Seminars in hematology最新文献

{"title":"Sickle Cell Disease: Expanding the Frontiers of Pathophysiology and Therapeutics","authors":"Swee Lay Thein","doi":"10.1053/j.seminhematol.2026.06.004","DOIUrl":"10.1053/j.seminhematol.2026.06.004","url":null,"abstract":"","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"63 1","pages":"Pages 1-2"},"PeriodicalIF":4.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular pathogenesis of HbSC disease","authors":"John Gibson,&nbsp;Rasiqh Wadud,&nbsp;Pengyi Ding,&nbsp;David Rees,&nbsp;John Brewin,&nbsp;Kathleen Connolly","doi":"10.1053/j.seminhematol.2026.05.002","DOIUrl":"10.1053/j.seminhematol.2026.05.002","url":null,"abstract":"<div><div>Sickle cell patients with HbSC genotype represent the second commonest form of sickle cell disease (SCD) amongst people of African origin. HbSC cells are markedly shrunken. Although containing only about half the amount of HbS as red cells from homozygous HbSS patients, HbS in HbSC cells will still polymerise on deoxygenation—which underlies the various clinical complications. The cause of dehydration is increased cation permeability mediated via three main transport systems: Piezo1, the Gárdos channel and the KCl cotransporter (KCC). Channel activity in HbSC cells is reduced in comparison with those homozygous for HbS. By contrast, KCC activity is higher, especially and unusually in the denser red cell fractions. Inhibition of KCC activity shifts the density of HbSC reticulocytes to less dense fractions. In HbSC patients, clinical severity correlates with KCC activity. Inhibition of KCC activity in HbSC patients therefore remains an obvious therapeutic strategy but has not been vigorously pursued. Clinical trials involving HbSC patients are few. Recent advances in culturing immortalized red cell lines containing the HbSC mutation and the recent generation of transgenic HbSC mice models offer the prospect of much needed impetus to facilitate research into this disease and into developing cost-effective chemotherapeutic interventions.</div></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"63 1","pages":"Pages 59-68"},"PeriodicalIF":4.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148144480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"More disease-modifying therapies for sickle cell disease: Are small molecules and drug repurposing the way forward?","authors":"Charles T. Quinn","doi":"10.1053/j.seminhematol.2026.04.001","DOIUrl":"10.1053/j.seminhematol.2026.04.001","url":null,"abstract":"<div><div>Despite advances in understanding the molecular and cellular pathophysiology of sickle cell disease (SCD), the development of effective pharmacologic therapies has been slow. Hydroxyurea, a small molecule repurposed decades ago, remains the cornerstone of disease-modifying therapy, and it is the benchmark against which new therapies are measured. Recent approvals of additional agents have expanded therapeutic options, yet their clinical benefits have been narrow, sometimes uncertain, or complicated by regulatory withdrawals, underscoring the persistent challenges of translating biologically plausible mechanisms into clinical benefits. The central pathogenic event in SCD, the polymerization of deoxygenated sickle hemoglobin (Hb), initiates a cascade of red blood cell (RBC) injury, hemolysis, vaso-occlusion, vasculopathy, inflammation, and progressive organ damage. Drugs that act proximally in this pathway are more likely to be broadly effective. Small molecules, in particular, are appealing because of oral bioavailability, ability to enter RBCs, and scalability in manufacturing. In parallel to development of new agents, drug repurposing can accelerate the process of drug development by using agents with known pharmacologic and safety profiles. This review highlights recent and emerging disease-modifying approaches for SCD, with emphasis on small molecules and repurposed drugs, including pyruvate kinase activators, epigenetic fetal hemoglobin inducers, Hb oxygen-affinity modulators, and iron restriction strategies. Each therapy addresses distinct yet interconnected aspects of SCD pathophysiology. No single therapy is likely to be completely protective across the lifespan. The future of SCD pharmacotherapy will likely include mechanism-based combination therapies concurrent with the advancements in genetic and cellular therapies.</div></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"63 1","pages":"Pages 28-36"},"PeriodicalIF":4.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147875421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pain in SCD—Many mechanisms and mysteries","authors":"Olufunke Y. Martin,&nbsp;Deepika S. Darbari","doi":"10.1053/j.seminhematol.2026.05.006","DOIUrl":"10.1053/j.seminhematol.2026.05.006","url":null,"abstract":"<div><div>Pain is the most common complication experienced by individuals living with sickle cell disease (SCD). While episodes of acute pain, also known as vaso-occlusive crises, are the hallmark of the disease, chronic pain is prevalent in SCD and is associated with many comorbidities. We review current understanding of pain in SCD across the lifespan, integrating definitions, mechanistic categories, and management within biologic, psychosocial, and environmental contexts. Acute vaso-occlusive pain, which emerges as early as infancy, evolves from intermittent nociceptive events driven by multicellular vaso-occlusion, hemolysis, inflammation, and ischemia-reperfusion injury. Chronic pain, which commonly emerges in adolescence and increases with age, reflects heterogeneous nociceptive, neuropathic, and nociplastic mechanisms shaped by SCD-related complications, psychological comorbidities, and social stressors. Chronic pain also contributes to the pathogenesis of acute pain through sensitization processes. Evaluation of mechanisms using tools such as quantitative sensory testing and functional neuroimaging supports hyperexcitability within the peripheral and central nervous system, which is likely important in the development and maintenance of chronic pain. Therapeutically, most guidelines to manage SCD pain are limited by low-certainty evidence; nonetheless, multimodal strategies emphasize timely individualized opioids with nonopioid and nonpharmacologic adjuncts, which are most effective when delivered within multidisciplinary, patient-centered care models. We propose that an individualized whole-person care approach guided by patient-report and biomarker-based framework is key in delineating mechanisms and advancing mechanistic interventions to address pain and related morbidities in SCD.</div></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"63 1","pages":"Pages 3-15"},"PeriodicalIF":4.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148376790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"outside front cover, PMS 8883 metallic AND 4/C","authors":"","doi":"10.1053/S0037-1963(26)00072-7","DOIUrl":"10.1053/S0037-1963(26)00072-7","url":null,"abstract":"","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"63 1","pages":"Page CO1"},"PeriodicalIF":4.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148647180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bone marrow failure in telomere biology disorders: Current understanding and the emerging landscape of non-transplant therapies.","authors":"Jennifer M Wen, Nicholas J Gloude, Christen L Ebens","doi":"10.1053/j.seminhematol.2026.03.002","DOIUrl":"10.1053/j.seminhematol.2026.03.002","url":null,"abstract":"<p><p>Telomere biology disorders (TBDs) are a heterogeneous group of inherited systemic diseases caused by pathogenic variants in genes encoding telomerase or proteins involved in telomere maintenance or protection. With very short and/or dysfunctional telomeres, patients with TBD have clinical manifestations clustered in tissues with high rates of cell proliferation. Bone marrow failure (BMF) is the most common hematologic complication of a TBD and can precede the development of more difficult-to-treat malignant transformation. However, not all patients with TBD develop BMF, and some genotype/phenotype correlations are emerging. While allogeneic hematopoietic cell transplant (HCT) is curative for BMF in TBD, toxicities of the conditioning regimen can be detrimental to other organs. Balancing the risk of malignant transformation with HCT toxicity is a core challenge for providers who care for patients with TBD-associated BMF. Herein, we review the clinical presentation, pathophysiology, surveillance, and non-HCT treatment of BMF in TBD, including supportive care, androgens, thrombopoietin receptor agonists, and investigational approaches.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":"473-478"},"PeriodicalIF":4.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147575209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diagnosis and management of hematologic malignancies in the context of telomere biology disorders.","authors":"Alejandro Ferrer, Mrinal M Patnaik","doi":"10.1053/j.seminhematol.2026.03.012","DOIUrl":"10.1053/j.seminhematol.2026.03.012","url":null,"abstract":"<p><p>Telomere biology disorders (TBDs) are inherited conditions characterized by premature telomere shortening, leading to multisystemic manifestations and a high predisposition to hematologic complications. These include mainly myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) that may show a unique mutational spectrum and cytogenetic abnormalities. Management of MDS/AML in TBD is challenging due to heightened sensitivity to DNA-damaging agents and transplant-related toxicity, necessitating individualized approaches and multidisciplinary care. Emerging therapies such as thymidine supplementation, gene therapy, and treatment with antisense oligonucleotides, offer promising results for improving clinical outcomes. Continued research and collaborative efforts are essential to optimize screening, risk stratification, and treatment strategies for this vulnerable population.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":"479-485"},"PeriodicalIF":4.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147820088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Telomere biology disorders and hepatic disease.","authors":"Sana A Pirzada, Wesam Aleyadeh, Sawsan Fathma, Christopher Koh, Aurélie Plessier, David E Kleiner, Theo Heller","doi":"10.1053/j.seminhematol.2026.05.004","DOIUrl":"10.1053/j.seminhematol.2026.05.004","url":null,"abstract":"<p><p>Telomere biology disorders (TBDs) are rare inherited conditions caused by defects in telomere maintenance genes, leading to premature cellular aging and multisystem disease. The liver is the third most affected organ after the bone marrow and the lungs. Liver involvement ranges from asymptomatic biochemical abnormalities to porto-sinusoidal vascular disease, early-onset cirrhosis, and hepatopulmonary syndrome, often presenting without classic extrahepatic features of TBDs and posing significant diagnostic challenges. Disease severity and age of onset are strongly influenced by telomere length and genetic inheritance patterns. Autosomal recessive, X-linked recessive, and de novo TINF2-associated inheritance patterns are associated with severe childhood liver disease, while autosomal dominant inheritance patterns present in adulthood with isolated liver pathology. Acquired liver disease may also independently lead to telomere attrition and accelerate cellular senescence and fibrosis progression. Currently, management of TBD-related liver disease is largely supportive, with limited evidence suggesting potential benefit from androgen therapy, and there is growing experience supporting liver transplantation, particularly for advanced disease or hepatopulmonary syndrome. Early recognition, multidisciplinary care, and genetic counseling are essential to optimize outcomes. Future clinical trials studying telomere-targeted therapies warrant focus on hepatic endpoints.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":"503-512"},"PeriodicalIF":4.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148056699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diagnosis and management of telomere biology disorders in developing countries.","authors":"Alfredo Rodríguez, Brenda A Avendaño-Robles, Marilia B Catto, Rocío Juárez-Velázquez, Rodrigo T Calado","doi":"10.1053/j.seminhematol.2026.04.004","DOIUrl":"10.1053/j.seminhematol.2026.04.004","url":null,"abstract":"<p><p>Telomere biology disorders (TBDs) have a heterogeneous presentation deepened by variable, age-dependent, multisystem manifestations. In low- and middle-income countries, delayed diagnosis is common due to limited access to confirmatory testing. As a result, diagnosis frequently relies on clinical pattern recognition by hematologists and geneticists. This review summarizes practical approaches to suspecting, evaluating, and managing TBDs in resource-constrained settings. We highlight pivotal clinical signs and \"red flag\" combinations that should strengthen the suspicion of a TBD, including persistent cytopenias, hypocellular bone marrow, mucocutaneous features, early-onset idiopathic pulmonary fibrosis, unexplained chronic liver disease, immunodeficiency, and early malignancy. We present pragmatic diagnostic algorithms when specialized tests are unavailable, emphasizing careful family history recording, thorough full-body examination, and use of basic laboratory test tools, such as serial complete blood counts (CBC), spirometry with diffusing capacity for carbon monoxide, and noninvasive hepatic assessment, for strong suspicion of TBDs. Current modalities for telomere length (TL) assessment are reviewed with attention to feasibility and limitations in LMICs, including Terminal Restriction Fragment analysis, quantitative PCR, Flow-fluorescence in situ hybridization, and emerging long-read sequencing approaches. Management requires structured, multidisciplinary surveillance for hematologic decline, detection of clonal evolution, pulmonary and hepatic complications, and cancer risk. We review implementable monitoring strategies and discuss key therapeutic considerations in LMICs, including androgen therapy as a widely applicable disease-modifying option and the substantial logistical barriers to hematopoietic stem cell transplantation, donor evaluation, and long-term follow-up. Resource-stratified care pathways and regional referral networks are essential to improve outcomes for patients with TBDs in developing countries.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":"521-531"},"PeriodicalIF":4.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148006231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Telomeres biology disorders: the past, the present and the future.","authors":"Emma M Groarke, Fernanda Gutierrez-Rodrigues","doi":"10.1053/j.seminhematol.2026.06.001","DOIUrl":"https://doi.org/10.1053/j.seminhematol.2026.06.001","url":null,"abstract":"","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"62 6","pages":"447-448"},"PeriodicalIF":4.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148212542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}