Continuous monitoring of anti-fibrinolytic therapy in cardiovascular surgery

描述（由申请人提供）： 心血管手术中发病率和死亡率的主要原因是术后出血过多，这通常通过抑制纤溶酶活性（PLact）来调节血凝块降解（纤维蛋白溶解）来控制。然而，唯一一种FDA批准的和心血管手术中最常用的PLact抑制剂，虽然可有效减少术后出血，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PLact以外的酶途径抑制（脱靶效应）。因此，在心血管手术后止血控制方法中出现了显著的空白。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"状态用于在心血管手术的背景下修饰PLact。这些赖氨酸类似物选择性修饰PLact的有效给药策略尚不清楚，因此这些化合物的临床给药算法仍然是经验性的。在本申请中开发的技术和产品通过提供在心血管手术期间和之后连续监测PLact的方法直接解决了这一问题和临床需求。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，以在给予原型赖氨酸类似物后特异性和连续地测量PLact;（2）完成并构建可轻松用于心血管手术环境的精制原型;（3）在体外循环大型动物模型中验证该验证样机的应用和实用性。技术改进和动物试验的结果将是一个完整的系统，可以很容易地部署在心血管外科环境中，用于连续监测PLact。该项目的临床获益将是抗纤溶药物（如赖氨酸类似物）个体化给药策略的一种手段，从而最大限度地实现止血控制并最大限度地减少脱靶效应。营销/技术转让获益是一种伴随诊断，可以很容易地与心血管手术中靶向纤溶级联的现有和未来药理学化合物结合。 公共卫生相关性： 仅在美国，就有近200万成人和儿童需要进行心脏直视手术。虽然这些心脏外科手术的总体结局非常好，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的过度出血。心脏手术后出血可能需要输血，给予可以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给药与一系列内在风险和并发症相关，成本高昂，并且可能供应短缺，因此一直在寻求改善心脏手术后血液凝固的替代策略。这些策略之一是通过抑制一种叫做纤溶酶的酶的活性来防止心脏手术后血凝块的分解。然而，到目前为止，还不可能在心脏手术环境和重症监护室中直接和连续地测量纤溶酶活性。本申请中待开发的技术和产品通过提供在心脏手术期间和之后连续监测纤溶酶活性的手段来直接解决该问题和临床需求。该项目的临床受益将是提供一种方法，使目前用于减少心脏手术后失血的药物的个体化给药策略。因此，数百万可能面临术后大出血风险的患者将直接受益于这项技术的发展。

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.