Blood Vessels, Thrombosis & Hemostasis最新文献_第2页

Comprehensive assessment of endothelial dysfunction before cellular therapy: EASIX, local imaging, and systemic biomarkers 细胞治疗前内皮功能障碍的综合评估：EASIX，局部成像和全身生物标志物

Blood Vessels, Thrombosis & Hemostasis

Pub Date : 2025-11-01 DOI: 10.1016/j.bvth.2025.100105

Laura Simons , Lina Alasfar , Muath Qadoura , Jule Buhl , Franziska Sunderer , Felix Korell , Ignatios Ikonomidis , Maximilian Dietrich , Silvia Seidlitz , Hans Vink , Lena Maier-Hein , Michael Schmitt , Richard F. Schlenk , Carsten Müller-Tidow , Peter Dreger , Thomas Luft

Abstract

Endothelial dysfunction contributes to mortality after cellular therapies, yet its clinical assessment remains challenging. In this prospective observational study, we evaluated 169 patients undergoing allogeneic stem cell transplantation or chimeric antigen receptor T-cell therapy and 102 healthy controls to determine whether a comprehensive endothelial profile, including the endothelial activation and stress index (EASIX), glycocalyx thickness (via sublingual GlycoCheck microscopy), digital perfusion (Tivita hyperspectral imaging), endothelial serum markers (angiopoietin-2, soluble thrombomodulin [CD141], chemokine (C-X-C motif) ligand 8, chemokine (C-X-C motif) ligand 9, interleukin-18, enzyme-linked immunosorbent assays), and platelet aggregation (flow cytometry), correlates with clinical outcomes. We observed significant intercorrelations among EASIX, perfused boundary region (PBR), tissue perfusion, and endothelial serum markers. Importantly, elevated EASIX, angiopoietin-2, impaired PBR, and reduced digital perfusion were significantly associated with early sepsis, whereas EASIX also independently predicted nonrelapse mortality. These findings highlight the heterogeneity of endothelial responses to systemic insult and reinforce the need for multimodal assessment in a larger study. EASIX, as a simple and routinely available marker, emerges as a valuable tool to stratify endothelial risk and guide monitoring in patients undergoing cellular therapy. This trial was registered at www.ClinicalTrials.gov as #NCT05502887.

内皮功能障碍与细胞治疗后的死亡率有关，但其临床评估仍然具有挑战性。在这项前瞻性观察性研究中，我们评估了169名接受同种异体干细胞移植或嵌合抗原受体t细胞治疗的患者和102名健康对照者，以确定全面的内皮特征，包括内皮激活和应激指数（EASIX）、糖calyx厚度（通过舌下糖检查显微镜）、数字灌注（Tivita高光谱成像）、内皮血清标志物(血管生成素-2、可溶性血栓调节素[CD141]、趋化因子（C-X-C基序）配体8，趋化因子（C-X-C基序）配体9，白细胞介素-18，酶联免疫吸附测定)和血小板聚集（流式细胞术），与临床结果相关。我们观察到EASIX、灌注边界区（PBR）、组织灌注和内皮血清标志物之间存在显著的相互关系。重要的是，EASIX升高、血管生成素-2、PBR受损和指端灌注减少与早期败血症显著相关，而EASIX也独立预测非复发死亡率。这些发现强调了内皮细胞对系统性损伤反应的异质性，并加强了在更大的研究中进行多模式评估的必要性。EASIX作为一种简单且常规可用的标志物，在接受细胞治疗的患者中成为内皮风险分层和指导监测的有价值的工具。该试验在www.ClinicalTrials.gov注册，编号为#NCT05502887。

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引用次数: 0

The Syk inhibitor BI 1002494 impairs thrombus infill in a murine femoral artery occlusion without affecting hemostasis Syk抑制剂BI 1002494在不影响止血的情况下损害小鼠股动脉闭塞的血栓充盈

Blood Vessels, Thrombosis & Hemostasis

Pub Date : 2025-11-01 DOI: 10.1016/j.bvth.2025.100108

Md. Omar Faruque , Irina D. Pokrovskaya , Kelly K. Ball , Michael W. Webb , Sung W. Rhee , Brian Storrie

Abstract

Knowing structural organization of a clot at the single-cell level could lead to the development of drugs targeting specific structural features. We tested this premise in a murine femoral artery occlusion model using a narrow ferric chloride (FeCl₃) application strip to limit induction intensity. Under these conditions, occlusive clot formation was sensitive to the spleen tyrosine kinase (Syk) inhibitor BI 1002494, an indication of normative platelet response. Samples perpendicular or longitudinal to blood flow were imaged by montaged electron microscopy. Platelets were the predominant cell type. Tightly packed platelets were anchored to FeCl₃-induced damaged portions of the vessel wall, and aggregates of tightly packed platelets extended inward. Overall, the clots had a structure in which loosely packed platelets, often discoid in shape and rich in α-granules, filled pockets within the clot surrounded by zones of tightly adherent platelets. Red blood cells (RBCs), mainly entrapped, squeezed, and polyhedral in shape, were distributed in scattered patches. Based on platelet morphology, any effect of RBCs on platelet activation extended for a short distance, ∼5 μm. In Syk inhibitor–treated mice, structural formation of an occlusion was strongly inhibited; infill was impaired, resulting in a highly porous clot rich in dispersedly aggregated discoid shaped platelets. Blood flow was normal, and inhibitor had no apparent effect on the structure of a femoral puncture wound clot. We suggest that BI 1002494 produced a selective inhibition of thrombus structure by depressing intraplatelet signaling below a crucial threshold in the high flow occlusion model, but not in the lower flow puncture wound model.

摘要在单细胞水平上了解血栓的结构组织有助于开发针对特定结构特征的药物。我们在小鼠股动脉闭塞模型中测试了这一前提，使用窄氯化铁（FeCl3）应用条来限制诱导强度。在这些条件下，闭塞性血块形成对脾脏酪氨酸激酶（Syk）抑制剂BI 1002494敏感，这是血小板反应正常的指示。与血流垂直或纵向的样品用蒙太奇电子显微镜成像。血小板是主要的细胞类型。紧密包裹的血小板被锚定在fecl3诱导的血管壁损伤部分，紧密包裹的血小板聚集物向内延伸。总的来说，血栓的结构是松散堆积的血小板，通常呈盘状，富含α-颗粒，填充在血栓内的口袋，周围是紧密粘附的血小板区。红细胞以包裹、挤压、多面体为主，呈散斑分布。根据血小板形态，红细胞对血小板活化的任何影响都延伸了很短的距离，约5 μm。在Syk抑制剂处理的小鼠中，闭塞的结构形成被强烈抑制；充盈受损，导致高度多孔的凝块富含分散聚集的盘状血小板。血流量正常，抑制剂对股穿刺伤口血块结构无明显影响。我们认为，在高流量闭塞模型中，BI 1002494通过将血小板内信号抑制到一个关键阈值以下，对血栓结构产生选择性抑制，而在低流量穿刺伤口模型中则没有作用。

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引用次数: 0

Validation of plasmin-cleaved VWF as a biomarker for microthrombosis in Japanese patients with acute immune-mediated TTP 血浆纤溶酶裂解VWF作为日本急性免疫介导TTP患者微血栓形成的生物标志物的验证

Blood Vessels, Thrombosis & Hemostasis

Pub Date : 2025-10-30 DOI: 10.1016/j.bvth.2025.100126

Hinde El Otmani , Claudia Tersteeg , Karen Vanhoorelbeke , Masanori Matsumoto , Kazuya Sakai

引用次数: 0

A transgenic mouse model for reticulated platelet detection reveals expansion after myocardial ischemia/reperfusion 一种用于检测网状血小板的转基因小鼠模型在心肌缺血/再灌注后显示扩张

Blood Vessels, Thrombosis & Hemostasis

Pub Date : 2025-10-28 DOI: 10.1016/j.bvth.2025.100125

Muataz Ali Hamad , Nancy Schanze , Krystin Krauel , Achim Lother , Stefanie Perez-Feliz , Pia Iaconianni , Mark Zurek , Lama Almushkab , Josef Madl , Marie A. Hollenhorst , Peter Kohl , Thomas G. Nührenberg , Daniel Duerschmied

Abstract

Reticulated platelets are newly formed, RNA-rich platelets with heightened reactivity. Although elevated levels are observed after myocardial ischemia/reperfusion injury, their functional contributions to postischemic pathology remains poorly defined. We aimed to determine whether reticulated platelets actively contribute to inflammation and repair following myocardial ischemia and reperfusion, rather than serving solely as biomarkers of platelet turnover. We generated Pf4-Cre:RiboTag mice, in which hemagglutinin-tagged ribosomal proteins are selectively expressed in megakaryocytes and platelets. Using hemagglutinin-based flow cytometry, we identified reticulated platelets without relying on nucleic acid dyes. Surface marker expression and agonist responsiveness were evaluated ex vivo. Bulk RNA sequencing was performed on sorted reticulated and non-reticulated platelets 48 hours after ischemia/reperfusion injury. Hemagglutinin-based detection revealed a time-dependent increase in circulating reticulated platelets after myocardial ischemia/reperfusion, confirmed by conventional dye-based methods. These platelets exhibited higher baseline expression of glycoprotein Ibα and greater agonist-induced activation of glycoprotein IIb/IIIa and P-selectin. Transcriptomic profiling demonstrated enrichment of genes associated with platelet activation, cytoskeletal reorganization, and wound healing. Ligand-receptor analysis suggested interactions between reticulated platelets and cardiac endothelial cells, fibroblasts, and macrophages. In conclusion, reticulated platelets constitute a transcriptionally distinct, hyperreactive platelet subset that may modulate post–ischemia/reperfusion inflammation and tissue remodeling. This genetic model provides a platform for mechanistic studies and may inform therapeutic strategies targeting platelet-mediated responses in cardiovascular disease.

网状血小板是新形成的富含rna的血小板，具有较高的反应性。尽管在心肌缺血/再灌注损伤后观察到其水平升高，但其对缺血后病理的功能贡献仍不明确。我们的目的是确定网状血小板是否积极参与心肌缺血和再灌注后的炎症和修复，而不仅仅是作为血小板更新的生物标志物。我们培育了Pf4-Cre:RiboTag小鼠，其中血凝素标记的核糖体蛋白在巨核细胞和血小板中选择性表达。使用基于血凝素的流式细胞术，我们鉴定了网状血小板，而不依赖于核酸染料。体外评估表面标记物表达和激动剂反应性。在缺血/再灌注损伤后48小时，对分选的网状和非网状血小板进行大量RNA测序。基于血凝素的检测显示心肌缺血/再灌注后循环网状血小板的时间依赖性增加，这是传统染料方法所证实的。这些血小板表现出更高的糖蛋白Ibα的基线表达和更大的激动剂诱导的糖蛋白IIb/IIIa和p -选择素的激活。转录组学分析显示与血小板活化、细胞骨架重组和伤口愈合相关的基因富集。配体-受体分析表明网状血小板与心脏内皮细胞、成纤维细胞和巨噬细胞之间存在相互作用。综上所述，网状血小板构成了一个转录上独特的、高反应性的血小板亚群，可能调节缺血/再灌注后的炎症和组织重塑。该遗传模型为机制研究提供了一个平台，并可能为针对血小板介导的心血管疾病反应的治疗策略提供信息。

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引用次数: 0

From oversight to insight: the curious case of the endothelial insulin receptor 从疏忽到洞察：内皮胰岛素受体的奇特案例

Blood Vessels, Thrombosis & Hemostasis

Pub Date : 2025-10-28 DOI: 10.1016/j.bvth.2025.100123

Rahul Rajala

Abstract

Insulin is produced in the pancreas and regulates blood glucose levels by binding to the insulin receptor (IR) thereby stimulating glucose uptake into cells. Inadequate insulin production or dysregulated IR signaling leads to diabetes. Most research, to date, has focused on enhancing insulin production or correcting impaired IR signaling in tissues of nutrient exchange, for example, muscle or fat. However, the transendothelial trafficking of insulin to target tissues is also crucial in regulating organismal responses to insulin. In fact, this process has been established as the rate-limiting step for glucose disposal. Initially, it was believed that the transendothelial trafficking of insulin was dependent on endothelial IR. Unfortunately, subsequent studies have demonstrated that mice lacking endothelial IR possess minimal changes in insulin sensitivity. These studies have contributed to the widespread belief that endothelial IR does not regulate insulin trafficking and insulin sensitivity. However, recent genetic studies from our laboratory, and others, have shown that enhancing endothelial IR activity improves insulin sensitivity. These studies underscore the crucial role of endothelial IR in regulating insulin trafficking and metabolism. Now that researchers have conclusively demonstrated the presence and function of IR on endothelial cells (ECs) in vivo, it is essential to clarify why this receptor has been so controversial. Additionally, this timely review aims to encourage vascular biology researchers to explore how endothelial IR is regulated and identify new roles for this receptor on ECs.

胰岛素在胰腺中产生，并通过与胰岛素受体（IR）结合从而刺激细胞对葡萄糖的摄取来调节血糖水平。胰岛素分泌不足或IR信号失调导致糖尿病。迄今为止，大多数研究都集中在增强胰岛素产生或纠正营养交换组织中受损的IR信号，例如肌肉或脂肪。然而，胰岛素的经内皮转运到靶组织在调节机体对胰岛素的反应中也是至关重要的。事实上，这个过程已经被确定为葡萄糖处理的限速步骤。最初，人们认为胰岛素的跨内皮转运依赖于内皮IR。不幸的是，随后的研究表明，缺乏内皮IR的小鼠在胰岛素敏感性方面的变化很小。这些研究使人们普遍认为内皮IR不调节胰岛素运输和胰岛素敏感性。然而，最近来自我们实验室和其他实验室的遗传学研究表明，增强内皮IR活性可以改善胰岛素敏感性。这些研究强调了内皮IR在调节胰岛素运输和代谢中的重要作用。既然研究人员已经在体内确凿地证明了IR在内皮细胞（ECs）上的存在和功能，那么有必要澄清为什么这种受体如此有争议。此外，这篇及时的综述旨在鼓励血管生物学研究人员探索内皮IR是如何调节的，并确定该受体在内皮细胞中的新作用。

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引用次数: 0

Transfusion-induced functional and metabolic shifts in stored platelets: limitations of in vitro assessment 输血诱导储存血小板的功能和代谢变化：体外评估的局限性

Blood Vessels, Thrombosis & Hemostasis

Pub Date : 2025-10-28 DOI: 10.1016/j.bvth.2025.100120

Tahsin Özpolat , Daire A. Byrne , S. Lawrence Bailey , Aastha Chauhan , Julie A. Reisz , Hannah J. Johnson , Jennifer Doan , Maria Ronquillo , Reheman Adili , Xiaoyun Fu , Angelo D’Alessandro , Moritz Stolla

Abstract

The impact of the stored platelet extracellular environment on function and the ability of platelets to change their function upon transfer into in vivo environments remain poorly understood. Human platelets were stored ex vivo at 20°C to 24°C (room temperature–stored platelets [RTPs]) or 1°C to 6°C (cold-stored platelets [CSPs]) and tested for function in the concomitant storage plasma or fresh plasma. In mice, we tested platelet function after ex vivo storage in concomitant plasma and after transfusion to mice ex vivo and in vivo. We also investigated stored platelet-rich plasma before and after transfusion to mice for metabolomics by liquid chromatography–tandem mass spectrometry. In in vitro, human RTPs showed a greater ability than CSPs to improve α_IIbβ₃ integrin activation upon dilution with fresh frozen plasma. Mouse RTPs’ in vitro integrin activation improved more than that for CSPs after transfusion. Surprisingly, in mice, CSPs facilitated significantly greater platelet accumulation than RTPs in vivo. In contrast, fibrin generation was significantly more robust in RTPs than in CSPs during the early stages of hemostasis. In mouse RTPs, more metabolites changed significantly upon transfusion than in mouse CSPs. Transfusion decreased carnitine species, fatty acid metabolites, and amino acids only in RTPs, whereas polyamines decreased only in CSPs. The recovery from storage-induced oxidative stress was more complete in RTPs than in CSPs. Our findings highlight the severe limitations of in vitro testing of stored platelets. Platelet-rich plasma undergoes profound changes in metabolomic composition following transfusion. We further demonstrate the ability of platelets to undergo marked changes upon transfusion in RTPs more so than CSPs.

摘要血小板细胞外储存环境对血小板功能的影响以及血小板在转移到体内环境后改变其功能的能力仍然知之甚少。将人血小板在20°C至24°C（室温储存血小板[RTPs]）或1°C至6°C（冷藏血小板[CSPs]）的离体条件下储存，并在同时储存的血浆或新鲜血浆中检测其功能。在小鼠中，我们检测了血小板在体外储存在伴随血浆中以及在体外和体内输注小鼠后的功能。我们还通过液相色谱-串联质谱法研究了输注小鼠前后储存的富血小板血浆的代谢组学。在体外实验中，人rtp用新鲜冷冻血浆稀释后，比csp更能改善αIIbβ3整合素的活化。输血后小鼠RTPs的体外整合素激活比CSPs改善更多。令人惊讶的是，在小鼠体内，CSPs比rtp促进了更大的血小板积累。相比之下，在止血的早期阶段，rtp的纤维蛋白生成明显比csp更强。在小鼠rtp中，与小鼠csp相比，更多的代谢物在输血后发生了显著变化。输血仅在rtp中减少肉毒碱种类、脂肪酸代谢物和氨基酸，而多胺仅在csp中减少。rtp比csp从储存诱导的氧化应激中恢复得更完全。我们的发现强调了体外检测储存血小板的严重局限性。输血后富血小板血浆代谢组学成分发生深刻变化。我们进一步证明血小板在rtp患者输血时比csp患者更容易发生显著变化。

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引用次数: 0

Acute pain in pediatric patients with SCD without chronic pain is associated with elevated VCAM-1 and P-selectin adhesion 无慢性疼痛的SCD患儿急性疼痛与VCAM-1和p -选择素粘连升高相关

Blood Vessels, Thrombosis & Hemostasis

Pub Date : 2025-10-28 DOI: 10.1016/j.bvth.2025.100121

Olufunke Y. Martin , Rasa Borhan , Aliya U. Zaidi , Xiufeng Gao , Kaleab Ribbiso , Deepika S. Darbari , Patrick C. Hines , Andrew D. Campbell

引用次数: 0

Elevated VWF with normal ADAMTS13 in pediatric sickle cell disease: links to crises and ischemic stroke 儿童镰状细胞病VWF升高与ADAMTS13正常：与危象和缺血性卒中相关

Blood Vessels, Thrombosis & Hemostasis

Pub Date : 2025-10-28 DOI: 10.1016/j.bvth.2025.100124

Fred Abala , Gordon Ogweno , Irene Nzamu , Eliud N. M. Njagi

Abstract

Sickle cell disease (SCD) remains a significant health care challenge associated with high burden or morbidity and mortality in sub-Saharan Africa, often resulting from vaso-occlusion and ischemic stroke. In under-resourced communities, inaccessibility of magnetic resonance imaging and computed tomography scanning complicates screening; therefore, there is a need for hematological assays as accessible cost-effective alternatives to bridge the gap. This cross-sectional study involving 80 pediatric patients with SCD and 32 healthy controls focused on the von Willebrand factor (VWF)–a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13 (ADAMTS13) axis, considered to be involved in vaso-occlusion and ischemia in SCD. Using hematological assays, the study evaluated full blood count (FBC), VWF antigen (VWF:Ag), VWF activity (VWF:Act), and ADAMTS13 antigen levels in patients with SCD and healthy controls. The study revealed elevated neutrophil counts coupled with reduced red blood cell (RBC) counts, lower hemoglobin levels, elevated nucleated RBCs, and lower platelet counts in pediatric SCD phenotypes compared with those in healthy controls. VOC was associated with elevated VWF:Ag, normal VWF:Act, and normal ADAMTS13 antigen, whereas ischemic stroke cases showed no significant differences in VWF:Ag, VWF:Act, and ADAMTS13 antigen levels compared with those in the healthy controls. Compared with healthy controls, patients with SCD in steady state had elevated ADAMTS13 antigen levels. These findings indicate chronic inflammation and hemolysis, likely sustained by neutrophil-linked proinflammatory mediators, might be involved in the dysregulation of the VWF-ADAMTS13 axis, increasing the risk of vaso-occlusion. Therefore, FBC, VWF:Ag, VWF:Act, and ADAMTS13 antigen may be used for risk stratification and the early diagnosis of pediatric SCD complications.

在撒哈拉以南非洲地区，镰状细胞病（SCD）仍然是一个重大的卫生保健挑战，与高负担或发病率和死亡率相关，通常由血管闭塞和缺血性中风引起。在资源不足的社区，无法获得磁共振成像和计算机断层扫描使筛查复杂化；因此，需要血液学分析作为可获得的具有成本效益的替代方法来弥补这一差距。这项横断面研究涉及80名SCD患儿和32名健康对照，重点研究血管性血友病因子(VWF) -一种具有血小板反应蛋白1型基元的崩解素和金属蛋白酶，成员13 （ADAMTS13）轴，被认为参与SCD的血管闭塞和缺血。通过血液学检测，该研究评估了SCD患者和健康对照者的全血细胞计数（FBC）、VWF抗原（VWF:Ag）、VWF活性（VWF:Act）和ADAMTS13抗原水平。该研究显示，与健康对照组相比，儿童SCD表型中中性粒细胞计数升高，红细胞计数降低，血红蛋白水平降低，有核红细胞升高，血小板计数降低。VOC与VWF:Ag、VWF:Act和ADAMTS13抗原升高有关，而缺血性脑卒中患者的VWF:Ag、VWF:Act和ADAMTS13抗原水平与健康对照组相比无显著差异。与健康对照组相比，稳态SCD患者ADAMTS13抗原水平升高。这些发现表明，慢性炎症和溶血，可能由中性粒细胞相关的促炎介质维持，可能参与VWF-ADAMTS13轴的失调，增加血管闭塞的风险。因此，FBC、VWF:Ag、VWF:Act和ADAMTS13抗原可用于儿童SCD并发症的风险分层和早期诊断。

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引用次数: 0

Automated natural language processing to identify venous thromboembolism from diagnostic imaging reports 从诊断成像报告中识别静脉血栓栓塞的自动自然语言处理

Blood Vessels, Thrombosis & Hemostasis

Pub Date : 2025-10-28 DOI: 10.1016/j.bvth.2025.100122

Naveen Subramanian , Hector Garcia Pleitez , Daniel Nguyen , Denái R. Milton , Partow Kebriaei , Elizabeth Shpall , Lee Cheng , Jing Lu , Shida Jin , Carol C. Wu , Rahul A. Sheth , Alessandra Ferrajoli , Katy M. Toale , Michael H. Kroll , Cristhiam M. Rojas-Hernandez

Abstract

The annual incidence of venous thromboembolism (VTE) may be 50-fold increased after allogeneic hematopoietic stem cell transplant (HSCT). Such incidence data, as well as data that establish clinical variables resulting in this enhanced risk, have generally required manual chart review. This cumbersome process can be improved by natural language processing (NLP) algorithms designed to detect VTE in electronic medical record systems. We describe the development of an institutional NLP algorithm for VTE detection, and our evaluation of its performance in detecting VTE in patients who recently underwent HSCT. We retrospectively reviewed adult patients between 2016 and 2020. NLP assessed patient records for acute VTE within 100 days of HSCT, and manual chart review was performed for comparison. NLP sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. A total of 1300 electronic health records were analyzed. The 100-day VTE incidence rate as determined via manual chart review and NLP was 10.3% and 8.8%, respectively. NLP’s specificity, sensitivity, PPV, and NPV were >0.85. Of the 19 events not identified by NLP, all were found in radiology or vascular laboratory reports overlooked by NLP. These results demonstrate excellent performance of NLP for identifying VTE in HSCT patients. Future refinement of NLP, and its combination with other detection methods should provide better detection of VTE in this and other at-risk cohorts.

摘要同种异体造血干细胞移植（HSCT）后静脉血栓栓塞（VTE）的年发病率可能增加50倍。这种发病率数据，以及建立导致这种风险增加的临床变量的数据，通常需要手工检查图表。这个繁琐的过程可以通过自然语言处理（NLP）算法来改进，该算法设计用于检测电子医疗记录系统中的静脉血栓栓塞。我们描述了一种用于静脉血栓栓塞检测的机构NLP算法的发展，以及我们对其在最近接受了HSCT的患者中检测静脉血栓栓塞的性能的评估。我们回顾性地回顾了2016年至2020年的成年患者。NLP评估了HSCT术后100天内急性静脉血栓栓塞的患者记录，并进行了手工图表回顾以进行比较。计算NLP的敏感性、特异性、阳性预测值（PPV）和阴性预测值（NPV）。共分析了1300份电子健康记录。通过手工图表检查和NLP确定的100天静脉血栓栓塞发生率分别为10.3%和8.8%。NLP的特异性、敏感性、PPV和NPV均为>；0.85。在NLP未发现的19个事件中，所有事件都是在被NLP忽略的放射学或血管实验室报告中发现的。这些结果表明NLP在鉴别HSCT患者的静脉血栓栓塞方面表现优异。未来对NLP的改进，以及与其他检测方法的结合，应该能更好地检测出这一人群和其他高危人群的静脉血栓栓塞。

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引用次数: 0

Treatment of canine hemophilia A via intraosseous delivery of a platelet-specific factor VIII–lentiviral vector 血小板特异性因子viii -慢病毒载体骨内递送治疗犬血友病A

Blood Vessels, Thrombosis & Hemostasis

Pub Date : 2025-10-24 DOI: 10.1016/j.bvth.2025.100119

Cameron W. Rementer ∗ , Chong Li ∗ , Timothy C. Nichols , Xiaohe Cai , Julia Joo , Xuefeng Wang , Mark Kloos , Nneka George , Ting-Yen Chao , Yuanyi Xu , Mortimer Poncz , Hans D. Ochs , David J. Rawlings , Carol H. Miao

Abstract

Hemophilia A (HemA) is a genetic disease resulting from a factor VIII (FVIII) deficiency. Traditional protein infusions to treat HemA are costly and inconvenient and require repeated dosing. We demonstrated previously that intraosseous (IO) gene therapy via delivery of lentiviral vectors (LVs) into bone marrow targeting FVIII expression in platelets successfully treated HemA mice. To facilitate the translation of this novel strategy to clinical application, we investigated the treatment of HemA dogs using IO gene therapy. The vesicular stomatitis virus–pseudotyped G-cF8-LV incorporating a platelet-specific promoter, Gp1bα, and canine F8 gene was injected into the tibia or iliac bones of 4 HemA dogs. All dogs recovered well from the procedure and had blood chemistry values within normal ranges. Canine FVIII can be detected in platelets with the highest expression ∼40 to 50 days after the procedure, and the expression persisted for the experimental duration in all treated dogs. Copy numbers of the transgene were persistently detected from the genomic DNA isolated from peripheral mononuclear blood cells. The shortened whole-blood clotting time and improved parameters evaluated through thromboelastography testing at multiple time points indicated improved hemostasis after gene therapy. Furthermore, the IO gene therapy was well tolerated and did not produce any toxicity in the treated dogs. Most significantly, the treated dogs experienced fewer bleeding events per year after gene therapy than before. Our study demonstrated a potentially safe and effective in vivo gene therapy strategy for treating people with HemA.

血友病A （HemA）是一种由因子VIII （FVIII）缺乏引起的遗传病。传统的蛋白输注治疗血HemA既昂贵又不方便，而且需要反复给药。我们之前证明，通过将慢病毒载体（lv）递送到骨髓中靶向血小板中FVIII表达的骨内（IO）基因治疗成功治疗了HemA小鼠。为了促进这种新策略的临床应用，我们研究了使用IO基因疗法治疗HemA犬。将含有血小板特异性启动子Gp1bα和犬F8基因的水泡性口炎病毒假型G-cF8-LV注射到4只HemA犬的胫骨或髂骨中。所有的狗都从手术中恢复良好，血液化学值在正常范围内。犬FVIII可在血小板中检测到，在手术后40至50天达到最高表达，并且在所有治疗犬的实验期间均持续表达。从外周血单核细胞分离的基因组DNA中持续检测到转基因的拷贝数。全血凝血时间缩短，多个时间点血栓弹性成像指标改善，表明基因治疗后止血改善。此外，IO基因疗法耐受性良好，对接受治疗的狗没有产生任何毒性。最重要的是，经过基因治疗的狗每年的出血事件比之前少。我们的研究证明了一种潜在安全有效的体内基因治疗策略可以治疗HemA患者。

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引用次数: 0