Pub Date : 2024-10-28DOI: 10.1016/j.jtha.2024.10.017
Elizabeth S York, Benjamin D Dratch, Jasmine Ito, Samantha M Horwitz, Sahand Emamian, Joseph A Ambarian, Surinder Gill, Jayre Jones, Satheesh Chonat, Pete Lollar, Shannon L Meeks, Katherine M Davis, Glaivy Batsuli
Background: The most significant treatment complication for patients with hemophilia A is the development of neutralizing immunoglobin G (IgG), termed inhibitors, against factor VIII (FVIII) which prevent FVIII replacement therapy. Low titers of FVIII-specific immunoglobin M (IgM) have been identified in hemophilia A patients with and without inhibitors, as well as healthy individuals. However, the duration and influence of IgM on the immune response to FVIII remains unclear.
Objective: To characterize the binding interactions of persistently secreted FVIII-specific IgM in hemophilia A mice and assess their effect on IgG antibody development.
Methods: Splenic-derived monoclonal antibodies (MAbs) from immunized FVIII knockout mice were isolated and purified using hybridoma technology. Binding interactions were assessed utilizing a novel fluid-phase ELISA and computational modeling with HADDOCK to account for weak IgM binding.
Results: Sixteen porcine cross-reactive and non-inhibitory FVIII-specific IgM MAbs were identified. RNA sequencing of FVIII-specific IgM revealed 13 unique VDJ/VJ sequences indicating derivation from 13 unique B cell clones. IgM demonstrated polyclonal and polyreactive binding to FVIII in vitro and in silico. Molecular docking studies with reconstructed IgM VDJ/VJ regions identified frequent IgM interactions with amino acid residues K376, T381, K437, R2215 or K2249 within the FVIII A2 and C2 domains. Injections of individual IgM prior to FVIII exposure and co-injection of FVIII/IgM immune complexes did not affect de novo FVIII antibody production.
Conclusion: Persistent FVIII-specific IgM are polyclonal but preferentially bind the A2 and C2 domains and FVIII/IgM immune complex formation do not significantly alter inhibitor development.
{"title":"Persistent Splenic-Derived IgM Preferentially Recognize Factor VIIIA2 and C2 Domain Epitopes but Do Not Alter Antibody Production.","authors":"Elizabeth S York, Benjamin D Dratch, Jasmine Ito, Samantha M Horwitz, Sahand Emamian, Joseph A Ambarian, Surinder Gill, Jayre Jones, Satheesh Chonat, Pete Lollar, Shannon L Meeks, Katherine M Davis, Glaivy Batsuli","doi":"10.1016/j.jtha.2024.10.017","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.10.017","url":null,"abstract":"<p><strong>Background: </strong>The most significant treatment complication for patients with hemophilia A is the development of neutralizing immunoglobin G (IgG), termed inhibitors, against factor VIII (FVIII) which prevent FVIII replacement therapy. Low titers of FVIII-specific immunoglobin M (IgM) have been identified in hemophilia A patients with and without inhibitors, as well as healthy individuals. However, the duration and influence of IgM on the immune response to FVIII remains unclear.</p><p><strong>Objective: </strong>To characterize the binding interactions of persistently secreted FVIII-specific IgM in hemophilia A mice and assess their effect on IgG antibody development.</p><p><strong>Methods: </strong>Splenic-derived monoclonal antibodies (MAbs) from immunized FVIII knockout mice were isolated and purified using hybridoma technology. Binding interactions were assessed utilizing a novel fluid-phase ELISA and computational modeling with HADDOCK to account for weak IgM binding.</p><p><strong>Results: </strong>Sixteen porcine cross-reactive and non-inhibitory FVIII-specific IgM MAbs were identified. RNA sequencing of FVIII-specific IgM revealed 13 unique VDJ/VJ sequences indicating derivation from 13 unique B cell clones. IgM demonstrated polyclonal and polyreactive binding to FVIII in vitro and in silico. Molecular docking studies with reconstructed IgM VDJ/VJ regions identified frequent IgM interactions with amino acid residues K376, T381, K437, R2215 or K2249 within the FVIII A2 and C2 domains. Injections of individual IgM prior to FVIII exposure and co-injection of FVIII/IgM immune complexes did not affect de novo FVIII antibody production.</p><p><strong>Conclusion: </strong>Persistent FVIII-specific IgM are polyclonal but preferentially bind the A2 and C2 domains and FVIII/IgM immune complex formation do not significantly alter inhibitor development.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-24DOI: 10.1016/j.jtha.2024.09.038
Neil A Goldenberg, Sam Schulman, John M Kittelson, Thomas C Abshire, James F Casella, Rita Dale, Jonathan L Halperin, Jade Hanson, Craig M Kessler, Marilyn J Manco-Johnson, Laurel McDevitt, Robert F Sidonio, Alex C Spyropoulos, P Gabriel Steg, Marc P Bonaca
Background: The Kids-DOTT multinational randomized clinical trial (RCT) revealed non-inferiority of a six-week versus three-month duration of anticoagulation for the treatment of provoked venous thromboembolism (VTE) in patients <21 years old, in regard to net clinical benefit at one year.
Objective: To evaluate non-inferiority at two years.
Patients/methods: Patients whose repeat imaging six weeks after VTE diagnosis did not show complete veno-occlusion were randomized to discontinue anticoagulation versus receive a total three-month course and followed for two years for the occurrence of symptomatic recurrent (SR-) VTE (efficacy outcome) and clinically-relevant bleeding (CRB, safety outcome). Outcomes were centrally adjudicated and net clinical benefit was compared between treatment arms via a pre-specified bivariate non-inferiority boundary, using 95% confidence intervals (CIs) in absolute risk differences (ARDs) between treatment arms.
Results: Kaplan-Meier estimates of two-year cumulative incidences in the six-week and three-months arms of the intention-to-treat (ITT) population (n=417) were 1.7% (95% CI: 0%, 3.7%) and 2.9% (95% CI: 0.3%, 5.4%) for SR-VTE and 1.1% (95% CI: 0%, 2.5%) and 3.2% (95% CI: 0.6%, 5.7%) for CRB. Bivariate analysis of the ARDs in the ITT population demonstrated that a six-week anticoagulation duration was non-inferior to a three-month course.
Conclusions: These findings support durability of the Kids-DOTT RCT findings of net clinical benefit at two years.
{"title":"Duration of Anticoagulation for Venous Thromboembolism in Pediatric Patients: Kids-DOTT Trial Outcomes at Two Years.","authors":"Neil A Goldenberg, Sam Schulman, John M Kittelson, Thomas C Abshire, James F Casella, Rita Dale, Jonathan L Halperin, Jade Hanson, Craig M Kessler, Marilyn J Manco-Johnson, Laurel McDevitt, Robert F Sidonio, Alex C Spyropoulos, P Gabriel Steg, Marc P Bonaca","doi":"10.1016/j.jtha.2024.09.038","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.09.038","url":null,"abstract":"<p><strong>Background: </strong>The Kids-DOTT multinational randomized clinical trial (RCT) revealed non-inferiority of a six-week versus three-month duration of anticoagulation for the treatment of provoked venous thromboembolism (VTE) in patients <21 years old, in regard to net clinical benefit at one year.</p><p><strong>Objective: </strong>To evaluate non-inferiority at two years.</p><p><strong>Patients/methods: </strong>Patients whose repeat imaging six weeks after VTE diagnosis did not show complete veno-occlusion were randomized to discontinue anticoagulation versus receive a total three-month course and followed for two years for the occurrence of symptomatic recurrent (SR-) VTE (efficacy outcome) and clinically-relevant bleeding (CRB, safety outcome). Outcomes were centrally adjudicated and net clinical benefit was compared between treatment arms via a pre-specified bivariate non-inferiority boundary, using 95% confidence intervals (CIs) in absolute risk differences (ARDs) between treatment arms.</p><p><strong>Results: </strong>Kaplan-Meier estimates of two-year cumulative incidences in the six-week and three-months arms of the intention-to-treat (ITT) population (n=417) were 1.7% (95% CI: 0%, 3.7%) and 2.9% (95% CI: 0.3%, 5.4%) for SR-VTE and 1.1% (95% CI: 0%, 2.5%) and 3.2% (95% CI: 0.6%, 5.7%) for CRB. Bivariate analysis of the ARDs in the ITT population demonstrated that a six-week anticoagulation duration was non-inferior to a three-month course.</p><p><strong>Conclusions: </strong>These findings support durability of the Kids-DOTT RCT findings of net clinical benefit at two years.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-24DOI: 10.1016/j.jtha.2024.07.035
Ferdows Atiq
{"title":"The molecular background of quantitative defects of von Willebrand factor","authors":"Ferdows Atiq","doi":"10.1016/j.jtha.2024.07.035","DOIUrl":"10.1016/j.jtha.2024.07.035","url":null,"abstract":"","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"22 11","pages":"Pages 3004-3006"},"PeriodicalIF":5.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-24DOI: 10.1016/j.jtha.2024.09.005
Yvonne X. Kong, Jose S. Perdomo, Freda H. Passam
{"title":"A new track for KDELivery of designer cargo by platelets","authors":"Yvonne X. Kong, Jose S. Perdomo, Freda H. Passam","doi":"10.1016/j.jtha.2024.09.005","DOIUrl":"10.1016/j.jtha.2024.09.005","url":null,"abstract":"","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"22 11","pages":"Pages 3007-3009"},"PeriodicalIF":5.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-24DOI: 10.1016/S1538-7836(24)00608-1
{"title":"Annoucements","authors":"","doi":"10.1016/S1538-7836(24)00608-1","DOIUrl":"10.1016/S1538-7836(24)00608-1","url":null,"abstract":"","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"22 11","pages":"Page 3331"},"PeriodicalIF":5.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142535129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-23DOI: 10.1016/j.jtha.2024.09.037
Leslie Skeith, Paula James, Peter Kouides, Kelsey Uminski, Lisa Duffett, Shannon Jackson, Michelle Sholzberg, Margaret V Ragni, Adam Cuker, Maeve O'Beirne, Julia Hews-Girard, Natalia Rydz, Dawn M Goodyear, Jill Baxter, Andra James, David Garcia, Sara K Vesely, Man-Chiu Poon
Background: While bleeding around pregnancy is well described in von Willebrand disease (VWD), risk of pregnancy loss is less certain. We aimed to describe the frequency of pregnancy loss in females with VWD, compared with those with a similar mucocutaneous bleeding phenotype and no VWD, or compared with non-bleeding disorder controls.
Methods: Female patients were consecutively approached in 8 specialty bleeding disorder clinics between 2014-2023. The VWD group was defined as having VWF:Antigen (Ag) and VWF:Activity (Act) levels, each <0.50 IU/mL on ≥2 occasions, and a Condensed MCMDM-1 score of ≥4. The non-VWD mucocutaneous bleeding disorder group had VWF levels ≥0.50 IU/mL on ≥2 occasions and a MCMDM-1 score ≥4. A non-bleeding disorder control group was recruited in pregnancy from a low-risk maternity clinic.
Results: There were 150 females in the VWD group, 145 in the non-VWD mucocutaneous bleeding disorder group, and 137 in the control group. There was a similar frequency of individuals with ≥1 loss in the VWD group (45.3%, 68/150), the non-VWD group (56.6%, 82/145) (-11.2%, 97.5% CI -24.2, 1.8%), and the non-bleeding disorder control group (37.2%, 51/137) (8.1%, 97.5% CI -4.9%, 21.1%). Using a logistic regression, the odds ratio of pregnancy losses in the VWD group versus non-VWD group was 0.94 (95% CI 0.65, 1.36). All groups experienced more recurrent losses compared to the literature.
Conclusions: There was no statistically significant difference in risk of pregnancy loss between females with VWD, females with a similar mucocutaneous bleeding phenotype, and with non-bleeding disorder controls.
背景:von-Willebrand病(VWD)患者妊娠期出血的情况已得到充分描述,但妊娠失败的风险却不太确定。我们旨在描述 VWD 女性患者的妊娠损失频率,并与具有相似粘膜出血表型但无 VWD 的女性患者进行比较,或与非出血性疾病对照组进行比较:2014-2023年间,8家出血性疾病专科门诊连续接诊了女性患者。VWD组被定义为具有VWF:抗原(Ag)和VWF:活性(Act)水平的患者:VWD组有150名女性,非VWD粘膜出血性疾病组有145名女性,对照组有137名女性。在 VWD 组(45.3%,68/150)、非 VWD 组(56.6%,82/145)(-11.2%,97.5% CI -24.2,1.8%)和非出血性疾病对照组(37.2%,51/137)(8.1%,97.5% CI -4.9%,21.1%)中,≥1 项损失的人数频率相似。通过逻辑回归,VWD 组与非 VWD 组的妊娠损失几率比为 0.94(95% CI 0.65,1.36)。与文献相比,所有组别都经历了更多的复发性流产:患有 VWD 的女性、具有相似粘膜出血表型的女性以及非出血障碍对照组的女性在妊娠损失风险方面没有明显的统计学差异。
{"title":"Pregnancy loss in individuals with von Willebrand disease and unspecified mucocutaneous bleeding disorders: A multicentre cohort study.","authors":"Leslie Skeith, Paula James, Peter Kouides, Kelsey Uminski, Lisa Duffett, Shannon Jackson, Michelle Sholzberg, Margaret V Ragni, Adam Cuker, Maeve O'Beirne, Julia Hews-Girard, Natalia Rydz, Dawn M Goodyear, Jill Baxter, Andra James, David Garcia, Sara K Vesely, Man-Chiu Poon","doi":"10.1016/j.jtha.2024.09.037","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.09.037","url":null,"abstract":"<p><strong>Background: </strong>While bleeding around pregnancy is well described in von Willebrand disease (VWD), risk of pregnancy loss is less certain. We aimed to describe the frequency of pregnancy loss in females with VWD, compared with those with a similar mucocutaneous bleeding phenotype and no VWD, or compared with non-bleeding disorder controls.</p><p><strong>Methods: </strong>Female patients were consecutively approached in 8 specialty bleeding disorder clinics between 2014-2023. The VWD group was defined as having VWF:Antigen (Ag) and VWF:Activity (Act) levels, each <0.50 IU/mL on ≥2 occasions, and a Condensed MCMDM-1 score of ≥4. The non-VWD mucocutaneous bleeding disorder group had VWF levels ≥0.50 IU/mL on ≥2 occasions and a MCMDM-1 score ≥4. A non-bleeding disorder control group was recruited in pregnancy from a low-risk maternity clinic.</p><p><strong>Results: </strong>There were 150 females in the VWD group, 145 in the non-VWD mucocutaneous bleeding disorder group, and 137 in the control group. There was a similar frequency of individuals with ≥1 loss in the VWD group (45.3%, 68/150), the non-VWD group (56.6%, 82/145) (-11.2%, 97.5% CI -24.2, 1.8%), and the non-bleeding disorder control group (37.2%, 51/137) (8.1%, 97.5% CI -4.9%, 21.1%). Using a logistic regression, the odds ratio of pregnancy losses in the VWD group versus non-VWD group was 0.94 (95% CI 0.65, 1.36). All groups experienced more recurrent losses compared to the literature.</p><p><strong>Conclusions: </strong>There was no statistically significant difference in risk of pregnancy loss between females with VWD, females with a similar mucocutaneous bleeding phenotype, and with non-bleeding disorder controls.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-23DOI: 10.1016/j.jtha.2024.09.036
Nathan Ponzar, Mathivanan Chinnaraj, Anna Pagotto, Vincenzo De Filippis, Robert Flaumenhaft, Nicola Pozzi
Background: Protein disulfide isomerase (PDI) is a promising target for combating thrombosis. Extensive research over the past decade has identified numerous PDI-targeting compounds. However, limited information exists regarding how these compounds control PDI activity, which complicates further development.
Objectives: To define the mechanism of action of 2 allosteric antithrombotic compounds of therapeutic interest, quercetin-3-O-rutinoside and bepristat-2a.
Methods: A multipronged approach that integrates single-molecule spectroscopy, steady-state kinetics, single-turnover kinetics, and site-specific mutagenesis.
Results: PDI is a thiol isomerase consisting of 2 catalytic a domains and 2 inactive b domains arranged in the order a-b-b'-a'. The active sites CGHC are located in the a and a' domains. The binding site of quercetin-3-O-rutinoside and bepristat-2a is in the b' domain. Using a library of 9 Förster resonance energy transfer sensors, we showed that quercetin-3-O-rutinoside and bepristat-2a globally alter PDI structure and dynamics, leading to ligand-specific modifications of its shape and reorientation of the active sites. Combined with enzyme kinetics and mutagenesis of the active sites, Förster resonance energy transfer data reveal that binding of quercetin-3-O-rutinoside results in a twisted enzyme with reduced affinity for the substrate. In contrast, bepristat-2a promotes a more compact conformation of PDI, in which a greater enzymatic activity is achieved by accelerating the nucleophilic step of the a domain, leading to faster formation of the covalent enzyme-substrate complex.
Conclusion: This work reveals the mechanistic basis underlying PDI regulation by antithrombotic compounds quercetin-3-O-rutinoside and bepristat-2a and points to novel strategies for furthering the development of PDI-targeting compounds into drugs.
{"title":"Mechanistic basis of activation and inhibition of protein disulfide isomerase by allosteric antithrombotic compounds.","authors":"Nathan Ponzar, Mathivanan Chinnaraj, Anna Pagotto, Vincenzo De Filippis, Robert Flaumenhaft, Nicola Pozzi","doi":"10.1016/j.jtha.2024.09.036","DOIUrl":"10.1016/j.jtha.2024.09.036","url":null,"abstract":"<p><strong>Background: </strong>Protein disulfide isomerase (PDI) is a promising target for combating thrombosis. Extensive research over the past decade has identified numerous PDI-targeting compounds. However, limited information exists regarding how these compounds control PDI activity, which complicates further development.</p><p><strong>Objectives: </strong>To define the mechanism of action of 2 allosteric antithrombotic compounds of therapeutic interest, quercetin-3-O-rutinoside and bepristat-2a.</p><p><strong>Methods: </strong>A multipronged approach that integrates single-molecule spectroscopy, steady-state kinetics, single-turnover kinetics, and site-specific mutagenesis.</p><p><strong>Results: </strong>PDI is a thiol isomerase consisting of 2 catalytic a domains and 2 inactive b domains arranged in the order a-b-b'-a'. The active sites CGHC are located in the a and a' domains. The binding site of quercetin-3-O-rutinoside and bepristat-2a is in the b' domain. Using a library of 9 Förster resonance energy transfer sensors, we showed that quercetin-3-O-rutinoside and bepristat-2a globally alter PDI structure and dynamics, leading to ligand-specific modifications of its shape and reorientation of the active sites. Combined with enzyme kinetics and mutagenesis of the active sites, Förster resonance energy transfer data reveal that binding of quercetin-3-O-rutinoside results in a twisted enzyme with reduced affinity for the substrate. In contrast, bepristat-2a promotes a more compact conformation of PDI, in which a greater enzymatic activity is achieved by accelerating the nucleophilic step of the a domain, leading to faster formation of the covalent enzyme-substrate complex.</p><p><strong>Conclusion: </strong>This work reveals the mechanistic basis underlying PDI regulation by antithrombotic compounds quercetin-3-O-rutinoside and bepristat-2a and points to novel strategies for furthering the development of PDI-targeting compounds into drugs.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-23DOI: 10.1016/j.jtha.2024.10.014
Magdalena D Lewandowska, Shelby Gordon, Anthony Betbadal, Amy D Shapiro
Background: Hereditary hemorrhagic telangiectasia (HHT) is a bleeding disorder characterized by arteriovenous malformations (AVMs), commonly presenting with epistaxis and gastrointestinal bleeding. Bleeding symptoms may be difficult to manage and may become life-threatening, with many patients developing dependence on parenteral iron and/or blood transfusion. There is a growing body of evidence that antiangiogenic therapies may be effective in management of bleeding symptoms, presumably targeting pathogenic HHT pathways such as vascular endothelial growth factor (VEGF) receptor.
Objectives: To report single-center, retrospective real-world use of pazopanib, an orally administered tyrosine kinase inhibitor that blocks VEGF receptors, in six patients with HHT-associated epistaxis and/or gastrointestinal (GI) bleeding.
Patient/methods: A retrospective observational analysis was performed to assess the safety/efficacy of pazopanib use in patients with confirmed HHT-associated epistaxis and/or GI bleeding between 01 January 2019 and 14 June 2023 The Indiana Hemophilia and Thrombosis (IHTC) institutional EMR was queried for HHT patients who were treated with pazopanib for >3 months. Patient data were obtained from patient documentation, physician/nursing notes, and on-call documentation Institutional IRB approval was obtained for data pull as an exempt study RESULTS AND CONCLUSIONS: Our observations on the real-world use of pazopanib in six HHT patients with moderate to severe bleeding showed improvement in hemoglobin levels, with reduction in iron infusions and red blood cell transfusion requirement. Pazopanib may be a reasonable option for patients with HHT with epistaxis or gastrointestinal bleeding that are refractory to standard treatment.
{"title":"Pazopanib in treatment of Hereditary Hemorrhagic Telangiectasia-related epistaxis and gastrointestinal bleeding.","authors":"Magdalena D Lewandowska, Shelby Gordon, Anthony Betbadal, Amy D Shapiro","doi":"10.1016/j.jtha.2024.10.014","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.10.014","url":null,"abstract":"<p><strong>Background: </strong>Hereditary hemorrhagic telangiectasia (HHT) is a bleeding disorder characterized by arteriovenous malformations (AVMs), commonly presenting with epistaxis and gastrointestinal bleeding. Bleeding symptoms may be difficult to manage and may become life-threatening, with many patients developing dependence on parenteral iron and/or blood transfusion. There is a growing body of evidence that antiangiogenic therapies may be effective in management of bleeding symptoms, presumably targeting pathogenic HHT pathways such as vascular endothelial growth factor (VEGF) receptor.</p><p><strong>Objectives: </strong>To report single-center, retrospective real-world use of pazopanib, an orally administered tyrosine kinase inhibitor that blocks VEGF receptors, in six patients with HHT-associated epistaxis and/or gastrointestinal (GI) bleeding.</p><p><strong>Patient/methods: </strong>A retrospective observational analysis was performed to assess the safety/efficacy of pazopanib use in patients with confirmed HHT-associated epistaxis and/or GI bleeding between 01 January 2019 and 14 June 2023 The Indiana Hemophilia and Thrombosis (IHTC) institutional EMR was queried for HHT patients who were treated with pazopanib for >3 months. Patient data were obtained from patient documentation, physician/nursing notes, and on-call documentation Institutional IRB approval was obtained for data pull as an exempt study RESULTS AND CONCLUSIONS: Our observations on the real-world use of pazopanib in six HHT patients with moderate to severe bleeding showed improvement in hemoglobin levels, with reduction in iron infusions and red blood cell transfusion requirement. Pazopanib may be a reasonable option for patients with HHT with epistaxis or gastrointestinal bleeding that are refractory to standard treatment.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Inherited platelet diseases are bleeding disorders characterized by either defects in platelet count or platelet function, the latter being less common and very heterogeneous. Numerous gene variants associated with abnormal receptors, granules, and signaling pathways have been reported. Despite significant advancements in our understanding, many patients still lack a precise diagnosis.
Objectives: To identify the genetic basis of a novel mild bleeding syndrome in a family exhibiting a selective defect of platelet aggregation.
Methods: Our study included 6 family members across 3 generations who displayed reduced platelet aggregation in response to adenosine diphosphate, protease-activated receptor 1-activating peptide, arachidonic acid, and epinephrine but not collagen. Platelet morphology, granule content, and expression of major surface glycoproteins were all found to be normal. Whole exome sequencing was performed for affected and nonaffected family members.
Results: We identified RGS18, which encodes the regulator of G protein signaling (RGS) 18, as a candidate gene for the platelet function defect observed in this family. The RGS18 protein serves as a crucial negative regulator of G protein-coupled receptor signaling and coordinates the signaling pathways of natural platelet inhibitors. The heterozygous RGS18 c.643C>T, p.Arg215∗ variant was found to cosegregate among all 6 affected subjects.
Conclusion: Truncation at Arg215 removes the S216 and S218 phosphorylation sites, which are crucial regulatory domains for RGS18 activation. The impaired platelet function is thought to arise from excessive platelet downregulation due to constitutive activation of RGS18, resulting from a loss of association of the truncated form with the 14-3-3 protein.
{"title":"A gain of function variant in RGS18 candidate for a familial mild bleeding syndrome.","authors":"Caroline Vayne, Maguelonne Roux, Yves Gruel, Marjorie Poggi, Claire Pouplard, Franck Peiretti, David-Alexandre Trégouët, Paquita Nurden, Marie-Christine Alessi","doi":"10.1016/j.jtha.2024.10.016","DOIUrl":"10.1016/j.jtha.2024.10.016","url":null,"abstract":"<p><strong>Background: </strong>Inherited platelet diseases are bleeding disorders characterized by either defects in platelet count or platelet function, the latter being less common and very heterogeneous. Numerous gene variants associated with abnormal receptors, granules, and signaling pathways have been reported. Despite significant advancements in our understanding, many patients still lack a precise diagnosis.</p><p><strong>Objectives: </strong>To identify the genetic basis of a novel mild bleeding syndrome in a family exhibiting a selective defect of platelet aggregation.</p><p><strong>Methods: </strong>Our study included 6 family members across 3 generations who displayed reduced platelet aggregation in response to adenosine diphosphate, protease-activated receptor 1-activating peptide, arachidonic acid, and epinephrine but not collagen. Platelet morphology, granule content, and expression of major surface glycoproteins were all found to be normal. Whole exome sequencing was performed for affected and nonaffected family members.</p><p><strong>Results: </strong>We identified RGS18, which encodes the regulator of G protein signaling (RGS) 18, as a candidate gene for the platelet function defect observed in this family. The RGS18 protein serves as a crucial negative regulator of G protein-coupled receptor signaling and coordinates the signaling pathways of natural platelet inhibitors. The heterozygous RGS18 c.643C>T, p.Arg215∗ variant was found to cosegregate among all 6 affected subjects.</p><p><strong>Conclusion: </strong>Truncation at Arg215 removes the S216 and S218 phosphorylation sites, which are crucial regulatory domains for RGS18 activation. The impaired platelet function is thought to arise from excessive platelet downregulation due to constitutive activation of RGS18, resulting from a loss of association of the truncated form with the 14-3-3 protein.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-23DOI: 10.1016/j.jtha.2024.10.015
Dieuwke Luijten, Denise Abbel, Suzanne C Cannegieter, Jeroen Eikenboom, Paul L den Exter, Jacobijn Gussekloo, Menno V Huisman, Thijs E van Mens, Lara Tahir, Stella Trompet, Simon P Mooijaart, Frederikus A Klok
Introduction: Managing older patients with acute pulmonary embolism (PE) is challenging due to their underrepresentation in clinical trials, comorbidities and increased complication risk. This study evaluates risk assessment and management outcomes in older PE patients focussing on home and reperfusion treatment.
Methods: A retrospective analysis was conducted on patients aged ≥70 years diagnosed with acute PE at an academic medical centre (2015-2022).
Results: 242 patients with a mean age of 77 years were included. All 59 patients with negative Hestia criteria were discharged ≤24h, and in total 81 patients (35%) received home treatment. Among these 14-day mortality and recurrent venous-thromboembolism were 0% and major bleeding occurred in 1.3% (one patient, 95%CI 0.11-6.1). European Society of Cardiology (ESC) risk-classification showed 9 low-risk PE (3.9%), 199 intermediate-risk (87%), and 20 high-risk PE patients (8.8). In 5 of the 20 high-risk patients, hypotension was mainly caused by another condition, i.e. sepsis. Eight high-risk patients received reperfusion therapy. Fourteen-day mortality was 51% in high-risk patients (95%CI 27-71); 5 out of 8 patients receiving reperfusion treatment died within 5 days. Patients with an Acute Presenting Older Patient (APOP) score of ≥45% had higher 14-day mortality (28%; 95%CI 12-46) compared to <45% (3.2%; 95%CI 0.85-8.3; HR 10.2; 95%CI 2.6-39).
Conclusion: Selecting for home treatment using Hestia was safe for older PE patients in our cohort. Mortality in the high-risk group was high also when receiving reperfusion treatment. The ESC risk-classification and APOP score identified patients at higher mortality risk, suggesting their potential utility in clinical decision-making.
{"title":"Risk assessment and management strategies in older patients with acute pulmonary embolism.","authors":"Dieuwke Luijten, Denise Abbel, Suzanne C Cannegieter, Jeroen Eikenboom, Paul L den Exter, Jacobijn Gussekloo, Menno V Huisman, Thijs E van Mens, Lara Tahir, Stella Trompet, Simon P Mooijaart, Frederikus A Klok","doi":"10.1016/j.jtha.2024.10.015","DOIUrl":"https://doi.org/10.1016/j.jtha.2024.10.015","url":null,"abstract":"<p><strong>Introduction: </strong>Managing older patients with acute pulmonary embolism (PE) is challenging due to their underrepresentation in clinical trials, comorbidities and increased complication risk. This study evaluates risk assessment and management outcomes in older PE patients focussing on home and reperfusion treatment.</p><p><strong>Methods: </strong>A retrospective analysis was conducted on patients aged ≥70 years diagnosed with acute PE at an academic medical centre (2015-2022).</p><p><strong>Results: </strong>242 patients with a mean age of 77 years were included. All 59 patients with negative Hestia criteria were discharged ≤24h, and in total 81 patients (35%) received home treatment. Among these 14-day mortality and recurrent venous-thromboembolism were 0% and major bleeding occurred in 1.3% (one patient, 95%CI 0.11-6.1). European Society of Cardiology (ESC) risk-classification showed 9 low-risk PE (3.9%), 199 intermediate-risk (87%), and 20 high-risk PE patients (8.8). In 5 of the 20 high-risk patients, hypotension was mainly caused by another condition, i.e. sepsis. Eight high-risk patients received reperfusion therapy. Fourteen-day mortality was 51% in high-risk patients (95%CI 27-71); 5 out of 8 patients receiving reperfusion treatment died within 5 days. Patients with an Acute Presenting Older Patient (APOP) score of ≥45% had higher 14-day mortality (28%; 95%CI 12-46) compared to <45% (3.2%; 95%CI 0.85-8.3; HR 10.2; 95%CI 2.6-39).</p><p><strong>Conclusion: </strong>Selecting for home treatment using Hestia was safe for older PE patients in our cohort. Mortality in the high-risk group was high also when receiving reperfusion treatment. The ESC risk-classification and APOP score identified patients at higher mortality risk, suggesting their potential utility in clinical decision-making.</p>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}