.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 1","pages":"Article 102678"},"PeriodicalIF":3.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143156332","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}
Pub Date : 2025-01-01DOI: 10.1016/j.rpth.2025.102688
Huiqiao Fan, Youssef Bessada, Craig I. Coleman
Background
Evaluations of andexanet alfa for the reversal of factor Xa inhibitor-associated bleeding have been small, with cohorts drawn from single/limited sites. Delays in providing anticoagulation reversal due to hospital transfer may result in poorer outcomes.
Objectives
To describe the characteristics and outcomes of andexanet alfa users and evaluate the association between delay in andexanet alfa administration due to transfer from a different acute care hospital and the incidence of all-cause inpatient mortality.
Methods
This was a retrospective study using National Inpatient Sample data. Hospitalizations with procedural codes for andexanet alfa and a billing code for bleeding were included. Descriptive analysis was performed, as was multivariable logistic regression, to estimate the odds ratio and 95% CI for the association between andexanet alfa delayed due to transfer from a different acute care hospital and all-cause inpatient mortality.
Results
From 2019 to 2021, 4210 hospitalizations occurred in adults receiving andexanet alfa and a bleed. Most were hospitalized with intracranial hemorrhage (62.0%). The incidence of all-cause inpatient mortality was 16.6% (95% CI, 14.3%-19.3%), mean hospital stays lasted 9.1 days (95% CI, 8.4-9.8), and mean hospital costs were $73,600 (95% CI, $65,000-$82,200). Of all cases, 18.5% were transferred from a different acute care hospital prior to receiving andexanet alfa. Cases with hospital transfer had an 82% increased odds of all-cause inpatient mortality (95% CI, 17%-183%) but did not reach statistical significance when the population was limited to intracranial hemorrhage (odds ratio, 1.51; 95% CI, 0.88-2.60).
Conclusion
Delay in administering andexanet alfa due to hospital transfer may be associated with increased all-cause mortality.
{"title":"Real-world andexanet alfa utilization and the association between delay in administration due to hospital transfer and all-cause inpatient mortality","authors":"Huiqiao Fan, Youssef Bessada, Craig I. Coleman","doi":"10.1016/j.rpth.2025.102688","DOIUrl":"10.1016/j.rpth.2025.102688","url":null,"abstract":"<div><h3>Background</h3><div>Evaluations of andexanet alfa for the reversal of factor Xa inhibitor-associated bleeding have been small, with cohorts drawn from single/limited sites. Delays in providing anticoagulation reversal due to hospital transfer may result in poorer outcomes.</div></div><div><h3>Objectives</h3><div>To describe the characteristics and outcomes of andexanet alfa users and evaluate the association between delay in andexanet alfa administration due to transfer from a different acute care hospital and the incidence of all-cause inpatient mortality.</div></div><div><h3>Methods</h3><div>This was a retrospective study using National Inpatient Sample data. Hospitalizations with procedural codes for andexanet alfa and a billing code for bleeding were included. Descriptive analysis was performed, as was multivariable logistic regression, to estimate the odds ratio and 95% CI for the association between andexanet alfa delayed due to transfer from a different acute care hospital and all-cause inpatient mortality.</div></div><div><h3>Results</h3><div>From 2019 to 2021, 4210 hospitalizations occurred in adults receiving andexanet alfa and a bleed. Most were hospitalized with intracranial hemorrhage (62.0%). The incidence of all-cause inpatient mortality was 16.6% (95% CI, 14.3%-19.3%), mean hospital stays lasted 9.1 days (95% CI, 8.4-9.8), and mean hospital costs were $73,600 (95% CI, $65,000-$82,200). Of all cases, 18.5% were transferred from a different acute care hospital prior to receiving andexanet alfa. Cases with hospital transfer had an 82% increased odds of all-cause inpatient mortality (95% CI, 17%-183%) but did not reach statistical significance when the population was limited to intracranial hemorrhage (odds ratio, 1.51; 95% CI, 0.88-2.60).</div></div><div><h3>Conclusion</h3><div>Delay in administering andexanet alfa due to hospital transfer may be associated with increased all-cause mortality.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 1","pages":"Article 102688"},"PeriodicalIF":3.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143445817","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}
Pub Date : 2025-01-01DOI: 10.1016/j.rpth.2024.102644
Mark J.R. Smeets , Pelle B. Petersen , Christoffer C. Jørgensen , Suzanne C. Cannegieter , Sisse R. Ostrowski , Henrik Kehlet , Banne Nemeth
Background
Venous thromboembolism (VTE) is a serious complication following total hip arthroplasty (THA) and total knee arthroplasty (TKA). Despite improvements with fast-track treatment protocols, 0.5% of patients still develop a VTE within 90-days postoperatively. Previously, the 5-single nucleotide polymorphism (SNP) genetic risk scores (weighted and simplified) were developed to identify people at a high risk for VTE within the general population.
Objectives
We aimed to assess whether the 5-SNP scores could be used to identify high-risk patients in a cohort of fast-track THA/TKA patients.
Methods
A subset of patients from the Lundbeck Centre for Fast-track Hip and Knee Replacement Database was included based on the availability of genetic information. The 5-SNP scores were calculated for these patients, and their discriminatory performance was determined by c-statistic. Furthermore, the 5-SNP scores were added to a simple logistic prediction model containing clinical predictors to assess the added predictive value.
Results
A total of 7753 THA and TKA procedures (6798 patients) were included in this study. The c-statistics for the weighted and simple 5-SNP scores were 0.50 (95% CI, 0.39-0.61) and 0.48 (95% CI, 0.38-0.58), respectively. For the model with clinical predictors, the c-statistic was 0.67 (95% CI, 0.56-0.77). Addition of either of the 5-SNP scores did not improve discrimination in this model.
Conclusion
These findings do not support genetic risk profiling in fast-track THA/TKA patients to predict VTE. Hence, efforts should be directed at optimizing prediction models with clinical predictors.
{"title":"Validation of the 5-SNP score for the prediction of venous thromboembolism in a Danish fast-track cohort of 6789 total hip and total knee arthroplasty patients","authors":"Mark J.R. Smeets , Pelle B. Petersen , Christoffer C. Jørgensen , Suzanne C. Cannegieter , Sisse R. Ostrowski , Henrik Kehlet , Banne Nemeth","doi":"10.1016/j.rpth.2024.102644","DOIUrl":"10.1016/j.rpth.2024.102644","url":null,"abstract":"<div><h3>Background</h3><div>Venous thromboembolism (VTE) is a serious complication following total hip arthroplasty (THA) and total knee arthroplasty (TKA). Despite improvements with fast-track treatment protocols, 0.5% of patients still develop a VTE within 90-days postoperatively. Previously, the 5-single nucleotide polymorphism (SNP) genetic risk scores (weighted and simplified) were developed to identify people at a high risk for VTE within the general population.</div></div><div><h3>Objectives</h3><div>We aimed to assess whether the 5-SNP scores could be used to identify high-risk patients in a cohort of fast-track THA/TKA patients.</div></div><div><h3>Methods</h3><div>A subset of patients from the Lundbeck Centre for Fast-track Hip and Knee Replacement Database was included based on the availability of genetic information. The 5-SNP scores were calculated for these patients, and their discriminatory performance was determined by c-statistic. Furthermore, the 5-SNP scores were added to a simple logistic prediction model containing clinical predictors to assess the added predictive value.</div></div><div><h3>Results</h3><div>A total of 7753 THA and TKA procedures (6798 patients) were included in this study. The c-statistics for the weighted and simple 5-SNP scores were 0.50 (95% CI, 0.39-0.61) and 0.48 (95% CI, 0.38-0.58), respectively. For the model with clinical predictors, the c-statistic was 0.67 (95% CI, 0.56-0.77). Addition of either of the 5-SNP scores did not improve discrimination in this model.</div></div><div><h3>Conclusion</h3><div>These findings do not support genetic risk profiling in fast-track THA/TKA patients to predict VTE. Hence, efforts should be directed at optimizing prediction models with clinical predictors.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 1","pages":"Article 102644"},"PeriodicalIF":3.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11731481/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142984634","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}
Congenital thrombotic thrombocytopenic purpura (cTTP) related to ADAMTS-13 deficiency is associated with a maternal risk of death of 10% and a risk of fetal loss greater than 50% without treatment.
Key Clinical Question
Is prophylactic use of recombinant (r)ADAMTS-13 during pregnancy in patients with cTTP safe and effective in preventing cTTP relapse?
Clinical Approach
rADAMTS-13 was given intravenously weekly (40 Units/kg) from 17 weeks’ gestation. ADAMTS-13 activity was undetectable before the first administration, reached 60% to 90% of normal levels 2 hours after, and became undetectable between days 4 and 6. A full dose was given in the hours preceding the delivery and on day 3. No flare-up of cTTP occurred during the pregnancy, and rADAMTS-13 was tolerated well. No anti–ADAMTS-13 antibodies developed.
Conclusion
Prophylactic use of rADAMTS-13 during pregnancy may prevent relapse of cTTP and reduce the risk of fetal loss, but an optimal regimen requires further attention.
{"title":"Prophylactic use of recombinant ADAMTS-13 during pregnancy for congenital thrombotic thrombocytopenic purpura","authors":"Éloïse Colliou , Agnès Ribes , Clotilde Gaible , Mathilde Marlas , David Ribes , Isabelle Labadens , Paul Guerby , Stanislas Faguer","doi":"10.1016/j.rpth.2025.102687","DOIUrl":"10.1016/j.rpth.2025.102687","url":null,"abstract":"<div><h3>Background</h3><div>Congenital thrombotic thrombocytopenic purpura (cTTP) related to ADAMTS-13 deficiency is associated with a maternal risk of death of 10% and a risk of fetal loss greater than 50% without treatment.</div></div><div><h3>Key Clinical Question</h3><div>Is prophylactic use of recombinant (r)ADAMTS-13 during pregnancy in patients with cTTP safe and effective in preventing cTTP relapse?</div></div><div><h3>Clinical Approach</h3><div>rADAMTS-13 was given intravenously weekly (40 Units/kg) from 17 weeks’ gestation. ADAMTS-13 activity was undetectable before the first administration, reached 60% to 90% of normal levels 2 hours after, and became undetectable between days 4 and 6. A full dose was given in the hours preceding the delivery and on day 3. No flare-up of cTTP occurred during the pregnancy, and rADAMTS-13 was tolerated well. No anti–ADAMTS-13 antibodies developed.</div></div><div><h3>Conclusion</h3><div>Prophylactic use of rADAMTS-13 during pregnancy may prevent relapse of cTTP and reduce the risk of fetal loss, but an optimal regimen requires further attention.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 1","pages":"Article 102687"},"PeriodicalIF":3.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143295797","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}
Pub Date : 2025-01-01DOI: 10.1016/j.rpth.2024.102666
Fien A. von Meijenfeldt , Ton Lisman , Alessandra Pacheco , Yoh Zen , William Bernal
Background
Liver disease is often characterized by the activation of coagulation and inflammation. Experimental studies suggest that the interaction between neutrophils and platelets with local activation of coagulation could contribute to liver injury progression, but there have been limited studies in humans.
Objectives
We studied the hemostatic components and neutrophil extracellular traps (NETs) in liver biopsies from patients with different inflammatory liver diseases.
Methods
Liver biopsies from patients with inflammatory liver disease (alcoholic steatohepatitis [ASH], autoimmune hepatitis, primary sclerosing cholangitis, metabolic-associated steatohepatitis, and allograft ischemia-reperfusion injury (IRI), each n = 20) were stained for fibrin(ogen), platelets, and NETs. The correlation of NET formation with deposition of hemostatic components and laboratory measures of disease severity was investigated.
Results
In 75% of the liver biopsies, no fibrin(ogen) was detectable, and only 20% of the biopsies showed minimal deposition. Overall, 50% of liver biopsies stained positive for NETs. Platelet deposition and NET formation were highest in IRI, where it correlated with histologic severity of injury (r = .61 [95% CI, .22-.84]; P < .01) and ASH. Platelet deposition was associated with NET formation (r = .44 [95% CI, .27-.59]; P < .001) and colocalized in the biopsies. NET formation, but not fibrin and platelet deposition, was moderately associated with the model of end-stage liver disease score (r = .29 [95% CI, .07-.49]; P < .01).
Conclusion
In contrast to experimental studies, we demonstrated minimal intrahepatic fibrin(ogen) deposition in different types of human inflammatory liver disease. Histologic evidence for intrahepatic NETs was common and most pronounced in acute ASH and IRI and was associated with platelet deposition and disease severity.
{"title":"Histologic evidence of neutrophil extracellular traps and fibrin(ogen) deposition in liver biopsies from patients with inflammatory liver disease","authors":"Fien A. von Meijenfeldt , Ton Lisman , Alessandra Pacheco , Yoh Zen , William Bernal","doi":"10.1016/j.rpth.2024.102666","DOIUrl":"10.1016/j.rpth.2024.102666","url":null,"abstract":"<div><h3>Background</h3><div>Liver disease is often characterized by the activation of coagulation and inflammation. Experimental studies suggest that the interaction between neutrophils and platelets with local activation of coagulation could contribute to liver injury progression, but there have been limited studies in humans.</div></div><div><h3>Objectives</h3><div>We studied the hemostatic components and neutrophil extracellular traps (NETs) in liver biopsies from patients with different inflammatory liver diseases.</div></div><div><h3>Methods</h3><div>Liver biopsies from patients with inflammatory liver disease (alcoholic steatohepatitis [ASH], autoimmune hepatitis, primary sclerosing cholangitis, metabolic-associated steatohepatitis, and allograft ischemia-reperfusion injury (IRI), each <em>n</em> = 20) were stained for fibrin(ogen), platelets, and NETs. The correlation of NET formation with deposition of hemostatic components and laboratory measures of disease severity was investigated.</div></div><div><h3>Results</h3><div>In 75% of the liver biopsies, no fibrin(ogen) was detectable, and only 20% of the biopsies showed minimal deposition. Overall, 50% of liver biopsies stained positive for NETs. Platelet deposition and NET formation were highest in IRI, where it correlated with histologic severity of injury (r = .61 [95% CI, .22-.84]; <em>P</em> < .01) and ASH. Platelet deposition was associated with NET formation (r = .44 [95% CI, .27-.59]; <em>P</em> < .001) and colocalized in the biopsies. NET formation, but not fibrin and platelet deposition, was moderately associated with the model of end-stage liver disease score (r = .29 [95% CI, .07-.49]; <em>P</em> < .01).</div></div><div><h3>Conclusion</h3><div>In contrast to experimental studies, we demonstrated minimal intrahepatic fibrin(ogen) deposition in different types of human inflammatory liver disease. Histologic evidence for intrahepatic NETs was common and most pronounced in acute ASH and IRI and was associated with platelet deposition and disease severity.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 1","pages":"Article 102666"},"PeriodicalIF":3.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143156206","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}
Pub Date : 2025-01-01DOI: 10.1016/j.rpth.2024.102639
Zhengping Li , Zekun Li , Xiaoling Cheng , Heng Zhang , Can Yang , Qian Xu , Zhenping Chen , Yingzi Zhen , Gang Li , Guoqing Liu , Wanru Yao , Min Zhou , Jiao Jin , Jie Huang , Yongjun Fang , Liangzhi Xie , Man-Chiu Poon , Runhui Wu
Background
Low-dose (LD) or intermediate-dose (MD) immune tolerance induction (ITI) is effective in children with severe hemophilia A (SHA) with high-titer inhibitors (HTIs) and is attractive in countries with economic constraints. However, high-quality evidence of their use is lacking.
Objectives
This was a multicenter randomized clinical trial comparing the efficacy, safety, and medication cost between LD-ITI and MD-ITI for SHA-HTI children.
Methods
Children with SHA aged <8 years with historical/pre-ITI inhibitor titer 5 to 200 Bethesda Units/mL in 3 centers were randomized 1:1 to receive LD-ITI (recombinant factor VIII [rFVIII] 50 IU/kg every other day) or MD-ITI (rFVIII 100 IU/kg/d) from January 2022 to June 2024 (ChiCTR2200056603, https://www.chictr.org.cn).
Results
Thirty-one patients (16 in MD-ITI and 15 in LD-ITI) were enrolled and followed for >24 months (median, 26.9; range, 24.0-29.5 months). The 2 groups had similar baseline clinical characteristics and similar success rates (93.8% [MD-ITI] vs 86.7% [LD-ITI]). Compared with LD-ITI, MD-ITI patients took a shorter median time to success (4.2 months vs 10.1 months) and partial success (2.7 months vs 6.6 months) and had lower mean rates for all bleeding (0.38/mo vs 1.40/mo) and joint bleeding (0.11/mo vs 0.83/mo). Between the 2 groups, although the MD-ITI group had higher rFVIII consumption (12,775 vs 7680 IU/kg), their total medication costs to success were similar (3626.49 vs 3240.38 US$/kg).
Conclusion
For SHA-HTI children, the success rate and cost for MD-ITI and LD-ITI regimens were similar. MD-ITI regimen would be a priority for regions with economic constraints, considering the shorter time to success, better bleeding control, and no increase in medication cost.
背景：低剂量（LD）或中剂量（MD）免疫耐受诱导（ITI）对患有高滴度抑制剂（HTIs）的重度甲型血友病（SHA）患儿有效，在经济拮据的国家很有吸引力。然而，目前还缺乏使用这种疗法的高质量证据：这是一项多中心随机临床试验，比较了 LD-ITI 和 MD-ITI 对 SHA-HTI 儿童的疗效、安全性和用药成本：方法：SHA-HTI 儿童：31名患者（16名接受MD-ITI治疗，15名接受LD-ITI治疗）接受了治疗，随访时间超过24个月（中位数为26.9个月；范围为24.0-29.5个月）。两组具有相似的基线临床特征和相似的成功率（93.8% [MD-ITI] vs 86.7% [LD-ITI]）。与 LD-ITI 相比，MD-ITI 患者的中位成功时间（4.2 个月 vs 10.1 个月）和部分成功时间（2.7 个月 vs 6.6 个月）更短，全部出血（0.38/月 vs 1.40/月）和关节出血（0.11/月 vs 0.83/月）的平均发生率更低。两组之间，虽然 MD-ITI 组的 rFVIII 消耗量更高（12,775 对 7680 IU/kg），但他们成功的总药费相似（3626.49 对 3240.38 美元/kg）：结论：对于 SHA-HTI 儿童，MD-ITI 和 LD-ITI 方案的成功率和成本相似。考虑到 MD-ITI 方案的成功时间更短、出血控制更好且不增加药物成本，经济拮据的地区应优先考虑 MD-ITI 方案。
{"title":"Intermediate-dose immune tolerance induction outperforms with faster success, less bleeding, and no added cost in comparison with low dose: a multicenter randomized clinical trial","authors":"Zhengping Li , Zekun Li , Xiaoling Cheng , Heng Zhang , Can Yang , Qian Xu , Zhenping Chen , Yingzi Zhen , Gang Li , Guoqing Liu , Wanru Yao , Min Zhou , Jiao Jin , Jie Huang , Yongjun Fang , Liangzhi Xie , Man-Chiu Poon , Runhui Wu","doi":"10.1016/j.rpth.2024.102639","DOIUrl":"10.1016/j.rpth.2024.102639","url":null,"abstract":"<div><h3>Background</h3><div>Low-dose (LD) or intermediate-dose (MD) immune tolerance induction (ITI) is effective in children with severe hemophilia A (SHA) with high-titer inhibitors (HTIs) and is attractive in countries with economic constraints. However, high-quality evidence of their use is lacking.</div></div><div><h3>Objectives</h3><div>This was a multicenter randomized clinical trial comparing the efficacy, safety, and medication cost between LD-ITI and MD-ITI for SHA-HTI children.</div></div><div><h3>Methods</h3><div>Children with SHA aged <8 years with historical/pre-ITI inhibitor titer 5 to 200 Bethesda Units/mL in 3 centers were randomized 1:1 to receive LD-ITI (recombinant factor VIII [rFVIII] 50 IU/kg every other day) or MD-ITI (rFVIII 100 IU/kg/d) from January 2022 to June 2024 (ChiCTR2200056603, <span><span>https://www.chictr.org.cn</span><svg><path></path></svg></span>).</div></div><div><h3>Results</h3><div>Thirty-one patients (16 in MD-ITI and 15 in LD-ITI) were enrolled and followed for >24 months (median, 26.9; range, 24.0-29.5 months). The 2 groups had similar baseline clinical characteristics and similar success rates (93.8% [MD-ITI] vs 86.7% [LD-ITI]). Compared with LD-ITI, MD-ITI patients took a shorter median time to success (4.2 months vs 10.1 months) and partial success (2.7 months vs 6.6 months) and had lower mean rates for all bleeding (0.38/mo vs 1.40/mo) and joint bleeding (0.11/mo vs 0.83/mo). Between the 2 groups, although the MD-ITI group had higher rFVIII consumption (12,775 vs 7680 IU/kg), their total medication costs to success were similar (3626.49 vs 3240.38 US$/kg).</div></div><div><h3>Conclusion</h3><div>For SHA-HTI children, the success rate and cost for MD-ITI and LD-ITI regimens were similar. MD-ITI regimen would be a priority for regions with economic constraints, considering the shorter time to success, better bleeding control, and no increase in medication cost.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 1","pages":"Article 102639"},"PeriodicalIF":3.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11732540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142984631","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}
Pub Date : 2025-01-01DOI: 10.1016/j.rpth.2024.102649
Hana Šinkovec , Paul A. Kyrle , Lisbeth Eischer , Paul Gressenberger , Thomas Gary , Marianne Brodmann , Georg Heinze , Sabine Eichinger
Background
The Vienna Prediction Model (VPM) identifies patients with a first unprovoked deep vein thrombosis of the leg and/or pulmonary embolism who have a low recurrence risk and may, therefore, not benefit from extended-phase anticoagulation.
Objectives
The aim of this study was to evaluate patients with a predicted high risk of recurrent venous thromboembolism (VTE).
Methods and Results
We prospectively followed 266 patients in whom the VPM had predicted a recurrence risk of more than 5.5% at 1 year for a median of 13.5 months. Their median age was 56 years, and 96% were men. After the VPM risk assessment, 196 patients restarted anticoagulation. While on anticoagulation, none of the patients experienced recurrent VTE, whereas 4 patients had nonmajor clinically relevant bleeding (absolute bleeding rate, 1.8 [95% CI, 0.5-4.5] events per 100 patient-years). Seventy patients were left untreated after VPM risk assessment for various reasons. Among patients not using anticoagulation, 15 had recurrence (absolute recurrence rate, 18.1 [95% CI, 10.1, 29.9] events per 100 person-years). According to the extended Kaplan–Meier analysis, the probability of VTE recurrence in patients not on anticoagulation was 10.1% and 17.9% at 6 and 12 months after VPM risk assessment, respectively.
Conclusion
Anticoagulant therapy is effective and safe in patients with an unprovoked VTE, in whom the VPM had predicted a high risk of recurrent VTE. If these patients are left untreated, the risk of recurrence is high.
{"title":"Management of patients with venous thromboembolism and a high recurrence risk estimated by the Vienna Prediction Model: a prospective cohort study","authors":"Hana Šinkovec , Paul A. Kyrle , Lisbeth Eischer , Paul Gressenberger , Thomas Gary , Marianne Brodmann , Georg Heinze , Sabine Eichinger","doi":"10.1016/j.rpth.2024.102649","DOIUrl":"10.1016/j.rpth.2024.102649","url":null,"abstract":"<div><h3>Background</h3><div>The Vienna Prediction Model (VPM) identifies patients with a first unprovoked deep vein thrombosis of the leg and/or pulmonary embolism who have a low recurrence risk and may, therefore, not benefit from extended-phase anticoagulation.</div></div><div><h3>Objectives</h3><div>The aim of this study was to evaluate patients with a predicted high risk of recurrent venous thromboembolism (VTE).</div></div><div><h3>Methods and Results</h3><div>We prospectively followed 266 patients in whom the VPM had predicted a recurrence risk of more than 5.5% at 1 year for a median of 13.5 months. Their median age was 56 years, and 96% were men. After the VPM risk assessment, 196 patients restarted anticoagulation. While on anticoagulation, none of the patients experienced recurrent VTE, whereas 4 patients had nonmajor clinically relevant bleeding (absolute bleeding rate, 1.8 [95% CI, 0.5-4.5] events per 100 patient-years). Seventy patients were left untreated after VPM risk assessment for various reasons. Among patients not using anticoagulation, 15 had recurrence (absolute recurrence rate, 18.1 [95% CI, 10.1, 29.9] events per 100 person-years). According to the extended Kaplan–Meier analysis, the probability of VTE recurrence in patients not on anticoagulation was 10.1% and 17.9% at 6 and 12 months after VPM risk assessment, respectively.</div></div><div><h3>Conclusion</h3><div>Anticoagulant therapy is effective and safe in patients with an unprovoked VTE, in whom the VPM had predicted a high risk of recurrent VTE. If these patients are left untreated, the risk of recurrence is high.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 1","pages":"Article 102649"},"PeriodicalIF":3.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742295/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143010680","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}
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