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Tissue Factor Pathway-Driven Initial Thrombin Generation is Associated with Hypercoagulability in Obesity.
IF 5 2区 医学 Q1 HEMATOLOGY Pub Date : 2025-03-06 DOI: 10.1055/a-2552-2050
Yuichi Kamikubo, Satomi Nagaya, Rina Inoue, Koichi Yamaguchi, Riyo Morimoto-Kamata, Eriko Morishita, Fahumiya Samad, Naoki Ohkura, Kenichi Inoue

Background and objectives: Initial thrombin (FIIa) generated via the tissue factor (TF) pathway plays a crucial role in amplifying coagulation. There is growing evidence that the TF pathway might contribute to hypercoagulation in obesity. However, it is unclear if the initial generation of FIIa (TG) is associated with hypercoagulation in obesity, due to the lack of appropriate assays. This study aims to evaluate association between TF pathway-driven initial TG and hypercoagulability in obesity.

Methods: We measured the initial TG levels in plasma from male Tsumura Suzuki obese diabetes (TSOD) mice and overweight subjects using the highly sensitive TG assay. To induce initial TG, TF was added to the plasma and incubated at 37 °C for up to 3 min. After quenching the TG, we quantified the generated FIIa by kinetically monitoring its amidolytic activity with a fluorogenic substrate.

Results and conclusions: We observed that initial TG levels were significantly higher in TSOD mice (n=31) compared to non-obese mice (n=32). Even in the absence of exogenous TF, initial TG levels in obese mice and overweight individuals were elevated when procoagulant phospholipids were added alone. Moreover, the increased initial TG that the inhibitory anti-TF antibody abolished was detectable in reconstituted plasma including pellets prepared by high-speed centrifugation of plasma from obese mice, not in plasma supernatant. We attributed the promotion of the initial TG to the increase in procoagulant TF-bearing microvesicles in circulation. Based on the findings, measuring TF pathway-driven initial TG could be a valuable method for assessing hypercoagulability in obesity.

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引用次数: 0
Middle-throughput LC-MS-based Platelet Proteomics with Minute Sample Amounts Using Semiautomated Positive Pressure FASP in 384-Well Format. 采用384孔格式(PF384)的半自动正压FASP,中通量LC-MS-based血小板蛋白质组学。
IF 5 2区 医学 Q1 HEMATOLOGY Pub Date : 2025-03-06 DOI: 10.1055/a-2516-1812
Stefan Loroch, Eleftherios Panagiotidis, Kristoffer Klewe, Frauke Swieringa, Johan W M Heemskerk, Jan-Paul Lerch, Andreas Greinacher, Ulrich Walter, Kerstin Jurk, Tobias John, Katalin Barkovits, Thomas Dandekar, Katrin Marcus, Johannes Balkenhol

Comprehensive characterization of platelets requires various functional assays and analytical techniques, including omics disciplines, each demanding a separate aliquot of the given sample. Consequently, sample material for each assay is often highly limited, necessitating the downscaling of methods to work with just a few micrograms of platelet protein.Here, we present a novel sample preparation platform for proteomics analysis using only 3 μg of purified platelet protein, corresponding to 2 × 106 platelets, which can be obtained from approximately 2 to 8 μL of blood from a healthy individual (1.5 × 105-4.5 × 105 platelets/μL) or approximately 100 μL of blood from a patient with severe thrombocytopenia (<2 × 104 platelets/µL).Using this platform, we detected a significant fraction of key players in the platelet activation cascade and, most importantly, identified 36 clinically relevant platelet disease markers even with a non-state-of-the art instrument. This makes LC-MS-based proteomics a highly attractive alternative to conventional assays, which often require milliliters of blood. Our platform transitions from our previously established 96-well proteomics workflow (PF96), which has been successfully employed in numerous platelet proteomics studies, into the 384-well format. This transition is accompanied by (1) a more than two-fold increase in sensitivity, (2) improved reproducibility, (3) a four-fold increase in throughput, allowing 1,536 samples to be processed per lab worker per week, and (4) reduced sample preparation costs.Thus, LC-MS-based platelet proteomics offers a compelling alternative to immunoaffinity assays (which depend on antibody availability and quality), as well as to genomic assays (which can only reveal genotypes). In summary, in conjunction with recent advances in LC-MS instrumentation, our platform represents a highly valuable tool for rapid phenotyping of platelets in research with extraordinary potential for future employment in companion or routine diagnostics.

血小板的全面表征需要各种功能测定和分析技术,包括组学学科,每一个都需要一个给定样本的单独的等量物。因此,每次测定的样品材料通常是高度有限的,缩小比例是有效样品开发的先决条件。在这里,我们介绍了我们最近引入的基于96孔的蛋白质组学工作流程(PF96)转移到384孔格式(PF384),允许在处理微量血小板蛋白量时显着提高灵敏度。此外,4倍高的吞吐量(每个实验室工作人员每周1500个样品)可以轻松满足现代LC-MS仪器的吞吐能力。我们确定了最佳的样品负载,然后强调了与我们之前的样品制备方法相比的优势,仅处理来自22个健康供体的纯化血小板蛋白3µg。主要优点有:(1)提高了鉴定和分析物回收率,特别是低拷贝数蛋白,信号强度分别提高了+ 130%和+ 107%(肽和蛋白水平)。(2)血小板激活的关键参与者,包括膜受体PAR4, P2X1, GPVI, GPV, GPIX和下游介质AKT, PKA, Rap1,Lyn (III)提高了再现性,将检测丰度较低/较高的疾病标志物的技术差异从22 / 25%降低到16 / 19%,(IV)将样品制备吞吐量提高了4倍。综上所述,PF384在临床蛋白质组学中具有广阔的应用前景,并可能为微量血小板蛋白质组学应用于分子诊断铺平道路。
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引用次数: 0
Inhibitor formation in the era of novel haemophilia treatment - a humanized mouse model to answer our questions?
IF 5 2区 医学 Q1 HEMATOLOGY Pub Date : 2025-03-06 DOI: 10.1055/a-2551-8561
Lize F D van Vulpen, Simon C Mastbergen

No Abstract.

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引用次数: 0
Inhibition of IP3 (Inositol 1,4,5-Trisphosphate) Receptors Retards SARS-CoV-2-Induced Endothelial von Willebrand Factor Secretion and Thrombosis.
IF 5 2区 医学 Q1 HEMATOLOGY Pub Date : 2025-03-06 DOI: 10.1055/a-2471-8767
Xin-Yi Yu, Xin-Yu Jia, Ting-Yu Wang, Yan-Hong Zhang, Hao Song, Kan Li, Zhuo-Zheng Chen, Yi Zhu, Liu Yao

Patients with coronavirus disease 2019 (COVID-19) are at high risk of developing a hypercoagulable state and thrombosis. The von Willebrand factor (vWF) produced by endothelial cells (ECs) is a critical thrombosis regulator. We previously found that cytoskeleton-associated protein 4 (CKAP4) is a novel receptor for the spike protein of severe acute respiratory syndrome coronavirus-2 and is involved in COVID-19-associated coagulopathy. However, the underlying mechanism involved remains unclear. This study aimed to explore the signaling pathways involved in spike protein-CKAP4-induced vWF secretion and thrombosis. Treatment of ECs with the spike protein significantly induced vWF secretion, coagulation factor VIII (FVIII)-vWF binding, and platelet adhesion to ECs, which were blocked by the selective intracellular calcium chelator, BAPTA-AM. Furthermore, using several calcium channel-blocking drugs and small-molecule inhibitors, we found that calcium released from the endoplasmic reticulum (ER) is involved in this process. IP3 (inositol 1,4,5-trisphosphate) receptors (IP3Rs) inhibition ameliorated spike protein-induced vWF secretion, FVIII-vWF binding affinity, and platelet adhesion to ECs. Specifically, the knockdown of IP3R1, a crucial type of IP3Rs, reversed spike protein-induced endothelial vWF secretion, and the procoagulant state. Moreover, KT-362, an investigational and clinically relevant antihypertensive drug targeting IP3Rs-mediated calcium release, repressed spike protein-induced endothelial vWF secretion. Conversely, the IP3Rs agonist promoted endothelial vWF secretion, which was not affected by CKAP4 knockdown. In vivo treatment of endothelial-specific human CKAP4 overexpression mice with KT-362 retarded spike protein-induced vWF secretion and thrombosis. Thus, IP3Rs mediated calcium release from the ER and contributed to spike protein-induced vWF secretion and thrombosis, making them potential therapeutic targets for COVID-19-associated coagulopathy.

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引用次数: 0
Differences in the Outcome of Cancer-Associated Thrombosis Depending on Cancer Type.
IF 5 2区 医学 Q1 HEMATOLOGY Pub Date : 2025-03-05 DOI: 10.1055/a-2535-7400
Ramón Lecumberri, María Marcos-Jubilar, José Hermida, Pedro Ruiz-Artacho

The outcome of venous thromboembolism in patients with cancer is worse than in patients without cancer, with a higher risk of recurrences, bleeding and death. However, these risks appear to vary depending on the cancer type. While in some tumours the risk of recurrences outweighs the risk of bleeding, in others the risk of major bleeding (MB) during the anticoagulation markedly exceeds the risk of a recurrent event. Balancing these risks could be helpful to tailor the management of cancer-associated thrombosis (CAT) and improve outcomes. In this article, published data from recent randomized clinical trials as well as from some large registries that have reported separated outcomes of CAT depending on cancer type were reviewed. A careful balance of the risk of recurrences and MB events could provide useful insights for clinicians for individualizing treatment strategies in order to improve the outcomes of CAT, as well as for the design of future clinical trials.

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引用次数: 0
Relationship between Surgery and Trauma and Risk of Recurrence in Patients with an Associated First Venous Thrombotic Event: A Nested Case-Control Study.
IF 5 2区 医学 Q1 HEMATOLOGY Pub Date : 2025-03-05 DOI: 10.1055/a-2535-7321
T Gregorio, K J Creeper, L Pagliani, R Providencia, A Buzea, C Wallenhorst, J I Weitz, A T Cohen

The duration of anticoagulation treatment for venous thromboembolism (VTE) depends on whether the event was provoked or unprovoked. Major surgery or trauma are well-established major provoking factors associated with a low risk of recurrence, but the magnitude of risk with VTE after minor surgery or trauma is uncertain.To compare the rate of recurrence in patients with VTE provoked by minor surgery or trauma with that in patients with VTE provoked by major surgery or trauma.Nested, case-control study of patients with a first VTE diagnosed within 90 days after major or minor surgery or trauma. Patients with unprovoked VTE or VTE provoked by cancer or nonsurgical risk factors were excluded. Crude and adjusted odds ratios with 95% confidence intervals (CI) were calculated and results were adjusted for potential confounders.A total of 319 patients with recurrent VTE (cases) were matched to 974 patients without recurrence (controls). The incidence of recurrence after VTE provoked by minor surgery (6.5%; 95% CI: 5.6-7.6) was more than double that after VTE provoked by major surgery (3.0%; 95% CI: 2.4-3.6), a difference that remained even after adjustment for known VTE risk factors. There were no differences in recurrence rates between VTE provoked by minor and major trauma.The risk of recurrence is higher in patients with VTE provoked by minor surgery than major surgery. These findings support the concept that the risk of recurrence is higher with minimally provoked VTE than with VTE provoked by major transient risk factors.

静脉血栓栓塞症(VTE)抗凝治疗的持续时间取决于事件是诱发的还是非诱发的。小手术或外伤引发的 VTE 患者的复发率与大手术或外伤引发的 VTE 患者的复发率进行比较。研究排除了无诱因的 VTE 患者或由癌症或非手术风险因素引发的 VTE 患者。共319名复发VTE患者(病例)与974名未复发患者(对照组)进行了配对。小手术引发 VTE 后的复发率(6.5%;95% CI:5.6-7.6)是大手术引发 VTE 后复发率(3.0%;95% CI:2.4-3.6)的两倍多,即使调整了已知的 VTE 风险因素,这一差异依然存在。小手术和大手术引发的 VTE 复发率没有差异。这些研究结果支持这样一种观点,即由轻微因素引发的 VTE 复发风险高于由重大短暂性风险因素引发的 VTE 复发风险。
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引用次数: 0
Binding Promiscuity of Therapeutic Factor VIII. 治疗因子 VIII 的结合杂合性。
IF 5 2区 医学 Q1 HEMATOLOGY Pub Date : 2025-03-01 Epub Date: 2024-07-01 DOI: 10.1055/a-2358-0853
Alejandra Reyes Ruiz, Aishwarya S Bhale, Krishnan Venkataraman, Jordan D Dimitrov, Sébastien Lacroix-Desmazes

The binding promiscuity of proteins defines their ability to indiscriminately bind multiple unrelated molecules. Binding promiscuity is implicated, at least in part, in the off-target reactivity, nonspecific biodistribution, immunogenicity, and/or short half-life of potentially efficacious protein drugs, thus affecting their clinical use. In this review, we discuss the current evidence for the binding promiscuity of factor VIII (FVIII), a protein used for the treatment of hemophilia A, which displays poor pharmacokinetics, and elevated immunogenicity. We summarize the different canonical and noncanonical interactions that FVIII may establish in the circulation and that could be responsible for its therapeutic liabilities. We also provide information suggesting that the FVIII light chain, and especially its C1 and C2 domains, could play an important role in the binding promiscuity. We believe that the knowledge accumulated over years of FVIII usage could be exploited for the development of strategies to predict protein binding promiscuity and therefore anticipate drug efficacy and toxicity. This would open a mutational space to reduce the binding promiscuity of emerging protein drugs while conserving their therapeutic potency.

蛋白质的结合杂合性决定了它们能够不加区分地结合多种不相关的分子。结合杂合性至少在一定程度上与潜在高效蛋白质药物的脱靶反应性、非特异性生物分布、免疫原性和/或短半衰期有关,从而影响了这些药物的临床应用。在这篇综述中,我们讨论了因子 VIII(FVIII)(一种用于治疗 A 型血友病的蛋白质)结合杂合性的现有证据,这种杂合性导致药代动力学不良和免疫原性升高。我们总结了 FVIII 在血液循环中可能建立的不同规范和非规范分子相互作用,这些相互作用可能是造成其治疗缺陷的原因。我们还提供了一些信息,表明 FVIII 轻链,尤其是其 C1 和 C2 结构域,可能在结合杂合性方面发挥重要作用。我们相信,多年来在 FVIII 使用过程中积累的知识可用于开发预测药物疗效和毒性的工具,并打开一个突变空间,以降低新生成的蛋白质药物的结合杂合性,同时保持其疗效。
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引用次数: 0
A European-Multicenter Network for the Implementation of Artificial Intelligence to Manage Complexity and Comorbidities of Atrial Fibrillation Patients: The ARISTOTELES Consortium. 欧洲多中心人工智能网络,用于管理心房颤动患者的复杂性和并发症:ARISTOTELES联合会。
IF 5 2区 医学 Q1 HEMATOLOGY Pub Date : 2025-03-01 Epub Date: 2025-01-20 DOI: 10.1055/a-2508-5708
Giuseppe Boriani, Davide Antonio Mei, Gregory Y H Lip
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引用次数: 0
Off-Label Dosing of Direct Oral Anticoagulants: Prescribing Error or Opportunity in Treating Patients with Atrial Fibrillation? 直接口服抗凝药的标示外剂量:治疗心房颤动患者的处方错误还是机会?
IF 5 2区 医学 Q1 HEMATOLOGY Pub Date : 2025-03-01 Epub Date: 2024-11-12 DOI: 10.1055/a-2441-8902
Daniela Poli
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引用次数: 0
Comparison of Clinical Outcomes in Patients with Active Cancer Receiving Rivaroxaban or Low-Molecular-Weight Heparin: The OSCAR-UK Study. 接受利伐沙班或低分子量肝素治疗的活动性癌症患者的临床疗效比较--OSCAR-UK 研究。
IF 5 2区 医学 Q1 HEMATOLOGY Pub Date : 2025-03-01 Epub Date: 2024-02-01 DOI: 10.1055/a-2259-0662
Alexander T Cohen, Christopher Wallenhorst, Marcella Rivera, Cihan Ay, Bernhard Schaefer, Khaled Abdelgawwad, George Psaroudakis, Gunnar Brobert, Anders Ekbom, Agnes Y Y Lee, Alok A Khorana, Cecilia Becattini, Marc Carrier, Craig I Coleman, Carlos Martinez

Background:  In most patients with cancer-associated venous thromboembolism (CT), essentially those not at high risk of bleeding, guidelines recommend treatment with direct oral anticoagulants as an alternative to low-molecular-weight heparins (LMWHs). Population-based studies comparing these therapies are scarce.

Objectives:  To compare the risk of venous thromboembolism (VTE) recurrences, significant bleeding, and all-cause mortality in patients with CT receiving rivaroxaban or LMWHs.

Patients/methods:  Using UK Clinical Practice Research Datalink data from 2013 to 2020, we generated a cohort of patients with first CT treated initially with either rivaroxaban or LMWH. Patients were observed 12 months for VTE recurrences, significant bleeds (major bleeds or clinically relevant nonmajor bleeding requiring hospitalization), and all-cause mortality. Overlap weighted sub-distribution hazard ratios (SHRs) compared rivaroxaban with LMWH in an intention-to-treat analysis.

Results:  The cohort consisted of 2,259 patients with first CT, 314 receiving rivaroxaban, and 1,945 LMWH, mean age 72.4 and 66.9 years, respectively. In the 12-month observational period, 184 person-years following rivaroxaban and 1,057 following LMWH, 10 and 66 incident recurrent VTE events, 20 and 102 significant bleeds, and 10 and 133 deaths were observed in rivaroxaban and LMWH users, respectively. The weighted SHR at 12 months for VTE recurrences in rivaroxaban compared with LMWH were 0.80 (0.37-1.73); for significant bleeds 1.01 (0.57-1.81); and for all-cause mortality 0.49 (0.23-1.06).

Conclusion:  Patients with CT, not at high risk of bleeding, treated with either rivaroxaban or LMWH have comparable effectiveness and safety outcomes. This supports the recommendation that rivaroxaban is a reasonable alternative to LMWH for the treatment of CT.

背景:对于大多数癌症相关静脉血栓栓塞症(CAT)患者,尤其是出血风险不高的患者,指南建议使用直接口服抗凝剂治疗,以替代低分子量肝素(LMWHs)。比较这些疗法的人群研究很少:比较接受利伐沙班或 LMWHs 治疗的 CAT 患者静脉血栓栓塞症(VTE)复发、大出血和全因死亡率的风险:利用英国临床实践研究数据链(UK Clinical Practice Research Datalink)2013-2020 年的数据,我们建立了首次接受利伐沙班或 LMWH 治疗的 CAT 患者队列。我们对患者进行了为期 12 个月的观察,以了解其 VTE 复发、严重出血(大出血或需要住院治疗的临床相关非大出血)和全因死亡率。在意向治疗分析中,比较了利伐沙班与 LMWH 的重叠加权亚危险比(SHR):队列由2259名首次CAT患者组成,其中314人接受利伐沙班治疗,1945人接受LMWH治疗,平均年龄分别为72.4岁和66.9岁。在为期12个月的观察期内,利伐沙班使用者和LMWH使用者分别接受利伐沙班治疗184人年和LMWH治疗1057人年,分别观察到10起和66起复发性VTE事件、20起和102起重大出血事件以及10起和133起死亡事件。与LMWH相比,利伐沙班在12个月内VTE复发的加权SHR为0.80(0.37-1.73);严重出血的加权SHR为1.01(0.57-1.81);全因死亡率的加权SHR为0.49(0.23-1.06):结论:出血风险不高的CAT患者接受利伐沙班或LMWH治疗的有效性和安全性结果相当。这支持了利伐沙班是治疗 CAT 的 LMWH 合理替代方案的建议。
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引用次数: 0
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Thrombosis and haemostasis
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