Abstract: The major challenges of gene therapy for hemophilia A using adeno-associated virus (AAV) vectors are reducing vector doses and the long-term maintenance of stable factor VIII (FVIII). In this study, we developed engineered human B-domain-deleted FVIIIs (FVIIISQ) with enhanced secretion and coagulation potential. Intracellular accumulation was markedly reduced in some engineered FVIIISQ, resulting in reduced unfolded protein responses. The administration of AAV vectors carrying engineered FVIIISQ to hemophilia A mice resulted in ∼8-fold higher FVIII activity and 4-fold higher FVIII antigen levels compared with wild-type FVIIISQ administration. The specific FVIII activity of the engineered FVIIISQ was 3.6 times higher than that of the wild-type FVIIISQ, and its binding to activated coagulation factor IX was significantly enhanced, which is supported by the structural analysis. In macaques, the administration of AAV5 vector carrying the engineered FVIIISQ without CpG sequences resulted in a supraphysiological increase in plasma FVIII activity at a dose one-thirtieth that of valoctocogene roxaparvovec (2 × 1012 vector genome per kg). The engineered FVIIISQ may thus provide stable, long-term therapeutic efficacy in AAV-mediated hemophilia A gene therapy even at low doses.
{"title":"Engineered coagulation factor VIII with enhanced secretion and coagulation potential for hemophilia A gene therapy.","authors":"Yuji Kashiwakura, Yuto Nakajima, Kio Horinaka, Tiago J S Lopes, Yuma Furuta, Yuki Yamaguchi, Nemekhbayar Baatartsogt, Morisada Hayakawa, Yuko Katakai, Susumu Uchiyama, Osamu Nureki, Keiji Nogami, Tsukasa Ohmori","doi":"10.1182/blood.2025028481","DOIUrl":"10.1182/blood.2025028481","url":null,"abstract":"<p><strong>Abstract: </strong>The major challenges of gene therapy for hemophilia A using adeno-associated virus (AAV) vectors are reducing vector doses and the long-term maintenance of stable factor VIII (FVIII). In this study, we developed engineered human B-domain-deleted FVIIIs (FVIIISQ) with enhanced secretion and coagulation potential. Intracellular accumulation was markedly reduced in some engineered FVIIISQ, resulting in reduced unfolded protein responses. The administration of AAV vectors carrying engineered FVIIISQ to hemophilia A mice resulted in ∼8-fold higher FVIII activity and 4-fold higher FVIII antigen levels compared with wild-type FVIIISQ administration. The specific FVIII activity of the engineered FVIIISQ was 3.6 times higher than that of the wild-type FVIIISQ, and its binding to activated coagulation factor IX was significantly enhanced, which is supported by the structural analysis. In macaques, the administration of AAV5 vector carrying the engineered FVIIISQ without CpG sequences resulted in a supraphysiological increase in plasma FVIII activity at a dose one-thirtieth that of valoctocogene roxaparvovec (2 × 1012 vector genome per kg). The engineered FVIIISQ may thus provide stable, long-term therapeutic efficacy in AAV-mediated hemophilia A gene therapy even at low doses.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"402-415"},"PeriodicalIF":23.1,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12883863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145457124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-22DOI: 10.1182/blood.2025032121
Qizhen Shi
{"title":"A Padua moment for factor VIII gene therapy.","authors":"Qizhen Shi","doi":"10.1182/blood.2025032121","DOIUrl":"https://doi.org/10.1182/blood.2025032121","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"101 1","pages":"322-323"},"PeriodicalIF":20.3,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015399","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}
Pub Date : 2026-01-22DOI: 10.1182/blood.2024026514
Jing Chen, Meinolf Suttorp, Nobuko Hijiya
Abstract: Chronic myeloid leukemia (CML) is rare in children and adolescents. Although outcomes have dramatically improved owing to tyrosine kinase inhibitors (TKIs) in the last 2 decades, there are still many challenges related to the management of pediatric CML, including the impact of TKIs on growth deceleration and unknown long-term adverse effects as well as defining the role of treatment-free remission. Unlike adult CML, which is driven by evidence-based guidelines, management of pediatric CML is often extrapolated from adult guidelines. However, pediatric CML differs from adult CML in many ways, presenting with different biological; molecular; and, most importantly, host factors that make it necessary for a different treatment approach. After the initial approval of first-generation imatinib for pediatric CML in 2003, 3 TKIs, all second-generation TKIs, have been approved, including dasatinib, nilotinib, and bosutinib, which have greatly expanded therapeutic options but also added complexity to treatment determination. The expanded treatment options also call into question the treatment choice for pediatric CML, long-term efficacy, and safety profiles of these TKIs. We present 3 cases commonly encountered in pediatric CML, their challenges and relevant issues, as well as recommended managements.
{"title":"How I treat chronic myeloid leukemia in children and adolescents.","authors":"Jing Chen, Meinolf Suttorp, Nobuko Hijiya","doi":"10.1182/blood.2024026514","DOIUrl":"10.1182/blood.2024026514","url":null,"abstract":"<p><strong>Abstract: </strong>Chronic myeloid leukemia (CML) is rare in children and adolescents. Although outcomes have dramatically improved owing to tyrosine kinase inhibitors (TKIs) in the last 2 decades, there are still many challenges related to the management of pediatric CML, including the impact of TKIs on growth deceleration and unknown long-term adverse effects as well as defining the role of treatment-free remission. Unlike adult CML, which is driven by evidence-based guidelines, management of pediatric CML is often extrapolated from adult guidelines. However, pediatric CML differs from adult CML in many ways, presenting with different biological; molecular; and, most importantly, host factors that make it necessary for a different treatment approach. After the initial approval of first-generation imatinib for pediatric CML in 2003, 3 TKIs, all second-generation TKIs, have been approved, including dasatinib, nilotinib, and bosutinib, which have greatly expanded therapeutic options but also added complexity to treatment determination. The expanded treatment options also call into question the treatment choice for pediatric CML, long-term efficacy, and safety profiles of these TKIs. We present 3 cases commonly encountered in pediatric CML, their challenges and relevant issues, as well as recommended managements.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"379-389"},"PeriodicalIF":23.1,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708471","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}
Pub Date : 2026-01-21DOI: 10.1182/blood.2025031287
Hannah R Davidson-Swinton,Sheila Iyer,Anna Kolchinski,Jasmine A Salem,Emily A DeBoy,Andrew G Kilada,Jisoo S Hwang,Tania Jain,Sioban B Keel,Christopher D Gocke,Ying S Zou,Kristen E Schratz,Mary Armanios
Long telomere length (TL) extends replicative capacity in vitro, and predisposes to clonal hematopoiesis. We characterized the cancer phenotype in 51 individuals from 24 families with mutant POT1, a negative regulator of telomerase elongation (median age 51, range 5-94). Hematologic malignancies were second in prevalence after melanoma (27%), and lymphoid subsets were more common. They clustered with history of sarcoma, thyroid cancer and chronic myeloproliferative neoplasms. UKB participants with pathogenic POT1 variants had long TL and higher lymphoid malignancy rates (45% by age 80, Hazard ratio 8.28, 95% CI, 5.29-13.0). Across cohorts, diagnoses encompassed acute lymphoblastic leukemia and Hodgkin lymphoma in children/young adults, and chronic lymphocytic leukemia/multiple myeloma in adults. They clustered in families manifesting as autosomal dominant pan-lymphoma with genetic anticipation at times. Lymphocyte TL was longer than granulocytes at baseline (age-adjusted mean +1 kb, P<0.0001), and was preserved longitudinally with aging. Ultra-long lymphocyte TL >99th percentile was more sensitive for identifying pathogenic variants (58% vs. 38% for granulocytes). Among asymptomatic POT1 variant carriers, 60% (12 of 20) had immunophenotype-detected B and/or T cell clonality with complete penetrance after age 65 (7 of 7). IGH CDR3 sequencing supported age-dependent pruning of the B cell repertoire, and cytogenetic and next-generation analyses uncovered preclinical clonal lymphoma-associated changes in nearly all POT1 variant carriers older than 60 (9 of 10). Our data identify extended cellular longevity due to long TL as an inherited risk factor for lymphoma explaining its syndromic association with solid tumors, and in some cases, myeloproliferative neoplasms.
{"title":"Lymphoid malignancy and clonality in the POT1-mediated long telomere syndrome.","authors":"Hannah R Davidson-Swinton,Sheila Iyer,Anna Kolchinski,Jasmine A Salem,Emily A DeBoy,Andrew G Kilada,Jisoo S Hwang,Tania Jain,Sioban B Keel,Christopher D Gocke,Ying S Zou,Kristen E Schratz,Mary Armanios","doi":"10.1182/blood.2025031287","DOIUrl":"https://doi.org/10.1182/blood.2025031287","url":null,"abstract":"Long telomere length (TL) extends replicative capacity in vitro, and predisposes to clonal hematopoiesis. We characterized the cancer phenotype in 51 individuals from 24 families with mutant POT1, a negative regulator of telomerase elongation (median age 51, range 5-94). Hematologic malignancies were second in prevalence after melanoma (27%), and lymphoid subsets were more common. They clustered with history of sarcoma, thyroid cancer and chronic myeloproliferative neoplasms. UKB participants with pathogenic POT1 variants had long TL and higher lymphoid malignancy rates (45% by age 80, Hazard ratio 8.28, 95% CI, 5.29-13.0). Across cohorts, diagnoses encompassed acute lymphoblastic leukemia and Hodgkin lymphoma in children/young adults, and chronic lymphocytic leukemia/multiple myeloma in adults. They clustered in families manifesting as autosomal dominant pan-lymphoma with genetic anticipation at times. Lymphocyte TL was longer than granulocytes at baseline (age-adjusted mean +1 kb, P<0.0001), and was preserved longitudinally with aging. Ultra-long lymphocyte TL >99th percentile was more sensitive for identifying pathogenic variants (58% vs. 38% for granulocytes). Among asymptomatic POT1 variant carriers, 60% (12 of 20) had immunophenotype-detected B and/or T cell clonality with complete penetrance after age 65 (7 of 7). IGH CDR3 sequencing supported age-dependent pruning of the B cell repertoire, and cytogenetic and next-generation analyses uncovered preclinical clonal lymphoma-associated changes in nearly all POT1 variant carriers older than 60 (9 of 10). Our data identify extended cellular longevity due to long TL as an inherited risk factor for lymphoma explaining its syndromic association with solid tumors, and in some cases, myeloproliferative neoplasms.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"192 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015348","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}
Pub Date : 2026-01-20DOI: 10.1182/blood.2025030223
Yanki Yarman,Xuefei Zhao,Hyunsook Ahn,Hannah A Thomson,Amrita Sarkar,Tian Yuan,Meghan E Roberts,Jeremy Wurtzel,Scott L Diamond,John J G Tesmer,Deborah L French,Maurizio Tomaiuolo,Ernest Turro,William Astle,Lawrence E Goldfinger,Steven E McKenzie,Jeffrey Benovic,Timothy J Stalker,Mortimer Poncz,Peisong Ma
Inherited genetic variants that modulate platelet function contribute significantly to thrombotic disorders, yet their mechanisms and clinical implications remain underexplored. Two genome-wide association studies identified an AàG variant (rs10886430) in the first intron of G protein-coupled-receptor kinase 5 (GRK5), found in homozygosity in ~5 million Americans. The homozygous GRK5 GG genotype has an increased risk of stroke and venous thromboembolism, but the mechanistic link between this variant and thrombotic risk has remained unclear. To investigate this, we identified three GG individuals. GRK5 protein levels in GG platelets were 90% lower than in AA controls. The significant reduction in GRK5 levels in GG platelets led to elevated platelet responsiveness to thrombin and a PAR1 agonist but not to a PAR4 agonist. These findings were corroborated in GRK5-/- iPSC-derived megakaryocytes, transgenic Grk5-deficient murine platelets, and AA platelets exposed to a GRK5 inhibitor. We demonstrated that PAR1 internalization was reduced in GG platelets, leading to enhanced PAR1 signaling. Under venous shear in an endothelialized microfluidic system, GG platelets exhibited increased accumulation, which was reversed by PAR1 inhibition with vorapaxar. In an arterial murine thrombosis model following human platelet infusion, GG platelets also showed enhanced thrombus formation in vivo. This study provides the first experimental evidence directly linking a highly prevalent human GRK5 variant to defective PAR1 regulation and increased thrombotic risk. Together, these findings establish that the GRK5 GG genotype confers increased thrombotic potential through impaired PAR1 desensitization, providing mechanistic insight that connects human genetics, thrombin receptor signaling, and thrombotic disease.
{"title":"Understanding how a highly prevalent GRK5 polymorphism affects platelets and enhances thrombotic risk.","authors":"Yanki Yarman,Xuefei Zhao,Hyunsook Ahn,Hannah A Thomson,Amrita Sarkar,Tian Yuan,Meghan E Roberts,Jeremy Wurtzel,Scott L Diamond,John J G Tesmer,Deborah L French,Maurizio Tomaiuolo,Ernest Turro,William Astle,Lawrence E Goldfinger,Steven E McKenzie,Jeffrey Benovic,Timothy J Stalker,Mortimer Poncz,Peisong Ma","doi":"10.1182/blood.2025030223","DOIUrl":"https://doi.org/10.1182/blood.2025030223","url":null,"abstract":"Inherited genetic variants that modulate platelet function contribute significantly to thrombotic disorders, yet their mechanisms and clinical implications remain underexplored. Two genome-wide association studies identified an AàG variant (rs10886430) in the first intron of G protein-coupled-receptor kinase 5 (GRK5), found in homozygosity in ~5 million Americans. The homozygous GRK5 GG genotype has an increased risk of stroke and venous thromboembolism, but the mechanistic link between this variant and thrombotic risk has remained unclear. To investigate this, we identified three GG individuals. GRK5 protein levels in GG platelets were 90% lower than in AA controls. The significant reduction in GRK5 levels in GG platelets led to elevated platelet responsiveness to thrombin and a PAR1 agonist but not to a PAR4 agonist. These findings were corroborated in GRK5-/- iPSC-derived megakaryocytes, transgenic Grk5-deficient murine platelets, and AA platelets exposed to a GRK5 inhibitor. We demonstrated that PAR1 internalization was reduced in GG platelets, leading to enhanced PAR1 signaling. Under venous shear in an endothelialized microfluidic system, GG platelets exhibited increased accumulation, which was reversed by PAR1 inhibition with vorapaxar. In an arterial murine thrombosis model following human platelet infusion, GG platelets also showed enhanced thrombus formation in vivo. This study provides the first experimental evidence directly linking a highly prevalent human GRK5 variant to defective PAR1 regulation and increased thrombotic risk. Together, these findings establish that the GRK5 GG genotype confers increased thrombotic potential through impaired PAR1 desensitization, providing mechanistic insight that connects human genetics, thrombin receptor signaling, and thrombotic disease.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"90 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005320","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}
The coagulation-anticoagulation balance is tightly regulated by endothelial-derived factors, which have not been clearly defined. Here, we report that clusterin, a component of Weibel-Palade bodies (WPBs), plays a crucial role in maintaining hemostatic equilibrium by sta bilizing von Willebrand factor (VWF) multimers in plasma. Clusterin was identified by proteomic analysis as a component of endothelial secretome under both chemical and physical conditions and demonstrated as a WPB component via immunostaining and co-transfection assays. Notably, a significant reduction of clusterin protein level was observed in type 2A von Willebrand disease (VWD) patient plasma. Furthermore, loss of clusterin in mice led to hemorrhagic diathesis and impaired thrombosis, accompanied by reduced high molecular weight (HMW) VWF levels. These defects were rescued by exogenous clusterin administration, underscoring its therapeutic potential. Mechanistically, clusterin binds to the D4N domain of VWF, which competitively inhibits ADAMTS13-mediated proteolysis under shear stress, and thereby preserves HMW VWF multimers essential for hemostasis. This study redefines WPBs as hubs for regulatory proteins and establishes clusterin as a key modulator of VWF multimer quality, offering a paradigm shift in targeting coagulation dysfunction through multimer stabilization rather than protein replacement. Our findings bridge a critical gap in understanding endothelial-driven coagulation homeostasis and suggest a potential therapeutic strategy targeting VWF multimer quality for bleeding disorder diseases.
{"title":"Clusterin maintains hemostatic equilibrium by stabilizing VWF multimers in plasma.","authors":"Ziqi Qiao,Yang Cao,Jingge Su,Shan Lu,Guoqin Wei,Shengyu Jin,Qiulan Ding,Yanjie Sun,Yingqing Huo,Mengqiu Dong,Jincai Luo,Pin Li","doi":"10.1182/blood.2025030643","DOIUrl":"https://doi.org/10.1182/blood.2025030643","url":null,"abstract":"The coagulation-anticoagulation balance is tightly regulated by endothelial-derived factors, which have not been clearly defined. Here, we report that clusterin, a component of Weibel-Palade bodies (WPBs), plays a crucial role in maintaining hemostatic equilibrium by sta bilizing von Willebrand factor (VWF) multimers in plasma. Clusterin was identified by proteomic analysis as a component of endothelial secretome under both chemical and physical conditions and demonstrated as a WPB component via immunostaining and co-transfection assays. Notably, a significant reduction of clusterin protein level was observed in type 2A von Willebrand disease (VWD) patient plasma. Furthermore, loss of clusterin in mice led to hemorrhagic diathesis and impaired thrombosis, accompanied by reduced high molecular weight (HMW) VWF levels. These defects were rescued by exogenous clusterin administration, underscoring its therapeutic potential. Mechanistically, clusterin binds to the D4N domain of VWF, which competitively inhibits ADAMTS13-mediated proteolysis under shear stress, and thereby preserves HMW VWF multimers essential for hemostasis. This study redefines WPBs as hubs for regulatory proteins and establishes clusterin as a key modulator of VWF multimer quality, offering a paradigm shift in targeting coagulation dysfunction through multimer stabilization rather than protein replacement. Our findings bridge a critical gap in understanding endothelial-driven coagulation homeostasis and suggest a potential therapeutic strategy targeting VWF multimer quality for bleeding disorder diseases.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"92 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005319","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}
Pub Date : 2026-01-20DOI: 10.1182/blood.2025030790
Caterina E Marx,Marc Carrier
Cancer patients face an increased risk of venous thromboembolism (VTE), and breakthrough thrombosis despite anticoagulation, with a six-month cumulative incidence of 5-8%. The management of these events is clinically challenging. Confirming suspected breakthrough thrombosis requires imaging review, ideally by comparison with post-index baseline studies, as residual thrombus is common and may mimic recurrence. When true breakthrough thrombosis is confirmed, several potential contributing factors should be assessed. Tumor extension can lead to mechanical vein compression and thrombus formation. Non-adherence is common among anticoagulated patients and should be evaluated through detailed medication history. Measurement of drug-specific plasma levels, when available, may assist in confirming non-adherence. In patients on LMWH, underlying prothrombotic conditions such as heparin-induced thrombocytopenia or acquired antithrombin-deficiency must also be considered. In patients receiving oral anticoagulants, drug-drug interactions and impaired gastrointestinal absorption should be excluded. Therapeutic strategies are guided by limited evidence, primarily from observational studies. Current practice generally favors switching to therapeutic low-molecular-weight heparin (LMWH) if the patient was on oral anticoagulation, escalating LMWH dosing by 25-33% if already on therapeutic LMWH, or increasing LMWH to weight-adjusted therapeutic dose if treatment was subtherapeutic. Despite treatment adjustments, recurrence and bleeding risks remain substantial. In this review, we outline common clinical scenarios of breakthrough thrombosis in cancer patients and critically appraise the available evidence to inform treatment decisions.
{"title":"How I treat breakthrough thrombosis in patients with cancer.","authors":"Caterina E Marx,Marc Carrier","doi":"10.1182/blood.2025030790","DOIUrl":"https://doi.org/10.1182/blood.2025030790","url":null,"abstract":"Cancer patients face an increased risk of venous thromboembolism (VTE), and breakthrough thrombosis despite anticoagulation, with a six-month cumulative incidence of 5-8%. The management of these events is clinically challenging. Confirming suspected breakthrough thrombosis requires imaging review, ideally by comparison with post-index baseline studies, as residual thrombus is common and may mimic recurrence. When true breakthrough thrombosis is confirmed, several potential contributing factors should be assessed. Tumor extension can lead to mechanical vein compression and thrombus formation. Non-adherence is common among anticoagulated patients and should be evaluated through detailed medication history. Measurement of drug-specific plasma levels, when available, may assist in confirming non-adherence. In patients on LMWH, underlying prothrombotic conditions such as heparin-induced thrombocytopenia or acquired antithrombin-deficiency must also be considered. In patients receiving oral anticoagulants, drug-drug interactions and impaired gastrointestinal absorption should be excluded. Therapeutic strategies are guided by limited evidence, primarily from observational studies. Current practice generally favors switching to therapeutic low-molecular-weight heparin (LMWH) if the patient was on oral anticoagulation, escalating LMWH dosing by 25-33% if already on therapeutic LMWH, or increasing LMWH to weight-adjusted therapeutic dose if treatment was subtherapeutic. Despite treatment adjustments, recurrence and bleeding risks remain substantial. In this review, we outline common clinical scenarios of breakthrough thrombosis in cancer patients and critically appraise the available evidence to inform treatment decisions.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"87 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005314","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}
Pub Date : 2026-01-20DOI: 10.1182/blood.2025030049
Giorgia Chiodin,Dylan James Tatterton,Philip J Rock,Luis Del Rio,Erin Snook,Sonya James,Patrick J Duriez,Miriam Di Re,Martijn Verdoes,Stuart Lanham,Daniel J Hodson,Richard Burack,Francesco Forconi
The occupation of the surface immunoglobulin antigen-binding site by oligomannose-type glycans (sIg-Mann) is a tumor-specific post-translational modification of classic follicular lymphoma (FL). SIg-Mann switches binding from antigen to dendritic cell-specific intercellular adhesion molecule 3 grabbing non-integrin (DC-SIGN), known to be expressed on interfollicular macrophages and FL-associated follicular dendritic cells (FDCs). The interaction with DC-SIGN induces reorganization of sIg-Mann in wider and less dense clusters than anti-Ig, consistent with inefficient DC-SIGN-induced endocytosis and a low-level intracellular signaling. However, ligand-specific cell clusters form between sIg-Mann-expressing lymphoma and DC-SIGN-expressing cells, raising a need to understand the functional consequences of the interaction of DC-SIGN with sIg-Mann on primary FL cells. This engagement induces adhesion of FL cells to vascular cell adhesion molecule-1 (VCAM-1) via B-cell receptor proximal kinases and actin regulators in a fashion similar to anti-Ig, but without initiating apoptosis in vitro. Instead, antibody blockade of sIg-Mann contact with DC-SIGN expressed on FDC-derived YK6/SIGN cells inhibits adhesion and survival of primary FL cells in vitro. These data highlight that the specific interaction with DC-SIGN induces FL cell adhesion to VCAM-1, likely allowing FL cell retention in the lymph node, and survival of the FL cells. Adhesion and survival are inhibited by an anti-DC-SIGN blocking antibody, indicating a new early therapeutic approach against FL retention and survival in adaptive tumor tissue niches.
{"title":"DC-SIGN Binding to the Surface Ig Oligomannose-type Glycans Promotes Follicular Lymphoma Cell Adhesion and Survival.","authors":"Giorgia Chiodin,Dylan James Tatterton,Philip J Rock,Luis Del Rio,Erin Snook,Sonya James,Patrick J Duriez,Miriam Di Re,Martijn Verdoes,Stuart Lanham,Daniel J Hodson,Richard Burack,Francesco Forconi","doi":"10.1182/blood.2025030049","DOIUrl":"https://doi.org/10.1182/blood.2025030049","url":null,"abstract":"The occupation of the surface immunoglobulin antigen-binding site by oligomannose-type glycans (sIg-Mann) is a tumor-specific post-translational modification of classic follicular lymphoma (FL). SIg-Mann switches binding from antigen to dendritic cell-specific intercellular adhesion molecule 3 grabbing non-integrin (DC-SIGN), known to be expressed on interfollicular macrophages and FL-associated follicular dendritic cells (FDCs). The interaction with DC-SIGN induces reorganization of sIg-Mann in wider and less dense clusters than anti-Ig, consistent with inefficient DC-SIGN-induced endocytosis and a low-level intracellular signaling. However, ligand-specific cell clusters form between sIg-Mann-expressing lymphoma and DC-SIGN-expressing cells, raising a need to understand the functional consequences of the interaction of DC-SIGN with sIg-Mann on primary FL cells. This engagement induces adhesion of FL cells to vascular cell adhesion molecule-1 (VCAM-1) via B-cell receptor proximal kinases and actin regulators in a fashion similar to anti-Ig, but without initiating apoptosis in vitro. Instead, antibody blockade of sIg-Mann contact with DC-SIGN expressed on FDC-derived YK6/SIGN cells inhibits adhesion and survival of primary FL cells in vitro. These data highlight that the specific interaction with DC-SIGN induces FL cell adhesion to VCAM-1, likely allowing FL cell retention in the lymph node, and survival of the FL cells. Adhesion and survival are inhibited by an anti-DC-SIGN blocking antibody, indicating a new early therapeutic approach against FL retention and survival in adaptive tumor tissue niches.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"64 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005316","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}
Pub Date : 2026-01-20DOI: 10.1182/blood.2025028733
Camila Cardoso,Antônio Felipe Silva Carvalho,Edvaldo S Lara,Fernanda Silva Carneiro,Isabella Zaidan,Lais C Grossi,Ana Clara M Montuori-Andrade,Jéssica A M Souza,Franciel B Felix,Adelson H A Monteiro,Erick Bryan de Sousa Lima,Isabella L Augusto,Rodrigo S Caixeta,Bárbara C M Barbosa,Celso Martins Queiroz-Junior,Remo C Russo,Vanessa Pinho,Juliana Priscila Vago,Michelle A Sugimoto,Vivian Vasconcelos Costa,Lindsey A Miles,Robert J Parmer,Fernão C Braga,Mauro Martins Teixeira,Luciana P Tavares,Lirlândia Pires Sousa
Accumulating evidence supports pro-resolving actions of the Plasminogen/Plasmin (Plg/Pla) system during inflammation, beyond its classical role in fibrin degradation. Here, we investigated the role of Plg/Pla on key features of inflammation resolution in a murine model of severe pneumococcal pneumonia. High levels of Plg were observed in the airways following infection, accompanied by increased levels of plasminogen activator inhibitor-1, neutrophil elastase and Plg degradation fragments as inflammation progressed. Pla treatment of mice infected with Streptococcus pneumoniae (Sp) decreased neutrophilic infiltration in airways and lungs, accompanied by lower concentrations of the neutrophil chemoattractive chemokines CXCL1 and CXCL2, as well as the pro-inflammatory cytokines TNF, IL-6, and IL-1β. Pla-treatment also enhanced neutrophil apoptosis and efferocytosis, and slightly reduced bacterial loads in bronchoalveolar lavage. In addition, Pla decreased damage and fibrin deposition in lungs, improving pneumonia-driven pulmonary mechanical dysfunction, and rescuing mice from lethality. Pla-induced resolution of Sp-evoked inflammation was associated with neutrophil apoptosis, as the caspase-3 specific inhibitor Z-DEVD-FMK blocked Pla protective actions. In addition to the effects on neutrophils, intranasal instillation of Pla in naïve mice increased the number of alveolar macrophages and guided them toward a regulatory phenotype marked by enhanced efferocytosis of apoptotic neutrophils and increased bacterial phagocytosis, ultimately promoting host protection against pneumococcus-induced inflammation and tissue damage. In sum, our findings demonstrate that plasmin modulates the lung inflammatory milieu and promotes key pro-resolving events, namely neutrophil apoptosis and expansion of alveolar macrophage with enhanced efferocytosis and phagocytic abilities, resulting in improved lung function and survival in pneumococcal pneumonia.
{"title":"Plasmin modulates neutrophilic inflammation and alveolar macrophage function, protecting mice from pneumococcal pneumonia.","authors":"Camila Cardoso,Antônio Felipe Silva Carvalho,Edvaldo S Lara,Fernanda Silva Carneiro,Isabella Zaidan,Lais C Grossi,Ana Clara M Montuori-Andrade,Jéssica A M Souza,Franciel B Felix,Adelson H A Monteiro,Erick Bryan de Sousa Lima,Isabella L Augusto,Rodrigo S Caixeta,Bárbara C M Barbosa,Celso Martins Queiroz-Junior,Remo C Russo,Vanessa Pinho,Juliana Priscila Vago,Michelle A Sugimoto,Vivian Vasconcelos Costa,Lindsey A Miles,Robert J Parmer,Fernão C Braga,Mauro Martins Teixeira,Luciana P Tavares,Lirlândia Pires Sousa","doi":"10.1182/blood.2025028733","DOIUrl":"https://doi.org/10.1182/blood.2025028733","url":null,"abstract":"Accumulating evidence supports pro-resolving actions of the Plasminogen/Plasmin (Plg/Pla) system during inflammation, beyond its classical role in fibrin degradation. Here, we investigated the role of Plg/Pla on key features of inflammation resolution in a murine model of severe pneumococcal pneumonia. High levels of Plg were observed in the airways following infection, accompanied by increased levels of plasminogen activator inhibitor-1, neutrophil elastase and Plg degradation fragments as inflammation progressed. Pla treatment of mice infected with Streptococcus pneumoniae (Sp) decreased neutrophilic infiltration in airways and lungs, accompanied by lower concentrations of the neutrophil chemoattractive chemokines CXCL1 and CXCL2, as well as the pro-inflammatory cytokines TNF, IL-6, and IL-1β. Pla-treatment also enhanced neutrophil apoptosis and efferocytosis, and slightly reduced bacterial loads in bronchoalveolar lavage. In addition, Pla decreased damage and fibrin deposition in lungs, improving pneumonia-driven pulmonary mechanical dysfunction, and rescuing mice from lethality. Pla-induced resolution of Sp-evoked inflammation was associated with neutrophil apoptosis, as the caspase-3 specific inhibitor Z-DEVD-FMK blocked Pla protective actions. In addition to the effects on neutrophils, intranasal instillation of Pla in naïve mice increased the number of alveolar macrophages and guided them toward a regulatory phenotype marked by enhanced efferocytosis of apoptotic neutrophils and increased bacterial phagocytosis, ultimately promoting host protection against pneumococcus-induced inflammation and tissue damage. In sum, our findings demonstrate that plasmin modulates the lung inflammatory milieu and promotes key pro-resolving events, namely neutrophil apoptosis and expansion of alveolar macrophage with enhanced efferocytosis and phagocytic abilities, resulting in improved lung function and survival in pneumococcal pneumonia.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"5 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005369","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}
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