BloodPub Date : 2025-05-01DOI: 10.1182/blood.2024025131
Carmelo Gurnari, Marie Robin, Lionel Adès, Mahmoud Aljurf, Antonio Almeida, Fernando Barroso Duarte, Elsa Bernard, Corey Cutler, Matteo Giovanni Della Porta, Theo De Witte, Amy DeZern, Joanna Drozd-Sokolowska, Eric Duncavage, Pierre Fenaux, Nico Gagelmann, Guillermo Garcia-Manero, Claudia Haferlach, Torsten Haferlach, Robert Hasserjian, Eva Hellström-Lindberg, Meagan Jacoby, Austin Kulasekararaj, R Coleman Lindsley, Jaroslaw P Maciejewski, Hideki Makishima, Luca Malcovati, Moshe Mittelman, Anders E Myhre, Seishi Ogawa, Francesco Onida, Elli Papaemmanuil, Jakob Passweg, Uwe Platzbecker, Lisa Pleyer, Kavita Raj, Valeria Santini, Anna Sureda, Magnus Tobiasson, Maria Teresa Voso, Ibrahim Yakoub-Agha, Amer Zeidan, Matthew Walter, Nicolaus Kröger, Donal P McLornan, Mario Cazzola
{"title":"Clinical-genomic profiling of MDS to inform allo-HCT: recommendations from an international panel on behalf of the EBMT.","authors":"Carmelo Gurnari, Marie Robin, Lionel Adès, Mahmoud Aljurf, Antonio Almeida, Fernando Barroso Duarte, Elsa Bernard, Corey Cutler, Matteo Giovanni Della Porta, Theo De Witte, Amy DeZern, Joanna Drozd-Sokolowska, Eric Duncavage, Pierre Fenaux, Nico Gagelmann, Guillermo Garcia-Manero, Claudia Haferlach, Torsten Haferlach, Robert Hasserjian, Eva Hellström-Lindberg, Meagan Jacoby, Austin Kulasekararaj, R Coleman Lindsley, Jaroslaw P Maciejewski, Hideki Makishima, Luca Malcovati, Moshe Mittelman, Anders E Myhre, Seishi Ogawa, Francesco Onida, Elli Papaemmanuil, Jakob Passweg, Uwe Platzbecker, Lisa Pleyer, Kavita Raj, Valeria Santini, Anna Sureda, Magnus Tobiasson, Maria Teresa Voso, Ibrahim Yakoub-Agha, Amer Zeidan, Matthew Walter, Nicolaus Kröger, Donal P McLornan, Mario Cazzola","doi":"10.1182/blood.2024025131","DOIUrl":"10.1182/blood.2024025131","url":null,"abstract":"<p><strong>Abstract: </strong>For patients with myelodysplastic neoplasm/syndrome (MDS), allogeneic hematopoietic cell transplantation (allo-HCT) represents the only potentially curative treatment, capable of eradicating disease-related mutant hematopoietic cells and establishing normal donor hematopoiesis. Biologic-assignment clinical trials have indicated that in eligible patients, allo-HCT is associated with superior clinical outcomes compared with nontransplant therapy. However, this therapeutic option is only available to a subset of patients, and the outcome is influenced by multiple factors inherent to the patient, the MDS subtype, and the allo-HCT procedure itself. In 2017, the European Society for Blood and Marrow Transplantation (EBMT) published recommendations for allo-HCT in MDS to guide practical decision making. In the contemporary era, genomic profiling has become routine clinical practice in many centers, and the most recent classification systems include MDS entities that are defined by genetic abnormalities. In particular, the molecular International Prognostic Scoring System offers more precise prognostication across all clinical end points and currently represents the standard tool for estimating patient survival in the absence of disease-modifying treatment. Evidence from multiple sources increasingly indicates that allo-HCT should be considered at the time of diagnosis in all eligible patients with MDS. Therefore, genomic profiling for somatic mutations and testing for germ line predisposition variants are integral to determining a patient's eligibility for transplantation. Although all patients with higher-risk MDS are potential candidates for immediate transplantation, a subset of those with lower-risk MDS may also derive benefit from this procedure at an earlier disease stage. Comprehensive recommendations on behalf of an expert international panel for clinical practice and future clinical studies of relevance are presented.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1987-2001"},"PeriodicalIF":21.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BloodPub Date : 2025-05-01DOI: 10.1182/blood.2024026446
Everett H Meyer, Anna Pavlova, Alejandro Villar-Prados, Cameron Bader, Bryan Xie, Lori Muffly, Paige Kim, Katherine Sutherland, Sushma Bharadwaj, Saurabh Dahiya, Matthew Frank, Sally Arai, Laura Johnston, David Miklos, Andrew Rezvani, Parveen Shiraz, Surbhi Sidana, Judy Shizuru, Wen-Kai Weng, Vaibhav Agrawal, Amy Putnam, Nathaniel Fernhoff, John Tamarisis, Ying Lu, Rahul D Pawar, J Scott McClellan, Robert Lowsky, Robert S Negrin
{"title":"Donor regulatory T-cell therapy to prevent graft-versus-host disease.","authors":"Everett H Meyer, Anna Pavlova, Alejandro Villar-Prados, Cameron Bader, Bryan Xie, Lori Muffly, Paige Kim, Katherine Sutherland, Sushma Bharadwaj, Saurabh Dahiya, Matthew Frank, Sally Arai, Laura Johnston, David Miklos, Andrew Rezvani, Parveen Shiraz, Surbhi Sidana, Judy Shizuru, Wen-Kai Weng, Vaibhav Agrawal, Amy Putnam, Nathaniel Fernhoff, John Tamarisis, Ying Lu, Rahul D Pawar, J Scott McClellan, Robert Lowsky, Robert S Negrin","doi":"10.1182/blood.2024026446","DOIUrl":"10.1182/blood.2024026446","url":null,"abstract":"<p><strong>Abstract: </strong>Allogeneic hematopoietic cell transplantation is a curative therapy limited by graft-versus-host disease (GVHD). In preclinical studies and early-phase clinical studies, enrichment of donor regulatory T cells (Tregs) appears to prevent GVHD and promote healthy immunity. We enrolled 44 patients in an open-label, single-center, phase 2 efficacy study investigating if a precision selected and highly purified Treg therapy manufactured from donor-mobilized peripheral blood improves 1-year GVHD-free relapse-free survival (GRFS) after myeloablative conditioning. We compared this study arm with a concomitant standard-of-care (SOC) cohort. All donor Treg products were successfully manufactured and administered without cryopreservation within 72 hours. Participants had a 1-year incidence of acute grade 3 to 4 GVHD of 7%, moderate to severe chronic GVHD of 11%, and nonrelapse mortality rate of 4.5%. The primary end point of significantly improved 1-year GRFS was achieved at 64% evaluated against a predicted incidence of 40% (P = .002) with a realized incidence of 36% in the SOC comparator. For those trial patients who developed grade 2 to 4 acute GVHD, 91% responded to front-line corticosteroid therapy, whereas 50% responded in the SOC comparator group. Trial participants had a reduced incidence and burden of GVHD and improved GRFS, compared with rates common to highly variable unmanipulated donor grafts and multiagent immune suppression. This trial was registered at www.clinicaltrials.gov as #NCT01660607.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2012-2024"},"PeriodicalIF":21.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142962182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BloodPub Date : 2025-05-01DOI: 10.1182/blood.2024026643
Michal Santocki, Anna Such, Dominika Drab, Gabriela Burczyk, Elzbieta Kolaczkowska
{"title":"NETs persisting in vasculature undergo self-renewal with consequences for subsequent infection: a mouse model study.","authors":"Michal Santocki, Anna Such, Dominika Drab, Gabriela Burczyk, Elzbieta Kolaczkowska","doi":"10.1182/blood.2024026643","DOIUrl":"10.1182/blood.2024026643","url":null,"abstract":"<p><strong>Abstract: </strong>Although key for pathogen immobilization, neutrophil extracellular traps (NETs) often cause severe bystander cell/tissue damage. This was hypothesized to depend on their prolonged presence in the vasculature, leading to cytotoxicity. Imaging of NETs (histones, neutrophil elastase, and extracellular DNA) with intravital microscopy in blood vessels of mouse livers in a pathogen-replicative-free environment (endotoxemia) led to detection of NET proteins attached to the endothelium for months despite the early disappearance of extracellular DNA. Intravascular liver macrophages (Kupffer cells) and neutrophils, but not monocytes, were involved in NET removal. They used scavenger receptors (SRs; SR-A) and Toll-like receptors (TLRs; TLR2/4) to recognize NET components. Despite the absence of further stimuli, 14 days later a second wave of NET formation occurred, initiated by remnants of NETs from the first wave. The second burst of NET production was triggered by histones, which induced an inflammatory milieu interleukin-1β and activated platelets and coagulation-related events, including factor VII-activating protease activity. This, in turn, recruited and activated neutrophils to release the second wave of NETs. In peptidyl arginine deiminase-deficient mice, not forming NETs, inflammation and liver damage were reduced compared with their wild-type counterparts. When mice were challenged with methicillin-resistant Staphylococcus aureus 14 or 165 days after the second NETs, the course of infection/injury was diminished and exacerbated, respectively. Our study demonstrates that the complete removal of NETs in vivo takes much longer than hypothesized, and a vicious cycle of NET formation/disassembly affects subsequent infection, depending on the time elapsed since its occurrence.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2070-2085"},"PeriodicalIF":21.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142999766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BloodPub Date : 2025-04-29DOI: 10.1182/blood.2025028390
Sumithira Vasu,Qiuhong Zhao,Elizabeth Greer Miller,Patrick Elder,Lucille Langenberg,Spero R Cataland,Stella M Davies,Nelli Bejanyan,Theresa Hahn
{"title":"High Incidence of Severe TA-TMA Increases Mortality in adult Allogeneic Transplant recipients: A prospective MIDAS Consortium study.","authors":"Sumithira Vasu,Qiuhong Zhao,Elizabeth Greer Miller,Patrick Elder,Lucille Langenberg,Spero R Cataland,Stella M Davies,Nelli Bejanyan,Theresa Hahn","doi":"10.1182/blood.2025028390","DOIUrl":"https://doi.org/10.1182/blood.2025028390","url":null,"abstract":"No prospective study has evaluated the incidence of TA-TMA in adult allogeneic hematopoietic cell transplant (HCT) recipients. The MIDAS (MIcroangiopathy, endothelial Damage in Adults undergoing Stem cell transplantation) consortium conducted the first multi-center study to prospectively screen for TA-TMA. Longitudinal blood samples and detailed clinical data were collected weekly through day +100 and at months 5, 6, 9 and 12 in first allogeneic HCT recipients at three sites (Ohio State University, Moffitt and Roswell Park Comprehensive Cancer Centers). Adjudication of TA-TMA diagnosis was reviewed in real time by three blinded independent reviewers. Incidence of TA-TMA was scored using 6 published criteria: Harmonization, Jodele, Li, BMT-CTN, IWG and Cho, as well as the center-reported diagnosis and MIDAS adjudication categorized as no TMA, non-severe, or severe TA-TMA. Incidence of severe TA-TMA by day +100 was similar across the three centers at 21.8%, with a median time to onset of 14.5 days in 239 patients. Incidence of non-relapse mortality was 42% in severe compared to 8.4% in non-severe and 5.8% in no TMA groups (p<0.001). Rise in serum creatinine as early as day +7 and occurrence of hypertension by day+14 post-HCT were early indicators of severe TA-TMA. Our prospective study of systematic screening for TA-TMA identifies a higher incidence of a clinically impactful phenotype of TA-TMA than previously reported in adult HCT recipients. Our natural history study provides an essential foundation for urgently needed studies of prophylaxis and treatment of TA-TMA in adults and suggests clinical value in our inexpensive screening strategy.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"91 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BloodPub Date : 2025-04-29DOI: 10.1182/blood.2025029042
Jeffrey L Carson,Paul C Hebert,John H Alexander
{"title":"Counterpoint: The Design and Interpretation of Blood Transfusion Randomized Clinical Trials.","authors":"Jeffrey L Carson,Paul C Hebert,John H Alexander","doi":"10.1182/blood.2025029042","DOIUrl":"https://doi.org/10.1182/blood.2025029042","url":null,"abstract":"A recent perspective suggested that prior evidence from over a decade ago established that a liberal rather than a restrictive blood transfusion strategy results in better outcomes in patients with anemia and either acute myocardial infarction or stable cardiovascular disease. Their premise was that physiological evidence, and a different interpretation of the TRICC trial should have been sufficient to establish clinical practice. They also suggest that a more personalized approach to the administration of transfusions would have been made possible by including a usual care arm in all transfusion trials. In this Counter-Point perspective, we describe how and why two discrete and common blood transfusion thresholds were selected in the TRICC, FOCUS, REALITY, and MINT trials. We explain why a usual-care-arm would have been uninformative. We also propose that we still do not have evidence to provide firm transfusion recommendations in several specific subpopulations of patients including those with stable atherosclerotic coronary artery disease. Finally, we provide our perspective on the state of existing evidence and on the clinical recommendations that should be adopted in practice.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"8 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BloodPub Date : 2025-04-29DOI: 10.1182/blood.2024026340
Tommaso Perini,Paola Zordan,Rossella Del Pizzo,Massimo Resnati,Lisa Viviani,Davide Stefanoni,Laura Cassina,Ugo Paolo Orfanelli,Matteo Trudu,Laura Oliva,Daniel Lacidogna,Mehmet K Samur,Maria Materozzi,Denise Drago,Annapaola Andolfo,Marco Patrone,Massimo Degano,Alessandra Boletta,Enrico Milan,Fabio Ciceri,Nikhil C Munshi,Matteo Bellone,Simone Cenci
{"title":"The mitochondrial protease ClpP is a metabolic vulnerability and an immunogenic trigger against multiple myeloma.","authors":"Tommaso Perini,Paola Zordan,Rossella Del Pizzo,Massimo Resnati,Lisa Viviani,Davide Stefanoni,Laura Cassina,Ugo Paolo Orfanelli,Matteo Trudu,Laura Oliva,Daniel Lacidogna,Mehmet K Samur,Maria Materozzi,Denise Drago,Annapaola Andolfo,Marco Patrone,Massimo Degano,Alessandra Boletta,Enrico Milan,Fabio Ciceri,Nikhil C Munshi,Matteo Bellone,Simone Cenci","doi":"10.1182/blood.2024026340","DOIUrl":"https://doi.org/10.1182/blood.2024026340","url":null,"abstract":"Orchestrating key homeostatic functions, mitochondria likely entail cancer vulnerabilities. Moreover, due to their bacterial ancestry they can release potent immunogenic signals. Here we show that the mitochondrial protease ClpP is both a cell-intrinsic metabolic vulnerability and an actionable immunogenic trigger in multiple myeloma (MM). We found that ClpP mRNA is higher in bone marrow (BM)-purified malignant plasma cells (PC) than in normal or premalignant counterparts and that MM lines rank first for ClpP expression among human cancers. Moreover, we demonstrated that human MM cells are highly vulnerable to ClpP inhibition in vitro and in vivo. Surprisingly, MM cell dependence on ClpP was not accounted for by its acknowledged oxidative phosphorylation surveillance activity. Proteomic discovery of proteolytic targets, metabolomics, and metabolic tracing identified a critical control exerted by ClpP on ornithine aminotransferase abundance to sustain cytosolic biosynthesis of polyamines, essential to MM cells. Transcriptomics and targeted validation also revealed activation of a cyclic GMP-AMP synthase (cGAS)-dependent type-I interferon (IFN-I) response in ClpP-silenced MM cells, whose supernatants boosted dendritic cell activation and ability to stimulate IFNg production by T cells. In vivo, ClpP silencing re-shaped the BM immune environment in immunocompetent mice, significantly expanding IFNg-producing CD4+ and CD8+ T cells and CD4+ T memory cells, while containing exhausted CD4+ T cells and myeloid derived suppressor cells. Thus, ClpP is a novel addiction of MM cells, whose inhibition not only exerts cell-intrinsic toxicity, but also triggers otherwise indolent anti-tumoral immunity. Our findings yield a novel immunogenic chemotherapeutic framework of potential relevance against myeloma.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"43 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BloodPub Date : 2025-04-25DOI: 10.1182/blood.2024028136
Tahereh Setayesh, Mengna Chi, Zachery Oestreicher, Masahide Sakabe, Katie Giger Seu, Zhenqi Zhu, Harsimran Kaur, Anifat Tijani, Mei Xin, Amy Shova, Kenneth D Greis, Tim M Townes, Jozsef Balla, Katherine VandenHeuvel, Yueh-Chiang Hu, Punam Malik
{"title":"A Novel Mouse Model of Hemoglobin SC Disease Reveals Mechanisms Underlying Beneficial Effects of Hydroxyurea.","authors":"Tahereh Setayesh, Mengna Chi, Zachery Oestreicher, Masahide Sakabe, Katie Giger Seu, Zhenqi Zhu, Harsimran Kaur, Anifat Tijani, Mei Xin, Amy Shova, Kenneth D Greis, Tim M Townes, Jozsef Balla, Katherine VandenHeuvel, Yueh-Chiang Hu, Punam Malik","doi":"10.1182/blood.2024028136","DOIUrl":"https://doi.org/10.1182/blood.2024028136","url":null,"abstract":"<p><p>Sickle cell hemoglobin-C (HbSC) disease results from compound heterozygosity of hemoglobin-S (HbS) and hemoglobin-C (HbC), comprising 30% of sickle cell disease (SCD). HbC induces RBC dehydration/xerocytosis, which promotes sickling. HbSC-SCD causes significant morbidity despite being milder than homozygous HbSS-SCD. Current research/treatment strategies have focused on HbSS-SCD, while HbSC patients are deprived of disease-modifying/transformative therapies due to lack of preclinical models. We generated HbSC mice, which resemble human HbSC-SCD: HbSC erythrocytes showed marked xerocytosis. Anemia, hemolysis, inflammation and organ damage were milder than HbSS mice, but hypoxia/reperfusion injury was similar. Retinopathy developed at higher frequency than HbSS mice (66.7% versus 16.7%; p<0.05), like HbSC-SCD patients. While HbSC RBCs sickled at lower pO2 than HbSS RBCs (43mmHg versus 24mmHg; P<0.0001), they did not completely recover deformability after hypoxia-reoxygenation. Using the HbSC mice developed herein, we studied the mechanism by which hydroxyurea causes significant clinical benefit in HbSC-SCD patients, despite minimal/modest increases in fetal-hemoglobin (HbF). We found hydroxyurea had distinct non-HbF and HbF effects. Hydroxyurea did not increase HbF in adult HbSC/HbSS mice, but reduced RBC ROS, Ferryl-hemoglobin, Heinz-body formation, thereby reducing membrane damage; however, RBC hydration was unaffected. When given to unborn pups before they switch off g-globin expression and continued postnatally, we could induce HbF in both HbSC/HbSS mice (higher HbF in HbSS versus HbSC mice). Minimal increases in HbF (~1%) improved HbSC RBC hydration. Peak HbF levels of 7% in HbSC mice abrogated sickling. Overall, this HbSC model will help bridge the knowledge-gap in mechanistic/therapeutic studies in this neglected disease.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BloodPub Date : 2025-04-25DOI: 10.1182/blood.2024027382
Florian Thibord, Jason Cunha, Jelisaveta Dzigurski, Bjoernar Tuftin, Jennifer E Huffman, Natàlia Pujol-Gualdo, Kelly Cho, Peter Wf Wilson, Jill M Johnsen, Laura M Raffield, Ming-Huei Chen, Triin Laisk, Andrew D Johnson
{"title":"Genome-wide Meta-Analysis of Heavy Menstrual Bleeding Reveals 36 Risk Loci.","authors":"Florian Thibord, Jason Cunha, Jelisaveta Dzigurski, Bjoernar Tuftin, Jennifer E Huffman, Natàlia Pujol-Gualdo, Kelly Cho, Peter Wf Wilson, Jill M Johnsen, Laura M Raffield, Ming-Huei Chen, Triin Laisk, Andrew D Johnson","doi":"10.1182/blood.2024027382","DOIUrl":"https://doi.org/10.1182/blood.2024027382","url":null,"abstract":"<p><p>Heavy menstrual bleeding (HMB) is a widespread occurrence among women of reproductive age and inflicts a substantial impact on well-being and healthcare expenses. To better characterize the genetic architecture of HMB, we meta-analyzed GWAS summary statistics from five biobanks, involving up to 84,633 HMB cases and 598,195 controls from several ancestries. Out of 21 signals significantly associated with HMB in a discovery GWAS meta-analysis combining four biobanks, 20 had a concordant direction of effect in the remaining cohort, including 10 significantly replicated. By combining the discovery and replication datasets, 15 additional signals were identified in subsequent meta-analyses. These genetic analyses resulted in 36 signals (33 novel) significantly associated with HMB, and subsequent gene prioritization techniques (e.g., TWAS, PoPS) revealed likely causal genes. Notable discoveries included the strong protective effect of the F5-Leiden variant (rs6025-T, OR=0.75, P=6.8×10-33), variants at the FSHB and LHB/CGB loci, both involved in hormone production regulation, and several signals near genes involved in the Wnt/ß-catenin signaling pathway. We also observed strong and significant genetic correlations with disorders of the female genital tract, including uterine fibroids, endometriosis or ovarian cysts. Overall, we identified 33 novel genetic loci associated with HMB, significantly improving our understanding of the genetic etiology of this condition, which may provide new targets for the development of therapeutic strategies.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BloodPub Date : 2025-04-25DOI: 10.1182/blood.2025028476
Bassem M Mohammed, Katherine Basore, Enrico Di Cera
{"title":"Cryo-EM structure of coagulation factor Va bound to activated protein C.","authors":"Bassem M Mohammed, Katherine Basore, Enrico Di Cera","doi":"10.1182/blood.2025028476","DOIUrl":"https://doi.org/10.1182/blood.2025028476","url":null,"abstract":"<p><p>Coagulation factor Va (fVa) is the cofactor component of the prothrombinase complex required for rapid generation of thrombin from prothrombin in the penultimate step of the coagulation cascade. In addition, fVa is a target for proteolytic inactivation by activated protein C (APC). Like other protein-protein interactions in the coagulation cascade, the fVa-APC interaction has long posed a challenge to structural biology and its molecular underpinnings remain unknown. A recent cryogenic electron microscopy (cryo-EM) structure of fVa has revealed the arrangement of its A1-A2-A3-C1-C2 domains and the environment of the sites of APC cleavage at R306 and R506. Here we report the cryo-EM structure of the fVa-APC complex at 3.15 Å resolution where the protease domain of APC engages R506 in the A2 domain of fVa mainly through electrostatic interactions between positively charged residues in the 30- and 70- loops of APC and an electronegative surface of fVa. The auxiliary Gla and EGF domains of APC are highly dynamic and point to solvent, without making contacts with fVa. Binding of APC displaces a large portion of the A2 domain of fVa and projects the 654VKCIPDDDEDSYEIFEP670 segment as a \"latch\", or exosite ligand, over the 70-loop of the enzyme. The latch induces a large conformational change of the autolysis loop of APC which in turn promotes docking of R506 into the primary specificity pocket. The cryo-EM structure of the fVa-APC complex validates the bulk of existing biochemical data and offers molecular context for a key regulatory interaction of the coagulation cascade.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143975402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BloodPub Date : 2025-04-25DOI: 10.1182/blood.2024028035
Ferdows Atiq,Robin Blok,Calvin van Kwawegen,Anne-Marije Hulshof,Dearbhla Doherty,Michelle Lavin,Johanna G van der Bom,Niamh M O'Connell,Joke de Meris,Kevin Ryan,Saskia E M Schols,Waander L van Heerde,Mairead M Doyle,Mary B Byrne,Floor C J I Heubel-Moenen,Karin P M van Galen,Roger J S Preston,Marjon H Cnossen,Karin Fijnvandraat,Ross Ian Baker,Karina Meijer,Paula D James,Jorge Di Paola,Jeroen C J Eikenboom,Frank W G Leebeek,James S O'Donnell
{"title":"Clinical phenotype and pathophysiological mechanisms underlying qualitative Low VWF.","authors":"Ferdows Atiq,Robin Blok,Calvin van Kwawegen,Anne-Marije Hulshof,Dearbhla Doherty,Michelle Lavin,Johanna G van der Bom,Niamh M O'Connell,Joke de Meris,Kevin Ryan,Saskia E M Schols,Waander L van Heerde,Mairead M Doyle,Mary B Byrne,Floor C J I Heubel-Moenen,Karin P M van Galen,Roger J S Preston,Marjon H Cnossen,Karin Fijnvandraat,Ross Ian Baker,Karina Meijer,Paula D James,Jorge Di Paola,Jeroen C J Eikenboom,Frank W G Leebeek,James S O'Donnell","doi":"10.1182/blood.2024028035","DOIUrl":"https://doi.org/10.1182/blood.2024028035","url":null,"abstract":"Previous reports have highlighted that some low VWF patients with significant bleeding were diagnosed based upon an isolated but persistent reduction in plasma VWF activity levels in the 30-50 IU/dL range. These patients had plasma VWF:Ag levels > 50 IU/dL and thus had 'qualitative' rather than 'quantitative' low VWF. Although the clinical importance of functional VWF defects in type 2 VWD is well recognized, the translational implications of mild functional defects in patients with qualitative low VWF (low VWF-QL) have not been defined. To address this clinically important question, we combined low VWF datasets from the low VWF in Ireland cohort and the low VWF in Erasmus MC studies. Overall, we observed that low VWF-QL was common and accounted for approximately 50% of our combined low VWF cohort. Importantly, our findings demonstrate that many of these patients with mild isolated functional VWF defects in the 30-50 IU/dl range had significant bleeding phenotypes, even though their plasma VWF:Ag levels were within the normal range. In addition, we further show that low VWF-QL is a distinct clinic-pathological entity compared to type 2 VWD. Finally, our studies highlight that low VWF-QL is predominantly due to abnormalities in VWF biosynthesis within endothelial cells that are occurring largely independent of identifiable pathological VWF sequence variants. Cumulatively, these novel observations have important clinical implications for the diagnosis and management of patients with mild functional VWF defects.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"24 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}