Continuous monitoring of anti-fibrinolytic therapy in cardiovascular surgery

描述(由申请人提供)： 心血管手术并发症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)从药物上改变血栓降解(纤溶)来进行治疗。然而，FDA唯一批准的、也是心血管手术中最常用的PLact抑制剂，虽然有效地减少了术后出血，但与血管外效应有关，并最终导致FDA停用。这些不良事件的可能机制包括高度可变的剂量方案和对PLact以外的酶途径的抑制(脱靶效应)。因此，心血管手术后止血控制的方法出现了显著的空白。目前，一类被称为赖氨酸类似物的药理化合物正在临床上以“非标签”状态用于在心血管手术中修改PLACT。这些赖氨酸类似物选择性修饰PLact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处于经验阶段。将在这一应用中开发的技术和产品通过提供在心血管手术期间和之后持续监测PLact的手段，直接解决这一问题和临床需求。通过使用微透析和微流体，这一开发项目的具体目标是：(1)完成原型的校准研究，并验证在注射原型赖氨酸类似物后特异性和连续测量PLact的验证方法；(2)完成并构建易于在心血管手术环境中使用的改进的原型；(3)在大型体外循环动物模型中演示该验证原型的应用和实用性。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，以持续监测PLACT。该项目的临床益处将是一种手段，使赖氨酸类似物等抗纤溶药物的剂量策略个体化，从而最大限度地控制止血，最大限度地减少偏离目标的影响。营销/技术转让的好处是可以很容易地与心血管手术中针对纤溶级联反应的现有和未来的药物化合物相结合的诊断方法。 公共卫生相关性： 仅在美国，就有近200万成年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果是很好的，但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，使用能够增强血液凝结的因子，甚至可能需要重新手术。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，而且可能供不应求，因此人们寻求替代策略来改善心脏手术后的血液凝结。这些策略之一是通过抑制一种名为纤溶酶的酶的活性来防止心脏手术后血液凝块的分解。然而，到目前为止，还不可能直接和连续地测量心脏手术环境和重症监护病房中的纤溶酶活性。将在这一应用中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手段，直接解决这一问题和临床需求。该项目的临床好处将是提供一种手段，使目前用于减少心脏手术后失血的药物的给药策略个体化。因此，数百万可能面临手术后大量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.