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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
Pneumococcal Neuraminidases Increase Platelet Killing by Pneumolysin. 肺炎球菌神经氨酸酶可增加肺炎溶素对血小板的杀伤力。
IF 5 2区 医学 Q1 HEMATOLOGY Pub Date : 2025-03-01 Epub Date: 2024-07-19 DOI: 10.1055/a-2369-8680
Kristin J Fritsch, Laura Krüger, Stefan Handtke, Thomas P Kohler, Arina Ozhiganova, Kristin Jahn, Jan Wesche, Andreas Greinacher, Sven Hammerschmidt

Background:  Platelets prevent extravasation of capillary fluids into the pulmonary interstitial tissue by sealing gaps in inflamed endothelium. This reduces respiratory distress associated with pneumonia. Streptococcus pneumoniae is the leading cause of severe community-acquired pneumonia. Pneumococci produce pneumolysin (PLY), which forms pores in membranes of eukaryotic cells including platelets. Additionally, pneumococci express neuraminidases, which cleave sialic acid residues from eukaryotic glycoproteins. In this study, we investigated the effect of desialylation on PLY binding and pore formation on platelets.

Materials and methods:  We incubated human platelets with purified neuraminidases and PLY, or nonencapsulated S. pneumoniae D39/TIGR4 and isogenic mutants deficient in PLY and/or NanA. We assessed platelet desialylation, PLY binding, and pore formation by flow cytometry. We also analyzed the inhibitory potential of therapeutic immunoglobulin G preparations (IVIG [intravenous immunoglobulin]).

Results:  Wild-type pneumococci cause desialylation of platelet glycoproteins by neuraminidases, which is reduced by 90 to 100% in NanA-deficient mutants. NanC, cleaving only α2,3-linked sialic acid, induced platelet desialylation. PLY binding to platelets then x2doubled (p = 0.0166) and pore formation tripled (p = 0.0373). A neuraminidase cleaving α2,3-, α2,6-, and α2,8-linked sialic acid like NanA was even more efficient. Addition of polyvalent IVIG (5 mg/mL) decreased platelet desialylation induced by NanC up to 90% (p = 0.263) and reduced pore formation >95% (p < 0.0001) when incubated with pneumococci.

Conclusion:  Neuraminidases are key virulence factors of pneumococci and desialylate platelet glycoproteins, thereby unmasking PLY-binding sites. This enhances binding of PLY and pore formation showing that pneumococcal neuraminidases and PLY act in concert to kill platelets. However, human polyvalent immunoglobulin G preparations are promising agents for therapeutic intervention during severe pneumococcal pneumonia.

背景:血小板通过封闭发炎内皮的缝隙,防止毛细血管液体外渗至肺间质组织。这可减轻肺炎引起的呼吸困难。肺炎链球菌是社区获得性重症肺炎的主要病因。肺炎球菌产生的肺炎溶菌素(PLY)可在包括血小板在内的真核细胞膜上形成孔隙。此外,肺炎球菌还能表达神经氨酸酶,这种酶能裂解真核糖蛋白的硅酸残基。在这项研究中,我们研究了去ialylation 对血小板上 PLY 结合和孔形成的影响:我们将人血小板与纯化的神经氨酸酶和 PLY、未包被的 D39/TIGR4 以及缺乏 PLY 和/或 NanA 的同源突变体培养。我们通过流式细胞术评估了血小板的脱ialylation、与 PLY 的结合和孔的形成。我们还分析了治疗用免疫球蛋白 G 制剂的抑制潜力:结果:肺炎球菌通过神经氨酸酶导致血小板糖蛋白脱ialyl,在 NanA 缺陷突变体中,这种作用降低了 90%-100%。仅能裂解 2,3 链接的硅酸的 NanC 可诱导血小板去硅烷基化。PLY 与血小板的结合增加一倍(p=0.0166),孔形成增加三倍(p=0.0373)。像 NanA 一样能裂解 2,3-、2,6- 和 2,8 链接的硅烷基酸的神经氨酸酶的效率更高。加入多价 IVIG 可使 NanC 诱导的血小板脱ialylation 减少 90% (p=0.263),并使孔隙形成减少 95% 以上(pConclusion):神经氨酸酶是肺炎球菌的关键致病因子,可使血小板糖蛋白脱氨酰基,从而解除 PLY 结合位点的屏蔽。这增强了 PLY 的结合力和孔隙的形成,表明肺炎球菌神经氨酸酶和 PLY 能协同杀死血小板。不过,人类多价 IgG 制剂是治疗重症肺炎球菌肺炎的有效药物。
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引用次数: 0
Percutaneous Coronary Intervention in Acute Coronary Syndrome with Mild-to-Moderate Thrombocytopenia. 急性冠状动脉综合征伴轻度至中度血小板减少时的经皮冠状动脉介入治疗。
IF 5 2区 医学 Q1 HEMATOLOGY Pub Date : 2025-03-01 Epub Date: 2023-12-11 DOI: 10.1055/a-2225-5263
Yicong Ye, Yongchen Hao, Xiliang Zhao, Jun Liu, Na Yang, Sidney C Smith, Yong Huo, Gregg C Fonarow, Junbo Ge, Louise Morgan, Zhaoqing Sun, Danqing Hu, Yiqian Yang, Chang-Sheng Ma, Dong Zhao, Yaling Han, Jing Liu, Yong Zeng

Background:  Baseline thrombocytopenia is commonly observed in patients with acute coronary syndrome (ACS) requiring percutaneous coronary intervention (PCI).

Aim:  The purpose of this analysis was to investigate safety and effectiveness of PCI in ACS patients with baseline mild-to-moderate thrombocytopenia.

Methods:  The data were collected from the Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome project. A total of 50,009 ACS patients were recruited between July 2017 and December 2019. Among them, there were 6,413 patients with mild-to-moderate thrombocytopenia, defined as a platelet count of ≥50 × 109/L and <150 × 109/L on admission. The primary outcome was in-hospital net adverse clinical events (NACE), consisting of major adverse cardiac events (MACE) and major bleeding events. The associations between PCI and in-hospital outcomes were analyzed by inverse probability treatment weighting (IPTW) method.

Results:  PCI was performed in 4,023 of 6,413 patients (62.7%). The IPTW analysis showed that PCI was significantly associated with a reduced risk of in-hospital MACE (odd ratio [OR]: 0.45; 95% confidence interval [CI]: 0.31-0.67; p < 0.01) and NACE (OR: 0.59; 95% CI: 0.42-0.83; p < 0.01). PCI was also associated with an increased risk of any bleeding (OR: 1.56; 95% CI: 1.09-2.22; p = 0.01) and minor bleeding (OR: 1.52; 95% CI: 1.00-2.30; p = 0.05), but not major bleeding (OR: 1.51; 95% CI: 0.76-2.98; p = 0.24).

Conclusion:  Compared with medical therapy alone, PCI is associated with better in-hospital outcomes in ACS patients with mild-to-moderate thrombocytopenia. Further studies with long-term prognosis are needed.

背景:急性冠脉综合征(ACS)患者需要经皮冠状动脉介入治疗(PCI)时,通常会观察到基线血小板减少的情况。目的:本分析旨在研究基线血小板轻度至中度减少的ACS患者接受PCI治疗的安全性和有效性:数据来自 "改善中国心血管病治疗--急性冠脉综合征 "项目。2017年7月至2019年12月期间,共招募了50,009名ACS患者。其中,轻中度血小板减少患者6413例,入院时血小板计数≥50×109/L且<150×109/L。主要结果是院内净不良临床事件(NACE),包括主要不良心脏事件(MACE)和主要出血事件。采用逆概率治疗加权法(IPTW)分析了PCI与院内预后之间的关系:结果:6413 例患者中有 4023 例(62.7%)进行了 PCI 治疗。IPTW分析显示,PCI与院内MACE(奇数比[OR]0.45;95% CI 0.31-0.67;P < 0.01)和NACE(OR 0.59;95% CI 0.42-0.83;P < 0.01)风险的降低显著相关。PCI也与任何出血(OR 1.56;95% CI 1.09-2.22;p = 0.01)和轻微出血(OR 1.52;95% CI 1.00-2.30;p = 0.05)风险增加有关,但与大出血(OR 1.51;95% CI 0.76-2.98;p = 0.24)无关:与单纯药物治疗相比,PCI 对轻度至中度血小板减少的 ACS 患者有更好的院内预后。需要对长期预后进行进一步研究。
{"title":"Percutaneous Coronary Intervention in Acute Coronary Syndrome with Mild-to-Moderate Thrombocytopenia.","authors":"Yicong Ye, Yongchen Hao, Xiliang Zhao, Jun Liu, Na Yang, Sidney C Smith, Yong Huo, Gregg C Fonarow, Junbo Ge, Louise Morgan, Zhaoqing Sun, Danqing Hu, Yiqian Yang, Chang-Sheng Ma, Dong Zhao, Yaling Han, Jing Liu, Yong Zeng","doi":"10.1055/a-2225-5263","DOIUrl":"10.1055/a-2225-5263","url":null,"abstract":"<p><strong>Background: </strong> Baseline thrombocytopenia is commonly observed in patients with acute coronary syndrome (ACS) requiring percutaneous coronary intervention (PCI).</p><p><strong>Aim: </strong> The purpose of this analysis was to investigate safety and effectiveness of PCI in ACS patients with baseline mild-to-moderate thrombocytopenia.</p><p><strong>Methods: </strong> The data were collected from the Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome project. A total of 50,009 ACS patients were recruited between July 2017 and December 2019. Among them, there were 6,413 patients with mild-to-moderate thrombocytopenia, defined as a platelet count of ≥50 × 10<sup>9</sup>/L and <150 × 10<sup>9</sup>/L on admission. The primary outcome was in-hospital net adverse clinical events (NACE), consisting of major adverse cardiac events (MACE) and major bleeding events. The associations between PCI and in-hospital outcomes were analyzed by inverse probability treatment weighting (IPTW) method.</p><p><strong>Results: </strong> PCI was performed in 4,023 of 6,413 patients (62.7%). The IPTW analysis showed that PCI was significantly associated with a reduced risk of in-hospital MACE (odd ratio [OR]: 0.45; 95% confidence interval [CI]: 0.31-0.67; <i>p</i> < 0.01) and NACE (OR: 0.59; 95% CI: 0.42-0.83; <i>p</i> < 0.01). PCI was also associated with an increased risk of any bleeding (OR: 1.56; 95% CI: 1.09-2.22; <i>p</i> = 0.01) and minor bleeding (OR: 1.52; 95% CI: 1.00-2.30; <i>p</i> = 0.05), but not major bleeding (OR: 1.51; 95% CI: 0.76-2.98; <i>p</i> = 0.24).</p><p><strong>Conclusion: </strong> Compared with medical therapy alone, PCI is associated with better in-hospital outcomes in ACS patients with mild-to-moderate thrombocytopenia. Further studies with long-term prognosis are needed.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":"218-229"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138800536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
An Inhibitory Single-Domain Antibody against Protein Z-Dependent Protease Inhibitor Promotes Thrombin Generation in Severe Hemophilia A and FXI Deficiency. 针对蛋白 Z 依赖性蛋白酶抑制剂的抑制性单域抗体可促进血友病 A 和 FXI 缺乏症患者凝血酶的生成。
IF 5 2区 医学 Q1 HEMATOLOGY Pub Date : 2025-03-01 Epub Date: 2024-07-25 DOI: 10.1055/a-2373-2829
Claire Auditeau, Tung-Son Nguyen, Floriane Devaux, François Saller, Ivan Peyron, Adeline Blandinières, Christelle Repérant, Sadyo Daramé, Cécile V Denis, Peter Lenting, Delphine Borgel, Elsa P Bianchini

Background:  Protein Z-dependent protease inhibitor (ZPI) is an anticoagulant serpin that targets factor Xa (FXa) in the presence of protein Z (PZ), and factor XIa (FXIa). In factor-VIII-deficient mice, PZ or ZPI gene knock-out mitigates the bleeding phenotype, and pharmacological inhibition of PZ enhances thrombin generation in plasma from patients with hemophilia.

Aims:  To develop a single-domain antibody (sdAb) directed against ZPI to inhibit its anticoagulant activity.

Methods:  We screened for anti-ZPI sdAbs in a llama-derived phage display immune library of sdAbs. The sdAbs that bound ZPI were produced and purified for characterization. The binding of sdAbs to ZPI or other serpins was evaluated using ELISAs, and ZPI inhibition was measured in an anti-FXa or anti-FXIa chromogenic assay. The sdAbs's procoagulant activity was assessed in a thrombin generation assay in normal plasma, factor VIII- and FXI-deficient plasma.

Results:  Of the four sdAbs found to bind to ZPI, one (referred to as ZPI-sdAb2) dose-dependently inhibited ZPI's anti-FXa and anti-FXIa activities with a mean half-maximal inhibitory concentration of 1.8 and 1.3 µM, respectively. ZPI-sdAb2 did not cross-react with other plasma serpins, such as antithrombin and α1-antitrypsin. ZPI-sdAb2 induced a significant increase in thrombin generation in plasma samples from healthy donors, patients with severe hemophilia A, and patients with FXI deficiency.

Conclusion:  ZPI-sdAb2 is the first specific, direct ZPI inhibitor found to exhibit procoagulant activity in plasma. This sdAb might have potential as a treatment for hemophilia or other bleeding disorders.

背景:蛋白 Z 依赖性蛋白酶抑制剂(ZPI)是一种抗凝血清蛋白,在蛋白 Z(PZ)和因子 XIa(FXIa)存在的情况下,它能靶向因子 Xa(FXa)。在因子 VIII 缺乏的小鼠中,PZ 或 ZPI 基因敲除可减轻出血表型,而药物抑制 PZ 可增强血友病患者血浆中凝血酶的生成。目的:开发针对 ZPI 的单域抗体(sdAb),以抑制其抗凝血活性:我们在源自骆驼的噬菌体展示免疫 sdAbs 库中筛选抗 ZPI 的 sdAbs。方法:我们在骆马来源的噬菌体展示免疫库中筛选了抗 ZPI 的 sdAbs。用酶联免疫吸附试验评估了 sdAbs 与 ZPI 或其他丝蛋白的结合情况,并用抗 FXa 或抗 FXIa 色原试验测定了 ZPI 抑制作用。在正常血浆、因子 VIII(FVIII)和 FXI 缺乏血浆中进行凝血酶生成试验(TGA),评估 sdAbs 的促凝血活性:结果:在与 ZPI 结合的四种 sdAb 中,一种(称为 ZPI-sdAb2)剂量依赖性地抑制了 ZPI 的抗 FXa 和抗 FXIa 活性,其平均半最大抑制浓度分别为 1.8 µM 和 1.3 µM。ZPI-sdAb2 与其他血浆血清素(如抗凝血酶和 α1-抗胰蛋白酶)没有交叉反应。ZPI-sdAb2能显著增加健康捐献者、严重A型血友病患者和FXI缺乏症患者血浆样本中凝血酶的生成:结论:ZPI-sdAb2 是首个被发现在血浆中具有促凝血活性的特异性直接 ZPI 抑制剂。这种 sdAb 可能具有治疗血友病或其他出血性疾病的潜力。
{"title":"An Inhibitory Single-Domain Antibody against Protein Z-Dependent Protease Inhibitor Promotes Thrombin Generation in Severe Hemophilia A and FXI Deficiency.","authors":"Claire Auditeau, Tung-Son Nguyen, Floriane Devaux, François Saller, Ivan Peyron, Adeline Blandinières, Christelle Repérant, Sadyo Daramé, Cécile V Denis, Peter Lenting, Delphine Borgel, Elsa P Bianchini","doi":"10.1055/a-2373-2829","DOIUrl":"10.1055/a-2373-2829","url":null,"abstract":"<p><strong>Background: </strong> Protein Z-dependent protease inhibitor (ZPI) is an anticoagulant serpin that targets factor Xa (FXa) in the presence of protein Z (PZ), and factor XIa (FXIa). In factor-VIII-deficient mice, PZ or ZPI gene knock-out mitigates the bleeding phenotype, and pharmacological inhibition of PZ enhances thrombin generation in plasma from patients with hemophilia.</p><p><strong>Aims: </strong> To develop a single-domain antibody (sdAb) directed against ZPI to inhibit its anticoagulant activity.</p><p><strong>Methods: </strong> We screened for anti-ZPI sdAbs in a llama-derived phage display immune library of sdAbs. The sdAbs that bound ZPI were produced and purified for characterization. The binding of sdAbs to ZPI or other serpins was evaluated using ELISAs, and ZPI inhibition was measured in an anti-FXa or anti-FXIa chromogenic assay. The sdAbs's procoagulant activity was assessed in a thrombin generation assay in normal plasma, factor VIII- and FXI-deficient plasma.</p><p><strong>Results: </strong> Of the four sdAbs found to bind to ZPI, one (referred to as ZPI-sdAb2) dose-dependently inhibited ZPI's anti-FXa and anti-FXIa activities with a mean half-maximal inhibitory concentration of 1.8 and 1.3 µM, respectively. ZPI-sdAb2 did not cross-react with other plasma serpins, such as antithrombin and α1-antitrypsin. ZPI-sdAb2 induced a significant increase in thrombin generation in plasma samples from healthy donors, patients with severe hemophilia A, and patients with FXI deficiency.</p><p><strong>Conclusion: </strong> ZPI-sdAb2 is the first specific, direct ZPI inhibitor found to exhibit procoagulant activity in plasma. This sdAb might have potential as a treatment for hemophilia or other bleeding disorders.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":"207-217"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141760998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Carbamylation-A Pathologic Posttranslational Modification Affecting Platelet and Von Willebrand Factor Function during Uremic Kidney Disease. 氨甲酰化--尿毒症肾病期间影响血小板和Von Willebrand因子功能的病理性翻译后修饰
IF 5 2区 医学 Q1 HEMATOLOGY Pub Date : 2025-03-01 Epub Date: 2024-09-27 DOI: 10.1055/s-0044-1791550
Rory R Koenen
{"title":"Carbamylation-A Pathologic Posttranslational Modification Affecting Platelet and Von Willebrand Factor Function during Uremic Kidney Disease.","authors":"Rory R Koenen","doi":"10.1055/s-0044-1791550","DOIUrl":"10.1055/s-0044-1791550","url":null,"abstract":"","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":"241-242"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11858601/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Risk of Depression after Venous Thromboembolism in Patients with Hematological Cancer: A Population-Based Cohort Study. 血液肿瘤患者静脉血栓栓塞后抑郁的风险:一项基于人群的队列研究。
IF 5 2区 医学 Q1 HEMATOLOGY Pub Date : 2025-03-01 Epub Date: 2023-12-11 DOI: 10.1055/a-2225-5428
Daniel Steiner, Erzsébet Horváth-Puhó, Helle Jørgensen, Kristina Laugesen, Cihan Ay, Henrik Toft Sørensen

Background:  Venous thromboembolism (VTE) may complicate the clinical course of cancer patients and add to their psychological burden.

Objectives:  We aimed to investigate the association between VTE and risk of subsequent depression in patients with hematological cancer.

Patients and methods:  We conducted a population-based cohort study using Danish national health registries. Between 1995 and 2020, we identified 1,190 patients with hematological cancer and incident VTE diagnosed within 6 months before to 1 year after cancer diagnosis. A comparison cohort of patients with hematological cancer without VTE (n = 5,325) was matched by sex, year of birth, cancer type, and year of cancer diagnosis. Patients were followed until diagnosis of depression, emigration, death, study end (2021), or for a maximum of 3 years. Depression was defined as hospital discharge diagnosis of depression or ≥1 prescription for antidepressants. Absolute risks of depression were computed with cumulative incidence functions, treating death as competing event. Hazard ratios (HRs) with 95% confidence intervals (CIs) were computed using Cox proportional hazards regression models, adjusting for comorbidities.

Results:  Depression was observed in 158 hematological cancer patients with and 585 without VTE. The 3-year absolute risks of depression were 13.3% (95% CI: 11.5-15.3%) in the VTE cancer cohort and 11.1% (95% CI: 10.3-12.0%) in the comparison cancer cohort, corresponding to a risk difference of 2.2% (95% CI: -1.8-6.5%). VTE was associated with an increased relative risk of depression (adjusted HR: 1.56, 95% CI: 1.28-1.90).

Conclusion:  VTE was associated with an elevated risk of subsequent depression in patients with hematological cancer.

背景 静脉血栓栓塞(VTE)可能会使癌症患者的临床病程复杂化,并加重他们的心理负担。目的 我们旨在研究血液肿瘤患者 VTE 与后续抑郁风险之间的关系。患者和方法 我们利用丹麦国家健康登记处开展了一项基于人群的队列研究。从 1995 年到 2020 年,我们共发现了 1,190 名血液肿瘤患者,这些患者在癌症确诊前六个月到确诊后一年内发生了 VTE。我们还根据性别、出生年份、癌症类型和癌症诊断年份,将未发生 VTE 的血液肿瘤患者(人数=5,325)组成了一个对比队列。对患者进行随访,直至确诊抑郁症、移民、死亡、研究结束(2021 年)或最长 3 年。抑郁症的定义是出院诊断为抑郁症或处方抗抑郁药≥1次。抑郁症的绝对风险采用累积发病率函数计算,将死亡作为竞争事件处理。在对合并症进行调整后,使用 Cox 比例危险回归模型计算出危险比 (HR) 和 95% 置信区间 (CI)。结果 在158名患有VTE的血液肿瘤患者和585名未患有VTE的患者中观察到抑郁症。VTE癌症队列中抑郁症的3年绝对风险为13.3%(95% CI,11.5%-15.3%),对比癌症队列中抑郁症的3年绝对风险为11.1%(95% CI,10.3%-12.0%),风险差异为2.2%(95% CI,-1.8%-6.5%)。VTE 与抑郁症相对风险增加有关(调整后 HR,1.56,95% CI,1.28-1.90)。结论 VTE 与血液肿瘤患者后续抑郁风险升高有关。
{"title":"Risk of Depression after Venous Thromboembolism in Patients with Hematological Cancer: A Population-Based Cohort Study.","authors":"Daniel Steiner, Erzsébet Horváth-Puhó, Helle Jørgensen, Kristina Laugesen, Cihan Ay, Henrik Toft Sørensen","doi":"10.1055/a-2225-5428","DOIUrl":"10.1055/a-2225-5428","url":null,"abstract":"<p><strong>Background: </strong> Venous thromboembolism (VTE) may complicate the clinical course of cancer patients and add to their psychological burden.</p><p><strong>Objectives: </strong> We aimed to investigate the association between VTE and risk of subsequent depression in patients with hematological cancer.</p><p><strong>Patients and methods: </strong> We conducted a population-based cohort study using Danish national health registries. Between 1995 and 2020, we identified 1,190 patients with hematological cancer and incident VTE diagnosed within 6 months before to 1 year after cancer diagnosis. A comparison cohort of patients with hematological cancer without VTE (<i>n</i> = 5,325) was matched by sex, year of birth, cancer type, and year of cancer diagnosis. Patients were followed until diagnosis of depression, emigration, death, study end (2021), or for a maximum of 3 years. Depression was defined as hospital discharge diagnosis of depression or ≥1 prescription for antidepressants. Absolute risks of depression were computed with cumulative incidence functions, treating death as competing event. Hazard ratios (HRs) with 95% confidence intervals (CIs) were computed using Cox proportional hazards regression models, adjusting for comorbidities.</p><p><strong>Results: </strong> Depression was observed in 158 hematological cancer patients with and 585 without VTE. The 3-year absolute risks of depression were 13.3% (95% CI: 11.5-15.3%) in the VTE cancer cohort and 11.1% (95% CI: 10.3-12.0%) in the comparison cancer cohort, corresponding to a risk difference of 2.2% (95% CI: -1.8-6.5%). VTE was associated with an increased relative risk of depression (adjusted HR: 1.56, 95% CI: 1.28-1.90).</p><p><strong>Conclusion: </strong> VTE was associated with an elevated risk of subsequent depression in patients with hematological cancer.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":"255-264"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138800703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Timing of Off-Label Dosing of Direct Oral Anticoagulants in Three Large Health Systems. 三个大型医疗系统中标示外直接口服抗凝药的给药时间。
IF 5 2区 医学 Q1 HEMATOLOGY Pub Date : 2025-03-01 Epub Date: 2024-07-15 DOI: 10.1055/a-2365-8681
Grace C Herron, Deborah DeCamillo, Xiaowen Kong, Brian Haymart, Scott Kaatz, Stacy Ellsworth, Mona A Ali, Christopher Giuliano, James B Froehlich, Geoffrey D Barnes

Background:  While direct oral anticoagulants (DOACs) may be viewed as simpler to manage then warfarin, they present their own unique management challenges resulting in frequent off-label dosing. It is unknown to what extent off-label dosing occurs when a patient is started on a DOAC versus later in their treatment.

Objectives:  We aimed to better characterize when off-label DOAC dosing is occurring and to evaluate the effectiveness of prescribing oversight using a registry-based intervention.

Methods:  We evaluated data from the Michigan Anticoagulation Quality Improvement Initiative (MAQI2) registry, a retrospective quality-improvement process using data abstractors, from 2018 to 2022 on the number of "alerts" that are generated in response to dosing deviating from the U.S. Food and Drug Administration instructions for atrial fibrillation (AF) and venous thromboembolism (VTE).

Results:  Among a sample of 789 to 1,022 annual AF patients and 381 to 484 annual VTE patients prescribed a DOAC in the MAQI2 registry, off-label dosing was relatively common. Over the 5-year period (2018-2022), there were 569 alerts for AF patients and 162 alerts for VTE patients. Alerts occurred more frequently during follow-up than at the time of initial prescribing in AF patients (78.2 vs. 21.8%), but more commonly at initial prescribing in VTE patients (59.9 vs. 40.1%). After initial review by quality-improvement abstractors, 19.3% of AF alerts and 14.8% of VTE alerts resulted in contact to the prescriber. When the prescriber was contacted, it led to an intervention about 75% of the time for both populations. The most common intervention was a change in DOAC dosing.

Conclusion:  This study demonstrates the benefit of DOAC prescribing oversight using a registry-based intervention to monitor for off-label dosing for the entirety of the time period a patient is prescribed DOAC, particularly for patients with AF, as off-label prescribing occurs frequently during the follow-up period.

背景:虽然直接口服抗凝药(DOACs)可能被认为比华法林更容易管理,但它们也有自己独特的管理难题,导致经常出现标签外用药。目前尚不清楚患者在开始使用 DOAC 时与治疗后期发生标示外用药的程度:我们旨在确定标示外 DOAC 用药的发生时间,并通过基于登记的干预措施评估处方监督的有效性:我们评估了密歇根州抗凝质量改进倡议(MAQI2)登记处的数据,这是一个使用数据抽取者的回顾性质量改进过程,从 2018 年到 2022 年,针对剂量偏离循证指南而产生的 "警报 "数量:在MAQI2登记的1261至1563名每年接受DOAC治疗的患者样本中,标签外用药相对普遍。从 2018 年到 2022 年的 5 年间,共有 735 次用药警报。与初次处方时相比,随访期间发生警报的频率更高,分别为 69.0%(507 例)和 31.0%(228 例)。在质量改进摘要员进行初步审查后,18.2% 的警报(134 例)导致与开处方者联系。在与开药者取得联系后,74.6% 的情况下会采取干预措施。最常见的干预措施是改变 DOAC 的剂量:这项研究证明了使用基于登记的干预措施对 DOAC 处方进行监督的益处,该干预措施可在患者处方 DOAC 的整个期间监控标示外剂量,因为在随访期间,循证处方的偏差经常发生。
{"title":"Timing of Off-Label Dosing of Direct Oral Anticoagulants in Three Large Health Systems.","authors":"Grace C Herron, Deborah DeCamillo, Xiaowen Kong, Brian Haymart, Scott Kaatz, Stacy Ellsworth, Mona A Ali, Christopher Giuliano, James B Froehlich, Geoffrey D Barnes","doi":"10.1055/a-2365-8681","DOIUrl":"10.1055/a-2365-8681","url":null,"abstract":"<p><strong>Background: </strong> While direct oral anticoagulants (DOACs) may be viewed as simpler to manage then warfarin, they present their own unique management challenges resulting in frequent off-label dosing. It is unknown to what extent off-label dosing occurs when a patient is started on a DOAC versus later in their treatment.</p><p><strong>Objectives: </strong> We aimed to better characterize when off-label DOAC dosing is occurring and to evaluate the effectiveness of prescribing oversight using a registry-based intervention.</p><p><strong>Methods: </strong> We evaluated data from the Michigan Anticoagulation Quality Improvement Initiative (MAQI<sup>2</sup>) registry, a retrospective quality-improvement process using data abstractors, from 2018 to 2022 on the number of \"alerts\" that are generated in response to dosing deviating from the U.S. Food and Drug Administration instructions for atrial fibrillation (AF) and venous thromboembolism (VTE).</p><p><strong>Results: </strong> Among a sample of 789 to 1,022 annual AF patients and 381 to 484 annual VTE patients prescribed a DOAC in the MAQI<sup>2</sup> registry, off-label dosing was relatively common. Over the 5-year period (2018-2022), there were 569 alerts for AF patients and 162 alerts for VTE patients. Alerts occurred more frequently during follow-up than at the time of initial prescribing in AF patients (78.2 vs. 21.8%), but more commonly at initial prescribing in VTE patients (59.9 vs. 40.1%). After initial review by quality-improvement abstractors, 19.3% of AF alerts and 14.8% of VTE alerts resulted in contact to the prescriber. When the prescriber was contacted, it led to an intervention about 75% of the time for both populations. The most common intervention was a change in DOAC dosing.</p><p><strong>Conclusion: </strong> This study demonstrates the benefit of DOAC prescribing oversight using a registry-based intervention to monitor for off-label dosing for the entirety of the time period a patient is prescribed DOAC, particularly for patients with AF, as off-label prescribing occurs frequently during the follow-up period.</p>","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":" ","pages":"278-285"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141620975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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Thrombosis and haemostasis
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