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Pathogenic but sweet: factor VIII inhibitor hits the hot spot 致病但甜蜜:因子 VIII 抑制剂击中热点
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-08-20 DOI: 10.1016/j.jtha.2024.06.013
Vladimir N. Kolyadko
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引用次数: 0
Cutting the Gordian knot of neutrophil extracellular traps research 解开中性粒细胞胞外捕获物研究的死结
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-08-20 DOI: 10.1016/j.jtha.2024.06.016
Frederik Denorme
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引用次数: 0
“2023 ISTH update of the 2022 ISTH guidelines for antithrombotic treatment in COVID-19”: reply "2023年ISTH对2022年ISTH COVID-19抗血栓治疗指南的更新":回复
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-08-20 DOI: 10.1016/j.jtha.2024.06.009
Sam Schulman , Helaine E. Resnick
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引用次数: 0
Rapid and ordered cleavage of prothrombin by Hopsarin D in the absence of phospholipid membranes 在没有磷脂膜的情况下,啤酒花素 D 能快速有序地裂解凝血酶原。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-08-14 DOI: 10.1016/j.jtha.2024.07.027
Fatma Işık Üstok, Ty E. Adams, James A. Huntington

Background

Thrombin is produced by the prothrombinase complex, composed of factor (f)Xa and fVa on a phospholipid (PL) membrane surface. Snakes of the Elapidae family have venom versions of these factors that cause coagulopathy in prey. Group C venoms contain both fⅩa and fⅤa orthologues. Group D venoms only contain a fXa orthologue and hijack fⅤa of the prey. Hopsarin D (HopD) is the venom fⅩa of the Stephen’s banded snake (Hoplocephalus stephensii).

Objectives

We set out to address the following: does HopD bind to human fⅤa with high affinity in the absence of PL? Does it process prothrombin through the meizothrombin pathway? Is the order of cleavage PL-dependent? Can HopD activate fⅤ?

Methods

We produced and characterized full-length and truncated HopD.

Results

HopD is only able to clot plasma that contains fⅤ and competes with human fⅩa for fⅤa binding. HopD binds to both human fⅤa and fⅤ with high affinity (dissociation constant, ∼10 nM), in contrast to fⅩa. HopD processes prothrombin down the meizothrombin route in the absence and presence of PL. Although HopD can bind to fⅤ, conversion to fⅤa is necessary for prothrombin processing. HopD initiates clotting in the blood of prey by activating fⅤ.

Conclusion

HopD binds to fⅤa with high affinity and rapidly activates prothrombin in the absence of PL, exclusively through the meizothrombin intermediate. HopD binds with high affinity to both fⅤa and fⅤ, suggesting that the B-domain does not sterically block fⅩa binding, but inhibits productive interaction in another way, and additionally prevents prothrombin binding.
背景:凝血酶由凝血酶原酶复合物产生,该复合物由磷脂(PL)膜表面的因子(f)Xa和fVa组成。Elapidae 科蛇的毒液中含有这些因子,可导致猎物发生凝血病。C 组毒液同时含有 fXa 和 fVa 直向同源物。D 组毒液只含有 fXa 直向同源物,并劫持猎物的 fV(a)。蛇毒素 D(HopD)是史蒂芬带蛇(Hoplocephalus stephensii)的毒液 fXa:我们的目的如下:在没有 PL 的情况下,HopD 与人类 fVa 的结合亲和力高吗?它是否通过 meizothrombin 途径处理凝血酶原?裂解顺序是否取决于 PL?HopD 能否激活 fV?我们制作并鉴定了全长和截短的HopD:结果:HopD只能凝结含有fV的血浆,并与人fXa竞争结合fVa。与 fXa 相反,HopD 与人类 fVa 和 fV 的结合亲和力都很高(Kd∼10nM)。在没有或有 PL 的情况下,HopD 通过 meizothrombin 途径处理凝血酶原。虽然 HopD 可与 fV 结合,但凝血酶原处理过程中必须将其转化为 fVa。HopD 通过激活 fV 启动了猎物血液中的凝血过程:结论:HopD能与fVa高亲和力结合,并在没有PL的情况下迅速激活凝血酶原,这完全是通过meizothrombin中间体实现的。HopD与fVa和fV都有很高的结合亲和力,这表明B-结构域并不是立体地阻断fXa的结合,而是以另一种方式抑制产生性相互作用,并阻止凝血酶原的结合。
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引用次数: 0
Endothelial protein disulfide isomerase A1 enhances membrane stiffness and platelet-endothelium interaction in hyperglycemia via SLC3A2 and LAMC1 内皮蛋白二硫化物异构酶-A1 通过 SLC3A2 和 LAMC1 增强高血糖时膜的硬度和血小板与内皮的相互作用
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-08-14 DOI: 10.1016/j.jtha.2024.08.001
Renato S. Gaspar , Álefe Roger Silva França , Percillia Victoria Santos Oliveira , Joel Félix Silva Diniz-Filho , Livia Teixeira , Iuri Cordeiro Valadão , Victor Debbas , Clenilton Costa dos Santos , Mariana Pereira Massafera , Silvina Odete Bustos , Luciana Magalhães Rebelo Alencar , Graziella Eliza Ronsein , Francisco R.M. Laurindo

Background

Diabetes carries an increased risk of cardiovascular disease and thromboembolic events. Upon endothelial dysfunction, platelets bind to endothelial cells to precipitate thrombus formation; however, it is unclear which surface proteins regulate platelet-endothelium interaction. We and others have shown that peri/epicellular protein disulfide isomerase A1 (pecPDI) influences the adhesion and migration of vascular cells.

Objectives

We investigated whether pecPDI regulates adhesion-related molecules on the surface of endothelial cells and platelets that influence the binding of these cells in hyperglycemia.

Methods

Immunofluorescence was used to assess platelet-endothelium interaction in vitro, cytoskeleton reorganization, and focal adhesions. Hydrogen peroxide production was assessed via Amplex Red assays (ThermoFisher Scientific). Cell biophysics was assessed using atomic force microscopy. Secreted proteins of interest were identified through proteomics (secretomics), and targets were knocked down using small interfering RNA. Protein disulfide isomerase A1 (PDI) contribution was assessed using whole-cell PDI or pecPDI inhibitors or small interfering RNA.

Results

Platelets of healthy donors adhered more onto hyperglycemic human umbilical vein endothelial cells (HUVECs). Endothelial, but not platelet, pecPDI regulated this effect. Hyperglycemic HUVECs showed marked cytoskeleton reorganization, increased H2O2 production, and elongated focal adhesions. Indeed, hyperglycemic HUVECs were stiffer compared with normoglycemic cells. PDI and pecPDI inhibition reversed the abovementioned processes in hyperglycemic cells. A secretomics analysis revealed 8 proteins secreted in a PDI-dependent manner by hyperglycemic cells. Among these, we showed that genetic deletion of LAMC1 and SLC3A2 decreased platelet-endothelium interaction and did not potentiate the effects of PDI inhibitors.

Conclusion

Endothelial pecPDI regulates platelet-endothelium interaction in hyperglycemia through adhesion-related proteins and alterations in endothelial membrane biophysics.
背景:糖尿病增加了心血管疾病和血栓栓塞事件的风险。当内皮功能障碍时,血小板会与内皮细胞结合,促使血栓形成,然而,目前还不清楚是哪些表面蛋白调节血小板与内皮的相互作用。我们和其他人已经证明,细胞周/细胞外(pec)蛋白二硫化物异构酶 A1(pecPDI)会影响血管细胞的粘附和迁移:我们研究了pecPDI是否调节内皮细胞和血小板表面的粘附相关分子,从而影响这些细胞在高血糖时的结合:免疫荧光用于评估体外血小板-内皮细胞相互作用、细胞骨架重组和病灶粘附。过氧化氢的产生通过 Amplex Red 试验进行评估。使用原子力显微镜评估了细胞生物物理学。通过蛋白质组学(分泌物组学)确定了感兴趣的分泌蛋白,并使用 siRNA 敲除了目标蛋白。使用全细胞 PDI 或 pecPDI 抑制剂或 siRNA 评估 PDI 的贡献:结果:健康供体的血小板更容易粘附在高血糖的 HUVECs 上。内皮细胞(而非血小板)的 pecPDI 可调节这种效应。高血糖 HUVECs 表现出明显的细胞骨架重组、H2O2 生成增加和局灶粘连拉长。事实上,与正常血糖的细胞相比,高血糖的HUVEC更加坚硬。抑制PDI和pecPDI可逆转高血糖细胞的上述过程。分泌组学分析发现,高血糖细胞以 PDI 依赖性方式分泌八种蛋白质。在这些蛋白中,我们发现基因缺失 LAMC1 和 SLC3A2 会降低血小板与内皮的相互作用,并且不会增强 PDI 抑制剂的作用:结论:高血糖时,内皮细胞PecPDI通过粘附相关蛋白和内皮膜生物物理学的改变调节血小板与内皮的相互作用。
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引用次数: 0
Hereditary antithrombin deficiency pilot project registry from the American Thrombosis and Hemostasis Network 美国血栓与止血网络(ATHN)遗传性抗凝血酶缺乏症试点项目登记处。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-08-14 DOI: 10.1016/j.jtha.2024.07.026
Maria T. DeSancho , Erin Suvar , Jonathan C. Roberts , Michael D. Tarantino , Jonathan Schwartz , Jessica Callis , Michael Recht

Background

Patients with hereditary antithrombin deficiency (HAD) have an increased risk of venous thromboembolism (VTE). The American Thrombosis and Hemostasis Network (ATHN) 12: HAD Pilot Project established a registry to collect data on patients with HAD.

Objectives

To inform current practice and serve as a platform to design a multicenter global registry for patients with HAD.

Methods

The HAD registry was designed in 2020 to identify 100 patients with HAD receiving care at ATHN-affiliated centers. Demographics, type of HAD, thrombotic events, risk factors, anticoagulants, and antithrombin (AT) concentrate administration were recorded.

Results

Ninety-four patients were included; 65% were females; 51% had type 1 HAD. Mean age at diagnosis was 26 years (SD, 18 years); 61% had VTE: 55% deep vein thrombosis and 27% pulmonary embolisms. Eight patients had arterial thrombosis. Recurrent thrombosis occurred in 58.6% of patients (44.8%) despite anticoagulation. The main risk factor for thrombosis in females was estrogen. Direct oral anticoagulants were prescribed in 30%, heparin in 34%, and warfarin in 32%. There were 139 pregnancies. Low-molecular-weight heparin was administered in 33% and AT concentrate in 19% and 11% prior to and after delivery, respectively. Twelve patients developed thrombosis in pregnancy. Seventy-nine patients underwent 239 surgeries or procedures, mainly gastrointestinal and vascular. Overall, 35% of participants received AT concentrate without adverse events.

Conclusion

In ATHN 12, VTE was the predominant manifestation, frequently recurrent. There was a trend toward using direct oral anticoagulants. Low-molecular-weight heparin was administered in one-third of pregnancies and AT concentrate in one-fifth without adverse events. These data should encourage prospective studies to optimize the management of these patients.
背景:遗传性抗凝血酶缺乏症(HAD)患者发生静脉血栓栓塞症(VTE)的风险增加。ATHN 12:HAD 试点项目建立了一个登记处,收集 HAD 患者的数据,为当前的实践提供信息,并作为设计 HAD 患者多中心全球登记处的平台:HAD 登记处的设计目标是在 2020 年确定 100 名在 ATHN 附属中心接受治疗的 HAD 患者。记录人口统计学特征、HAD类型、血栓事件、风险因素、抗凝药物和AT浓缩剂的使用情况:共纳入 94 名患者,其中 65% 为女性,51% 为 1 型 HAD。诊断时的平均年龄为 26 岁(SD18);61% 的患者患有 VTE:55% 为深静脉血栓,27% 为肺栓塞。8名患者患有动脉血栓。58.6%的患者出现血栓复发:(44.8%) 尽管进行了抗凝治疗。女性血栓形成的主要风险因素是雌激素。30%的患者服用了直接口服抗凝剂,34%服用了肝素,32%服用了华法林。共有 139 例妊娠。33%的孕妇在产前和产后使用了低分子量肝素,19%和11%的孕妇在产前和产后使用了AT浓缩剂。有 12 名患者在怀孕期间出现血栓。79名患者接受了239次手术或程序,主要分别是胃肠道手术和血管手术。总体而言,35%的参与者接受了AT浓缩液治疗,未发生不良事件:在 ATHN 12 中,VTE 是主要的表现形式,而且经常复发。使用 DOACs 是一种趋势。三分之一的孕妇使用了 LMWH,五分之一的孕妇使用了 AT 浓缩液,但未出现不良反应。这些数据应鼓励开展前瞻性研究,以优化对这些患者的管理。
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引用次数: 0
Rapid diagnosis of coagulopathies from vitamin K deficiency in a consecutive case cohort evaluated by comparative assessment of factor II by 1-stage assays with prothrombin time vs Ecarin reagents 通过凝血酶原时间与 Ecarin 试剂的单阶段测定法对因子 II 进行比较评估,评估连续病例队列中维生素 K 缺乏所致凝血病的快速诊断。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-08-14 DOI: 10.1016/j.jtha.2024.08.002
Alex Bourguignon , Natalie Mathews , Subia Tasneem , James Douketis , Catherine P.M. Hayward

Background

Vitamin K (VK) deficiency (VKD) impairs γ-carboxylation of VK-dependent factors (VKDFs), resulting in higher factor (F)II levels measured by Ecarin (FIIE) reagents (that convert des-γ-carboxylated FII to meizothrombin) than by prothrombin time (FII) reagents.

Objectives

To evaluate FII/FIIE abnormalities among patients assessed for coagulopathies and identify findings predictive of coagulopathy improvement after VK.

Methods

We retrospectively assessed consecutive cases from 2002 to 2021 with FII/FIIE tests and the sensitivity and specificity of FII/FIIE ratios and FIIE-FII differences for VKD defined as international normalized ratio correction/improvement of ≥0.5 after VK.

Results

Two hundred ninety-two patients (males, 58.2%; adults, 85.6%; median age, 73 years) were evaluated (84.2% hospitalized, 48.3% in intensive care, 71.6% with active liver disease, and 28% deceased at discharge) and 25% to 38% had FII/FIIE findings suggestive of VKD. Among 170 patients assessed for response to VK, FII/FIIE ratios of ≤0.84 to 0.91 and FIIE-FII differences of >0.04 U/mL had similar modest sensitivity (47.7%-69.3%) and modest to good specificity (67.1%-91.5%) for VKD. FII/FIIE ratios of <0.86, suggestive of VKD (sensitivity, 47.7%; specificity, 90.2%), were more common in patients deficient in only VKDF (P = .0001), but were detected in 16% with non-VKDF deficiencies. Low FIIE was commonly associated with active liver disease (P = .0002). Patients with and without probable VKD (based on FII/FIIE ratios of <0.86) had similar mortality, bleeding, and rates of prothrombin complex concentrate and red cell transfusions (P ≥ .78), but fewer with probable VKD received plasma and fibrinogen replacement (P ≤ .024).

Conclusion

FII/FIIE comparison aids the diagnosis of VKD and predicts clinical responses to VK treatment among patients with coagulopathies.
背景:维生素 K(VK)缺乏症(VKD)会影响 VK 依赖性凝血因子(VKDF)的γ-羧化,导致用 Ecarin(FIIE)试剂(将去γ-羧化的 FII 转化为凝血酶原时间(FII)试剂)测量的因子 II(FII)水平高于凝血酶原时间(FII)试剂:评估接受凝血病评估的患者的 FII/FIIE 异常,并确定可预测 VK 后凝血病改善的结果:我们回顾性评估了 2002-2021 年间连续病例的 FII/FIIE 检测结果,以及 FII/FIIE 比率和 FIIE-FII 差异对 VKD 的敏感性和特异性,VKD 定义为 VK 后 INR 纠正/改善≥0.5。结果:292 名患者(男性 58.2%;成人 85.6%;中位年龄 73 岁)接受了评估(84.2% 住院,48.3% 重症监护;71.6% 有活动性肝病;28% 出院时死亡),25-38% 的 FII/FIIE 结果提示 VKD。在对 VK 反应进行评估的 170 名患者中,FII/FIIE 比率≤0.84-0.91 和 FIIE-FII 差异 >0.04 U/mL对于 VKD 有类似的适度敏感性(47.7-69.3%)和适度到良好的特异性(67.1-91.5%)。FII/FIIE 比值 结论:FII/FIIE 比值有助于诊断 VKD 并预测凝血病患者对 VK 治疗的临床反应。
{"title":"Rapid diagnosis of coagulopathies from vitamin K deficiency in a consecutive case cohort evaluated by comparative assessment of factor II by 1-stage assays with prothrombin time vs Ecarin reagents","authors":"Alex Bourguignon ,&nbsp;Natalie Mathews ,&nbsp;Subia Tasneem ,&nbsp;James Douketis ,&nbsp;Catherine P.M. Hayward","doi":"10.1016/j.jtha.2024.08.002","DOIUrl":"10.1016/j.jtha.2024.08.002","url":null,"abstract":"<div><h3>Background</h3><div>Vitamin K (VK) deficiency (VKD) impairs γ-carboxylation of VK-dependent factors (VKDFs), resulting in higher factor (F)II levels measured by Ecarin (FIIE) reagents (that convert des-γ-carboxylated FII to meizothrombin) than by prothrombin time (FII) reagents.</div></div><div><h3>Objectives</h3><div>To evaluate FII/FIIE abnormalities among patients assessed for coagulopathies and identify findings predictive of coagulopathy improvement after VK.</div></div><div><h3>Methods</h3><div>We retrospectively assessed consecutive cases from 2002 to 2021 with FII/FIIE tests and the sensitivity and specificity of FII/FIIE ratios and FIIE-FII differences for VKD defined as international normalized ratio correction/improvement of ≥0.5 after VK.</div></div><div><h3>Results</h3><div>Two hundred ninety-two patients (males, 58.2%; adults, 85.6%; median age, 73 years) were evaluated (84.2% hospitalized, 48.3% in intensive care, 71.6% with active liver disease, and 28% deceased at discharge) and 25% to 38% had FII/FIIE findings suggestive of VKD. Among 170 patients assessed for response to VK, FII/FIIE ratios of ≤0.84 to 0.91 and FIIE-FII differences of &gt;0.04 U/mL had similar modest sensitivity (47.7%-69.3%) and modest to good specificity (67.1%-91.5%) for VKD. FII/FIIE ratios of &lt;0.86, suggestive of VKD (sensitivity, 47.7%; specificity, 90.2%), were more common in patients deficient in only VKDF (<em>P</em> = .0001), but were detected in 16% with non-VKDF deficiencies. Low FIIE was commonly associated with active liver disease (<em>P</em> = .0002). Patients with and without probable VKD (based on FII/FIIE ratios of &lt;0.86) had similar mortality, bleeding, and rates of prothrombin complex concentrate and red cell transfusions (<em>P</em> ≥ .78), but fewer with probable VKD received plasma and fibrinogen replacement (<em>P</em> ≤ .024).</div></div><div><h3>Conclusion</h3><div>FII/FIIE comparison aids the diagnosis of VKD and predicts clinical responses to VK treatment among patients with coagulopathies.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995971","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
Universal clinical decision support tool for thromboprophylaxis in hospitalized COVID-19 patients: post hoc analysis of the IMPROVE-DD cluster randomized trial COVID-19住院患者血栓预防的通用临床决策支持工具:IMPROVE-DD 群组随机试验的事后分析。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-08-14 DOI: 10.1016/j.jtha.2024.07.025
Mark Goldin , Nikolaos Tsaftaridis , Ioannis Koulas , Jeffrey Solomon , Michael Qiu , Tungming Leung , Kolton Smith , Kanta Ochani , Thomas McGinn , Alex C. Spyropoulos

Background

Inpatient and extended postdischarge thromboprophylaxis of COVID-19 patients remains suboptimal despite antithrombotic guidelines.

Objectives

To determine whether a novel electronic health record–agnostic clinical decision support (CDS) tool incorporating the International Medical Prevention Registry on Venous Thromboembolism plus D-dimer (IMPROVE-DD) venous thromboembolism (VTE) scores increases appropriate inpatient and extended postdischarge thromboprophylaxis and improves outcomes in COVID-19 inpatients.

Methods

This post hoc analysis of the IMPROVE-DD cluster randomized trial evaluated thromboprophylaxis CDS among COVID-19 inpatients at 4 New York hospitals between December 21, 2020, and January 21, 2022. Hospitals were randomized 1:1 to CDS (intervention, n = 2) vs no CDS (usual care, n = 2). The primary outcome was rate of appropriate thromboprophylaxis. Secondary outcomes included rates of major thromboembolism, all-cause and VTE-related readmissions and death, major bleeding (MB), and all-cause mortality 30 days after discharge.

Results

Two thousand four hundred fifty-two COVID-19 inpatients were analyzed (CDS, 1355; no CDS, 1097). Mean age was 73.7 ± 9.37 years; 50.1% of participants were male. CDS adoption was 96.8% (intervention group). CDS was associated with increased appropriate at-discharge extended thromboprophylaxis (42.6% vs 28.8%; odds ratio [OR], 1.83; 95% CI, 1.39-2.41; P < .001). CDS was associated with reduced VTE (OR, 0.54; 95% CI, 0.39-0.75; P < .001), arterial thromboembolism (OR, 0.10; 95% CI, 0.01-0.81; P = .01), total thromboembolism (OR, 0.50; 95% CI, 0.36-0.69; P < .001), and 30-day all-cause readmission/death (OR, 0.78; 95% CI, 0.62-0.99; P = .04). There were no differences in MB, VTE-related readmissions/death, or all-cause mortality.

Conclusion

Electronic health record–agnostic CDS incorporating IMPROVE-DD VTE scores had high adoption, was associated with increased appropriate at-discharge extended thromboprophylaxis, and reduced thromboembolism and all-cause readmission/death without increasing MB in COVID-19 inpatients.
背景:尽管有抗血栓指南,但COVID-19患者的住院和出院后血栓预防仍不理想:目的:确定一种新型电子健康记录(EHR)诊断性临床决策支持(CDS)工具是否结合了IMPROVE-DD VTE评分,以提高住院患者和出院后延长血栓预防的适当性,并改善COVID-19住院患者的预后:这项 IMPROVE-DD 分组随机试验的事后分析评估了 2020 年 12 月 21 日至 2022 年 1 月 21 日期间纽约四家医院 COVID-19 住院患者的血栓预防 CDS。医院按 1:1 的比例随机接受 CDS(干预,N=2)与不接受 CDS(常规护理,N=2)。主要结果是适当血栓预防率。次要结果包括主要血栓栓塞率、全因和与 VTE 相关的再入院率和死亡率、大出血 (MB) 率以及出院后 30 天的全因死亡率。结果:分析了 2,452 名 COVID-19 住院患者(1,355 名接受 CDS;1,097 名未接受 CDS)。平均年龄为 73.7 ± 9.37 岁;50.1% 的参与者为男性。采用 CDS 的比例为 96.8%(干预组)。CDS 与出院时适当延长血栓预防时间的增加有关(42.6% 对 28.8%,几率比 [OR] 1.83,95% 置信区间 [CI] 1.39 - 2.41,p 结论:纳入 IMPROVE-DD VTE 评分的电子病历诊断 CDS 采用率很高,与出院时适当的扩大血栓预防措施增加有关,并在不增加 COVID-19 住院患者 MB 的情况下减少了 TE 和全因再入院/死亡。
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引用次数: 0
Novel GPIb-independent platelet aggregation induced by botrocetin: implications for diagnosis and antithrombotic therapy 肉毒杆菌素诱导的新型 GPIb 依赖性血小板聚集:对诊断和抗血栓治疗的意义。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-08-13 DOI: 10.1016/j.jtha.2024.06.030
Chuanbin Shen , Daniel T. Mackeigan , Aron A. Shoara , Preeti Bhoria , Guangheng Zhu , Danielle Karakas , Wenjing Ma , Zi Yan Chen , Runjia Xu , Sladjana Slavkovic , Dachuan Zhang , Viktor Prifti , Zhenze Liu , Eric G. Cerenzia , Pingguo Chen , Miguel A.D. Neves , Huiyuan Li , Feng Xue , Renchi Yang , Junling Liu , Heyu Ni

Background

Snake venom botrocetin facilitates von Willebrand factor (VWF) binding to platelet GPIbα and has been widely used for the diagnosis of von Willebrand disease and GPIb-related disorders. Botrocetin is also commonly employed for the development/characterization of antithrombotics targeting the GPIb-VWF axis.

Objectives

To explore the alternative receptor(s)/mechanisms that participate in botrocetin-induced platelet aggregation.

Methods

The effects of botrocetin on platelet aggregation were examined using platelets from wild-type, VWF- and fibrinogen-deficient, GPIbα-deficient, IL4Rα/GPIbα-transgenic, ITGA2B and ITGB3-deficient mice, and Bernard–Soulier syndrome and healthy human samples. Platelet-fibrinogen and platelet-VWF interaction were measured using flow cytometry. GPIbα-VWF binding was evaluated utilizing enzyme-linked immunosorbent assay. Botrocetin-αIIbβ3 and botrocetin-GPIbα interactions were measured using enzyme-linked immunosorbent assay and fluorescence anisotropy assays. Heparinized whole blood from healthy donors was examined for thrombus formation and growth in a perfusion chamber.

Results

Botrocetin could induce aggregation of platelets from a Bernard–Soulier syndrome patient and GPIbα-deficient mice as well as platelets lacking the N-terminal extracellular domain of GPIbα. Botrocetin could interact with αIIbβ3 and facilitated αIIbβ3-VWF interaction independent of GPIb. Botrocetin competitively bound to the ligand-binding domain of activated rather than resting αIIbβ3. Although botrocetin-induced platelet aggregation requires VWF, strikingly, in the absence of VWF, botrocetin blocked fibrinogen and other ligand binding to αIIbβ3 and inhibited platelet aggregation and thrombus formation. Consistently, recombinant botrocetin defective in VWF binding inhibited αIIbβ3- and GPIb-mediated platelet aggregation, spreading, and thrombus formation.

Conclusion

Our study provides insights into avoiding the misdiagnosis of GPIb-related disorders and developing botrocetin mutants as potential new antithrombotics that may simultaneously target both αIIbβ3 and GPIbα.
背景:蛇毒肉毒素能促进von Willebrand因子(VWF)与血小板GPIbα的结合,已被广泛用于von Willebrand疾病和GPIb相关疾病的诊断。Botrocetin 也常用于开发/表征针对 GPIb-VWF 轴的抗血栓药物:探索参与肉毒杆菌素诱导血小板聚集的替代受体/机制:方法:使用野生型、VWF和纤维蛋白原缺陷型、GPIbα缺陷型、IL4Rα/GPIbα转基因和αIIbβ3缺陷型小鼠、Bernard-Soulier综合征(BSS)和健康人样本的血小板,研究肉毒杆菌素对血小板聚集的影响。使用流式细胞术测量了血小板-纤维蛋白原和血小板-VWF的相互作用。利用 ELISA 评估了 GPIbα-VWF 的结合情况。肉毒杆菌素-αⅡbβ3和肉毒杆菌素-GPIbα之间的相互作用是通过酶联免疫吸附法和荧光各向异性法测定的。在灌注室中对健康献血者的肝素化全血进行了血栓形成和生长的检测:结果:肉毒昔丁能诱导 BSS 患者和 GPIbα 缺陷小鼠的血小板以及缺乏 GPIbα N 端细胞外结构域的血小板聚集。肉毒杆菌素能与αIIbβ3相互作用,并能促进αIIbβ3-VWF相互作用,而与GPIb无关。肉毒杆菌素能竞争性地与活化而非静止的αIIbβ3的配体结合域结合。虽然肉毒杆菌素诱导的血小板聚集需要 VWF,但令人吃惊的是,在没有 VWF 的情况下,肉毒杆菌素也能阻断纤维蛋白原和其他配体与 αIIbβ3 的结合,并抑制血小板聚集和血栓形成。同样,重组肉毒杆菌素与 VWF 结合缺陷抑制了 αIIbβ3 和 GPIb 介导的血小板聚集、扩散和血栓形成:我们的研究为避免 GPIb 相关疾病的误诊以及开发 botrocetin 突变体作为潜在的新型抗血栓药物提供了见解,这种药物可同时针对 αIIbβ3 和 GPIbα。
{"title":"Novel GPIb-independent platelet aggregation induced by botrocetin: implications for diagnosis and antithrombotic therapy","authors":"Chuanbin Shen ,&nbsp;Daniel T. Mackeigan ,&nbsp;Aron A. Shoara ,&nbsp;Preeti Bhoria ,&nbsp;Guangheng Zhu ,&nbsp;Danielle Karakas ,&nbsp;Wenjing Ma ,&nbsp;Zi Yan Chen ,&nbsp;Runjia Xu ,&nbsp;Sladjana Slavkovic ,&nbsp;Dachuan Zhang ,&nbsp;Viktor Prifti ,&nbsp;Zhenze Liu ,&nbsp;Eric G. Cerenzia ,&nbsp;Pingguo Chen ,&nbsp;Miguel A.D. Neves ,&nbsp;Huiyuan Li ,&nbsp;Feng Xue ,&nbsp;Renchi Yang ,&nbsp;Junling Liu ,&nbsp;Heyu Ni","doi":"10.1016/j.jtha.2024.06.030","DOIUrl":"10.1016/j.jtha.2024.06.030","url":null,"abstract":"<div><h3>Background</h3><div>Snake venom botrocetin facilitates von Willebrand factor (VWF) binding to platelet GPIbα and has been widely used for the diagnosis of von Willebrand disease and GPIb-related disorders. Botrocetin is also commonly employed for the development/characterization of antithrombotics targeting the GPIb-VWF axis.</div></div><div><h3>Objectives</h3><div>To explore the alternative receptor(s)/mechanisms that participate in botrocetin-induced platelet aggregation.</div></div><div><h3>Methods</h3><div>The effects of botrocetin on platelet aggregation were examined using platelets from wild-type, <em>VWF</em>- and <em>fibrinogen</em>-deficient, <em>GPIbα</em>-deficient, <em>IL4Rα/GPIbα</em>-transgenic, <em>ITGA2B</em> and <em>ITGB3</em>-deficient mice, and Bernard–Soulier syndrome and healthy human samples. Platelet-fibrinogen and platelet-VWF interaction were measured using flow cytometry. GPIbα-VWF binding was evaluated utilizing enzyme-linked immunosorbent assay. Botrocetin-α<sub>IIb</sub>β<sub>3</sub> and botrocetin-GPIbα interactions were measured using enzyme-linked immunosorbent assay and fluorescence anisotropy assays. Heparinized whole blood from healthy donors was examined for thrombus formation and growth in a perfusion chamber.</div></div><div><h3>Results</h3><div>Botrocetin could induce aggregation of platelets from a Bernard–Soulier syndrome patient and <em>GPIbα</em>-deficient mice as well as platelets lacking the N-terminal extracellular domain of GPIbα. Botrocetin could interact with α<sub>IIb</sub>β<sub>3</sub> and facilitated α<sub>IIb</sub>β<sub>3</sub>-VWF interaction independent of GPIb. Botrocetin competitively bound to the ligand-binding domain of activated rather than resting α<sub>IIb</sub>β<sub>3</sub>. Although botrocetin-induced platelet aggregation requires VWF, strikingly, in the absence of VWF, botrocetin blocked fibrinogen and other ligand binding to α<sub>IIb</sub>β<sub>3</sub> and inhibited platelet aggregation and thrombus formation. Consistently, recombinant botrocetin defective in VWF binding inhibited α<sub>IIb</sub>β<sub>3</sub>- and GPIb-mediated platelet aggregation, spreading, and thrombus formation.</div></div><div><h3>Conclusion</h3><div>Our study provides insights into avoiding the misdiagnosis of GPIb-related disorders and developing botrocetin mutants as potential new antithrombotics that may simultaneously target both α<sub>IIb</sub>β<sub>3</sub> and GPIbα.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988263","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
Sensitivity and specificity of strategies to identify patients with hemostasis abnormalities leading to an increased risk of bleeding before scheduled intervention: the Hemorisk study 在计划干预前识别止血异常导致出血风险增加的患者策略的敏感性和特异性:Hemorisk 研究。
IF 5.5 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-08-10 DOI: 10.1016/j.jtha.2024.07.024
Nadine Ajzenberg , Dan Longrois , Dorothée Faille , Christian de Tymowski , Emmanuelle De Raucourt , Larbi Boudaoud , Stéphanie Sigaut , Isabelle Martin-Toutain , Mathieu Raux , Dominique Helley , Julien Josserand , Claire Flaujac , Jérome Duchemin , Charles-Marc Samama , Isabelle Gouin-Thibault , Hélène Beloeil , Edith Peynaud-Debayle , Hawa Keita-Meyer , Marie-Charlotte Bourrienne , Caroline Quintin , Florence Tubach

Background

Preoperative identification of patients with hemostasis abnormalities leading to an increased bleeding risk is based on routine hemostasis tests: prothrombin time (PT), activated partial thromboplastin time (APTT), and platelet count. Because of their low predictive performance, guidelines recommend replacing them with structured bleeding risk questionnaires, but none is validated in this population.

Objectives

To assess the diagnostic accuracy of 3 strategies, performed at the preanesthesia visit before scheduled interventions, and to identify patients with hemostasis abnormalities leading to an increased bleeding risk

Methods

A multicenter study was performed in 7 French academic hospitals, involving patients scheduled for surgical intervention, without antiplatelet/anticoagulant treatment. The 3 strategies consisted of 1-a structured screening questionnaire; 2-PT, APTT, and platelet count ordered in selected patients; and 3-systematic PT, APTT, and platelet count. The reference standard comprised von Willebrand factor activity/antigen, factor (F)VIII, FIX, FXI, platelet function analyzer, and, when required, FII, FV, FX, and FVII and hemostasis consultation.

Results

Eighteen (1.2%) of 1484 patients had a hemostasis abnormality leading to an increased bleeding risk according to reference standard. In the overall cohort, sensitivity of the questionnaire-based strategy was 50% (95% CI, 26%-74%; specificity, 87% [95% CI, 85%-88%]); sensitivity was 0% (95% CI, 0%-41%) in men vs 82% (95% CI, 48%-98%) in women. For selective routine tests, sensitivity was 33% (95% CI, 13%-59%) and specificity 97% (95% CI, 96%-98%). Corresponding values for systematic routine tests were 44% (95% CI, 22%-69%) and 93% (95% CI, 91%-94%).

Conclusion

Sensitivity was low for all 3 strategies investigated. The structured screening questionnaire had clinically acceptable diagnostic accuracy only in women.
背景:术前通过常规止血检测:凝血酶原时间(PT)、活化凝血酶原时间(aPTT)和血小板计数来识别有止血异常并导致出血风险增加的患者。由于这些方法的预测性较低,指南建议用结构化出血风险问卷取代它们,但没有一种方法在这一人群中得到验证:目的:评估在麻醉前就诊时,在预定的介入治疗前进行的 3 种策略的诊断准确性,以确定有止血异常并导致出血风险增加的患者 患者和方法:在法国 7 家学术医院进行的多中心研究,涉及预定进行外科介入治疗的患者,他们未接受抗血小板/抗凝治疗。3种策略包括:1-结构化筛查问卷;2-对选定患者进行PT、aPTT和血小板计数检查;3-系统性PT、aPTT和血小板计数检查。参考标准包括冯-威廉因子活性/抗原、因子 VIII、IX 和 XI、血小板功能分析仪,必要时还包括 FII、FV、FX 和 FVII 以及止血咨询:根据参考标准,1484 名患者中有 18 人(1.2%)出现止血异常,导致出血风险增加。在整个队列中,基于问卷调查策略的灵敏度为 50%(95%CI,26-74;特异性为 87%(95%CI,85-88);男性的灵敏度为 0(95%CI,0-41),而女性的灵敏度为 82%(95%CI,48-98)。选择性常规检测的敏感性为 33%(95%CI,13-59),特异性为 97%(95%CI,96-98)。系统性常规检测的相应数值分别为 44% (95%CI, 22-69) 和 93% (95%CI, 91-94):所有 3 种调查策略的灵敏度都较低。结构化筛查问卷仅对女性具有临床可接受的诊断准确性。
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引用次数: 0
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Journal of Thrombosis and Haemostasis
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