Continuous monitoring of anti-fibrinolytic therapy in cardiovascular surgery

心血管手术中抗纤溶治疗的持续监测

基本信息

批准号：
8213199
负责人：
FRANCIS G SPINALE
金额：
$ 37.26万
依托单位：
MICRO VIDE, LLC
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-05 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8213199
关键词：
Address Adult Adverse effects Adverse event Algorithms Animal Model Animal Testing Antifibrinolytic Agents Aprotinin Biochemical Biological Blood Clot Blood Platelets Blood Transfusion Blood coagulation Calibration Cardiac Cardiac Surgery procedures Cardiopulmonary Bypass Cardiovascular Surgical Procedures Cardiovascular system Catheters Child Clinical Coagulation Process Companions Coupled Detection Development Diagnostic Dose Effectiveness Environment Equilibrium FDA approved Family Fiber Fibrin Fibrinolysis Fluorescence Fluorogenic Substrate Future Generic Drugs Goals Hemorrhage Hemostatic Agents In Vitro Intensive Care Units Label Legal patent Marketing Measurement Measures Methods Microdialysis Microfluidics Monitor Morbidity - disease rate Operative Surgical Procedures Outcome Pathway interactions Patients Peptide Hydrolases Perioperative Pharmaceutical Preparations Plasma Proteins Plasmin Plasmin Inhibitor Plasminogen Postoperative Period Process Program Development Prospective Studies Protocols documentation Recovery Regimen Reporting Reproducibility Retrospective Studies Risk Risk Factors Sensitivity and Specificity Serine Protease Serine Proteinase Inhibitors Serious Adverse Event Simulate Site Structure System Technology Technology Transfer Testing Therapeutic Thrombolytic Therapy Time United States Validation Weight Withdrawal base blood product digital enzyme activity enzyme pathway improved interstitial lysine analog mortality operation prevent protein structure prototype public health relevance research clinical testing response subcutaneous technology development

项目摘要

DESCRIPTION (provided by applicant): A major cause of morbidity and mortality in cardiovascular surgery is excessive bleeding post- operatively, which is commonly managed by pharmacologically modifying clot degradation (fibrinolysis), through inhibition of plasmin activity (PLact). However, the only FDA approved and most commonly used inhibitor of PLact in cardiovascular surgery, while effective in reducing post-operative bleeding, was associated with extravascular effects and ultimately led to FDA withdrawal. The likely mechanisms for these adverse events include highly variable dosing regimens and inhibition of enzyme pathways other than PLact (off target effects). As a consequence, a significant void in approaches for haemostatic control following cardiovascular surgery has developed. Presently, a class of pharmacological compounds called lysine analogues is being used clinically in an "off label" status to modify PLact in the context of cardiovascular surgery. The effective dosing strategy of these lysine analogues to selectively modify PLact is unknown, and therefore clinical dosing algorithms for these compounds remain empirical. The technology and product to be developed in this application directly addresses this problematic issue and clinical need by providing a means to continuously monitor PLact during and following cardiovascular surgery. Through the use of microdialysis and microfluidics, the specific aims of this development project are (1) to complete calibration studies of a prototype and validated method to specifically and continuously measure PLact following administration of a prototypical lysine analogue; (2) to complete and construct a refined prototype that can be easily used in the setting of cardiovascular surgery; (3) to demonstrate the application and utility of this validated prototype in a large animal model of cardiopulmonary bypass. The outcomes from the technology refinement and animal testing will be a complete system that can be easily deployed in the cardiovascular surgical setting for continuously monitoring PLact. The clinical benefit from this project will be a means to individualize dosing strategies of antifibrinolytics such as lysine analogues and thereby maximizing haemostatic control and minimizing off target effects. The marketing/technology transfer benefit is a companion diagnostic that can be easily coupled to existing and future pharmacological compounds targeting the fibrinolytic cascade in cardiovascular surgery. PUBLIC HEALTH RELEVANCE: In the United States alone, almost 2 million adults and children require open heart surgery. While the overall outcomes from these cardiac surgical procedures is excellent, one of the factors that can cause a difficult early recovery from cardiac surgery is excessive bleeding in the early post-surgical period. Bleeding in the post cardiac surgical period can require blood transfusions, administration of factors that can enhance blood clotting, and may even require re-operation. Since blood transfusions and blood product administration is associated with a set of intrinsic risks and complications, is costly, and can be in short supply, alternative strategies to improve blood clotting following cardiac surgery have been pursued. One of these strategies is to prevent the breakdown of a blood clot following cardiac surgery by inhibiting the activity of an enzyme called plasmin. However, up to now, it has not been possible to directly and continuously measure plasmin activity in the cardiac surgery setting and in the intensive care unit. The technology and product to be developed in this application directly addresses this problematic issue and clinical need by providing a means to continuously monitor plasmin activity during and following cardiac surgery. The clinical benefit from this project will be to provide a means to individualize dosing strategies of drugs currently used to reduce blood loss following cardiac surgery. As a consequence, millions of patients that may be at risk for significant post-surgical bleeding will directly benefit from the development of this technology.

描述（由申请人提供）：心血管手术中发病率和死亡率的一个主要原因是术后出血过多，通常通过抑制纤溶酶活性（PLact）以药物方式改变凝块降解（纤维蛋白溶解）来控制。然而，FDA 唯一批准且在心血管手术中最常用的 PLAt 抑制剂虽然能有效减少术后出血，但与血管外效应相关，最终导致 FDA 撤回。这些不良事件的可能机制包括高度可变的给药方案和除 PLAt 之外的酶途径的抑制（脱靶效应）。因此，心血管手术后的止血控制方法出现了明显的空白。目前，一类称为赖氨酸类似物的药理学化合物正在临床上以“标签外”状态使用，以在心血管手术中修饰 PLAt。这些赖氨酸类似物选择性修饰 PLAt 的有效剂量策略尚不清楚，因此这些化合物的临床剂量算法仍然是经验性的。本申请中要开发的技术和产品通过提供一种在心血管手术期间和术后持续监测PLact的方法，直接解决了这一难题和临床需求。通过使用微透析和微流体技术，该开发项目的具体目标是（1）完成原型和验证方法的校准研究，以在施用原型赖氨酸类似物后专门连续地测量PLact；（2）完成并构建一个易于在心血管外科环境中使用的精致原型； (3) 展示该验证原型在体外循环大型动物模型中的应用和效用。技术改进和动物测试的结果将是一个完整的系统，可以轻松部署在心血管外科环境中，以连续监测 PLAt。该项目的临床益处将是一种个体化赖氨酸类似物等抗纤维蛋白溶解剂的给药策略的方法，从而最大限度地提高止血控制并最大限度地减少脱靶效应。营销/技术转让的好处是一种伴随诊断，可以轻松地与现有和未来针对心血管手术中纤溶级联的药理学化合物结合。公共卫生相关性：仅在美国，就有近 200 万成人和儿童需要接受心脏直视手术。虽然这些心脏外科手术的总体结果非常好，但可能导致心脏手术早期恢复困难的因素之一是术后早期出血过多。心脏手术后的出血可能需要输血、施用可增强血液凝固的因子，甚至可能需要再次手术。由于输血和血液制品管理与一系列内在风险和并发症相关，成本高昂且供应短缺，因此人们一直在寻求改善心脏手术后血液凝固的替代策略。其中一种策略是通过抑制称为纤溶酶的酶的活性来防止心脏手术后血栓的分解。然而，到目前为止，还不可能在心脏手术环境和重症监护病房中直接连续测量纤溶酶活性。本申请中要开发的技术和产品通过提供一种在心脏手术期间和之后持续监测纤溶酶活性的方法，直接解决了这一难题和临床需求。该项目的临床效益将是提供一种方法，对目前用于减少心脏手术后失血的药物进行个体化给药策略。因此，数百万可能面临术后严重出血风险的患者将直接受益于这项技术的发展。