Contact Pathway Activation on Vascular Devices

血管装置上的接触通路激活

• 批准号: 10675588
• 负责人: Monica T Hinds
• 金额: $ 72.14万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675588
• 关键词: Animal Model; Antibodies; Anticoagulant therapy; Anticoagulants; Anticoagulation; Antiplatelet Drugs; Back; Basic Science; Biochemical; Biophysical Process; Blood; Blood Coagulation Factor; Blood Platelets; Blood Vessels; Blood coagulation; Blood flow; Brain hemorrhage; Cardiovascular system; Clinical; Clinical Trials; Clinical Trials Design; Coagulation Process; Contact Inhibition; Critical Illness; Data; Dedications; Deposition; Development; Devices; Dose Limiting; End stage renal failure; Equipment Malfunction; Event; Exposure to; Extracorporeal Membrane Oxygenation; Failure; Fibrin; Fibrinolytic Agents; Future; Generations; Grant; Growth; Hemodialysis; Hemorrhage; Hemostatic Agents; Heparin; Impairment; In Vitro; Incidence; Interruption; Intervention; Kininogenase; Knowledge; Legal patent; Lung; Marketing; Medical; Medical Device; Medicine; Membrane Oxygenators; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Neonatal; Organ; Oxygenators; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Plasma Kallikrein; Platelet Activation; Platelet Count measurement; Preclinical Testing; Prekallikrein; Prevention; Pump; Recombinants; Research; Risk; Role; Safety; Severities; Stents; Surface; System; Therapeutic; Therapeutic Uses; Thrombin; Thrombosis; Thrombus; Toxic effect; Translating; Tube; Work; biomaterial interface; combinatorial; design; efficacy evaluation; experience; gastrointestinal; improved; improved outcome; in vitro Model; in vivo; inhibitor; member; mortality; neonate; novel; pharmacologic; platelet function; pre-clinical; prevent; programs; side effect; small molecule inhibitor; thrombotic; thrombotic complications; validation studies

Project Summary This project evaluates the contribution of contact activation to the progression of vascular device-related blood coagulation and thrombus formation. Our work and findings to date have opened the window towards the development of safer antithrombotic strategies. Our research will generate new knowledge supporting the development of novel anticoagulants that lack dose-limiting toxicity, and cause less bleeding than current drugs, while also helping to identify medical conditions that could benefit from the therapeutic use of these contact activation inhibitors. Vascular devices such as stents, grafts, hemodialyzers and oxygenators can activate blood and often require the use of systemic antithrombotics to reduce the incidence or severity of device failure and thrombotic events. Currently marketed antithrombotic drugs can help reduce clot formation on vascular devices, but all increase the risk of bleeding. For instance, 30% of severely ill neonates that are treated with extracorporeal membrane oxygenation (ECMO) experience severe bleeding complications, including gastrointestinal, pulmonary and brain hemorrhage, which contribute to the high mortality rate of neonatal ECMO. These and other vascular device-associated thrombotic and treatment-associated bleeding complications signify the unmet medical need to improve the outcome of vascular interventions, including permanent intravascular devices like stents and various forms of temporal extracorporeal organ support. This program will now take a new direction to study the molecular mechanisms by which vascular devices activate FXII to initiate thrombus formation at the blood-biomaterial interface, and evaluate the utility of inhibiting the contact activation pathway in combination with anticoagulants or reduced platelet function. We focus on FXII and FXI because (1) there appears to be a causal relationship between contact activation and vascular device failure, and (2) targeting the contact activation pathway as a therapeutic approach is less likely to have bleeding side effects for patients. Each Aim will have 3 subaims that will translate our (A) mechanistic in vitro studies to (B) ex vivo blood flow studies of artificial surface-related thrombus formation and (C) in vivo studies of vascular device-related thrombus propagation in 2 distinct animal models. The potential significance of this translational project is that the knowledge generated will lead to verification of promising, safe, and druggable molecular targets within the contact activation pathway to both prevent and interrupt vascular device-related thrombosis. Our research may ultimately support the rationale for the development of selective contact activation inhibitors that could benefit a large number of patients exposed to vascular interventions and devices.

项目摘要 该项目评估接触激活对血管装置相关的进展的贡献 血液凝血和血栓形成。我们迄今为止的工作和发现打开了 制定更安全的抗血栓形成策略。我们的研究将产生新的知识支持 缺乏限制剂量毒性的新型抗凝剂的发展，并引起比电流更少的出血 药物，同时还有助于确定可以从治疗使用中受益的医疗状况 接触激活抑制剂。 血管装置，例如支架，移植物，血液聚会器和氧合剂可以激活血液，并且经常 需要使用全身抗杀菌剂来减少设备故障的发病率或严重程度 血小板事件。目前，销售的抗血栓药物可以帮助减少血管形成 设备，但都增加了出血的风险。例如，有30％的严重疾病的新生儿接受治疗 体外膜氧合（ECMO）经历严重的出血并发症，包括 胃肠道，肺和脑出血，这有助于新生儿的高死亡率 ECMO。这些和其他血管装置相关的血栓形成和治疗相关的出血 并发症表示改善血管干预结果的未满足医疗需求，包括 永久性血管内装置，例如支架和各种形式的颞外器官支撑。 现在，该程序将迈出新的方向来研究血管设备的分子机制 激活FXII以在血液生物材料界面启动血栓形成，并评估 抑制与抗凝剂或血小板功能降低的接触激活途径。我们 专注于FXII和FXI，因为（1）在接触激活和 血管装置故障，（2）将接触激活途径作为治疗方法较少 可能对患者产生出血的副作用。每个目标都会有3个subiaim，可以翻译我们的（a） （b）人造表面相关血栓形成的体外研究 （c）在2种不同的动物模型中，血管器械相关的血栓传播的体内研究。 这个翻译项目的潜在意义是，产生的知识将导致验证 在接触激活途径中有希望，安全和可毒的分子靶标的 和中断血管装置相关的血栓形成。我们的研究最终可能支持 开发可能受益于大量患者的选择性接触激活抑制剂 进行血管干预和设备。

项目成果

Ponatinib and other CML Tyrosine Kinase Inhibitors in Thrombosis.

• DOI: 10.3390/ijms21186556
• 发表时间: 2020-09-08
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Zeng P;Schmaier A
• 通讯作者: Schmaier A

Illustrated State-of-the-Art Capsules of the ISTH 2020 Congress.

• DOI: 10.1002/rth2.12532
• 发表时间: 2021-07
• 期刊: Research and practice in thrombosis and haemostasis
• 影响因子: 4.6
• 作者: Krishnaswamy S;Ageno W;Arabi Y;Barbui T;Cannegieter S;Carrier M;Cleuren AC;Collins P;Panicot-Dubois L;Freedman JE;Freson K;Hogg P;James AH;Kretz CA;Lavin M;Leebeek FWG;Li W;Maas C;Machlus K;Makris M;Martinelli I;Medved L;Neerman-Arbez M;O'Donnell JS;O'Sullivan J;Rajpurkar M;Schroeder V;Spiegel PC Jr;Stanworth SJ;Green L;Undas A
• 通讯作者: Undas A

Single cell morphological metrics and cytoskeletal alignment regulate VCAM-1 protein expression.

• DOI: 10.1016/j.bbrc.2021.03.129
• 发表时间: 2021-05-28
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Fallon ME;Hinds MT
• 通讯作者: Hinds MT

Factor XI as a target for preventing venous thromboembolism.

• DOI: 10.1111/jth.15628
• 发表时间: 2022-03
• 期刊: Journal of thrombosis and haemostasis : JTH

The hereditary angioedema syndromes.

遗传性血管性水肿综合征。

• DOI: 10.1172/jci125378
• 发表时间: 2019
• 期刊: The Journal of clinical investigation
• 作者: Schmaier,AlvinH