Pub Date : 2024-07-01DOI: 10.1016/j.rpth.2024.102517
Background
Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal complication of hematopoietic stem cell transplantation and is characterized by severe thrombocytopenia, hemolytic anemia, and organ dysfunction. In response to several possible triggers, dynamic multimetric change in von Willebrand factor (VWF) may contribute to inducing microthrombi in circulation in TA-TMA.
Objectives
By performing VWF multimer analysis and measuring VWF-degradation product (DP), we unraveled the relationship between multimeric changes in circulating VWF and the pathogenesis of TA-TMA.
Methods
This study analyzed 135 plasma samples from 14 patients who underwent allogeneic hematopoietic stem cell transplantation at a single institute. VWF-associated markers, namely VWF:antigen (VWF:Ag), VWF-DP/VWF:Ag ratio, VWF:ristocetin cofactor activity, VWF:ristocetin cofactor activity/VWF:Ag ratio, and ADAMTS13 activity, were analyzed in these samples collected every 7 days.
Results
There were 2 patients with definite thrombotic microangiopathy (TMA) and 6 patients who presented with probable TMA that did not progress to definite TMA. Each plasma sample was classified into 3 groups: definite TMA, probable TMA, and non-TMA. VWF multimer analysis showed the absence of high-molecular-weight VWF multimers in probable TMA, whereas the appearance of unusually large VWF multimers was observed in definite TMA. The median value of the VWF-DP/VWF:Ag ratio in probable TMA was elevated to 4.17, suggesting that excessive cleavage of VWF multimers by VWF cleaving enzyme, ADAMTS13, resulted in the loss of high-molecular-weight VWF multimers.
Conclusion
During the transition from probable to definite TMA, drastic VWF multimer changes imply a switch from bleeding to thrombotic tendencies. Extensive VWF-DP and VWF multimer analyses provided novel insights.
{"title":"Excessive cleavage of von Willebrand factor multimers by ADAMTS13 may predict the progression of transplant-associated thrombotic microangiopathy","authors":"","doi":"10.1016/j.rpth.2024.102517","DOIUrl":"10.1016/j.rpth.2024.102517","url":null,"abstract":"<div><h3>Background</h3><p>Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal complication of hematopoietic stem cell transplantation and is characterized by severe thrombocytopenia, hemolytic anemia, and organ dysfunction. In response to several possible triggers, dynamic multimetric change in von Willebrand factor (VWF) may contribute to inducing microthrombi in circulation in TA-TMA.</p></div><div><h3>Objectives</h3><p>By performing VWF multimer analysis and measuring VWF-degradation product (DP), we unraveled the relationship between multimeric changes in circulating VWF and the pathogenesis of TA-TMA.</p></div><div><h3>Methods</h3><p>This study analyzed 135 plasma samples from 14 patients who underwent allogeneic hematopoietic stem cell transplantation at a single institute. VWF-associated markers, namely VWF:antigen (VWF:Ag), VWF-DP/VWF:Ag ratio, VWF:ristocetin cofactor activity, VWF:ristocetin cofactor activity/VWF:Ag ratio, and ADAMTS13 activity, were analyzed in these samples collected every 7 days.</p></div><div><h3>Results</h3><p>There were 2 patients with definite thrombotic microangiopathy (TMA) and 6 patients who presented with probable TMA that did not progress to definite TMA. Each plasma sample was classified into 3 groups: definite TMA, probable TMA, and non-TMA. VWF multimer analysis showed the absence of high-molecular-weight VWF multimers in probable TMA, whereas the appearance of unusually large VWF multimers was observed in definite TMA. The median value of the VWF-DP/VWF:Ag ratio in probable TMA was elevated to 4.17, suggesting that excessive cleavage of VWF multimers by VWF cleaving enzyme, ADAMTS13, resulted in the loss of high-molecular-weight VWF multimers.</p></div><div><h3>Conclusion</h3><p>During the transition from probable to definite TMA, drastic VWF multimer changes imply a switch from bleeding to thrombotic tendencies. Extensive VWF-DP and VWF multimer analyses provided novel insights.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924002127/pdfft?md5=c0f7431e9d869991dfd0adb36b8e95f0&pid=1-s2.0-S2475037924002127-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141851658","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 : 2024-07-01DOI: 10.1016/j.rpth.2024.102501
Background
The role of anticoagulation in ovarian vein thrombosis (OVT) is uncertain.
Objectives
We aimed to evaluate safety and efficacy of anticoagulant treatment in OVT patients.
Methods
A systematic search was conducted in MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases up to April 2024. Eligible studies included randomized controlled trials and observational studies enrolling at least 10 adult patients with objectively diagnosed OVT and treated with any anticoagulants. The protocol was prospectively registered in the International Prospective Register of Systematic Reviews (CRD42021270883).
Results
We included 17 observational studies (621 anticoagulated and 376 nonanticoagulated OVT patients); 9 studies enrolled mainly pregnancy/puerperium-related OVT. Most patients received heparins alone (45.7%) or proceeded to vitamin K antagonists (39.2%). The average treatment duration was ≤3 months in 8 studies (47.1%), >3 to ≤6 months in 6 studies (35.3%), and >6 months in 3 studies (17.6%). In treated patients, mortality rate was 2.43% (95% CI, 0.54%-5.41%; I2 = 53.8%; 12/406 patients; 13 studies), major bleeding was 1.27% (95% CI, 0.48%-2.38%; I2 = 2.5%; 7/583 patients; 15 studies), recurrent venous thromboembolism (VTE) was 3.49% (95% CI, 1.12%-6.95%; I2 = 63.5%; 22/482 patients; 15 studies), and vessel recanalization was 89.4% (95% CI, 74.6%-98.6%; I2 = 80.6%; 163/184 patients; 8 studies). The rate of recurrent VTE in untreated patients was 8.65% (95% CI, 2.61%-17.35%); however, the difference compared with treated patients was not statistically significant (risk ratio, 0.70; 95% CI, 0.36-1.37). At subgroup analyses, the rates of major bleeding and recurrent VTE were 0.80% (95% CI, 0.0-2%.17%) and 3.81% (95% CI, 0.42%-9.63%) in pregnancy/puerperium-related OVT, respectively, and 1.12% (95% CI, 0.32%-2.34%) and 1.78% (95% CI, 0.62%-3.46%), respectively, when analyzing only full-text studies.
Conclusion
There is paucity of literature regarding OVT. Our results suggest that anticoagulation is associated with low rates of major bleeding and recurrent VTE.
{"title":"Safety and efficacy of anticoagulant treatment in patients with ovarian vein thrombosis: a systematic review and meta-analysis of observational studies","authors":"","doi":"10.1016/j.rpth.2024.102501","DOIUrl":"10.1016/j.rpth.2024.102501","url":null,"abstract":"<div><h3>Background</h3><p>The role of anticoagulation in ovarian vein thrombosis (OVT) is uncertain.</p></div><div><h3>Objectives</h3><p>We aimed to evaluate safety and efficacy of anticoagulant treatment in OVT patients.</p></div><div><h3>Methods</h3><p>A systematic search was conducted in MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases up to April 2024. Eligible studies included randomized controlled trials and observational studies enrolling at least 10 adult patients with objectively diagnosed OVT and treated with any anticoagulants. The protocol was prospectively registered in the International Prospective Register of Systematic Reviews (CRD42021270883).</p></div><div><h3>Results</h3><p>We included 17 observational studies (621 anticoagulated and 376 nonanticoagulated OVT patients); 9 studies enrolled mainly pregnancy/puerperium-related OVT. Most patients received heparins alone (45.7%) or proceeded to vitamin K antagonists (39.2%). The average treatment duration was ≤3 months in 8 studies (47.1%), >3 to ≤6 months in 6 studies (35.3%), and >6 months in 3 studies (17.6%). In treated patients, mortality rate was 2.43% (95% CI, 0.54%-5.41%; I<sup>2</sup> = 53.8%; 12/406 patients; 13 studies), major bleeding was 1.27% (95% CI, 0.48%-2.38%; I<sup>2</sup> = 2.5%; 7/583 patients; 15 studies), recurrent venous thromboembolism (VTE) was 3.49% (95% CI, 1.12%-6.95%; I<sup>2</sup> = 63.5%; 22/482 patients; 15 studies), and vessel recanalization was 89.4% (95% CI, 74.6%-98.6%; I<sup>2</sup> = 80.6%; 163/184 patients; 8 studies). The rate of recurrent VTE in untreated patients was 8.65% (95% CI, 2.61%-17.35%); however, the difference compared with treated patients was not statistically significant (risk ratio, 0.70; 95% CI, 0.36-1.37). At subgroup analyses, the rates of major bleeding and recurrent VTE were 0.80% (95% CI, 0.0-2%.17%) and 3.81% (95% CI, 0.42%-9.63%) in pregnancy/puerperium-related OVT, respectively, and 1.12% (95% CI, 0.32%-2.34%) and 1.78% (95% CI, 0.62%-3.46%), respectively, when analyzing only full-text studies.</p></div><div><h3>Conclusion</h3><p>There is paucity of literature regarding OVT. Our results suggest that anticoagulation is associated with low rates of major bleeding and recurrent VTE.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924001961/pdfft?md5=0560109527ebf9f8f11ce5cbccbdb570&pid=1-s2.0-S2475037924001961-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141697913","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 : 2024-07-01DOI: 10.1016/j.rpth.2024.102509
Background
Previous research on the association between serum albumin (ALB) and venous thromboembolism (VTE) has produced inconclusive results. The polygenic risk score is constructed from a set of independent risk variants associated with a disorder, enabling the identification of a larger fraction of the population at comparable or greater disease risk. It is still unknown whether ALB and genetic factors jointly contribute to the incidence of VTE.
Objectives
The present study aimed to explore ALB, genetic susceptibility, and the risk of VTE.
Methods
The present investigation was an analysis of prospectively collected data from UK Biobank, a population-based, longitudinal cohort. Cox proportional models were used to calculate hazard ratios and 95% CIs for VTE. The Kaplan–Meier curve was utilized to visualize the cumulative risk of VTE according to different serum ALB levels, and the restricted cubic spline model was leveraged to explore the exposure–response relationship among ALB levels and VTE risk.
Results
During median follow-up of 13.5 years, 11,502 cases with VTE were diagnosed among 417,113 participants in the UK Biobank. The lower ALB levels were associated with a higher risk for VTE. Individuals with both a high genetic risk and lowest ALB level had the highest risk of VTE (hazard ratio, 3.89; 95% CI, 3.41-4.43), compared with those with low genetic risk and highest ALB level. The positive joint effects of low ALB and polygenic risk score increased the risk of VTE in individuals with high genetic risk. This study excluded non-European patients and primarily focused on the European population, which may limit the generalizability of the findings.
Conclusion
Low serum ALB levels were linked to an increased risk of VTE, which was in accordance with a linear dose–response relationship. There was a positive additive effect of ALB and genetic susceptibility on the risk of VTE. ALB could serve as a biomarker for predicting the risk of VTE.
{"title":"Serum albumin, genetic susceptibility, and risk of venous thromboembolism","authors":"","doi":"10.1016/j.rpth.2024.102509","DOIUrl":"10.1016/j.rpth.2024.102509","url":null,"abstract":"<div><h3>Background</h3><p>Previous research on the association between serum albumin (ALB) and venous thromboembolism (VTE) has produced inconclusive results. The polygenic risk score is constructed from a set of independent risk variants associated with a disorder, enabling the identification of a larger fraction of the population at comparable or greater disease risk. It is still unknown whether ALB and genetic factors jointly contribute to the incidence of VTE.</p></div><div><h3>Objectives</h3><p>The present study aimed to explore ALB, genetic susceptibility, and the risk of VTE.</p></div><div><h3>Methods</h3><p>The present investigation was an analysis of prospectively collected data from UK Biobank, a population-based, longitudinal cohort. Cox proportional models were used to calculate hazard ratios and 95% CIs for VTE. The Kaplan–Meier curve was utilized to visualize the cumulative risk of VTE according to different serum ALB levels, and the restricted cubic spline model was leveraged to explore the exposure–response relationship among ALB levels and VTE risk.</p></div><div><h3>Results</h3><p>During median follow-up of 13.5 years, 11,502 cases with VTE were diagnosed among 417,113 participants in the UK Biobank. The lower ALB levels were associated with a higher risk for VTE. Individuals with both a high genetic risk and lowest ALB level had the highest risk of VTE (hazard ratio, 3.89; 95% CI, 3.41-4.43), compared with those with low genetic risk and highest ALB level. The positive joint effects of low ALB and polygenic risk score increased the risk of VTE in individuals with high genetic risk. This study excluded non-European patients and primarily focused on the European population, which may limit the generalizability of the findings.</p></div><div><h3>Conclusion</h3><p>Low serum ALB levels were linked to an increased risk of VTE, which was in accordance with a linear dose–response relationship. There was a positive additive effect of ALB and genetic susceptibility on the risk of VTE. ALB could serve as a biomarker for predicting the risk of VTE.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924002048/pdfft?md5=50a667e25a74a3677a25b2400dcdffc8&pid=1-s2.0-S2475037924002048-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141713558","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 : 2024-05-01DOI: 10.1016/j.rpth.2024.102500
{"title":"Starving in the land of plenty: the challenge of studying menstruation in anticoagulated patients","authors":"","doi":"10.1016/j.rpth.2024.102500","DOIUrl":"10.1016/j.rpth.2024.102500","url":null,"abstract":"","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S247503792400195X/pdfft?md5=759e2cf6a4d47f7f1b418d5178dd827e&pid=1-s2.0-S247503792400195X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141638263","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 : 2024-05-01DOI: 10.1016/j.rpth.2024.102436
Daniel Gonçalves Chaves , Brendon Ayala da Silva Santos , Luciana Werneck Zucherato , Maíse Moreira Dias , Claudia Santos Lorenzato , Andrea Gonçalves de Oliveira , Mônica Hermida Cerqueira , Rosângela de Albuquerque Ribeiro , Leina Yukari Etto , Vivian Karla Brognoli Franco , Maria do Rosário Ferraz Roberti , Fábia Michelle Rodrigues de Araújo Callado , Maria Aline Ferreira de Cerqueira , Ieda Pinto , Ricardo Mesquita Camelo , Suely Meireles Rezende
Background
Immune tolerance induction (ITI) is the treatment of choice to eradicate neutralizing anti–factor (F)VIII alloantibodies (inhibitors) in people with inherited hemophilia A. However, it is not successful in 10% to 40% of the cases. The biological mechanisms and biomarkers associated with ITI outcome are largely unknown.
Objectives
The aim of this study was to investigate the association of plasma cytokines (interferon-γ, tumor necrosis factor, interleukin [IL]-2, IL-4, IL-5, IL-6, IL-10, and IL-17A), chemokines (IL-8/CXCL8, RANTES/CCL5, MIG/CXCL9, MCP-1/CCL2, and IP-10/CXCL10), and anti-FVIII immunoglobulin (Ig) G total, IgG1, and IgG4 with ITI outcome.
Methods
In this cross-sectional analysis of the Brazilian Immune Tolerance Study, we assessed plasma levels of anti-FVIII IgGs using an enzyme-linked immunosorbent assay with plasma-derived FVIII and recombinant FVIII as target antigens, immobilized in microplates.
Results
We assayed 98 plasma samples of moderately severe and severe (FVIII activity, <2%) people with hemophilia A after completion of a first ITI course. Levels of anti–recombinant FVIII IgG total and IgG4 were higher in people with hemophilia A who failed ITI (IgG total optical density [OD], 0.37; IQR, 0.15-0.73; IgG4 OD, 2.19; IQR, 0.80-2.52) than in those who had partial (IgG total OD, 0.03; IQR, 0.00-0.14; IgG4 OD, 0.39; IQR, 0.09-1.11; P < .0001 for both) or complete success (IgG total OD, 0.04; IQR, 0.00-0.07; IgG4 OD, 0.07; IQR, 0.06-0.40; P < .0001 for both). Plasma cytokines, chemokines, and anti-FVIII IgG1 were not associated with ITI outcome.
Conclusion
Our results show that high levels of plasma anti-FVIII IgG4 and IgG total are associated with ITI failure.
{"title":"High levels of anti–factor VIII immunoglobulin G4 and immunoglobulin G total are associated with immune tolerance induction failure in people with congenital hemophilia A and high-responding inhibitors","authors":"Daniel Gonçalves Chaves , Brendon Ayala da Silva Santos , Luciana Werneck Zucherato , Maíse Moreira Dias , Claudia Santos Lorenzato , Andrea Gonçalves de Oliveira , Mônica Hermida Cerqueira , Rosângela de Albuquerque Ribeiro , Leina Yukari Etto , Vivian Karla Brognoli Franco , Maria do Rosário Ferraz Roberti , Fábia Michelle Rodrigues de Araújo Callado , Maria Aline Ferreira de Cerqueira , Ieda Pinto , Ricardo Mesquita Camelo , Suely Meireles Rezende","doi":"10.1016/j.rpth.2024.102436","DOIUrl":"10.1016/j.rpth.2024.102436","url":null,"abstract":"<div><h3>Background</h3><p>Immune tolerance induction (ITI) is the treatment of choice to eradicate neutralizing anti–factor (F)VIII alloantibodies (inhibitors) in people with inherited hemophilia A. However, it is not successful in 10% to 40% of the cases. The biological mechanisms and biomarkers associated with ITI outcome are largely unknown.</p></div><div><h3>Objectives</h3><p>The aim of this study was to investigate the association of plasma cytokines (interferon-γ, tumor necrosis factor, interleukin [IL]-2, IL-4, IL-5, IL-6, IL-10, and IL-17A), chemokines (IL-8/CXCL8, RANTES/CCL5, MIG/CXCL9, MCP-1/CCL2, and IP-10/CXCL10), and anti-FVIII immunoglobulin (Ig) G total, IgG1, and IgG4 with ITI outcome.</p></div><div><h3>Methods</h3><p>In this cross-sectional analysis of the Brazilian Immune Tolerance Study, we assessed plasma levels of anti-FVIII IgGs using an enzyme-linked immunosorbent assay with plasma-derived FVIII and recombinant FVIII as target antigens, immobilized in microplates.</p></div><div><h3>Results</h3><p>We assayed 98 plasma samples of moderately severe and severe (FVIII activity, <2%) people with hemophilia A after completion of a first ITI course. Levels of anti–recombinant FVIII IgG total and IgG4 were higher in people with hemophilia A who failed ITI (IgG total optical density [OD], 0.37; IQR, 0.15-0.73; IgG4 OD, 2.19; IQR, 0.80-2.52) than in those who had partial (IgG total OD, 0.03; IQR, 0.00-0.14; IgG4 OD, 0.39; IQR, 0.09-1.11; <em>P</em> < .0001 for both) or complete success (IgG total OD, 0.04; IQR, 0.00-0.07; IgG4 OD, 0.07; IQR, 0.06-0.40; <em>P</em> < .0001 for both). Plasma cytokines, chemokines, and anti-FVIII IgG1 were not associated with ITI outcome.</p></div><div><h3>Conclusion</h3><p>Our results show that high levels of plasma anti-FVIII IgG4 and IgG total are associated with ITI failure.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924001250/pdfft?md5=6ccc54497bda662fb96e9b7d07eeb275&pid=1-s2.0-S2475037924001250-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141040972","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 : 2024-05-01DOI: 10.1016/j.rpth.2024.102416
Richard J. Kelly , Hisakazu Nishimori , Regina Horneff , Peter Hillmen , Mohammed Al-Adhami , Stacie Lallier , Gloria F. Gerber
Background
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disease characterized by complement-mediated hemolysis and thrombosis. Complement component 5 (C5) inhibitors have decreased PNH-related thrombosis rates and reduced mortality compared with those of age-matched controls. A small but significantly increased risk of life-threatening Neisseria infections, especially N meningitidis, represents a long-term safety risk of complement inhibition.
Objectives
To evaluate the rates of thrombosis and meningococcal infections in patients with PNH treated with the complement component 3–targeted therapy pegcetacoplan.
Methods
Cumulative patient-year exposure to pegcetacoplan was calculated, and thrombotic events and meningococcal infections were reviewed in 7 clinical trials and in the postmarketing setting. The clinical trial protocols and pegcetacoplan labeling required vaccination against Streptococcus pneumoniae, N meningitidis, and Haemophilus influenzae before pegcetacoplan use; the label allowed for prophylactic antibiotic use if pegcetacoplan must be administered before vaccination.
Results
As of November 13, 2022, 464 patients with PNH had 619.4 patient-years of pegcetacoplan exposure in completed/ongoing clinical trials and the postmarketing setting. Seven thrombotic events were reported: 5 in clinical trials (2 in the same patient) and 2 in the postmarketing setting. The overall thrombosis rate was 1.13 events per 100 patient-years (clinical trials: 1.22 events/100 patient-years in 409.4 years; postmarketing: 0.95 events/100 patient-years in 210.0 years). No infections with meningococcal bacteria were reported.
Conclusion
Event rates for thrombosis were comparable between pegcetacoplan and previously reported rates of C5 inhibitors in patients with PNH, and no cases of meningococcal infection were reported with pegcetacoplan. Continued follow-up is required.
{"title":"Thrombosis and meningococcal infection rates in pegcetacoplan-treated patients with paroxysmal nocturnal hemoglobinuria in the clinical trial and postmarketing settings","authors":"Richard J. Kelly , Hisakazu Nishimori , Regina Horneff , Peter Hillmen , Mohammed Al-Adhami , Stacie Lallier , Gloria F. Gerber","doi":"10.1016/j.rpth.2024.102416","DOIUrl":"10.1016/j.rpth.2024.102416","url":null,"abstract":"<div><h3>Background</h3><p>Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disease characterized by complement-mediated hemolysis and thrombosis. Complement component 5 (C5) inhibitors have decreased PNH-related thrombosis rates and reduced mortality compared with those of age-matched controls. A small but significantly increased risk of life-threatening <em>Neisseria</em> infections, especially <em>N meningitidis</em>, represents a long-term safety risk of complement inhibition.</p></div><div><h3>Objectives</h3><p>To evaluate the rates of thrombosis and meningococcal infections in patients with PNH treated with the complement component 3–targeted therapy pegcetacoplan.</p></div><div><h3>Methods</h3><p>Cumulative patient-year exposure to pegcetacoplan was calculated, and thrombotic events and meningococcal infections were reviewed in 7 clinical trials and in the postmarketing setting. The clinical trial protocols and pegcetacoplan labeling required vaccination against <em>Streptococcus pneumoniae</em>, <em>N meningitidis</em>, and <em>Haemophilus influenzae</em> before pegcetacoplan use; the label allowed for prophylactic antibiotic use if pegcetacoplan must be administered before vaccination.</p></div><div><h3>Results</h3><p>As of November 13, 2022, 464 patients with PNH had 619.4 patient-years of pegcetacoplan exposure in completed/ongoing clinical trials and the postmarketing setting. Seven thrombotic events were reported: 5 in clinical trials (2 in the same patient) and 2 in the postmarketing setting. The overall thrombosis rate was 1.13 events per 100 patient-years (clinical trials: 1.22 events/100 patient-years in 409.4 years; postmarketing: 0.95 events/100 patient-years in 210.0 years). No infections with meningococcal bacteria were reported.</p></div><div><h3>Conclusion</h3><p>Event rates for thrombosis were comparable between pegcetacoplan and previously reported rates of C5 inhibitors in patients with PNH, and no cases of meningococcal infection were reported with pegcetacoplan. Continued follow-up is required.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924001055/pdfft?md5=6030424480b28682a2199a03feeac463&pid=1-s2.0-S2475037924001055-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140773949","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 : 2024-05-01DOI: 10.1016/j.rpth.2024.102415
Guy Young , Steven W. Pipe , Gili Kenet , Johannes Oldenburg , Mariam Safavi , Tuende Czirok , Francis Nissen , Johnny Mahlangu
Background
With the treatment landscape continually evolving, it is vital that the hemophilia community have an overview of all published data for approved therapies, such as emicizumab, to support shared decision making.
Objectives
To bring together the clinical and real-world data for emicizumab use in people with congenital hemophilia A, regardless of age, disease severity, or factor VIII inhibitor status. Key focus areas were safety, efficacy, and quality of life (QoL).
Methods
This scoping review used citation databases (PubMed, Embase, and the Cochrane Library) and manual searches of abstract books. Publications reporting original data for emicizumab in people with hemophilia A, published in English after December 2014, and reporting select endpoints were included. This narrative synthesis focused on zero bleeds, treated annualized bleeding rate (ABR), adverse events, and QoL measures.
Results
Overall, 97 publications were included (cut-off: August 9, 2022). Treated ABR remained low (calculated mean and median treated ABRs ranged between 0.7-1.3 and 0.0-1.4, respectively), and the median percentage of people with zero treated bleeds was 66.7%. The proportion of people experiencing treatment-related adverse events ranged from 0.0% to 60.0%; most were injection-site reactions. Across 37 publications reporting on safety and enrolling >2300 individuals, 11 thrombotic events and 4 thrombotic microangiopathies were reported. Data from well-established tools show QoL benefits with emicizumab.
Conclusion
This scoping review consolidates the global published experience for emicizumab in people with hemophilia A and supports the fact that emicizumab has an acceptable safety profile, is effective and efficacious in bleed prevention, and is associated with improvements in QoL.
{"title":"Emicizumab is well tolerated and effective in people with congenital hemophilia A regardless of age, severity of disease, or inhibitor status: a scoping review","authors":"Guy Young , Steven W. Pipe , Gili Kenet , Johannes Oldenburg , Mariam Safavi , Tuende Czirok , Francis Nissen , Johnny Mahlangu","doi":"10.1016/j.rpth.2024.102415","DOIUrl":"10.1016/j.rpth.2024.102415","url":null,"abstract":"<div><h3>Background</h3><p>With the treatment landscape continually evolving, it is vital that the hemophilia community have an overview of all published data for approved therapies, such as emicizumab, to support shared decision making.</p></div><div><h3>Objectives</h3><p>To bring together the clinical and real-world data for emicizumab use in people with congenital hemophilia A, regardless of age, disease severity, or factor VIII inhibitor status. Key focus areas were safety, efficacy, and quality of life (QoL).</p></div><div><h3>Methods</h3><p>This scoping review used citation databases (PubMed, Embase, and the Cochrane Library) and manual searches of abstract books. Publications reporting original data for emicizumab in people with hemophilia A, published in English after December 2014, and reporting select endpoints were included. This narrative synthesis focused on zero bleeds, treated annualized bleeding rate (ABR), adverse events, and QoL measures.</p></div><div><h3>Results</h3><p>Overall, 97 publications were included (cut-off: August 9, 2022). Treated ABR remained low (calculated mean and median treated ABRs ranged between 0.7-1.3 and 0.0-1.4, respectively), and the median percentage of people with zero treated bleeds was 66.7%. The proportion of people experiencing treatment-related adverse events ranged from 0.0% to 60.0%; most were injection-site reactions. Across 37 publications reporting on safety and enrolling >2300 individuals, 11 thrombotic events and 4 thrombotic microangiopathies were reported. Data from well-established tools show QoL benefits with emicizumab.</p></div><div><h3>Conclusion</h3><p>This scoping review consolidates the global published experience for emicizumab in people with hemophilia A and supports the fact that emicizumab has an acceptable safety profile, is effective and efficacious in bleed prevention, and is associated with improvements in QoL.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924001043/pdfft?md5=262a387e07a7b4b6c675ace3b7e09dd2&pid=1-s2.0-S2475037924001043-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140775476","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 : 2024-05-01DOI: 10.1016/j.rpth.2024.102440
Jeffrey A. Lowell , Garvita Sharma , Keith Sultan
{"title":"Earlier onset of acute venous thromboembolism with upadacitinib compared with tofacitinib during Janus kinase inhibitor therapy","authors":"Jeffrey A. Lowell , Garvita Sharma , Keith Sultan","doi":"10.1016/j.rpth.2024.102440","DOIUrl":"10.1016/j.rpth.2024.102440","url":null,"abstract":"","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924001298/pdfft?md5=2215366a9acc1d9a55b8019e8319c9de&pid=1-s2.0-S2475037924001298-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141054517","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 : 2024-05-01DOI: 10.1016/j.rpth.2024.102435
Wei Du , Lin Mei
Background
Paroxysmal nocturnal hemoglobinuria (PNH), a rare hematologic disease, is associated with high maternal and fetal mortality rates. Only 1 medication approved for PNH, the complement component 5 inhibitor eculizumab, has published evidence of use during pregnancy.
Key Clinical Question
What were the circumstances and outcomes of the first use of pegcetacoplan, a complement component 3 inhibitor, by a pregnant woman with PNH?
Clinical Approach
The patient, with a history of 2 miscarriages and a suboptimal response to eculizumab, had hematologic improvement after switching to pegcetacoplan. She continued pegcetacoplan throughout her pregnancy. At gestational week 30, she developed abruptio placentae and breakthrough hemolysis. She delivered a normal-appearing male infant via emergency cesarean section. The breakthrough hemolysis resolved quickly with short-term intensive pegcetacoplan dosing and add-on eculizumab. To date, her laboratory values remain normal, and she has had no thromboembolic events; her son has not demonstrated growth defects.
Conclusion
This is the first report of pegcetacoplan treatment for PNH throughout pregnancy. The mother recovered promptly from breakthrough hemolysis that prompted an emergency delivery. Her son, who was born prematurely but healthy, has developed normally.
{"title":"A case report of pegcetacoplan use for a pregnant woman with paroxysmal nocturnal hemoglobinuria","authors":"Wei Du , Lin Mei","doi":"10.1016/j.rpth.2024.102435","DOIUrl":"10.1016/j.rpth.2024.102435","url":null,"abstract":"<div><h3>Background</h3><p>Paroxysmal nocturnal hemoglobinuria (PNH), a rare hematologic disease, is associated with high maternal and fetal mortality rates. Only 1 medication approved for PNH, the complement component 5 inhibitor eculizumab, has published evidence of use during pregnancy.</p></div><div><h3>Key Clinical Question</h3><p>What were the circumstances and outcomes of the first use of pegcetacoplan, a complement component 3 inhibitor, by a pregnant woman with PNH?</p></div><div><h3>Clinical Approach</h3><p>The patient, with a history of 2 miscarriages and a suboptimal response to eculizumab, had hematologic improvement after switching to pegcetacoplan. She continued pegcetacoplan throughout her pregnancy. At gestational week 30, she developed abruptio placentae and breakthrough hemolysis. She delivered a normal-appearing male infant via emergency cesarean section. The breakthrough hemolysis resolved quickly with short-term intensive pegcetacoplan dosing and add-on eculizumab. To date, her laboratory values remain normal, and she has had no thromboembolic events; her son has not demonstrated growth defects.</p></div><div><h3>Conclusion</h3><p>This is the first report of pegcetacoplan treatment for PNH throughout pregnancy. The mother recovered promptly from breakthrough hemolysis that prompted an emergency delivery. Her son, who was born prematurely but healthy, has developed normally.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924001249/pdfft?md5=be1b26017c2da734838174cfc754c573&pid=1-s2.0-S2475037924001249-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141031191","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 : 2024-05-01DOI: 10.1016/j.rpth.2024.102459
Tanya T. Marar , Michael B. Boffa
Background
Thrombin-activatable fibrinolysis inhibitor (TAFI) is a plasma zymogen that provides a molecular link between coagulation and fibrinolysis. Studies have shown that the presence of glycosaminoglycans accelerates TAFI activation by plasmin and stabilizes activated TAFI (TAFIa).
Objectives
We aimed to define the elements of TAFI structure that allow these effects.
Methods
Based on crystallographic studies and homology to heparin-binding proteins, we performed mutagenesis of surface-exposed charged residues on TAFI that putatively constitute heparin-binding sites. We determined heparin binding, kinetics of activation by plasmin in the presence or absence of heparin, thermal stability, and antifibrinolytic potential of each variant.
Results
Mutagenesis of Lys211 and Lys212 did not impair heparin binding but affected the ability of TAFI to be activated by plasmin. Mutagenesis of Lys306 and His308 did not impair heparin binding, but mutation of His308 had a severe negative effect on TAFI/TAFIa function. Mutation of Arg320 and Lys324 in combination markedly decreased heparin binding but had no effect on heparin-mediated acceleration of TAFI activation by plasmin while somewhat decreasing TAFIa stabilization by heparin. Mutagenesis of Lys327 and Arg330 decreased (but did not eliminate) heparin binding while decreasing the ability of heparin to accelerate plasmin-mediated TAFI activation, stabilize TAFIa, and increase the antifibrinolytic ability of TAFIa. A quadruple mutant of Arg320, Lys324, Lys327, and Arg330 completely lost heparin-binding ability and stabilization of the enzyme by heparin.
Conclusion
Basic residues in the dynamic flap of TAFIa define a functionally relevant heparin-binding site, but additional heparin-binding sites may be present on TAFI.
{"title":"Identification of heparin interaction sites on thrombin-activatable fibrinolysis inhibitor that modulate plasmin-mediated activation, thermal stability, and antifibrinolytic potential","authors":"Tanya T. Marar , Michael B. Boffa","doi":"10.1016/j.rpth.2024.102459","DOIUrl":"https://doi.org/10.1016/j.rpth.2024.102459","url":null,"abstract":"<div><h3>Background</h3><p>Thrombin-activatable fibrinolysis inhibitor (TAFI) is a plasma zymogen that provides a molecular link between coagulation and fibrinolysis. Studies have shown that the presence of glycosaminoglycans accelerates TAFI activation by plasmin and stabilizes activated TAFI (TAFIa).</p></div><div><h3>Objectives</h3><p>We aimed to define the elements of TAFI structure that allow these effects.</p></div><div><h3>Methods</h3><p>Based on crystallographic studies and homology to heparin-binding proteins, we performed mutagenesis of surface-exposed charged residues on TAFI that putatively constitute heparin-binding sites. We determined heparin binding, kinetics of activation by plasmin in the presence or absence of heparin, thermal stability, and antifibrinolytic potential of each variant.</p></div><div><h3>Results</h3><p>Mutagenesis of Lys211 and Lys212 did not impair heparin binding but affected the ability of TAFI to be activated by plasmin. Mutagenesis of Lys306 and His308 did not impair heparin binding, but mutation of His308 had a severe negative effect on TAFI/TAFIa function. Mutation of Arg320 and Lys324 in combination markedly decreased heparin binding but had no effect on heparin-mediated acceleration of TAFI activation by plasmin while somewhat decreasing TAFIa stabilization by heparin. Mutagenesis of Lys327 and Arg330 decreased (but did not eliminate) heparin binding while decreasing the ability of heparin to accelerate plasmin-mediated TAFI activation, stabilize TAFIa, and increase the antifibrinolytic ability of TAFIa. A quadruple mutant of Arg320, Lys324, Lys327, and Arg330 completely lost heparin-binding ability and stabilization of the enzyme by heparin.</p></div><div><h3>Conclusion</h3><p>Basic residues in the dynamic flap of TAFIa define a functionally relevant heparin-binding site, but additional heparin-binding sites may be present on TAFI.</p></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2475037924001481/pdfft?md5=05263e211803d4bcd013c4ab5e949f7e&pid=1-s2.0-S2475037924001481-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141433875","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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